PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS

Abstract

A method for treating an inflammatory or autoimmune disease with compounds of Formula 0, Formula I, and Formula II and methods of use as Interleukin-1 Receptor Associated Kinase (IRAK4) inhibitors are described herein.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 16/775,650, filed Jan. 29, 2020, which is a continuation of U.S. application Ser. No. 16/014,231, filed Jun. 21, 2018, which is a continuation of International Application No. PCT/EP2016/081810, filed Dec. 19, 2016, which claims priority to U.S. provisional application Ser. No. 62/271,171, filed Dec. 22, 2015; U.S. provisional application Ser. No. 62/279,459, filed Jan. 15, 2016; and U.S. provisional application Ser. No. 62/398,341, filed Sep. 22, 2016, each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention pertains to compounds useful for inhibition of Interleukin-1 Receptor Associated Kinase 4 (IRAK4).

BACKGROUND OF THE INVENTION

TIR-domain (Toll-Interleukin 1 Receptor-domain) containing cell surface receptors such as the Toll-like receptors (TLR) and the IL-1 and IL-18 receptors play critical roles in innate immunity and have been implicated in the pathogenesis of autoimmunity. TLRs, for example, recognize pathogenic or endogenous ligands and provide a requisite signal for dendritic cell maturation and antigen presentation to T cell. Similarly, proteins that mediate signaling from these receptors have also been shown to play important roles in the pathogenesis of autoimmune disorders. For example mice deficient in MyD88, an adaptor protein that directly interacts with the TIR domain, are more susceptible to bacterial, fungal and parasitic infections. In addition, MyD88 deficient mice are resistant to experimental autoimmune encephalomyelitis (EAE) and streptococcal cell wall-induced arthritis.

The Interleukin-1 Receptor Associated Kinase (IRAK) family is comprised of four family members IRAK1, IRAK2, IRAK3 (also termed IRAK-M), and IRAK4. These proteins are characterized by a typical N-terminal death domain that mediates interaction with MyD88-family adaptor proteins and a centrally located kinase domain. Whereas IRAK1 and IRAK4 have kinase activity, IRAK2 and IRAK3 are catalytically inactive. Upon activation of their upstream cognate receptors, IRAK4 is thought to phosphorylate IRAK1, resulting in the activation and autophosphorylation of IRAK1 and subsequent phosphorylation of downstream substrates. The hyperphosphorylation of IRAK1 directs its dissociation from the receptor complex and its eventual ubiquitylation and proteasomal degradation. Phosphorylation of downstream substrates such as Pellino-2 ultimately leads to the activation of the MAPKs such as p 38 and c-Jun N-terminal kinase (JNK) and NF-kB followed by production of pro-inflammatory cytokines, chemokines, and destructive enzyme.

The role of IRAK4 in innate immunity and in the pathogenesis of autoimmune diseases is emerging. See, e.g., Li et al., “IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase,” PNAS 2002, 99(8), 5567-5572; Flannery et al., “The interleukin-1 receptor-associated kinases: Critical regulators of innate immune signaling,” Biochem Pharm 2010, 80(12), 1981-1991. Patients with destabilizing or null mutations in IRAK4 demonstrate defects in TLR signaling and the production of pro-inflammatory cytokines such as IL-1 and TNF as well as antiviral cytokines such as IFNα and IFNβ. These patients demonstrate an increased susceptibility to gram-positive bacterial infections although they are generally resistant to gram-negative bacterial, viral, and fungal infections. Similarly, IRAK4 deficient mice have defects in TLR- and IL-1-mediated cytokine production and exhibit an increased susceptibility to infection. IRAK1 deficient mice demonstrate a loss of responsiveness to lipopolysaccharides (LPS), IL-1, and IL-18 as well as impaired Th1 development. These mice were resistant to experimental autoimmune encephalomyelitis, exhibiting little or no CNS inflammation.

Accordingly, compounds that modulate the function of IRAK4 represent an attractive approach to the development of therapeutic agents for the treatment of diseases such as inflammatory, cell proliferative and immune-related conditions and diseases associated with IRAK-mediated signal transduction, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, lupus, diabetes, obesity, allergic disease, psoriasis, asthma, graft rejection, cancer and sepsis.

SUMMARY OF THE INVENTION

One aspect of the invention includes a compound of Formula 0:

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

R¹ is hydrogen or halogen;

R³ is hydrogen, halogen, CN, OH, C_1-3alkyl, C_2-3alkenyl, C_3-7cycloalkyl group, C₁-C₃alkanoyl, —(C₀-C₃alkyl)C(O)NR⁶R⁷, —(C_2-3alkenyl)C(O)NR⁶R⁷, —S(O)_1-2NR⁶R⁷, —NR⁸R⁹, —O—C_1-3alkyl, a 3-7 membered monocyclic saturated or partially saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, or a 5-6 membered monocyclic aryl ring,

wherein any alkyl, alkanoyl, or alkenyl is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, or C_1-3haloalkoxy, and

wherein any cycloalkyl group, heterocyclic group, heteroaryl ring, or aryl ring is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, or C_1-3haloalkyl;

R⁴ is hydrogen, halogen, C_1-3alkyl, C_2-3alkenyl, —(C₀-C₃alkyl)C(O)R¹³—(C_2-3alkenyl)C(O)NR¹⁰R¹¹, —S(O)_1-2NR¹⁰R¹¹, a 3-7 membered monocyclic saturated or partially saturated heterocyclic group, —C(O)NR⁸R⁹, or —NR⁸R⁹,

wherein any alkyl, alkenyl, or heterocyclic group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, C_1-3haloalkoxy, or a 3-7 membered monocyclic saturated or partially saturated heterocyclic group that may be optionally substituted with oxo;

R⁵ is hydrogen, —CN, C_1-6alkyl, C_1-6alkoxy, C_3-10cycloalkyl group, —NR⁸R⁹, —C(O)NR⁸R⁹, —O(C_3-7cycloalkyl group), —O(C_1-3alkyl)-3-8 membered cycloalkyl group, —O(C_0-3alkyl)-3-8 membered saturated or partially saturated heterocyclic group, —O(C_1-3alkyl)-phenyl, a —O(C_1-3alkyl)-5-6 membered heteroaryl ring, a 3-11 membered saturated or partially saturated heterocyclic group, or a 5-6 membered monocyclic heteroaryl ring,

wherein any alkyl or alkoxy is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, C_1-3haloalkoxy, or a 3-11 membered saturated or partially saturated heterocyclic group that may be optionally substituted with (i) —C(O)(C_1-3alkyl) optionally substituted with halogen or (ii) with C_1-3alkyl optionally substituted with halogen, and

wherein any cycloalkyl group, heterocyclic group, phenyl, or heteroaryl ring is optionally substituted by halogen; oxo; CN; OH; C_1-6alkoxy; —NR⁸R⁹; —C(O)(C_1-3alkyl); —(C_0-3alkyl)C(O)NR¹⁰R¹¹; —S(O)_1-2NR⁸R⁹; —OP(O)(OC_1-3alkyl)₂; C_3-10cycloalkyl group optionally substituted with OH or halogen; a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C_1-3alkyl; a 5-6 membered monocyclic heteroaryl ring optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, or C_1-3haloalkyl; or C_1-4alkyl optionally substituted by halogen, oxo, CN, OH, —O—C_1-3 alkyl, —S—C_1-3alkyl, —SO₂—C_1-3alkyl, —NR⁸R⁹, —C(O)NR⁸R⁹, phenyl, C_3-10cycloalkyl, a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C_1-3 alkyl, or a 5-6 membered monocyclic heteroaryl ring optionally substituted with oxo, halogen, or C_1-3alkyl;

A is a 3-11 membered heterocyclic group optionally substituted by halogen, oxo, CN, OH, C_1-6alkyl, —(C_0-3alkyl)-C_3-6cycloalkyl group, a —(C_0-3alkyl)-3-11 membered heterocyclic group, —NR⁸R⁹, —NR¹²C(O)R¹³, —NR¹²S(O)_1-2R¹³, —C(O)(C_1-3alkyl), —C(O)NR¹⁰R¹¹, —C(O)OR¹³, —S(O)_1-2NR¹⁰R¹¹, or —(C_0-3alkyl)-OP(O)(OC_1-3alkyl)₂,

wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted by halogen; oxo; CN; OR¹³; C_1-3haloalkoxy; —C(O)(C_1-3alkyl); —S—C_1-3alkyl; or C_1-3alkyl optionally substituted with OH, halogen, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, or a 3-8 membered heterocyclic group, and

wherein when A is a 5-membered nitrogen containing heterocyclic group, the nitrogen atom is substituted;

R⁶ and R⁷ are, independently at each occurrence, hydrogen, C_1-3alkyl, or C_3-6cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

R⁸, R⁹, R¹⁰ and R¹¹ are, independently at each occurrence, hydrogen, C_1-6alkyl, C_3-6cycloalkyl group, —(C_0-3alkyl)-phenyl, a 3-11 membered saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, —C(O)R¹³, —C(O)OR¹³, —C(O)NR⁶R⁷, or —S(O)_1-2R¹³, or R¹⁰ and R¹¹ are taken together to form a 5-8 membered heterocyclic group,

wherein any alkyl, cycloalkyl group, phenyl, heterocyclic group, or heteroaryl ring is independently optionally substituted by halogen, oxo, CN, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, —OR¹³, —NR⁶R⁷, or a 5-6 membered monocyclic heteroaryl ring;

R¹² is, independently at each occurrence, hydrogen, C_1-6alkyl or C_3-6cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

R¹³ is, independently at each occurrence, hydrogen, C_1-6alkyl, C_3-10cycloalkyl group, or a 3-11 membered saturated heterocyclic group,

wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, —OR¹², or —NR⁶R⁷; and

R¹⁶ is hydrogen, halogen, CN, or C_1-3alkyl optionally substituted with —NH₂, halogen, or CN.

Another aspect of the invention includes a compound of Formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

R¹ is hydrogen or halogen;

R³ is hydrogen, halogen, CN, OH, C_1-3alkyl, C_2-3alkenyl, C_3-7cycloalkyl group, C₁-C₃alkanoyl, —(C₀-C₃alkyl)C(O)NR⁶R⁷, —(C_2-3alkenyl)C(O)NR⁶R⁷, —S(O)_1-2NR⁶R⁷, —NR⁸R⁹, a 3-7 membered monocyclic saturated or partially saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, or a 5-6 membered monocyclic aryl ring,

wherein any alkyl, alkanoyl, or alkenyl is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, or C_1-3haloalkoxy, and

any cycloalkyl group or other ring is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, or C_1-3haloalkyl;

R⁴ is hydrogen, halogen, C_1-3alkyl, C_2-3alkenyl, —(C₀-C₃alkyl)C(O)R¹³, —(C_2-3alkenyl)C(O)NR¹⁰R¹¹, —S(O)_1-2NR¹⁰R¹¹, or —NR⁸R⁹;

wherein any alkyl or alkenyl is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, or C_1-3haloalkoxy;

R⁵ is hydrogen, C_1-6alkyl, C_1-6alkoxy, C_3-10cycloalkyl group, —NR⁸R⁹, —O(C_3-7cycloalkyl group), —O(C_1-3alkyl)-3-8 membered cycloalkyl group, —O(C_1-3alkyl)-3-8 membered saturated or partially saturated heterocyclic group, —O(C_1-3alkyl)-phenyl, a —O(C_1-3alkyl)-5-6 membered heteroaryl ring, a 3-11 membered saturated or partially saturated heterocyclic group, or a 5-6 membered monocyclic heteroaryl ring,

wherein any alkyl or alkoxy is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, or C_1-3haloalkoxy, and

any cycloalkyl group or other ring is optionally substituted by halogen, oxo, CN, OH, C_1-6alkoxy, —C(O)(C_1-3alkyl), —(C_0-3alkyl)C(O)NR¹⁰R¹¹, —S(O)_1-2NR⁸R⁹, —OP(O)(OC_1-3alkyl)₂, a 5-6 membered monocyclic heteroaryl ring optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, or C_1-3haloalkyl, or C_1-3alkyl optionally substituted by halogen, oxo, CN, OH, phenyl, a 3-8 membered saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, or —NR⁸R⁹;

A is a 3-11 membered heterocyclic group optionally substituted by halogen, oxo, CN, OH, C_1-6alkyl, —(C_0-3alkyl)-C_3-6cycloalkyl group, a —(C_0-3alkyl)-3-11 membered heterocyclic group optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, or C_1-3haloalkyl, —NR⁸R⁹, —NR¹²C(O)R¹³, —NR¹²S(O)_1-2R¹³, —C(O)(C_1-3alkyl), —C(O)NR¹⁰R¹¹, —C(O)OR¹³, —S(O)_1-2NR¹⁰R¹¹, or —OP(O)(OC_1-3alkyl)₂,

wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, or a 3-8 membered heterocyclic group;

wherein when A is a 5-membered nitrogen containing heterocyclic group, the nitrogen atom is substituted;

R⁶ and R⁷ are, independently at each occurrence, hydrogen, C_1-3alkyl, or C_3-6cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

R⁸, R⁹, R¹⁰ and R¹¹ are, independently at each occurrence, hydrogen, C_1-6alkyl, C_3-6cycloalkyl group, —(C_0-3alkyl)-phenyl, a 3-11 membered saturated heterocyclic group, —C(O)R¹³, —C(O)OR¹³, —C(O)NR⁶R⁷, or —S(O)_1-2R¹³, or R¹⁰ and R¹¹ are taken together to form a 5-8 membered heterocyclic group optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

wherein any alkyl, cycloalkyl group, or other ring is independently optionally substituted by halogen, oxo, CN, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, —OR¹³, or —NR⁶R⁷;

R¹² is, independently at each occurrence, hydrogen, C_1-6alkyl or C_3-6cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

R¹³ is, independently at each occurrence, hydrogen, C_1-6alkyl, C_3-10cycloalkyl group, or a 3-11 membered saturated heterocyclic group,

wherein any alkyl, cycloalkyl group, or other ring is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, —OR¹², or —NR⁶R⁷; and

R¹⁶ is H, —Cl, —CN, or —CH₃.

Yet another aspect of the invention includes a compound of Formula II:

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

R¹ is hydrogen or halogen;

R³ is hydrogen, halogen, CN, OH, C_1-3alkyl, C_2-3alkenyl, C_3-7cycloalkyl group, C₁-C₃alkanoyl, —(C₀-C₃alkyl)C(O)NR⁶R⁷, —(C_2-3alkenyl)C(O)NR⁶R⁷, —S(O)_1-2NR⁶R⁷, —NR⁸R⁹, a 3-7 membered monocyclic saturated or partially saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, or a 5-6 membered monocyclic aryl ring,

wherein any alkyl, alkanoyl, or alkenyl is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, or C_1-3haloalkoxy, and

any cycloalkyl group or other ring is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, or C_1-3haloalkyl;

R⁴ is hydrogen, halogen, C_1-3alkyl, C_2-3alkenyl, —(C₀-C₃alkyl)C(O)R¹³, —(C_2-3alkenyl)C(O)NR¹⁰R¹¹, —S(O)_1-2NR¹⁰R¹¹, or —NR⁸R⁹;

wherein any alkyl or alkenyl is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, or C_1-3haloalkoxy;

R⁵ is hydrogen, C_1-6alkyl, C_1-6alkoxy, C_3-10cycloalkyl group, —NR⁸R⁹, —O(C_3-7cycloalkyl group), a 3-11 membered saturated or partially saturated heterocyclic group, or a 5-6 membered monocyclic heteroaryl ring,

wherein any alkyl or alkoxy is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, or C_1-3haloalkoxy, and

any cycloalkyl group or other ring is optionally substituted by halogen, oxo, CN, OH, —(C_0-3alkyl)C(O)NR¹⁰R¹¹, —OP(O)(OC_1-3alkyl)₂, or C_1-3alkyl optionally substituted by halogen, oxo, CN, OH, or —NR⁸R⁹;

A is a 3-11 membered heterocyclic group optionally substituted by halogen, oxo, CN, OH, C_1-6alkyl, C_3-6cycloalkyl group, —NR⁸R⁹, —NR¹²C(O)R¹³, —NR¹²S(O)_1-2R¹³, —C(O)NR¹⁰R¹¹, —C(O)OR¹³, or —S(O)_1-2NR¹⁰R¹¹,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3a 1 kyL C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

wherein when A is a 5-membered nitrogen containing heterocyclic group, the nitrogen atom is substituted;

R⁶ and R⁷ are, independently at each occurrence, hydrogen, C_1-3alkyl, or C_3-6cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

R⁸, R⁹, R¹⁰ and R¹¹ are, independently at each occurrence, hydrogen, C_1-6alkyl, C_3-6 cycloalkyl group, a 3-11 membered saturated heterocyclic group, —C(O)R¹³, —C(O)OR¹³, —C(O)NR⁶R⁷, or —S(O)_1-2R¹³,

wherein any alkyl, cycloalkyl group or other ring is independently optionally substituted by halogen, oxo, CN, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, —OR¹³, or —NR⁶R⁷;

R¹² is, independently at each occurrence, hydrogen, C_1-6alkyl or C_3-6cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

R¹³ is, independently at each occurrence, hydrogen, C_1-6alkyl, C_3-10cycloalkyl group, or a 3-11 membered saturated heterocyclic group,

wherein any alkyl, cycloalkyl group, or other ring is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, —OR¹², or —NR⁶R⁷; and

R¹⁶ is H, —Cl, —CN, or —CH₃.

Also provided is a pharmaceutical composition that comprises a compound of the invention and a pharmaceutically acceptable carrier, diluent or excipient.

Another aspect includes a compound of the invention for use in therapy, such as the treatment of an inflammatory disease, an autoimmune disease or cancer.

Another aspect includes a method of preventing, treating or lessening the severity of a disease or condition responsive to the inhibition of IRAK4, in a patient. The method can comprise administering to the patient a therapeutically effective amount of a compound of the invention.

Another aspect includes the use of a compound of the invention in the manufacture of a medicament for the treatment of a disease responsive to the inhibition of IRAK4.

Another aspect includes a kit for treating a disease or disorder responsive to the inhibition of IRAK4. The kit can comprise a first pharmaceutical composition comprising a compound of the invention, and instructions for use.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

“Halogen” or “halo” refers to F, Cl, Br or I. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhalo alkyl.

The term “alkyl” refers to a saturated linear or branched-chain monovalent hydrocarbon radical, wherein the alkyl radical may be optionally substituted. In one example, the alkyl radical is one to eighteen carbon atoms (C₁-C₁₈). In other examples, the alkyl radical is C₀-C₆, C₀-C₅, C₀-C₃, C₁-C₁₂, C₁-C₁₀, C₁-C₈, C₁-C₆, C₁-C₅, C₁-C₄, or C₁-C₃. C₀ alkyl refers to a bond. Examples of alkyl groups include methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl (—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl (—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl (—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl (—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂), 3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, 1-heptyl and 1-octyl. In some embodiments, substituents for “optionally substituted alkyls” include one to four instances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and heterocyclic portions thereof may be optionally substituted, such as by one to four instances of substituents selected from this same list.

“Aryl” refers to a carbocyclic aromatic group, whether or not fused to one or more groups, having the number of carbon atoms designated, or if no number is designated, up to 14 carbon atoms. One example includes aryl groups having 6-14 carbon atoms. Another example includes aryl groups having 6-10 carbon atoms. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, 1,2,3,4-tetrahydronaphthalenyl, 1H-indenyl, 2,3-dihydro-1H-indenyl, and the like (see, e.g., Lang's Handbook of Chemistry (Dean, J. A., ed.) 13^th ed. Table 7-2 [1985]). A particular aryl is phenyl. Substituted phenyl or substituted aryl means a phenyl group or aryl group substituted with one, two, three, four or five substituents, for example, 1-2, 1-3 or 1-4 substituents, such as chosen from groups specified herein (see “optionally substituted” definition), such as F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and heterocyclic portions thereof may be optionally substituted, such as by one to four instances of substituents selected from this same list. Examples of the term “substituted phenyl” include a mono- or di(halo)phenyl group such as 2-chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4-hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenyl group, for example, 4-cyanophenyl; a mono- or di(alkyl)phenyl group such as 4-methylphenyl, 2,4-dimethylphenyl, 2-methylphenyl, 4-(isopropyl)phenyl, 4-ethylphenyl, 3-(n-propyl)phenyl and the like; a mono or di(alkoxy)phenyl group, for example, 3,4-dimethoxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-ethoxyphenyl, 4-(isopropoxy)phenyl, 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 3- or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such 4-carboxyphenyl, a mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono- or di(N-(methylsulfonylamino))phenyl such as 3-(N-methylsulfonylamino))phenyl. Also, the term “substituted phenyl” represents disubstituted phenyl groups where the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl, 2-chloro-5-difluoromethoxy and the like, as well as trisubstituted phenyl groups where the substituents are different, for example 3-methoxy-4-benzyloxy-6-methyl sulfonylamino, 3-methoxy-4-benzyloxy-6-phenyl sulfonylamino, and tetrasubstituted phenyl groups where the substituents are different such as 3-methoxy-4-benzyloxy-5-methyl-6-phenyl sulfonylamino.

The terms “compound(s) of the invention,” and “compound(s) of the present invention” and the like, unless otherwise indicated, include compounds of Formula 0, Formula I, Formula II, and the compounds of Tables 1, 2 and 3 herein, including stereoisomers (including atropisomers), geometric isomers, tautomers, solvates, metabolites, isotopes, salts (e.g., pharmaceutically acceptable salts), and prodrugs thereof. In some embodiments, solvates, metabolites, isotopes or prodrugs are excluded, or any combination thereof.

“Cycloalkyl” refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring group wherein the cycloalkyl group may be optionally substituted independently with one or more substituents described herein. In one example, the cycloalkyl group is 3 to 12 carbon atoms (C₃-C₁₂). In other examples, cycloalkyl is C₃-C₈, C₃-C₁₀ or C₅-C₁₀. In other examples, the cycloalkyl group, as a monocycle, is C₃-C₈, C₃-C₆ or C₅-C₆. In another example, the cycloalkyl group, as a bicycle, is C₇-C₁₂. In another example, the cycloalkyl group, as a spiro system, is C₅-C₁₂. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Examples of spiro cycloalkyl include, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane. In some embodiments, substituents for “optionally substituted cycloalkyls” include one to four instances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereof may be optionally substituted, such as by one to four instances of substituents selected from this same list.

“Heterocyclic group”, “heterocyclic”, “heterocycle”, “heterocyclyl”, or “heterocyclo” are used interchangeably and refer to any mono-, bi-, tricyclic or spiro, saturated, partially saturated or unsaturated, aromatic (heteroaryl) or non-aromatic (e.g., heterocycloalkyl), ring system, having 3 to 20 ring atoms, where the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. If any ring atom of a cyclic system is a heteroatom, that system is a heterocycle, regardless of the point of attachment of the cyclic system to the rest of the molecule. In one example, heterocyclyl includes 3-11 ring atoms (“members”) and includes monocycles, bicycles, tricycles and spiro ring systems, wherein the ring atoms are carbon, where at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. In one example, heterocyclyl includes 1 to 4 heteroatoms. In one example, heterocyclyl includes 1 to 3 heteroatoms. In another example, heterocyclyl includes 3- to 7-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 4- to 6-membered monocycles having 1-2, 1-3 or 1-4 heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 3-membered monocycles. In another example, heterocyclyl includes 4-membered monocycles. In another example, heterocyclyl includes 5-6 membered monocycles, e.g., 5-6 membered heteroaryl. In another example, heterocyclyl includes 3-11 membered heterocycloyalkyls, such as 4-11 membered heterocycloalkyls. In some embodiments, a heterocycloalkyl includes at least one nitrogen. In one example, the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO₂), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR₄]⁺C₁, [NR₄]⁺OH⁻). Example heterocycles are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, 1,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazindionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azaspiro[4.5]decan-2-only, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5-membered heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as 1,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. Example 5-membered ring heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3-triazol-5-yl, 1,2,4-triazol-5-yl, and tetrazolyl, such as 1H-tetrazol-5-yl. Example benzo-fused 5-membered heterocycles are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example 6-membered heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the 1,3,4-triazin-2-yl groups, are other example heterocycle groups. Heterocycles may be optionally substituted. For example, substituents for “optionally substituted heterocycles” include one to four instances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereof may be optionally substituted, such as by one to four instances of substituents selected from this same list.

“Heteroaryl” refers to any mono-, bi-, or tricyclic ring system where at least one ring is a 5- or 6-membered aromatic ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in an example embodiment, at least one heteroatom is nitrogen. See, for example, Lang's Handbook of Chemistry (Dean, J. A., ed.) 13^th ed. Table 7-2 [1985]. Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to an aryl ring, wherein the aryl ring or the heteroaryl ring is joined to the remainder of the molecule. In one embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen. Example heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazol[1,2-a]pyrimidinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl. Heteroaryl groups can be optionally substituted. In some embodiments, substituents for “optionally substituted heteroaryls” include one to four instances of F, Cl, Br, I, OH, SH, CN, NH₂, NHCH₃, N(CH₃)₂, NO₂, N₃, C(O)CH₃, COOH, CO₂CH₃, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, SO₂, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, phenyl and heterocyclic portions thereof may be optionally substituted, such as by one to four instances of substituents selected from this same list.

In particular embodiments, a heterocyclyl group is attached at a carbon atom of the heterocyclyl group. By way of example, carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine ring, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline ring.

In certain embodiments, the heterocyclyl group is N-attached. By way of example, nitrogen bonded heterocyclyl or heteroaryl groups include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline.

The term “alkoxy” refers to a linear or branched monovalent radical represented by the formula —OR in which R is alkyl, as defined herein. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, mono-, di- and tri-fluoromethoxy and cyclopropoxy. “Haloalkoxy” refers to a haloalkyl group, as that term is defined herein, as R.

The term “alkanoyl” refers to group (alkyl)-C(═O)—, wherein alkyl is as defined herein. For example, C₁-C₆alkanoyl refers to a group of formula (C₁-C₅alkyl)-C(═O)—. Alkanoyl groups include, formyl, acetyl, propanoyl, isopropanoyl, butanoyl, isobutanoyl, pentanoyl, 3-methylpentanoyl, and hexanoyl.

“Optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range derivable therein) of the substituents listed for that group in which said substituents may be the same or different. In an embodiment, an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents. In another embodiment an optionally substituted group has 3 substituents. In another embodiment an optionally substituted group has 4 substituents. In another embodiment an optionally substituted group has 5 substituents.

As used herein a wavy line “” that intersects a bond in a chemical structure indicate the point of attachment of the atom to which the wavy bond is connected in the chemical structure to the remainder of a molecule, or to the remainder of a fragment of a molecule. In some embodiments, an arrow together with an asterisk is used in the manner of a wavy line to indicate a point of attachment.

In certain embodiments, divalent groups are described generically without specific bonding configurations. It is understood that the generic description is meant to include both bonding configurations, unless specified otherwise. For example, in the group R¹-R²-R³, if the group R² is described as —CH₂C(O)—, then it is understood that this group can be bonded both as R¹—CH₂C(O)—R³, and as R¹—C(O)CH₂—R³, unless specified otherwise.

The phrase “pharmaceutically acceptable” refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate.

Compounds of the invention may be in the form of a salt, such as a pharmaceutically acceptable salt. “Pharmaceutically acceptable salts” include both acid and base addition salts. “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Particular base addition salts are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particular organic non-toxic bases include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

In some embodiments, a salt is selected from a hydrochloride, hydrobromide, trifluoroacetate, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate, p-toluenesulphonate, bisulphate, benzenesulphonate, ethanesulphonate, malonate, xinafoate, ascorbate, oleate, nicotinate, saccharinate, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furoate or 3-furoate), napadisylate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), edisylate (ethane-1,2-disulfonate or ethane-1-(sulfonic acid)-2-sulfonate), isothionate (2-hydroxyethylsulfonate), 2-mesitylenesulphonate, 2-naphthalenesulphonate, 2,5-dichlorobenzenesulphonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, esylate, malonate, mesitylate (2-mesitylenesulphonate), napsylate (2-naphthalenesulfonate), camsylate (camphor-10-sulphonate, for example (1S)-(+)-10-camphorsulfonic acid salt), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotate, xylate (p-xylene-2-sulphonate), and pamoic (2,2′-dihydroxy-1,1′-dinaphthylmethane-3,3′-dicarboxylate).

A “sterile” formulation is aseptic or free from all living microorganisms and their spores.

“Stereoisomers” refer to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like.

“Chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.

“Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

“Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereo selection or stereo specificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

Certain compounds of the invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. A “solvate” refers to an association or complex of one or more solvent molecules and a compound of the present invention. Examples of solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. Certain compounds of the invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are intended to be within the scope of the present invention. The term “hydrate” refers to the complex where the solvent molecule is water.

A “metabolite” refers to a product produced through metabolism in the body of a specified compound or salt thereof. Such products can result, for example, from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.

Metabolite products typically are identified by preparing a radiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention, administering it in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to a human, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS, LC/MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art. The metabolite products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.

“Amino-protecting group” as used herein refers to a derivative of the groups commonly employed to block or protect an amino group while reactions are carried out on other functional groups on the compound. Examples of such protecting groups include carbamates, amides, alkyl and aryl groups, and imines, as well as many N-heteroatom derivatives which can be removed to regenerate the desired amine group. Particular amino protecting groups are Pmb (p-Methoxybenzyl), Boc (tert-Butyloxycarbonyl), Fmoc (9-Fluorenylmethyloxycarbonyl) and Cbz (Carbobenzyloxy). Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, “Protecting Groups in Organic Synthesis, 3^rd ed., John Wiley & Sons, Inc., 1999. The term “protected amino” refers to an amino group substituted with one of the above amino-protecting groups.

“Carboxy-protecting group” as used herein refers to those groups that are stable to the conditions of subsequent reaction(s) at other positions of the molecule, which may be removed at the appropriate point without disrupting the remainder of the molecule, to give the unprotected carboxy-group. Examples of carboxy protecting groups include, ester groups and heterocyclyl groups. Ester derivatives of the carboxylic acid group may be employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such ester groups include substituted arylalkyl, including substituted benzyls, such as 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4′-dimethoxybenzhydryl, 2,2′,4,4′-tetramethoxybenzhydryl, alkyl or substituted alkyl esters such as methyl, ethyl, t-butyl allyl or t-amyl, triphenylmethyl (trityl), 4-methoxytrityl, 4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl, 2-phenylprop-2-yl, thioesters such as t-butyl thioester, silyl esters such as trimethylsilyl, t-butyldimethylsilyl esters, phenacyl, 2,2,2-trichloroethyl, beta-(trimethylsilyl)ethyl, beta-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. Another example of carboxy-protecting groups are heterocyclyl groups such as 1,3-oxazolinyl. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, “Protecting Groups in Organic Synthesis, 3^rd ed., John Wiley & Sons, Inc., 1999. The term “protected carboxy” refers to a carboxy group substituted with one of the above carboxy-protecting groups.

“Hydroxy-protecting group” as used herein refers to a derivative of the hydroxy group commonly employed to block or protect the hydroxy group while reactions are carried out on other functional groups on the compound. Examples of such protecting groups include tetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, and silylethers (e.g., TBS, TBDPS) groups. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, “Protecting Groups in Organic Synthesis, 3^rd ed., John Wiley & Sons, Inc., 1999. The term “protected hydroxy” refers to a hydroxy group substituted with one of the above hydroxy-protecting groups.

Compounds of the invention may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastereomers, enantiomers or mixtures thereof. The syntheses of the compounds may employ racemates, diastereomers or enantiomers as starting materials or as intermediates. Mixtures of particular diastereomeric compounds may be separated, or enriched in one or more particular diastereomers, by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated, or enantiomerically enriched, using the same techniques or others known in the art. Each of the asymmetric carbon or nitrogen atoms may be in the R or S configuration and both of these configurations are within the scope of the invention.

In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. Unless otherwise specified, if solid wedges or dashed lines are used, relative stereochemistry is intended.

Another aspect includes prodrugs of the compounds of the invention including known amino-protecting and carboxy-protecting groups which are released, for example hydrolyzed, to yield the compound of the present invention under physiologic conditions.

The term “prodrug” refers to a precursor or derivative form of a pharmaceutically active substance that is less efficacious to the patient compared to the parent drug and is capable of being enzymatically or hydrolytically activated or converted into the more active parent form. See, e.g., Wilman, “Prodrugs in Cancer Chemotherapy” Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast (1986) and Stella et al., “Prodrugs: A Chemical Approach to Targeted Drug Delivery,” Directed Drug Delivery, Borchardt et al., (ed.), pp. 247-267, Humana Press (1985). Prodrugs include, but are not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, β-lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs or optionally substituted phenylacetamide-containing prodrugs, and 5-fluorocytosine and 5-fluorouridine prodrugs.

A particular class of prodrugs are compounds in which a nitrogen atom in an amino, amidino, aminoalkyleneamino, iminoalkyleneamino or guanidino group is substituted with a hydroxy group, an alkylcarbonyl (—CO—R) group, an alkoxycarbonyl (—CO—OR), or an acyloxyalkyl-alkoxycarbonyl (—CO—O—R—O—CO—R) group where R is a monovalent or divalent group, for example alkyl, alkylene or aryl, or a group having the Formula —C(O)—O—CP1P2-haloalkyl, where P1 and P2 are the same or different and are hydrogen, alkyl, alkoxy, cyano, halogen, alkyl or aryl. In a particular embodiment, the nitrogen atom is one of the nitrogen atoms of the amidino group of the compounds of the invention. Prodrugs may be prepared by reacting a compound of the present invention with an activated group, such as acyl groups, to bond, for example, a nitrogen atom in the compound to the exemplary carbonyl of the activated acyl group. Examples of activated carbonyl compounds are those containing a leaving group bonded to the carbonyl group, and include, for example, acyl halides, acyl amines, acyl pyridinium salts, acyl alkoxides, acyl phenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, and difluorophenoxy acyl. The reactions are generally carried out in inert solvents at reduced temperatures such as −78 to about 50° C. The reactions may also be carried out in the presence of an inorganic base, for example potassium carbonate or sodium bicarbonate, or an organic base such as an amine, including pyridine, trimethylamine, triethylamine, triethanolamine, or the like.

Additional types of prodrugs are also encompassed. For instance, a free carboxyl group of a compound of the invention can be derivatized as an amide or alkyl ester. As another example, compounds of the invention comprising free hydroxy groups can be derivatized as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem., (1996), 39:10. More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl, N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl, alpha-amino(C₁-C₄)alkanoyl, arylacyl and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where each alpha-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁-C₆)aikyl)₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate). “Leaving group” refers to a portion of a first reactant in a chemical reaction that is displaced from the first reactant in the chemical reaction. Examples of leaving groups include, but are not limited to, halogen atoms, alkoxy and sulfonyloxy groups. Example sulfonyloxy groups include, but are not limited to, alkylsulfonyloxy groups (for example methyl sulfonyloxy (mesylate group) and trifluoromethylsulfonyloxy (triflate group)) and arylsulfonyloxy groups (for example p-toluenesulfonyloxy (tosylate group) and p-nitrosulfonyloxy (nosylate group)).

A “subject,” “individual,” or “patient” is a vertebrate. In certain embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, farm animals (such as cows), sport animals, pets (such as guinea pigs, cats, dogs, rabbits and horses), primates, mice and rats. In certain embodiments, a mammal is a human. In embodiments comprising administration of a compound of to a patient, the patient is typically in need thereof.

The terms “inhibiting” and “reducing,” or any variation of these terms, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of activity (e.g., IRAK4 activity) compared to normal.

In some embodiments, a compound of Formula 0, Formula I, or Formula II, such as a compound of Tables 1, 2 or 3, is selective for inhibition of IRAK4 over IRAK1. By “selective for inhibition” it is meant that the compound is at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, better inhibitor of IRAK4 activity compared to IRAK1 activity, or is at least a 2-, 3-, 4-, 5-, 10-, 25-, 50-, 100-, 250-, or 500-fold better inhibitor of IRAK4 activity compared to IRAK1 activity.

A “therapeutically effective amount” means an amount of a compound of the present invention, such as a compound of Formula 0, Formula I, or Formula II (e.g., a compound of Tables 1, 2 or 3), that (i) treats or prevents the particular disease, condition or disorder, or (ii) attenuates, ameliorates or eliminates one or more symptoms of the particular disease, condition, or disorder, and optionally (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein. In some embodiments, the therapeutically effective amount is an amount sufficient to decrease or alleviate the symptoms of an autoimmune or inflammatory disease (e.g., lupus). In some embodiments, a therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly decrease the activity or number of B-cells. In the case of cancer, the therapeutically effective amount of the drug may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the drug may prevent growth or kill existing cancer cells, it may be cytostatic or cytotoxic. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) or determining the response rate (RR).

“Treatment” (and variations such as “treat” or “treating”) refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized (i.e., not worsening) state of disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and remission or improved prognosis. In some embodiments, compounds of the invention, are used to delay development of a disease or disorder or to slow the progression of a disease or disorder. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation) or those in which the condition or disorder is to be prevented.

“Inflammatory disorder” refers to any disease, disorder or syndrome in which an excessive or unregulated inflammatory response leads to excessive inflammatory symptoms, host tissue damage, or loss of tissue function. “Inflammatory disorder” also refers to a pathological state mediated by influx of leukocytes or neutrophil chemotaxis.

“Inflammation” refers to a localized, protective response elicited by injury or destruction of tissues, which serves to destroy, dilute, or wall off (sequester) both the injurious agent and the injured tissue. Inflammation is notably associated with influx of leukocytes or neutrophil chemotaxis. Inflammation can result from infection with pathogenic organisms and viruses and from noninfectious means such as trauma or reperfusion following myocardial infarction or stroke, immune responses to foreign antigens, and autoimmune responses. Accordingly, inflammatory disorders amenable to treatment with a compound of the present invention, such as a compound of Formula 0, Formula I, or Formula II (e.g., a compound of Tables 1, 2 or 3), encompass disorders associated with reactions of the specific defense system as well as with reactions of the nonspecific defense system.

“Specific defense system” refers to the component of the immune system that reacts to the presence of specific antigens. Examples of inflammation resulting from a response of the specific defense system include the classical response to foreign antigens, autoimmune diseases, and delayed type hypersensitivity responses mediated by T-cells. Chronic inflammatory diseases, the rejection of solid transplanted tissue and organs, e.g., kidney and bone marrow transplants, and graft versus host disease (GVHD), are further examples of inflammatory reactions of the specific defense system.

The term “nonspecific defense system” refers to inflammatory disorders that are mediated by leukocytes that are incapable of immunological memory (e.g., granulocytes, and macrophages). Examples of inflammation that result, at least in part, from a reaction of the nonspecific defense system include inflammation associated with conditions such as adult (acute) respiratory distress syndrome (ARDS) or multiple organ injury syndromes; reperfusion injury; acute glomerulonephritis; reactive arthritis; dermatoses with acute inflammatory components; acute purulent meningitis or other central nervous system inflammatory disorders such as stroke; thermal injury; inflammatory bowel disease; granulocyte transfusion associated syndromes; and cytokine-induced toxicity.

“Autoimmune disease” refers to any group of disorders in which tissue injury is associated with humoral or cell-mediated responses to the body's own constituents. Non-limiting examples of autoimmune diseases include rheumatoid arthritis, lupus and multiple sclerosis.

“Allergic disease” as used herein refers to any symptoms, tissue damage, or loss of tissue function resulting from allergy. “Arthritic disease” as used herein refers to any disease that is characterized by inflammatory lesions of the joints attributable to a variety of etiologies. “Dermatitis” as used herein refers to any of a large family of diseases of the skin that are characterized by inflammation of the skin attributable to a variety of etiologies. “Transplant rejection” as used herein refers to any immune reaction directed against grafted tissue, such as organs or cells (e.g., bone marrow), characterized by a loss of function of the grafted and surrounding tissues, pain, swelling, leukocytosis, and thrombocytopenia. The therapeutic methods of the present invention include methods for the treatment of disorders associated with inflammatory cell activation.

“Inflammatory cell activation” refers to the induction by a stimulus (including, but not limited to, cytokines, antigens or auto-antibodies) of a proliferative cellular response, the production of soluble mediators (including but not limited to cytokines, oxygen radicals, enzymes, prostanoids, or vasoactive amines), or cell surface expression of new or increased numbers of mediators (including, but not limited to, major histocompatability antigens or cell adhesion molecules) in inflammatory cells (including but not limited to monocytes, macrophages, T lymphocytes, B lymphocytes, granulocytes (i.e., polymorphonuclear leukocytes such as neutrophils, basophils, and eosinophils), mast cells, dendritic cells, Langerhans cells, and endothelial cells). It will be appreciated by persons skilled in the art that the activation of one or a combination of these phenotypes in these cells can contribute to the initiation, perpetuation, or exacerbation of an inflammatory disorder.

In some embodiments, inflammatory disorders which can be treated according to the methods of this invention include, but are not limited to, asthma, rhinitis (e.g., allergic rhinitis), allergic airway syndrome, atopic dermatitis, bronchitis, rheumatoid arthritis, psoriasis, lupus, chronic obstructive pulmonary disease (COPD), contact dermatitis, chronic obstructive pulmonary disease and delayed hypersensitivity reactions.

The terms “cancer” and “cancerous”, “neoplasm”, and “tumor” and related terms refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A “tumor” comprises one or more cancerous cells. Examples of cancer include carcinoma, blastoma, sarcoma, seminoma, glioblastoma, melanoma, leukemia, and myeloid or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer) and lung cancer including small-cell lung cancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung. Other cancers include skin, keratoacanthoma, follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx (oral), lip, tongue, mouth, salivary gland, esophageal, larynx, hepatocellular, gastric, stomach, gastrointestinal, small intestine, large intestine, pancreatic, cervical, ovarian, liver, bladder, hepatoma, breast, colon, rectal, colorectal, genitourinary, biliary passage, thyroid, papillary, hepatic, endometrial, uterine, salivary gland, kidney or renal, prostate, testis, vulval, peritoneum, anal, penile, bone, multiple myeloma, B-cell lymphoma, diffuse large B-Cell lymphoma (DLBCL), central nervous system, brain, head and neck, Hodgkin's, and associated metastases. Examples of neoplastic disorders include myeloproliferative disorders, such as polycythemia vera, essential thrombocytosis, myelofibrosis, such as primary myelofibrosis, and chronic myelogenous leukemia (CML).

A “chemotherapeutic agent” is an agent useful in the treatment of a given disorder, for example, cancer or inflammatory disorders. Examples of chemotherapeutic agents are well-known in the art and include examples such as those disclosed in U.S. Publ. Appl. No. 2010/0048557, incorporated herein by reference. Additionally, chemotherapeutic agents include pharmaceutically acceptable salts, acids or derivatives of any of chemotherapeutic agents, as well as combinations of two or more of them.

Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the invention, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Isotopically-labeled compounds (e.g., those labeled with ³H and ¹⁴C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds of the invention, one or more carbon atoms are replaced by ¹³C- or ¹⁴C-enriched carbon. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

It is specifically contemplated that any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or to utilize any compound or composition of the invention.

If any discrepancy exists between a structure and its name, the structure prevails.

The use of the term “or” is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternative are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.”

Throughout this application, the term “about” is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.

As used herein, “a” or “an” means one or more, unless clearly indicated otherwise. As used herein, “another” means at least a second or more.

Headings used herein are intended only for organizational purposes.

IRAK4 Inhibitors

As noted, one aspect of the invention includes a compound of Formula 0:

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

R¹ is hydrogen or halogen;

R³ is hydrogen, halogen, CN, OH, C_1-3alkyl, C_2-3alkenyl, C_3-7cycloalkyl group, C₁-C₃alkanoyl, —(C₀-C₃alkyl)C(O)NR⁶R⁷, —(C_2-3alkenyl)C(O)NR⁶R⁷, —S(O)_1-2NR⁶R⁷, —NR⁸R⁹, —O—C_1-3alkyl, a 3-7 membered monocyclic saturated or partially saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, or a 5-6 membered monocyclic aryl ring,

wherein any alkyl, alkanoyl, or alkenyl is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, or C_1-3haloalkoxy, and

wherein any cycloalkyl group, heterocyclic group, heteroaryl ring, or aryl ring is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, or C_1-3haloalkyl;

R⁴ is hydrogen, halogen, C_1-3alkyl, C_2-3alkenyl, —(C₀-C₃alkyl)C(O)R¹³, —(C_2-3alkenyl)C(O)NR¹⁰R¹¹, —S(O)_1-2NR¹⁰R¹¹, a 3-7 membered monocyclic saturated or partially saturated heterocyclic group, —C(O)NR⁸R⁹, or —NR⁸R⁹,

wherein any alkyl, alkenyl, or heterocyclic group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, C_1-3haloalkoxy, or a 3-7 membered monocyclic saturated or partially saturated heterocyclic group that may be optionally substituted with oxo;

R⁵ is hydrogen, —CN, C_1-6alkyl, C_1-6alkoxy, C_3-10cycloalkyl group, —NR⁸R⁹, —C(O)NR⁸R⁹, —O(C_3-7cycloalkyl group), —O(C_1-3alkyl)-3-8 membered cycloalkyl group, —O(C_0-3alkyl)-3-8 membered saturated or partially saturated heterocyclic group, —O(C_1-3alkyl)-phenyl, a —O(C_1-3alkyl)-5-6 membered heteroaryl ring, a 3-11 membered saturated or partially saturated heterocyclic group, or a 5-6 membered monocyclic heteroaryl ring,

wherein any alkyl or alkoxy is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, C_1-3haloalkoxy, or a 3-11 membered saturated or partially saturated heterocyclic group that may be optionally substituted with (i) —C(O)(C_1-3alkyl) optionally substituted with halogen or (ii) with C_1-3alkyl optionally substituted with halogen, and

wherein any cycloalkyl group, heterocyclic group, phenyl, or heteroaryl ring is optionally substituted by halogen; oxo; CN; OH; C_1-6alkoxy; —NR⁸R⁹; —C(O)(C_1-3alkyl); —(C_0-3alkyl)C(O)NR¹⁰R¹¹; —S(O)_1-2NR⁸R⁹; —OP(O)(OC_1-3alkyl)₂; C_3-10cycloalkyl group optionally substituted with OH or halogen; a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C_1-3alkyl; a 5-6 membered monocyclic heteroaryl ring optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, or C_1-3haloalkyl; or C_1-4alkyl optionally substituted by halogen, oxo, CN, OH, —O—C_1-3 alkyl, —S—C_1-3alkyl, —SO₂—C_1-3alkyl, —NR⁸R⁹, —C(O)NR⁸R⁹, phenyl, C_3-10cycloalkyl, a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C_1-3 alkyl, or a 5-6 membered monocyclic heteroaryl ring optionally substituted with oxo, halogen, or C_1-3alkyl;

A is a 3-11 membered heterocyclic group optionally substituted by halogen, oxo, CN, OH, C_1-6alkyl, —(C_0-3alkyl)-C_3-6cycloalkyl group, a —(C_0-3alkyl)-3-11 membered heterocyclic group, —NR⁸R⁹, —NR¹²C(O)R¹³, —NR¹²S(O)_1-2R¹³, —C(O)(C_1-3alkyl), —C(O)NR¹⁰R¹¹, —C(O)OR¹³, —S(O)_1-2NR¹⁰R¹¹, or —(C_0-3alkyl)-OP(O)(OC_1-3alkyl)₂,

wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted by halogen; oxo; CN; OR¹³; C_1-3haloalkoxy; —C(O)(C_1-3alkyl); —S—C_1-3alkyl; or C_1-3alkyl optionally substituted with OH, halogen, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, or a 3-8 membered heterocyclic group, and

wherein when A is a 5-membered nitrogen containing heterocyclic group, the nitrogen atom is substituted;

R⁶ and R⁷ are, independently at each occurrence, hydrogen, C_1-3alkyl, or C_3-6cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

R⁸, R⁹, R¹⁰ and R¹¹ are, independently at each occurrence, hydrogen, C_1-6alkyl, C_3-6cycloalkyl group, —(C_0-3alkyl)-phenyl, a 3-11 membered saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, —C(O)R¹³, —C(O)OR¹³, —C(O)NR⁶R⁷, or —S(O)_1-2R¹³, or R¹⁰ and R¹¹ are taken together to form a 5-8 membered heterocyclic group,

wherein any alkyl, cycloalkyl group, phenyl, heterocyclic group, or heteroaryl ring is independently optionally substituted by halogen, oxo, CN, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, —OR¹³, —NR⁶R⁷, or a 5-6 membered monocyclic heteroaryl ring;

R¹² is, independently at each occurrence, hydrogen, C_1-6alkyl or C_3-6cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

R¹³ is, independently at each occurrence, hydrogen, C_1-6alkyl, C_3-10cycloalkyl group, or a 3-11 membered saturated heterocyclic group,

wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, —OR¹², or —NR⁶R⁷; and

R¹⁶ is hydrogen, halogen, CN, or C_1-3alkyl optionally substituted with —NH₂, halogen, or CN.

Another aspect of the invention includes a compound of Formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

R¹ is hydrogen or halogen;

R³ is hydrogen, halogen, CN, OH, C_1-3alkyl, C_2-3alkenyl, C_3-7cycloalkyl group, C₁-C₃alkanoyl, —(C₀-C₃alkyl)C(O)NR⁶R⁷, —(C_2-3alkenyl)C(O)NR⁶R⁷, —S(O)_1-2NR⁶R⁷, —NR⁸R⁹, a 3-7 membered monocyclic saturated or partially saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, or a 5-6 membered monocyclic aryl ring,

wherein any alkyl, alkanoyl, or alkenyl is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, or C_1-3haloalkoxy, and

any cycloalkyl group or other ring is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, or C_1-3haloalkyl;

R⁴ is hydrogen, halogen, C_1-3alkyl, C_2-3alkenyl, —(C₀-C₃alkyl)C(O)R¹³, —(C_2-3alkenyl)C(O)NR¹⁰R¹¹, —S(O)_1-2NR¹⁰R¹¹, or —NR⁸R⁹;

wherein any alkyl or alkenyl is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, or C_1-3haloalkoxy;

R⁵ is hydrogen, C_1-6alkyl, C_1-6alkoxy, C_3-10cycloalkyl group, —NR⁸R⁹, —O(C_3-7cycloalkyl group), —O(C_1-3alkyl)-3-8 membered cycloalkyl group, —O(C_1-3alkyl)-3-8 membered saturated or partially saturated heterocyclic group, —O(C_1-3alkyl)-phenyl, a —O(C_1-3alkyl)-5-6 membered heteroaryl ring, a 3-11 membered saturated or partially saturated heterocyclic group, or a 5-6 membered monocyclic heteroaryl ring,

wherein any alkyl or alkoxy is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, or C_1-3haloalkoxy, and

any cycloalkyl group or other ring is optionally substituted by halogen, oxo, CN, OH, C_1-6alkoxy, —C(O)(C_1-3alkyl), —(C_0-3alkyl)C(O)NR¹⁰R¹¹, —S(O)_1-2NR⁸R⁹, —OP(O)(OC_1-3alkyl)₂, a 5-6 membered monocyclic heteroaryl ring optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, or C_1-3haloalkyl, or C_1-3alkyl optionally substituted by halogen, oxo, CN, OH, phenyl, a 3-8 membered saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, or —NR⁸R⁹;

A is a 3-11 membered heterocyclic group optionally substituted by halogen, oxo, CN, OH, C_1-6alkyl, —(C_0-3alkyl)-C_3-6cycloalkyl group, a —(C_0-3alkyl)-3-11 membered heterocyclic group optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, or C_1-3haloalkyl, —NR⁸R⁹, —NR¹²C(O)R¹³, —NR¹²S(O)_1-2R¹³, —C(O)(C_1-3alkyl), —C(O)NR¹⁰R¹¹, —C(O)OR¹³, —S(O)_1-2NR¹⁰R¹¹, or —OP(O)(OC_1-3alkyl)₂,

wherein any alkyl, cycloalkyl group, or heterocyclic group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, or a 3-8 membered heterocyclic group;

wherein when A is a 5-membered nitrogen containing heterocyclic group, the nitrogen atom is substituted;

R⁶ and R⁷ are, independently at each occurrence, hydrogen, C_1-3alkyl, or C_3-6cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

R⁸, R⁹, R¹⁰ and R¹¹ are, independently at each occurrence, hydrogen, C_1-6alkyl, C_3-6cycloalkyl group, —(C_0-3alkyl)-phenyl, a 3-11 membered saturated heterocyclic group, —C(O)R¹³, —C(O)OR¹³, —C(O)NR⁶R⁷, or —S(O)_1-2R¹³, or R¹⁰ and R¹¹ are taken together to form a 5-8 membered heterocyclic group optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

wherein any alkyl, cycloalkyl group, or other ring is independently optionally substituted by halogen, oxo, CN, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, —OR¹³, or —NR⁶R⁷;

R¹² is, independently at each occurrence, hydrogen, C_1-6alkyl or C_3-6cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

R¹³ is, independently at each occurrence, hydrogen, C_1-6alkyl, C_3-10cycloalkyl group, or a 3-11 membered saturated heterocyclic group,

wherein any alkyl, cycloalkyl group, or other ring is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, —OR¹², or —NR⁶R⁷; and

R¹⁶ is H, —Cl, —CN, or —CH₃.

Another aspect of the invention includes a compound of Formula II:

or a stereoisomer or pharmaceutically acceptable salt thereof,

wherein:

R¹ is hydrogen or halogen;

R³ is hydrogen, halogen, CN, OH, C_1-3alkyl, C_2-3alkenyl, C_3-7cycloalkyl group, C₁-C₃alkanoyl, —(C₀-C₃alkyl)C(O)NR⁶R⁷, —(C_2-3alkenyl)C(O)NR⁶R⁷, —S(O)_1-2NR⁶R⁷, —NR⁸R⁹, a 3-7 membered monocyclic saturated or partially saturated heterocyclic group, a 5-6 membered monocyclic heteroaryl ring, or a 5-6 membered monocyclic aryl ring,

wherein any alkyl, alkanoyl, or alkenyl is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, or C_1-3haloalkoxy, and

any cycloalkyl group or other ring is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, or C_1-3haloalkyl;

R⁴ is hydrogen, halogen, C_1-3alkyl, C_2-3alkenyl, —(C₀-C₃alkyl)C(O)R¹³, —(C_2-3alkenyl)C(O)NR¹⁰R¹¹, —S(O)_1-2NR¹⁰R¹¹, or —NR⁸R⁹;

wherein any alkyl or alkenyl is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, or C_1-3haloalkoxy;

R⁵ is hydrogen, C_1-6alkyl, C_1-6alkoxy, C_3-10cycloalkyl group, —NR⁸R⁹, —O(C_3-7cycloalkyl group), a 3-11 membered saturated or partially saturated heterocyclic group, or a 5-6 membered monocyclic heteroaryl ring,

wherein any alkyl or alkoxy is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkoxy, or C_1-3haloalkoxy, and

any cycloalkyl group or other ring is optionally substituted by halogen, oxo, CN, OH, —(C_0-3alkyl)C(O)NR¹⁰R¹¹, —OP(O)(OC_1-3alkyl)₂, or C_1-3alkyl optionally substituted by halogen, oxo, CN, OH, or —NR⁸R⁹;

A is a 3-11 membered heterocyclic group optionally substituted by halogen, oxo, CN, OH, C_1-6alkyl, C_3-6cycloalkyl group, —NR⁸R⁹, —NR¹²C(O)R¹³, —NR¹²S(O)_1-2R¹³, —C(O)NR¹⁰R¹¹, —C(O)OR¹³, or —S(O)_1-2NR¹⁰R¹¹,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

wherein when A is a 5-membered nitrogen containing heterocyclic group, the nitrogen atom is substituted;

R⁶ and R⁷ are, independently at each occurrence, hydrogen, C_1-3alkyl, or C_3-6cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy; R⁸, R⁹, R¹⁰ and R¹¹ are, independently at each occurrence, hydrogen, C_1-6alkyl, C_3-6cycloalkyl group, a 3-11 membered saturated heterocyclic group, —C(O)R¹³, —C(O)OR¹³, —C(O)NR⁶R⁷, or —S(O)_1-2R¹³,

wherein any alkyl, cycloalkyl group or other ring is independently optionally substituted by halogen, oxo, CN, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, —OR¹³, or —NR⁶R⁷;

R¹² is, independently at each occurrence, hydrogen, C_1-6alkyl or C_3-6cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

R¹³ is, independently at each occurrence, hydrogen, C_1-6alkyl, C_3-10cycloalkyl group, or a 3-11 membered saturated heterocyclic group,

wherein any alkyl, cycloalkyl group, or other ring is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, —OR¹², or —NR⁶R⁷; and

R¹⁶ is H, —Cl, —CN, or —CH₃.

In some embodiments, R¹ and R⁴ are each hydrogen, and R³ is hydrogen, OH, halogen, CH₃, CH₂OH, CH₂F, OCHF₂, CHF₂, CF₃, cyclopropyl, azetidinyl, CN, —C(O)CH₃, —C(O)NH₂, —C(O)NHCH₃, —NHCH₃, —SO₂—NH₂, or —SO₂—NHCH₃.

In some embodiments, R¹ and R⁴ are each hydrogen, and R³ is hydrogen, halogen, CH₃, CH₂F, CHF₂, CF₃, cyclopropyl, or —C(O)CH₃.

In some embodiments, R¹ and R⁴ are each hydrogen, and R³ is hydrogen, OH, CH₃, or CH₂OH.

In some embodiments, R¹ and R⁴ are each hydrogen, and R³ is Br, Cl, F, OCHF₂, CHF₂, or CF₃.

In some embodiments, R¹ and R⁴ are each hydrogen, and R³ is cyclopropyl, azetidinyl, CN, —C(O)CH₃, —C(O)NH₂, —C(O)NHCH₃, —NHCH₃, —SO₂—NH₂, or —SO₂—NHCH₃.

In some embodiments, R¹ and R³ are each hydrogen, and R⁴ is Cl, CHF₂,

or a stereoisomer thereof.

In some embodiments, R¹ and R³ are each hydrogen, and R⁴ is hydrogen or CH₃.

In some embodiments, R¹, R⁴ and R³ are each hydrogen.

In some embodiments, R¹⁶ is H. In some embodiments, R¹⁶ is —Cl, —CN, or —CH₃.

In some embodiments, R⁵ is a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted by halogen; oxo; CN; OH; C_1-6alkoxy; —NR⁸R⁹; —C(O)(C_1-3alkyl); —(C_0-3alkyl)C(O)NR¹⁰R¹¹; —S(O)_1-2NR⁸R⁹; —OP(O)(OC_1-3alkyl)₂; C_3-10cycloalkyl group optionally substituted with OH or halogen; a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C_1-3alkyl; a 5-6 membered monocyclic heteroaryl ring optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, or C_1-3haloalkyl; or C_1-4alkyl optionally substituted by halogen, oxo, CN, OH, —O—C_1-3 alkyl, —S—C_1-3alkyl, —SO₂—C_1-3alkyl, —NR⁸R⁹, —C(O)NR⁸R⁹, phenyl, C_3-10cycloalkyl, a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C_1-3 alkyl, or a 5-6 membered monocyclic heteroaryl ring optionally substituted with oxo, halogen, or C_1-3alkyl.

In some embodiments, R⁵ is a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted by halogen, oxo, CN, OH, —(C_0-3alkyl)C(O)NR¹⁰R¹¹, —OP(O)(OC_1-3alkyl)₂, or C_1-3alkyl optionally substituted by halogen, oxo, CN, OH, or —NR⁸R⁹. In some embodiments, R⁵ is an N-linked 3-11 membered saturated heterocyclic group optionally substituted by halogen, oxo, CN, OH, —(C_0-3alkyl)C(O)NR¹⁰R¹¹, —OP(O)(OC_1-3alkyl)₂, or C_1-3alkyl optionally substituted by halogen, oxo, CN, OH, or —NR⁸R⁹.

In some embodiments, the ring heteroatoms of the 3-11 membered saturated or partially saturated heterocyclic group of R⁵ are selected from nitrogen and oxygen.

In some embodiments, R⁵ is piperidinyl, piperazinyl, or morpholinyl, wherein any R⁵ is optionally substituted by halogen; oxo; CN; OH; C_1-6alkoxy; —NR⁸R⁹; —C(O)(C_1-3alkyl); —(C_0-3alkyl)C(O)NR¹⁰R¹¹; —S(O)_1-2NR⁸R⁹; —OP(O)(OC_1-3alkyl)₂; C_3-10cycloalkyl group optionally substituted with OH or halogen; a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C_1-3alkyl; a 5-6 membered monocyclic heteroaryl ring optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, or C_1-3haloalkyl; or C_1-4alkyl optionally substituted by halogen, oxo, CN, OH, —O—C_1-3 alkyl, —S—C_1-3alkyl, —SO₂—C_1-3alkyl, —NR⁸R⁹, —C(O)NR⁸R⁹, phenyl, C_3-10cycloalkyl, a 3-11 membered saturated or partially saturated heterocyclic group optionally substituted with oxo or C_1-3 alkyl, or a 5-6 membered monocyclic heteroaryl ring optionally substituted with oxo, halogen, or C_1-3alkyl.

In some embodiments, R⁵ is N-linked piperidinyl, N-linked piperazinyl, or N-linked morpholinyl, wherein any R⁵ is optionally substituted by halogen, oxo, CN, OH, or C_1-3alkyl optionally substituted by halogen, oxo, CN, or OH.

In some embodiments, R⁵ is:

—CH₂CH₃, —C(CH₃)₂, Cl, CN, cyclopropyl, —C(O)NH₂, —OCH₃, —OCH₂CF₃, —OCH₂CHF₂, —CF₃, —CHF₂, —OCF₃, —OCHF₂, —NHCH₃, —N(CH₃)₂,

or a stereoisomer thereof.

In some embodiments, R⁵ is:

or a stereoisomer thereof.

In some embodiments, R⁵ is

As previously noted, when A is a 5-membered nitrogen containing heterocyclic ring, the nitrogen atom is substituted. In embodiments wherein A comprises one or more nitrogen atoms, e.g., 2, 3, or more nitrogen atoms, each nitrogen atom is substituted. More particularly, in some embodiments, the compound is not

In some embodiments, A is a 3-11 membered, non-aromatic heterocyclic group.

In some embodiments, A is a 3-11 membered heterocyclic group comprising at least one oxygen as a ring atom and is optionally substituted by halogen, oxo, CN, OH, C_1-6alkyl, C_3-6cycloalkyl group, —NR⁸R⁹, —NR¹²C(O)R¹³, —NR¹²S(O)_1-2R¹³, —C(O)NR¹⁰R¹¹, —C(O)OR¹³, or —S(O)_1-2NR¹⁰R¹¹, wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy.

In some embodiments, the following portion of Formula 0, Formula I, or Formula II,

is further defined as 0-A, I-A, or II-A:

wherein A is a 5 or 6 membered ring optionally containing an additional ring heteroatom and

wherein A is optionally substituted by halogen, oxo, CN, OH, C_1-6alkyl, C_3-6cycloalkyl group, —NR⁸R⁹, —NR¹²C(O)R¹³, —NR¹²S(O)_1-2R¹³, —C(O)NR¹⁰R¹¹, —C(O)OR¹³, or —S(O)_1-2NR¹⁰R¹¹,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy.

In some embodiments, 0-A, I-A, or II-A is further defined as 0-B, I—B, or II-B:

wherein R¹⁴ and R¹⁵ are each selected from halogen, oxo, CN, OH, C_1-6alkyl, C_3-6cycloalkyl group, —NR⁸R⁹, —NR¹²C(O)R¹³, —NR¹²S(O)_1-2R¹³, —C(O)NR¹⁰R¹¹, —C(O)OR¹³, and —S(O)_1-2NR¹⁰R¹¹,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy;

or R¹⁴ and R¹⁵ together form a C_3-6cycloalkyl group or saturated or partially saturated 3-6 membered heterocyclic group,

wherein any cycloalkyl group or other ring is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy.

In some embodiments, A does not contain oxygen as a ring atom and is optionally substituted by halogen, oxo, CN, OH, C_1-6alkyl, C_3-6cycloalkyl group, —NR⁸R⁹, —NR¹²C(O)R¹³, —NR¹²S(O)_1-2R¹³, —C(O)NR¹⁰R¹¹, —C(O)OR¹³, or —S(O)_1-2NR¹⁰R¹¹, wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy.

In some embodiments, the following portion of Formula 0, Formula I, or Formula II,

is further defined as 0-C, I-C, or II-C:

wherein the nitrogen comprises a substituent as defined herein.

In some embodiments, the following portion of Formula 0, Formula I, or Formula II,

is further defined as 0-C, I-C, or II-C:

wherein the nitrogen of A is substituted by C_1-6alkyl or C_3-6cycloalkyl group,

wherein any alkyl or cycloalkyl group is independently optionally substituted by halogen, oxo, CN, OH, C_1-3alkyl, C_1-3haloalkyl, C_1-3alkoxy, or C_1-3haloalkoxy.

In some embodiments, the following portion of Formula 0, Formula I, or Formula II,

is selected from

and stereoisomers thereof.

In some embodiments, the following portion of Formula 0, Formula I, or Formula II,

is selected from

and stereoisomers thereof.

In some embodiments, a compound is selected from the group consisting of the compounds of Tables 1, 2 and 3, shown below, or a stereoisomer or pharmaceutically acceptable salt thereof.

TABLE 1
Exemplary compounds of the present invention. Salts of such compounds are also
contemplated. See the Examples section for preparation of such compounds.
Ex.	Structure	Name
1		N-[7-[4-(hydroxymethyl)-1-piperidyl]- 3,4-dihydro-2H-1,4-benzoxazin-6- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
2		N-[7-[4-(hydroxymethyl)-1-piperidyl]- 3-oxo-4H-1,4-benzoxazin-6- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
3		N-[2,2-dimethyl-6-[2- (methylaminomethyl)-1,3-dioxan-5- yl]-3H-benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
4		N-[6-[4-(hydroxymethyl)-1-piperidyl]- 2,2-dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
5		N-(2,2-dimethyl-7-morpholino-3,4- dihydro-1,4-benzoxazin-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
6		N-[2-(hydroxymethyl)-2-methyl-6- morpholino-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
7		N-[7-[4-(hydroxymethyl)-1-piperidyl]- 3,4-dihydro-2H-1,4-benzoxazin-6-yl]- 6-methyl-pyrazolo[1,5-a]pyrimidine-3- carboxamide
8		N-[6-[4-(2,2-difluoroethyl)piperazin-1- yl]-2,2-dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
9		N-(7-morpholino-3,4-dihydro-2H-1,4- benzoxazin-6-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
10		N-(3-methyl-7-morpholino-3,4- dihydro-2H-1,4-benzoxazin-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
11		N-(2-methyl-7-morpholino-3,4- dihydro-2H-1,4-benzoxazin-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
12		N-[6-[4-(hydroxymethyl)-1-piperidyl]- 2,2-dimethyl-3H-benzofuran-5-yl]-6- methyl-pyrazolo[1,5-a]pyrimidine-3- carboxamide
13		N-[6-[(3S)-3- (hydroxymethyl)pyrrolidin-1-yl]-2,2- dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
14		N-(2-methyl-6-morpholino-2,3- dihydrobenzofuran-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
15		N-[6-[(3R)-3- (hydroxymethyl)pyrrolidin-1-yl]-2,2- dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
16		N-[2-(hydroxymethyl)-6-[4- (hydroxymethyl)-1-piperidyl]-2- methyl-3H-benzofuran-5-yl]-6-methyl- pyrazolo[1,5-a]pyrimidine-3- carboxamide
17		N-[6-(2,2-dimethylmorpholin-4-yl)-2- (hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
18		N-[6-[3-(hydroxymethyl)-3-methyl- pyrrolidin-1-yl]-2,2-dimethyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
19		N-[6-[4-(2,2-difluoroethyl)piperazin-1- yl]-2-(hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
20		N-[2,2-dimethyl-6-[2- (methylaminomethyl)-1,3-dioxan-5- yl]-3H-benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
21		N-(2-ethyl-2-methyl-6-morpholino-3H- benzofuran-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
22		N-(2-cyclopropyl-2-methyl-6- morpholino-3H-benzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
23		N-[2-(dimethylcarbamoyl)-2-methyl-6- morpholino-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
24		N-[6-[4-(1-amino-2,2,2-trifluoro- ethyl)-1-piperidyl]-2,2-dimethyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
25		N-[2-(methoxymethyl)-2-methyl-6- morpholino-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
26		N-[6-(4,4-difluoro-1-piperidyl)-2- (hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
27 and  28		N-(3-hydroxy-3-methyl-7-morpholino- chroman-6-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-(3-hydroxy-3-methyl-7-morpholino- chroman-6-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
29 and  30		N-[2-(hydroxymethyl)-2-methyl-6- morpholino-3H-benzofuran-5-yl]-6- methyl-pyrazolo[1,5-a]pyrimidine-3- carboxamide and N-[2-(hydroxymethyl)-2-methyl-6- morpholino-3H-benzofuran-5-yl]-6- methyl-pyrazolo[1,5-a]pyrimidine-3- carboxamide
31 and  32		N-[(2R)-2-(hydroxymethyl)-2-methyl- 6-morpholino-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide and N-[(2S)-2-(hydroxymethyl)-2-methyl- 6-morpholino-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
33		N-(2,2-dimethyl-6-morpholino-3H- benzofuran-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
34		N-(6-methoxy-2,2-dimethyl-3H- benzofuran-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
35		N-(8-morpholino-2,3,4,5-tetrahydro- 1,5-benzoxazepin-7-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
36 and  37		N-[(2R)-6-(2,2-dimethylmorpholin-4- yl)-2-(hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2S)-6-(2,2-dimethylmorpholin-4- yl)-2-(hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
38		2-methyl-6-morpholino-5- (pyrazolo[1,5-a]pyrimidine-3- carbonylamino)-3H-benzofuran-2- carboxylic acid
39		N-(6-morpholinospiro[3H-benzofuran- 2,4′-tetrahydropyran]-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
40		N-[6-[4-fluoro-4-(hydroxymethyl)-1- piperidyl]-2,2-dimethyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
41		N-[6-(1,1-dioxo-1,4-thiazinan-4-yl)- 2,2-dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
42 and  43		N-[(2S)-2-(hydroxymethyl)-2-methyl- 6-[(1R,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2R)-2-(hydroxymethyl)-2-methyl- 6-[(1R,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
44 and  45		N-[(2R)-6-[4-fluoro-4- (hydroxymethyl)-1-piperidyl]-2- (hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2S)-6-[4-fluoro-4- (hydroxymethyl)-1-piperidyl]-2- (hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
46 and  47		N-[(2S)-2-(hydroxymethyl)-2-methyl- 6-[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2R)-2-(hydroxymethyl)-2-methyl- 6-[(1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl]-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
48 and  49		N-[(2S)-2-methyl-2- (methylcarbamoyl)-6-morpholino-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2R)-2-methyl-2- (methylcarbamoyl)-6-morpholino-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
50 and  51		N-[(2R)-2-(difluoromethyl)-2-methyl- 6-morpholino-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide and N-[(2S)-2-(difluoromethyl)-2-methyl- 6-morpholino-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
52 and  53		N-[(2R)-2-(hydroxymethyl)-6-[4-(1- hydroxy-1-methyl-ethyl)-1-piperidyl]- 2-methyl-3H-benzofuran-5-yl]-6- methyl-pyrazolo[l,5-a]pyrimidine-3- carboxamide and N-[(2S)-2-(hydroxymethyl)-6-[4-(1- hydroxy-1-methyl-ethyl)-1-piperidyl]- 2-methyl-3H-benzofuran-5-yl]-6- methyl-pyrazolo[l,5-a]pyrimidine-3- carboxamide
54 and  55		6-fluoro-N-[(2R)-2-(hydroxymethyl)-2- methyl-6-morpholino-3H-benzofuran- 5-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide and 6-fluoro-N-[(2S)-2-(hydroxymethyl)-2- methyl-6-morpholino-3H-benzofuran- 5-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
56 and  57		N-[(2S)-6-[(3S)-3-fluoropyrrolidin-1- yl]-2-(hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2R)-6-[(3S)-3-fluoropyrrolidin-1- yl]-2-(hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
58 and  59		N-[(2R)-6-[(3R)-3-fluoropyrrolidin-1- yl]-2-(hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2S)-6-[(3R)-3-fluoropyrrolidin-1- yl]-2-(hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
60		N-[6-[4-(2-hydroxyethyl)piperazin-1- yl]-2,2-dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
61		6-cyclopropyl-N-(2,2-dimethyl-6- morpholino-3H-benzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
62		N-[2,2-dimethyl-6-(4-piperidyl)-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
63		N-[2,2-dimethyl-6-(1-methyl-4- piperidyl)-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
64 and  65		N-[6-(4-hydroxycyclohexoxy)-2,2- dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide and N-[6-(4-hydroxycyclohexoxy)-2,2- dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
66 and  67		N-[(2R)-6-(3,3-difluoropyrrolidin-1- yl)-2-(hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2S)-6-(3,3-difluoropyrrolidin-1- yl)-2-(hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
68		N-[6-(3,3-difluoro-4-hydroxy- pyrrolidin-1-yl)-2,2-dimethyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
69		N-(2,2-dimethyl-6-morpholino-3H- benzofuran-5-yl)-6- (trifluoromethyl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
70		N-[2,2-dimethyl-6-(2,2,2- trifluoroethoxy)-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
71 and  72		N-[(2R)-2-(hydroxymethyl)-2-methyl- 6-(trifluoromethyl)-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide and N-[(2S)-2-(hydroxymethyl)-2-methyl- 6-(trifluoromethyl)-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
73 and  74		N-[(2R)-6-(difluoromethyl)-2- (hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2S)-6-(difluoromethyl)-2- (hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
75		6-(difluoromethyl)-N-[2- (hydroxymethyl)-2-methyl-6- morpholino-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
76 and  77		N-[(2R)-2-methyl-6-morpholino-2- (trifluoromethyl)-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide and N-[(2S)-2-methyl-6-morpholino-2- (trifluoromethyl)-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
78 and  79		N-[(2R)-2-(hydroxymethyl)-2-methyl- 6-[(1S,4S)-5-(2,2,2-trifluoroethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2S)-2-(hydroxymethyl)-2-methyl- 6-[(1S,4S)-5-(2,2,2-trifluoroethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
80 and  81		N-[(2R)-7-chloro-2-(hydroxymethyl)- 2-methyl-6-morpholino-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2S)-7-chloro-2-(hydroxymethyl)-2- methyl-6-morpholino-3H-benzofuran- 5-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
82		N-(3,3-dimethyl-7-morpholino-2,4- dihydro-1,4-benzoxazin-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
83 and  84		N-[(2R)-2-(hydroxymethyl)-2,7- dimethyl-6-morpholino-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2S)-2-(hydroxymethyl)-2,7- dimethyl-6-morpholino-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
85 and  86		6-acetyl-N-[(2R)-2-(hydroxymethyl)-2- methyl-6-morpholino-3H-benzofuran- 5-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide and 6-acetyl-N-[(2S)-2-(hydroxymethyl)-2- methyl-6-morpholino-3H-benzofuran- 5-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
87 and  88		N-[(2R)-6-[4-(2- hydroxyethyl)piperazin-1-yl]-2- (hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2S)-6-[4-(2- hydroxyethyl)piperazin-1-yl]-2- (hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
89		N-[6-[1-(2,2-difluoroethyl)-4- piperidyl]-2,2-dimethyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
90		N-[2,2-dimethyl-6-[1-(2,2,2- trifluoroethyl)-4-piperidyl]-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
91		6-(difluoromethyl)-N-(2,2-dimethyl-6- morpholino-3H-benzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
92 and  93		N-[(2S)-2-(hydroxymethyl)-6-[4- (hydroxymethyl)-1-piperidyl]-2- methyl-3H-benzofuran-5-yl]-6-methyl- pyrazolo[1,5-a]pyrimidine-3- carboxamide and N-[(2R)-2-(hydroxymethyl)-6-[4- (hydroxymethyl)-1-piperidyl]-2- methyl-3H-benzofuran-5-yl]-6-methyl- pyrazolo[1,5-a]pyrimidine-3- carboxamide
94 and  95		N-[6-[(3S)-3-(hydroxymethyl)-3- methyl-pyrrolidin-1-yl]-2,2-dimethyl- 3H-benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[6-[(3R)-3-(hydroxymethyl)-3- methyl-pyrrolidin-1-yl]-2,2-dimethyl- 3H-benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
96 and  97		N-(2-ethyl-2-methyl-6-morpholino-3H- benzofuran-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-(2-ethyl-2-methyl-6-morpholino-3H- benzofuran-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
98 and  99		N-[6-[4-(2,2-difluoroethyl)piperazin-1- yl]-2-(hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[6-[4-(2,2-difluoroethyl)piperazin-1- yl]-2-(hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
100		N-[6-(6,8-dihydro-5H-imidazo[1,5- a]pyrazin-7-yl)-2,2-dimethyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyridine-3-carboxamide
101		N-[2,2-dimethyl-6-(5,6,8,9- tetrahydroimidazo[1,5-d][1,4]diazepin- 7-yl)-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
102		N-[6-[4-(hydroxymethyl)imidazol-1- yl]-2,2-dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
103		N-(6-imidazol-1-yl-2,2-dimethyl-3H- benzofuran-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
104		N-[2,2-dimethyl-6-(2- methylpyrrolidin-1-yl)-3H-benzofuran- 5-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
105		N-[6-(3-hydroxy-3-methyl-azetidin-1- yl)-2,2-dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
106		N-[2,2-dimethyl-6-(2-oxa-8- azaspiro[4.5]decan-8-yl)-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
107		N-[2,2-dimethyl-6-(2-oxa-7- azaspiro[3.4]octan-7-yl)-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
108		N-[2,2-dimethyl-6-(2-oxa-7- azaspiro[4.4]nonan-7-yl)-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
109		N-[6-(4-hydroxy-8-azaspiro[4.5]decan- 8-yl)-2,2-dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
110		N-[6-(2-hydroxy-7-azaspiro[3.5]nonan- 7-yl)-2,2-dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
111		N-[2,2-dimethyl-6-(3-oxo-2,7- diazaspiro[3.5]nonan-7-yl)-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
112		N-[6-(6,6-difluoro-3- azabicyclo[3.1.0]hexan-3-yl)-2,2- dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
113		N-[2,2-dimethyl-6-(6-oxo-1H-pyridin- 3-yl)-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
114		N-[2,2-dimethyl-6-(2-oxa-7- azaspiro[3.5]nonan-7-yl)-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
115		N-[6-(3-fluoro-4-hydroxy-1-piperidyl)- 2,2-dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
116		N-[6-(1,4-diazepan-1-yl)-2,2-dimethyl- 3H-benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
117		N-[2,2-dimethyl-6-(1,4-oxazepan-4- yl)-3H-benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
118		N-(2,2-dimethyl-6-morpholino-1,1- dioxo-3H-benzothiophen-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
119 and 120		N-[(2S)-2-(hydroxymethyl)-2-methyl- 6-[(1R,4R)-5-(2,2,2-trifluoroethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[3-[3-(2-hydroxyethyl)-2-oxo- imidazolidin-1-yl]-1-methyl-pyrazol-4- yl]-2-[2-(2,2,2-trifluoroethylamino)-4- pyridyl]oxazole-4-carboxamide
121 and 122		N-[(2R)-6-(4,4-difluoro-1-piperidyl)-2- (hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2S)-6-(4,4-difluoro-1-piperidyl)-2- (hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
123 and 124		N-[(2R)-6-[(1R,4R)-5-(2,2- difluoroethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-2- (hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2S)-6-[(1R,4R)-5-(2,2- difluoroethyl)-2,5- diazabicyclo[2.2.1]heptan-2-yl]-2- (hydroxymethyl)-2-methyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
125 and 126		N-[(2S)-2-(hydroxymethyl)-2-methyl- 6-(2-oxa-8-azaspiro[4.5]decan-8-yl)- 3H-benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2R)-2-(hydroxymethyl)-2-methyl- 6-(2-oxa-8-azaspiro[4.5]decan-8-yl)- 3H-benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
127 and 128		N-[(2R)-2-(hydroxymethyl)-2-methyl- 6-(4-methylpiperazin-1-yl)-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2S)-2-(hydroxymethyl)-2-methyl- 6-(4-methylpiperazin-1-yl)-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
129 and 130		N-[(2S)-2-(hydroxymethyl)-6-[4- (hydroxymethyl)-1-piperidyl]-2- methyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide and N-[(2R)-2-(hydroxymethyl)-6-[4- (hydroxymethyl)-1-piperidyl]-2- methyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
131		N-(6-(4-(2,2-difluoroethyl)piperazin-1- yl)-2-(hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5-yl)-6- fluoropyrazolo[1,5-a]pyrimidine-3- carboxamide
132 and 133		(S)-N-(6-(4-(2,2- Difluoroethyl)piperazin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5-yl)-6- fluoropyrazolo[1,5-a]pyrimidine-3- carboxamide and (R)-N-(6-(4-(2,2- Difluoroethyl)piperazin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5-yl)-6- fluoropyrazolo[1,5-a]pyrimidine-3- carboxamide
134 and 135		(R)-N-(2-isopropyl-2-methyl-6- morpholino-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and (S)-N-(2-isopropyl-2-methyl-6- morpholino-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
136		N-(6-Methyl-2-morpholino-7-oxo-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-3- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
137		N-[6-[4-(2-Hydroxy-1,1-dimethyl- ethyl)piperazin-1-yl]-2,2-dimethyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
138		N-(2-isopropyl-6-morpholino-1-oxo- isoindolin-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
139		N-[2-[(2R)-2-fluoro-3-hydroxy-3- methyl-butyl]-6-morpholino-1-oxo- isoindolin-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
140		N-(2-methyl-6-morpholino-1-oxo- isoindolin-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
141		N-[2-(hydroxymethyl)-2-methyl-7- morpholino-chroman-6- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
142		N-(6-morpholinospiro[3H-benzofuran- 2,4′-piperidine]-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
143		N-(7-cyano-2,2-dimethyl-6- morpholino-3H-benzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
144		N-[2-(difluoromethyl)-2-methyl-6- morpholino-3H-benzofuran-5-yl]-6- methyl-pyrazolo[1,5-a]pyrimidine-3- carboxamide
145		[1-[2,2-dimethyl-5-(pyrazolo[1,5- a]pyrimidine-3-carbonylamino)-3H- benzofuran-6-yl]-4-piperidyl]methyl diethylphosphate
146		N-(1-methyl-6′-morpholino-3′H- spiro[azetidine-3,2′-benzofuran]-5′- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
147		N-[1′-(2,2-difluoroethyl)-6- morpholino-spiro[3H-benzofuran-2,3′- azetidine]-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
148		N-[6-morpholino-1′-(2,2,2- trifluoroethyl)spiro[3H-benzofuran- 2,3′-azetidine]-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
149		N-[6-[4-(2,2-difluoroethyl)-1,4- diazepan-1-yl]-2,2-dimethyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
150		N-(2-isopropyl-2-methyl-6- morpholino-3H-benzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
151		N-[2-(hydroxymethyl)-6-[4-(2- hydroxy-2-methyl-propyl)piperazin-1- yl]-2-methyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
152		N-(1′-methyl-6-morpholino-spiro[3H- benzofuran-2,4′-piperidine]-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
153 and 154		N-[(2R)-2-(hydroxymethyl)-6- morpholino-2-(trifluoromethyl)-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2S)-2-(hydroxymethyl)-6- morpholino-2-(trifluoromethyl)-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
155 and 156		N-[(2S)-2-(difluoromethoxymethyl)-2- methyl-6-morpholino-3H-benzofuran- 5-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide and N-[(2R)-2-(difluoromethoxymethyl)-2- methyl-6-morpholino-3H-benzofuran- 5-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
157 and 158		N-[(2R)-2-(1-hydroxy-1-methyl-ethyl)- 2-methyl-6-morpholino-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2S)-2-(1-hydroxy-1-methyl-ethyl)- 2-methyl-6-morpholino-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
159 and 160		N-[(2R)-2-cyclopropyl-6-[4-(2,2- difluoroethyl)piperazin-1-yl]-2-methyl- 3H-benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide and N-[(2S)-2-cyclopropyl-6-[4-(2,2- difluoroethyl)piperazin-1-yl]-2-methyl- 3H-benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
161 and 162		N-[(2R)-2-cyclopropyl-6-[4-fluoro-4- (hydroxymethyl)-1-piperidyl]-2- methyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide and N-[(2S)-2-cyclopropyl-6-[4-fluoro-4- (hydroxymethyl)-1-piperidyl]-2- methyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
163 and 164		6-chloro-N-[(2S)-2-(hydroxymethyl)-6- [4-(hydroxymethyl)-1-piperidyl]-2- methyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide and 6-chloro-N-[(2R)-2-(hydroxymethyl)- 6-[4-(hydroxymethyl)-1-piperidyl]-2- methyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
165 and 166		6-chloro-N-[(2S)-2-(hydroxymethyl)-2- methyl-6-morpholino-3H-benzofuran- 5-yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide and 6-chloro-N-[(2R)-2-(hydroxymethyl)- 2-methyl-6-morpholino-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
167		6-chloro-N-[2,2-dimethyl-6-(2-oxa-8- azaspiro[4.5]decan-8-yl)-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide

TABLE 2
Additional exemplary compounds of the present invention. Salts of such compounds
are also contemplated. See the Examples section for preparation of such compounds.
168                    N-(6-(4-(2,2- Difluoroethyl)piperazin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5-yl)-6- methylpyrazolo[1,5- a]pyrimidine-3-carboxamide
169 and 170            (S)-6-Chloro-N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-6-Chloro-N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)
171 and 172            (R)-N-(2-(Hydroxymethyl)-2- methyl-6-(trifluoromethoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (S)-N-(2-(hydroxymethyl)-2- methyl-6-(trifluoromethoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
173                    N-[6-Morpholino-1-oxo-2-(2,2,2- trifluoroethyl)isoindolin-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
174                    N-[2-(2,2-difluoroethyl)-6- morpholino-1-oxo-isoindolin-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
175                    N-[2-(3-hydroxy-3-methyl- butyl)-6-morpholino-1-oxo- isoindolin-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
176                    N-[2-(2-hydroxy-2-methyl- propyl)-6-morpholino-1-oxo- isoindolin-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
177                    N-[6-[4-(2-amino-2-oxo- ethyl)piperazin-1-yl]-1-oxo-2- tetrahydropyran-4-yl-isoindolin- 5-yl]pyrazolo[1,5-a]pyrimidine- 3-carboxamide
178                    N-[2-(2-methoxyethyl)-6- morpholino-1-oxo-isoindolin-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
179                    N-[2-(2-hydroxyethyl)-6- morpholino-1-oxo-isoindolin-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
180                    N-[2-(1-methyl-4-piperidyl)-6- morpholino-1-oxo-isoindolin-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
181                    N-[2-(4-hydroxycyclohexyl)-6- morpholino-1-oxo-isoindolin-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
182                    N-[2,2-dimethyl-6-[(1S,5R)-6- (methylcarbamoyl)-3- azabicyclo[3.1.0]hexan-3-yl]-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
183                    N-[2,2-dimethyl-6-[4-[2- (methylamino)-2-oxo-ethyl]-1- piperidyl]-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
184                    N-[6-(4-carbamoyl-4-methyl-1- piperidyl)-2,2-dimethyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
185                    N-[6-(4-hydroxyazepan-1-yl)-2,2- dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
186                    N-[6-[(1S,5R)-6-carbamoyl-3- azabicyclo[3.1.0]hexan-3-yl]-2,2- dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
187                    N-[6-[4-(2-amino-2-oxo- ethyl)piperazin-1-yl]-2,2- dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
188                    N-[2,2-dimethyl-6-[3-(3- methylimidazol-4-yl)pyrrolidin- 1-yl]-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
189                    N-[6-(5,7-dihydropyrrolo[3,4- b]pyridin-6-yl)-2,2-dimethyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
190                    N-[2,2-dimethyl-6-[3-(1H- pyrazol-5-yl)-1-piperidyl]-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
191                    N-[6-(1,3,3a,4,6,6a- hexahydrofuro[3,4-c]pyrrol-5-yl)- 2,2-dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
192                    N-[2,2-dimethyl-6-[3-(1H- pyrazol-3-yl)pyrrolidin-1-yl]-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
193                    N-[6-(5,5-difluoro-2- azabicyclo[2.2.1]heptan-2-yl)- 2,2-dimethyl-3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
194                    N-[2,2-dimethyl-6-(6-oxa-2- azaspiro[3.5]nonan-2-yl)-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
195                    N-[2,2-dimethyl-6-[3- (trifluoromethyl)pyrrolidin-1-yl]- 3H-benzofuran-5- yl]pyrazolo[1,5-a]pyrimidine-3- carboxamide
196                    N-(6-(3,3-difluoropiperidin-1-yl)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
197                    N-(6-((3aR,6aS)-5,5- difluorohexahydrocyclopenta[c] pyrrol-2(1H)-yl)-2,2-dimethyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
198                    N-(6-(2- (methoxymethyl)morpholino)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
199                    N-(6-(6,6-difluoro-3- azabicyclo[3.2.0]heptan-3-yl)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
200                    N-(6-((3aR,6aS)-4,4- difluorohexahydrocyclopenta[c] pyrrol-2(1H)-yl)-2,2-dimethyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
201                    N-(6-(2- (hydroxymethyl)pyrrolidin-1-yl)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
202                    N-(6-(3-(1H-imidazol-2- yl)piperidin-1-yl)-2,2-dimethyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
203                    N-(6-((3R,4S)-3,4- difluoropyrrolidin-1-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
204                    N-(6-(5,5-difluoro-2- azaspiro[3.3]heptan-2-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
205                    N-(6-((4- cyanobenzyl)(methyl)amino)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
206                    N-(6-(4-(1H-imidazol-1- yl)piperidin-1-yl)-2,2-dimethyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
207                    N-(6-(4,4-difluoroazepan-1-yl)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
208                    N-(6-((1R,5S,6r)-6-carbamoyl-3- azabicyclo[3.1.0]hexan-3-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
209                    N-(6-(4-hydroxyazepan-1-yl)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
210                    N-(6-(4-carbamoyl-4- methylpiperidin-1-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
211                    N-(2,2-dimethyl-6-(4-(2- (methylamino)-2- oxoethyl)piperidin-1-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
212                    N-(2,2-dimethyl-6-((1R,5S,6r)-6- (methylcarbamoyl)-3- azabicyclo[3.1.0]hexan-3-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
213                    N-(2,2-dimethyl-6-(3-oxo-2,8- diazaspiro[4.5]decan-8-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
214                    N-(2,2-dimethyl-6-(pyrrolidin-1- yl)-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
215                    N-(6-(6-(hydroxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
216                    N-(6-(4-cyanopiperidin-1-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
217                    N-(6-(3,3-difluoropyrrolidin-1- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
218                    N-(2,2-dimethyl-6-(4- (trifluoromethyl)piperidin-1-yl)- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
219                    N-(6-(4-isobutyrylpiperazin-1- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
220                    N-(6-(4-acetyl-1,4-diazepan-1- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
221                    N-(2,2-dimethyl-6-(3-oxo-2,8- diazaspiro[4.5]decan-8-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
222 and 223            (R)-N-(2,2-dimethyl-6-(2-oxa-7- azaspiro[4.4]nonan-7-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (S)-N-(2,2-dimethyl-6-(2-oxa-7- azaspiro[4.4]nonan-7-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide (stereochemistry assigned arbitrarily)
224                    N-[6-(6-hydroxy-4-methyl-1,4- diazepan-1-yl)-2,2-dimethyl-3H- benzofuran-5-yl]pyrazolo[1,5- a]pyrimidine-3-carboxamide
225                    N-(6-(4-(2-(Isopropylamino)-2- oxoethyl)piperazin-1-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
226                    N-(6-(4-(1-Amino-2-methyl-1- oxopropan-2-yl)piperazin-1-yl)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
227                    N-(6-((3R,5S)-4-(2-Amino-2- oxoethyl)-3,5-dimethylpiperazin- 1-yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
228                    N-(2,2-Dimethyl-6-(4-(2- morpholino-2- oxoethyl)piperazin-1-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
229                    N-(2,2-Dimethyl-6-(3-(2- methylpyrimidin-4-yl)pyrrolidin- 1-yl)-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
230                    N-(2,2-Dimethyl-6-(4- ((tetrahydrofuran-2- yl)methyl)piperazin-1-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
231                    N-(6-(4-(2-(1H-Imidazol-1- yl)ethyl)piperazin-1-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
232                    N-(6-(4-(2-(Dimethylamino)-2- oxoethyl)piperazin-1-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
233                    N-(6-(5,6-Dihydroimidazo[1,2- a]pyrazin-7(8H)-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
234                    N-(6-(Hexahydro-5H-furo[2,3- c]pyrrol-5-yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
235                    N-(6-(4-(1,3,4-Oxadiazol-2- yl)piperidin-1-yl)-2,2-dimethyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
236                    N-(6-(3-Carbamoylpyrrolidin-1- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
237                    N-(6-(9-Hydroxy-3-oxa-7- azabicyclo[3.3.1]nonan-7-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
238                    N-(2,2-Dimethyl-6-(1,4,6,7- tetrahydro-5H-imidazo[4,5- c]pyridin-5-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
239                    N-(6-(7-Methoxy-2- azabicyclo[2.2.1]heptan-2-yl)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
240                    N-(6-(2-Azabicyclo[3.1.0]hexan- 2-yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
241                    N-(2,2-Dimethyl-6-(3- sulfamoylpyrrolidin-1-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
242                    N-(6-(4-(2-(Cyclopropylamino)- 2-oxoethyl)piperazin-1-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
243                    N-(2,2-Dimethyl-6-(4-(2-oxo-2- (pyrrolidin-1-yl)ethyl)piperazin- 1-yl)-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
244                    N-(6-(4-(1-(Cyclopropylamino)- 1-oxopropan-2-yl)piperazin-1- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
245                    N-(2,2-Dimethyl-6-(4-(2,2,2- trifluoro-1- hydroxyethyl)piperidin-1-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
246                    N-(6-(4,6-dihydropyrrolo[3,4- c]pyrazol-5(1H)-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
247                    N-(2,2-dimethyl-6-(3-methyl-4,6- dihydropyrrolo[3,4-c]pyrazol- 5(1H)-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
248                    N-(6-(2-(2,2-Difluoroethyl)-2,7- diazaspiro[3.5]nonan-7-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
249                    N-(2,2-dimethyl-6-(2-(2,2,2- trifluoroethyl)-2,7- diazaspiro[3.5]nonan-7-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
250                    N-[2-(2-Hydroxy-1,1-dimethyl- ethyl)-6-morpholino-1-oxo- isoindolin-5-yl]pyrazolo[1,5-a] pyrimidine-3-carboxamide
251                    N-(6-morpholino-2-(oxetan-3-yl)- 1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
252                    N-(6-morpholino-2-(2-(oxetan-3- yl)ethyl)-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
253                    N-(2-(cyanomethyl)-6- morpholino-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
254                    N-(6-morpholino-1-oxo-2- (tetrahydrofuran-3-yl)isoindolin- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
255                    N-(6-morpholino-1-oxo-2- (tetrahydro-2H-pyran-4- yl)isoindolin-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
256                    N-(2-(3-methoxy-3-methylbutyl)- 6-morpholino-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
257                    N-(6-morpholino-1-oxo-2- ((tetrahydro-2H-pyran-2- yl)methyl)isoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
258                    (R)-N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (2-fluoro-3-hydroxy-3- methylbutyl)-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
259 and 260            N-(2-((R)-2-fluoro-3-hydroxy-3- methylbutyl)-1-oxo-6-(4-((S)- 2,2,2-trifluoro-1- hydroxyethyl)piperidin-1- yl)isoindolin-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide and
                       N-(2-((R)-2-fluoro-3-hydroxy-3- methylbutyl)-1-oxo-6-(4-((R)- 2,2,2-trifluoro-1- hydroxyethyl)piperidin-1- yl)isoindolin-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
261                    (R)-N-(6-(3,3-difluoropyrrolidin- 1-yl)-2-(2-fluoro-3-hydroxy-3- methylbutyl)-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
262                    N-(2-(((1r,3r)-3- hydroxycyclobutyl)methyl)-6- morpholino-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
263                    N-(6-(4- (hydroxymethyl)piperidin-1-yl)- 1-oxo-2-(2,2,2- trifluoroethyl)isoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
264                    (R)-N-(2-(2-fluoro-3-hydroxy-3- methylbutyl)-6-morpholino-1- oxoisoindolin-5-yl)-6- methylpyrazolo[1,5- a]pyrimidine-3-carboxamide
265                    N-(6-(4-(2-amino-2- oxoethyl)piperazin-1-yl)-1-oxo- 2-(2,2,2-trifluoroethyl)isoindolin- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
266                    N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-1- oxo-2-(2,2,2- trifluoroethyl)isoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
267                    N-(2-(3-hydroxy-2,2- dimethylpropyl)-6-morpholino-1- oxoisoindolin-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
268                    N-(2-((3-(hydroxymethyl)oxetan- 3-yl)methyl)-6-morpholino-1- oxoisoindolin-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
269                    (R)-6-bromo-N-(2-(2-fluoro-3- hydroxy-3-methylbutyl)-6- morpholino-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
270                    N-(2-(2,2-difluoro-3-hydroxy-3- methylbutyl)-6-morpholino-1- oxoisoindolin-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
271                    (R)-6-chloro-N-(2-(2-fluoro-3- hydroxy-3-methylbutyl)-6- morpholino-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
272                    N-(6-(4-(2-amino-2- oxoethyl)piperazin-1-yl)-2- isopropyl-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
273                    N-(2-(2,2-difluoro-3- hydroxypropyl)-6-morpholino-1- oxoisoindolin-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
274                    (R)-N-(6-(4-cyanopiperidin-1-yl)- 2-(2-fluoro-3-hydroxy-3- methylbutyl)-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
275 and 276            (S)-N-(6-morpholino-1-oxo-2- (tetrahydrofuran-3-yl)isoindolin- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide and
                       (R)-N-(6-morpholino-1-oxo-2- (tetrahydrofuran-3-yl)isoindolin- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
277 and 278            (R)-N-(6-morpholino-1-oxo-2- ((tetrahydro-2H-pyran-2- yl)methyl)isoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (S)-N-(6-morpholino-1-oxo-2- ((tetrahydro-2H-pyran-2- yl)methyl)isoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
279                    N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (3-hydroxy-3-methylbutyl)-1- oxoisoindolin-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
280                    N-(6-(4-(2-amino-2- oxoethyl)piperazin-1-yl)-2-(3- hydroxy-3-methylbutyl)-1- oxoisoindolin-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
281                    N-(6-(4-(2-amino-2- oxoethyl)piperazin-1-yl)-2-(1- methylpiperidin-4-yl)-1- oxoisoindolin-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
282 and 283            N-(6-(4-((R)-2,2-difluoro-1- hydroxyethyl)piperidin-1-yl)-2- ((R)-2-fluoro-3-hydroxy-3- methylbutyl)-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       N-(6-(4-((S)-2,2-difluoro-1- hydroxyethyl)piperidin-1-yl)-2- ((R)-2-fluoro-3-hydroxy-3- methylbutyl)-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
284                    (R)-N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (2-fluoro-3-hydroxy-3- methylbutyl)-1-oxoisoindolin-5- yl)-6-methylpyrazolo[1,5- a]pyrimidine-3-carboxamide
285                    (R)-6-chloro-N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (2-fluoro-3-hydroxy-3- methylbutyl)-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
286                    (R)-N3-(2-(2-fluoro-3-hydroxy-3- methylbutyl)-6-morpholino-1- oxoisoindolin-5-yl)pyrazolo[1,5- a]pyrimidine-3,6-dicarboxamide
287                    N-(2-isopropyl-6-morpholino- 1,1-dioxido-2,3- dihydrobenzo[d]isothiazol-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
288                    N-(2-(2-hydroxy-2- methylpropyl)-6-morpholino-1,1- dioxido-2,3- dihydrobenzo[d]isothiazol-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
289                    (R)-N-(2-(2-fluoro-3-hydroxy-3- methylbutyl)-6-morpholino-1,1- dioxido-2,3- dihydrobenzo[d]isothiazol-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
290                    diethyl ((2-methyl-6-morpholino- 5- (pyrazolo[1,5-a]pyrimidine-3- carboxamido)-2,3- dihydrobenzofuran-2-yl)methyl) phosphate
291                    (R)-N-(2,2-dimethyl-6- (pyrrolidin-2-ylmethoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
292                    (R)-N-(6-((1-(2,2- difluoroethyl)pyrrolidin-2- yl)methoxy)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
293                    N-(6-(((1S,3S,5S)-2-(2,2- difluoroethyl)-2- azabicyclo[3.1.0]hexan-3- yl)methoxy)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
294                    N-(6-((1R,5S,6r)-3-(2,2- difluoroethyl)-3- azabicyclo[3.1.0]hexan-6- yl)methoxy)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
295                    N-(6-(((1R,5S,6r)-3- azabicyclo[3.1.0]hexan-6- yl)methoxy)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
296                    N-(2,2-dimethyl-6- ((tetrahydrofuran-3-yl)methoxy)- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
297                    N-(2,2-dimethyl-6-(pyridin-3- ylmethoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
298                    N-(6-(cyclopropylmethoxy)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
299                    N-(2,2-dimethyl-6-((3- methyloxetan-3-yl)methoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
300                    N-(2,2-dimethyl-6-((1-methyl- 1H-pyrazol-4-yl)methoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
301                    N-(2,2-dimethyl-6-(pyridin-4- ylmethoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
302                    N-(6-(2,2-difluoroethoxy)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
303                    N-(2,2-dimethyl-6-(1-(1-methyl- 1H-pyrazol-4-yl)ethoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
304                    N-(2,2-dimethyl-6-((1- methylpiperidin-3-yl)oxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
305 and 306            (S)-N-(2,2-dimethyl-6-((2- oxopiperidin-4-yl)methoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(2,2-dimethyl-6-((2- oxopiperidin-4-yl)methoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
307 and 308            (R)-N-(2,2-dimethyl-6-((5- oxopyrrolidin-3-yl)methoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (S)-N-(2,2-dimethyl-6-((5- oxopyrrolidin-3-yl)methoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
309                    N-(2,2-dimethyl-6-(piperidin-4- ylmethoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
310 and 311            (S)-N-(6-(2,2-difluoroethoxy)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(6-(2,2-difluoroethoxy)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
312 and 313            N-((S)-6-(((1S,4R)-4- hydroxycyclohexyl)oxy)-2-(2- hydroxypropan-2-yl)-2-methyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       N-((R)-6-(((1S,4S)-4- hydroxycyclohexyl)oxy)-2-(2- hydroxypropan-2-yl)-2-methyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
314 and 315            N-((S)-6-(((1r,4S)-4- hydroxycyclohexyl)oxy)-2-(2- hydroxypropan-2-yl)-2-methyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       N-((R)-6-(((1r,4R)-4- hydroxycyclohexyl)oxy)-2-(2- hydroxypropan-2-yl)-2-methyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
316 and 317            (R)-N-(2-(hydroxymethyl)-6-(4- (hydroxymethyl)piperidin-1-yl)- 2-(trifluoromethyl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (S)-N-(2-(hydroxymethyl)-6-(4- (hydroxymethyl)piperidin-1-yl)- 2-(trifluoromethyl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
318 and 319            (S)-N-(6-(4-fluoro-4- (hydroxymethyl)piperidin-1-yl)- 2-(hydroxymethyl)-2- (trifluoromethyl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(6-(4-fluoro-4- (hydroxymethyl)piperidin-1-yl)- 2-(hydroxymethyl)-2- (trifluoromethyl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
320 and 321            (R)-N-(2-(hydroxymethyl)-2- methyl-6-(1-oxo-2,7- diazaspiro[3.5]nonan-7-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (S)-N-(2-(hydroxymethyl)-2- methyl-6-(1-oxo-2,7- diazaspiro[3.5]nonan-7-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
322                    N-(2-(hydroxymethyl)-6-(6- (hydroxymethyl)-3- azabicyclo[3.1.0]hexan-3-yl)-2- methyl-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
323 and 324            (S)-N-(2-(hydroxymethyl)-6-(4- (2-hydroxypropan-2-yl)piperidin- 1-yl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(2-(hydroxymethyl)-6-(4- (2-hydroxypropan-2-yl)piperidin- 1-yl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
325                    N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (1-hydroxypropan-2-yl)-2,3- dihydrobenzofuran-5-yl)-6- methylpyrazolo[1,5- a]pyrimidine-3-carboxamide
326 and 327            (S)-N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5-yl)-6- methylpyrazolo[1,5- a]pyrimidine-3-carboxamide and
                       (R)-N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5-yl)-6- methylpyrazolo[1,5- a]pyrimidine-3-carboxamide
328                    N-(6-(4-fluoro-4- (hydroxymethyl)piperidin-1-yl)- 2-(hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5-yl)-6- methylpyrazolo[1,5- a]pyrimidine-3-carboxamide
329, 330, 331, and 332 N-((R)-6-((S)-4-hydroxy-4- methylazepan-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide;
                       N-((R)-6-((R)-4-hydroxy-4- methylazepan-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide;
                       N-((S)-6-((S)-4-hydroxy-4- methylazepan-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide;
                       N-((S)-6-((R)-4-hydroxy-4- methylazepan-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
333 and 334            (S)-N-(6-(4-(2-amino-2- oxoethyl)piperidin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(6-(4-(2-amino-2- oxoethyl)piperidin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
335 and 336            (S)-N-(6-(4-cyanopiperidin-1-yl)- 2-(hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(6-(4-cyanopiperidin-1-yl)- 2-(hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
337, 338, 339, and 340 N-((S)-6-((S)-4-hydroxyazepan-1- yl)-2-(hydroxymethyl)-2-methyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide;
                       N-((R)-6-((S)-4-hydroxyazepan- 1-yl)-2-(hydroxymethyl)-2- methyl-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide;
                       N-((S)-6-((R)-4-hydroxyazepan- 1-yl)-2-(hydroxymethyl)-2- methyl-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide;
                       N-((R)-6-((R)-4-hydroxyazepan- 1-yl)-2-(hydroxymethyl)-2- methyl-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
341 and 342            (R)-N-(6-(4-(1- hydroxycyclopropyl)piperidin-1- yl)-2-(hydroxymethyl)-2-methyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (S)-N-(6-(4-(1- hydroxycyclopropyl)piperidin-1- yl)-2-(hydroxymethyl)-2-methyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
343                    N-(2-(hydroxymethyl)-2-methyl- 6-(4-propionylpiperidin-1-yl)- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
344 and 345            (S)-N-(6-(4-(1H-imidazol-1- yl)piperidin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(6-(4-(1H-imidazol-1- yl)piperidin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
346 and 347            (S)-N-(6-(4-fluoro-4- (hydroxymethyl)piperidin-1-yl)- 2-(hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(6-(4-fluoro-4- (hydroxymethyl)piperidin-1-yl)- 2-(hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
348 and 349            N-((S)-6-((1R,5S,6R)-6- carbamoyl-3- azabicyclo[3.1.0]hexan-3-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       N-((R)-6-((1R,58,6S)-6- carbamoyl-3- azabicyclo[3.1.0]hexan-3-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
350 and 351            (R)-N-(2-(hydroxymethyl)-2- methyl-6-((1-methyl-1H-pyrazol- 4-yl)methoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (S)-N-(2-(hydroxymethyl)-2- methyl-6-((1-methyl-1H-pyrazol- 4-yl)methoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
352                    N-(6-(4-(2,2-difluoro-1- hydroxyethyl)piperidin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
353                    N-(6-(4-fluoro-4- (hydroxymethyl)piperidin-1-yl)- 2-(2-hydroxypropan-2-yl)-2- methyl-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
354 and 355            (S)-N-(6-(4- (hydroxymethyl)piperidin-1-yl)- 2-(2-hydroxypropan-2-yl)-2- methyl-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(6-(4- (hydroxymethyl)piperidin-1-yl)- 2-(2-hydroxypropan-2-yl)-2- methyl-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
356                    N-(6-(4-(2-amino-2- oxoethyl)piperazin-1-yl)-2-(2- hydroxypropan-2-yl)-2-methyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
357                    N-(6-(1-(2- hydroxyethyl)piperidin-4-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
358                    N-(3-hydroxy-2,2-dimethyl-5- morpholino-2,3- dihydrobenzofuran-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
359                    N-(2,2-dimethyl-5-morpholino-3- oxo-2,3-dihydrobenzofuran-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
360 and 361            (S)-N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (2-hydroxypropan-2-yl)-2- methyl-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (2-hydroxypropan-2-yl)-2- methyl-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
362                    N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- ((difluoromethoxy)methyl)-2- methyl-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
363                    N-(6-(4- (hydroxymethyl)piperidin-1-yl)- 2-(2-hydroxypropan-2-yl)-2- methyl-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
364                    N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (difluoromethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
365 and 366            (R)-N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (hydroxymethyl)-2- (trifluoromethyl)-2,3- yl)pyrazolo[1,5-a]pyrimidine-3- dihydrobenzofuran-5- carboxamide and
                       (S)-N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (hydroxymethyl)-2- (trifluoromethyl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
367 and 368            (S)-N-(2-(2,2-difluoroethyl)-2- methyl-6-morpholino-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(2-(2,2-difluoroethyl)-2- methyl-6-morpholino-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
369                    N-(1′-(2-hydroxyethyl)-6- morpholino-3H- spiro[benzofuran-2,4′-piperidin]- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
370                    N-(1′-(2,2-difluoroethyl)-6- morpholino-3H- spiro[benzofuran-2,4′-piperidin]- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
371                    N-(6-(4- (hydroxymethyl)piperidin-1-yl)- 1′-methyl-3H-spiro[benzofuran- 2,4′-piperidin]-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
372                    N-(1′-isopropyl-6-morpholino- 3H-spiro[benzofuran-2,4′- piperidin]-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
373                    N-(6-(4-(2-amino-2- oxoethyl)piperazin-1-yl)-1′- methyl-3H-spiro[benzofuran-2,4′- piperidin]-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
374                    N-(1′-acetyl-6-(4-(2-amino-2- oxoethyl)piperazin-1-yl)-3H- spiro[benzofuran-2,4′-piperidin]- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
375                    N-(6-(4-(2-(cyclopropylamino)-2- oxoethyl)piperazin-1-yl)-3H- spiro[benzofuran-2,4′-piperidin]- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
376                    N-(6-(4-(2-(cyclopropylamino)-2- oxoethyl)piperazin-1-yl)-1'- methyl-3H-spiro[benzofuran-2,4'- piperidin]-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
377                    N-(6-(2,2-difluoroethoxy)-3H- spiro[benzofuran-2,4′-piperidin]- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
378                    N-(6-(2,2-difluoroethoxy)-1′- methyl-3H-spiro[benzofuran-2,4′- piperidin]-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
379                    N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)-6- (methylamino)pyrazolo[1,5- a]pyrimidine-3-carboxamide
380                    N-(1′-methyl-6-morpholino-3H- spiro[benzofuran-2,4′-piperidin]- 5-yl)-6- (methylamino)pyrazolo[1,5- a]pyrimidine-3-carboxamide
381 and 382            (S)-N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5-yl)-6- (methylamino)pyrazolo[1,5- a]pyrimidine-3-carboxamide and
                       (R)-N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5-yl)-6- (methylamino)pyrazolo[1,5- a]pyrimidine-3-carboxamide
383                    N-(6-(4-(2,2- difluoroethyl)piperazin-1-yl)- 2′,3′,5′,6′-tetrahydro-3H- spiro[benzofuran-2,4′-pyran]-5- yl)-6-(methylamino)pyrazolo[l,5- a]pyrimidine-3-carboxamide
384                    N-(6-cyclopropyl-2,2-dimethyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
385                    N-(2-methyl-6-morpholino-1,1- dioxido-2,3- dihydrobenzo[d]isothiazol-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
386                    N-(2-(cyanomethyl)-2-methyl-6- morpholino-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
387 and 388            (S)-N-(2-(2-hydroxyethyl)-2- methyl-6-morpholino-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(2-(2-hydroxyethyl)-2- methyl-6-morpholino-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
389                    N-(6-(4-(aminomethyl)-4- fluoropiperidin-1-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
390 and 391            (R)-N-(1′-methyl-6-morpholino- 3H-spiro[benzofuran-2,3′- pyrrolidin]-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide and
                       (S)-N-(1′-methyl-6-morpholino- 3H-spiro[benzofuran-2,3′- pyrrolidin]-5-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
392                    N-(2-(1-fluoro-2-hydroxy-2- methylpropyl)-2-methyl-6- morpholino-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
393                    N-(6-morpholino-3H- spiro[benzofuran-2,3′-pyrrolidin]- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
394                    N-(2,2-bis(hydroxymethyl)-6- morpholino-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
395                    N-(2,2-dimethyl-6-(2- (methylcarbamoyl)cyclopropyl)- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
396                    N-(6-((1R,2R)-2- carbamoylcyclopropyl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
397                    N-(6-((1R,2R)-2- (hydroxymethyl)cyclopropyl)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
398                    N-(2-isopropyl-6-morpholino-1- oxoisoindolin-5-yl)-6- (methylamino)pyrazolo[1,5- a]pyrimidine-3-carboxamide
399 and 400            N-(2-((3R,4S)-3- fluorotetrahydro-2H-pyran-4-yl)- 6-morpholino-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       N-(2-((3S,4R)-3- fluorotetrahydro-2H-pyran-4-yl)- 6-morpholino-1-oxoisoindolin-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
401                    N-(2-methyl-7-morpholino-1- oxo-1,2,3,4- tetrahydroisoquinolin-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
402                    N-(7-morpholino-1,1-dioxido- 3,4-dihydro-2H- benzo[b][1,4]thiazin-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
403                    N-(3,3-dimethyl-7-morpholino- 1,1-dioxido-3,4-dihydro-2H- benzo[b][1,4]thiazin-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
404                    N-(2,2-dimethyl-6-(1-methyl-1H- pyrazol-4-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
405                    N-(6-(5-cyanopyridin-3-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
406                    N-(2,2-dimethyl-6-(1-methyl-1H- imidazol-2-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
407                    6-cyano-N-(2,2-dimethyl-6- morpholino-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
408                    1-(2-amino-2-oxoethyl)-4-(2,2- dimethyl-5-(pyrazolo[1,5- a]pyrimidine-3-carboxamido)- 2,3-dihydrobenzofuran-6-yl)-1- methylpiperazin-1-ium
409, 410, 411, and 412 N-((R)-2-(hydroxymethyl)-2- methyl-6-(4-((R)-1,1,1-trifluoro- 2-hydroxypropan-2-yl)piperidin- 1-yl)-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide;
                       N-((R)-2-(hydroxymethyl)-2- methyl-6-(4-((S)-1,1,1-trifluoro- 2-hydroxypropan-2-yl)piperidin- 1-yl)-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide;
                       N-((S)-2-(hydroxymethyl)-2- methyl-6-(4-((R)-1,1,1-trifluoro- 2-hydroxypropan-2-yl)piperidin- 1-yl)-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide;
                       N-((S)-2-(hydroxymethyl)-2- methyl-6-(4-((S)-1,1,1-trifluoro- 2-hydroxypropan-2-yl)piperidin- 1-yl)-2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
413 and 414            N-((S)-6-((1R,5S,6S)-6- carbamoyl-3- azabicyclo[3.1.0]hexan-3-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       N-((R)-6-((1R,5S,6R)-6- carbamoyl-3- azabicyclo[3.1.0]hexan-3-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
415 and 416            (S)-N-(6-(4-(2-amino-2- oxoethyl)piperazin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(6-(4-(2-amino-2- oxoethyl)piperazin-1-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
417 and 418            (S)-N-(2-(hydroxymethyl)-2- methyl-6-(3-oxo-2,8- diazaspiro[4.5]decan-8-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(2-(hydroxymethyl)-2- methyl-6-(3-oxo-2,8- diazaspiro[4.5]decan-8-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
419 and 420            (S)-N-(6-(5,7-dihydro-6H- pyrrolo[3,4-b]pyridin-6-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(6-(5,7-dihydro-6H- pyrrolo[3,4-b]pyridin-6-yl)-2- (hydroxymethyl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
421, 422, and 423      N-((S)-3-hydroxy-3-methyl-7-(4- ((S)-1,1,1-trifluoro-2- hydroxypropan-2-yl)piperidin-1- yl)chroman-6-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;
                       N-((R)-3-hydroxy-3-methyl-7-(4- ((S)-1,1,1-trifluoro-2- hydroxypropan-2-yl)piperidin-1- yl)chroman-6-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide;
                       N-(3-hydroxy-3-methyl-7-(4- ((R)-1,1,1-trifluoro-2- hydroxypropan-2-yl)piperidin-1- yl)chroman-6-yl)pyrazolo[1,5- a]pyrimidine-3-carboxamide
424 and 425            (R)-N-(7-(4-(2-amino-2- oxoethyl)piperazin-1-yl)-3- hydroxy-3-methylchroman-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (S)-N-(7-(4-(2-amino-2- oxoethyl)piperazin-1-yl)-3- hydroxy-3-methylchroman-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
426 and 427            (R)-N-(1-(4-cyanopiperidin-1-yl)- 3-hydroxy-3-methylchroman-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (S)-N-(7-(4-cyanopiperidin-1-yl)- 3-hydroxy-3-methylchroman-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
428 and 429            (R)-N-(7-(4-(1H-imidazol-1- yl)piperidin-1-yl)-3-hydroxy-3- methylchroman-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (S)-N-(7-(4-(1H-imidazol-1- yl)piperidin-1-yl)-3-hydroxy-3- methylchroman-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
430 and 431            (S)-N-(3-hydroxy-3-methyl-7-((1- methyl-1H-pyrazol-4- yl)methoxy)chroman-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(3-hydroxy-3-methyl-7- ((1-methyl-1 H-pyrazol-4- yl)methoxy)chroman-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
432 and 433            (S)-N-(2-(hydroxymethyl)-2- methyl-7-morpholinochroman-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide and
                       (R)-N-(2-(hydroxymethyl)-2- methyl-7-morpholinochroman-6- yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide
434                    N-(6-(4-(2-hydroxy-2- methylpropyl)piperazin-1-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide
435                    N-(6-(4-(2-ethyl-2- hydroxybutyl)piperazin-1-yl)-2,2- dimethyl-2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5-a]pyrimidine- 3-carboxamide

TABLE 3
Additional exemplary compounds of the present invention. Salts of such compounds
are also contemplated. See the Examples section for preparation of such compounds.
Ex.	Structure	Name
436		(S)-N-(2- (hydroxymethyl)-2- methyl-7- morpholinochroman-6- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
437		(R)-N-(2- (hydroxymethyl)-2- methyl-7- morpholinochroman-6- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
438		(S)-N-(2- (dimethylcarbamoyl)-2- methyl-6-morpholino- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
439		(R)-N-(2- (dimethylcarbamoyl)-2- methyl-6-morpholino- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
440		N-(2,2-dimethyl-6-(4-(2- oxo-2-(((tetrahydrofuran- 2-yl)methyl)amino)ethyl) piperazin-1-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
441		N-(2,2-dimethyl-6-(4-(2- oxo-2-(thiazol-2- ylamino)ethyl)piperazin- 1-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
442		(S)-N-(6- (hexahydropyrrolo[1,2- a]pyrazin-2(1H)-yl)-2,2- dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
443		(R)-N-(6- (hexahydropyrrolo[1,2- a]pyrazin-2(1H)-yl)-2,2- dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
444		(R)-N-(2-methyl-2-(2- (methylthio)ethyl)-6- morpholino-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
445		(R)-N-(6-((1-(2-amino-2- oxoethyl)pyrrolidin-3- yl)oxy)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
446		N-(6-((1-(2- hydroxyethyl)azetidin-3- yl)oxy)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
447		(S)-N-(6-((1-(2-amino-2- oxoethyl)pyrrolidin-3- yl)oxy)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
448		N-(6-((1-ethyl-1H- pyrazol-4-yl)methoxy)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
449		N-(2-(((2R,5R)-5-amino- 1,3-dioxan-2-yl)methyl)- 6-morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
450		N-(2,2-dimethyl-6-(4-(2- (methylsulfonyl)ethyl) piperazin-1-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
451		5-(((1R,2S)-2- aminocyclohexyl)amino)- N-(6-methoxy-2,2- dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
452		N-(6-carbamoyl-2,2- dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
453		N-(6-(4-ethylpiperazin-1- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
454		N-(2,2-dimethyl-6-(4-(2- (methylthio)ethyl) piperazin-1-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
455		N-(6-(4-(3-amino-3- oxopropyl)piperazin-1- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
456		N-(6-(4- (cyanomethyl)piperazin- 1-yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
457		N-(6-(4-(2- cyanoethyl)piperazin-1- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
458		N-(6-(4-(cyclo- propylmethyl)piperazin- 1-yl)-2,2-dimethyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
459		N-(2,2-dimethyl-6-(4-((3- methyl-1,2,4-oxadiazol- 5-yl)methyl)piperazin-1- yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
460		N-(2,2-dimethyl-6-(4-((1- methyl-1H-pyrazol-4- yl)methyl)piperazin-1- yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
461		N-(2,2-dimethyl-6-(4-((5- methyl-1,2,4-oxadiazol- 3-yl)methyl)piperazin-1- yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
462		N-(6-(4-(2-(1H-pyrazol- 1-yl)ethyl)piperazin-1- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
463		N-(2,2-dimethyl-6-(4-((5- methyl-1,3,4-oxadiazol- 2-yl)methyl)piperazin-1- yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
464		N-(2,2-dimethyl-6-(4- ((tetrahydro-2H-pyran-4- yl)methyl)piperazin-1- yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
465		N-(6-(4-(3- methoxypropyl)piperazin- 1-yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
466		N-(6-(4-(cyclo- butylmethyl)piperazin- 1-yl)-2,2-dimethyl- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
467		N-(2,2-dimethyl-6-(4-(2- oxopyrrolidin-3- yl)piperazin-1-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
468		N-(2,2-dimethyl-6-(4-((5- oxopyrrolidin-2- yl)methyl)piperazin-1- yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
469		N-(6-(4-(2,3- dihydroxypropyl)piperazin- 1-yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
470		N-(2,2-dimethyl-6-(4-(2- (2-oxopyrrolidin-1- yl)ethyl)piperazin-1-yl)- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
471		N-(2,2-dimethyl-6- morpholino-2,3- dihydrobenzofuran-5-yl)- 6-(hydroxy- methyl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
472		(R)-N-(6-(4-(1-amino-1- oxopropan-2- yl)piperazin-1-yl)-2,2- dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
473		(S)-N-(6-(4-(1-amino-1- oxopropan-2- yl)piperazin-1-yl)-2,2- dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
474		(S)-N-(6-(4-(2- hydroxypropyl)piperazin- 1-yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
475		(R)-N-(6-(4-(2- hydroxypropyl)piperazin- 1-yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
476		N-(6-(4-(2-amino-2- methylpropyl)piperazin- 1-yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
477		(R)-N-(6-(4-(2- aminopropyl)piperazin-1- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
478		(S)-N-(6-(4-(2- aminopropyl)piperazin-1- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
479		N-(2,2-dimethyl-6-(4-((5- methyl-2-oxo-2,3- dihydrooxazol-4- yl)methyl)piperazin-1- yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
480		(S)-N-(2,2-dimethyl-6-(4- (1-(methylamino)-1- oxopropan-2- yl)piperazin-1-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
481		(R)-N-(2,2-dimethyl-6-(4- (1-(methylamino)-1- oxopropan-2- yl)piperazin-1-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
482		(S)-N-(6-(4-(1-amino-4- hydroxy-1-oxobutan-2- yl)piperazin-1-yl)-2,2- dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
483		(R)-N-(6-(4-(1-amino-4- hydroxy-1-oxobutan-2- yl)piperazin-1-yl)-2,2- dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
484		5-(difluoromethyl)-N-(2- isopropyl-6-morpholino- 1-oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
485		6-cyano-N-(2-isopropyl- 6-morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
486		N3-(2-isopropyl-6- morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3,6- dicarboxamide
487		(R)-N-(6-cyclopropyl-2- (2-fluoro-3-hydroxy-3- methylbutyl)-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
488		N-(2,2-dimethyl-6-(1- methyl-1H-imidazol-4- yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
489		N-(2,2-dimethyl-6-(1- methyl-1H-pyrazol-3-yl)- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
490		6-(azetidin-3-yl)-N-(2,2- dimethyl-6-morpholino- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide hydrochloride
491		N3-(2,2-dimethyl-6- morpholino-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3,6- dicarboxamide
492		(R)-N3-(2-(2-fluoro-3- hydroxy-3-methylbutyl)- 6-morpholino-1- oxoisoindolin-5-yl)-N6- methylpyrazolo[1,5- a]pyrimidine-3,6- dicarboxamide
493		6-(difluoromethoxy)-N- (2,2-dimethyl-6- morpholino-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
494		(R)-6-fluoro-N-(2- (hydroxymethyl)-2- methyl-6-morpholino- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
495		(S)-6-fluoro-N-(2- (hydroxymethyl)-2- methyl-6-morpholino- 2,3-dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
496		(R)-N-(6- (cyclopropylmethoxy)-2- (2-fluoro-3-hydroxy-3- methylbutyl)-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
497		N-((2R,3′S)-1′,3′- dimethyl-6-morpholino- 3H-spiro[benzofuran- 2,4′-piperidin]-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
498		N-((2R,3′R)-1′,3′- dimethyl-6-morpholino- 3H-spiro[benzofuran- 2,4′-piperidin]-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
499		N-(2,2-dimethyl-6- morpholino-1-oxo-2,3- dihydro-1H-inden-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
500		(R)-N-(2-(2-fluoro-3- hydroxy-3-methylbutyl)- 1-oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
501		N-(1′-(2-fluoroethyl)-6- morpholino-3H- spiro[benzofuran-2,4′- piperidin]-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
502		N-(1′-ethyl-6- morpholino-3H- spiro[benzofuran-2,4′- piperidin]-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
503		N-(6-(4-((1H-imidazol-2- yl)methyl)piperazin-1- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
504		N-(6-(4-(isoxazol-4- ylmethyl)piperazin-1-yl)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
505		N-(6-(4-((1H-pyrazol-5- yl)methyl)piperazin-1- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
506		N-(2,2-dimethyl-6-(4-((1- methyl-1H-imidazol-5- yl)methyl)piperazin-1- yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
507		N-(2,2-dimethyl-6-(4-((2- methyl-1H-imidazol-4- yl)methyl)piperazin-1- yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
508		N-(6-(4- isopropylpiperazin-1-yl)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
509		N-(6-(4-((1H-imidazol-4- yl)methyl)piperazin-1- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
510		(R)-N-(7-(4-(2,2- difluoroethyl)piperazin-1- yl)-3-hydroxy-3- methylchroman-6- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
511		(S)-N-(7-(4-(2,2- difluoroethyl)piperazin-1- yl)-3-hydroxy-3- methylchroman-6- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
512		(S)-N-(6-cyclopropyl-2,2- dimethyl-2,3- dihydrobenzofuran-5-yl)- 5-((5-oxopyrrolidin-3- yl)methyl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
513		(R)-N-(6-cyclopropyl- 2,2-dimethyl-2,3- dihydrobenzofuran-5-yl)- 5-((5-oxopyrrolidin-3- yl)methyl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
514		(R)-N-(6-cyclopropyl- 2,2-dimethyl-2,3- dihydrobenzofuran-5-yl)- 5-((2-oxopyrrolidin-3- yl)methyl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
515		(S)-N-(6-cyclopropyl-2,2- dimethyl-2,3- dihydrobenzofuran-5-yl)- 5-((2-oxopyrrolidin-3- yl)methyl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
516		(S)-N-(1-hydroxy-2,2- dimethyl-6-morpholino- 2,3-dihydro-1H-inden-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
517		(R)-N-(1-hydroxy-2,2- dimethyl-6-morpholino- 2,3-dihydro-1H-inden-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
518		N-(4- (dimethylphosphoryl)-2- morpholinophenyl) pyrazolo[1,5-a]pyrimidine- 3-carboxamide
519		(R)-N-(3-(cyanomethyl)- 3-methyl-7- morpholinochroman-6- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
520		(S)-N-(3-(cyanomethyl)- 3-methyl-7- morpholinochroman-6- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
521		(R)-N-(6-chloro-2-(2- fluoro-3-hydroxy-3- methylbutyl)-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
522		(R)-N-(6-(4-((1H- imidazol-4- yl)methyl)piperazin-1- yl)-2-(2-hydroxypropan- 2-yl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
523		(S)-N-(6-(4-((1H- imidazol-4- yl)methyl)piperazin-1- yl)-2-(2-hydroxypropan- 2-yl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
524		(S)-N-(6-(4-(2-amino-2- oxoethyl)piperazin-1-yl)- 2-(2-hydroxypropan-2- yl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
525		(R)-N-(6-(4-(2-amino-2- oxoethyl)piperazin-1-yl)- 2-(2-hydroxypropan-2- yl)-2-methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
526		(R)-N-(2-(2-hydroxy-2- methylpropyl)-2-methyl- 6-morpholino-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
527		(S)-N-(2-(2-hydroxy-2- methylpropyl)-2-methyl- 6-morpholino-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
528		(R)-N-(6-ethyl-2-(2- fluoro-3-hydroxy-3- methylbutyl)-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
529		(R)-N-(2-(2-fluoro-3- hydroxy-3-methylbutyl)- 6-isopropyl-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
530		N-(2,2-dimethyl-6- morpholino-2,3- dihydrobenzofuran-5-yl)- 6-hydroxypyrazolo[1,5- a]pyrimidine-3- carboxamide
531		N-(6-(4- carbamoylpiperidin-1-yl)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
532		N-(6-(4- (dimethylamino)piperidin- 1-yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
533		N-(2,2-dimethyl-6- (piperazin-1-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
534		N-(6-(4-carbamoyl-4- fluoropiperidin-1-yl)-2,2- dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
535		N-(6-(4-(2-amino-2- oxoethyl)-4- methylpiperidin-1-yl)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
536		N-(6-(4-(2-amino-2- oxoethyl)-4- hydroxypiperidin-1-yl)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
537		N-(6-(dimethylamino)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
538		N-(2,2-dimethyl-6-((1- methyl-1H-imidazol-4- yl)methoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
539		N-(6-((1H-imidazol-4- yl)methoxy)-2,2- dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
540		(R)-N-(2,2-dimethyl-6- ((5-oxopyrrolidin-2- yl)methoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
541		(S)-N-(2,2-dimethyl-6- ((5-oxopyrrolidin-2- yl)methoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
542		N-(2,2-dimethyl-6-((5- methyl-1H-pyrazol-3- yl)methoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
543		N-(2,2-dimethyl-6-((2- methyl-1H-imidazol-4- yl)methoxy)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
544		(R)-N-(2-(4-hydroxy-4- methylpentan-2-yl)-6- morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
545		(S)-N-(2-(4-hydroxy-4- methylpentan-2-yl)-6- morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
546		N-(2-(1-methylazetidin-3- yl)-6-morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
547		N-(2-((1S,4S)-4-(2- hydroxypropan-2- yl)cyclohexyl)-6- morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
548		N-(2-((1R,4R)-4-(2- hydroxypropan-2- yl)cyclohexyl)-6- morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
549		N-(2-(((1R,2S)-2- hydroxycyclopentyl) methyl)-6-morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
550		N-(2-(((1S,2R)-2- hydroxycyclopentyl) methyl)-6-morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
551		(S)-N-(6-morpholino-2- (2-morpholinopropyl)-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
552		(R)-N-(6-morpholino-2- (2-morpholinopropyl)-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
553		(R)-N-(2-(1-methyl-2- oxopyrrolidin-3-yl)-6- morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
554		(S)-N-(2-(1-methyl-2- oxopyrrolidin-3-yl)-6- morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
555		(S)-N-(6-morpholino-1- oxo-2-((tetrahydrofuran- 3-yl)methyl)isoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
556		(R)-N-(6-morpholino-1- oxo-2-((tetrahydrofuran- 3-yl)methyl)isoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
557		N-(2-((2R,3S)-2-fluoro-3- hydroxybutyl)-6- morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
558		N-(2-((2S,3R)-2-fluoro-3- hydroxybutyl)-6- morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
559		N-(2-(((1S,2S)-2- hydroxycyclopentyl) methyl)-6-morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
560		N-(2-(((1R,2R)-2- hydroxycyclopentyl) methyl)-6-morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
561		N-(2-((2S,3S)-2-fluoro-3- hydroxybutyl)-6- morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
562		N-(2-((2R,3R)-2-fluoro-3- hydroxybutyl)-6- morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
563		(R)-N-(6-(azetidin-1-yl)- 2-(2-fluoro-3-hydroxy-3- methylbutyl)-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
564		N-(2-((1S,2R)-2- (hydroxymethyl)cyclo- pentyl)-6-morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
565		N-(2-((1R,2S)-2- (hydroxymethyl)cyclo- pentyl)-6-morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
566		N-(2-((1S,2S)-2- (hydroxymethyl)cyclo- pentyl)-6-morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
567		N-(2-((1R,2R)-2- (hydroxymethyl)cyclo- pentyl)-6-morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
568		(R)-N-(2-(2-fluoro-3- hydroxy-3-methylbutyl)- 6-((2-hydroxy- ethyl)(methyl)amino)- 1-oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
569		(R)-N-(6-(4-cyano-4- methylpiperidin-1-yl)-2- (2-fluoro-3-hydroxy-3- methylbutyl)-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide
570		(R)-N-(6- (dimethylamino)-2-(2- fluoro-3-hydroxy-3- methylbutyl)-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide

Synthesis of IRAK4 Inhibitors

Compounds of the present invention can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below. The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, vol. 1-21; R. C. FaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A. R. Katritzky and C. W. Rees (Eds.) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New York, 1991, vol. 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application.

For illustrative purposes, reaction Schemes below provide routes for synthesizing the compounds of the invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used. Although some specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be substituted to provide a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about −78° C. to about 150° C., more preferably from about 0° C. to about 125° C., and most preferably and conveniently at about room (or ambient) temperature, or, about 20° C.

Some compounds in following schemes are depicted with generalized substituents; however, one skilled in the art will immediately appreciate that the nature of the R groups can varied to afford the various compounds contemplated in this invention. Moreover, the reaction conditions are exemplary and alternative conditions are well known. The reaction sequences in the following examples are not meant to limit the scope of the invention as set forth in the claims.

Some compounds in following schemes are depicted with generalized substituents; however, one skilled in the art will immediately appreciate that the nature of the R groups can varied to afford the various compounds contemplated in this invention. Moreover, the reaction conditions are exemplary and alternative conditions are well known. The reaction sequences in the following examples are not meant to limit the scope of the invention as set forth in the claims.

Regarding Scheme I, requisite 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl derivatives can be prepared by nitration of 7-halo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl derivatives I-1a to afford I-1b followed by displacement of the halogen with an amine to afford I-2a. Typical amines include morpholine and 3-hydroxymethyl piperidine. Reduction of the nitro group and condensation with pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (I-3), or an activated derivative thereof, affords the desired amides. The requisite precursors are commercially available or are prepared as described herein.

Aromatic nitration is well known and can be conducted under a variety of conditions known in the art. Nitration can be carried out, for example, by exposing an aromatic compound to concentrated nitric acid and sulfuric acid. Active substrates can be nitrated with HNO₃ alone or in H₂O, HOAc and acetic anhydride and active compounds may be oxidized by mixtures of HNO₃ and H₂SO₄. Other nitrating reagents include NaNO₃/TFA, Cu(NO₃)₂/HOAc/Ac₂O, N₂O₄, NO₂⁺BF₄⁻, NO₂⁺PF6⁻ and NO₂⁺CF₃SO⁴⁻. See, e.g., J. March, Advanced Organic Chemistry, John Wiley & Sons: New York, N.Y., 1992, pp. 522-23.

Reduction of the nitro group can be carried out with a variety of well-known reducing agents. For example, the nitro can be reduced under a hydrogen atmosphere in the presence of an inert solvent and in the presence of a metal effective to catalyze hydrogenation reactions such as platinum or palladium. The reduction can also be carried out with an activated metal such as activated iron, zinc or tin (produced for example by washing iron powder with a dilute acid solution such as dilute hydrochloric acid).

Coupling of the amine 2b intermediate with 3 is achieved with commonly used coupling reagents or, alternatively, 3 can be converted to the corresponding acid chloride and condensed with 2b.

Acylation of a primary amine with an acid chloride is typically carried out in an inert solvent such as DMF, DCM, THF, pyridine with or without water as a co-solvent, at temperatures between 0° C. and 60° C. generally in the presence of a base such as Na₂CO₃, NaHCO₃, K₂CO₃, DIPEA, TEA or pyridine and the like to afford the corresponding amide. Carboxylic acids can be converted into their acid chlorides using standard reagents well known to someone skilled in the art, such as thionyl chloride, oxalyl chloride, phosphoryl chloride and the like. Those reagents can be used in presence of bases such as DIPEA, TEA or pyridine.

Alternatively a carboxylic acid can be converted in situ into activated derivatives by utilizing reagents developed for peptide synthesis which are well known to those skilled in the art. These activated acids were reacted directly with the amines as described to afford the corresponding amide. Common coupling reagents include EDC, DCC, benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP), 2-fluoro-1-methylpyridinium p-toluenesulphonate (Mukaiyama's reagent), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 1-hydroxy-7-azabenzotriazole (HOAt) or (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (PyAOP) optionally in the presence of modifiers such as HOBt, with or without a base such NMM, TEA or DIPEA in an inert solvent such as DMF or DCM at temperatures between 0° C. and 60° C. Acylation of amines (see, e.g., J. March, supra pp. 417-425; H. G. Benz, Synthesis of Amides and Related Compounds in Comprehensive Organic Synthesis, E. Winterfeldt, ed., vol. 6, Pergamon Press, Oxford 1991 pp. 381-411; R. C. Larock, Comprehensive Organic Transformations—A Guide to Functional Group Preparations, 1989, VCH Publishers Inc., New York; pp. 972-976) has been reviewed.

5,6-Diamino-2,2-dimethyl-3H-benzofuran derivatives exemplified herein can be prepared utilizing a 2,2-dimethyl-5-nitro-6-halo-3H-benzofuran II-3b as the key intermediate as depicted in Scheme II. Addition of a methyl Grignard to methyl 5-chloro-2-fluoro-phenylacetate affords the tertiary alcohol II-2 which undergoes an intra-molecular cyclization to afford the II-3a. Nitration and displacement of the chloride with an amine followed by reduction of the nitro and acylation with I-3 is carried out in analogy with Scheme I. One skilled in the art will appreciate that the corresponding 5-fluoro and 5-bromo derivatives are readily available from methyl 2,5-difluorophenylacetate and methyl 5-bromo-2-fluorophenylacetate, respectively.

With respect to Scheme III, introduction of substituents other than amines at the 2-position can be easily accomplished by addition of an organometallic to 1-(4-chloro-2-fluorophenyl)propan-2-one, or a derivative thereof, and carry on further transformations as described herein. Compounds wherein the 5-amino-2,2-dimethyl-3H-benzofuran-6-yl moiety is linked to a substituent by a carbon-carbon bond were prepared by a palladium-catalyzed coupling of II-3b with a boric acid derivative or a boronic ester. Similarly ether substituents can be readily prepared by reacting 5-amino-2,2-dimethyl-6-fluoro-3H-benzofuran (III-2b) with a alcohol in the presence of potassium tert-butoxide or other suitable strong base. Subsequent reduction of the nitro group, acylation of the resulting amine and any subsequent deprotection which may be required are carried out using standard methodology.

Compounds with a hydroxymethyl substituent attached to the dihydrofuran ring are accessible by condensation of 5-chloro-2-fluorobenzyl magnesium bromide with methyl pyruvate which afforded IV-2. (Scheme IV) Intramolecular cyclization and reduction of the pendant carboxylic acid affords IV-b which is transformed to the final compounds using protocols analogous to those previously described.

With respect to Scheme V, 3H-benzothiophene-1,1-dioxide derivatives can be prepared by intramolecular cyclization methyl 2-methylsulfonyl-4-morpholino-5-nitro-benzoate (V-3b) to afford morpholino-5-nitro-1,1-dioxo-benzothiophen-3-one (V-4) which is subsequently reduced to V-6b utilizing a two-step sequence comprising sodium borohydride reduction followed by triethylsilane/TFA reduction that is carried on as previously described. Reduction of the nitro group and acylation of the resulting amine is carried out as described previously.

Methods of Treatment with and Uses of IRAK 4 Inhibitors

Compounds of the present invention are useful as IRAK4 inhibitors. Accordingly, in one embodiment is provided a method of contacting a cell, such as an ex vivo cell, with a compound of the present invention to inhibit IRAK4 activity in the cell.

Also provided is a pharmaceutical composition comprising a compound of Formula 0, Formula I, or Formula II, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, carrier or diluent. Compounds of the invention, including pharmaceutical compositions comprising such compounds, may be used in the methods described herein.

Further provided is a method of preventing, treating, or lessening the severity of a disease or condition responsive to the inhibition of IRAK4 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof.

Also provided is a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof.

Further provided is a method for treating an inflammatory or autoimmune disease in a patient, comprising administering to the patient a therapeutically effective amount of a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof. In some embodiments, the disease is selected from the group consisting of Crohn's disease, ulcerative colitis, Irritable Bowel Disorder (IBD), asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, systemic onset juvenile idiopathic arthritis, multiple sclerosis, neuropathic pain, gout, and gouty arthritis.

In some embodiments, other diseases and conditions responsive to the inhibition of IRAK4 that can be treated using a compound of the present invention include metabolic syndromes, atherosclerosis, and neurodegeneration.

Further provided is the use of a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof, in therapy. In some embodiments, use of a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof, is provided in the treatment of an inflammatory disease. In some embodiments, use of a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof, is provided for the preparation of a medicament for the treatment of an inflammatory disease. Furthermore, in some embodiments, a compound of the present invention, or a stereoisomer or pharmaceutically acceptable salt thereof, is provided for use in the treatment of an inflammatory disease.

Also provided is a method of inhibiting IRAK4 in a patient in need of therapy, comprising administering to the patient a compound of the present invention.

Dosage & Administration

The present invention provides pharmaceutical compositions or medicaments containing the compounds of the invention and at least one therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of Formula 0, Formula I, or Formula II, or a stereoisomer or pharmaceutically acceptable salt thereof, with the desired degree of purity may be formulated by mixing with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a dosage form at ambient temperature and at the appropriate pH. The pH of the formulation depends mainly on the particular use and the concentration of compound, but typically ranges anywhere from about 3 to about 8. In one example, a compound of Formula 0, Formula I, or Formula II is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of Formula 0, Formula I, or Formula II are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the severity of the disorder, the particular patient being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The “effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit IRAK4 activity. Typically such amount may be below the amount that is toxic to normal cells, or the patient as a whole.

The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of Formula 0, Formula I, or Formula II, or a stereoisomer or pharmaceutically acceptable salt thereof, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(−)-3-hydroxybutyric acid.

A dose to treat human patients may range from about 0.1 mg to about 1000 mg of a compound of Formula 0, Formula I, or Formula II, or a stereoisomer or pharmaceutically acceptable salt thereof. A typical dose may be about 1 mg to about 300 mg of the compound. A dose may be administered once a day (QD), twice per day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound. In addition, toxicity factors may influence the dosage and administration regimen. When administered orally, the pill, capsule, or tablet may be ingested daily or less frequently for a specified period of time. The regimen may be repeated for a number of cycles of therapy.

The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, H. C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, R. C., Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

For oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials, therefore, include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.

An example of a suitable oral dosage form is a tablet containing about 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of the compound of the invention compounded with about 90-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such as sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.

In one embodiment, the pharmaceutical composition also includes at least one additional anti-proliferative agent.

An embodiment, therefore, includes a pharmaceutical composition comprising a compound of Formula 0, Formula I, or Formula II, or a stereoisomer or pharmaceutically acceptable salt thereof. A further embodiment includes a pharmaceutical composition comprising a compound of Formula 0, Formula I, or Formula II, or a stereoisomer or pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

Combination Therapy

The compounds of Formula 0, Formula I, or Formula II may be employed alone or in combination with other therapeutic agents for the treatment of a disease or disorder described herein. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of Formula 0, Formula I, or Formula II such that they do not adversely affect each other. The combination therapy may provide “synergy” and prove “synergistic”, i.e., the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.

The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. The combined administration includes co-administration, using separate formulations or a single pharmaceutical formulation, and consecutive administration in either order, wherein preferably there is a time period while both (or all) active agents simultaneously exert their biological activities.

Combination therapies according to the present invention thus comprise the administration of at least one compound of Formula 0, Formula I, or Formula II, or a stereoisomer or pharmaceutically acceptable salt thereof, and the use of at least one other treatment method. The amounts of the compound(s) of Formula 0, Formula I, or Formula II and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

Articles of Manufacture

In another embodiment of the invention, an article of manufacture, or “kit”, containing materials useful for the treatment of the diseases and disorders described above is provided. In one embodiment, the kit comprises a container comprising a compound of Formula 0, Formula I, or Formula II, or a stereoisomer or pharmaceutically acceptable salt thereof. The kit may further comprise a label or package insert on or associated with the container. The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister pack, etc. The container may be formed from a variety of materials such as glass or plastic. The container may hold a compound of Formula 0, Formula I, or Formula II or a formulation thereof which is effective for treating the condition and may have a sterile access port (for example, the container may be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound of Formula 0, Formula I, or Formula II. Alternatively, or additionally, the article of manufacture may further comprise a second container comprising a pharmaceutical diluent, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

In another embodiment, the kits are suitable for the delivery of solid oral forms of a compound of Formula 0, Formula I, or Formula II, such as tablets or capsules. Such a kit can include a number of unit dosages. An example of such a kit is a “blister pack”. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms.

EXAMPLES

The following examples illustrate the preparation and biological evaluation of compounds within the scope of the invention. These examples and preparations which follow are provided to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

Intermediate 1. 6-Chloro-2,2-dimethyl-5-nitro-3H-benzofuran

Step A. Methyl 2-(4-chloro-2-fluoro-phenyl)acetate

A mixture of 2-(4-chloro-2-fluoro-phenyl)acetic acid (8.4 g, 44.5 mmol) and concentrated sulfuric acid (3.0 mL) in methanol (50 mL) was stirred at reflux for 18 h. After concentration under reduced pressure, the residue was dissolved in DCM (200 ml). The organic phase was washed with sodium bicarbonate saturated solution, brine and dried over sodium sulfate. After concentration under reduced pressure, it was afforded crude methyl 2-(4-chloro-2-fluoro-phenyl)acetate (7.6 g) as a yellow oil, which was used without further purification. MS (ESI): m/z=203.1 [M+1]⁺.

Step B. 1-(4-Chloro-2-fluoro-phenyl)-2-methyl-propan-2-ol

To a solution of methyl 2-(4-chloro-2-fluoro-phenyl)acetate (7.6 g, 37.51 mmol) in anhydrous THF (70 mL) was added methyl magnesium bromide (3 m in ethyl ether, 37.5 mL, 112.5 mmol) drop wise at −78° C. The reaction was warmed to room temperature and stirred for 30 min. Saturated ammonium chloride solution was added. The aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with brine and dried over sodium sulfate. The crude was concentrated under reduced pressure to afford 1-(4-chloro-2-fluoro-phenyl)-2-methyl-propan-2-ol (6.9 g) as a yellow oil, which was used without further purification. MS (ESI): m/z=185.1 [M-OH]⁺.

Step C. 6-Chloro-2,2-dimethyl-3H-benzofuran

A mixture of 1-(4-chloro-2-fluoro-phenyl)-2-methyl-propan-2-ol (6.9 g, 34.05 mmol) and potassium tert-butanolate (9.55 g, 85.12 mmol) in THF (170 mL) was stirred at 65° C. for 18 h. 1N hydrogen chloride solution was added until pH=3.0. Ethyl acetate (200 mL) was added. The organic phase was separated and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:20 to 1:10) as eluting solvents to afford 6-chloro-2,2-dimethyl-3H-benzofuran (4.3 g, 69%) as a colorless oil. ¹H NMR (400 MHz, CDCl3): δ 6.99 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.88 (s, 1H), 2.93 (s, 2H), 1.44 (s, 3H).

Step D. 6-Chloro-2,2-dimethyl-5-nitro-3H-benzofuran

To a solution of 6-chloro-2,2-dimethyl-3H-benzofuran (4.3 g, 23.54 mmol) in DCM (45 mL) at 25° C. was slowly added fuming nitric acid (4.5 mL) until starting material was disappeared. Water and ethyl acetate (100 mL) were added. The organic phase was separated and dried over sodium sulfate. After concentration under reduced pressure, it was afforded 6-chloro-2,2-dimethyl-5-nitro-3H-benzofuran (5.0 g) as orange solid, which was used without further purification. ¹H NMR (400 MHz, CDCl₃): δ 7.84 (s, 1H), 6.83 (s, 1H), 3.04 (s, 2H), 1.52 (s, 3H).

Intermediate 2. (6-Chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol

Step A. Methyl 3-(4-chloro-2-fluoro-phenyl)-2-hydroxy-2-methyl-propanoate

To a solution of magnesium (1350.0 mg, 56.25 mmol) and iodine (100.0 mg, 0.39 mmol) in diethyl ether (50 mL) at reflux was added 1-(bromomethyl)-4-chloro-2-fluoro-benzene (5.0 g, 22.4 mmol) drop wise. The reaction was stirred for 30 min. This solution was then added to a solution of methyl pyruvate (2.3 g, 22.5 mmol) in diethyl ether (50 mL) at −78° C. and stirred for 30 min followed by warming to room temperature for 2 h. Saturated ammonium chloride solution and ethyl acetate (200 mL) was added. The organic phase was separated and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:20 to 1:10) as eluting solvents to afford methyl 3-(4-chloro-2-fluoro-phenyl)-2-hydroxy-2-methyl-propanoate (2.8 g, 51%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.33-7.25 (m, 1H), 7.18-7.09 (m, 2H), 3.73 (s, 3H), 3.03 (s, 2H), 1.39 (s, 3H).

Step B. 6-Chloro-2-methyl-3H-benzofuran-2-carboxylic acid

The mixture of methyl 3-(4-chloro-2-fluoro-phenyl)-2-hydroxy-2-methyl-propanoate (493.0 mg, 2 mmol) and potassium tert-butanolate (561.0 mg, 5 mmol) in THE (10 mL) was stirred at 60° C. for 18 h. After cooling to room temperature, water and 1N hydrogen chloride solution was added until pH=3.0. Ethyl acetate (20 mL) was added. The organic phase was separated and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:1 to 2:1) as eluting solvents to afford 6-chloro-2-methyl-3H-benzofuran-2-carboxylic acid (271 mg, 64%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.95-10.24 (m, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.87 (dd, J=1.6, 9.2 Hz, 1H), 6.85 (s, 1H), 3.59 (d, J=16 Hz, 1H), 3.13 (d, J=16 Hz, 1H), 1.73, (s, 3H).

Step C. 6-Chloro-2-methyl-5-nitro-3H-benzofuran-2-carboxylic acid

To a solution of 6-chloro-2-methyl-3H-benzofuran-2-carboxylic acid (230.0 mg, 1.08 mmol) in DCM (10 mL) at 25° C. was slowly added fuming nitric acid (0.5 mL) and stirred for 5 min. Water and ethyl acetate (20 mL) were added. The organic phase was separated and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:4 to 1:3) as eluting solvents to afford 6-chloro-2-methyl-5-nitro-3H-benzofuran-2-carboxylic acid (150 mg, 54%) as orange solid. ¹H NMR (400 MHz, CDCl₃) δ 7.84 (s, 1H), 6.99 (s, 1H), 3.68 (d, J=16.8 Hz, 1H), 3.23 (d, J=16.8 Hz, 1H), 1.80 (s, 3H).

Step D. (6-Chloro-2-methyl-5-nitro-3H-benzofuran-2-yl)methanol

The mixture of 6-chloro-2-methyl-5-nitro-3H-benzofuran-2-carboxylic acid (1.93 g, 7.5 mmol) and borane (1 M in THF, 14.0 mL, 14 mmol) in THF (75 mL) was stirred at 25° C. for 2 h. After slowly adding methanol (10 mL) and then concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford (6-chloro-2-methyl-5-nitro-3H-benzofuran-2-yl)methanol (580 mg, 32%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆): δ 7.84 (s, 1H), 6.99 (s, 1H), 6.60-5.80 (m, 1H), 3.68 (d, J=16.8 Hz, 1H), 3.23 (d, J=16.8 Hz, 1H), 1.80 (s, 3H). MS (ESI): m/z=244.1 [M+1]⁺.

Intermediate 3. (6-Fluoro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol

Step A. Methyl 3-(2,4-difluorophenyl)-2-hydroxy-2-methyl-propanoate

To a solution of magnesium (3290.81 mg, 137.12 mmol) and iodine (243.76 mg, 0.96 mmol) in diethyl ether (50 mL) at reflux was added 2,4-difluorobenzyl bromide (11291.0 mg, 54.54 mmol) drop wise and stirred for 30 min. This solution was then added to a solution of methyl pyruvate (5606.57 mg, 54.92 mmol) in diethyl ether (50 mL) at −78° C. and stirred for 30 min followed by room temperature for 2 h. Saturated ammonium chloride solution and ethyl acetate (200 mL) was added. The organic phase was separated and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether from 1:20 to 1:10 as eluting solvents to afford methyl 3-(2,4-difluorophenyl)-2-hydroxy-2-methyl-propanoate (8.9 g, 71%) as a yellow oil. MS (ESI): m/z=231.1 [M+1]⁺.

Step B. 6-Fluoro-2-methyl-2,3-dihydrobenzofuran-2-carboxylic acid

A mixture of methyl 3-(2,4-difluorophenyl)-2-hydroxy-2-methyl-propanoate (8.0 g, 34.75 mmol) and potassium tert-butanolate (9.73 g, 86.9 mmol) in THE (200 mL) was stirred at room temperature for 18 h. Another portion of potassium tert-butanolate (9.73 g, 86.9 mmol) was added. The mixture was stirred at 50° C. for 10 h. After cooling to room temperature, the mixture was brought to pH 3 with 2N HCl. The organic phase was separated and concentrated under reduced pressure to afford 6-fluoro-2-methyl-3H-benzofuran-2-carboxylic acid (8.0 g) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=197.1 [M+1]⁺.

Step C. Methyl 6-fluoro-2-methyl-2,3-dihydrobenzofuran-2-carboxylate

A mixture of 6-fluoro-2-methyl-3H-benzofuran-2-carboxylic acid (8 g, 40.81 mmol) and cesium carbonate (19.8 g, 60.7 mmol) in DMF (150 mL) was added methyl iodide (6.92 g, 48.7 mmol).

The mixture was stirred at room temperature for 18 h. The mixture was extracted with ethyl acetate (200 mL). The organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using petroleum ether to afford methyl 6-fluoro-2-methyl-2,3-dihydrobenzofuran-2-carboxylate (5 g) as a brown oil, which was used directly to next step without further purification. MS (ESI): m/z=211.1 [M+1]⁺.

Step D. Methyl 6-fluoro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-carboxylate

A mixture of methyl 6-fluoro-2-methyl-2,3-dihydrobenzofuran-2-carboxylate (5 g, 23.7 mmol) in DCM (70 mL) was added drop wise fuming nitric acid (5 mL) at room temperature. The mixture was stirred at room temperature for 30 min, poured into ice water and extracted with ethyl acetate (150 mL). The organic phase was concentrated to afford methyl 6-fluoro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-carboxylate as a brown oil (5 g) as orange oil, which was used directly to next step without further purification. MS (ESI): m/z=256.1 [M+1]⁺.

Step E. (6-fluoro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol

To a mixture of methyl 6-fluoro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-carboxylate (5 g, 19.53 mmol) in THE (100 mL) and ethanol (25 mL) was added sodium borohydride (2.22 g, 58.6 mmol) followed by lithium chloride (2.5 g, 58.6 mmol) at 0° C. The mixture was stirred at room temperature for 3 h, quenched with saturated ammonium chloride and extracted with DCM. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford (6-fluoro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (3.0 g, 98%) as a brown oil. ¹H NMR (400 MHz, DMSO-d₆): δ 7.94 (d, J=8.0 Hz, 1H), 6.60 (d, J=11.6 Hz, 1H), 3.78 (dd, J=5.6, 12.0 Hz, 1H), 3.66 (dd, J=7.2, 12.0 Hz, 1H), 3.34 (d, J=15.6 Hz, 1H), 2.93 (d, J=15.6 Hz, 1H), 1.84 (t, J=6.4 Hz, 1H), 1.49 (s, 3H). MS (ESI): m/z=228.1 [M+1]⁺.

Intermediate 4. 6-Bromo-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran

Step A. Methyl 2-(4-bromo-2-fluorophenyl)acetate

A mixture of 2-(4-bromo-2-fluorophenyl)acetic acid (20.2 g, 86.6 mmol) and concentrated sulfuric acid (7 mL) in methanol (200 mL) was heated to reflux for 18 h. After removal of solvent, the residue was diluted with DCM (200 mL) and washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. After concentration, it was afforded methyl 2-(4-bromo-2-fluorophenyl)acetate (21.1 g, 99%) as a brown oil. MS (ESI): m/z=280.1 [M+1]⁺.

Step B. 1-(4-Bromo-2-fluorophenyl)-2-methylpropan-2-ol

To a solution of methyl 2-(4-bromo-2-fluorophenyl)acetate (16.0 g, 64.8 mmol) in THE (160 mL) at −78° C. was added methyl magnesium bromide (3 M in diethyl ether, 225 mmol, 75 mL) drop-wise under nitrogen atmosphere. The reaction was stirred at −78° C. for 30 min followed by room temperature for 2 h. The reaction was quenched with saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over sodium sulfate. After filtration and removal of solvent, the residue was purified by silica gel chromatography using ethyl acetate:hexane (from 0 to 1:20) as eluting solvents to afford 1-(4-bromo-2-fluorophenyl)-2-methylpropan-2-ol as a colorless oil (15.5 g), which was used directly to next step without further purification. MS (ESI): m/z=263.1 [M+1]⁺.

Step C. 1-(4-Bromo-2-fluorophenyl)-2-methylpropan-2-ol

To a solution of 1-(4-bromo-2-fluorophenyl)-2-methylpropan-2-ol (15.5 g, 52.7 mmol) in anhydrous THE (300 mL) was added potassium tert-butanolate (17.6 g, 156.8 mmol). The mixture was heated at 65° C. for 18 h. The reaction was brought to pH 3 with 2N HCl. The aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was dried over sodium sulfate. After filtration and removal of solvent, the residue was purified by silica gel chromatography using ethyl acetate:hexane (from 0 to 1:20) as eluting solvents to afford 1-(4-bromo-2-fluorophenyl)-2-methylpropan-2-ol (8.9 g, 63%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 6.98 (d, J=8.0 Hz, 1H), 6.93 (dd, J=1.6, 8.0 Hz, 1H), 6.87 (d, J=1.6 Hz, 1H), 2.94 (s, 2H), 1.46 (s, 6H).

Step D. 6-Bromo-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran

To a solution of 1-(4-bromo-2-fluorophenyl)-2-methylpropan-2-ol (2.88 g, 12.7 mmol) in DCM (60 mL) was added concentrated nitric acid (60 mL) slowly. The mixture was stirred at room temperature for 30 min. The reaction was quenched with water (100 mL) and the aqueous phase was extracted with ethyl acetate (100 mL). The organic solution was dried over sodium sulfate. After filtration and removal of solvent, the residue was purified by silica gel chromatography using ethyl acetate:hexane (3:50) as eluting solvents to afford 6-bromo-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran (2.83 g, 78%) as a yellowish solid. ¹H NMR (400 MHz, CDCl₃): δ 7.83 (s, 1H), 7.03 (s, 1H), 3.03 (d, J=1.6, 1.2 Hz, 2H), 1.53 (s, 6H). MS (ESI): m/z=274.0 [M+1]⁺.

Example 1. N-(7-(4-(Hydroxymethyl)piperidin-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (1-(6-Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)piperidin-4-yl)methanol

A mixture of commercial available 7-fluoro-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (300 mg, 1.51 mmol), piperidin-4-ylmethanol (183 mg, 1.59 mmol) and N-ethyl-N-isopropylpropan-2-amine (391 mg, 3.03 mmol) in N-methyl-2-pyrrolidone (5 mL) was stirred at 120° C. for 18 h. After cooling to room temperature, the mixture was poured into water and the aqueous phase was extracted with ethyl acetate (2×50 mL). The organic phases were combined and washed with water and brine. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford (1-(6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)piperidin-4-yl)methanol (300 mg, 67%) as a yellow solid. MS (ESI): m/z=294.1 [M+1]⁺.

Step B. (1-(6-Amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)piperidin-4-yl)methanol

A mixture of (1-(6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)piperidin-4-yl)methanol (300 mg, 1.02 mmol) and 10% palladium on carbon (30 mg) in 2-methylpropan-2-ol (10 mL) was stirred at 50° C. for 18 h under an atmosphere of hydrogen. After the mixture was cooled to room temperature and filtered, the filtrate was concentrated under reduced pressure to afford (1-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)piperidin-4-yl)methanol as a white solid (260 mg), which was used directly in the next step without purification. MS (ESI): m/z=264.1 [M+1]⁺.

Step C. N-(7-(4-(Hydroxymethyl)piperidin-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (322 mg, 1.97 mmol), (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (1.03 g, 1.97 mmol) and N-ethyl-N-isopropylpropan-2-amine (510 mg, 3.95 mmol) in DMF (10 mL) was stirred at room temperature for 30 min. (1-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)piperidin-4-yl)methanol (260 mg, 0.99 mmol) was added. The resulting mixture was stirred at room temperature for 18 h. After concentration, the residue was purified by preparative HPLC ((Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 10-20%; B: 10 mM ammonium bicarbonate in water) to afford N-(7-(4-(hydroxymethyl)piperidin-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid (165 mg, 41%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.58 (s, 1H), 9.36 (d, J=7.2 Hz, 1H), 8.89 (d, J=4.0 Hz, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.33 (dd, J=4.0, 6.8 Hz, 1H), 6.62 (s, 1H), 5.71 (s, 1H), 4.58 (t, J=5.2 Hz, 1H), 4.21-3.95 (m, 2H), 3.41 (t, J=4.5 Hz, 2H), 3.29-3.15 (m, 2H), 2.95-2.74 (m, 2H), 2.71-2.54 (m, 2H), 1.85-1.29 (m, 5H). MS (ESI): m/z=409.1 [M+1]⁺.

Example 2. N-(7-(4-(Hydroxymethyl)piperidin-1-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 7-(4-(Hydroxymethyl)piperidin-1-yl)-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one

A mixture of 7-fluoro-6-nitro-4H-1,4-benzoxazin-3-one (300 mg, 1.41 mmol), 4-piperidinylmethanol (162 mg, 1.41 mmol) and N,N-diisopropylethylamine (342 mg, 2.82 mmol) in 4-methyl-2-pentanone (5 mL) was stirred at 30° C. for 16 h in a sealed tube. Water and ethyl acetate (2×30 mL) were added. The organic phases were combined and washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:5) as eluting solvents to afford 7-(4-(hydroxymethyl)piperidin-1-yl)-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (400 mg, 92%) as a yellow solid. MS (ESI): m/z=308.2 [M+1]⁺.

Step B. 6-Amino-7-(4-(hydroxymethyl)piperidin-1-yl)-2H-benzo[b][1,4]oxazin

A mixture of 7-(4-(hydroxymethyl)piperidin-1-yl)-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (350 mg, 1.14 mmol) and 10% palladium on carbon (35 mg) in methanol (10 mL) was stirred at room temperature under an atmosphere of hydrogen for 1 h. The solid was filtered off and the filtrate was concentrated under reduced pressure to afford 6-amino-7-(4-(hydroxymethyl)piperidin-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one (300 mg) as a colorless oil, which was used directly to next step without further purification. MS (ESI): m/z=278.2 [M+1]⁺.

Step C. N-(7-(4-(Hydroxymethyl)piperidin-1-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 6-amino-7-[4-(hydroxymethyl)-1-piperidyl]-4H-1,4-benzoxazin-3-one (250 mg, 0.90 mmol), (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (100 mg, 0.19 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (145 mg, 0.89 mmol) and N,N-diisopropylethylamine (23 mg, 0.19 mmol) in DMF (5 mL) was stirred at room temperature for 18 h. The crude reaction was purified by preparative HPLC ((Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 15-30%; B: 10 mM ammonium bicarbonate in water)) to afford N-(7-(4-(hydroxymethyl)piperidin-1-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (68 mg, 18%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.72 (s, 1H), 10.62 (s, 1H), 9.38 (d, J=6.0 Hz, 1H), 8.91 (d, J=4.0 Hz, 1H), 8.70 (s, 1H)), 8.25 (s, 1H), 7.53 (dd, J=4.0, 6.8 Hz, 1H), 6.93 (s, 1H), 4.59 (t, J=5.6 Hz, 1H), 4.53 (s, 2H), 3.41 (d, J=5.2 Hz, 2H), 2.92-2.89 (m, 2H), 2.67-2.61 (m, 2H), 1.73-1.51 (m, 5H). MS (ESI): m/z=423.2 [M+1]⁺.

Example 3. Trans-N-[2, 2-dimethyl-6-[2-(methylaminomethyl)-1,3-dioxan-5-yl]-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 2-Trimethylsilylethyl N-(2, 2-dimethoxyethyl)carbamate

To the mixture of 2,2-dimethoxyethanamine (608.0 mg, 5.78 mmol) and triethylamine (1.07 mL, 7.71 mmol) in THE (10 mL) was added 1-[2-(trimethylsilyl)ethoxycarbonyloxy]pyrrolidin-2,5-dione (1.0 g, 3.86 mmol) at 0° C. and the mixture was stirred at room temperature for 1 h. The reaction was concentrated to dryness under reduced pressure. The residue was dissolved in DCM (150 mL) and the organic phase was washed with water and brine, dried over sodium sulfate and concentrated to afford 2-trimethylsilylethyl N-(2,2-dimethoxyethyl)carbamate (945 mg) as a colorless oil, which was used directly in the next step without further purification. ¹HNMR (400 MHz, CDCl₃) δ 4.76 (brs, 1H), 4.33 (t, J=5.6 Hz, 1H), 4.12 (t, J=8.4 Hz, 2H), 3.36 (s, 6H), 3.27 (t, J=5.6 Hz, 2H), 0.94 (t, J=8.4 Hz, 2H), 0.00 (s, 9H).

Step B. Pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride

To the mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (500.0 mg, 3.07 mmol) in DCM (12 mL) was added oxalyl chloride (0.65 mL, 7.64 mmol) and DMF (100.0 mg, 1.37 mmol) at 0° C. followed by room temperature for 2 h. The mixture was concentrated to dryness to afford pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (550 mg) as brown solid, which was used directly to the next step without further purification. MS (ESI): m/z=178.1 [M-Cl+MeO]⁺.

Step C. Methyl 2-(2, 4-difluorophenyl)acetate

The mixture of 2-(2,4-difluorophenyl)acetic acid (2.0 g, 11.62 mmol) and concentrated sulfuric acid (2 mL) in methanol (40 mL) was stirred at 70° C. for 16 h. After concentration, the residue was dissolved in ethyl acetate (300 mL). The organic phase was washed with saturated sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated to afford methyl 2-(2, 4-difluorophenyl)acetate (2.1 g) as a colorless oil, which was used directly to the next step without further purification. MS (ESI): m/z=187.1 [M+1]⁺.

Step D. 1-(2,4-Difluorophenyl)-2-methyl-propan-2-ol

To a mixture of methyl 2-(2,4-difluorophenyl)acetate (1.8 g, 9.67 mmol) in THF (20 mL) was drop-wise added methyl magnesium bromide (3.0 m in diethyl ether, 9.67 mL, 29.01 mmol) under an atmosphere of nitrogen at −78° C. The mixture was warmed and stirred at room temperature for 1 h. The reaction was quenched by saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure to afford 1-(2,4-difluorophenyl)-2-methyl-propan-2-ol (1.8 g) as a yellow oil, which was used directly to the next step without further purification. MS (ESI): m/z=169.1 [M-OH]⁺.

Step E. 6-Fluoro-2,2-dimethyl-3H-benzofuran

A mixture of 1-(2,4-difluorophenyl)-2-methyl-propan-2-ol (1.8 g, 9.67 mmol) and potassium tert-butanolate (2720.0 mg, 24.24 mmol) in THF (50 mL) was stirred at 65° C. for 90 min. After concentration, the residue was dissolved in ethyl acetate (150 mL). The organic phase was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:100) as eluting solvents to afford 6-fluoro-2,2-dimethyl-3H-benzofuran (1.14 g, 71%) as a colorless oil. MS (ESI): m/z=167.1 [M+1]⁺.

Step F. 6-Fluoro-2,2-dimethyl-5-nitro-3H-benzofuran

To a solution of 6-fluoro-2,2-dimethyl-3H-benzofuran (1.1 g, 6.9 mmol) in DCM (20 mL) was added into nitric acid (1.0 mL) drop-wise over 10 min at 25° C. and stirred for 20 min. The mixture was poured into ice water. The aqueous phase was extracted with ethyl acetate (150 mL). The organic phase was washed with saturated sodium bicarbonate solution, water and brine and dried over sodium sulfate before concentration under reduced pressure. The residue was purified by silica gel chromatography eluting using ethyl acetate:petroleum ether (1:10) as eluting solvents to afford 6-fluoro-2,2-dimethyl-5-nitro-3H-benzofuran (1.04 g, 72%) as gray solid. ¹HNMR (400 MHz, CDCl₃) δ 7.92 (d, J=7.6 Hz, 1.2 Hz, 1H), 6.55 (d, J=11.6 Hz, 1H), 3.03 (s, 2H), 1.56 (s, 6H). MS (ESI): m/z=212.1 [M+1]⁺.

Step G. Dimethyl 2-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)propanedioate

To the mixture of 6-fluoro-2,2-dimethyl-5-nitro-3H-benzofuran (420.0 mg, 1.99 mmol) and dimethyl malonate (0.68 mL, 5.96 mmol) in DMF (8 mL) was added cesium carbonate (1296.0 mg, 3.98 mmol) and stirred at 20° C. for 16 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with water and brine and dried over sodium sulfate before concentration to dryness. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:5) as eluting solvents to afford dimethyl 2-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)propanedioate (280 mg, 44%) as a yellow oil. MS (ESI): m/z=324.1 [M+1]⁺.

Step H. 2-(2, 2-Dimethyl-5-nitro-3H-benzofuran-6-yl)propane-1,3-diol

To a solution of diisobutylaluminium hydride (1 M in toluene, 5.2 mL, 5.2 mmol) in THF (2.5 mL) was drop-wise added the solution of dimethyl 2-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)propanedioate (280.0 mg, 0.87 mmol) in THF (10 mL) under an atmosphere of nitrogen at 0° C. and maintained there for 1 h followed by 1 h at room temperature. To the mixture was added sodium sulfate decahydrate and the mixture was stirred for 1 h. After filtration and concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:3) as eluting solvents to afford 2-(2, 2-dimethyl-5-nitro-3H-benzofuran-6-yl)propane-1,3-diol (75 mg, 32%) as yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 7.78 (s, 1H), 6.81 (s, 1H), 4.02 (d, J=1.2 Hz, 2H), 4.00 (s, 2H), 3.83-3.75 (m, 1H), 3.04 (s, 2H), 1.51 (s, 6H). MS (ESI): m/z=290.0 [M+Na]⁺.

Step I. Trans-2-trimethylsilylethyl N-[[5-(2, 2-dimethyl-5-nitro-3H-benzofuran-6-yl)-1,3-dioxan-2-yl]methyl]carbamate

The mixture of 2-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)propane-1,3-diol (80.0 mg, 0.30 mmol), 2-trimethylsilylethyl N-(2,2-dimethoxyethyl)carbamate (223.99 mg, 0.90 mmol) and 4-toluene sulfonic acid (3.0 mg, 0.02 mmol) in toluene (5 mL) was stirred at 110° C. in a sealed tube for 72 h. The mixture was neutralized with triethylamine then concentrated to dryness. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:5) as eluting solvents to afford trans-2-trimethylsilylethyl N-[[5-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-1,3-dioxan-2-yl]methyl]carbamate (61 mg, 45%) as a yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 7.72 (s, 1H), 6.53 (s, 1H), 4.92 (brs, 1H), 4.65 (t, J=4.0 Hz, 1H), 4.26-4.17 (m, 2H), 4.18-4.07 (m, 2H), 3.84-3.68 (m, 3H), 3.35 (t, J=4.8 Hz, 2H), 3.00 (s, 2H), 1.47 (s, 6H), 0.95 (t, J=8.4 Hz, 2H), 0.00 (s, 9H).

Step J. Trans-2-trimethylsilylethyl N-[[5-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate

To the mixture of trans-2-trimethylsilylethyl N-[[5-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-1, 3-dioxan-2-yl]methyl]carbamate (61.0 mg, 0.13 mmol) in DMF (2.5 mL) was added sodium hydride (35.0 mg, 0.88 mmol) in ice water bath and stirred for 10 min. To the mixture was added methyl iodide (0.02 mL, 0.35 mmol) and stirred at 20° C. for 1 h. The mixture was poured into water and the aqueous phase was extracted with ethyl acetate (50 mL). The organics was washed with water and brine and dried over sodium sulfate before concentration under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:5) as eluting solvents to afford trans-2-trimethylsilylethyl N-[[5-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate (47 mg, 75%) as a yellow solid. MS (ESI): m/z=489.2 [M+Na]⁺.

Step K. Trans-2-trimethylsilylethyl N-[[5-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate

A mixture of trans-2-trimethylsilylethyl N-[[5-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate (47.0 mg, 0.10 mmol) and 10% palladium on carbon (20.0 mg) in methanol (8 mL) was stirred under a hydrogen atmosphere at 20° C. for 1 h. After filtration and concentration, it was afforded trans-2-trimethylsilylethyl N-[[5-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate (42 mg) as a colorless oil, which was used directly to the next step without further purification. MS (ESI): m/z=437.2 [M+1]⁺.

Step L. Trans-2-trimethylsilylethyl N-[[5-[2,2-dimethyl-5-(pyrazolo[1, 5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate

To the mixture of trans-2-trimethylsilylethyl N-[[5-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)-1, 3-dioxan-2-yl]methyl]-N-methyl-carbamate (42.0 mg, 0.10 mmol), triethylamine (0.04 mL, 0.30 mmol) and 4-dimethylaminopyridine (3.0 mg, 0.02 mmol) in THE (5 mL) was added pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (25.0 mg, 0.14 mmol) and stirred for 1 h. To the mixture was added methanol (2 mL). After concentration, the residue was purified by silica gel chromatography using ethyl actate:petroleum ether (1:1) as eluting solvents to afford trans-2-trimethylsilylethyl N-[[5-[2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate (31 mg, 55%) as a yellow oil. MS (ESI): m/z=604.2 [M+Na]⁺.

Step M. Trans-N-[2,2-dimethyl-6-[2-(methylaminomethyl)-1,3-dioxan-5-yl]-3H-benzofuran-5-yl]pyrazolo[1, 5-a]pyrimidine-3-carboxamide

To the mixture of trans-2-trimethylsilylethyl N-[[5-[2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate (31.0 mg, 0.05 mmol) in DCM (0.50 mL) was added trifluoroacetic acid (250 μL) at 0° C. and stirred for 1 h. The mixture was neutralized with triethylamine. After concentration, the residue was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 μm; A: acetonitrile 25-55%; B: 10 mM ammonium bicarbonatein water) to afford trans-N-[2,2-dimethyl-6-[2-(methylaminomethyl)-1,3-dioxan-5-yl]-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (17.8 mg, 76%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.73 (s, 1H), 8.84 (dd, J=1.6, 6.8 Hz, 1H), 8.75 (s, 1H), 8.74 (dd, J=1.6, 4.0 Hz, 1H), 7.72 (s, 1H), 7.06 (dd, J=3.6, 7.2 Hz, 1H), 6.55 (s, 1H), 4.75 (t, J=4.8 Hz, 1H), 4.28 (dd, J=4.4, 11.2 Hz, 2H), 3.84 (t, J=7.2 Hz, 2H), 3.65-3.55 (m, 1H), 3.03 (s, 2H), 2.76 (d, J=4.8 Hz, 2H), 2.46 (s, 3H), 1.48 (s, 6H). MS (ESI): m/z=438.2 [M+1]⁺.

Example 4. N-(6-(4-(Hydroxymethyl)piperidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (1-(2,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)methanol

A mixture of 6-chloro-2,2-dimethyl-5-nitro-3H-benzofuran (Intermediate 1) (1.14 g, 5.01 mmol) and 4-piperidinylmethanol (5.77 g, 50.08 mmol) was stirred at 110° C. for 18 h. The reaction was concentrated to dryness. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:4 to 2:3) to afford[1-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-4-piperidyl]methanol (1.53 g, 97%) as orange oil. MS (ESI): m/z=307.2 [M+1]⁺.

Step B. (1-(5-Amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)methanol

A mixture of [1-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-4-piperidyl]methanol (1.16 g, 3.75 mmol) and 10% palladium on carbon (116 mg) in methanol (30 mL) was stirred at 25° C. under hydrogen atmosphere for 2 h. After filtration and concentration under reduced pressure, [1-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)-4-piperidyl]methanol was afforded (1.29 g) as an orange oil, which was used directly to next step without further purification. MS (ESI): m/z=277.2 [M+1]⁺.

Step C. N-(6-(4-(Hydroxymethyl)piperidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of [1-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)-4-piperidyl]methanol (990.0 mg, 3.58 mmol) and triethylamine (1087.4 mg, 10.75 mmol) in DCM (10 mL) was stirred at 0° C. To the mixture was a added solution of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (Example 3, Step B) (975.67 mg, 5.37 mmol) in DCM (10 mL) and the reaction was stirred at 25° C. for 1 h. After concentration, the residue was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A:acetonitrile 45-55%; B: 10 mM ammonium bicarbonate in water) to afford N-[6-[4-(hydroxymethyl)-1-piperidyl]-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (916 mg, 61%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 10.50 (s, 1H), 8.82-8.72 (m, 3H), 8.43 (s, 1H), 7.01 (dd, J=4, 6.8 Hz, 1H), 6.65 (s, 1H), 3.67-3.57 (m, 2H), 3.14-3.06 (m, 2H), 3.03 (s, 2H), 2.72-2.61 (m, 2H), 1.82-1.61 (m, 5H), 1.48 (s, 6H). MS (ESI): m/z=422.1 [M+1]⁺.

Example 5. N-(2,2-Dimethyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 7-Fluoro-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one

A mixture of 2-amino-5-fluorophenol (150 mg, 1.18 mmol), ethyl 2-bromo-2-methylpropanoate (345 mg, 1.77 mmol), cesium carbonate (1.1 g, 3.54 mmol) in 1,4-dioxane (8 mL) was stirred at 110° C. for 4 h. The reaction was filtered, concentrated under reduced pressure and purified by silica gel chromatography using ethyl acetate:petroleum ether (1:4) to afford 7-fluoro-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (95 mg, 39%) as grey solid. MS (ESI): m/z=196.1 [M+1]⁺.

Step B. 7-Fluoro-2,2-dimethyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one

To a solution of 7-fluoro-2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one (95 mg, 0.49 mmol) in sulfuric acid (4 mL) was added guanidine nitrate (59 mg, 0.49 mmol) drop-wise at 0° C. and stirred for 30 min. The mixture was poured into ice water and the aqueous was extracted with ethyl acetate (30 mL). The organic phase was dried over sodium sulfate and concentrated to afford 7-fluoro-2,2-dimethyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one as grey solid (108 mg), which was used directly to next step without further purification. MS (ESI): m/z=241.1 [M+1]⁺.

Step C. 2,2-Dimethyl-7-morpholino-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one

A mixture of 7-fluoro-2,2-dimethyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (100 mg, 0.41 mmol), morpholine (43 mg, 0.50 mmol) and N,N-diisopropylethylamine (86 mg, 0.67 mmol) in acetonitrile (10 mL) was stirred at room temperature for 18 h. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford 2,2-dimethyl-7-morpholino-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (122 mg, 97%) as grey oil. MS (ESI): m/z=308.1 [M+1]⁺.

Step D. 2,2-Dimethyl-7-morpholino-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of 2,2-dimethyl-7-morpholino-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (122 mg, 0.40 mmol) in THF (4 mL) was added borane (1M in THF, 1.59 mL, 1.59 mmol) at room temperature. Then the mixture was stirred at 65° C. for 2 h. The mixture was cooled to 0° C. Methanol (10 mL) was added drop wise. The mixture was stirred at reflux for 1 h. After concentration, it was afforded 2-methyl-7-morpholino-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (120 mg) as red oil, which was used to next step without further purification. MS (ESI): m/z=294.2 [M+1]⁺.

Step E. 2,2-Dimethyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine

A mixture of 2-methyl-7-morpholino-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (120 mg, 0.41 mmol) and 10% palladium on carbon (30.0 mg) in ethyl acetate (30 mL) was stirred at 40° C. under hydrogen atmosphere for 2 h. The solid was filtered off and the filtrate was concentrated under reduced pressure to afford 2,2-dimethyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine (110 mg) as black oil, which was used to next step without further purification. MS (ESI): m/z=264.1 [M+1]⁺.

Step F. N-(2,2-Dimethyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 2,2-dimethyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine as black oil (110 mg, 0.42 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (82 mg, 0.50 mmol), (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (327 mg, 0.63 mmol) and diisopropylethylamine (152 mg, 1.25 mmol) in DMF (10 mL) was stirred at 25° C. for 4 h. The mixture was purified by preparative HPLC (phenomenex, Gemini C18, 21.2×100 mm. 5 um, 110 A, A: acetonitrile 30-40%; B: 0.05% formic acid in water) to afford N-(2,2-dimethyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (70 mg, 41%) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆): δ 10.51 (s, 1H), 9.36 (dd, J=1.6, 7.2 Hz, 1H), 8.92 (dd, J=1.6, 4.4 Hz, 1H), 8.66 (s, 1H), 7.89 (s, 1H), 7.33 (dd, J=4.4, 7.2 Hz, 1H), 6.61 (s, 1H), 5.82 (s, 1H), 3.89-3.73 (m, 4H), 2.95 (s, 2H), 2.82-2.69 (m, 4.0 Hz, 4H), 1.24 (s, 6H). MS (ESI): m/z=409.1 [M+1]⁺.

Example 6. N-(2-(Hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (2-Methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (6-chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (900 mg, 3.70 mmol) in morpholine (5 mL) was stirred at 120° C. for 18 h. The mixture was concentrated under reduced pressure and the residue purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford (2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (780 mg, 72%) as a yellow oil. MS (ESI): m/z=295.1 [M+1]⁺.

Step B. (5-Amino-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-yl)methanol (780 mg, 2.65 mmol) and 10% palladium on carbon (200 mg) in methanol (30 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to afford (5-amino-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)methanol (550 mg) as light green oil, which was used directly to next step without further purification. MS (ESI): m/z=265.1 [M+1]⁺.

Step C. N-(2-(Hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of (5-amino-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)methanol (550 mg, 2.08 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (407 mg, 2.5 mmol), (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (1.63 g, 3.12 mmol) and diisopropyethylamine (756 mg, 6.24 mmol) in DMF (10 mL) was stirred at 25° C. for 3 h. Water was added. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using methanol:DCM (3:100) as eluting solvents to afford N-[2-(hydroxymethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (490 mg, 58%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.47 (s, 1H), 8.83 (dd, J=1.5, 7.2 Hz, 1H), 8.78 (s, 1H), 8.77 (dd, J=1.6, 4.0 Hz, 1H), 7.07 (dd, J=4.0, 7.2 Hz, 1H), 6.67 (s, 1H), 3.94-3.96 (m, 4H), 3.67 (d, J=5.6 Hz, 2H), 3.25 (d, J=15.6 Hz, 1H), 2.95 (d, J=15.6 Hz, 1H), 2.91-2.93 (m, 4H), 1.46 (s, 3H). MS (ESI): m/z=410.1 [M+1]⁺.

Example 7. N-(7-(4-(Hydroxymethyl)piperidin-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 6-Methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A solution of 5-amino-1H-pyrazole-4-carboxylic acid (2000 mg, 15.74 mmol) and (E)-3-(dimethylamino)-2-methylacrylaldehyde (1780 mg, 15.74 mmol) in acetic acid (3 mL) and ethanol (1 mL) was heated at 70° C. for 1 h. The resulting mixture was cooled to room temperature and the solid was collected by filtration, washed with water and dried in vacuum to afford 6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1610 mg, 58%) as a white solid. MS (ESI): m/z=178.1 [M+1]⁺.

Step B. (1-(6-Nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)piperidin-4-yl)methanol

A mixture of 7-fluoro-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (300 mg, 1.51 mmol), piperidin-4-ylmethanol (183 mg, 1.59 mmol) and N-ethyl-N-isopropylpropan-2-amine (391 mg, 3.03 mmol) in N-methyl-2-pyrrolidone (5 mL) was stirred at 120° C. for 18 h. After cooling to room temperature, the mixture was poured into water and the aqueous phase was extracted with ethyl acetate (2×50 mL). The organic phases were combined and washed with water, brine and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford (1-(6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)piperidin-4-yl)methanol (300 mg, 67%) as a yellow solid. MS (ESI): m/z=294.1 [M+1]⁺.

Step C. (1-(6-Amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)piperidin-4-yl)methanol

A mixture of (1-(6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)piperidin-4-yl)methanol (300 mg, 1.02 mmol) and 10% palladium on carbon (30 mg) in 2-methylpropan-2-ol (10 mL) was stirred at 50° C. for 18 h under hydrogen atmosphere. After the mixture was cooled down to room temperature, the reaction was filtered and the filtrate was concentrated under reduced pressure to afford (1-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)piperidin-4-yl)methanol (260 mg) as a white solid, which was used directly to the next step without purification. MS (ESI): m/z=264.1 [M+1]⁺.

Step D. N-(7-(4-(Hydroxymethyl)piperidin-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (58 mg, 0.33 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (215 mg, 0.41 mmol), (1-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl)piperidin-4-yl)methanol (85 mg, 0.27 mmol) and N-ethyl-N-isopropylpropan-2-amine (71 mg, 0.55 mmol) in DMF (5 mL) was stirred at room temperature for 18 h. After filtration and concentration, the residue was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-55%; B: 10 mM ammonium bicarbonate in water) to afford N-(7-(4-(hydroxymethyl)piperidin-1-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide (35 mg, 30%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.21 (s, 1H), 8.83 (d, J=2.8 Hz, 1H), 8.57 (s, 1H), 7.88 (s, 1H), 6.61 (s, 1H), 5.68 (s, 1H), 4.6 (t, J=2.8 Hz, 2H), 4.08 (t, J=4.4 Hz, 2H), 3.43 (t, J=5.2 Hz, 2H), 3.25-3.22 (m, 2H), 2.86-2.83 (m, 2H), 2.62-2.56 (m, 2H), 2.42 (s, 3H), 1.73-1.63 (m, 4H), 1.51-1.47 (m, 1H).

MS (ESI): m/z=423.1 [M+1]⁺.

Example 8. N-[6-[4-(2, 2-Difluoroethyl)piperazin-1-yl]-2, 2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1, 5-a]pyrimidine-3-carboxamide

Step A. 1-(2,2-Difluoroethyl)-4-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)piperazine

A mixture of 6-fluoro-2,2-dimethyl-5-nitro-3H-benzofuran (80.0 mg, 0.38 mmol), 1-(2,2-difluoroethyl)piperazine hydrochloride (212.0 mg, 1.14 mmol) and cesium carbonate (556.0 mg, 1.71 mmol) in DMF (4 mL) was stirred at 20° C. for 5 h. The mixture was poured into water (20 mL) and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was washed with water and brine and dried over sodium sulfate before concentration to dryness. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:6) as eluting solvents to afford 1-(2,2-difluoroethyl)-4-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)piperazine (88 mg, 68%) as yellow oil. MS (ESI): m/z=342.1 [M+1]⁺.

Step B. 6-[4-(2,2-Difluoroethyl)piperazin-1-yl]-2,2-dimethyl-3H-benzofuran-5-amine

A mixture of 1-(2,2-difluoroethyl)-4-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)piperazine (84.0 mg, 0.25 mmol) and 10% palladium on carbon (50.0 mg) in methanol (12 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. After filtration and concentration under reduced pressure, it was afforded 6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2,2-dimethyl-3H-benzofuran-5-amine (75 mg) as a yellow oil, which was used directly in the next step without further purification. MS (ESI): m/z=312.2 [M+1]⁺.

Step C. N-[6-[4-(2, 2-Difluoroethyl)piperazin-1-yl]-2, 2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1, 5-a]pyrimidine-3-carboxamide

To the mixture of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (63.0 mg, 0.35 mmol), triethylamine (0.1 mL, 0.69 mmol) and 4-dimethylaminopyridine (7.0 mg, 0.06 mmol) in THE (10 mL) was added 6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2,2-dimethyl-3H-benzofuran-5-amine (70.0 mg, 0.22 mmol) and the mixture was stirred at 25° C. for 1 h. To the mixture was added methanol (4 mL) and stirred for 30 min. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether:DCM (2:1:1) as eluting solvents to afford N-[6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (84.1 mg, 82%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (brs, 1H), 9.37 (dd, J=1.6, 7.2 Hz, 1H), 8.95 (dd, J=1.2, 4.4 Hz, 1H), 8.68 (s, 1H), 8.32 (s, 1H), 7.35 (dd, J=4.0, 6.8 Hz, 1H), 6.71 (s, 1H), 6.20 (tt, J=4.4, 55.6 Hz, 1H), 3.00 (s, 2H), 2.94-2.73 (m, 10H), 1.41 (s, 6H). MS (ESI): m/z=457.2 [M+1]⁺.

Example 9. N-(7-Morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 7-Morpholino-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

A mixture of morpholine (176 mg, 2.02 mmol), 7-fluoro-6-nitro-3,4-dihydro-2H-1,4-benzoxazine (200 mg, 1.01 mmol), potassium carbonate (488 mg, 3.53 mmol) and sodium iodide (530 mg, 3.53 mmol) in acetonitrile (20 mL) was stirred at 85° C. for 16 h. After filtration and concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford 7-morpholino-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine as red-brown oil (250 mg, 93%). MS (ESI): m/z=266.2 [M+1]⁺.

Step B. 7-Morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine

A mixture of 7-morpholino-6-nitro-3,4-dihydro-2H-1,4-benzoxazine (125 mg, 0.47 mmol) and 10% palladium on carbon (50.0 mg) in ethyl acetate (20 mL) was stirred at 45° C. under an atmosphere of hydrogen for 3 h. After filtration and concentration, it was afforded 7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine as a brown solid (100 mg), which was used directly to next step without further purification. MS (ESI): m/z=236.2 [M+1]⁺.

Step C. N-(7-Morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 7-morpholino-3,4-dihydro-2H-1,4-benzoxazin-6-amine (95.0 mg, 0.40 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (79.0 mg, 0.48 mmol), and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (307 mg, 0.810 mmol) in DMF (5 mL) and diisopropyethylamine (260 mg, 2.02 mmol) was stirred at 25° C. for 16 h. After concentration, the residue was purified by preparative HPLC (Boston ODS 40 g flash, A: MeCN25-35%; B: 0.5% ammonium bicarbonate in H2O) to afford N-(7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (22.9 mg, 15%) as pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.52 (s, 1H), 9.36 (dd, J=1.6, 6.8 Hz, 1H), 8.93 (dd, J=1.2, 4.0 Hz, 1H), 8.66 (s, 1H), 7.87 (s, 1H), 7.33 (dd, J=4.0, 6.8 Hz, 1H), 6.64 (s, 1H), 5.76 (s, 1H), 4.10-4.08 (m, 2H), 3.89-3.74 (m, 4H), 3.28-3.22 (m, 2H), 2.79-2.69 (m, 4H). MS (ESI): m/z=381.2 [M+1]⁺.

Example 10. N-(3-Methyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 4-Benzyl-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one

A mixture of 7-fluoro-4H-1,4-benzoxazin-3-one (200 mg, 1.2 mmol), (chloromethyl)benzene (159 mg, 1.26 mmol) and cesium carbonate (1.95 g, 5.98 mmol) in 1,4-dioxane (10 mL) was stirred at 110° C. for 4 h. After filtration, the filtrate was concentrated and purified by silica gel chromatography using ethyl acetate:petroleum ether (1:4) as eluting solvents to afford 4-benzyl-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (250 mg, 75%) as a white solid. MS (ESI): m/z=258.1 [M+1]⁺.

Step B. 4-Benzyl-7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a mixture of 4-benzyl-7-fluoro-2H-benzo[b][1,4]oxazin-3(4H)-one (250 mg, 0.97 mmol) in THE (10 mL) was added methyl magnesium bromide (3M in diethyl ether, 1.3 mL, 3.89 mmol) drop-wise at 0° C. The mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and acetic acid (2 mL) was added followed by addition of sodium borohydride (92 mg, 2.43 mmol). The reaction mixture was stirred at room temperature for 12 h and then poured into ice water. The aqueous phase was extracted with ethyl acetate (10 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:4) as eluting solvents to afford 4-benzyl-7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (220 mg, 67%) as a white solid. MS (ESI): m/z=258.2 [M+1]⁺.

Step C. 7-Fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

A mixture of 4-benzyl-7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (220 mg, 0.86 mmol) and 10% palladium on carbon (40 mg) in ethanol (20 mL) was stirred at 40° C. under hydrogen atmosphere for 4 h. The solid was filtered off and the filtrate was concentrated under reduced pressure to afford 7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (100 mg) as a light oil, which was used directly in the next step without purification. MS (ESI): m/z=168.2 [M+1]⁺.

Step D. 7-Fluoro-3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of 7-fluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (100 mg, 0.60 mmol) in concentrated sulfuric acid (4 mL) was added guanidine nitrate (73 mg, 0.60 mmol) at 0° C. Then the mixture was stirred at 0° C. for 30 min and poured into ice water. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried over sodium sulfate and concentrated to afford 7-fluoro-3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (80 mg) as red solid, which was used directly in the next step without purification. MS (ESI): m/z=213.2 [M+1]⁺.

Step E. 3-Methyl-7-morpholino-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

A mixture of 7-fluoro-3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (80 mg, 0.38 mmol), morpholine (49 mg, 0.57 mmol) and cesium carbonate (246 mg, 0.75 mmol) in acetonitrile (5 mL) was stirred at 85° C. for 18 h. The mixture was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:4) as eluting solvents to afford 3-methyl-7-morpholino-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (80 mg, 61%) as a red oil. MS (ESI): m/z=280.1 [M+1]⁺.

Step F. N-(3-Methyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 3-methyl-7-morpholino-3,4-dihydro-2H-1,4-benzoxazin-6-amine (43 mg, 0.17 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (33 mg, 0.21 mmol), (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (107 mg, 0.21 mmol) and diisopropyethylamine (44 mg, 0.34 mmol) in DMF (5 mL) was stirred at 20° C. for 16 h. The crude was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-55%; B: 10 mM ammonium bicarbonate in water) to afford N-(3-methyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (15 mg, 22%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.52 (s, 1H), 9.36 (dd, J=1.2, 6.8 Hz, 1H), 8.93 (dd, J=1.6, 4 Hz, 1H), 8.67 (s, 1H)), 7.78 (s, 1H), 7.33 (dd, J=4.4, 7.2 Hz, 1H), 6.66 (s, 1H), 5.81 (s, 1H), 4.13-4.08 (m, 1H), 3.87-3.80 (m, 4H), 3.61 (dd, J=8, 10 Hz, 1H), 3.41-3.33 (m, 1H), 2.78-2.71 (m, 4H), 1.08 (d, J=6.4 Hz, 3H). MS (ESI): m/z=395.2 [M+1]⁺.

Example 11. N-(2-Methyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 7-Chloro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

A mixture of 2-amino-5-chlorophenol (2.26 g, 15.73 mmol), ethyl 2-bromopropanoate (4.27 g, 23.6 mmol) and cesium carbonate (15.39 g, 47.2 mmol) in 1,4-dioxane (20 mL) was stirred at 20° C. for 18 h. After filtration and concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:4) as eluting solvents to afford 7-chloro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one as grey solid (1.4 g, 42%). MS (ESI): m/z=198.1 [M+1]⁺.

Step B. 7-Chloro-2-methyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one

To a solution of 7-chloro-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one (664 mg, 3.36 mmol) in concentrated sulfuric acid (10 mL) was added guanidine nitrate (410 mg, 3.36 mmol) at 0° C. The mixture was stirred for 30 min then poured to ice water. The aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure to afford 7-chloro-2-methyl-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (660 mg) as a grey solid, which was used directly to next step without further purification. MS (ESI): m/z=243.1 [M+1]⁺.

Step C. 2-Methyl-7-morpholino-6-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one

A mixture of 7-chloro-2-methyl-6-nitro-4H-1,4-benzoxazin-3-one (151 mg, 0.62 mmol) in morpholine (2 mL) was stirred at 120° C. in a sealed tube for 16 h. The mixture was concentrated and the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford 2-methyl-7-morpholino-6-nitro-4H-1,4-benzoxazin-3-one (180 mg, 78%) as red oil. MS (ESI): m/z=294.2 [M+1]⁺.

Step D. 2-Methyl-7-morpholino-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of 2-methyl-7-morpholino-6-nitro-4H-1,4-benzoxazin-3-one (183.0 mg, 0.62 mmol) in THF (4 mL) was added borane (1M in THF, 2.5 mL, 2.5 mmol). The mixture was stirred at 65° C. for 2 h. The mixture was cooled to 0° C. and methanol (10 mL) was added drop wise. The mixture was stirred at reflux for 1 h. After concentration, it was afforded 2-methyl-7-morpholino-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (180 mg) as red oil, which was used directly to next step without further purification. MS (ESI): m/z=280.2 [M+1]⁺.

Step E. 2-Methyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine

A mixture of 2-methyl-7-morpholino-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (180 mg, 0.64 mmol) and 10% palladium on carbon (40.0 mg) in ethyl acetate (30 mL) was stirred at 40° C. under hydrogen atmosphere for 2 h. After filtration, the filtrate was concentrated under reduced pressure to afford 2-methyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine as dark grey oil (162 mg), which was used directly to next step without further purification. MS (ESI): m/z=250.2 [M+1]⁺.

Step F. N-(2-Methyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 2-methyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine (162 mg, 0.65 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (127 mg, 0.78 mmol), diisopropyethylamine (236 mg, 1.95 mmol) and (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (508 mg, 0.97 mmol) in DMF (10 mL) was stirred at 25° C. for 4 h. The residue was purified by preparative HPLC (phenomenex, Gemini C18, 21.2×100 mm. 5 um, 110 A; A: acetonitrile 25-35%; B: 0.05% TFAin water) to afford N-(2-methyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 39%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s, 1H), 9.35 (dd, J=1.6, 6.8 Hz, 1H), 8.92 (dd, J=1.6, 4.0 Hz, 1H), 8.66 (s, 1H), 7.87 (s, 1H), 7.33 (dd, J=4.0, 6.8 Hz, 1H), 6.65 (s, 1H), 5.76 (s, 1H), 4.05-4.08 (m, 1H), 3.82-3.84 (m, 4H), 3.26-3.29 (m, 1H), 2.87-2.92 (m, 1H), 2.74-2.76 (m, 4H), 1.26 (d, J=5.6 Hz, 3H). MS (ESI): m/z=395.1 [M+1]⁺.

Example 12. N-(6-(4-(Hydroxymethyl)piperidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A flask equipped with a stir bar was charged with the 6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Example 7, Step A) (127.53 mg, 0.72 mmol) and charged with nitrogen atmosphere. DMF (10 mL) was added and the mixture was cooled 0° C. (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (359.01 mg, 0.69 mmol) was added followed by addition of 2,4,6-trimethylpyridine (83.44 mg, 0.69 mmol). [1-(5-Amino-2,2-dimethyl-3H-benzofuran-6-yl)-4-piperidyl]methanol (Example 4, Step B) (173.0 mg, 0.63 mmol) was added and the ice bath was removed allowing the reaction to stir at room temperature for 3 h. After concentration, the residue was purified by preparative HPLC (Xbridge Prep C18 10 um OBD, 19*250 mm, A: acetonitrile 45-75% and 0.01% NH₃; B: 10 mM ammonium bicarbonate in water) to afford N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide (173.0 mg, 63%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 10.45 (s, 1H), 8.69 (s, 1H), 8.63 (d, J=2 Hz, 1H), 8.59-8.56 (m, 1H), 8.42 (s, 1H), 6.64 (s, 1H), 3.64 (s, 2H), 3.14-3.06 (m, 2H), 3.03 (s, 2H), 2.72-2.63 (m, 2H), 2.46 (s, 2H), 1.83-1.62 (m, 5H), 1.48 (s, 6H). MS (ESI): m/z=436.3 [M+1]⁺.

Example 13. (S)—N-(6-(3-(hydroxymethyl)pyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (S)-(1-(2,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)pyrrolidin-3-yl)methanol

A mixture of 6-fluoro-2,2-dimethyl-5-nitro-3H-benzofuran (Example 3, Step F) (133.0 mg, 0.62 mmol), (S)-pyrrolidin-3-ylmethanol (94.83 mg, 0.94 mmol) and potassium carbonate (215.5 mg, 3.15 mmol) in acetonitrile (30 mL) was stirred at 25° C. for 18 h. After filtration and concentration under reduced pressure, it was afforded [(3S)-1-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)pyrrolidin-3-yl]methanol (254 mg) as a yellow oil, which was used directly to next step without further purification. MS (ESI): m/z=293.2 [M+1]⁺.

Step B. (S)-(1-(5-Amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)pyrrolidin-3-yl)methanol

A mixture of [(3S)-1-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)pyrrolidin-3-yl]methanol (254.0 mg, 0.87 mmol) and 10% palladium on carbon (25 mg) in methanol (10 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. After filtration and concentration, the residue was purified on silica gel chromatography using ethyl acetate:petroleum ether (2:1) as eluting solvents to afford[(3S)-1-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)pyrrolidin-3-yl]methanol (102 mg, 44%) as red oil. MS (ESI): m/z=263.2 [M+1]⁺.

Step C. (S)—N-(6-(3-(Hydroxymethyl)pyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of [(3S)-1-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)pyrrolidin-3-yl]methanol (78.0 mg, 0.30 mmol) and trimethylamine (90.26 mg, 0.89 mmol) in DCM (15 mL) was stirred at 0° C. To the mixture was added the solution of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (Example 3, Step B) (80.98 mg, 0.45 mmol) in DCM (10 mL). The reaction was stirred at 25° C. for 1 h. The residue was purified by preparative HPLC (Xbridge Prep C18 10 um OBD, 19*250 mm, A:acetonitrile 45-75% and 0.01% ammonia; B: 10 mM ammonium bicarbonate in water) to afford (S)—N-(6-(3-(hydroxymethyl)pyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (78.5 mg, 68%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 9.97 (s, 1H), 8.04 (dd, J=2.0, 7.2 Hz, 1H), 8.78 (s, 1H), 8.75 (dd, J=1.6, 4.0 Hz, 1H), 8.20 (s, 1H), 7.02 (dd, J=4.0, 6.8 Hz, 1H), 6.58 (s, 1H), 3.74 (d, J=6.4 Hz, 2H), 3.56-3.22 (m, 2H), 3.02 (s, 2H), 2.97-2.82 (m, 2H), 2.61-2.48 (m, 1H), 2.16-2.05 (m, 1H), 1.84-1.68 (m, 2H), 1.48 (s, 6H). MS (ESI): m/z=408.3 [M+1]⁺.

Example 14. N-(2-Methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 2-(4-Chloro-2-fluorophenyl)-N-methoxy-N-methylacetamide

A mixture of 2-(4-chloro-2-fluoro-phenyl)acetic acid (5.00 g, 26.51 mmol), N,O-dimethylhydroxylamine hydrochloride (7.76 g, 79.54 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.62 g, 39.77 mmol) and 4-dimethylaminopyridine (4.85 g, 39.77 mmol) in DCM (100 mL) was stirred at 20° C. for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:5) as eluting solvents to afford 2-(4-chloro-2-fluoro-phenyl)-N-methoxy-N-methyl-acetamide (4.65 g, 73%) as a colorless oil. MS (ESI): m/z=232.1 [M+1]⁺.

Step B. 1-(4-Chloro-2-fluorophenyl)propan-2-one

To a mixture of 2-(4-chloro-2-fluoro-phenyl)-N-methoxy-N-methyl-acetamide (4.65 g, 20.07 mmol) in DCM (50 mL) at −78° C. under nitrogen gas, was added methyl magnesium bromide (3.0 m in diethyl ether, 8.03 mL, 24.09 mmol) drop-wise. The reaction mixture was stirred at 25° C. for 30 min. The reaction was quenched by addition of 50 mL of water. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified on silica gel chromatography using ethyl acetate:petroleum ether (1:3) as eluting solvents to afford 1-(4-chloro-2-fluoro-phenyl)propan-2-one (2.65 g, 67.2%) as light yellow foam. MS (ESI): m/z=187.1 [M+1]⁺.

Step C. 1-(4-Chloro-2-fluoro-5-nitrophenyl)propan-2-one

To a solution of 1-(4-chloro-2-fluoro-phenyl)propan-2-one (373.22 mg, 2 mmol) in sulfuric acid (1 mL) at 0° C. was added 2-oxohydrazinecarboximidamide 2-oxide (229.0 mg, 2.20 mmol). The resultant mixture was stirred at 0° C. for 2 h. The mixture was poured into ice water and ethyl acetate (50 mL) was added. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo to afford 1-(4-chloro-2-fluoro-5-nitro-phenyl)propan-2-one (400 mg, 78%) as a yellow solid. MS (ESI): m/z=232.1 [M+1]⁺.

Step D. 1-(4-Chloro-2-fluoro-5-nitrophenyl)propan-2-ol

To a solution of 1-(4-chloro-2-fluoro-5-nitro-phenyl)propan-2-one (200 mg, 0.86 mmol) in methanol (4 mL) at 0° C. was added sodium borohydride (65 mg, 1.72 mmol). The resultant mixture was stirred at 0° C. for 1 h. The reaction was quenched by addition of saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with water, dried over sodium sulfate and concentrated in vacuo to afford 1-(4-chloro-2-fluoro-5-nitrophenyl)propan-2-ol (160 mg) as light yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=234.2 [M+1]⁺.

Step E. 6-Chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran

A mixture of 1-(4-chloro-2-fluoro-5-nitro-phenyl)propan-2-ol (105 mg, 0.45 mmol) and potassium tert-butanolate (100 mg, 0.90 mmol) in THE (5 mL) was stirred at 60° C. for 16 h. After cooling to room temperature, the reaction was concentrated in vacuo and the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:5) as eluting solvents to afford 6-chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran (50 mg, 52.1%) as light yellow foam. MS (ESI): m/z=214.2 [M+1]⁺.

Step F. 4-(2-Methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine

A mixture of 6-chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran (100.0 mg, 0.47 mmol) in morpholine (2 mL) was stirred at 110° C. for 16 h in a sealed tube. After cooling to room temperature, the reaction was concentrated in vacuo and the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (5:1) as eluting solvents to afford 4-(2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine (85 mg, 65%) as light yellow solid. MS (ESI): m/z=265.2 [M+1]⁺.

Step G. 2-Methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine

A mixture of 4-(2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine (85 mg, 0.32 mmol) and 10% palladium on carbon (8.5 mg) in methanol (5 mL) was stirred at room temperature under hydrogen atmosphere for 1 h. The solid was filtered off and the filtrate was concentrated under reduced pressure to afford 2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine (55 mg) as a colorless foam, which was used directly to next step without further purification. MS (ESI): m/z=235.2 [M+1]⁺.

Step H. N-(2-Methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine (55 mg, 0.23 mmol) and triethylamine (23 mg, 0.23 mmol) in DCM (4 mL) was stirred at 0° C. A solution of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (Example 3, Step B) (42 mg, 0.23 mmol) in DCM (2 mL) was added. The resultant mixture was stirred at 20° C. for 1 h. Methanol (2 mL) was added. After concentration, the residue was purified by preparative HPLC ((Xbridge Prep C18 10 um OBD, 19*250 mm, A: acetonitrile 45-75% and 0.01% NH₃; B: 10 mM ammonium bicarbonate in water) to afford N-(2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (45 mg, 51%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 10.47 (s, 1H), 8.83 (dd, J=1.6, 6.8 Hz, 1H), 8.78 (s, 1H), 8.77 (dd, J=2, 4.4 Hz, 1H), 8.45 (s, 1H), 7.07 (dd, J=4.0, 6.8 Hz, 1H), 6.67 (s, 1H), 4.97-4.92 (m, 1H), 3.96-3.94 (m, 4H), 3.34 (dd, J=8.8, 15.6 Hz, 1H), 2.93-2.91 (m, 4H), 2.84 (dd, J=7.6, 15.6 Hz, 1H), 1.47 (d, J=6.4 Hz, 3H). MS (ESI): m/z=380.2 [M+1]⁺.

Example 15. (R)—N-(6-(3-(Hydroxymethyl)pyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (R)-(1-(2,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)pyrrolidin-3-yl)methanol

A mixture of 6-fluoro-2,2-dimethyl-5-nitro-3H-benzofuran (141.0 mg, 0.67 mmol), (R)-pyrrolidin-3-ylmethanol (101.3 mg, 1 mmol) and potassium carbonate (230.19 mg, 1.67 mmol) in acetonitrile (30 mL) was stirred at 25° C. for 18 h. After filtration and concentration under reduced pressure, it was afforded [(3R)-1-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)pyrrolidin-3-yl]methanol (272 mg) as a yellow oil, which was used directly to next step without further purification. MS (ESI): m/z=293.2 [M+1]⁺.

Step B. (R)-(1-(5-Amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)pyrrolidin-3-yl)methanol

A mixture of [(3R)-1-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)pyrrolidin-3-yl]methanol (272.0 mg, 0.93 mmol) and 10% palladium on carbon (27 mg) in methanol (10 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. After filtration and concentration under reduced pressure, the residue was purified on silica gel column eluted ethyl acetate/petroleum ether (2:1) to afford[(3R)-1-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)pyrrolidin-3-yl]methanol (108 mg, 43%) as red oil. MS (ESI): m/z=263.2 [M+1]⁺.

Step C. (R)—N-(6-(3-(Hydroxymethyl)pyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of [(3R)-1-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)pyrrolidin-3-yl]methanol (108.0 mg, 0.41 mmol) and trimethylamine (124.97 mg, 1.23 mmol) in DCM (15 mL) was stirred at 0° C. To the mixture was added a solution of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (Example 3, Step B) (112.12 mg, 0.62 mmol) in DCM (10 mL). The reaction was stirred at 25° C. for 1 h. The residue was purified by preparative HPLC (Xbridge Prep C18 10 um OBD, 19*250 mm, A: acetonitrile 45-75% and 0.01% NH₃; B: 10 mM ammonium bicarbonate in water) to afford (R)—N-(6-(3-(hydroxymethyl)pyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (101.3 mg 60%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 9.90 (s, 1H), 8.73 (dd, J=1.2, 6.7 Hz, 1H), 8.70 (s, 1H), 8.68 (dd, J=1.6, 4.4 Hz, 1H), 8.12 (s, 1H), 6.95 (dd, J=4.0, 6.8 Hz, 1H), 6.51 (s, 1H), 3.67 (d, J=6.4 Hz, 2H), 3.28-3.16 (m, 2H), 2.95 (s, 2H), 2.91-2.75 (m, 2H), 2.53-2.42 (m, 1H), 2.08-1.98 (m, 1H), 1.78-1.63 (m, 2H), 1.41 (s, 6H). MS (ESI): m/z=408.2 [M+1]⁺.

Example 16. N-(2-(Hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (1-(2-(Hydroxymethyl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)methanol

A mixture of (6-chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol, piperidin-4-ylmethanol (Intermediate 2) (150 mg, 0.62 mmol) in piperidin-4-ylmethanol (1.42 g, 12.31 mmol) was stirred at 110° C. for 18 h. The mixture was concentrated and the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford (1-(2-(hydroxymethyl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)methanol (100 mg, 50%) as a yellow oil. MS (ESI): m/z=323.1 [M+1]⁺.

Step B. (1-(5-Amino-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)methanol

A mixture of (1-(2-(hydroxymethyl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)methanol (100 mg, 0.31 mmol) and 10% palladium on carbon (25 mg) in methanol (10 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. The solid was filtered. The filtrate was concentrated under reduced pressure to afford (1-(5-amino-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)methanol (80 mg) as light green oil, which was used directly to next step without further purification. MS (ESI): m/z=293.2 [M+1]⁺.

Step C. N-(2-(Hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of (1-(5-amino-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)methanol (80 mg, 0.27 mmol), 6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (69 mg, 0.39 mmol), (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (255 mg, 0.49 mmol) and diisopropyethylamine (118 mg, 0.98 mmol) in DMF (10 mL) was stirred at 25° C. for 3 h. The mixture was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-55%; B: 10 mM ammonium bicarbonate in water) to afford N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide (65 mg, 53%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 8.69 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.57-8.58 (m, 1H), 8.43 (s, 1H), 6.65 (s, 1H), 3.64-3.66 (m, 4H), 3.23 (d, J=16.0 Hz, 1H), 3.07-3.10 (m, 2H), 2.93 (d, J=15.6 Hz, 1H), 2.63-2.69 (m, 2H), 2.45 (s, 3H), 2.00-2.02 (m, 1H), 1.64-1.80 (m, 5H), 1.54 (s, 1H), 1.46 (s, 3H). MS (ESI): m/z=452.2 [M+1]⁺.

Example 17. N-(6-(2,2-Dimethylmorpholino)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (6-(2,2-Dimethylmorpholino)-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (6-chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (Intermediate 2) (130 mg, 0.53 mmol) in 2,2-dimethylmorpholine (1 mL) was stirred at 100° C. for 18 h in a sealed tube. After cooling to room temperature and concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (2:1) as eluting solvents to afford (6-(2,2-dimethylmorpholino)-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (95 mg, 55%) as a yellow solid. MS (ESI): m/z=323.2 [M+1]⁺.

Step B. (5-Amino-6-(2,2-dimethylmorpholino)-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (6-(2,2-dimethylmorpholino)-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (95 mg, 0.29 mmol) and 10% palladium on carbon (9.5 mg) in methanol (10 mL) was stirred at room temperature under hydrogen atmosphere for 1 h. The solid was filtered off and the filtrate was concentrated under reduced pressure to afford (5-amino-6-(2,2-dimethylmorpholino)-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol (55 mg) as a colorless foam, which was used directly to the next step without purification. MS (ESI): m/z=293.2 [M+1]⁺.

Step C. N-(6-(2,2-Dimethylmorpholino)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (34 mg, 0.21 mmol), (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (109 mg, 0.21 mmol) and 2,3,4-trimethylpyridine (46 mg, 0.38 mmol) in DMF (5 mL) was stirred at room temperature for 30 min. (5-Amino-6-(2,2-dimethylmorpholino)-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol (55 mg, 0.19 mmol) was added and stirred for 18 h. To the reaction was added water. The aqueous phase was extracted with ethyl acetate (2×30 mL). The combined phases were washed with brine, dried over sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (20:1) as eluting solvents to afford desired product. The product was further purified by preparative HPLC ((Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 15-30%; B:10 mM ammonium bicarbonate in water)) to afford N-(6-(2,2-dimethylmorpholino)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (48 mg, 58%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.97 (s, 1H), 9.37 (dd, J=1.6, 7.2 Hz, 1H), 8.84 (dd, J=1.6, 4.4 Hz, 1H), 8.70 (s, 1H), 8.20 (s, 1H), 7.33 (dd, J=4.4, 6.8 Hz, 1H), 6.61 (s, 1H), 5.05 (t, J=6.0 Hz, 1H), 3.82-3.74 (m, 2H), 3.48-3.40 (m, 2H), 3.20 (d, J=16 Hz, 1H), 2.83 (d, J=15.6 Hz, 1H), 2.73-2.69 (m, 2H), 2.67-2.62 (m, 2H), 1.35 (s, 6H), 1.34 (s, 3H). MS (ESI): m/z=438.3 [M+1]⁺.

Example 18. N-(6-(3-(Hydroxymethyl)-3-methylpyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (1-(2,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-3-methylpyrrolidin-3-yl)methanol

A mixture of 6-fluoro-2,2-dimethyl-5-nitro-3H-benzofuran (100 mg, 0.47 mmol), (3-methylpyrrolidin-3-yl)methanol hydrochloride (144 mg, 0.95 mmol) and cesium carbonate (308 mg, 0.94 mmol) in DMF (6 mL) was stirred at 25° C. for 18 h. Water was added. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) to afford (1-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-3-methylpyrrolidin-3-yl)methanol (149 mg, 95%) as a yellow oil. MS (ESI): m/z=307.1 [M+1]⁺.

Step B. (1-(5-Amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)-3-methylpyrrolidin-3-yl)methanol

A mixture of (1-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-3-methylpyrrolidin-3-yl)methanol (100 mg, 0.33 mmol) and 10% palladium on carbon (40 mg) in methanol (10 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to afford (1-(5-amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)-3-methylpyrrolidin-3-yl)methanol (90 mg, 49%) as a light green oil. MS (ESI): m/z=277.1 [M+1]⁺.

Step C. N-(6-(3-(Hydroxymethyl)-3-methylpyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of (1-(5-amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)-3-methylpyrrolidin-3-yl)methanol (90 mg, 0.32 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (64 mg, 0.39 mmol) and (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (118 mg, 0.98 mmol) in DMF (10 mL) was stirred at 25° C. for 2 h. After concentration under reduced pressure, the residue was purified by preparative HPLC (Xbridge Prep C18 10 um, 19*250 mm, A:acetonitrile 25-55%; B: 10 mM ammonium bicarbonatein water) to afford N-(6-(3-(hydroxymethyl)-3-methylpyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 36%) as a yellow solid. 1H NMR (400 MHz, DMSO-d₆) δ 9.82 (s, 1H), 8.76-8.80 (m, 3H), 8.12 (s, 1H), 7.01 (dd, J=4.0, 6.8 Hz, 1H), 6.55 (s, 1H), 3.63-3.66 (m, 2H), 3.34-3.39 (m, 1H), 3.10 (d, J=9.2 Hz, 1H), 3.00 (s, 2H), 2.86-2.93 (m, 2H), 2.39 (s, 1H), 1.94-2.01 (m, 1H), 1.60-1.66 (m, 1H), 1.47 (s, 6H), 1.20 (s, 3H). MS (ESI): m/z=422.2 [M+1]⁺.

Example 19. N-[6-[4-(2, 2-Difluoroethyl)piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1, 5-a]pyrimidine-3-carboxamide

Step A. [6-[4-(2, 2-Difluoroethyl)piperazin-1-yl]-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol

The mixture of (6-chloro-2-methyl-5-nitro-3H-benzofuran-2-yl)methanol (120.0 mg, 0.49 mmol), 1-(2, 2-difluoroethyl)piperazine hydrochloride (720.0 mg, 3.86 mmol) and cesium carbonate (820.0 mg, 2.52 mmol) in DMSO (5 mL) was stirred at 90° C. for 5 d. The reaction mixture was diluted with ethyl acetate (30 mL) and water. The organic phase was isolated and dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford[6-[4-(2, 2-difluoroethyl)piperazin-1-yl]-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol (65 mg, 37%) as a yellow oil. MS (ESI): m/z=358.2 [M+1]⁺.

Step B. [5-Amino-6-[4-(2, 2-difluoroethyl)piperazin-1-yl]-2-methyl-3H-benzofuran-2-yl]methanol

A mixture of [6-[4-(2, 2-difluoroethyl)piperazin-1-yl]-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol (65.0 mg, 0.18 mmol) and 10% palladium on carbon (25.0 mg) in methanol (8 mL) was stirred under hydrogen atmosphere at 25° C. for 1 h. After filtration and concentration, it was afforded [5-amino-6-[4-(2, 2-difluoroethyl)piperazin-1-yl]-2-methyl-3H-benzofuran-2-yl]methanol (55 mg, 92%) as a brown oil, which was used directly to the next step without purification. MS (ESI): m/z=328.1 [M+1]⁺.

Step C. N-[6-[4-(2, 2-Difluoroethyl)piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1, 5-a]pyrimidine-3-carboxamide

To the mixture of pyrazolo[1, 5-a]pyrimidine-3-carboxylic acid (44.0 mg, 0.27 mmol) and diisopropyethylamine (0.08 mL, 0.51 mmol) in DMF (2 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (130.0 mg, 0.34 mmol). The mixture was stirred at 25° C. for 30 min. To the mixture was added a solution of [5-amino-6 [4-(2, 2-difluoroethyl)piperazin-1-yl]-2-methyl-3H-benzofuran-2-yl]methanol (55.0 mg, 0.17 mmol) in DMF (2 mL) and the mixture was stirred at 25° C. for 3 h. After concentration, the residue was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-55%; B: 10 mM ammonium bicarbonate in water) to afford N-[6-[4-(2, 2-difluoroethyl)piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (36.4 mg, 46%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H), 9.37 (dd, J=2.0, 7.2 Hz, 1H), 8.95 (dd, J=1.6, 4.0 Hz, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 7.35 (dd, J=4, 6.8 Hz, 1H), 6.70 (s, 1H), 6.20 (tt, J=4.4, 14 Hz, 1H), 5.05 (t, J=5.6 Hz, 1H), 3.49-3.37 (m, 2H), 3.19 (d, J=16 Hz, 1H), 2.94-2.72 (m, 11H), 1.34 (s, 3H). MS (ESI): m/z=473.2 [M+1]⁺.

Example 20. Cis-N-[2,2-dimethyl-6-[2-(methylaminomethyl)-1, 3-dioxan-5-yl]-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. Cis-2-trimethylsilylethyl N-[[5-(2, 2-dimethyl-5-nitro-3H-benzofuran-6-yl)-1, 3-dioxan-2-yl]methyl]carbamate

The mixture of 2-(2, 2-dimethyl-5-nitro-3H-benzofuran-6-yl)propane-1, 3-diol (80.0 mg, 0.30 mmol), 2-trimethylsilylethyl N-(2, 2-dimethoxyethyl)carbamate (223.99 mg, 0.90 mmol) and 4-toluene sulfonic acid (3.0 mg, 0.02 mmol) in toluene (5 mL) was stirred at 110° C. in a sealed tube for 72 h. The mixture was neutralized with triethylamine. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:5) as eluting solvents to afford cis-2-trimethylsilylethyl N-[[5-(2, 2-dimethyl-5-nitro-3H-benzofuran-6-yl)-1, 3-dioxan-2-yl]methyl]carbamate (40 mg, 30%) as a yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 7.83 (s, 1H), 7.57 (s, 1H), 4.90 (brs, 1H), 4.70 (t, J=4.4 Hz, 1H), 4.24-4.06 (m, 6H), 3.40-3.37 (m, 1H), 3.33-3.29 (m, 2H), 3.01 (s, 2H), 1.49 (s, 6H), 0.94 (t, J=8.4 Hz, 2H), 0.00 (s, 9H). MS (ESI): m/z=475.1 [M+Na]⁺.

Step B. Cis-2-trimethylsilylethyl-N-[[5-(2, 2-dimethyl-5-nitro-3H-benzofuran-6-yl)-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate

To the mixture of cis-2-trimethylsilylethyl N-[[5-(2, 2-dimethyl-5-nitro-3H-benzofuran-6-yl)-1, 3-dioxan-2-yl]methyl]carbamate (45.0 mg, 0.10 mmol) in DMF (2 mL) was added sodium hydride (30.0 mg, 0.75 mmol) at 0° C. and stirred for 10 min. To the mixture was added methyl iodide (0.02 mL, 0.28 mmol) and reaction was stirred at 20° C. for 1 h. The mixture was poured into water. The aqueous phase was extracted with ethyl acetate (50 mL). The organics washed with water, brine and dried over sodium sulfate before concentration under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:5) as eluting solvents to afford cis-2-trimethylsilylethyl N-[[5-(2, 2-dimethyl-5-nitro-3H-benzofuran-6-yl)-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate (37 mg, 80%) as a yellow oil. MS (ESI): m/z=489.1 [M+Na]⁺.

Step C. Cis-2-trimethylsilylethyl N-[[5-(5-amino-2, 2-dimethyl-3H-benzofuran-6-yl)-1, 3-dioxan-2-yl]methyl]-N-methyl-carbamate

The mixture of cis-2-trimethylsilylethyl N-[[5-(2, 2-dimethyl-5-nitro-3H-benzofuran-6-yl)-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate (37.0 mg, 0.08 mmol) and 10% palladium on carbon (15.0 mg) in methanol (8 mL) was stirred under hydrogen atmosphere at 20° C. for 1 h. After filtration and concentration, it was afforded cis-2-trimethylsilylethyl-N-[[5-(5-amino-2, 2-dimethyl-3H-benzofuran-6-yl)-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate (33 mg, 95%) as a colorless oil, which was used directly to next step without further purification. MS (ESI): m/z=437.2 [M+1]⁺.

Step D. Cis-2-trimethylsilylethyl-N-[[5-[2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate

To the mixture of cis-2-trimethylsilylethyl-N-[[5-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate (32.0 mg, 0.07 mmol), triethylamine (25.0 mg, 0.25 mmol) and 4-dimethylaminopyridine (2.0 mg, 0.02 mmol) in THE (5 mL) was added pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (20.0 mg, 0.11 mmol) and stirred at 20° C. for 1 h. To the mixture was added methanol (2 mL) then the mixture was concentrated to dryness. The residue was purified by silica gel chromatography using methanol:DCM (1:20) as eluting solvents to afford cis-2-trimethylsilylethyl-N-[[5-[2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate (17 mg, 40%) as a yellow oil. MS (ESI): m/z=604.2 [M+Na]⁺.

Step E. Cis-N-[2,2-dimethyl-6-[2-(methylaminomethyl)-1,3-dioxan-5-yl]-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To the mixture of cis-2-trimethylsilylethyl N-[[5-[2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]-1,3-dioxan-2-yl]methyl]-N-methyl-carbamate (17.0 mg, 0.03 mmol) in DCM (0.40 mL) was added trifluoroacetic acid (200.0 uL) at 0° C. and stirred for 1 h. The mixture was neutralized with triethylamine. After concentration, the residue was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um, A: acetonitrile 25-55%; B: 10 mM ammonium bicarbonate in water) to afford cis-N-[2,2-dimethyl-6-[2-(methylaminomethyl)-1,3-dioxan-5-yl]-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (7.9 mg, 62%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.31 (s, 1H), 8.84 (dd, J=1.6, 6.8 Hz, 1H), 8.74 (s, 1H), 8.65 (dd, J=1.6, 4.0 Hz, 1H), 7.53 (s, 1H), 7.50 (s, 1H), 7.05 (dd, J=4.4, 7.2 Hz, 1H), 4.81 (t, J=5.2 Hz, 1H), 4.31 (d, J=11.6 Hz, 2H), 4.18 (dd, J=3.2, 11.6 Hz, 2H), 3.04 (s, 2H), 2.98-2.93 (m, 1H), 2.81 (d, J=4.8 Hz, 2H), 2.46 (s, 3H), 1.50 (s, 6H). MS (ESI): m/z=438.3 [M+1]⁺.

Example 21. N-(2-Ethyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 1-(4-Chloro-2-fluorophenyl)-2-methylbutan-2-ol

To a solution of 1-(4-chloro-2-fluoro-phenyl)propan-2-one (300 mg, 1.61 mmol) in THF (10 mL) was added ethyl magnesium bromide (1 m in THF, 1.93 mL, 1.93 mmol) drop-wise at −78° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated ammonium chloride solution. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried over sodium sulfate and concentrated to afford 1-(4-chloro-2-fluoro-phenyl)-2-methyl-butan-2-ol (300 mg) as a colorles soil, which was used directly to next step without further purification. MS (ESI): m/z=199.1 [M-OH]⁺.

Step B. 6-Chloro-2-ethyl-2-methyl-2,3-dihydrobenzofuran

A mixture of 1-(4-chloro-2-fluoro-phenyl)-2-methyl-butan-2-ol (300 mg, 1.38 mmol) and potassium tert-butanolate (387 mg, 3.46 mmol) in THF (20 mL) was stirred at 65° C. for 3 h. Water was added and the aqueous was extracted with ethyl acetate (20 mL). The organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica chromatography using ethyl acetate:petroleum ether (1:100) to afford 6-chloro-2-ethyl-2-methyl-3H-benzofuran (132 mg, 49%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.01 (d, J=8.0 Hz, 1H), 6.77 (dd, J=1.6, 7.6 Hz, 1H), 6.71 (d, J=1.6 Hz, 1H), 3.02 (d, J=15.6 Hz, 1H), 2.86 (d, J=15.6 Hz, 1H), 1.74 (t, J=7.2 Hz, 2H), 1.41 (s, 3H), 0.95 (q, J=7.2 Hz, 3H).

Step C. 4-(2-Ethyl-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine

A mixture of 6-chloro-2-ethyl-2-methyl-3H-benzofuran (132 mg, 0.67 mmol) in DCM (10 mL) was added nitric acid (0.5 mL) drop-wise and the mixture was stirred for 30 min. The mixture was poured into ice water. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure to afford 6-chloro-2-ethyl-2-methyl-5-nitro-3H-benzofuran (126 mg, 67%) as black solid. MS (ESI): m/z=242.1 [M+1]⁺.

Step D. 4-(2-Ethyl-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine

A mixture of 6-chloro-2-ethyl-2-methyl-5-nitro-3H-benzofuran (132 mg, 0.55 mmol) in morpholine (2 mL) was stirred at 120° C. for 18 h. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (15:100) to afford 4-(2-ethyl-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine (106 mg, 42%) as a yellow oil. MS (ESI): m/z=293.2 [M+1]⁺.

Step E. 2-Ethyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine

A mixture of 4-(2-ethyl-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine (106 mg, 0.35 mmol) and 10% palladium on carbon (40 mg) in methanol (10 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to afford (2-ethyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine (77 mg, 68%) as light green oil. MS (ESI): m/z=263.3 [M+1]⁺.

Step F. N-(2-Ethyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a mixture of 2-ethyl-2-methyl-6-morpholino-3H-benzofuran-5-amine (80 mg, 0.30 mmol) and triethylamine (92 mg, 0.91 mmol) in DCM (15 mL) was added pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (Example 3, Step B) (83 mg, 0.46 mmol). The mixture was stirred at room temperature for 3 h, concentrated and purified by preparative HPLC (Xbridge Prep C18 10 um OBD, 19*250 mm, A: acetonitrile 45-75% and 0.01% ammonia; B: 10 mM ammonium bicarbonate in water) to yield N-(2-ethyl-2-methyl-6-morpholino-3H-benzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid (70 mg, 56%). ¹HNMR (400 MHz, CDCl₃): δ 10.46 (s, 1H), 8.83 (dd, J=1.6, 6.8 Hz, 1H), 8.78 (s, 1H), 8.75 (dd, J=2.0, 4.0 Hz, 1H), 8.42 (s, 1H), 7.06 (dd, J=1.6, 6.8 Hz, 1H), 3.94-3.96 (m, 4H), 3.09 (d, J=15.2 Hz, 1H), 2.94 (d, J=15.2 Hz, 1H) 2.91-2.93 (m, 4H), 1.78 (q, J=7.6 Hz, 2H), 0.98 (t, J=7.2 Hz, 3H). MS (ESI): m/z=408.2 [M+1]⁺.

Example 22. N-(2-Cyclopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 1-(4-Chloro-2-fluorophenyl)-2-cyclopropylpropan-2-ol

A mixture of 1-(4-chloro-2-fluoro-phenyl)propan-2-one (300 mg, 1.61 mmol) in THF (10 mL) was added drop-wise cyclopropyl magnesium bromide (0.5 M in THF, 3.86 mL, 1.93 mmol) at 78° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL). The organic phase was dried over sodium sulfate and concentrated to afford 1-(4-chloro-2-fluorophenyl)-2-cyclopropylpropan-2-ol as light oil (350 mg), which was used directly to next step without further purification. MS (ESI): m/z=211.1 [M-OH]+

Step B. 6-Chloro-2-cyclopropyl-2-methyl-2,3-dihydrobenzofuran

A mixture of 1-(4-chloro-2-fluorophenyl)-2-cyclopropylpropan-2-ol (317 mg, 1.38 mmol) and potassium tert-butanolate (387 mg, 3.46 mmol) in THF (20 mL) was stirred at 65° C. for 3 h. Water was added and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:100) to afford 6-chloro-2-cyclopropyl-2-methyl-2,3-dihydrobenzofuran (82 mg, 28%) as light oil. ¹H NMR (400 MHz, CDCl₃) δ 7.00 (d, J=7.6 Hz, 1H), 6.77 (dd, J=1.6, 8.0 Hz, 1H), 6.69 (d, J=1.6 Hz, 1H), 3.02 (d, J=15.6 Hz, 1H), 2.90 (d, J=15.6 Hz, 1H), 1.42 (s, 3H), 1.11-1.16 (m, 1H), 0.44-0.49 (m, 3H), 0.33-0.37 (m, 1H).

Step C. 6-Chloro-2-cyclopropyl-2-methyl-5-nitro-2,3-dihydrobenzofuran

To a solution of 6-chloro-2-cyclopropyl-2-methyl-2,3-dihydrobenzofuran (82 mg, 0.38 mmol) in DCM (10 mL) was added drop-wise nitric acid (0.5 mL) at 25° C. and the mixture was stirred for 30 min. The mixture was poured into ice water and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure to afford 6-chloro-2-cyclopropyl-2-methyl-5-nitro-2,3-dihydrobenzofuran as black solid (100 mg, crude). MS (ESI): m/z=254.1 [M+1]⁺.

Step D. 4-(2-Cyclopropyl-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine

A mixture of 6-chloro-2-cyclopropyl-2-methyl-5-nitro-2,3-dihydrobenzofuran (100 mg, 0.39 mmol) in morpholine (2 mL) was stirred at 120° C. for 18 h. The mixture was concentrated and the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (15:100) as eluting solvents to afford 4-(2-cyclopropyl-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine (130 mg, 49%) as a yellow oil. MS (ESI): m/z=305.1 [M+1]⁺.

Step E. 2-Cyclopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine

A mixture of 4-(2-cyclopropyl-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine (130 mg, 0.35 mmol) and 10% palladium on carbon (40 mg) in methanol (10 mL) was stirred at 25° C. under H2 atmosphere for 1 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to afford 2-cyclopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine (63 mg) as light green oil, which was used directly to next step without further purification. MS (ESI): m/z=275.2 [M+1]⁺.

Step F. N-(2-Cyclopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 2-cyclopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine (63 mg, 0.23 mmol) and triethylamine (70 mg, 0.69 mmol) in DCM (15 mL) was added pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (Example 3, Step B) (63 mg, 0.34 mmol). The mixture was stirred at 25° C. for 3 h. After concentration, the residue was purified by preparative HPLC (Xbridge Prep C18 10 um OBD, 19*250 mm, A: acetonitrile 45-75% and 0.01% NH₃; B:10 mM ammonium bicarbonate in water) to afford N-(2-cyclopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid (30 mg, 31%). ¹HNMR (400 MHz, CDCl₃): δ 10.45 (s, 1H), 8.82 (dd, J=2.0, 7.2 Hz, 1H), 8.78 (s, 1H), 8.76 (dd, J=2.0, 4.0 Hz, 1H), 8.40 (s, 1H), 7.06 (d, J=4.0, 6.8 Hz), 6.63 (s, 1H), 3.93-3.95 (m, 4H), 3.12 (d, J=16.4 Hz, 1H), 2.96 (d, J=16.4 Hz, 1H), 2.89-2.92 (m, 4H), 1.43 (s, 3H), 1.15-1.19 (m, 1H), 0.40-0.49 (m, 4H). MS (ESI): m/z=420.2 [M+1]⁺.

Example 23. N-(2-(Dimethylcarbamoyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 3-(2,4-Difluorophenyl)-2-hydroxy-2-methyl-propanoate

To a solution of magnesium (1206.62 mg, 50.28 mmol) and iodine (89.38 mg, 0.35 mmol) in diethyl ether (50 mL) at reflux was added 2,4-difluorobenzyl bromide (4140.0 mg, 20 mmol) drop-wise and the resulting mixture was stirred for 30 min. This solution was then added to a solution of methyl pyruvate (2055.73 mg, 20.14 mmol) in diethyl ether (50 mL) at −78° C. followed by 2 h at room temperature. Saturated ammonium chloride and ethyl acetate (200 mL) were added. The organic phase was separated and dried over ethyl acetate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:20 to 1:10) as eluting solvent to afford methyl 3-(2,4-difluorophenyl)-2-hydroxy-2-methyl-propanoate (4000 mg, 87%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.25-7.10 (m, 1H) 6.84-6.70 (m, 2H), 3.75 (s, 3H), 3.09 (d, J=14 Hz, 1H), 2.92 (d, d, J=13.6 Hz, 1H), 1.47 (s, 3H).

Step B. 6-Fluoro-2-methyl-2,3-dihydrobenzofuran-2-carboxylic acid

A mixture of methyl 3-(2,4-difluorophenyl)-2-hydroxy-2-methyl-propanoate (4000.0 mg, 17.38 mmol) and potassium tert-butanolate (4874.2 mg, 43.44 mmol) was stirred in THE (180 mL) at 65° C. for 18 h. After cooling to room temperature, the reaction was acidified to pH 3 with 1N HCl. Ethyl acetate (200 mL) was added and the organic phase was separated, dried over sodium sulfate and concentration. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (3:2) to afford 6-fluoro-2-methyl-2,3-dihydrobenzofuran-2-carboxylic acid (650 mg, 18%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.11-6.98 (m, 1H), 6.66-6.50 (m, 2H), 3.60 (d, J=16 Hz, 1H), 3.14 (d, J=16 Hz), 1.77 (s, 3H).

Step C. 6-Fluoro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-carboxylic acid

To a solution of 6-fluoro-2-methyl-3H-benzofuran-2-carboxylic acid (500.0 mg, 2.55 mmol) in DCM (20 mL) was added fuming nitric acid (845.23 mg, 12.74 mmol) drop-wise at 20° C. The mixture was stirred for 30 min. The mixture was poured into ice water. The aqueous phase was extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with water, dried over sodium sulfate and concentrated in vacuo to afford 6-fluoro-2-methyl-5-nitro-3H-benzofuran-2-carboxylic acid (580 mg) as light yellow foam, which was used directly to next step without further purification. MS (ESI): m/z=242.0 [M+1]⁺.

Step D. 2-Methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carboxylic acid

A mixture of 6-fluoro-2-methyl-5-nitro-3H-benzofuran-2-carboxylic acid (280.00 mg, 1.16 mmol), morpholine (202.29 mg, 2.32 mmol) and cesium carbonate (1513.12 mg, 4.64 mmol) in acetonitrile (5 mL) was stirred at 20° C. for 16 h. The mixture was filtered and the filtrate was concentrated in vacuo to obtain 2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-carboxylic acid (300 mg) as a brown oil, which was used directly to next step without further purification. MS (ESI): m/z=309.1 [M+1]⁺.

Step E. N,N, 2-Trimethyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carboxamide

A mixture of 2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-carboxylic acid (120.0 mg, 0.39 mmol), N,N-dimethylamine hydrochloride (63.48 mg, 0.78 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (296.0 mg, 0.78 mmol) and diisopropyethylamine (201.10 mg, 1.56 mmol) in DMF (5 mL) was stirred at 20° C. for 2 h. Water was added and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with water, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) to afford N,N, 2-trimethyl-6-morpholino-5-nitro-3H-benzofuran-2-carboxamide (100 mg, 69%) as light yellow solid. MS (ESI): m/z=336.2 [M+1]⁺.

Step F. 5-Amino-N,N, 2-trimethyl-6-morpholino-2,3-dihydrobenzofuran-2-carboxamide

A mixture of N,N, 2-trimethyl-6-morpholino-5-nitro-3H-benzofuran-2-carboxamide (100.00 mg, 0.30 mmol) and 10% palladium on carbon (10 mg) in methanol (10 mL) was stirred at room temperature under hydrogen atmosphere for 1 h. The reaction was filtered and the filtrate was concentrated under reduced pressure to afford 5-amino-N,N, 2-trimethyl-6-morpholino-3H-benzofuran-2-carboxamide (100 mg, crude) as a colorless oil, which was used directly to next step without further purification. MS (ESI): m/z=306.2 [M+1]⁺.

Step G. N-(2-(Dimethylcarbamoyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 5-amino-N,N, 2-trimethyl-6-morpholino-3H-benzofuran-2-carboxamide (100.00 mg, 0.33 mmol) and triethylamine (66.27 mg, 0.65 mmol) in DCM (5 mL) was stirred at 0° C. The solution of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (Example 3, Step B) (71.36 mg, 0.39 mmol) in DCM (5 mL) was added drop-wise. The mixture was stirred at 20° C. for 1 h. Methanol (3 mL) was added. After concentration, the residue was purified by preparative HPLC ((Xbridge Prep C18 10 um OBD, 19*250 mm, A: acetonitrile 50-70% and 0.01% NH₃; B:10 mM ammonium bicarbonate in water) to afford N-[2-(dimethylcarbamoyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (60 mg, 41%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.46 (s, 1H), 9.38 (d, J=6.8 Hz, 1H), 8.95 (d, J=1.6, 4 Hz, 1H), 8.69 (s, 1H), 8.35 (s, 1H), 7.35 (dd, J=4.4, 6.8 Hz, 1H), 6.85 (s, 1H), 3.90 (d, J=16 Hz, 1H), 3.86-3.83 (m, 4H), 3.16 (s, 3H), 3.05 (d, J=16.4 Hz, 1H), 2.88 (s, 3H), 2.84-2.81 (m, 4H), 1.58 (s, 3H). MS (ESI): m/z=451.2 [M+1]⁺.

Example 24. N-[6-[4-(1-Amino-2,2,2-trifluoro-ethyl)-1-piperidyl]-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. tert-Butyl 4-((4-methoxybenzylimino)methyl)piperidine-1-carboxylate

The mixture of tert-butyl 4-formyl-1-piperidinecarboxylate (1.07 g, 5 mmol) 4-methoxybenzylamine (685.9 mg, 5 mmol) 4 Å molecular sieves (1.00 g, 5 mmol) in methanol (10 mL) was stirred for 18 h. After filtration and concentration, it was afforded tert-butyl 4-((4-methoxybenzylimino)methyl)piperidine-1-carboxylate (1.66 g) as a colorless oil, which used directly to next step without further purification. MS (ESI): m/z=333.3 [M+1]⁺.

Step B. tert-Butyl 4-(2,2,2-trifluoro-1-(4-methoxybenzylamino)ethyl)piperidine-1-carboxylate

To the mixture of tert-butyl 4-[(Z)-(4-methoxyphenyl)methyliminomethyl]piperidine-1-carboxylate (1.66 g, 5 mmol), (trifluoromethyl)trimethylsilane (1.07 g, 7.5 mmol) and potassium hydrogen fluoride (585.0 mg, 7.5 mmol) in acetonitrile (10 mL) was added trifluoroacetic acid (427.5 mg, 3.75 mmol) drop-wise at room temperature. The mixture was stirred at room temperature for 18 h. Water was added and the aqueous phase was extracted by ethyl acetate (3×20 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:10 to 1:6) as eluting solvents to afford tert-butyl 4-[2,2,2-trifluoro-1-[(4-methoxyphenyl)methylamino]ethyl]piperidine-1-carboxylate (1.08 g, 50%) as a colorless oil. MS (ESI): m/z=303.2 [M-100]⁺

Step C. 2,2,2-Trifluoro-N-[(4-methoxyphenyl)methyl]-1-(4-piperidyl)ethanamine trifluoroacetic acid salt

To a solution of tert-butyl 4-[2,2,2-trifluoro-1-[(4-methoxyphenyl)methylamino]ethyl]piperidine-1-carboxylate (150 mg, 0.37 mmol) in DCM (5 mL) was added 2,2,2-trifluoroacetic acid (0.3 mL) and the resulting mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated to dryness to afford 2,2-trifluoro-N-[(4-methoxyphenyl)methyl]-1-(4-piperidyl)ethanamine (100 mg) as the trifluoroacetic acid salt, which was used directly to the next step without further purification. MS (ESI): m/z=303.1 [M+1]⁺.

Step D. 1-[1-(2,2-Dimethyl-5-nitro-3H-benzofuran-6-yl)-4-piperidyl]-2,2,2-trifluoro-N-[(4-methoxyphenyl)methyl]ethanamine

A mixture of 6-fluoro-2,2-dimethyl-5-nitro-3H-benzofuran (100 mg, 0.47 mmol), 2,2,2-trifluoro-N-[(4-methoxyphenyl)methyl]-1-(4-piperidyl)ethanamine trifluoroacetic acid salt (170 mg, 0.56 mmol) and cesium carbonate (490 mg, 1.5 mmol) in DMF (5 mL) was stirred at 25° C. for 18 h. Then water was added and the aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate:petroleum ether (0-25%) as eluting solvents to afford 1-[1-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-4-piperidyl]-2,2,2-trifluoro-N-[(4-methoxyphenyl)methyl]ethanamine (190 mg, 74%) as a yellow oil. MS (ESI): m/z=494.3 [M+1]⁺.

Step E. tert-Butyl 4-[(4-amino-3-pyridyl)oxy]piperidine-1-carboxylate

A mixture of 1-[1-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-4-piperidyl]-2,2,2-trifluoro-N-[(4-methoxyphenyl)methyl]ethanamine (180 mg, 0.36 mmol), iron powder (420 mg, 7.52 mmol) and ammonium chloride (396 mg, 7.4 mmol) in ethanol (10 mL) and water (2 mL) was stirred at 80° C. for 2 h. After filtration and concentration, the residue was purified by silica gel column chromatography using ethyl acetate:petroleum ether (20%-50%) to afford tert-butyl 4-[(4-amino-3-pyridyl)oxy]piperidine-1-carboxylate as a yellow solid (110 mg, 97%). MS (ESI): m/z=464.3 [M+1]⁺.

Step F. N-(2,2-Dimethyl-6-(4-(2,2,2-trifluoro-1-((4-methoxybenzyl)amino)ethyl)piperidin-1-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 2,2-dimethyl-6-[4-[2,2,2-trifluoro-1-[(4-methoxyphenyl)methylamino]ethyl]-1-piperidyl]-3H-benzofuran-5-amine (105 mg, 0.23 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (60 mg, 0.37 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (140 mg, 0.37 mmol) and diisopropyethylamine (165 mg, 1.28 mmol) in DMF (5 mL) was stirred at 25° C. for 3 h. The mixture was purified by preparative HPLC to afford N-[2,2-dimethyl-6-[4-[2,2,2-trifluoro-1-[(4-methoxyphenyl)methylamino]ethyl]-1-piperidyl]-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (95 mg, 66%) as a yellow solid. MS (ESI): m/z=609.3 [M+1]⁺.

Step G. N-[6-[4-(1-Amino-2,2,2-trifluoro-ethyl)-1-piperidyl]-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of N-[2,2-dimethyl-6-[4-[2,2,2-trifluoro-1-[(4-methoxyphenyl) methylamino]ethyl]-1-piperidyl]-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (90 mg, 0.15 mmol) and 2,2,2-trifluoroacetic acid (1.5 mL) was stirred at 85° C. for 1 h. The reaction was basified to pH 8 with 2N ammonia in methanol. Upon concentration, the residue was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A:acetonitrile 25-55%; B: 10 mM ammonium bicarbonate in water) to afford N-[6-[4-(1-amino-2,2,2-trifluoro-ethyl)-1-piperidyl]-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (29.4 mg, 41%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H), 9.35 (dd, J=1.6, 7.2 Hz, 1H), 9.13 (dd, J=1.6, 4.4 Hz, 1H), 8.67 (s, 1H), 8.33 (s, 1H), 7.30 (dd, J=4.4, 7.2 Hz, 1H), 6.69 (s, 1H), 3.24-3.12 (m, 1H), 3.03-2.90 (m, 4H), 2.74-2.56 (m, 2H), 2.10-1.87 (m, 3H), 1.84-1.55 (m, 4H), 1.408 (s, 6H). MS (ESI): m/z=489.3 [M+1]⁺.

Example 25. N-(2-(Methoxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (2-Methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (6-chloro-2-methyl-5-nitro-3H-benzofuran-2-yl)methanol (Intermediate 2) (310.0 mg, 1.27 mmol) and morpholine (10 mL) was stirred at 120° C. for 18 h. The reaction was concentrated to dryness. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:4 to 2:3) to afford (2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-yl)methanol (239 mg, 64%) as an orange oil. MS (ESI): m/z=295.1 [M+1]⁺.

Step B. 4-(2-(Methoxymethyl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine

To a solution of (2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-yl)methanol (81.0 mg, 0.28 mmol) in THE (3 mL) was added sodium hydride (9.91 mg, 0.41 mmol) at 0° C. The mixture was stirred for 20 min. Methyl iodide (87.9 mg, 0.62 mmol) was added and the mixture was warmed to room temperature while stirring for 18 h. Ethyl acetate (10 mL) and saturated ammonium chloride were added. The organic phase was separated and dried over sodium sulfate before concentration to afford 4-[2-(methoxymethyl)-2-methyl-5-nitro-3H-benzofuran-6-yl]morpholine (121 mg), which was used directly to next step without further purification. MS (ESI): m/z=309.1 [M+1]⁺.

Step C. 2-(Methoxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine

A mixture of [1-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-4-piperidyl]methanol (121.0 mg, 0.39 mmol) and 10% palladium on carbon (10 mg) in methanol (30 mL) was stirred at 25° C. under hydrogen atmosphere for 2 h. The reaction was filtered and the filtrate was concentrated in vacuo to afford[1-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)-4-piperidyl]methanol (106 mg) as a red oil, which was used directly to next step without further purification. MS (ESI): m/z=279.3[M+1]⁺.

Step D. N-(2-(Methoxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 2-(methoxymethyl)-2-methyl-6-morpholino-3H-benzofuran-5-amine (106.0 mg, 0.38 mmol) in DMF (10 mL) under nitrogen atmosphere at 0° C. was added (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (218.4 mg, 0.42 mmol) followed by 2,4,6-trimethylpyridine (50.76 mg, 0.42 mmol). Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (71.44 mg, 0.44 mmol) was then introduced and the ice bath was removed allowing the reaction to stir at room temperature for 18 h. After concentration, the residue was purified by preparative HPLC (Xbridge Prep C18 10 um OBD, 19*250 mm, A:acetonitrile 45-75% and 0.01% NH₃; B: 10 mM ammonium bicarbonate in water) to afford[1-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)-4-piperidyl]methanol (34.9 mg, 22%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 10.47 (s, 1H), 8.61 (dd, J=1.6, 5.6 Hz, 1H), 8.78 (s, 1H), 8.75 (dd, J=1.6, 3.6 Hz, 1H), 8.42 (s, 1H), 7.07 (dd, J=3.6, 5.6 Hz, 1H), 6.69 (s, 1H), 3.98-3.90 (m, 4H), 3.47 (s, 2H), 3.43 (s, 3H), 3.22 (d, J=12.8 Hz, 1H), 2.95-2.88 (m, 5H), 1.48 (s, 3H). MS (ESI): m/z=424.1 [M+1]⁺.

Example 26. N-[6-(4,4-Difluoro-1-piperidyl)-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. [6-(4,4-Difluoro-1-piperidyl)-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol

The mixture of (6-chloro-2-methyl-5-nitro-3H-benzofuran-2-yl)methanol (Intermediate 2) (104.0 mg, 0.43 mmol), 4,4-difluoropiperidine hydrochloride (670.0 mg, 4.25 mmol) and cesium carbonate (920.0 mg, 2.82 mmol) in DMSO (5 mL) was stirred at 90° C. for 16 h. The mixture was poured into water and the aqueous phase was extracted with ethyl acetate (150 mL). The organic phase was washed with water and brine and dried over sodium sulfate before concentration to dryness. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:3) as eluting solvents to afford[6-(4, 4-difluoro-1-piperidyl)-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol (100 mg, 71%) as a brown oil. MS (ESI): m/z=329.1 [M+1]⁺.

Step B. [5-Amino-6-(4,4-difluoro-1-piperidyl)-2-methyl-3H-benzofuran-2-yl]methanol

The mixture of [6-(4, 4-difluoro-1-piperidyl)-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol (63.0 mg, 0.19 mmol) and 10% palladium on carbon (28.0 mg) in methanol (8 mL) was stirred under hydrogen atmosphere at 20° C. for 1 h. After filtration and concentration, it was afforded [5-amino-6-(4, 4-difluoro-1-piperidyl)-2-methyl-3H-benzofuran-2-yl]methanol (55 mg) as a brown oil, which was used directly in the next step without purification. MS (ESI): m/z=299.1 [M+1]⁺.

Step C. N-[6-(4,4-Difluoro-1-piperidyl)-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To the mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (45.0 mg, 0.28 mmol) and diisopropyethylamine (0.09 mL, 0.56 mmol) in DMF (2 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (141.0 mg, 0.37 mmol) and the mixture was stirred at 20° C. for 30 min. To the mixture was added the solution of [5-amino-6-(4, 4-difluoro-1-piperidyl)-2-methyl-3H-benzofuran-2-yl]methanol (55.0 mg, 0.18 mmol) in DMF (2 mL) and the mixture was stirred at 20° C. for 16 h. After concentration, the residue was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 5-75%; B: 10 mM ammonium bicarbonate in water) to afford N-[6-(4, 4-difluoro-1-piperidyl)-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (35 mg, 43%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 9.39 (dd, J=2.0, 6.8 Hz, 1H), 8.75 (dd, J=2.0, 4.4 Hz, 1H), 8.70 (s, 1H), 8.32 (s, 1H), 7.37 (dd, J=4.0, 6.8 Hz, 1H), 6.73 (s, 1H), 5.05 (t, J=6.0 Hz, 1H), 3.49-3.37 (m, 2H), 3.20 (d, J=16.0 Hz, 1H), 2.98-2.90 (m, 4H), 2.83 (d, J=16.0 Hz, 1H), 2.34-2.14 (m, 4H), 1.34 (s, 3H). MS (ESI): m/z=444.1 [M+1]⁺.

Examples 27 and 28. (R)—N-(3-hydroxy-3-methyl-7-morpholinochroman-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(3-hydroxy-3-methyl-7-morpholinochroman-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 2-Chloro-4-((2-methylallyl)oxy)-1-nitrobenzene

To a solution of 3-chloro-4-nitrophenol (25.2 g, 145 mmol) in acetonitrile (184 mL) was added 3-bromo-2-methylpropene (16.1 mL, 159 mmol) and potassium carbonate (28.0 g, 203 mmol). The reaction mixture was stirred at 55° C. for 18 h. The mixture was diluted with isopropyl acetate, filtered and the precipitate was washed with isopropyl acetate and dichloromethane. The combined filtrates were concentrated under reduced pressure and purified by silica gel chromatography eluting using (3:1) isopropyl acetate/MeOH in heptanes (0-40%) as eluting solvents to afford the title compound as a light yellow oil (32.712 g, 99%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (d, J=9.1 Hz, 1H), 7.34 (d, J=2.7 Hz, 1H), 7.14 (dd, J=9.2, 2.7 Hz, 1H), 5.13-5.03 (m, 1H), 5.05-4.97 (m, 1H), 4.66 (s, 2H), 1.83-1.68 (m, 3H).

Step B. 4-(5-((2-Methylallyl)oxy)-2-nitrophenyl)morpholine

To a mixture of 2-chloro-4-((2-methylallyl)oxy)-1-nitrobenzene (3.01 g, 13.2 mmol), and potassium carbonate (6.03 g, 43.7 mmol) in dimethyl sulfoxide (20.1 mL, 280 mmol) was added morpholine (1.15 g, 13.2 mmol) and the mixture was heated to 100° C. in a sealed tube for 1 h. The mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, water and brine and dried over sodium sulfate before concentration under reduced pressure. The crude residue was purified by silica gel chromatography using 0-50% isopropyl acetate in heptane as the eluting solvents to afford the title compound as a bright yellow solid (3.22 g, 11.6 mmol, 88%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.90 (d, J=9.0 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 6.68 (dd, J=9.0, 2.6 Hz, 1H), 5.08 (d, J=0.8 Hz, 1H), 4.99 (s, 1H), 4.59 (s, 2H), 3.76-3.63 (m, 4H), 3.06-2.95 (m, 4H), 1.82-1.72 (m, 3H).

Step C. 2-(2-methylallyl)-5-morpholino-4-nitrophenol

4-(5-((2-Methylallyl)oxy)-2-nitrophenyl)morpholine (5.0 g, 18 mmol) was dissolved in DMF (15 mL, 190 mmol) and heated at 220° C. in the microwave for 60 min in quintuplicate. The reaction mixtures were combined, concentrated under reduced pressure and brought up in isopropyl acetate and washed with water and brine. The aqueous layer was extracted with isopropyl acetate. The combined organic phases were dried over sodium sulfate before concentration under reduced pressure. The crude residue was purified by silica gel chromatography using 0-50% isopropyl acetate in heptane to afford the title compound as a dark orange oil (3.53 g, 12.7 mmol, 12%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (s, 1H), 7.74 (s, 1H), 6.59 (s, 1H), 4.80-4.74 (m, 1H), 4.67-4.60 (m, 1H), 3.71 (q, J=4.0, 3.6 Hz, 4H), 3.20 (s, 2H), 2.95-2.90 (m, 4H), 1.66 (s, 3H). ¹H NMR (400 MHz, Chloroform-d) δ 7.82 (s, 1H), 6.54 (s, 1H), 6.02 (s, 1H), 5.03-4.96 (m, 1H), 4.94-4.92 (m, 1H), 3.92-3.83 (m, 4H), 3.36 (s, 2H), 3.04 (dd, J=5.5, 3.7 Hz, 4H), 1.75 (s, 3H).

Step D. 1-(2-Hydroxy-4-morpholino-5-nitrophenyl)propan-2-one

To a solution of 2-(2-methylallyl)-5-morpholino-4-nitrophenol (3.77 g, 13.5 mmol) in water (169 mL, 9.40 mol) and dioxane (521 mL, 6.1 mol) was first added osmium tetroxide (0.08 mol/L, catalytic) in tert-butyl alcohol (700 mg, 0.677 mml) followed by sodium periodate (5.79 g, 27.1 mmol). The suspension formed was stirred overnight at room temperature and poured onto water. The aqueous layer was acidified to neutral pH with 1M HCl and extracted into DCM. The organic phase was dried over sodium sulfate before concentration under reduced pressure. The crude residue was purified by silica gel chromatography using 0-100% isopropyl acetate in heptane to afford the title compound (1.95 g, 6.94 mmol, 51%). ¹H NMR (400 MHz, Chloroform-d) δ 8.26 (s, 1H), 7.78 (s, 1H), 6.61 (s, 1H), 3.89-3.79 (m, 4H), 3.73 (s, 2H), 3.08-2.99 (m, 4H), 2.36 (s, 3H).

Step E. 1-(2-Methoxy-4-morpholino-5-nitrophenyl)propan-2-one

A suspension of sodium hydride (60% in oil, 319 mg, 7.98 mmol) in anhydrous tetrahydrofuran (19.8 mL, 243 mmol) was heated to reflux. Dimethylsulfoxide (19.8 mL, 280 mmol) was slowly added and the reaction was continued for 15 min at reflux. The mixture was then cooled to ambient temperature and trimethylsulfoxonium iodide (1.70 g, 243 mmol) was added. Stirring was continued for 30 min at room temperature. A solution of 1-(2-Hydroxy-4-morpholino-5-nitrophenyl)propan-2-one (1.44 g, 5.15 mmol) dissolved in tetrahydrofuran (5.48 mL) was added and the reaction mixture was stirred at room temperature for 30 min followed by heating at 50° C. for 18 h. Water was then added and the mixture was extracted with DCM (6×). The combined organic phases were washed water (3×), and dried over sodium sulfate before concentration under reduced pressure. The crude residue was purified by silica gel chromatography using 0-100% isopropyl acetate in heptane to afford the crude product as a yellow foam/oil residue.

Step F. 1-(5-Amino-2-methoxy-4-morpholinophenyl)propan-2-one

1-(2-Methoxy-4-morpholino-5-nitrophenyl)propan-2-one (1.03 g, 3.51 mmol) was dissolved in ethanol (17.2 mL, 295 mmol) and treated with 10% palladium activated carbon (373 mg, 0.3509 mmol) and the flask was put under a hydrogen atmosphere. After 4 h the reaction mixture was filtered through celite and concentrated under reduced pressure. The crude material was carried on without further purification.

Step G. (R)—N-(3-hydroxy-3-methyl-7-morpholinochroman-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(3-hydroxy-3-methyl-7-morpholinochroman-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A 100 mL RBF equipped with a stir bar was charged with pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (745 mg, 4.335 mmol) and purged with nitrogen. DMF (12.4 mL, 161 mmol) was added and the mixture was cooled 0° C. (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (2.28 g, 4.146 mmol) was then added, followed by 2,4,6-trimethylpyridine (0.55 mL, 4.146 mmol). Crude 1-(5-amino-2-methoxy-4-morpholinophenyl)propan-2-one (1.000 g, 3.77 mmol) was then introduced and the reaction was allowed to stir at room temperature for 18 h. The reaction mixture was filtered through a plug of silica and concentrated under reduced pressure. The crude material was purified and resolved via Chiral SFC to afford the title compounds as yellow solids. Stereochemistry was arbitrarily assigned based on peak elution.

Example 27, Peak 1 (37 mg, 2.5%): Purified via Chiral SFC (Thar 350 SFC (Lux Cellulose-1, 30×250 mm, 5 um), 40% MeOH isocratic (0.1% NH₄OH) in CO₂). ¹H NMR (400 MHz, DMSO-d6) δ 10.37 (s, 1H), 9.37 (dd, J=7.0, 1.6 Hz, 1H), 8.95 (dd, J=4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.16 (s, 1H), 7.34 (dd, J=7.0, 4.2 Hz, 1H), 6.70 (s, 1H), 4.83 (s, 1H), 3.90-3.80 (m, 4H), 3.76 (s, 2H), 2.87-2.79 (m, 4H), 2.76-2.60 (m, 2H), 1.20 (s, 3H). MS (ESI): m/z=410.2 [M+1]⁺.

Example 28, Peak 2 (41 mg, 2.7%): Purified via Chiral SFC (Thar 350 SFC (Chiral Technologies AD-H, 50×250 mm, 5 um), 40% MeOH isocratic (0.1% NH₄OH) in CO₂)¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.37 (dd, J=7.0, 1.6 Hz, 1H), 8.95 (dd, J=4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.16 (s, 1H), 7.34 (dd, J=7.0, 4.2 Hz, 1H), 6.70 (s, 1H), 4.83 (s, 1H), 3.88-3.79 (m, 4H), 3.76 (s, 2H), 2.89-2.76 (m, 4H), 2.76-2.58 (m, 2H), 1.20 (s, 3H). MS (ESI): m/z=410.2 [M+1]⁺.

Examples 29 and 30. (R)—N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution of 6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (58 mg, 0.33 mmol) in DMF (1.0 mL) was purged with nitrogen and cooled to 0° C. (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (170 mg, 0.31 mmol) was then added followed by 2,4,6-trimethylpyridine (0.04 mL, 0.31 mmol). (5-amino-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)methanol (75 mg, 0.28 mmol) was then introduced and the reaction was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was filtered through a plug of silica, washed with a solution of 20% methanol in DCM. The filtrate was then concentrated and purified and resolved via chiral SFC (PIC 100 SFC (Lux Cellulose-3, 21.1*150 mm, Sum), 25% MeOH isocratic (0.1% NH₄OH) in CO₂) to afford the title compounds as solids. Stereochemistry was arbitrarily assigned based on peak elution.

Example 29, Peak 1: (23 mg, 20%): ¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.23 (dd, J=2.0, 1.1 Hz, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.59 (s, 1H), 8.29 (s, 1H), 6.69 (s, 1H), 5.03 (t, J=5.8 Hz, 1H), 3.89-3.80 (m, 4H), 3.42 (q, J=5.5 Hz, 2H), 3.20 (d, J=16.5 Hz, 1H), 2.88-2.77 (m, 5H), 2.47-2.41 (m, 3H), 1.34 (s, 3H). MS (ESI): m/z=424.2[M+1]⁺.

Example 30, Peak 2: (23 mg, 20%): ¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 9.23 (dd, J=2.0, 1.1 Hz, 1H), 8.86 (d, J=2.0 Hz, 1H), 8.59 (s, 1H), 8.29 (s, 1H), 6.69 (s, 1H), 5.03 (t, J=5.8 Hz, 1H), 3.89-3.80 (m, 4H), 3.42 (q, J=5.5 Hz, 2H), 3.20 (d, J=16.5 Hz, 1H), 2.88-2.77 (m, 5H), 2.47-2.41 (m, 3H), 1.34 (s, 3H). MS (ESI): m/z=424.2[M+1]⁺.

Examples 31 and 32. (R)—N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 6) was resolved via chiral SFC (PIC 100 SFC (Lux Cellulose-3, 21.1*150 mm, Sum), 25% MeOH isocratic (0.1% NH₄OH) in CO₂) to afford the title compounds as solids. Stereochemistry was arbitrarily assigned based on peak elution.

Example 31, Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 9.37 (dd, J=7.0, 1.6 Hz, 1H), 8.94 (dd, J=4.2, 1.6 Hz, 1H), 8.68 (s, 1H), 8.29 (s, 1H), 7.34 (dd, J=7.0, 4.2 Hz, 1H), 6.70 (s, 1H), 5.10-4.98 (m, 1H), 3.91-3.74 (m, 4H), 3.43 (t, J=5.7 Hz, 2H), 3.20 (dd, J=15.9, 0.7 Hz, 1H), 2.90-2.73 (m, 5H), 1.34 (s, 3H). MS (ESI): m/z=410.2 [M+1]⁺.

Example 32, Peak 2: ¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 9.37 (dd, J=7.0, 1.6 Hz, 1H), 8.94 (dd, J=4.2, 1.6 Hz, 1H), 8.68 (s, 1H), 8.29 (s, 1H), 7.34 (dd, J=7.0, 4.2 Hz, 1H), 6.70 (s, 1H), 5.10-4.98 (m, 1H), 3.91-3.74 (m, 4H), 3.43 (t, J=5.7 Hz, 2H), 3.20 (dd, J=15.9, 0.7 Hz, 1H), 2.90-2.73 (m, 5H), 1.34 (s, 3H). MS (ESI): m/z=410.2 [M+1]⁺.

Example 33. N-(2,2-dimethyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 4-(2,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine

2-(2-Methylallyl)-5-morpholino-4-nitrophenol (1.0 g, 3.6 mmol) was dissolved in MeOH (12 mL) and cooled to 0° C. A solution of 35% aqueous HCl (12 mL) was added and the reaction mixture was allowed to warm to ambient temperature and then heated at reflux for 60 h. The reaction was cooled to room temperature, neutralized with saturated sodium bicarbonate and extracted with isopropyl acetate. The organic phase was dried over sodium sulfate, filtered, and absorbed onto celite under reduced pressure. The crude residue was purified by silica gel chromatography using (0-30%) isopropyl acetate in heptane to afford the title compound as a yellow foam/oil residue (520 mg, 1.87 mmol, 52%). ¹H NMR (400 MHz, DMSO-d₆) δ 7.85 (t, J=1.2 Hz, 1H), 6.60 (s, 1H), 3.76-3.61 (m, 4H), 3.01 (d, J=1.1 Hz, 2H), 2.98-2.90 (m, 4H), 1.44 (s, 6H). ¹H NMR (400 MHz, Chloroform-d) δ 7.85 (t, J=1.2 Hz, 1H), 6.44 (s, 1H), 3.90-3.79 (m, 4H), 3.05-3.01 (m, 4H), 3.00 (d, J=1.1 Hz, 2H), 1.51 (s, 6H).

Step B. 2,2-Dimethyl-6-morpholino-3H-benzofuran-5-amine

The mixture of 4-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)morpholine (60 mg, 0.22 mmol) and 10% palladium on carbon (30 mg) in methanol (8 mL) was stirred under hydrogen atmosphere at 25° C. for 1 h. After filtration through a plug of celite and concentration, it was afforded 2,2-dimethyl-6-morpholino-3H-benzofuran-5-amine (50 mg) as a yellow oil, which was directly used in the next step without purification. MS (ESI): m/z=249.2[M+1]⁺.

Step C. N-(2,2-dimethyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (370 mg, 2.1 mmol) in DMF (6.2 mL) was purged with nitrogen and cooled to 0° C. (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.1 g, 2.1 mmol) was then added followed by 2,4,6-trimethylpyridine (0.27 mL, 2.1 mmol). 2,2-Dimethyl-6-morpholino-2,3-dihydrobenzofuran-5-amine (460 mg, 1.9 mmol) was then introduced and the reaction was allowed to warm to ambient temperature and stirred for 18 h. The reaction mixture was filtered through a plug of silica, washed with 20% methanol in DCM and the filtrate was then concentrated and purified via Prep-HPLC ((Gemini-NX 50*30 mm c18, Sum, 110 A), acetonitrile 20-60% (0.1% NH₄OH) in water) to afford 330 mg of the title compound as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 9.41-9.32 (m, 1H), 8.98-8.91 (m, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 7.34 (dd, J=7.0, 4.2 Hz, 1H), 6.71 (s, 1H), 3.89-3.77 (m, 4H), 3.04-2.96 (m, 2H), 2.86-2.78 (m, 4H), 1.42 (s, 6H). MS (ESI): m/z=394.2 [M+1]⁺.

Example 34. N-(6-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 6-Methoxy-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran

The mixture of cesium carbonate (300.0 mg, 0.92 mmol), palladium diacetate (12.8 mg, 0.06 mmol), 6-bromo-2,2-dimethyl-5-nitro-3H-benzofuran (Intermediate 1) (156.0 mg, 0.57 mmol) and racemic-2-(di-tert-butylphosphino)-1,1′-binaphthyl (228.2 mg, 0.57 mmol) in methanol (0.50 mL) and toluene (5.0 mL) was heated in a sealed tube at 80° C. under microwave condition for 3 h. The reaction was concentrated to dryness under reduced pressure and then purified by silica gel chromatography using ethyl acetate:petroleum ether (1:10) to afford 6-methoxy-2,2-dimethyl-5-nitro-3H-benzofuran (155 mg, 97%) as red solid. MS (ESI): m/z=224.2 [M+1]⁺.

Step B. 6-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-amine

A mixture of 10% palladium on carbon (31.0 mg) and 6-methoxy-2,2-dimethyl-5-nitro-3H-benzofuran (155.0 mg, 0.69 mmol) in methanol (15 mL) was stirred at 25° C. under hydrogen atmosphere for 2 h. After filtration over a plug of celite and concentration under reduced pressure, 6-methoxy-2,2-dimethyl-3H-benzofuran-5-amine (111 mg, 62%) was afforded as a yellow oil. MS (ESI): m/z=194.2 [M+1]⁺.

Step C. N-(6-Methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (107.76 mg, 0.66 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (329.44 mg, 0.63 mmol), N-ethyl-N-isopropylpropan-2-amine (222.72 mg, 1.72 mmol) and 6-methoxy-2,2-dimethyl-3H-benzofuran-5-amine (111.0 mg, 0.57 mmol) in DMF (10 mL) was stirred at room temperature for 18 h. After filtration and concentration, the residue was purified by preparativeHPLC reverse phase chromatography (phenomenex, Gemini C18, 21.2×100 mm. 5 um, 110 A, A: acetonitrile 25-45%; B: 0.05% formic acid in water) to afford N-(6-methoxy-2,2-dimethyl-3H-benzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (110 mg, 57%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 10.04 (s, 1H), 8.80 (dd, J=1.6, 7.2 Hz, 1H), 8.75 (s, 1H), 8.71 (dd, J=1.6, 4.0 Hz, 1H), 8.29 (s, 1H), 7.02 (dd, J=4.0, 7.2 Hz, 1H), 6.43 (s, 2H), 3.91 (s, 3H), 3.02 (s, 2H), 1.49 (s, 6H). MS (ESI): m/z=339.2 [M+1]⁺.

Example 35. N-(8-Morpholino-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. N-(4-Chloro-2-hydroxyphenyl)benzamide

To a solution of 2-amino-5-chlorophenol (1.45 g, 10.1 mmol) in ethyl acetate (30 mL) and water (30 mL) was added sodium bicarbonate (1.27 g, 15.15 mmol) and benzoyl chloride (1.42 g, 10.1 mmol). The mixture was stirred at room temperature for 1 h. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was washed with petroleum ether to afford N-(4-chloro-2-hydroxy-phenyl)benzamide (2.34 g, 94%) as a brown solid. MS (ESI): m/z=248.1 [M+1]⁺.

Step B. (8-Chloro-3,4-dihydrobenzo[b][1,4]oxazepin-5(2H)-yl)(phenyl)methanone

To a solution of N-(4-chloro-2-hydroxy-phenyl)benzamide (2.08 g, 8.4 mmol) in acetonitrile (16 mL) and DCM (24 mL) was added 1,3-dibromopropane (6781.83 mg, 33.59 mmol) and aliquot 336 (tri-n-octylmethylammonium chloride) (339.41 mg, 0.84 mmol). Then sodium hydride (1343.67 mg, 33.59 mmol, 60% wt with mineral oil) were added. The mixture was heated at 60° C. for 3 h. Saturated ammonium chloride solution was added. The aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic phases were washed with brine and dried over sodium sulfate. After filtration and concentration, the residue was purified by silica gel column eluted ethyl acetate:petroleum ether (1:1) to afford (8-chloro-3,4-dihydro-2H-1,5-benzoxazepin-5-yl)-phenyl-methanone (1.3 g, 54%) as off-white solid. MS (ESI): m/z=288.1 [M+1]⁺.

Step C. 8-Chloro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine

(8-Chloro-3,4-dihydro-2H-1,5-benzoxazepin-5-yl)-phenyl-methanone (1.0 g, 3.48 mmol) was dissolved in 1,4-dioxane (20 mL) and 6 m hydrogen chloride solution (87.11 mL, 522.66 mmol) was added. The mixture was heated at reflux for 20 h. Saturated ammonium chloride solution was added and the aqueous phase was extracted with ethyl acetate (100 mL). The organic extract was washed with brine and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:3) as eluting solvents to afford (8-chloro-3,4-dihydro-2H-1,5-benzoxazepin-5-yl)-phenyl-methanone (808 mg, 100%) as a brown solid. MS (ESI): m/z=184.1 [M+1]⁺.

Step D. 8-Chloro-7-nitro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine

To a solution of 8-chloro-2,3,4,5-tetrahydro-1,5-benzoxazepine (183.0 mg, 1 mmol) in concentrated sulfuric acid (4 mL) was slowly added guanidine nitrate (121.58 mg, 1 mmol) at 0° C. The reaction was stirred for 30 min. The mixture was poured into ice water. The solution was adjusted to pH=7.0 by saturated aqueous sodium carbonate. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phase wash was concentrated under reduced pressure to afford 8-chloro-7-nitro-2,3,4,5-tetrahydro-1,5-benzoxazepine (185 mg) as a red solid, which was used directly to next step without further purification. MS (ESI): m/z=229.0 [M+1]⁺.

Step E. 8-Morpholino-7-nitro-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine

A mixture of 8-chloro-7-nitro-2,3,4,5-tetrahydro-1,5-benzoxazepine (185.0 mg, 0.81 mmol) and morpholine (10 mL) was stirred at 120° C. for 18 h. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:5 to 1:3) to afford 8-morpholino-7-nitro-2,3,4,5-tetrahydro-1,5-benzoxazepine (193 mg, 64.1%) as orange solid. MS (ESI): m/z=280.1 [M+1]⁺.

Step F. 8-Morpholino-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-amine

A mixture of 10% palladium on carbon (40.0 mg) and 8-morpholino-7-nitro-2,3,4,5-tetrahydro-1,5-benzoxazepine (193.0 mg, 0.69 mmol) in methanol (15 mL) was stirred at 25° C. under hydrogen atmosphere for 2 h. After filtration and concentration in vacuo, it was afforded 8-morpholino-2,3,4,5-tetrahydro-1,5-benzoxazepin-7-amine (154 mg, 89%) as a red oil. MS (ESI): m/z=20.1 [M+1]⁺.

Step G. N-(8-Morpholino-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 8-morpholino-2,3,4,5-tetrahydro-1,5-benzoxazepin-7-amine (193.0 mg, 0.77 mmol) and triethylamine (235.0 mg, 2.32 mmol) in DCM (10 mL) was stirred at 0° C. To this mixture was added pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (Example 3, Step B) (210.85 mg, 1.16 mmol) and then the reaction was stirred at 25° C. for 1 h. After concentration under reduced pressure, the residue was purified by preparative HPLC (Phenomenex, Gemini C18, 21.2×100 mm. 5 um, 110 A, A: acetonitrile 25-45%; B: 0.05% formic acid in water) to afford N-(8-morpholino-2,3,4,5-tetrahydro-1,5-benzoxazepin-7-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (35 mg, 12%) as dark yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 10.60 (s, 1H), 8.83 (dd, J=1.6, 7.2 Hz, 1H), 8.79-8.76 (m, 1H), 8.20 (s, 1H), 7.07 (dd, J=4.0, 7.2 Hz, 1H), 6.88 (s, 1H), 4.07 (t, J=5.6 Hz, 2H), 3.98-3.93 (m, 4H), 3.22 (t, J=5.6 Hz, 2H), 2.92-2.85 (m, 4H), 2.04-1.96 (m, 2H). m/z=395.1 [M+1]⁺.

Example 36 and 37. (R)—N-(6-(2,2-dimethylmorpholino)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(6-(2,2-dimethylmorpholino)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (6-(2,2-Dimethylmorpholino)-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (6-chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (Intermediate 2) (130 mg, 0.53 mmol) in 2,2-dimethylmorpholine (0.5 mL) was stirred at 100° C. for 18 h in a sealed tube. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford (6-(2,2-dimethylmorpholino)-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (95 mg, 55%) as a yellow solid. MS (ESI): m/z=323.3 [M+1]⁺.

Step B. (5-Amino-6-(2,2-dimethylmorpholino)-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (6-(2,2-dimethylmorpholino)-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (95 mg, 0.29 mmol) and 10% palladium on carbon (10 mg) in methanol (5 mL) was stirred at room temperature for 1 h under an atmosphere of hydrogen. The reaction was then filtered over a plug of celite and the filtrate was concentrated under reduced pressure to afford (5-amino-6-(2,2-dimethylmorpholino)-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol (55 mg), which was used directly in the next step without purification. MS (ESI): m/z=293.1 [M+1]⁺.

Step C. (R)—N-(6-(2,2-dimethylmorpholino)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(6-(2,2-dimethylmorpholino)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (31 mg, 0.19 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (98 mg, 0.19 mmol) and collidine (68 mg, 0.57 mmol) in DMF (5 mL) was stirred at room temperature for 30 min. (5-amino-6-(2,2-dimethylmorpholino)-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol (55 mg, 0.19 mmol) was added. The resulting mixture was stirred at room temperature for 18 h. After concentration, the residue was purified by preparative HPLC(Xbridge Prep C18 10 um OBD, 19*250 mm, 10 um; A: acetonitrile 45-75% and 0.01% NH₃; B: 10 mM ammonium bicarbonate in water) to afford N-(6-(2,2-dimethylmorpholino)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as a yellow solid (50 mg, 0.11 mmol, 61%). The enantiomers were then resolved by chiral SFC to give (R)—N-(6-(2,2-dimethylmorpholino)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(6-(2,2-dimethylmorpholino)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with absolute stereochemistry assigned arbitrarily.

Example 36, Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1H), 9.37 (dd, J=7.0, 1.6 Hz, 1H), 8.84 (dd, J=4.2, 1.7 Hz, 1H), 8.69 (s, 1H), 8.19 (d, J=0.9 Hz, 1H), 7.33 (dd, J=7.0, 4.2 Hz, 1H), 6.60 (s, 1H), 5.07-4.99 (m, 1H), 3.79 (d, J=4.6 Hz, 2H), 3.43 (t, J=5.8 Hz, 2H), 3.23-3.16 (m, 1H), 2.82 (dd, J=15.6, 1.1 Hz, 1H), 2.71 (s, 2H), 2.65 (s, 2H), 1.38-1.32 (m, 9H). MS (ESI): m/z=438.2 [M+1]⁺.

Example 37, Peak 2: ¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1H), 9.37 (dd, J=7.0, 1.6 Hz, 1H), 8.84 (dd, J=4.2, 1.7 Hz, 1H), 8.69 (s, 1H), 8.19 (d, J=0.9 Hz, 1H), 7.33 (dd, J=7.0, 4.2 Hz, 1H), 6.60 (s, 1H), 5.03 (t, J=5.8 Hz, 1H), 3.79 (d, J=5.8 Hz, 2H), 3.48-3.38 (m, 2H), 3.20 (ddt, J=15.6, 0.9, 0.5 Hz, 1H), 2.86-2.77 (m, 1H), 2.71 (s, 2H), 2.65 (d, J=5.3 Hz, 2H), 1.35 (d, J=4.4 Hz, 9H). MS (ESI): m/z=438.2 [M+1]⁺.

Example 38. 2-Methyl-6-morpholino-5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2,3-dihydrobenzofuran-2-carboxylic acid

Step A. Methyl 6-chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-carboxylate

A mixture of 6-chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-carboxylic acid (Intermediate 2, Step C) (1.60 g, 6.21 mol), methyl iodide (1.76 g, 12.42 mmol) and potassium carbonate (1.72 g, 12.42 mmol) in DMF (10 mL) was stirred at room temperature. Water and ethyl acetate (50 mL) was added upon consumption of starting material. The organic phase was separated and dried over sodium sulfate. After filtration and concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:6 to 1:4) as eluting solvents to afford methyl 6-chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-carboxylate (550 mg, 33%) as orange solid. MS (ESI): m/z=272.1 [M+1]⁺.

Step B. 2-Methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carboxylic acid

A mixture of methyl 6-chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-carboxylate (550 mg, 2.02 mmol) in morpholine (3 mL) was stirred at 110° C. for 18 h in a sealed tube. The mixture was concentrated under reduced pressure to afford 2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carboxylic acid (260 mg) as a yellow oil, which was used directly in the next step without purification. MS (ESI): m/z=309.1 [M+1]⁺.

Step C. Methyl 2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carboxylate

A mixture of 2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carboxylic acid (260 mg, 0.84 mol), iodomethane (239 mg, 1.69 mmol) and potassium carbonate (233 mg, 1.69 mmol) in DMF (10 mL) was stirred at room temperature. Upon consumption of starting material, water and ethyl acetate (50 mL) were added. The organic phase was separated and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:4 to 1:2) as eluting solvents to afford methyl 2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carboxylate (200 mg, 74%) as orange solid. MS (ESI): m/z=323.2 [M+1]⁺.

Step D. Methyl 5-amino-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-carboxylate

A mixture of methyl 2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carboxylate (200 mg, 0.62 mmol) and 10% palladium on carbon (20 mg) in methanol (10 mL) was stirred at room temperature for 1 h under an atmosphere of hydrogen. The reaction was then filtered over a plug of celite and the filtrate was concentrated under reduced pressure to afford methyl 5-amino-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-carboxylate as a white solid (150 mg), which was used directly to the next step without purification. MS (ESI): m/z=292.3 [M+1]⁺.

Step E. Methyl 2-methyl-6-morpholino-5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2,3-dihydrobenzofuran-2-carboxylate

A mixture of methyl 5-amino-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-carboxylate (150 mg, 0.51 mmol) and triethylamine (103 mg, 1.02 mmol) in DCM (10 mL) was stirred at 0° C. To the mixture was added a solution of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (Example 3, Step B) (93 mg, 0.51 mmol) in DCM (10 mL) and then the reaction was stirred at 25° C. for 1 h. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:1 to 10:1) as eluting solvents to afford methyl 2-methyl-6-morpholino-5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2,3-dihydrobenzofuran-2-carboxylateas a white solid (160 mg, 71%). MS (ESI): m/z=438.1 [M+1]⁺.

Step F. 2-Methyl-6-morpholino-5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2,3-dihydrobenzofuran-2-carboxylic acid

A mixture of methyl 2-methyl-6-morpholino-5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2,3-dihydrobenzofuran-2-carboxylate (70 mg, 0.16 mmol) and sodium hydroxide (13 mg, 0.32 mmol) in THE (5 mL) and water (1 mL) was stirred at 25° C. for 1 h. The reaction was then purified by preparative HPLC (Xbridge Prep C18 10 um OBD, 19*250 mm, 10 um; A: acetonitrile 35-65% and 0.01% NH₃; B: 10 mM ammonium bicarbonate in water) to afford 2-methyl-6-morpholino-5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2,3-dihydrobenzofuran-2-carboxylic acid (10 mg, 15%) as a yellow solid. ¹HNMR (400 MHz, DMSO-d₆): δ 10.45 (s, 1H), 9.37 (dd, J=1.6, 7.2 Hz, 1H), 8.95 (dd, J=1.6, 4.0 Hz, 1H), 8.68 (s, 1H), 8.30 (s, 1H), 7.34 (dd, J=4.0, 7.2 Hz, 1H), 6.80 (s, 1H), 3.89-3.78 (m, 4H), 3.54-3.48 (m, 1H), 3.13-3.07 (m, 1H), 2.88-2.75 (m, 4H), 1.57 (s, 3H). MS (ESI): m/z=424.2 [M+1]⁺.

Example 39. N-(6-Morpholino-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran]-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 4-(2,4-Difluorobenzyl)tetrahydro-2H-pyran-4-ol

To a solution of magnesium (1.20 g, 45.59 mmol) and iodine (90.0 mg, 0.35 mmol) in diethyl ether (20 mL) at 40° C. was slowly added 1-(bromomethyl)-2,4-difluorobenzene (4.10 g, 19.8 mmol). The solution was then cooled to room temperature and added to dihydro-2H-pyran-4(3H)-one (3.00 g, 29.96 mmol) in diethyl ether (50 mL) at −78° C. and the reaction was stirred at room temperature for 18 h. After quenching with saturated ammonium chloride solution, ethyl acetate (100 mL) was added. The organic phase was separated and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:10) as eluting solvents to afford 4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-ol (1.80 g, 40%) as a colorless oil. MS (ESI): m/z=229.1 [M+1]⁺.

Step B. 6-Fluoro-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran]

A mixture of methyl 4-(2,4-difluorobenzyl)tetrahydro-2H-pyran-4-ol (1.81 g, 7.93 mmol) and potassium tert-butoxide (2.67 g, 23.79 mmol) in THE (50 mL) was stirred at 60° C. for 18 h. After cooling to room temperature, 1N hydrogen chloride solution was added to reach pH=3.0. Ethyl acetate (100 mL) was added and the organic phase was separated and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:3 to 1:2) as eluting solvents to afford 6-fluoro-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran](1.53 g, 93%) as a yellow solid. MS (ESI): m/z=209.1 [M+1]⁺.

Step C. 6-Fluoro-5-nitro-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran]

To a solution of 6-fluoro-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran](1.53 g, 7.35 mmol) in DCM (50 mL) at 25° C. was slowly added fuming nitric acid (2 mL) and the reaction was stirred for 15 min. Water and ethyl acetate (100 mL) was added. The organic phase was separated and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:6 to 1:4) as eluting solvents to afford 6-fluoro-5-nitro-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran] (1.29 g, 69%) as orange solid. MS (ESI): m/z=254.3 [M+1]⁺.

Step D. 4-(5-Nitro-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran]-6-yl)morpholine

A mixture of 6-fluoro-5-nitro-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran] (150 mg, 0.59 mmol), morpholine (103 mg, 1.18 mmol) and cesium carbonate (579 mg, 1.78 mmol) in acetonitrile (5 mL) was stirred at room temperature for 18 h. Upon consumption of starting material, the mixture was poured into water and the aqueous phase was extracted with ethyl acetate (2×50 mL). The organic phases were combined and washed with water and brine. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:2) as eluting solvents to afford (4-(5-nitro-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran]-6-yl)morpholine (180 mg, 95%) as a yellow solid. MS (ESI): m/z=321.1 [M+1]⁺.

Step E. 6-Morpholino-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran]-5-amine

A mixture of 4-(5-nitro-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran]-6-yl)morpholine (180 mg, 0.56 mmol) and 10% palladium on carbon (18 mg) in methanol (10 mL) was stirred at room temperature for 1 h under an atmosphere of hydrogen. Upon filtration through a plug of celite, the filtrate was concentrated under reduced pressure to afford (6-morpholino-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran]-5-amine as a white solid (150 mg), which was used directly in the next step without purification. MS (ESI): m/z=291.1 [M+1]⁺.

Step F. N-(6-Morpholino-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran]-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 6-morpholino-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran]-5-amine (150 mg, 0.52 mmol) and triethylamine (157 mg, 1.55 mmol) in DCM (5 mL) was stirred at 0° C. To the mixture was added a solution of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (Example 3, Step B) (113 mg, 0.62 mmol) in DCM (5 mL) and the reaction was stirred at 25° C. for 1 h. After filtration, the residue was purified by preparative HPLC(Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-55%; B: 10 mM ammonium bicarbonate in water) to afford N-(6-morpholino-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran]-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (60 mg, 27%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.45 (s, 1H), 9.37 (dd, J=2.0, 7.2 Hz, 1H), 8.94 (dd, J=1.6, 4.0 Hz, 1H), 8.68 (s, 1H)), 8.33 (s, 1H), 7.35 (dd, J=4.0, 7.2 Hz, 1H), 6.79 (s, 1H), 3.83-3.85 (m, 4H), 3.74-3.80 (m, 2H), 3.61-3.66 (m, 2H), 3.06 (s, 2H), 2.81-2.82 (m, 4H), 1.79-1.81 (m, 4H). MS (ESI): m/z=436.2 [M+1]⁺.

Example 40. N-(6-(4-Fluoro-4-(hydroxymethyl)piperidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 4-Fluoropiperidin-4-yl)methanol 2,2,2-trifluoroacetate

A mixture of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (300 mg, 1.29 mmol) in trifluoroacetic acid (1 mL) and DCM (2 mL) was stirred at 20° C. for 1 h. The mixture was concentrated under reduced pressure to afford (4-fluoropiperidin-4-yl)methanol trifluoroacetic acid salt (300 mg) as a colorless oil, which was used directly without purification. MS (ESI): m/z=134.1 [M+1]⁺.

Step B. (1-(2,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-4-fluoropiperidin-4-yl)methanol

A mixture of 6-chloro-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran (Intermediate 2) (107 mg, 0.47 mmol), (4-fluoropiperidin-4-yl)methanol 2,2,2-trifluoroacetate (232 mg, 0.94 mmol) and cesium carbonate (459 mg, 1.41 mmol) in acetonitrile (1 mL) was stirred at 100° C. for 18 h in a sealed tube. The mixture was poured into water and the aqueous phase was extracted with ethyl acetate (2×50 mL). The organic phases were combined, washed with water and brine, concentrated under reduced pressure and purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford (1-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-4-fluoropiperidin-4-yl)methanol (95 mg, 62%) as a yellow solid. MS (ESI): m/z=325.3 [M+1]t

Step C. (1-(5-Amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)-4-fluoropiperidin-4-yl)methanol

A mixture of (1-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-4-fluoropiperidin-4-yl)methanol (95 mg, 0.29 mmol) and 10% palladium on carbon (10 mg) in methanol (5 mL) was stirred at room temperature for 1 h under an atmosphere of hydrogen. Upon filtration over a plug of celite, the filtrate was concentrated under reduced pressure to afford (1-(5-amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)-4-fluoropiperidin-4-yl)methanol (60 mg), which was used directly in the next step without purification. MS (ESI): m/z=295.1 [M+1]⁺.

Step D. N-(6-(4-Fluoro-4-(hydroxymethyl)piperidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of (1-(5-amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)-4-fluoropiperidin-4-yl)methanol (60 mg, 0.20 mmol) and triethylamine (61 mg, 0.60 mmol) in DCM (10 mL) was stirred at 0° C. To the mixture was added a solution of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (Example 3, Step B) (54 mg, 0.30 mmol) in DCM (10 mL) and the reaction was stirred at 25° C. for 1 h. The crude reaction was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 35-55%; B: 10 mM ammonium bicarbonate in water) to afford N-(6-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (55 mg, 65%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.43 (s, 1H), 9.36 (dd, J=1.6, 7.2 Hz, 1H), 8.89 (dd, J=1.6, 4.0 Hz, 1H), 8.68 (s, 1H)), 8.34 (s, 1H), 7.53 (dd, J=4.0, 7.2 Hz, 1H), 6.71 (s, 1H), 5.18 (br, 1H), 3.53 (d, J=17.6 Hz, 2H), 3.37 (s, 2H), 2.81-2.91 (m, 4H), 1.98-2.10 (m, 2H). 1.83-1.88 (m, 2H). 1.42 (s, 6H). MS (ESI): m/z=440.2 [M+1]⁺.

Example 41. N-[6-(1,1-Dioxo-thiomorpholin-4-yl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 4-(2,2-Dimethyl-5-nitro-2,3-dihydro-1-benzofuran-6-yl)-thiomorpholine-1,1-dione

A mixture of 6-chloro-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran (Intermediate 1) (100 mg, 0.44 mmol), thiomorpholine-1,1-dione (119 mg, 0.88 mmol) and cesium carbonate (429 mg, 1.32 mmol) in acetonitrile (5 mL) was stirred 100° C. for 18 h. Upon consumption of starting material, the mixture was poured into water and the aqueous phase was extracted with ethyl acetate (2×50 mL). The organic phases were combined and washed with water and brine. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:2) as eluting solvents to afford 4-(2,2-dimethyl-5-nitro-2,3-dihydro-1-benzofuran-6-yl)-thiomorpholine-1,1-dione (70 mg, 49%) as a yellow solid. MS (ESI): m/z=327.1 [M+1]⁺.

Step B. 4-(5-Amino-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)-thiomorpholine-1,1-dione

A mixture of 4-(2,2-dimethyl-5-nitro-2,3-dihydro-1-benzofuran-6-yl)-thiomorpholine-1,1-dione (70 mg, 0.21 mmol) and 15% palladium on carbon (10 mg) in methanol (10 mL) was stirred at room temperature for 1 h under an atmosphere of hydrogen. Upon filtration over a plug of celite, the filtrate was concentrated under reduced pressure to afford 4-(5-amino-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)-thiomorpholine-1,1-dione (50 mg, 81%), which was used directly to the next step without purification. MS (ESI): m/z=297.1 [M+1]⁺.

Step C. N-[6-(1,1-Dioxo-thiomorpholin-4-yl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (28 mg, 0.17 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (88 mg, 0.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (65 mg, 0.51 mmol) in DMF (5 mL) was stirred at room temperature for 30 min. 4-(5-Amino-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-yl)-thiomorpholine-1,1-dione (50 mg, 0.17 mmol) was added and the resulting mixture was stirred at room temperature for 18 h. The residue was purified by preparative HPLC(Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-55%; B:10 mM ammonium bicarbonate in water) to afford N-[6-(1,1-dioxo-thiomorpholin-4-yl)-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid (25 mg, 34%). ¹H NMR (400 MHz, DMSO-d₆): δ10.43 (s, 1H), 9.39 (dd, J=1.2, 6.8 Hz, 1H), 8.84 (dd, J=1.6, 4.4 Hz, 1H), 8.69 (s, 1H)), 8.36 (s, 1H), 7.42 (dd, J=4.4, 7.2 Hz, 1H), 6.83 (s, 1H), 3.46-3.47 (m, 4H), 3.34-3.35 (m, 4H), 3.01 (s, 2H), 1.41 (s, 6H). MS (ESI): m/z=442.2 [M+1]⁺.

Examples 42 and 43. N—((R)-6-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and N—((S)-6-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (6-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (6-chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (Intermediate 2) (85 mg, 0.35 mmol), (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (95 mg, 0.70 mmol) and cesium carbonate (455 mg, 1.40 mmol) in acetonitrile (1 mL) was stirred 100° C. for 18 h in sealed tube. After filtered and concentrated, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:2) as eluting solvents to afford (6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol(60 mg, 56%) as a yellow solid. MS (ESI): m/z=307.3 [M+1]⁺.

Step B. (5-Amino-6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (60 mg, 0.20 mmol) and 10% palladium on carbon (12 mg) in methanol (5 mL) was stirred at room temperature for 1 h under an atmosphere of hydrogen. Upon filtration over a plug of celite, the filtrate was concentrated under reduced pressure to afford (5-amino-6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol(50 mg) as a yellow oil, which was used directly to the next step without purification. MS (ESI): m/z=277.1 [M+1]⁺.

Step C. N—((R)-6-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and N—((S)-6-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of (5-amino-6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol (50 mg, 0.18 mmol) and triethylamine (55 mg, 0.54 mmol) in DCM (5 mL) was stirred at 0° C. To the mixture was added a solution of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (Example 3, Step B) (49 mg, 0.27 mmol) in DCM (5 mL) and then the reaction was stirred at 25° C. for 1 h. After concentration under reduced pressure the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (15:1) as eluting solvents to afford the desired product and then it was separated by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-55%; B:10 mM ammonium bicarbonate in water) to obtain

N—((R)-6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and N—((S)-6-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (10 mg each, 12% each) as a yellow solids with absolute stereochemistry assigned arbitrarily.

Example 42, Peak 1: ¹H NMR (400 MHz, CDCl₃): δ 10.10 (s, 1H), 8.82 (dd, J=1.6, 7.2 Hz, 1H), 8.77 (s, 1H), 8.71 (dd, J=1.6, 4.0 Hz, 1H), 8.14 (s, 1H), 7.04 (dd, J=4.0, 7.2 Hz, 1H), 6.57 (s, 1H), 4.57 (s, 1H), 4.13 (d, J=7.2 Hz, 1H), 4.04 (s, 1H), 3.78 (dd, J=1.6-7.2 Hz, 1H), 3.67 (d, J=4.0 Hz, 2H), 3.60 (d, J=9.6 Hz, 1H), 3.22 (d, J=15.2 Hz, 1H), 3.08 (dd, J=1.6, 9.6 Hz, 1H), 2.93 (d, J=15.6 Hz, 1H), 2.10 (dd, J=1.6, 9.6 Hz, 1H), 1.96-1.89 (m, 2H), 1.47 (s, 3H). MS (ESI): m/z=422.2[M+1]⁺.

Example 43, Peak 2. ¹H NMR (400 MHz, CDCl₃): δ 10.09 (s, 1H), 8.82 (dd, J=1.6, 7.2 Hz, 1H), 8.77 (s, 1H), 8.72 (dd, J=1.6, 4.0 Hz, 1H), 8.14 (s, 1H), 7.04 (dd, J=4.0, 7.2 Hz, 1H), 6.57 (s, 1H), 4.57 (s, 1H), 4.13 (d, J=7.6 Hz, 1H), 4.05 (s, 1H), 3.78 (dd, J=2.0, 7.2 Hz, 1H), 3.67 (d, J=5.6 Hz, 2H), 3.59 (d, J=9.6 Hz, 1H), 3.22 (d, J=16.0 Hz, 1H), 3.10 (dd, J=1.6, 9.6 Hz, 1H), 2.92 (d, J=16.0 Hz, 1H), 2.10 (dd, J=1.6, 9.6 Hz, 1H), 1.96-1.89 (m, 2H), 1.46 (s, 3H). MS (ESI): m/z=422.1 [M+1]⁺.

Examples 44 and 45. (R)—N-(6-(4-Fluoro-4-(hydroxymethyl)piperidin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(6-(4-Fluoro-4-(hydroxymethyl)piperidin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (4-Fluoropiperidin-4-yl)methanol 2,2,2-trifluoroacetate

A mixture of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (300 mg, 1.29 mmolin trifluoroacetic acid (1 mL) and DCM (2 mL) was stirred 20° C. for 1 h. Upon consumption of starting material, the mixture was concentrated under reduced pressure to afford (4-fluoropiperidin-4-yl)methanol trifluoroacetic acid salt (300 mg) as a colorless oil, which was used directly to next step without further purification MS (ESI): m/z=134.1 [M+1]⁺.

Step B. (4-Fluoro-1-(2-(hydroxymethyl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)methanol

A mixture of (6-chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (80 mg, 0.33 mmol), (4-fluoropiperidin-4-yl)methanol 2,2,2-trifluoroacetate (162 mg, 0.66 mmol) and cesium carbonate (428 mg, 1.32 mmol) in acetonitrile (1 mL) was stirred 100° C. for 18 h in sealed tube. Upon filtration and concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:2) as eluting solvents to afford (4-fluoro-1-(2-(hydroxymethyl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)methanol (100 mg, 90%) as a yellow solid. MS (ESI): m/z=341.1 [M+1]⁺.

Step C. (1-(5-Amino-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-6-yl)-4-fluoropiperidin-4-yl)methanol

A mixture of (4-fluoro-1-(2-(hydroxymethyl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)methanol(100 mg, 0.29 mmol) and 10% palladium on carbon (10 mg) in methanol (5 mL) was stirred at room temperature for 1 h under an atmosphere of hydrogen. Upon filtration over a plug of celite, the filtrate was concentrated under reduced pressure to afford (1-(5-amino-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-6-yl)-4-fluoropiperidin-4-yl)methanol(90 mg) as a yellow oil, which was used directly in the next step without purification. MS (ESI): m/z=311.1 [M+1]⁺.

Step D. (R)—N-(6-(4-Fluoro-4-(hydroxymethyl)piperidin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(6-(4-Fluoro-4-(hydroxymethyl)piperidin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of (1-(5-amino-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-6-yl)-4-fluoropiperidin-4-yl)methanol(90 mg, 0.29 mmol) and triethylamine (88 mg, 0.87 mmol) in DCM (5 mL) was stirred at 0° C. To the mixture was added a solution of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (Example 3, Step B) (105 mg, 0.58 mmol) in DCM (5 mL) and the reaction was stirred at 25° C. for 1 h. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (15:1) as eluting solvents to afford the desired product then it was separated by chiral HPLC(OJ 20*250 mm, 5 u at CO₂/methanol{0.2% Ammonia (7 m methanol)}=80/20, 80 g/min, 100 bar, 35° C.) to obtain

(R)—N-(6-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(6-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (15 mg, 11%) (10 mg, 8%) as a yellow solids with absolute stereochemistry assigned arbitrarily.

Example 44, Peak 1: ¹H NMR (400 MHz, DMSO-d₆): δ 10.42 (s, 1H), 9.36 (dd, J=1.6, 7.2 Hz, 1H), 8.89 (dd, J=1.6, 4.4 Hz, 1H), 8.68 (s, 1H)), 8.32 (s, 1H), 7.33 (dd, J=4.4, 7.2 Hz, 1H), 6.69 (s, 1H), 5.16 (t, J=6.0 Hz, 1H), 5.05 (t, J=5.6 Hz, 1H), 3.57-3.49 (m, 2H), 3.43 (t, J=6.0 Hz, 2H), 3.23-3.16 (m, 1H), 2.93-2.77 (m, 5H), 2.15-1.95 (m, 2H), 1.90-1.79 (m, 2H), 1.34 (s, 3H). MS (ESI): m/z=456.2 [M+1]⁺.

Example 45, Peak 2: ¹H NMR (400 MHz, DMSO-d₆): δ 10.43 (s, 1H), 9.36 (dd, J=1.6, 6.8 Hz, 1H), 8.89 (dd, J=1.6, 4.0 Hz, 1H), 8.68 (s, 1H)), 8.32 (s, 1H), 7.32 (dd, J=4.0, 6.8 Hz, 1H), 6.69 (s, 1H), 5.16 (t, J=6.0 Hz, 1H), 5.05 (t, J=5.6 Hz, 1H), 3.57-3.49 (m, 2H), 3.43 (t, J=6.0 Hz, 2H), 3.23-3.16 (m, 1H), 2.93-2.77 (m, 5H), 2.15-1.94 (m, 2H), 1.91-1.79 (m, 2H), 1.34 (s, 3H). MS (ESI): m/z=456.2 [M+1]⁺.

Examples 46 and 47. N—((S)-6-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and N—((R)-6-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (6-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (6-chloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol(Intermediate 2) (126 mg, 0.52 mmol), (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (140 mg, 1.03 mmol) and cesium carbonate (674 mg, 2.07 mmol) in acetonitrile (2 mL) was stirred 100° C. for 18 h in a sealed tube. After filtered and concentrated, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:2) as eluting solvents to afford (6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (120 mg, 76%) as a yellow solid. MS (ESI): m/z=307.3 [M+1]⁺.

Step B. (5-Amino-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (120 mg, 0.39 mmol) and 10% palladium on carbon (12 mg) in methanol (5 mL) was stirred at room temperature for 1 h under an atmosphere of hydrogen. Upon filtration over a plug of celite, the filtrate was concentrated under reduced pressure to afford (5-amino-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol(100 mg) as a yellow oil, which was used directly to the next step without purification. MS (ESI): m/z=277.1 [M+1]⁺.

Step C. N—((S)-6-((1S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and N—((R)-6-((1 S,4S)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of (5-amino-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol (100 mg, 0.36 mmol) and triethylamine (109 mg, 1.08 mmol) in DCM (5 mL) was stirred at 0° C. To the mixture was added a solution of pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (Example 3, Step B) (98 mg, 0.54 mmol) in DCM (5 mL) and the reaction was stirred at 25° C. for 1 h. After filtration, the residue was purified by preparative HPLC(Xbridge 21.2*250 mm c18, 10 um, acenitrile 25-55% (10 mM ammonium bicarbonate) in water) to afford N-(6-morpholino-2′,3′,5′,6′-tetrahydro-3H-spiro[benzofuran-2,4′-pyran]-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (120 mg, 0.24 mmol, 79%) as a yellow solid and it was separated by chiral pre-SFC(Column: AD 20*250 mm, Sum (Dacel), Mobile phase: CO2/methanol{0.5% Ammonia (7 m methanol)}=60/40) to obtain N—((S)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and N—((R)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (42 mg, 28%) (45 mg, 31%) as a yellow solids with absolute stereochemistry assigned arbitrarily.

Example 46, Peak 1: ¹H NMR (400 MHz, DMSO-d₆): δ 9.89 (s, 1H), 9.37 (dd, J=1.6, 7.2 Hz, 1H), 8.85 (dd, J=1.6, 4.0 Hz, 1H), 8.67 (s, 1H)), 7.88 (s, 1H), 7.32 (dd, J=4.0, 7.2 Hz, 1H), 6.52 (s, 1H), 5.04 (t, J=6.0 Hz, 1H), 4.49 (s, 1H), 4.10 (s, 1H), 3.90 (d, J=7.6 Hz, 1H), 3.66 (d, J=6.0 Hz, 1H), 3.48-3.38 (m, 2H), 3.30 (d, J=8.8 Hz, 1H), 3.20-3.07 (m, 2H), 2.79 (d, J=15.6 Hz, 1H), 2.00 (d, J=9.6 Hz, 1H), 1.80 (d, J=8.8 Hz, 1H), 1.34 (s, 3H). MS (ESI): m/z=422.1 [M+1]⁺.

Example 47, Peak 2: ¹H NMR (400 MHz, DMSO-d₆): δ 9.87 (s, 1H), 9.37 (dd, J=1.6, 7.2 Hz, 1H), 8.85 (dd, J=1.6, 4.0 Hz, 1H), 8.67 (s, 1H)), 7.86 (s, 1H), 7.32 (dd, J=4.0, 7.2 Hz, 1H), 6.51 (s, 1H), 5.05 (t, J=6.0 Hz, 1H), 4.49 (s, 1H), 4.10 (s, 1H), 3.93 (d, J=7.6 Hz, 1H), 3.67 (d, J=7.2 Hz, 1H), 3.48-3.38 (m, 2H), 3.25 (d, J=9.2 Hz, 1H), 3.20-3.10 (m, 2H), 2.79 (d, J=16.0 Hz, 1H), 2.00 (d, J=8.0 Hz, 1H), 1.80 (d, J=9.2 Hz, 1H), 1.34 (s, 3H). MS (ESI): m/z=422.1 [M+1]⁺.

Examples 48 and 49. (S)—N-(2-Methyl-2-(methylcarbamoyl)-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)—N-(2-Methyl-2-(methylcarbamoyl)-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. N, 2-Dimethyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carboxamide

A mixture of 2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carboxylic acid (100 mg, 0.32 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (338 mg, 0.65 mmol) and N-ethyl-N-isopropylpropan-2-amine (168 mg, 1.30 mmol) in DMF (10 mL) was stirred at room temperature for 30 min. Then methyl amine hydrochloride (44 mg, 0.65 mmol) was added. The resulting mixture was stirred at room temperature for 18 h. Water and ethyl acetate (50 mL) was added. The organic phase was separated and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:3 to 1:1) as eluting solvents to afford N, 2-dimethyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carboxamide (80 mg, 77%) as orange solid. MS (ESI): m/z=322.1 [M+1]t

Step B. 5-Amino-N, 2-dimethyl-6-morpholino-2,3-dihydrobenzofuran-2-carboxamide

A mixture of N, 2-dimethyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carboxamide (80 mg, 0.25 mmol) and 10% palladium on carbon (8 mg) in methanol (10 mL) was stirred at room temperature for 1 h under an atmosphere of hydrogen. Upon filtration over a plug of celite, the filtrate was concentrated under reduced pressure to afford 5-amino-N, 2-dimethyl-6-morpholino-2,3-dihydrobenzofuran-2-carboxamide as a white solid (60 mg), which was used directly in the next step without purification. MS (ESI): m/z=292.1 [M+1]⁺.

Step C. (S)—N-(2-Methyl-2-(methylcarbamoyl)-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)—N-(2-Methyl-2-(methylcarbamoyl)-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (34 mg, 0.21 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (107 mg, 0.21 mmol) and N-ethyl-N-isopropylpropan-2-amine (53 mg, 0.42 mmol) in DMF (5 mL) was stirred at room temperature for 30 min. 5-Amino-N, 2-dimethyl-6-morpholino-2,3-dihydrobenzofuran-2-carboxamide (The absolute structure was assigned arbitrarily) (60 mg, 0.21 mmol) was then added and the resulting mixture was stirred at room temperature for 18 h. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (15:1) as eluting solvents to afford the desired product separated by chiral SFC(AS 20*250 mm, Sum (Dacel), CO₂/methanol{0.2% Ammonia (7 m methanol)}=70/30) to obtain (S)—N-(2-methyl-2-(methylcarbamoyl)-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)—N-(2-methyl-2-(methylcarbamoyl)-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (12 mg, 13%) (10 mg, 11%) as a yellow solid with absolute stereochemistry assigned arbitrarily.

Example 48, Peak 1: ¹H NMR (400 MHz, MeOD-d₄): δ 9.14 (dd, J=1.6, 6.8 Hz, 1H), 8.94 (dd, J=1.6, 4.4 Hz, 1H), 8.67 (s, 1H)), 8.27 (s, 1H), 7.30 (dd, J=4.4, 7.2 Hz, 1H), 6.90 (s, 1H), 3.95-3.97 (m, 4H), 3.55 (d, J=16.0 Hz, 1H), 3.19 (d, J=16.0 Hz, 1H), 2.92-2.94 (m, 4H), 2.78 (s, 3H), 1.65 (s, 3H). MS (ESI): m/z=437.2 [M+1]⁺.

Example 49, Peak 2: ¹H NMR (400 MHz, MeOD-d₄): δ 9.03 (dd, J=1.5, 7.2 Hz, 1H), 8.81 (dd, J=1.6, 4.4 Hz, 1H), 8.56 (s, 1H)), 8.15 (s, 1H), 7.18 (dd, J=4.4, 7.2 Hz, 1H), 6.78 (s, 1H), 3.83-3.86 (m, 4H), 3.43 (d, J=16.4 Hz, 1H), 3.06 (d, J=16.4 Hz, 1H), 2.80-2.82 (m, 4H), 2.62 (s, 3H), 1.20 (s, 3H). MS (ESI): m/z=437.1 [M+1]⁺.

Examples 50 and 51. (R)—N-(2-(Difluoromethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(Difluoromethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. Methyl 2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carboxylate

A mixture of morpholine (270 mg, 3.1 mmol), methyl 6-fluoro-2-methyl-5-nitro-3H-benzofuran-2-carboxylate (Intermediate 3, Step D) (500 mg, 1.55 mmol) and potassium carbonate (427 mg, 3.1 mmol) in acetonitrile (10 mL) was stirred at 25° C. for 18 h. Water was added. The aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was dried over sodium sulfate and concentrated to afford methyl 2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-carboxylate (382 mg) as a yellow oil, which was used directly to next step without further purification. MS (ESI): m/z=323.1 [M+1]⁺.

Step B. 2-Methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carbaldehyde

To a mixture of methyl 2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-carboxylate (382 mg, 1.08 mmol) in DCM (10 mL) was added diisobutylaluminium hydride (1.62 mL, 1 m in hexane, 1.62 mmol) drop wise at −78° C. over 5 min and the reaction was maintained at −78° C. for 2 h with stirring. The mixture was quenched with sodium sulfate decahydrate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford 2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-carbaldehyde (230 mg, 73%) as a yellow solid. MS (ESI): m/z=325.1 [M+methanol]⁺.

Step C. 4-(2-(Difluoromethyl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine

To a mixture of 2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-carbaldehyde (180 mg, 0.62 mmol) in DCM (30 mL) was added drop wise diethylaminosulfur trifluoride (620 mg, 80%, 3.08 mmol) at −78° C. The mixture was stirred at 25° C. for for 18 h. The mixture was concentrated and purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:3 to 2:3) as eluting solvents to afford 4-[2-(difluoromethyl)-2-methyl-5-nitro-3H-benzofuran-6-yl]morpholine (110 mg, 53% yield) as a yellow solid. MS (ESI): m/z=323.1 [M+1]⁺.

Step D. 2-(Difluoromethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine

A mixture of 4-[2-(difluoromethyl)-2-methyl-5-nitro-3H-benzofuran-6-yl]morpholine (110 mg, 0.35 mmol) and 10% palladium on carbon (40 mg) in methanol (20 mL) was stirred at 25° C. under an atmosphere of hydrogen for 1 h. Upon filtration over a plug of celite, the filtrate was concentrated under reduced pressure to afford 2-(difluoromethyl)-2-methyl-6-morpholino-3H-benzofuran-5-amine (140 mg) as light green oil, which was used directly to next step without further purification. MS (ESI): m/z=285.1 [M+1]⁺.

Step E. N-(2-(Difluoromethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 2-(difluoromethyl)-2-methyl-6-morpholino-3H-benzofuran-5-amine (90 mg, 0.32 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (62 mg, 0.38 mmol) (3-Hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (247 mg, 0.47 mmol) and diisopropylethylamine (115 mg, 0.95 mmol) in DMF (5 mL) was stirred at 25° C. for 2 h. Water was added. The aqueous was extracted with ethyl acetate (70 mL). The organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (9:1) as eluting solvents to afford N-(2-(difluoromethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 73%) as a yellow solid. MS (ESI): m/z=430.1 [M+1]⁺.

Step F. (R)—N-(2-(Difluoromethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(Difluoromethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The N-(2-(difluoromethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.23 mmol) was purified by chiral separation (OJ 20*250 mm, 5 u at CO₂/methanol{0.2% Ammonia (7 m methanol)}=80/20, 80 g/min, 100 bar, 35° C.) to afford (R)—N-(2-(difluoromethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(difluoromethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 30%) (40 mg, 40%) as a yellow solids with absolute stereochemistry assigned arbitrarily.

Example 50, Peak 1: ¹H NMR (400 MHz, CDCl₃) δ 10.47 (s, 1H), 8.84 (dd, J=1.6, 6.8 Hz, 1H), 8.78 (s, 1H), 8.77 (dd, J=1.6, 4.0 Hz, 1H), 8.46 (s, 1H), 7.07 (dd, J=4.0, 6.8 Hz, 1H), 5.75 (t, J=56.0 Hz, 1H), 3.94-3.96 (m, 4H), 3.43 (d, J=16.0 Hz, 1H), 3.03 (d, J=16.0 Hz, 1H), 2.90-2.93 (m, 4H), 1.54 (s, 3H). MS (ESI): m/z=430.1 [M+1]⁺.

Example 51, Peak 2: ¹H NMR (400 MHz, CDCl₃) δ 10.48 (s, 1H), 8.84 (dd, J=1.6, 6.8 Hz, 1H), 8.78 (s, 1H), 8.77 (dd, J=1.6, 4.0 Hz, 1H), 8.46 (s, 1H), 7.07 (dd, J=4.0, 6.8 Hz, 1H), 5.75 (t, J=56.0 Hz, 1H), 3.94-3.96 (m, 4H), 3.43 (d, J=16.0 Hz, 1H), 3.03 (d, J=16.0 Hz, 1H), 2.90-2.93 (m, 4H), 1.54 (s, 3H). MS (ESI): m/z=430.1 [M+1]⁺.

Examples 52 and 53. (R)—N-(2-(Hydroxymethyl)-6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(Hydroxymethyl)-6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (2-(1-(2-(Hydroxymethyl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)propan-2-ol

A mixture of 2-(4-piperidyl)-2-propanol (76 mg, 0.53 mmol) (6-fluoro-2-methyl-5-nitro-3H-benzofuran-2-yl)methanol (100 mg, 0.44 mmol) and potassium (91 mg, 0.66 mmol) in acetonitrile (10 mL) was stirred at 25° C. for 18 h. Water was added. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phase dried over sodium sulfate and concentrated to afford 2-[1-[2-(hydroxymethyl)-2-methyl-5-nitro-3H-benzofuran-6-yl]-4-piperidyl]propan-2-ol (150 mg) as a yellow oil, which was used directly to next step without further purification. MS (ESI): m/z=351.1 [M+1]⁺.

Step B. 2-(1-(5-Amino-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-6-yl)piperidin-4-yl)propan-2-ol

A mixture of 2-[1-[2-(hydroxymethyl)-2-methyl-5-nitro-3H-benzofuran-6-yl]-4-piperidyl]propan-2-ol (150 mg, 0.43 mmol) and 10% palladium on carbon (40 mg, 0.43 mmol) in methanol (30 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. After filtration, the filtrate was concentrated under reduced pressure to afford 2-[1-[5-amino-2-(hydroxymethyl)-2-methyl-3H-benzofuran-6-yl]-4-piperidyl]propan-2-ol (160 mg, 82%) as a brown oil. MS (ESI): m/z=321.1 [M+1]⁺.

Step C. N-(2-(Hydroxymethyl)-6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 2-[1-[5-amino-2-(hydroxymethyl)-2-methyl-3H-benzofuran-6-yl]-4-piperidyl]propan-2-ol (160 mg, 0.50 mmol), 6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (106 mg, 0.60 mmol), (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (390 mg, 0.75 mmol) and diisopropylethylamine (181 mg, 1.50 mmol) in DMF (5 mL) was stirred at 25° C. for 2 h. Water was added. The aqueous phase was extracted with ethyl acetate (70 mL). The organic phase was washed with brine, dried over sodiumsulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (9:1) as eluting solvents to afford N-(2-(hydroxymethyl)-6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 42%) as a yellow solid. MS (ESI): m/z=480.1 [M+1]⁺.

Step D. (R)—N-(2-(Hydroxymethyl)-6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(Hydroxymethyl)-6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

The N-(2-(hydroxymethyl)-6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide was purified by chiral separation (OJ 20*250 mm, 5 u at CO₂/methanol{0.2% Ammonia (7 m methanol)}=80/20, 80 g/min, 100 bar, 35° C.) to afford (R)—N-(2-(hydroxymethyl)-6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(hydroxymethyl)-6-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide (40 mg, 40%) (50 mg, 50%) as a yellow solids with absolute stereochemistry assigned arbitrarily.

Example 52, Peak 1: ¹H NMR (400 MHz, CDCl₃) δ 10.42 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.68 (s, 1H), 8.57-8.58 (m, 1H), 8.39 (s, 1H), 6.64 (s, 1H), 3.65-3.67 (m, 2H), 3.23 (d, J=16.0 Hz, 1H), 3.12-3.15 (m, 2H), 2.94 (d, J=16.0 Hz, 1H), 2.58-2.64 (m, 2H), 2.42 (s, 3H), 2.02-2.06 (m, 2H), 1.71-1.84 (m, 4H), 1.46 (s, 3H), 1.25 (s, 6H). MS (ESI): m/z=480.2 [M+1]⁺.

Example 53, Peak 2: ¹H NMR (400 MHz, CDCl₃) δ 10.43 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.68 (s, 1H), 8.57-8.58 (m, 1H), 8.39 (s, 1H), 6.64 (s, 1H), 3.65-3.67 (m, 2H), 3.23 (d, J=16.0 Hz, 1H), 3.12-3.15 (m, 2H), 2.94 (d, J=16.0 Hz, 1H), 2.58-2.64 (m, 2H), 2.42 (s, 3H), 2.02-2.06 (m, 2H), 1.71-1.84 (m, 4H), 1.46 (s, 3H), 1.25 (s, 6H). MS (ESI): m/z=480.2 [M+1]⁺.

Examples 54 and 55. (R)-6-Fluoro-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)-6-Fluoro-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (Z)-2,3,3-Trifluoroprop-1-enyl 4-methylbenzenesulfonate

A mixture of 2,2,3,3-tetrafluoropropyl 4-methylbenzenesulfonate (3.0 g, 10.49 mmol) in THF (30 mL), was cooled to −78° C. n-butyllithium (9.23 mL, 23.08 mmol, 2.5 M in hexane) was added drop wise and the reaction was stirred at −78° C. for 10 min. The reaction was quenched with water and allowed to warm to room temperature. The aqueous phase was extracted with DCM (2×50 mL). The organic phases were dried over sodium sulfate and concentrated in vacuo to afford (Z)-2,3,3-trifluoroprop-1-enyl 4-methylbenzenesulfonate (1.96 g, 70%) as a yellow oil, which was used directly to next step without further purification. MS (ESI): m/z=267.0 [M+1]⁺

Step B. (Z)-3-(Diethylamino)-2-fluoroacrylaldehyde

To a solution of diethylamine (362 mg, 1.96 mmol), triethylamine (456 mg, 4.51 mmol), and a catalytic amount of tetrabutylammonium fluoride (0.45 mmol, 0.45 mL, 1 m in THF) in acetonitrile (3 mL), was added a solution of (Z)-2,3,3-trifluoroprop-1-enyl 4-methylbenzenesulfonate (1200 mg, 4.51 mmol) in acetonitrile (6 mL) at 0° C. The mixture was stirred at room temperature for 3 h and quenched with brine. The aqueous phase was extracted with DCM (2×30 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:4 to 1:1) as eluting solvents to afford (Z)-3-(diethylamino)-2-fluoroacrylaldehyde (558 mg, 85%) as a yellow oil.

MS (ESI): m/z=146.1 [M+1]⁺

Step C. Ethyl 6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate

A mixture of (Z)-3-(diethylamino)-2-fluoroacrylaldehyde (400 mg, 2.76 mmol) and ethyl 5-amino-1H-pyrazole-4-carboxylate (428 mg, 2.76 mmol) in acetic acid (5 mL) was stirred at 80° C. for 1 h. After concentration in vacuo, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:5) as eluting solvents to afford ethyl 6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate (180 mg, 26%) as a yellow solid. MS (ESI): m/z=210.1 [M+1]⁺.

Step D. 6-Fluoropyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A mixture of ethyl 6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate (70 mg, 0.33 mmol) and hydroxyl lithium hydrate (13 mg, 0.33 mmol) in methanol (1 mL), THE (1 mL) and water (1 mL), was stirred at 100° C. under microwave for 10 min. After concentration in vacuo, it was afforded 6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (47 mg) as a yellow solid, which as used directly to next step without further purification. MS (ESI): m/z=204.0 [M+1]⁺.

Step E. (5-Amino-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (Example 6, Step B) (128 mg, 0.44 mmol) and 10% palladium on carbon (30 mg) in methanol (5 mL) was stirred at 20° C. under hydrogen atmosphere for 2 h. Upon filtration through a plug of celite, the filtrate was concentrated under reduced pressure to afford (5-amino-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)methanol (102 mg, 89%) as a brown solid. MS (ESI): m/z=265.1 [M+1]⁺.

Step F. 6-Fluoro-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (47 mg, 0.26 mmol), (5-amino-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)methanol (82 mg, 0.31 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (148 mg, 0.39 mmol) and diisopropylethylamine (101 mg, 0.78 mmol) in DMF (5 mL) was stirred at 20° C. for 2 h. The crude reaction was purified by preparative HPLC(Xbridge 21.2*250 mm c18, 10 um, A: acetonitrile 15-40%; B: 10 mM ammonium bicarbonate in water) to afford 6-fluoro-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (46 mg, 42%) as a yellow solid.

Step G. (R)-6-Fluoro-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)-6-Fluoro-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

6-Fluoro-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2, 3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (46 mg, 0.11 mmol) was separated by chiral separation (SFC-80 (Thar, Waters), OJ 20*250 mm, 5 um (Dacel), C Mobile phase: CO2/methanol{0.5% Ammonia (7 m methanol)}=70/30) to afford (R)-6-fluoro-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)-6-fluoro-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (8.4 mg each, 37% each) as a yellow solids with absolute stereochemistry assigned arbitrarily.

Example 54, Peak 1: ¹H NMR (400 MHz, DMSO-d₆): δ 10.28 (s, 1H), 9.82 (dd, J=2.4, 4.4 Hz, 1H), 9.20 (d, J=2.4 Hz, 1H), 8.70 (s, 1H), 8.26 (s, 1H), 6.70 (s, 1H), 5.04 (t, J=6.0 Hz, 1H), 3.83-3.81 (m, 4H), 3.47-3.38 (m, 2H), 3.22-3.18 (m, 1H), 2.84-2.79 (m, 5H), 1.34 (s, 3H). MS (ESI): m/z=428.2 [M+1]⁺.

Example 55, Peak 2: ¹H NMR (400 MHz, DMSO-d₆): δ 10.28 (s, 1H), 9.82 (dd, J=2.4, 4.4 Hz, 1H), 9.20 (d, J=2.4 Hz, 1H), 8.70 (s, 1H), 8.26 (s, 1H), 6.70 (s, 1H), 5.04 (t, J=6.0 Hz, 1H), 3.83-3.81 (m, 4H), 3.47-3.38 (m, 2H), 3.22-3.18 (m, 1H), 2.84-2.79 (m, 5H), 1.34 (s, 3H). MS (ESI): m/z=428.2 [M+1]⁺.

Examples 56 and 57. N-[(2S)-6-[(3S)-3-Fluoropyrrolidin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2R)-6-[(3S)-3-Fluoropyrrolidin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. [6-[(35)-3-Fluoropyrrolidin-1-yl]-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol

A mixture of (6-chloro-2-methyl-5-nitro-3H-benzofuran-2-yl)methanol (Intermediate 2) (150 mg, 0.62 mmol), (S)-3-fluoropyrrolidine hydrochloride (110 mg, 1.23 mmol) and cesium carbonate (600 mg, 1.84 mmol) in DMSO (2 mL) was stirred at 90° C. for 3 h. The mixture was then poured into water and the aqueous phase was extracted with ethyl acetate (2×30 mL). The organic phases were combined and washed with water, brine and dried over sodium sulfate before concentration to dryness. The residue was purified by preparative TLC using ethyl acetate:petroleum ether (1:3) as eluting solvents to afford[6-[(3S)-3-fluoropyrrolidin-1-yl]-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol (102 mg, 55%) as a yellow oil. MS (ESI): m/z=297.1 [M+1].

Step B. [5-Amino-6-[(35)-3-Fluoropyrrolidin-1-yl]-2-methyl-3H-benzofuran-2-yl]methanol

A mixture of [6-[(3S)-3-fluoropyrrolidin-1-yl]-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol (102 mg, 0.34 mmol) and 10% palladium on carbon (10 mg) in methanol (10 mL) was stirred at room temperature under hydrogen atmosphere for 1 h. The reaction was filtered through a plug of celite and the filtrate was concentrated under reduced pressure to afford[5-amino-6-[(3R)-3-fluoropyrrolidin-1-yl]-2-methyl-3H-benzofuran-2-yl]methanol (96 mg) as a brown oil, which was used directly to next step without further purification. MS (ESI): m/z=297.1 [M+1].

Step C. N-[(25)-6-[(35)-3-Fluoropyrrolidin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2R)-6-[(35)-3-Fluoropyrrolidin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (118 mg, 0.72 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (340 mg, 0.89 mmol) and diisopropylethylamine (0.24 mL, 1.45 mmol) was stirred in DMF (3 mL) at room temperature for 10 min. To this mixture was added [5-amino-6-[(3S)-3-fluoropyrrolidin-1-yl]-2-methyl-3H-benzofuran-2-yl]methanol (96 mg, 0.36 mmol) in DMF (2 mL) and stirred for 16 h. The final products was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um, A: acetonitrile 25-70%; B:10 mM ammonium bicarbonate in water) and then the product was resolved by chiral separation (SFC (AD-H 20*250 mm, Sum, CO₂/methanol(0.5% Ammonia (7 m methanol))=50/50, 35° C.) to afford N-[(2S)-6-[(3S)-3-fluoropyrrolidin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2R)-6-[(3S)-3-fluoropyrrolidin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (16 mg, 11%) (19 mg, 13%) as a yellow solids with absolute stereochemistry assigned arbitrarily.

Example 56, Peak 1: ¹H NMR (400 MHz, CDCl₃) δ 10.25 (s, 1H), 8.81 (dd, J=1.6, 6.8 Hz, 1H), 8.77 (s, 1H), 8.69 (dd, J=2.0, 4.0, Hz, 1H), 8.26 (s, 1H), 7.02 (dd, J=4.4, 7.2, Hz, 1H), 6.59 (s, 1H), 5.42-5.25 (m, 1H), 3.67 (s, 2H), 355-3.44 (m, 1H), 3.43-3.40 (m, 1H), 3.36-3.32 (m, 1H), 3.24 (d, J=15.5 Hz, 1H), 2.95-2.86 (m, 2H), 2.34-2.21 (m, 2H), 2.08-1.89 (m, 1H), 1.46 (s, 3H). MS (ESI): m/z=412.1 [M+1]

Example 57, Peak 2: ¹H NMR (400 MHz, CDCl₃) δ 10.24 (s, 1H), 8.81 (dd, J=2.0, 7.2 Hz, 1H), 8.76 (s, 1H), 8.67 (dd, J=1.6, 4.0 Hz, 1H), 8.25 (s, 1H), 7.02 (dd, J=4.0, 7.2 Hz, 1H), 6.59 (s, 1H), 5.46-5.23 (m, 1H), 3.67 (s, 2H), 3.54-3.46 (m, 1H), 3.44-3.39 (m, 1H), 3.36-3.32 (m, 1H), 3.23 (d, J=16.0 Hz, 1H), 2.94 (d, J=16.0 Hz, 1H), 2.93-2.85 (m, 1H), 2.40-2.13 (m, 2H), 2.08-1.85 (m, 1H), 1.46 (s, 3H). MS (ESI): m/z=412.2 [M+1]

Examples 58 and 59. N-[(2R)-6-[(3R)-3-Fluoropyrrolidin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-6-[(3R)-3-Fluoropyrrolidin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. [6-[(3R)-3-Fluoropyrrolidin-1-yl]-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol

A mixture of (6-chloro-2-methyl-5-nitro-3H-benzofuran-2-yl)methanol (Intermediate 1) (150 mg, 0.62 mmol), (3R)-3-fluoropyrrolidine hydrochloride (440 mg, 3.5 mmol) and cesium carbonate (780 mg, 2.4 mmol) in DMSO (2 mL) was stirred at 90° C. for 7 h. The mixture was poured into water and extracted ethyl acetate (100 mL) and the organics washed with water brine and dried over sodium sulfate before concentration to dryness. The residue was then purified by preparative TLC using ethyl acetate:petroleum ether (1:3) as eluting solvents to afford[6-[(3R)-3-fluoropyrrolidin-1-yl]-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol(135 mg, 74%) as a yellow oil. MS (ESI): m/z=297.1 [M+1]⁺.

Step B. [5-Amino-6-[(3R)-3-fluoropyrrolidin-1-yl]-2-methyl-3H-benzofuran-2-yl]methanol

A mixture of [6-[(3R)-3-Fluoropyrrolidin-1-yl]-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol (135 mg, 0.46 mmol) and 10% palladium on carbon (50 mg) in methanol (12 mL) was stirred under hydrogen atmosphere at 25° C. for 1 h. After filtration through a plug of celite and concentration, it was afforded [5-amino-6-[(3R)-3-fluoropyrrolidin-1-yl]-2-methyl-3H-benzofuran-2-yl]methanol (110 mg) as a brown oil which was directly used to the next step without further purification. MS (ESI): m/z=267.1 [M+1]⁺.

Step C. N-[(2R)-6-[(3R)-3-Fluoropyrrolidin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(25)-6-[(3R)-3-Fluoropyrrolidin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of diisopropylethylamine (0.2 mL, 1.24 mmol) and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (102 mg, 0.63 mmol) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (314 mg, 0.83 mmol) then was stirred at 25° C. for 20 min. To the mixture was added the solution of [5-amino-6-[(3R)-3-fluoropyrrolidin-1-yl]-2-methyl-3H-benzofuran-2-yl]methanol (110 mg, 0.41 mmol) in DMF (3 mL) and the mixture was stirred at 25° C. for 16 h. The crude was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um, A: acetonitrile 25-55%; B: 10 mM ammonium bicarbonate in water) and resolved by chiral separation (SFC-80 (Thar, Waters), AD 20*250 mm, Sum (Dacel), CO₂/methanol{0.5% Ammonia (7 m methanol)}=50/50) to afford N-[(2R)-6-[(3R)-3-fluoropyrrolidin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-6-[(3R)-3-fluoropyrrolidin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (24 mg, 14%) (29 mg, 17%) as a yellow solids with absolute stereochemistry assigned arbitrarily.

Example 58, Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 10.11 (s, 1H), 9.36 (dd, J=1.6, 7.2 Hz, 1H), 8.81 (dd, J=1.6, 4.0 Hz, 1H), 8.68 (s, 1H), 8.05 (s, 1H), 7.31 (dd, J=4.0, 7.2 Hz, 1H), 6.59 (s, 1H), 5.39 (td, J=4.4, 55.2 Hz, 1H), 5.04 (t, J=5.6 Hz, 1H), 3.56-3.34 (m, 4H), 3.22-3.07 (m, 2H), 2.93-2.85 (m, 1H), 2.81 (d, J=16.0 Hz, 1H), 2.36-2.05 (m, 2H), 1.34 (s, 3H). MS (ESI): m/z=412.1 [M+1]⁺.

Example 59, Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 10.11 (s, 1H), 9.36 (dd, J=1.6, 7.2 Hz, 1H), 8.81 (dd, J=1.6, 4.0 Hz, 1H), 8.68 (s, 1H), 8.05 (s, 1H), 7.31 (dd, J=4.0, 7.2 Hz, 1H), 6.60 (s, 1H), 5.39 (td, J=4.4, 54.4 Hz, 1H), 5.04 (t, J=5.6 Hz, 1H), 3.56-3.34 (m, 4H), 3.22-3.07 (m, 2H), 2.93-2.85 (m, 1H), 2.81 (d, J=16.0 Hz, 1H), 2.36-2.07 (m, 2H), 1.34 (s, 3H). MS (ESI): m/z=412.2 [M+1]⁺.

Example 60. N-[6-[4-(2-Hydroxyethyl)piperazin-1-yl]-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidiine-3-carboxamide

Step A. 2-[4-(2,2-Dimethyl-5-nitro-3H-benzofuran-6-yl)piperazin-1-yl]ethanol

A mixture of 6-chloro-2,2-dimethyl-5-nitro-3H-benzofuran (Intermediate 1) (100 mg, 0.44 mmol) and 1-piperazineethanol (572 mg, 4.39 mmol) in DMSO (1 mL) was stirred at 110° C. for 16 h. The mixture was poured into water and the aqueous phase was extracted by ethyl acetate (100 mL). The organic phase was washed with water, brine and dried over sodium sulfate before concentration to dryness. The residue was purified by preparative TLC using methanol:DCM=1:20 as eluting solvents to afford 2-[4-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)piperazin-1-yl]ethanol (110 mg, 78%) as a brown oil. MS (ESI): m/z=322.1 [M+1]⁺.

Step B. 2-[4-(5-Amino-2,2-dimethyl-3H-benzofuran-6-yl)piperazin-1-yl]ethanol

A mixture of 2-[4-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)piperazin-1-yl]ethanol (59 mg, 0.18 mmol) and 10% palladium on carbon (29 mg) in methanol (8 mL) was stirred under hydrogen atmosphere at 20° C. for 1 h. After filtration and concentration, 2-[4-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)piperazin-1-yl]ethanol (50 mg) was afforded as a brown oil, which was used to the next step without further purification. MS (ESI): m/z=392.2 [M+1]⁺.

Step C. N-[6-[4-(2-Hydroxyethyl)piperazin-1-yl]-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To the mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (42 mg, 0.26 mmol) and diisopropylethylamine (0.09 mL, 0.52 mmol) in DMF (2 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (131 mg, 0.34 mmol) then the mixture was stirred at 25° C. for 15 min. To the mixture was added a solution of 2-[4-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)piperazin-1-yl]ethanol (50 mg, 0.17 mmol) in DMF (2 mL) and the resulting mixture was stirred at 25° C. for 16 h. The mixture was purified by preparative HPLC(Xbridge 21.2*250 mm c18, 10 um, A: acetonitrile 10-70%; B:10 mM ammonium bicarbonate in water) to afford N-[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (45 mg, 60%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 9.37 (dd, J=1.6, 7.2 Hz, 1H), 8.92 (dd, J=1.6, 4.4 Hz, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 7.36 (dd, J=4.4, 7.2 Hz, 1H), 6.69 (s, 1H), 4.45 (t, J=5.2 Hz, 1H), 3.54 (q, J=5.6 Hz, 2H), 3.00 (s, 2H), 2.84-2.78 (m, 4H), 2.74-2.61 (m, 4H), 2.50 (t, J=5.6 Hz, 2H), 1.41 (s, 6H). MS (ESI): m/z=437.3 [M+1]⁺.

Example 61. 6-Cyclopropyl-N-(2,2-dimethyl-6-morpholino-3H-benzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. Ethyl 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylate

To a mixture of ethyl 3-amino-1H-pyrazole-4-carboxylate (3.0 g, 19.34 mmol) and 2-bromomalonaldehyde (3.21 g, 21.26 mmol) in ethanol (10 mL) was added acetic acid (30 mL). The mixture was stirred for 2 h at 70° C. The reaction was concentrated to dryness. The residue was dissolved in ethyl acetate and saturated sodium bicarbonate solution was added. The organic phase was extracted and dried over sodium sulfate before concentration to dryness. The residue was then purified by silica gel chromatography using ethyl acetate:petroleum ether (1:3) as eluting solvents to afford ethyl 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylate (3.3 g, 63%) as a white solid. MS (ESI): m/z=270.0 [M+1]⁺.

Step B. Ethyl 6-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxylate

A mixture of ethyl 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylate (400 mg, 1.48 mmol), cyclopropylboronicacid (200 mg, 2.33 mmol), palladium diacetate (56 mg, 0.25 mmol), triphenylphosphine (168 mg, 0.60 mmol) and potassium phosphate (1260 mg, 5.94 mmol) in toluene (6 mL) and water (1 mL) in a sealed tube was stirred under N₂ atmosphere at 120° C. for 2 h. The mixture was poured onto water (30 mL) and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was washed with water and brine and dried over sodium sulfate before concentration to dryness. The residue was purified by preparative TLC using ethyl acetate:petroleum ether (1:3) to afford ethyl 6-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxylate (205 mg, 60%) as a yellow solid. MS(ESI): m/z=232.1 [M+1]⁺.

Step C. 6-Cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid

The mixture of ethyl 6-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxylate (60 mg, 0.26 mmol) and lithium hydroxide (12 mg, 0.29 mmol) in THE (3 mL), methanol (3 mL) and water (3 mL) was stirred at 100° C. for 10 min. The mixture was neutralized with 1N hydrogen chloride solution. The aqueous phase was extracted with EtOAc (20 mL). The organic phase was separated, dried over sodium sulfate and concentrated under reduced pressure to afford 6-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (52 mg) as a yellow solid, which was directly used in the next step without further purification. MS (ESI): m/z=204.1[M+1]⁺.

Step E. 6-Cyclopropyl-N-(2,2-dimethyl-6-morpholino-3H-benzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a mixture of 6-cyclopropylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (61 mg, 0.30 mmol) and diisopropylethylamine (0.11 mL, 0.66 mmol) in DMF (2 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (154 mg, 0.41 mmol) and the mixture was stirred at 25° C. for 20 min. To the mixture was added a solution of 2,2-dimethyl-6-morpholino-3H-benzofuran-5-amine (50 mg, 0.20 mmol) in DMF (2 mL) and the mixture was stirred at 25° C. for 16 h. The product was crushed out. After filtration, the solid was collected and washed with methanol to afford 6-cyclopropyl-N-(2,2-dimethyl-6-morpholino-3H-benzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (61 mg, 70%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 8.70 (s, 1H), 8.65 (d, J=2.0 Hz, 1H), 8.50 (dd, J=0.8 Hz, 2.0 Hz, 1H), 8.43 (s, 1H), 6.65 (s, 1H), 3.97 (t, J=4.4 Hz, 4H), 3.04 (s, 2H), 2.92 (t, J=4.4 Hz, 4H), 2.09-2.00 (m, 1H), 1.49 (s, 6H), 1.20-1.13 (m, 2H), 0.86-0.79 (m, 2H). MS (ESI): m/z=434.1[M+1]⁺.

Example 62. N— [2, 2-Dimethyl-6-(4-piperidyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. tert-Butyl 4-(2, 2-dimethyl-5-nitro-3H-benzofuran-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate

A mixture of N-Boc-1,2,5,6-tetrahydropyridine-4-boronicacidpinacolester (1350 mg, 4.37 mmol) 6-chloro-2,2-dimethyl-5-nitro-3H-benzofuran (Intermediate 1) (345 mg, 1.52 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (99 mg, 0.14 mmol) and cesium carbonate (1120 mg, 3.44 mmol) in 1,4-dioxane (10 mL) and water (1 mL) in a sealed tube was stirred at 90° C. under microwave conditions for 2 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (200 mL). The organic phase was washed with water and brine and dried over sodium sulfate before concentration to dryness. The residue was then purified by preparative TLC using ethyl acetate:petroleum ether (1:5) to afford tert-butyl 4-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (550 mg, 87%) as a yellow oil. MS (ESI): m/z=397.2[M+Na]⁺.

Step B. tert-Butyl 4-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)piperidine-1-carboxylate

A mixture of tert-butyl 4-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (100 mg, 0.27 mmol) and 10% palladium on carbon (50 mg) in methanol (10 mL) was stirred under hydrogen atmosphere at 20° C. for 2 h. After filtration through a plug of celite and concentration under reduced pressure, it was afforded tert-butyl 4-(5-amino-2, 2-dimethyl-3H-benzofuran-6-yl)piperidine-1-carboxylate (85 mg) as a brown oil, which was directly used in the next step without further purification. MS (ESI): m/z=291.1[M-tBu]⁺.

Step C. tert-Butyl4-[2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]piperidine-1-carboxylate

To a mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (60 mg, 0.37 mmol) and diisopropylethylamine (0.12 mL, 0.74 mmol) in DMF (2 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and stirred for 20 min at 25° C. To the mixture was added a solution of tert-butyl 4-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)piperidine-1-carboxylate (85 mg, 0.25 mmol) in DMF (2 mL) and stirred at 25° C. for 16 h. The mixture was poured into water and the aqueous phase was extracted with ethyl acetate (100 mL). The organic phase was washed with water and brine and dried over sodium sulfate before concentration to dryness. The residue was purified by preparative TLC using ethyl acetate:petroleum ether (3:2) as eluting solvents to afford tert-butyl 4-[2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]piperidine-1-carboxylate (63 mg, 52%) as a yellow solid. MS (ESI): m/z=492.2[M+1]⁺.

Step D. N-[2,2-Dimethyl-6-(4-piperidyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of tert-butyl 4-[2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]piperidine-1-carboxylate (63 mg, 0.13 mmol) in DCM (4 mL) was added trifluoroacetic acid (0.29 mL, 3.95 mmol) and the mixture was stirred at 25° C. for 2 h. The mixture was neutralized by triethylamine. After concentration, the residue was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-55%; B: 10 mM ammonium bicarbonate in water) to afford N-[2,2-dimethyl-6-(4-piperidyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (33 mg, 66%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (s, 1H), 9.40 (dd, J=1.6, 6.8 Hz, 1H), 8.87 (dd, J=1.6, 4.4 Hz, 1H), 8.69 (s, 1H), 7.74 (s, 1H), 7.34 (dd, J=4.4, 6.8 Hz, 1H), 6.63 (s, 1H), 3.02 (t, J=12.0 Hz, 2H), 3.00 (s, 2H), 2.97-2.87 (m, 1H), 2.59 (t, J=12.0 Hz, 2H), 1.69 (d, J=11.2 Hz, 2H), 1.59-1.45 (m, 2H), 1.42 (s, 6H). MS (ESI): m/z=392.2[M+1]⁺.

Example 63. N-[2,2-Dimethyl-6-(1-methyl-4-piperidyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. N-[2,2-Dimethyl-6-(1-methyl-4-piperidyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of N-[2,2-dimethyl-6-(4-piperidyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 62) (39 mg, 0.10 mmol) in methanol (4 mL) was added formaldehyde (200 mg, 2.46 mmol, 30 wt %) and the mixture was stirred at 25° C. for 30 min. To the mixture was added sodium cyanoborohydride (30 mg, 0.5 mmol) the reaction was stirred at 25° C. for 1 h. Water was added and the mixture was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-55%; B: 10 mM ammonium bicarbonate in water) to afford N-[2,2-dimethyl-6-(1-methyl-4-piperidyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (23 mg, 57%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.61 (s, 1H), 9.40 (dd, J=1.6, 6.8 Hz, 1H), 8.87 (dd, J=1.6, 4.4 Hz, 1H), 8.69 (s, 1H), 7.73 (s, 1H), 7.35 (dd, J=4.4, 6.8 Hz, 1H), 6.65 (s, 1H), 3.00 (s, 2H), 2.88 (d, J=11.6 Hz, 2H), 2.83-2.73 (m, 1H), 2.18 (s, 3H), 1.96 (t, J=9.6 Hz, 2H), 1.77-1.59 (m, 4H), 1.42 (s, 6H). MS (ESI): m/z=406.2[M+1]⁺.

Examples 64 and 65. Cis-N-[6-(4-hydroxycyclohexoxy)-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and Trans-N-[6-(4-hydroxycyclohexoxy)-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. tert-Butyl-[4-[(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)oxy]cyclohexoxy]-diphenyl-silane

To a mixture of 4-[tert-butyl(diphenyl)silyl]oxycyclohexanol (255 mg, 0.72 mmol), potassium tert-butanolate (130 mg, 1.16 mmol) and 6-fluoro-2,2-dimethyl-5-nitro-3H-benzofuran (Example 3, Step F) (265 mg, 1.25 mmol) in 1,4-dioxane (7 mL) was stirred at 40° C. for 36 h. The mixture was purified by reverse phase chromatography (C18, 80 g, 40-60 um, 10 um; A: acetonitrile 0.1% to 100%; 10 mM in water) to afford tert-butyl-[4-[(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)oxy]cyclohexoxy]-diphenyl-silane (110 mg, 28%) as a yellow oil. MS (ESI): m/z=568.2[M+Na]⁺.

Step B. 4-[(2,2-Dimethyl-5-nitro-3H-benzofuran-6-yl)oxy]cyclohexanol

The mixture of tert-butyl-[4-[(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)oxy]cyclohexoxy]-diphenyl-silane (100.0 mg, 0.18 mmol) in methanol (10 mL) was added 12N hydrogen chloride solution (0.3 mL, 3.6 mmol) and the mixture was stirred at 25° C. for 5 h. The mixture was neutralized by triethylamine to pH=8.0 and concentrated under reduced pressure. The residue was purified by preparative TLC using ethyl acetate:petroleum ether (1:3) to afford 4-[(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)oxy]cyclohexanol (53 mg, 94%) as a yellow oil. MS (ESI): m/z=330.1[M+Na]⁺.

Step C. 4-[(5-Amino-2,2-dimethyl-3H-benzofuran-6-yl)oxy]cyclohexanol

A mixture of 4-[(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)oxy]cyclohexanol (53 mg, 0.17 mmol) and 10% palladium on carbon (25 mg) in methanol (6 mL) was stirred under a hydrogen atmosphere at 25° C. for 1 h. After filtration through a plug of celite and concentration, it was afforded 4-[(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)oxy]cyclohexanol (45 mg) as a brown oil which was directly used in the next step without further purification. MS (ESI): m/z=278.1[M+1]⁺.

Step D. Cis-N-[6-(4-hydroxycyclohexoxy)-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and Trans-N-[6-(4-hydroxycyclohexoxy)-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To the mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40 mg, 0.25 mmol) and diisopropylethylamine (0.08 mL, 0.50 mmol) in DMF (2 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (123 mg, 0.32 mmol) then the mixture was stirred at 25° C. for 20 min. To the mixture was added the solution of 4-[(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)oxy]cyclohexanol (45 mg, 0.16 mmol) in DMF (2 mL) and the mixture was stirred at 25° C. for 16 h. The crude was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-55%; B: 10 mM ammonium bicarbonate in water) to afford Cis-N-[6-(4-hydroxycyclohexoxy)-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (26 mg, 38%) and Trans-N-[6-(4-hydroxycyclohexoxy)-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (10 mg, 15%) as a yellow solids.

Cis-N-[6-(4-hydroxycyclohexoxy)-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide: ¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (s, 1H), 9.36 (dd, J=1.6, 7.2 Hz, 1H), 8.83 (dd, J=1.6, 4.4 Hz, 1H), 8.66 (s, 1H), 8.28 (s, 1H), 7.31 (dd, J=4.4, 7.2 Hz, 1H), 6.63 (s, 1H), 4.57 (d, J=4.4 Hz, 1H), 4.42-4.34 (m, 1H), 3.62-3.51 (m, 1H), 2.97 (s, 2H), 2.12-2.01 (m, 2H), 1.95-1.85 (m, 2H), 1.65-1.52 (m, 2H), 1.41 (s, 6H), 1.39-1.28 (m, 2H). MS (ESI): m/z=423.2[M+1]⁺.

Trans-N-[6-(4-hydroxycyclohexoxy)-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide: ¹H NMR (400 MHz, DMSO-d₆) δ 10.11 (s, 1H), 9.37 (dd, J=1.6, 7.2 Hz, 1H), 8.98 (dd, J=1.6, 4.4 Hz, 1H), 8.67 (s, 1H), 8.26 (s, 1H), 7.35 (dd, J=4.4, 7.2 Hz, 1H), 6.60 (s, 1H), 4.61 (d, J=3.2 Hz, 1H), 4.54-4.47 (m, 1H), 3.69-3.61 (m, 1H), 2.97 (s, 2H), 2.04-1.94 (m, 2H), 1.82-1.72 (m, 2H), 1.72-1.65 (m, 2H), 1.64-1.55 (m, 2H), 1.41 (s, 6H). MS (ESI): m/z=423.2[M+1]⁺.

Examples 66 and 67. N-[(2R)-6-(3,3-Difluoropyrrolidin-1-yl)-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-6-(3,3-Difluoropyrrolidin-1-yl)-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5a]pyrimidine-3-carboxamide

Step A. [6-(3,3-Difluoropyrrolidin-1-yl)-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol

To a solution of (6-fluoro-2-methyl-5-nitro-3H-benzofuran-2-yl)methanol (Intermediate 3) (150.0 mg, 0.66 mmol) and potassium carbonate (228.0 mg, 1.65 mmol) in acetonitrile (5 mL) was added 3,3-difluoropyrrolidine hydrochloride (114.0 mg, 0.79 mmol) and the mixture was stirred for 16 h. Water (10 mL) was added to the mixture. The aqueous phase was extracted with DCM (3×20 mL). The organic phases were combined and washed with water, dried over sodium sulfate and concentrated in vacuo to afford the [6-(3,3-difluoropyrrolidin-1-yl)-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol (208 mg) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=315.1 [M+1]⁺.

Step B. [5-Amino-6-(3,3-difluoropyrrolidin-1-yl)-2-methyl-3H-benzofuran-2-yl]methanol

A mixture of [6-(3,3-difluoropyrrolidin-1-yl)-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol (208.0 mg, 0.66 mmol) and 10% palladium on carbon (20.0 mg, 0.66 mmol) in methanol (5 mL) was stirred at room temperature under hydrogen atmosphere for 1 h. The reaction was filtered through a plug of celite and the filtrate was concentrated under reduced pressure to afford[5-amino-6-(3,3-difluoropyrrolidin-1-yl)-2-methyl-3H-benzofuran-2-yl]methanol (188 mg) as a colorless oil, which was used directly to next step without further purification. MS (ESI): m/z=285.1 [M+1]⁺.

Step C. N-[(2R)-6-(3,3-Difluoropyrrolidin-1-yl)-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(25)-6-(3,3-Difluoropyrrolidin-1-yl)-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of [5-amino-6-(3,3-difluoropyrrolidin-1-yl)-2-methyl-3H-benzofuran-2-yl]methanol (181.0 mg, 0.64 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (104.0 mg, 0.64 mmol) and diisopropylethylamine (0.22 mL, 1.33 mmol) in DMF (5 mL) was added 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (364.0 mg, 0.90 mmol) at 25° C. The mixture was stirred at 25° C. for 16 h. The mixture was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A:acetonitrile 25-55%; B:10 mM ammonium bicarbonate in water) and followed chiral resolution by SFC(SFC-80 (Thar, Waters), OD 20*250 mm, 5 um (Dacel), CO₂/methanol {0.2% Ammonia (7 m methanol)}=65/35) to afford N-[(2R)-6-(3,3-difluoropyrrolidin-1-yl)-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-6-(3,3-difluoropyrrolidin-1-yl)-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (32.3 mg, 12%) (38.6 mg, 14%) as a yellow solids with absolute stereochemistry assigned arbitrarily.

Example 66, Peak 1: ¹H NMR (400 MHz, DMSO-d₆): δ: 10.25 (s, 1H), 9.37 (dd, J=1.6, 6.8 Hz, 1H), 8.79 (dd, J=1.6, 4.0 Hz, 1H), 8.68 (s, 1H), 8.21 (s, 1H), 7.33 (dd, J=4.0, 6.8 Hz, 1H), 6.72 (s, 1H), 5.05 (t, J=5.6 Hz, 1H), 3.52-3.39 (m, 4H), 3.24-3.15 (m, 3H), 2.83 (d, J=15.6 Hz, 1H), 1.34 (s, 3H). MS (ESI): m/z=430.2 [M+1]⁺.

Example 67, Peak 1: ¹H NMR (400 MHz, DMSO-d₆): δ: 10.24 (s, 1H), 9.37 (dd, J=1.6, 6.8 Hz, 1H), 8.79 (dd, J=1.6, 4.0 Hz, 1H), 8.68 (s 1H), 8.21 (s, 1H), 7.34 (dd, J=4.0, 7.2 Hz, 1H), 6.72 (s, 1H), 5.05 (t, J=5.6 Hz, 1H), 3.53-3.39 (m, 4H), 3.24-3.15 (m, 3H), 2.83 (d, J=15.6 Hz, 1H), 1.34 (s, 3H). MS (ESI): m/z=430.1 [M+1]⁺.

Example 68. N-(6-(3,3-Difluoro-4-hydroxypyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 4,4-Difluoropyrrolidin-3-ol trifluoroacetic acid salt

A mixture of tert-butyl 3,3-difluoro-4-hydroxypyrrolidine-1-carboxylate (100 mg, 0.45 mmol) and trifluoroacetic acid (1 mL) in DCM (5 mL), was stirred at 20° C. for 2 h. After removal of solvents under reduced pressure, it was afforded 4,4-difluoropyrrolidin-3-ol trifluoroacetic acid salt (46 mg) as a brown oil, which was used directly to next step without further purification. MS (ESI): m/z=124.1 [M+1]⁺.

Step B. 1-(2,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-4,4-difluoropyrrolidin-3-ol

A mixture of 4,4-difluoropyrrolidin-3-ol trifluoroacetic acid salt (46 mg, 0.35 mmol), 6-fluoro-2,2-dimethyl-5-nitro-3H-benzofuran (Example 3, Step F) (75 mg, 0.35 mmol) and potassium carbonate (145 mg, 1.05 mmol) in acetonitrile (5 mL) was stirred at 90° C. for 20 h. After removal of the solvents under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:4 to 1:1) to afford 1-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-4,4-difluoropyrrolidin-3-ol (62 mg, 53%) as a yellow solid. MS (ESI): m/z=315.1 [M+1]⁺.

Step C. 1-(5-Amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)-4,4-difluoropyrrolidin-3-ol

A mixture of 1-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-4,4-difluoropyrrolidin-3-ol (62 mg, 0.20 mmol) and 10% palladium on carbon (15 mg) in methanol (5 mL) was stirred at 20° C. under hydrogen atmosphere for 2 h. After filtration and careful concentration (product is volatile), it was afforded 1-(5-amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)-4,4-difluoropyrrolidin-3-ol (52 mg, 80%) as a yellow solid. MS (ESI): m/z=285.0 [M+1]⁺.

Step D. N-(6-(3,3-Difluoro-4-hydroxypyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 1-(5-amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)-4,4-difluoropyrrolidin-3-ol (52 mg, 0.15 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (30 mg, 0.18 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (119 mg, 0.23 mmol) and diisopropylethylamine (59 mg, 0.46 mmol) in DMF (3 mL) was stirred at 20° C. for 16 h. The crude was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A:acetonitrile 15-40%; B: 10 mM ammonium bicarbonate in water) to afford N-(6-(3,3-difluoro-4-hydroxypyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (51.2 mg, 78%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.07 (s, 1H), 9.37 (dd, J=1.6, 6.8 Hz, 1H), 8.77 (dd, J=2.0, 4.4 Hz, 1H), 8.68 (s, 1H), 8.10 (s, 1H), 7.35 (dd, J=4.0, 6.8 Hz, 1H), 6.65 (s, 1H), 5.92 (d, J=5.6 Hz, 1H), 4.37-4.32 (m, 1H), 3.60-3.45 (m, 3H), 2.99 (s, 2H), 2.91-2.87 (m, 1H), 1.42 (s, 3H), 1.41 (s, 3H). MS (ESI): m/z=430.1 [M+1]⁺.

Example 69. N-(2,2-Dimethyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. Methylpyrazolo[1,5-a]pyrimidine-3-carboxylate

To a solution of pyrrolo[1,2-a]pyrimidine-8-carboxylic acid (4.97 g, 30.7 mmol) in methanol (120 mL) was added concentrated sulfuric acid (5 mL). The reaction mixture was stirred for 18 h at reflux. After concentration, saturated sodium bicarbonate solution was added slowly. The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine and dried over sodium sulfate. After filtration and concentration, methyl pyrrolo[1,2-a]pyrimidine-8-carboxylate (4.50 g, 83%) was afforded as a yellow solid. MS (ESI): m/z=200.0 [M+Na].

Step B. Methyl 6-iodopyrazolo[1,5-a]pyrimidine-3-carboxylate

To a mixture of methyl pyrrolo[1,2-a]pyrimidine-8-carboxylate (3.43 g, 19.47 mmol) and sodium acetate (15.97 g, 194.74 mmol) in acetic acid (80 mL) was added iodine monochloride (3.79 g, 23.37 mmol). The reaction mixture was stirred for 18 h at 25° C. After concentration, saturated sodium bicarbonate solution was added. The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic phases were washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:4) as eluting solvents to afford methyl 6-iodopyrazolo[1,5-a]pyrimidine-3-carboxylate (2.97 g, 51%) as a yellow solid. MS (ESI): m/z=325.9 [M+Na].

Step C. Methyl 6-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate

A mixture of methyl 6-iodopyrazolo[1,5-a]pyrimidine-3-carboxylate (400.0 mg, 1.32 mmol) and (1,10-phenanthroline)(trifluoromethyl)copper(I) (619.2 mg, 1.98 mmol) in DMF (0.5 mL) was heated to 50° C. and stirred for 18 h in glove box. Water and ethyl acetate (50 mL) was added and the organic phase was washed with water, brine and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatographyt using ethyl acetate:petroleum ether (1:4) as eluting solvents to afford methyl 6-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg, 31%) as a yellow solid. MS (ESI): m/z=246.0 [M+1]⁺.

Step D. 6-(Trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A mixture of methyl 6-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (50.0 mg, 0.20 mmol) in concentrated hydrochloric acid (2 mL) was stirred for 4hat 100° C. The reaction was concentrated to dryness and the residue was purified by preparative HPLC (A:acetonitrile 25-37%; B: 0.05% formic acid in water) to afford 6-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (25 mg, 53%) as a white solid. MS (ESI): m/z=232.0 [M+1]⁺.

Step E. N-(2,2-Dimethyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 2,2-dimethyl-6-morpholino-3H-benzofuran-5-amine (Example 33, step B) (34.0 mg, 0.14 mmol), 6-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (25 mg, 0.11 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (78.09 mg, 0.21 mmol) and diisopropylethylamine (52.99 mg, 0.41 mmol) in DMF (5 mL) was stirred for 18 h at 25° C. The crude was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-55%; B:10 mmol/L ammonium bicarbonate in water) to afford N-(2,2-dimethyl-6-morpholino-3H-benzofuran-5-yl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (34 mg, 67%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 10.26 (s, 1H), 10.12 (d, J=0.8 Hz, 1H), 9.23 (d, J=2.0 Hz, 1H), 8.88 (s, 1H), 8.27 (s, 1H), 6.72 (s, 1H), 3.83-8.10 (m, 4H), 3.01 (s, 2H), 2.83-2.79 (m, 4H), 1.42 (s, 6H). MS (ESI): m/z=462.1 [M+1]⁺.

Example 70. N-[2,2-Dimethyl-6-(2,2,2-trifluoroethoxy)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 2,2-Dimethyl-5-nitro-6-(2,2,2-trifluoroethoxy)-3H-benzofuran

The mixture of cesium carbonate (125.0 mg, 0.38 mmol), palladium diacetate (5.0 mg, 0.02 mmol), 6-bromo-2,2-dimethyl-5-nitro-3H-benzofuran (Intermediate 4) (52.0 mg, 0.19 mmol) and racemic-2-(di-tert-butylphosphino)-1,1′-binaphthyl (77.0 mg, 0.19 mmol) in 2,2,2-trifluoroethanol (0.30 mL) and toluene (3.0 mL) was heated in a sealed tube at 80° C. under microwave condition and the reaction was stirred for 3 h. The reaction was concentrated to dryness under reduced pressure and then purified by silica gel chromatography using ethyl acetate:petroleum ether (1:10) as eluting solvents to afford 2,2-dimethyl-5-nitro-6-(2,2,2-trifluoroethoxy)-3H-benzofuran (37 mg, 56%) as a colorless oil. MS (ESI): m/z=292.0 [M+1]⁺.

Step B. 2,2-Dimethyl-6-(2,2,2-trifluoroethoxy)-3H-benzofuran-5-amine

A mixture of 10% palladium on carbon (5.0 mg) and 2,2-dimethyl-5-nitro-6-(2,2,2-trifluoroethoxy)-3H-benzofuran (37.0 mg, 0.13 mmol) in methanol (2 mL) was stirred at 25° C. under hydrogen atmosphere for 2 h. After filtration and concentration under reduced pressure, it was afforded 2,2-dimethyl-6-(2,2,2-trifluoroethoxy)-3H-benzofuran-5-amine (33 mg) as a colorless oil, which was used to next step without further purification. MS (ESI): m/z=262.1 [M+1]⁺.

Step C. N-[2,2-Dimethyl-6-(2,2,2-trifluoroethoxy)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (21.0 mg, 0.13 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (99.0 mg, 0.19 mmol), N-ethyl-N-isopropylpropan-2-amine (0.04 mL, 0.25 mmol) and 2,2-dimethyl-6-(2,2,2-trifluoroethoxy)-3H-benzofuran-5-amine (33.0 mg, 0.13 mmol) in DMF (5 mL) was stirred at room temperature for 18 h. After filtration and concentration, the residue was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-55%; B:10 mM ammonium bicarbonate in water) to afford N-[2,2-dimethyl-6-(2,2,2-trifluoroethoxy)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (9.1 mg, 17%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 10.27 (s, 1H), 8.80 (dd, J=1.6, 6.8 Hz, 1H), 8.74 (s, 1H), 8.68 (dd, J=1.6, 4.0 Hz, 1H), 8.46 (s, 1H), 7.03 (dd, J=4.0, 7.2 Hz, 1H), 6.35 (s, 1H), 4.41 (q, J=8.0 Hz, 2H), 3.03 (s, 2H), 1.48 (s, 6H). MS (ESI): m/z=407.1 [M+1]⁺.

Examples 71 and 72. N-[(2R)-2-(Hydroxymethyl)-2-methyl-6-(trifluoromethyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-2-(hydroxymethyl)-2-methyl-6-(trifluoromethyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 4-(2-Methylallyloxy)-1-nitro-2-(trifluoromethyl) benzene

A mixture of 4-nitro-3-(trifluoromethyl)phenol (1000 mg, 4.83 mmol), 3-bromo-2-methylpropene (0.65 mL, 6.5 mmol), cesium carbonate (3080 mg, 9.45 mmol) in DMF (12 mL) was stirred at 50° C. for 2 h. The mixture was poured into water (50 mL) and extracted by ethyl acetate (150 ml) and the organics washed with water and brine. The organic phases were then separated and dried over anhydrous sodium sulfate then was concentration to dryness to afford 4-(2-methylallyloxy)-1-nitro-2-(trifluoromethyl)benzene (1.2 g) as a yellow oil, which was directly used to the next step without purification. MS (ESI): m/z=262.0 [M+1]⁺.

Step B. 2-(2-Methylallyl)-4-nitro-5-(trifluoromethyl)phenol

A mixture of 4-(2-methylallyloxy)-1-nitro-2-(trifluoromethyl)benzene (1200 mg, 4.59 mmol) in DMF (14 mL) was stirred at 200° C. in a sealed tube under microwave condition for 3 h. The mixture was purified by reverse phase chromatography (C18, 120 g, acetonitrile 18-22%; B: 0.1% ammonium bicarbonate in water) to afford 2-(2-methylallyl)-4-nitro-5-(trifluoromethyl)phenol (222 mg, 19%) as a yellow oil. MS (ESI): m/z=262.0 [M+1]⁺

Step C. [2-Methyl-5-nitro-6-(trifluoromethyl)-3H-benzofuran-2-yl]methanol

A mixture of 2-(2-methylallyl)-4-nitro-5-(trifluoromethyl)phenol (222 mg, 0.85 mmol) in DCM (15 mL) was added 3-chloroperbenzoic acid (222 mg, 1.13 mmol) at 0° C. then was stirred at 25° C. for 18 h. The reaction mixture was diluted with DCM (30 mL) then was washed with sodium sulfite solution, sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, 60 g, acetonitrile 25-27%; B: 0.1% ammonium bicarbonate in water) to afford[2-methyl-5-nitro-6-(trifluoromethyl)-3H-benzofuran-2-yl]methanol (66 mg, 28%) as a yellow oil. MS (ESI): m/z=278.0 [M+1]⁺.

Step D. [5-Amino-2-methyl-6-(trifluoromethyl)-3H-benzofuran-2-yl]methanol

The mixture of [2-methyl-5-nitro-6-(trifluoromethyl)-3H-benzofuran-2-yl]methanol (66 mg, 0.24 mmol) and 10% palladium on carbon (20 mg) in methanol (10 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. After filtration and concentration under reduced pressure, it was afforded [5-amino-2-methyl-6-(trifluoromethyl)-3H-benzofuran-2-yl]methanol (55 mg, 93%) as a brown oil. MS (ESI): m/z=248.1 [M+1]⁺.

Step E. N-[(25)-2-(hydroxymethyl)-2-methyl-6-(trifluoromethyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2R)-2-(hydroxymethyl)-2-methyl-6-(trifluoromethyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

The mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (55 mg, 0.34 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (170 mg, 0.45 mmol), N,N-diisopropylethylamine (0.11 mL, 0.68 mmol) and [5-amino-2-methyl-6-(trifluoromethyl)-3H-benzofuran-2-yl]methanol (55 mg, 0.22 mmol) in DMF (4 mL) was stirred at 75° C. for 24 h. After cooling room temperature, the mixture was purified by preparative HPLC(Xbridge 21.2*250 mm c18, 10 um, A: acetonitrile 25-55%; B:10 mM ammonium bicarbonate) in water) and then the product was resolved by chiral-HPLC [SFC-80 (Thar, Waters), AD 20*250 mm, Sum (Dacel), carbon dioxide/methanol{0.5% ammonia (7 m methanol)}=65/35] to afford N-[(2R)-2-(hydroxymethyl)-2-methyl-6-(trifluoromethyl)-3H-benzofuran-5-yl]pyrazol[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-2-(hydroxymethyl)-2-methyl-6-(trifluoromethyl)-3H-benzofuran-5-yl]pyrazol[1,5-a]pyrimidine-3-carboxamide (5.6 mg, 6%) (8.1 mg, 9%) as a white solids with absolute stereochemistry assigned arbitrarily.

Example 70, Peak 1: ¹H NMR (400 MHz, CDCl₃) δ 9.94 (s, 1H), 8.82 (dd, J=1.6, 7.2 Hz, 1H), 8.76 (s, 1H), 8.70 (dd, J=1.6, 4.0 Hz, 1H), 8.00 (s, 1H), 7.05 (dd, J=4.0, 7.2 Hz, 1H), 7.03 (s, 1H), 3.76-3.61 (m, 2H), 3.36 (d, J=16.4 Hz, 1H), 3.00 (d, J=16.4 Hz, 1H), 1.89 (t, J=6.0 Hz, 1H), 1.47 (s, 3H). MS (ESI): m/z=393.1 [M+1]⁺.

Example 71, Peak 2: ¹H NMR (400 MHz, CDCl₃) δ 9.94 (s, 1H), 8.82 (dd, J=1.6, 7.2 Hz, 1H), 8.76 (s, 1H), 8.70 (dd, J=1.6, 4.0 Hz, 1H), 8.00 (s, 1H), 7.05 (dd, J=4.0, 7.2 Hz, 1H), 7.03 (s, 1H), 3.76-3.61 (m, 2H), 3.36 (d, J=16.4 Hz, 1H), 3.00 (d, J=16.4 Hz, 1H), 1.89 (t, J=6.0 Hz, 1H), 1.47 (s, 3H). MS (ESI): m/z=393.1 [M+1]⁺.

Examples 73 and 74. N-[(2S)-6-(Difluoromethyl)-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2R)-6-(difluoromethyl)-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 5-(2-Methylallyloxy)-2-nitro-benzaldehyde

A mixture of 5-hydroxy-2-nitrobenzaldehyde (1000 mg, 5.98 mmol), 3-bromo-2-methylpropene (0.81 mL, 8.0 mmol), cesium carbonate (4000 mg, 12.28 mmol) in DMF (10 mL) was stirred at 50° C. for 2 h. The mixture was poured into water (50 mL). The aqueous phase was extracted by ethyl acetate (150 mL) and the organic phase was washed with water and brine and dried over anhydrous sodium sulfate. The organic phase was concentration to dryness to afford 5-(2-methylallyloxy)-2-nitro-benzaldehyde (1.25 g) as a yellow oil, which was directly used to the next step without purification. MS (ESI): m/z=222.1 [M+1]⁺.

Step B. 2-(Difluoromethyl)-4-(2-methylallyloxy)-1-nitro-benzene

The mixture of 5-(2-methylallyloxy)-2-nitro-benzaldehyde (1250 mg, 5.65 mmol) in DCM (25 mL) was added diethylaminosulfurtrifluoride (1.88 mL, 14.13 mmol) at 0° C. then was stirred at 25° C. for 8 h. The mixture was diluted with DCM (200 mL) then was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silicagel chromatography using ethyl acetate:petroleum ether (1:20) as eluting solvents to afford 2-(difluoromethyl)-4-(2-methylallyloxy)-1-nitro-benzene (1310 mg, 95%) as a yellow oil. MS (ESI): m/z=244.1 [M+1]⁺.

Step C. 5-(Difluoromethyl)-2-(2-methylallyl)-4-nitro-phenol

The mixture of 2-(difluoromethyl)-4-(2-methylallyloxy)-1-nitro-benzene (1300 mg, 5.35 mmol) in DMF (16 mL) was stirred at 200° C. in a sealed tube under microwave condition for 3 h. The mixture was purified by reverse phase chromatography (C18, 120 g, A: acetonitrile 22-25%; B: 0.1% ammonium bicarbonate in water) to afford 5-(difluoromethyl)-2-(2-methylallyl)-4-nitro-phenol (310 mg, 24%) as a yellow oil. MS (ESI): m/z=244.1 [M+1]⁺.

Step D. [6-(Difluoromethyl)-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol

A mixture of 5-(difluoromethyl)-2-(2-methylallyl)-4-nitro-phenol (310 mg, 1.27 mmol) in DCM (15 mL) was added 3-chloroperbenzoic acid (375 mg, 1.91 mmol) at 0° C. then was stirred at 25° C. for 18 h. The reaction mixture was diluted with DCM (50 mL). The organic phase was washed with sodium bicarbonate solution, water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase chromatography (C18, 80 g, A: acetonitrile 20-27%; B: 0.1% ammonium bicarbonate in water) to afford[6-(difluoromethyl)-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol (156 mg, 47%) as a yellow oil. MS (ESI): m/z=260.1 [M+1]⁺.

Step E. [5-Amino-6-(difluoromethyl)-2-methyl-3H-benzofuran-2-yl]methanol

The mixture of [6-(difluoromethyl)-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol (140 mg, 0.54 mmol) and 10% palladium on carbon (50 mg) in methanol (15 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. After filtration and concentration under reduced pressure, it was afforded [5-amino-6-(difluoromethyl)-2-methyl-3H-benzofuran-2-yl]methanol (115 mg) as a brown oil, which was used directly to next step without further purification. MS (ESI): m/z=230.1 [M+1]⁺.

Step F. N-[(25)-6-(difluoromethyl)-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2R)-6-(difluoromethyl)-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

The mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (120 mg, 0.74 mmol), N,N-diisopropylethylamine (0.26 mL, 1.56 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (395 mg, 1.04 mmol) and [5-amino-6-(difluoromethyl)-2-methyl-3H-benzofuran-2-yl]methanol (115 mg, 0.50 mmol) in DMF (6 mL) was stirred at 65° C. for 16 h. After cooling room temperature, the mixture was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-55%; B: 10 mM ammonium bicarbonate in water) and Chiral-HPLC [SFC-80 (Thar, Waters), AY 20*250 mm, Sum (Dacel), carbon dioxide/methanol{0.5% ammonia (7 m methanol)}=60/40] to afford N-[(2R)-6-(difluoromethyl)-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-6-(difluoromethyl)-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (44.4 mg, 24%) (32.7 mg, 17%) as yellow solids with absolute stereochemistry assigned arbitrarily.

Example 73, Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (s, 1H), 9.38 (dd, J=1.6, 7.2 Hz, 1H), 8.87 (dd, J=1.6, 4.4 Hz, 1H), 8.70 (s, 1H), 7.67 (s, 1H), 7.33 (dd, J=4.4, 7.2 Hz, 1H), 7.042 (t, J=55.2 Hz, 1H), 6.90 (s, 1H), 5.11 (t, J=6.0 Hz, 1H), 3.53-3.40 (m, 2H), 3.29 (d, J=16.0 Hz, 1H), 2.92 (d, J=16.0 Hz, 1H), 1.37 (s, 3H). MS (ESI): m/z=375.1 [M+1]⁺.

Example 74, Peak 2: ¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (s, 1H), 9.38 (dd, J=1.6, 7.2 Hz, 1H), 8.87 (dd, J=1.6, 4.4 Hz, 1H), 8.70 (s, 1H), 7.67 (s, 1H), 7.33 (dd, J=4.4, 7.2 Hz, 1H), 7.042 (t, J=55.2 Hz, 1H), 6.90 (s, 1H), 5.11 (t, J=6.0 Hz, 1H), 3.53-3.40 (m, 2H), 3.29 (d, J=16.0 Hz, 1H), 2.92 (d, J=16.0 Hz, 1H), 1.37 (s, 3H). MS (ESI): m/z=375.1 [M+1]⁺.

Example 75.6-(Difluoromethyl)-N-[2-(hydroxymethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 6-Formylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid

The mixture of 5-amino-1H-pyrazole-4-carboxylic acid (270 mg, 2.12 mmol) and methanetricarbaldehyde (205 mg, 2.05 mmol) in ethanol (1.5 mL) and acetic acid (0.50 mL) was stirred at 25° C. for 1 h and at 70° C. for 1 h. After cooling to room temperature, the mixture was filtered, the solid was washed with ethanol and dryness in vacuo to afford 6-formylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (135 mg, 33.2%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (brs, 1H), 10.06 (s, 1H), 9.93 (d, J=2.0 Hz, 1H), 9.11 (d, J=2.0 Hz, 1H), 8.79 (s, 1H). MS (ESI): m/z=192.1 [M+1]⁺.

Step B. 6-Formyl-N-[2-(hydroxymethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

The mixture of 6-formylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (110 mg, 0.58 mmol), N,N-diisopropylethylamine (0.22 mL, 1.35 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (330 mg, 0.87 mmol) and (5-amino-2-methyl-6-morpholino-3H-benzofuran-2-yl)methanol (Example 6, Step B) (115 mg, 0.44 mmol) in DMF (6 mL) was stirred at 25° C. for 3 h. Water and ethyl acetate (150 mL) was added. The organic phase was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Methyl alcohol (1 mL) was added then the solid was collected after filtration to afford 6-formyl-N-[2-(hydroxymethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (115 mg) and as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=438.1 [M+1]⁺.

Step C. 6-(Difluoromethyl)-N-[2-(hydroxymethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To the mixture of 6-formyl-N-[2-(hydroxymethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (70 mg, 0.16 mmol) in DCM (10 mL) was added diethylaminosulfurtrifluoride (0.21 mL, 1.55 mmol) under at 0° C. and the mixture was stirred for 2 h. The reaction mixture was diluted with DCM (10 mL) and water. The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC (A: acetonitrile 25-45%; B: 0.05% formic acid in water) to afford 6-(difluoromethyl)-N-[2-(hydroxymethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (10.9 mg, 15%) as a yellow solid. ¹H NMR (400 MHz, MeOD-d₄) δ 9.46 (d, J=1.6 Hz, 1H), 9.07 (d, J=1.6 Hz, 1H), 8.78 (s, 1H), 8.26 (s, 1H), 7.15 (t, J=55.2 Hz, 1H), 6.73 (s, 1H), 4.01-3.90 (m, 4H), 3.65-3.56 (m, 2H), 3.27 (d, J=15.2 Hz, 1H), 2.99-2.90 (m, 5H), 1.44 (s, 3H). MS (ESI): m/z=460.1 [M+1]⁺.

Examples 76 and 77. (R)—N-(2-Methyl-6-morpholino-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-methyl-6-morpholino-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 6-Chloro-2-methyl-2-(trifluoromethyl)-2,3-dihydrobenzofuran

The mixture of 3-(4-chloro-2-fluorophenyl)-1,1,1-trifluoro-2-methylpropan-2-ol (500 mg, 1.95 mmol) and tert-butoxypotassium (875 mg, 7.80 mmol) in THE (20 mL) was stirred at 65° C. for 18 h. After cooling to room temperature, water was added. The organic phase was separated and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:4 to 1:3) as eluting solvents to afford 6-chloro-2-methyl-2-(trifluoromethyl)-2,3-dihydrobenzofuran (200 mg, 22%) as a colorless oil. MS (ESI): m/z=237.1 [M+1]⁺.

Step B. 6-Chloro-2-methyl-5-nitro-2-(trifluoromethyl)-2,3-dihydrobenzofuran

To a solution of 6-chloro-2-methyl-2-(trifluoromethyl)-2,3-dihydrobenzofuran (250 mg, 1.06 mmol) in DCM (20 mL) at 25° C. was slowly added fuming nitric acid (0.5 mL) and stirred for 15 min. Water and ethyl acetate (30 mL) was added. The organic phase was separated and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:6 to 1:4) as eluting solvents to afford 6-chloro-2-methyl-5-nitro-2-(trifluoromethyl)-2,3-dihydrobenzofuran (250 mg, 82%) as orange solid. MS (ESI): m/z=282.2 [M+1]⁺.

Step C. 4-(2-Methyl-5-nitro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-6-yl)morpholine

A mixture of 6-chloro-2-methyl-5-nitro-2-(trifluoromethyl)-2,3-dihydrobenzofuran (250 mg, 0.89 mmol) in morpholine (1 mL) in a sealed vial was stirred at 65° C. for 18 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:3) as eluting solvents to afford 4-(2-methyl-5-nitro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-6-yl)morpholine (150 mg, 84%) as a yellow solid. MS (ESI): m/z=333.1 [M+1]⁺.

Step D. 2-Methyl-6-morpholino-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-amine

A mixture of 4-(2-methyl-5-nitro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-6-yl)morpholine (150 mg, 0.45 mmol) and 10% palladium on carbon (15 mg) in methanol (6 mL) was stirred at room temperature for Thunder an atmosphere of hydrogen. The catalyst was filtered off. The filtrate was concentrated under reduced pressure to afford 2-methyl-6-morpholino-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-amine (100 mg) as a colorless oil, which was used directly in the next step without purification. MS (ESI): m/z=303.1 [M+1]⁺.

Step E. (R)—N-(2-Methyl-6-morpholino-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and(S)—N-(2-Methyl-6-morpholino-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (54 mg, 0.33 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (172 mg, 0.33 mmol) and N-ethyl-N-isopropylpropan-2-amine (85 mg, 0.66 mmol) in DMF (5 mL) was stirred at room temperature for 30 min. 2-Methyl-6-morpholino-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-amine (100 mg, 0.33 mmol) was added. The resulting mixture was stirred at room temperature for 18 h. Water and ethyl acetate (30 mL) was added. The organic phase was separated and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (10:1) as eluting solvents to afford the desired product and then it was resolved by chiral HPLC(Column:CE-4, Mobile Phase: Hexane/ethanol/DEA=70/30/0.1) to afford (R)—N-(2-methyl-6-morpholino-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-methyl-6-morpholino-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (48 mg each, 33.3% each) as a yellow solids with absolute stereochemistry assigned arbitrarily.

Example 76, Peak 1: ¹H NMR (400 MHz, DMSO-d₆): δ 10.48 (s, 1H), 9.38 (dd, J=1.6, 6.8 Hz, 1H), 8.96 (dd, J=1.6, 4.4 Hz, 1H), 8.69 (s, 1H)), 8.40 (s, 1H), 7.35 (dd, J=4.0, 6.8 Hz, 1H), 6.93 (s, 1H), 3.85-3.83 (m, 4H), 3.52 (d, J=16.8 Hz, 1H), 3.30 (d, J=16.8 Hz, 1H), 2.85-2.83 (m, 4H), 1.62 (s, 3H). MS (ESI): m/z=448.2 [M+1]⁺.

Example 77, Peak 2: ¹H NMR (400 MHz, DMSO-d₆): δ10.48 (s, 1H), 9.38 (dd, J=1.6, 6.8 Hz, 1H), 8.95 (dd, J=1.6, 4.0 Hz, 1H), 8.69 (s, 1H)), 8.40 (s, 1H), 7.35 (dd, J=4.0, 6.8 Hz, 1H), 6.93 (s, 1H), 3.85-3.83 (m, 4H), 3.52 (d, J=16.8 Hz, 1H), 3.30 (d, J=16.8 Hz, 1H), 2.90-2.80 (m, 4H), 1.62 (s, 3H). MS (ESI): m/z=448.2 [M+1]⁺.

Examples 78 and 79. N—((S)-2-(Hydroxymethyl)-2-methyl-6-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and N—((R)-2-(hydroxymethyl)-2-methyl-6-((1 S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (1S,4S)-tert-Butyl 5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

The mixture of (1S,4S)-tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (70 mg, 0.35 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (81 mg, 0.35 mmol) and potassium carbonate (97 mg, 0.70 mmol) in acetonitrile (5 mL) was stirred at room temperature for 18 h. After filtration, the filtrate was concentrated in vacuo to afford (1S,4S)-tert-butyl 5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (95 mg) as a colorless oil, which was used directly to the next step without purification. MS (ESI): m/z=281.1 [M+1]⁺.

Step B. (1S,4S)-2-(2,2,2-Trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptane

A mixture of (1S,4S)-tert-butyl 5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (95 mg, 0.34 mmol) in 2,2,2-trifluoroacetic acid (1 mL) and DCM (2 mL) was stirred at room temperature for anh. The mixture was concentrated in vacuo to afford ((1S,4S)-2-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptane 2,2,2-trifluoroacetic acid salt (55 mg) as a colorless oil, which was used directly to the next step without purification. MS (ESI): m/z=181.1 [M+1]⁺.

Step C. (2-Methyl-5-nitro-6-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (6-fluoro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (70 mg, 0.31 mmol), (1S,4S)-2-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptane (55 mg, 0.31 mmol) and cesium carbonate (303 mg, 0.93 mmol) in acetonitrile (5 mL) was stirred at room temperature for 18 h. The mixture was poured into water and the aqueous phase was extracted with ethyl acetate (2×30 mL). The organic phases were combined, washed with water and brine. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:3) as eluting solvents to afford (2-methyl-5-nitro-6-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol (110 mg, 92%) as a yellow solid. MS (ESI): m/z=388.1 [M+1]⁺.

Step D. (5-Amino-2-methyl-6-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (2-methyl-5-nitro-6-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol (110 mg, 0.28 mmol) and 10% palladium on carbon (11 mg) in methanol (5 mL) was stirred at room temperature for Thunder an atmosphere of hydrogen. After filtration and concentration under reduced pressure, it was afforded (5-amino-2-methyl-6-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol (80 mg, 79%) as a colorless oil, which was used directly to the next step without purification. MS (ESI): m/z=358.1 [M+1]⁺.

Step E. N—((S)-2-(Hydroxymethyl)-2-methyl-6-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and N—((R)-2-(Hydroxymethyl)-2-methyl-6-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (36 mg, 0.22 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (115 mg, 0.22 mmol) and N-ethyl-N-isopropylpropan-2-amine (85 mg, 0.66 mmol) in DMF (5 mL) was stirred at room temperature for 30 min. (5-Amino-2-methyl-6-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-2-yl)methanol (80 mg, 0.22 mmol) was added. The resulting mixture was stirred at room temperature for 18 h. Water and ethyl acetate (30 mL) was added. The organic phase was separated and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (10:1) as eluting solvents to afford the desired product and then it was resolved by chiral pre-SFC (Column: OD 4.6*250 mm, Sum (Decial), Column temperature: 35° C., Mobile phase: CO2/Methanol(0.2% Methanol Ammonia)=70/30) to afford N—((S)-2-(hydroxymethyl)-2-methyl-6-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and N—((R)-2-(hydroxymethyl)-2-methyl-6-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (8 mg each, 7% each) as yellow solids with absolute stereochemistry assigned arbitrarily.

Example 78, Peak 1: ¹H NMR (400 MHz, DMSO-d₆): δ9.74 (s, 1H), 9.37 (dd, J=1.6, 6.8 Hz, 1H), 8.85 (dd, J=1.6, 4.0 Hz, 1H), 8.69 (s, 1H)), 7.80 (s, 1H), 7.33 (dd, J=4.0, 6.8 Hz, 1H), 6.48 (s, 1H), 5.04 (t, J=6.0 Hz, 1H), 3.93 (s, 1H), 3.51 (s, 1H), 3.45-3.41 (m, 2H), 3.32-3.25 (m, 3H), 3.16 (d, J=16.0 Hz, 1H), 3.07-3.04 (m, 1H), 2.92-2.88 (m, 2H), 2.78 (d, J=15.6 Hz, 1H), 1.89-1.76 (m, 2H), 1.34 (s, 3H). MS (ESI): m/z=503.3 [M+1]⁺.

Example 79, Peak 2: ¹H NMR (400 MHz, DMSO-d₆): δ9.72 (s, 1H), 9.37 (dd, J=1.6, 6.8 Hz, 1H), 8.85 (dd, J=1.6, 4.0 Hz, 1H), 8.68 (s, 1H)), 7.78 (s, 1H), 7.33 (dd, J=4.0, 6.8 Hz, 1H), 6.47 (s, 1H), 5.04 (t, J=6.0 Hz, 1H), 3.93 (s, 1H), 3.50 (s, 1H), 3.45-3.41 (m, 2H), 3.32-3.25 (m, 3H), 3.16 (d, J=16.0 Hz, 1H), 3.07-3.04 (m, 1H), 2.92-2.88 (m, 2H), 2.78 (d, J=15.6 Hz, 1H), 1.89-1.76 (m, 2H), 1.34 (s, 3H). MS (ESI): m/z=503.3 [M+1]⁺.

Examples 80 and 81. (R)—N-(7-Chloro-2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(7-chloro-2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 1,2-Dichloro-3-(2-methylallyloxy)benzene

A mixture of 2,3-dichlorophenol (500 mg, 3.07 mmol), 3-bromo-2-methylpropene (497 mg, 3.68 mmol) and potassium carbonate (848 mg, 6.14 mmol) in acetonitrile (10 mL) was stirred at 25° C. for 18 h. The reaction was then filtered, concentrated and purified by silica gel chromatography using petroleum ether to afford 1,2-dichloro-3-(2-methylallyloxy)benzene (659 mg, 99%) as a colorless oil. MS (ESI): m/z=218.1 [M+1]⁺.

Step B. 2,3-Dichloro-6-(2-methylallyl)phenol

A mixture of 1,2-dichloro-3-(2-methylallyloxy)benzene (600 mg, 2.76 mmol) in DMF (3 mL) was stirred at 220° C. under microwave for 2 h. Water was added and the mixture was extracted with ethyl acetate (10 mL). The organic phase was washed with brine, dried over sodium sulfate and concentrated to afford 2,3-dichloro-6-(2-methylallyl)phenol (400 mg) as light yellow oil, which was used directly to next step without further purification.

Step C. (6,7-Dichloro-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of 3-chloro-2-methyl-6-(2-methylallyl)phenol (400 mg, 1.84 mmol) in DCM (10 mL) was added 3-chloroperoxybenzoic acid (558 mg, 2.76 mmol) under ice-cooling. The mixture was stirred at 25° C. for 18 h. The reaction was filtered and the filtrate was concentrated to afford (6,7-dichloro-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol (300 mg, 70%) as a yellow oil, which was used directly to next step without purification further. MS (ESI): m/z=233.1 [M+1]⁺.

Step D. (6,7-Dichloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol

To a mixture of (6,7-dichloro-2-methyl-2,3-dihydrobenzofuran-2-yl)methanol (300 mg, 1.29 mmol) in DCM (10 mL) was added drop-wise fuming nitric acid (0.5 mL) at 25° C. The mixture was stirred at 25° C. for 30 min and poured into ice water. The aqueous phase was extracted with ethyl acetate (30 mL). The organic phase was dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:4) as eluting solvents to afford (6,7-dichloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (220 mg, 61%) as light grey solid. MS (ESI): m/z=279.1 [M+1]⁺.

Step E. (7-Chloro-2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (6,7-dichloro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (220 mg, 0.79 mmol) in morpholine (2 mL) in a sealed tube was stirred at 110° C. for 18 h. The mixture was concentrated and purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford (7-chloro-2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (200 mg, 77%) as a yellow oil. MS (ESI): m/z=329.1 [M+1]⁺.

Step F. (5-Amino-7-chloro-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (7-chloro-2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (100 mg, 0.30 mmol) and 10% palladium on carbon (10 mg) in methanol (10 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. After filtration and concentration under reduced pressure, it was afforded (5-amino-7-chloro-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)methanol (60 mg) as a green oil, which was used directly to next step without further purification. MS (ESI): m/z=299.1[M+1]⁺.

Step G. (R)—N-(7-Chloro-2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(7-chloro-2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (33 mg, 0.20 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (104 mg, 0.69 mmol), N-ethyl-N-isopropylpropan-2-amine (78 mg, 0.60 mmol) and (5-amino-7-chloro-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)methanol (60 mg, 0.20 mmol) in DMF (5 mL) was stirred at room temperature for 18 h. Water was added and the mixture was extracted with ethyl acetate (10 mL). The organic phase was washed with brine and dried over sodium sulfate. After concentration under reduced pressure and the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (10:1) as eluting solvents to afford N-(7-chloro-2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (40 mg, 45%) as a yellow solid. Then the desired product was resolved by chiral pre-SFC(Column: AD 20*250 mm, Sum (Dacel), Column temperature: 35° C., Mobile phase: CO₂/Ethanol{0.5% Ammonia (7 m methanol)}=70/30) to obtain (R)—N-(7-chloro-2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(7-chloro-2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (15 mg each, 17% each) as a yellow solids with absolute stereochemistry assigned arbitrarily.

Example 80, Peak 1: ¹H NMR (400 MHz, DMSO-d₆):δ 10.73 (s, 1H), 9.39 (dd, J=1.6, 7.2 Hz, 1H), 8.91 (dd, J=1.6, 4.0 Hz, 1H), 8.70 (s, 1H)), 8.44 (s, 1H), 7.37 (dd, J=4.0, 7.2 Hz, 1H), 5.13 (t, J=5.6 Hz, 1H), 4.02-3.93 (m, 2H), 3.89-3.83 (m, 2H), 3.70 (t, J=10.8 Hz, 2H), 3.54-3.41 (m, 2H), 3.38-3.34 (m, 1H), 2.96 (d, J=16.4 Hz, 1H), 2.69 (d, J=11.6 Hz, 2H), 1.38 (s, 3H). MS (ESI): m/z=444.1 [M+1]⁺.

Example 81, Peak 2: ¹H NMR (400 MHz, DMSO-d₆): δ 10.73 (s, 1H), 9.39 (dd, J=1.6, 7.2 Hz, 1H), 8.91 (dd, J=1.6, 4.4 Hz, 1H), 8.70 (s, 1H)), 8.44 (s, 1H), 7.37 (dd, J=4.4, 6.8 Hz, 1H), 5.13 (t, J=5.6 Hz, 1H), 4.02-3.93 (m, 2H), 3.89-3.82 (m, 2H), 3.70 (t, J=10.0 Hz, 2H), 3.55-3.41 (m, 2H), 3.38-3.34 (m, 1H), 2.96 (d, J=16.4 Hz, 1H), 2.69 (d, J=12.0 Hz, 2H), 1.38 (s, 3H). MS (ESI): m/z=444.1 [M+1]⁺.

Example 82. N-(3,3-Dimethyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 4-Fluoro-2-(2-methylallyloxy)-1-nitrobenzene

A mixture of 5-fluoro-2-nitrophenol (2.0 g, 12.73 mmol), 3-bromo-2-methylpropene (1.54 mL, 15.3 mmol) and potassium carbonate (3.5 g, 25.46 mmol) in acetonitrile (50 mL) was stirred at 50° C. for 18 h. The reaction was filtered and the filtrate was concentrated and purified by silica gel chromatography using petroleum ether to afford 4-fluoro-2-(2-methylallyloxy)-1-nitro-benzene (780 mg, 29%) as light oil. MS (ESI): m/z=230.2 [M+H₂O]⁺.

Step B. 4-Fluoro-2-(2-methylallyloxy)aniline

A mixture of 4-fluoro-2-(2-methylallyloxy)-1-nitro-benzene (780 mg, 3.69 mmol), iron powder (1.0 g, 18.47 mmol) and ammonium chloride (978 mg, 18.47 mmol) in ethanol (30 mL) and water (4 mL) was stirred at 70° C. for 2 h. The reaction was filtered and the filtrate was dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:30) to afford 4-fluoro-2-(2-methylallyloxy)aniline (560 mg, 84%) as light oil. MS (ESI): m/z=182.1 [M+1]⁺.

Step C. 1-Azido-4-fluoro-2-(2-methylallyloxy)benzene

To a mixture of 4-fluoro-2-(2-methylallyloxy)aniline (100 mg, 0.55 mmol) in acetonitrile (10 mL) was added tert-butyl nitrite (85 mg, 0.83 mmol) followed by trimethylsilylazid (95 mg, 0.83 mmol) at 0° C. The mixture was stirred at 25° C. for 1 h. Water was added and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was separated, dried over sodium sulfate. The filtrate was concentrated under reduced pressure to afford 1-azido-4-fluoro-2-(2-methylallyloxy)benzene (99 mg) as a yellow oil, which was used directly to next step without further purification. MS (ESI): m/z=208.0 [M+1]⁺.

Step D. 5-Fluoro-1a-methyl-1a, 2-dihydro-1H-azirino[1,2-d]benzo[b][1,4]oxazine

A mixture of 1-azido-4-fluoro-2-(2-methylallyloxy)benzene (99 mg, 0.48 mmol) in toluene (5 mL) was stirred at 110° C. for 18 h. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:15) as eluting solvents to afford 5-fluoro-1a-methyl-1,2-dihydroazirino[2,1-c][1,4]benzoxazine (38 mg, 44%) as a colorless oil. ¹HNMR (400 MHz, CDCl₃): 7.00-7.03 (m, 1H), 6.75-6.79 (m, 1H), 6.66-6.71 (m, 1H), 4.13 (d, J=11.2 Hz, 1H), 3.95 (d, J=11.2 Hz, 1H), 2.30 (s, 2H), 1.37 (s, 3H).

Step E. 7-Fluoro-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

A mixture of 10% palladium on carbon (60 mg) and 5-fluoro-1a-methyl-1,2-dihydroazirino[2,1-c][1,4]benzoxazine (300 mg, 1.67 mmol) in ethanol (20 mL) was stirred at 25° C. under hydrogen atmosphere for 2 h. After filtration and concentration under reduced pressure, it was afforded 7-fluoro-3,3-dimethyl-2,4-dihydro-1,4-benzoxazine (200 mg) as a brown solid, which was used directly to next step without further purification. MS (ESI): m/z=182.1 [M+1]⁺.

Step F. 7-Fluoro-3,3-dimethyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a mixture of 7-fluoro-3,3-dimethyl-2,4-dihydro-1,4-benzoxazine (160 mg, 0.88 mmol) in sulfuric acid (4 mL) was added slowly guanidine nitrate (108 mg, 0.88 mmol) at 0° C. The mixture was stirred at 0° C. for 3 h. The mixture was poured into ice water and neutralized with sodium carbonate. The aqueous phase was extracted with ethyl acetate (20 mL). The organic phase was dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:4) as eluting solvents to afford 7-fluoro-3,3-dimethyl-6-nitro-2,4-dihydro-1,4-benzoxazine (70 mg, 35%) as a brown solid. MS (ESI): m/z=227.1 [M+1]⁺.

Step G. 3,3-Dimethyl-7-morpholino-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

A mixture of 7-fluoro-3,3-dimethyl-6-nitro-2,4-dihydro-1,4-benzoxazine (70 mg, 0.31 mmol), morpholine (40 mg, 0.46 mmol) and cesium carbonate (202 mg, 0.62 mmol) in acetonitrile (10 mL) was stirred at 85° C. for 18 h. The reaction was filtered and the filtrate was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford 3,3-dimethyl-7-morpholino-6-nitro-2,4-dihydro-1,4-benzoxazine (69 mg, 56%) as a yellow oil. MS (ESI): m/z=294.1 [M+1]⁺.

Step H. 3,3-Dimethyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine

A mixture of 10% palladium on carbon (15 mg) and 3-dimethyl-7-morpholino-6-nitro-2,4-dihydro-1,4-benzoxazine (69 mg, 0.24 mmol) in ethyl acetate (15 mL) was stirred at 40° C. under hydrogen atmosphere for 2 h. After filtration and concentration under reduced pressure, it was afforded 3,3-dimethyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine (50 mg, 76%) as dark solid. MS (ESI): m/z=264.1 [M+1]⁺.

Step I. N-(3,3-Dimethyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (37 mg, 0.23 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (148 mg, 0.28 mmol), N-ethyl-N-isopropylpropan-2-amine (69 mg, 0.57 mmol) and 3,3-dimethyl-7-morpholino-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine (50 mg, 0.19 mmol) in DMF (10 mL) was stirred at room temperature for 18 h. Water was added. The aqueous phase was extracted with ethyl acetate (10 mL). The organic phase was washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (9:1) as eluting solvents to afford N-(6-methoxy-2,2-dimethyl-3H-benzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (10 mg, 13%) as a yellow solid. ¹HNMR (400 MHz, CDCl₃): 10.48 (s, 1H), 8.82 (dd, J=1.6, 7.2 Hz, 1H), 8.79 (s, 1H), 8.75 (dd, J=1.6, 4.0 Hz, 1H), 8.18 (s, 1H), 7.05 (dd, J=4.0, 7.2 Hz, 1H), 6.47 (s, 1H), 5.36 (brs, 1H), 3.93-3.95 (m, 4H), 3.83 (s, 2H), 2.88-2.89 (m, 4H), 1.24 (s, 6H). MS (ESI): m/z=409.2 [M+1]⁺.

Examples 83 and 84. (R)—N-(2-(Hydroxymethyl)-2,7-dimethyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(hydroxymethyl)-2,7-dimethyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 1-Chloro-2-methyl-3-(2-methylallyloxy)benzene

A mixture of 3-chloro-2-methylphenol (2.0 g, 14.03 mmol), 3-bromo-2-methylpropene (1.7 mL, 16.86 mmol) and potassium carbonate (3.87 g, 28.05 mmol) in acetonitrile (50 mL) was stirred at 25° C. for 18 h. The reaction was filtered and the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using petroleum ether to afford 1-chloro-2-methyl-3-(2-methylallyloxy)benzene (2.3 g, 83%) as a colorless oil. ¹HNMR (400 MHz, CDCl₃): 7.03-7.07 (m, 1H), 6.96-6.98 (m, 1H), 6.72 (d, J=8.0 Hz, 1H), 5.10 (s, 1H), 4.99 (s, 1H), 4.42 (s, 1H), 2.31 (s, 3H), 1.84 (s, 3H).

Step B. 3-Chloro-2-methyl-6-(2-methylallyl)phenol

A mixture of 1-chloro-2-methyl-3-(2-methylallyloxy)benzene (300 mg, 1.53 mmol) in DMF (4.5 mL) was stirred at 220° C. under microwave condition for 2 h. Water was added and the mixture was extracted with ethyl acetate (10 mL). The organic phase was washed with brine and dried over sodium sulfate. The reaction was filtered and the filtrate was concentrated to afford 3-chloro-2-methyl-6-(2-methylallyl)phenol (322 mg, 86%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 6.90 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 5.42 (s, 1H), 4.96 (s, 1H), 4.91 (s, 1H), 3.34 (s, 1H), 2.28 (s, 3H), 1.57 (s, 3H).

Step C. (6-Chloro-2,7-dimethyl-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of 3-chloro-2-methyl-6-(2-methylallyl)phenol (300 mg, 1.53 mmol) in DCM (10 mL) was added 3-chloroperoxybenzoic acid (306 mg, 1.83 mmol) at 0° C. The mixture was stirred at 25° C. for 18 h. The reaction was filtered and the filtrate was concentrated to afford (6-chloro-2,7-dimethyl-3H-benzofuran-2-yl)methanol (500 mg) as a yellow oil, which was used directly to next step without further purification. MS (ESI): m/z=213.1 [M+1]⁺.

Step D. (6-Chloro-2,7-dimethyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (6-chloro-2,7-dimethyl-3H-benzofuran-2-yl)methanol (500 mg, 2.35 mmol) in DCM (10 mL) was added drop wise fuming nitric acid (0.3 mL) at 25° C. The mixture was stirred at 25° C. for 30 min. The mixture was poured into ice water and extracted with ethyl acetate (30 mL). The organic phase was dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:4) as eluting solvents to afford (6-chloro-2,7-dimethyl-5-nitro-3H-benzofuran-2-yl)methanol (182 mg, 50%) as light grey solid. MS (ESI): m/z=258.1 [M+1]⁺.

Step E. (2,7-Dimethyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of (6-chloro-2,7-dimethyl-5-nitro-3H-benzofuran-2-yl)methanol (182 mg, 0.71 mmol) in morpholine (4 mL) was stirred at 110° C. for 18 h. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford (2,7-dimethyl-6-morpholino-5-nitro-3H-benzofuran-2-yl)methanol (200 mg, 79%) as a yellow oil. MS (ESI): m/z=309.1 [M+1]⁺.

Step F. (5-Amino-2,7-dimethyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of 10% palladium on carbon (60 mg) and (2,7-dimethyl-6-morpholino-5-nitro-3H-benzofuran-2-yl)methanol (200 mg, 0.65 mmol) in methanol (20 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. After filtration and concentration under reduced pressure, it was afforded (5-amino-2,7-dimethyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)methanol (183 mg) as a green oil, which was used directly to next step without further purification. MS (ESI): m/z=279.1[M+1]⁺.

Step G. (R)—N-(2-(Hydroxymethyl)-2,7-dimethyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(Hydroxymethyl)-2,7-dimethyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (90 mg, 0.55 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (360 mg, 0.69 mmol), N-ethyl-N-isopropylpropan-2-amine (167 mg, 1.38 mmol) and (5-amino-2,7-dimethyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)methanol (183 mg, 0.46 mmol) in DMF (10 mL) was stirred at room temperature for 18 h. Water was added and the mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with brine and dried over sodium sulfate and concentration under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (9:1) as eluting solvents to afford N-(2-(hydroxymethyl)-2,7-dimethyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (80 mg, 41%) as a yellow solid. The product was resolved by chiral pre-SFC(Column: AD 20*250 mm, Sum (Dacel), Mobile phase: CO₂/methanol {0.5% Ammonia (7 m methanol)}=70/30) to obtain (R)—N-(2-(hydroxymethyl)-2,7-dimethyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(hydroxymethyl)-2,7-dimethyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 37%) (35 mg, 44%) as a yellow solids with absolute stereochemistry assigned arbitrarily.

Example 83, Peak 1: ¹H NMR (400 MHz, CDCl₃) δ 10.62 (s, 1H), 8.83 (dd, J=1.8, 7.2 Hz, 1H), 8.79 (s, 1H), 8.77 (dd, J=1.8, 4.0 Hz, 1H), 8.36 (s, 1H), 7.07 (dd, J=4.4, 7.2 Hz, 1H), 4.08-4.12 (m, 2H), 3.89-3.91 (m, 2H), 3.64-3.67 (m, 2H), 3.52-3.57 (m, 2H), 3.26 (d, J=15.6 Hz, 1H), 2.94 (d, J=15.6 Hz, 1H), 2.84 (d, J=11.6 Hz, 2H), 2.30 (s, 3H), 2.06 (br, 1H), 1.45 (s, 3H). MS (ESI): m/z=424.1[M+1]⁺.

Example 84, Peak 2: ¹H NMR (400 MHz, CDCl₃) δ 10.62 (s, 1H), 8.83 (dd, J=1.8, 7.2 Hz, 1H), 8.79 (s, 1H), 8.77 (dd, J=1.8, 4.0 Hz, 1H), 8.36 (s, 1H), 7.07 (dd, J=4.4, 7.2 Hz, 1H), 4.08-4.12 (m, 2H), 3.89-3.91 (m, 2H), 3.64-3.67 (m, 2H), 3.52-3.57 (m, 2H), 3.26 (d, J=15.6 Hz, 1H), 2.94 (d, J=15.6 Hz, 1H), 2.84 (d, J=11.6 Hz, 2H), 2.30 (s, 3H), 2.06 (br, 1H), 1.45 (s, 3H). MS (ESI): m/z=424.1[M+1]⁺.

Examples 85 and 86. (R)-6-Acetyl-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)-6-Acetyl-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 6-Bromopyrazolo[1,5-a]pyrimidine-3-carboxylic acid

The mixture of 2-bromomalonaldehyde (754.8 mg, 5 mmol) and 5-amino-1H-pyrazole-4-carboxylic acid (635.5 mg, 5 mmol) was stirred at 90° C. in acetic acid (6 mL) and ethanol (2 mL) for 4 h. After cooling to room temperature and concentration, the residue was filtered and solid was washed with water and ethyl acetate to afford 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (680 mg, 52.1%) as pale brown solid. MS (ESI): m/z=244.0[M+1]⁺.

Step B. 6-Bromo-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (88 mg, 0.36 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (237 mg, 0.45 mmol), N-ethyl-N-isopropylpropan-2-amine (110 mg, 0.91 mmol) and (5-amino-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)methanol (Example 6, Step B) (80 mg, 0.30 mmol) in DMF (10 mL) was stirred at room temperature for 18 h. Water was added and the mixture was extracted with ethyl acetate (20 mL). The organic phase was washed with brine and dried over sodium sulfate and concentration. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (9:1) as eluting solvents to afford 6-bromo-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (66 mg, 45%) as a yellow solid. MS (ESI): m/z=488.1[M+1]⁺.

Step C. (R)-6-Acetyl-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)-6-Acetyl-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of tributyl(1-ethoxyvinyl)stannane (98 mg, 0.27 mmol), 6-bromo-N-[2-(hydroxymethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (66 mg, 0.14 mmol) and tetrakis(triphenylphosphine)palladium (16 mg, 0.01 mmol) in toluene (15 mL) was stirred at 100° C. under nitrogen atmosphere for 18 h. After cooling down to room temperature, the mixture was added hydrochloride solution (6 mL, 4 m in dioxane). The mixture was stirred at room temperature for 1 hs. After concentration under reduced pressure, the residue was purified by preparative HPLC (Gilson 281, Xbridge 21.2*250 mm c18, 10 um, A:acetonitrile, 25-55%; B:10 mM ammonium bicarbonate in water) to afford 6-acetyl-N-[(2R)-2-(hydroxymethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (40 mg, 65%) as a yellow solid. The product was resolved by chiral pre-SFC(Column: OJ 30*250 mm, Sum (Dacel), Mobile phase: CO₂/methanol {0.2% Ammonia (7 m methanol)}, 75/25) to afford (R)-6-acetyl-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)-6-acetyl-N-(2-(hydroxymethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (5.3 mg, 0.08%) (2.8 mg, 0.04%) as a yellow solid.

Example 85, Peak 1: ¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 9.35 (d, J=2.0 Hz, 1H), 9.24 (d, J=2.0 Hz, 1H), 8.90 (s, 1H), 8.42 (s, 1H), 6.68 (s, 1H), 3.94-3.97 (m, 4H), 3.66 (s, 2H), 3.25 (d, J=16.4 Hz, 1H), 2.94 (d, J=16.4 Hz, 1H), 2.90-2.92 (m, 4H), 1.98-2.02 (m, 1H), 1.88-1.92 (m, 1H), 1.46 (s, 3H). MS (ESI): m/z=452.1[M+1]⁺.

Example 86, Peak 2: ¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 9.35 (d, J=2.0 Hz, 1H), 9.24 (d, J=2.0 Hz, 1H), 8.90 (s, 1H), 8.42 (s, 1H), 6.68 (s, 1H), 3.94-3.97 (m, 4H), 3.66 (s, 2H), 3.25 (d, J=16.4 Hz, 1H), 2.94 (d, J=16.4 Hz, 1H), 2.90-2.92 (m, 4H), 1.98-2.02 (m, 1H), 1.88-1.92 (m, 1H), 1.46 (s, 3H). MS (ESI): m/z=452.1[M+1]⁺.

Examples 87 and 88. N-[(2R)-6-[4-(2-Hydroxyethyl)piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-6-[4-(2-Hydroxyethyl)piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 2-[4-[2-(Hydroxymethyl)-2-methyl-5-nitro-3H-benzofuran-6-yl]piperazin-1-yl]ethanol

A mixture of (6-chloro-2-methyl-5-nitro-3H-benzofuran-2-yl)methanol (Intermediate 2) (150 mg, 0.62 mmol) and 1-piperazineethanol (320 mg, 2.46 mmol) in DMSO (2 mL) was stirred at 90° C. for 3 h. The mixture was purified by silica gel chromatography using methanol:DCM (1:10) as eluting solvents to afford 2-[4-[2-(Hydroxymethyl)-2-methyl-5-nitro-3H-benzofuran-6-yl]piperazin-1-yl]ethanol (110 mg, 49%) as a yellow oil. MS (ESI): m/z=338.2 [M+1]⁺.

Step B. 2-[4-[5-Amino-2-(hydroxymethyl)-2-methyl-3H-benzofuran-6-yl]piperazin-1-yl]ethanol

A mixture of 2-[4-[2-(hydroxymethyl)-2-methyl-5-nitro-3H-benzofuran-6-yl]piperazin-1-yl]ethanol (110.0 mg, 0.33 mmol) and 10% palladium on carbon (11 mg) in methanol (10 mL) was stirred at room temperature under hydrogen atmosphere for 1 h. The solid was filtered off and the filtrate was concentrated under reduced pressure to afford 2-[4-[5-amino-2-(hydroxymethyl)-2-methyl-3H-benzofuran-6-yl]piperazin-1-yl]ethanol (102 mg) as a yellow oil, which was used directly to next step without further purification. MS (ESI): m/z=308.2 [M+1]⁺.

Step C. N-[(2R)-6-[4-(2-Hydroxyethyl)piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(25)-6-[4-(2-Hydroxyethyl)piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (110 mg, 0.67 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (320 mg, 0.84 mmol) and diisopropylethylamine (0.22 mL, 1.34 mmol) was stirred in DMF (3 mL) at room temperature for 10 min. To this mixture was added 2-[4-[5-amino-2-(hydroxymethyl)-2-methyl-3H-benzofuran-6-yl]piperazin-1-yl]ethanol (102 mg, 0.33 mmol) in DMF (2 mL) and the mixture was stirred for an additional 16 h. The crude reaction was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um, A: acetonitrile 25-70%; B:10 mM ammonium bicarbonate in water) and then the product was resolved by chiral separation (SFC (OD-H 20*250 mm, 5 um, CO₂/methanol(0.2% Ammonia (7 m methanol))=75/25, 35° C.) to afford N-[(2R)-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (10.1 mg each, 7% each) as a yellow solids with absolute stereochemistry assigned arbitrarily.

Example 87, Peak 1: ¹H NMR (400 MHz, CDCl₃) δ 10.40 (s, 1H), 8.83 (dd, J=1.6, 7.2 Hz, 1H), 8.79 (s, 1H), 8.72 (dd, J=1.6, 4.0 Hz, 1H), 8.42 (s, 1H), 7.06 (dd, J=4.0, 7.2 Hz, 1H), 6.67 (s, 1H), 3.73-3.62 (m, 4H), 3.25 (d, J=15.8 Hz, 1H), 2.99-2.89 (m, 5H), 2.71-2.83 (m, 4H), 2.68-2.61 (m, 2H), 1.46 (s, 3H). MS (ESI): m/z=453.3 [M+1]⁺.

Example 88, Peak 2: ¹H NMR (400 MHz, CDCl₃) δ 10.40 (s, 1H), 8.83 (dd, J=1.6, 7.2 Hz, 1H), 8.79 (s, 1H), 8.72 (dd, J=1.6, 4.0 Hz, 1H), 8.42 (s, 1H), 7.05 (dd, J=4.0, 7.2 Hz, 1H), 6.67 (s, 1H), 3.71-3.64 (m, 4H), 3.25 (d, J=15.7 Hz, 1H), 2.98-2.90 (m, 5H), 2.71-2.83 (m, 4H), 2.68-2.61 (m, 2H), 1.46 (s, 3H). MS (ESI): m/z=453.3 [M+1]⁺.

Example 89. N-[6-[1-(2,2-Difluoroethyl)-4-piperidyl]-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. tert-Butyl 4-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate

The mixture of tert-butyl 4-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate, 6-bromo-2,2-dimethyl-5-nitro-3H-benzofuran (Intermediate 4) (1.0 g, 3.68 mmol), [1,1′-bis (diphenylphosphino)ferrocene]dichloropalladium (II) (135 mg, 0.18 mmol) and cesium carbonate (2.4 g, 7.37 mmol) in 1,4-dioxane (10 mL) and water (1 mL) in sealed tube was stirred at 90° C. under microwave condition for 2 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (100 mL). The organic phases were washed with water and brine and dried over sodium sulfate before concentration to dryness. The residue was purified by preparative TLC using ethyl acetate:petroleum ether (1:4) as eluting solvents to afford tert-butyl 4-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.28 g, 93%) as a yellow solid. MS (ESI): m/z=397.1 [M+Na]⁺.

Step B. tert-Butyl 4-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)piperidine-1-carboxylate

A mixture of tert-butyl 4-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (50 mg, 0.13 mmol) and 10% palladium on carbon (8 mg) in methanol (10 mL) was stirred at room temperature under a hydrogen atmosphere for 1 h. The solid was filtered off and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)piperidine-1-carboxylate (960 mg) as a brown oil, which was used directly to next step without further purification.

Step C. tert-Butyl 4-[2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]piperidine-1-carboxylate

A solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (860 mg, 5.27 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (2.0 g, 5.26 mmol) and diisopropylethylamine (2 mL, 8.13 mmol) was stirred in DMF (10 mL) at room temperature for 10 min. To this mixture [5-tert-butyl 4-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)piperidine-1-carboxylate (910 mg, 2.63 mmol) in DMF (4 mL) was added and stirred for additional 16 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The organics washed with water, brine and dried over sodium sulfate before concentration to dryness. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford tert-butyl 4-[2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]piperidine-1-carboxylate (1.2 g, 84%) as a yellow solid. MS (ESI): m/z=492.2[M+1]⁺.

Step D. N-[2,2-Dimethyl-6-(4-piperidyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of tert-butyl 4-[2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]piperidine-1-carboxylate (1.2 g, 2.20 mmol) in DCM (5 mL) was added trifluoroacetic acid (2.9 mL, 39.5 mmol) and the mixture was stirred at 25° C. for 2 h. The mixture was neutralized by triethylamine. After concentration, it was afforded N-[2,2-dimethyl-6-(4-piperidyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (950 mg) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=392.2[M+1]⁺.

Step E. N-[6-[1-(2,2-Difluoroethyl)-4-piperidyl]-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of N-[2,2-dimethyl-6-(4-piperidyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (160 mg, 0.41 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (262 mg, 1.22 mmol) and cesium carbonate (400 mg, 1.23 mmol) was stirred in DMF (10 mL) at 25° C. for 15 h. The mixture was purified by preparative HPLC(Xbridge 19*250 mm c18, 10 um; A: acetonitrile 30-60%; B: 10 mM ammonium bicarbonate in water) to afford N-[6-[1-(2,2-difluoroethyl)-4-piperidyl]-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (25 mg, 14%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (s, 1H), 9.39 (dd, J=1.6, 6.8 Hz, 1H), 8.89 (dd, J=1.6, 4.0 Hz 1H), 8.68 (s, 1H), 7.74 (s, 1H), 7.34 (dd, J=4.0, 6.8 Hz, 1H), 6.66 (s, 1H), 6.15 (tt, J=3.6, 56.0 Hz, 1H), 3.12-2.90 (m, 4H), 2.75 (m, 3H), 2.36-2.20 (m, 2H), 1.71 (m, 5H), 1.42 (s, 6H). MS (ESI): m/z=457.3 [M+1].

Example 90. N-[2,2-Dimethyl-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of N-[2,2-dimethyl-6-(4-piperidyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (184 mg, 0.47 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (300 mg, 2.75 mmol) and potassium carbonate (260 mg, 4.0 mmol) was stirred in DMF (10 mL) at 25° C. for 15 h. The mixture was purified by preparative HPLC(Xbridge 21.2*250 mm c18, 10 um, A: acetonitrile 25-55%; B: 10 mM ammonium bicarbonate in water) to afford N-[2,2-dimethyl-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (42 mg, 19%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (s, 1H), 9.39 (dd, J=1.6, 7.0 Hz, 1H), 8.88 (dd, J=1.6, 4.0 Hz, 1H), 8.69 (s, 1H), 7.74 (s, 1H), 7.35 (dd, J=4.0, 7.0 Hz, 1H), 6.67 (s, 1H), 3.19 (q, J=10.3 Hz, 2H), 3.06-2.99 (m, 4H), 2.86-2.78 (m, 1H), 2.50-2.39 (m, 2H), 1.77-1.65 (m, 4H), 1.42 (s, 6H). MS (ESI): m/z=475.3 [M+1].

Example 91. 6-(Difluoromethyl)-N-(2,2-dimethyl-6-morpholino-3H-benzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. N-(2,2-Dimethyl-6-morpholino-3H-benzofuran-5-yl)-6-formyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution of 6-formylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Example 75, step A) (191 mg, 1.0 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (750 mg, 1.97 mmol) and diisopropylethylamine (0.5 mL, 3.0 mmol) was stirred in DMF (2 mL) at room temperature for 10 min. To this mixture was added 2,2-dimethyl-6-morpholino-3H-benzofuran-5-amine (245 mg, 0.98 mmol) in DMF (1 mL) and the reaction was stirred for additional 16 h. The mixture was poured into water (20 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with water, brine and dried over sodium sulfate before concentration to dryness. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:10) as eluting solvents to afford N-(2,2-dimethyl-6-morpholino-3H-benzofuran-5-yl)-6-formyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide (283 mg, 61%) as a yellow solid. MS (ESI): m/z=422.2[M+1]⁺.

Step B. 6-(Difluoromethyl)-N-(2,2-dimethyl-6-morpholino-3H-benzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of N-(2,2-dimethyl-6-morpholino-3H-benzofuran-5-yl)-6-formyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide (120 mg, 0.28 mmol) in DCM (8 mL), diethylaminosulfurtrifluoride (0.17 mL, 1.28 mmol) was added at 0° C. The mixture was stirred at 25° C. for 8 h. The mixture was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um acetonitrile 30-70% (10 mM ammonium bicarbonate) in water) to afford 6-(difluoromethyl)-N-(2,2-dimethyl-6-morpholino-3H-benzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (10.1 mg, 7.4%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (s, 1H), 9.75 (d, J=1.6 Hz, 1H), 9.12 (d, J=1.6 Hz, 1H), 8.80 (s, 1H), 8.30 (s, 1H), 7.32 (t, J=54.6 Hz, 2H), 6.73 (s, 1H), 3.90-3.78 (m, 4H), 3.01 (s, 2H), 2.87-2.73 (m, 4H), 1.42 (s, 6H). MS (ESI): m/z=444.2 [M+1].

Examples 92 and 93. (S)—N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)—N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Example 16 was chirally resolved using chiral SFC to provide (S)—N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)—N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide with absolute stereochemistry assigned arbitrarily.

Example 92, Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.21 (dd, J=2.1, 1.2 Hz, 1H), 8.83 (d, J=2.0 Hz, 1H), 8.58 (s, 1H), 8.33-8.27 (m, 1H), 6.66 (s, 1H), 5.02 (t, J=5.8 Hz, 1H), 4.58 (t, J=5.2 Hz, 1H), 3.49-3.33 (m, 4H), 3.18 (dd, J=15.7, 1.2 Hz, 1H), 2.92 (d, J=11.2 Hz, 2H), 2.86-2.77 (m, 1H), 2.62 (td, J=11.3, 3.1 Hz, 2H), 2.41 (d, J=1.1 Hz, 3H), 1.73-1.57 (m, 4H), 1.50 (dq, J=10.4, 5.3 Hz, 1H), 1.34 (s, 3H). MS (ESI): m/z=452.2 [M+1].

Example 93, Peak 2: ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.21 (dq, J=1.9, 0.9 Hz, 1H), 8.83 (d, J=2.0 Hz, 1H), 8.58 (s, 1H), 8.30 (d, J=0.9 Hz, 1H), 6.66 (s, 1H), 5.02 (t, J=5.8 Hz, 1H), 4.58 (t, J=5.2 Hz, 1H), 3.49-3.32 (m, 4H), 3.32-3.14 (m, 1H), 2.92 (d, J=11.2 Hz, 2H), 2.81 (dd, J=15.5, 1.2 Hz, 1H), 2.62 (td, J=11.4, 3.2 Hz, 2H), 2.41 (d, J=1.1 Hz, 3H), 1.66 (qd, J=11.8, 10.6, 4.2 Hz, 4H), 1.50 (dq, J=10.6, 5.3 Hz, 1H), 1.34 (s, 3H). MS (ESI): m/z=452.2 [M+1].

Examples 94 and 95. (S)—N-(6-(3-(hydroxymethyl)-3-methylpyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)—N-(6-(3-(hydroxymethyl)-3-methylpyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The enantiomers of Example 18 were resolved using chiral SFC to provide (S)—N-(6-(3-(hydroxymethyl)-3-methylpyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)—N-(6-(3-(hydroxymethyl)-3-methylpyrrolidin-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with absolute stereochemistry assigned arbitrarily.

Example 94, Peak 1: ¹H NMR (400 MHz, Chloroform-d) δ 9.84 (s, 1H), 9.37 (dd, J=7.0, 1.6 Hz, 1H), 8.87 (dd, J=4.2, 1.6 Hz, 1H), 8.69 (s, 1H), 8.03 (d, J=1.0 Hz, 1H), 7.34 (dd, J=7.0, 4.2 Hz, 1H), 6.54 (s, 1H), 4.70 (t, J=5.3 Hz, 1H), 3.38 (s, 6H), 3.15-3.05 (m, 1H), 3.04-2.95 (m, 5H), 2.74 (d, J=9.0 Hz, 1H), 1.84 (ddd, J=12.1, 8.0, 6.3 Hz, 1H), 1.54 (ddd, J=12.1, 8.0, 5.6 Hz, 1H), 1.42 (s, 7H), 1.14 (s, 3H). MS (ESI): m/z=422.2 [M+1].

Example 95, Peak 2: ¹H NMR (400 MHz, DMSO-d₆) δ 9.83 (s, 1H), 9.36 (dd, J=7.0, 1.6 Hz, 1H), 8.86 (dd, J=4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.02 (d, J=1.0 Hz, 1H), 7.33 (dd, J=7.0, 4.2 Hz, 1H), 6.53 (s, 1H), 4.69 (t, J=5.4 Hz, 1H), 3.47-3.32 (m, 2H), 3.14-2.94 (m, 5H), 2.73 (d, J=9.0 Hz, 1H), 1.83 (ddd, J=12.2, 7.9, 6.2 Hz, 1H), 1.53 (ddd, J=12.2, 8.0, 5.6 Hz, 1H), 1.41 (s, 6H), 1.13 (s, 3H). MS (ESI): m/z=422.2 [M+1].

Examples 96 and 97. (S)—N-(2-ethyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)—N-(2-ethyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The enantiomers of Example 21 were resolved using chiral SFC to provide (S)—N-(2-ethyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)—N-(2-ethyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with absolute stereochemistry assigned arbitrarily.

Example 96, Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 9.37 (dd, J=7.0, 1.6 Hz, 1H), 8.94 (dd, J=4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.30 (d, J=1.0 Hz, 1H), 7.34 (dd, J=7.0, 4.2 Hz, 1H), 6.72 (s, 1H), 3.88-3.80 (m, 4H), 3.13-3.01 (m, 1H), 2.96-2.86 (m, 1H), 2.86-2.77 (m, 4H), 1.71 (q, J=7.4 Hz, 2H), 1.35 (s, 3H), 0.92 (t, J=7.4 Hz, 3H). MS (ESI): m/z=408.2 [M+1].

Example 97, Peak 2: ¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 9.37 (dd, J=7.0, 1.6 Hz, 1H), 8.94 (dd, J=4.2, 1.6 Hz, 1H), 8.68 (s, 1H), 8.30 (d, J=1.0 Hz, 1H), 7.34 (dd, J=7.0, 4.2 Hz, 1H), 6.72 (s, 1H), 3.88-3.79 (m, 4H), 3.04 (d, J=1.2 Hz, 1H), 2.97-2.86 (m, 1H), 2.86-2.76 (m, 4H), 1.70 (t, J=7.4 Hz, 2H), 1.35 (s, 3H), 0.92 (t, J=7.4 Hz, 3H). MS (ESI): m/z=408.2 [M+1].

Examples 98 and 99. N-[(2R)-6-[4-(2,2-Difluoroethyl)piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. [6-[4-(2, 2-Difluoroethyl)piperazin-1-yl]-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol

A mixture of (6-chloro-2-methyl-5-nitro-3H-benzofuran-2-yl)methanol (Intermediate 2) (440 mg, 1.81 mmol), 1-(2, 2-difluoroethyl)piperazine hydrochloride (3000 mg, 16.1 mmol) and potassium carbonate (1480 mg, 10.72 mmol) in acetonitrile (15 mL) was stirred at 85° C. for 4d. After filtration and concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford[6-[4-(2, 2-difluoroethyl)piperazin-1-yl]-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol (486 mg, 75%) as yellow oil. MS (ESI): m/z=358.2 [M+1]⁺.

Step B. [5-Amino-6-[4-(2, 2-difluoroethyl)piperazin-1-yl]-2-methyl-3H-benzofuran-2-yl]methanol

The mixture of [6-[4-(2, 2-difluoroethyl)piperazin-1-yl]-2-methyl-5-nitro-3H-benzofuran-2-yl]methanol (512 mg, 1.43 mmol) and palladium on carbon (150 mg) in methanol (20 mL) was stirred under hydrogen atmosphere at 25° C. for 1 h. After filtration and concentration under reduced pressure, it was afforded [5-amino-6-[4-(2, 2-difluoroethyl)piperazin-1-yl]-2-methyl-3H-benzofuran-2-yl]methanol (430 mg, 92%) as a brown oil, which was used directly in the next step without further purification. MS (ESI): m/z=328.1 [M+1]⁺.

Step C. N-[(2R)-6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(25)-6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (344 mg, 2.11 mmol), N,N-diisopropylethylamine (0.66 mL, 3.99 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (1016 mg, 2.67 mmol) and [5-amino-6-(difluoromethyl)-2-methyl-3H-benzofuran-2-yl]methanol (430 mg, 1.31 mmol) in DMF (15 mL) was stirred at 25° C. for 16 h. The mixture was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-75%; B: 10 mM ammonium bicarbonate in water) and then the product was resolved by Chiral-HPLC [Gilson-281, IA 20*250 mm, 5 um (Dacel), hexane (0.1% n,n-diethylamine)/ethanol(0.1% n,n-diethylamine)=70/30] to afford N-[(2R)-6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (121 mg, 20%) (118 mg, 19%) as yellow solids with absolute stereochemistry assigned arbitrarily.

Example 98, Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H), 9.37 (dd, J=1.6, 7.2 Hz, 1H), 8.95 (dd, J=1.6, 4.4 Hz, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 7.35 (dd, J=4.4, 7.2 Hz, 1H), 6.70 (s, 1H), 6.20 (tt, J=4.0, 55.6 Hz, 1H), 5.04 (t, J=6.0 Hz, 1H), 3.48-3.38 (m, 2H), 3.19 (d, J=16 Hz, 1H), 2.93-2.71 (m, 11H), 1.34 (s, 3H). MS (ESI): m/z=473.2 [M+1]⁺.

Example 99, Peak 2: ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H), 9.37 (dd, J=1.6, 7.2 Hz, 1H), 8.95 (dd, J=1.6, 4.4 Hz, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 7.35 (dd, J=4.4, 7.2 Hz, 1H), 6.70 (s, 1H), 6.20 (tt, J=4.0, 55.6 Hz, 1H), 5.04 (t, J=6.0 Hz, 1H), 3.48-3.38 (m, 2H), 3.19 (d, J=16 Hz, 1H), 2.93-2.71 (m, 11H), 1.34 (s, 3H). MS (ESI): m/z=473.2 [M+1]⁺.

TABLE 4
The following examples were made in a manner similar to that for Example 4:
Ex.	Name	Structure	NMR, MS
100	N-[6-(6,8-dihydro-5H- imidazo[1,5-a]pyrazin-7- yl)-2,2-dimethyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyridine-3- carboxamide		1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.27 (dd, J = 7.0, 1.6 Hz, 1H), 8.64 (s, 1H), 8.41 (d, J = 1.0 Hz, 1H), 7.71 (s, 1H), 7.61 (dd, J = 4.2, 1.7 Hz, 1H), 7.17 (dd, J = 7.0, 4.2 Hz, 1H), 6.83 (s, 1H), 6.63 (s, 1H), 4.27-4.19 (m, 2H), 4.03 (s, 2H), 3.40-3.23 (m, 2H), 3.13-3.00 (m, 2H), 1.43 (s, 6H). MS (ESI): m/z = 430.2 [M + 1]+.
101	N-[2,2-dimethyl-6- (5,6,8,9- tetrahydroimidazo[1,5- d][1,4]diazepin-7-yl)- 3H-benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 10.70 (s, 1H), 9.34 (dd, J = 7.0, 1.6 Hz, 1H), 8.73- 8.64 (m, 2H), 8.35 (d, J = 1.0 Hz, 1H), 7.53 (d, J = 1.1 Hz, 1H), 7.26 (dd, J = 7.0, 4.2 Hz, 1H), 6.75-6.66 (m, 2H), 4.33 (dd, J = 6.1, 2.5 Hz, 2H), 3.12-3.01 (m, 4H),2.94 (dd, J = 6.8, 3.2 Hz, 2H), 1.40 (s, 6H). MS (ESI): m/z = 444.2 [M + 1]+.
102	N-[6-[4- (hydroxymethyl)imidazo 1-1-yl]-2,2-dimethyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 9.73 (s, 1H), 9.30 (dd, J = 7.0, 1.6 Hz, 1H), 8.65- 8.55 (m, 2H), 8.29 (t, J = 1.0 Hz, 1H), 7.76 (d, J = 1.4 Hz, 1H), 7.25 (dd, J = 7.0, 4.2 Hz, 1H), 7.18 (dt, J = 1.5, 0.8 Hz, 1H), 6.75 (s, 1H), 4.96 (t, J = 5.5 Hz, 1H), 4.43 (dd, J = 5.5, 0.9 Hz, 2H), 3.12 (d, J = 1.3 Hz, 2H), 1.46 (s, 6H). MS (ESI): m/z = 405.1 [M + 1]+.
103	N-(6-imidazol-1-yl-2,2- dimethyl-3H- benzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 9.64 (s, 1H), 9.30 (dd, J = 7.0, 1.7 Hz, 1H), 8.63 (s, 1H), 8.50 (dd, J = 4.2, 1.7 Hz, 1H), 8.22 (d, J = 1.1 Hz, IH), 7.85 (t, J = 1.1 Hz, 1H), 7.37 (t, J = 1.3 Hz, 1H), 7.26 (dd, J = 7.0, 4.2 Hz, 1H), 7.14 (t, J = 1.1 Hz, 1H), 6.79 (s, 1H), 3.13 (d, J = 1.3 Hz, 2H), 1.47 (s, 6H). MS (ESI): m/z = 375.1 [M + 1]+.
104	N-[2,2-dimethyl-6-(2- methylpyrrolidin-1-yl)- 3H-benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 10.67 (s, 1H), 9.34 (dd, J = 7.0, 1.6 Hz, 1H), 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.66 (s, 1H), 8.31 (d, J = 1.0 Hz, 1H), 7.29 (dd, J = 7.0, 4.1 Hz, 1H), 6.69 (s, 1H), 3.44-3.29 (m, 4H), 3.00 (s, 2H), 2.65 (q, J = 8.3 Hz, 1H), 2.20-2.10 (m, 1H), 1.95 (d, J = 7.3 Hz, 2H), 1.86 (td, J = 8.2, 4.1 Hz, 1H), 1.71-1.56 (m, 1H), 1.41 (d, J = 4.7 Hz, 6H), 0.93 (d, J = 6.0 Hz, 3H. MS (ESI): m/z = 392.2 [M + 1]+.
105	N-[6-(3-hydroxy-3- methyl-azetidin-1-yl)- 2,2-dimethyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 9.37 (dd, J = 7.0, 1.6 Hz, 1H), 9.23 (s, 1H), 8.86 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 7.51 (d, J = 0.9 Hz, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 6.13 (s, 1H), 5.31 (s, 1H), 3.77-3.70 (m, 2H), 3.55-3.49 (m, 2H), 3.41-3.26 (m, 4H), 2.93 (d, J = 1.3 Hz, 2H), 1.43 (d, J = 19.0 Hz, 10H). MS (ESI): m/z = 394.2 [M + 1]+.
106	N-(2,2-dimethyl-6-(2- oxa-8- azaspiro[4.5]decan-8- yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.82 (dd, J = 1.6, 6.8 Hz, 1H), 8.79 (s, 1H), 8.63 (dd, J = 2.0, 4.4 Hz, 1H), 8.40 (s, 1H), 7.05 (dd, J = 4.0, 7.2 Hz, 1H), 6.63 (s, 1H), 3.90 (t, J = 7.2 Hz, 2H), 3.64 (s, 2H), 3.03 (s, 2H), 2.86-2.84 (m, 4H), 1.89-1.84 (m, 6H), 1.49 (s, 6H). MS (ESI): m/z = 448.3 [M + 1]+.
107	N-(2,2-dimethyl-6-(2- oxa-6- azaspiro[3.4]octan-6-yl)- 2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 8.81 (dd, J = 1.6, 7.2 Hz, 1H), 8.78 (s, 1H), 8.60 (d, J = 2.8 Hz, 1H), 8.08 (s, 1H), 7.02 (dd, J = 4.0, 6.8 Hz, 1H), 6.52 (s, 1H), 4.68 (s, 4H), 3.39 (s, 2H), 3.11 (t, J = 6.8 Hz, 2H), 3.02 (s, 2H), 2.24 (t, J = 6.8 Hz, 2H), 1.48 (s, 6H). MS (ESI): m/z = 420.2 [M + 1]+.
108	N-(2,2-dimethyl-6-(2- oxa-7- azaspiro[4.4]nonan-7- yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 9.80 (s, 1H), 9.36 (d, J = 6.8 Hz, 1H), 8.83 (d, J = 4.0 Hz, 1H), 8.68 (s, 1H), 7.98 (s, 1H), 7.32 (dd, J = 4.0, 6.8 Hz, 1H), 6.56 (s, 1H), 3.82-3.64 (m, 3H), 3.59 (d, J = 8.4 Hz, 1H), 3.15- 3.07 (m, 2H), 3.05 (s, 2H), 2.97 (s, 2H), 2.01-1.91 (m, 4H), 1.41 (s, 6H). MS (ESI): m/z = 434. [M + 1]+.
109	N-(6-(1-hydroxy-8- azaspiro[4.5]decan-8- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 10.55 (s, 1H), 9.35 (dd, J = 1.6, 6.8 Hz, 1H), 9.03 (dd, J = 2.8, 4.4 Hz, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 7.32 (dd, J = 4.4, 6.8 Hz, 1H), 6.70 (s, 1H), 4.63 (s, 1H), 3.67 (d, J = 5.2 Hz, 1H), 3.22 (d, J = 1.2 Hz, 2H), 2.99-2.68 (m, 4H), 2.04-1.99 (m, 1H), 1.89- 1.83 (m, 2H), 1.73-1.64 (m, 2H), 1.52-1.46 (m, 2H), 1.41 (s, 7H), 1.30- 1.27 (m, 1H). MS (ESI): m/z = 462.3 [M + 1]+.
110	N-(6-(2-hydroxy-7- azaspiro[3.5]nonan-7- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6): δ 10.46 (s, 1H), 9.36 (d, J = 6.8 Hz, 1H), 8.74 (d, J = 2.8 Hz, 1H), 8.67 (s, 1H), 8.30 (s, 1H), 7.35 (dd, J = 4.0, 6.8 Hz, 1H), 6.64 (s, 1H), 4.18-4.05 (m, 1H), 2.99 (s, 2H), 2.74-2.58 (m, 4H), 2.29-2.14 (m, 2H), 1.81-1.67 (m, 4H), 1.67-1.54 (m, 2H), 1.41(s, 6H). MS (ESI): m/z = 448.3 [M + 1]+.
111	N-[2,2-dimethyl-6-(3- oxo-2,7- diazaspiro[3.5]nonan-7- yl)-3H-benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3) δ 10.68 (s, 1H), 9.15 (d, J = 2.4 Hz, 1H), 8.79 (dd, J = 1.6, 7.2 Hz, 1H), 8.77 (s, 1H), 8.54 (s, 1H), 7.11 (dd, J = 4.0, 7.2 Hz, 1H), 6.59 (s, 1H), 5.65 (s, 1H), 3.31 (s, 2H), 3.11-3.05 (m, 2H), 3.03 (s, 2H), 2.74-2.64 (m, 2H), 2.56-2.46 (m, 2H), 1.93-1.86 (m, 2H), 1.48(s, 6H). MS (ESI): m/z = 447.3 [M + 1]+.
112	N-(6-(6,6-difluoro-3- azabicyclo[3.1.0]hexan- 3-yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6):δ 9.70 (s, 1H), 9.36 (dd, J = 1.6, 7.2 Hz, 1H), 8.82 (dd, J = 1.6, 4.0 Hz, 1H), 8.67 (s, 1H), 7.85 (s, 1H),7.32 (dd, J = 4, 6.8 Hz, 1H), 6.57 (s, 1H), 3.50-3.40 (m, 4H), 2.97 (s, 2H), 2.59-2.52 (m, 2H), 1.41(s, 6H). MS (ESI): m/z = 426.2 [M + 1]+.
113	N-[2,2-Dimethyl-6-(6- oxo-1H-pyridin-3-yl)- 3H-benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 9.65 (s, 1H), 9.34 (dd, J = 1.6, 7.0 Hz, 1H), 8.64 (s, 1H), 8.52 (dd, J = 1.6, 4.0 Hz, 1H), 8.13 (s, 1H), 7.47- 7.40 (m, 2H), 7.32 (dd, J = 4.0, 7.0 Hz, 1H), 6.65 (s, 1H), 6.39 (d, J = 9.1 Hz, 1H), 3.07 (s, 2H), 1.44 (s, 6H). MS (ESI): m/z = 402.2 [M + 1]
114	N-(2,2-Dimethyl-6-(2- oxa-7- azaspiro[3.5]nonan-7- yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6): δ 10.44 (s, 1H), 9.35 (d, J = 6.8 Hz, 1H), 8.73 (d, J = 2.0 Hz, 1H), 8.67 (s, 1H), 8.31 (s, 1H), 7.32-7.30 (m, 1H), 6.63 (s, 1H), 4.51-4.29 (m, 4H), 3.08-2.91 (m, 2H), 2.81-2.57 (m, 4H), 2.14-1.89 (m, 4H), 1.40 (s, 6H). MS (ESI): m/z = 434.2 [M + 1]+.
115	N-(6-(3-Fluoro-4- hydroxypiperidin-1-yl)- 2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6): δ 10.39 (s, 1H), 9.36 (dd, J = 1.6, 7.2 Hz, 1H), 8.89 (dd, J = 1.6, 4.0 Hz, 1H), 8.67 (s, 1H), 8.31 (s, 1H), 7.32 (dd, J = 4.0, 7.2 Hz, 1H), 6.68 (s, 1H), 5.08-5.07 (d, J = 6.0 Hz, 1H), 4.86-4.72 (m, 1H), 3.95-3.90 (m, 1H), 3.17-3.11 (m, 1H), 3.03-2.89 (m, 4H), 2.58-2.51 (m, 1H), 2.02-2.00 (m, 1H), 1.99-1.78 (m, 1H), 1.41 (s, 1H). MS (ESI): m/z = 426.2 [M + 1]+.
116	N-(6-(1,4-diazepan-1- yl)-2,2-dimethyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6): δ 10.37 (s, 1H), 9.38 (d, J = 6.6 Hz, 1H), 9.00 (d, J = 4.4 Hz, 1H), 8.68 (s, 1H), 8.38 (s, 1H), 8.27 (s, 1H), 7.35 (dd, J = 4.4, 6.6 Hz, 1H), 6.72 (s, 1H), 3.20-3.22 (m, 4H), 3.14-3.15 (m, 2H), 2.99-3.02 (m, 4H), 1.98-1.99 (m, 2H), 1.41 (s, 6H). MS (ESI): m/z = 407.3 [M + 1]+.
117	N-(2,2-dimethyl-6-(1,4- oxazepan-4-yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3): δ 10.52 (s, 1H), 8.82 (dd, J = 6.8 Hz, 1H), 8.78 (s, 1H), 8.75 (dd, J = 4.4 Hz, 1H), 8.37 (s, 1H), 7.05 (dd, J = 4.4, 6.8 Hz, 1H), 6.65 (s, 1H), 3.99 (t, J = 7.0 Hz, 2H), 3.91-3.93 (m, 2H), 3.11-3.14 (m, 4H), 3.03 (s, 2H), 2.06-2.12 (m, 2H), 1.45 (s, 6H). MS (ESI): m/z = 408.2 [M + 1]+.

Example 118. N-[2,2-Dimethyl-6-(morpholin-4-yl)-1,1-dioxo-2,3-dihydro-benzothiophen-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. Methyl 4-chloro-2-fluoro-5-nitro-benzoate

To a mixture of 4-chloro-2-fluoro-5-nitro-benzoic acid (5.06 g, 23.05 mmol) in methyl alcohol (15 mL) was added drop wise sulfurous dichloride (10 mL). The mixture was stirred at 90° C. for 16 h. The mixture was concentrated to afford methyl 4-chloro-2-fluoro-5-nitro-benzoate (5.2 g, 92%) as a white solid, which was used directly to next step without further purification. MS (ESI): m/z=234.1[M+1]⁺.

Step B. 4-Chloro-2-methylsulfanyl-5-nitro-benzoate

A mixture of methyl 4-chloro-2-fluoro-5-nitro-benzoate (800.0 mg, 3.43 mmol) in tetrahydrofuran (20 mL) was added sodium methanethiolate (20% wt in water, 1.2 g, 3.43 mmol). The mixture was stirred at 25° C. for 4 h. Water and ethyl acetate (30 mL) was added. The organic layer was separated, dried over sodium sulfate and concentrated to afford methyl 4-chloro-2-methylsulfanyl-5-nitro-benzoate (800 mg) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=262.0[M+1]⁺.

Step C. Methyl 2-methylsulfanyl-4-morpholino-5-nitro-benzoate

A mixture of methyl 4-chloro-2-methylsulfanyl-5-nitro-benzoate (600.0 mg, 2.29 mmol) in morpholine (3995.15 mg, 45.86 mmol) was stirred at 60° C. overnight. The mixture was concentrated and the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:4) as eluting solvents to afford methyl 2-methylsulfanyl-4-morpholino-5-nitro-benzoate (506 mg, 70%) as yellow solid. MS (ESI): m/z=313.0[M+1]⁺.

Step D. Methyl 2-methylsulfonyl-4-morpholino-5-nitro-benzoate

To a mixture of methyl 2-methylsulfanyl-4-morpholino-5-nitro-benzoate (506.0 mg, 1.62 mmol) in methyl alcohol (10 mL) and water (10 mL) was added oxone (1082.16 mg, 6.48 mmol). The mixture was stirred at 50° C. for 5 h. Ethyl acetate (30 mL) and water was added and the organic layer was separated, dried over sodium sulfate and concentrated to afford methyl 2-methylsulfonyl-4-morpholino-5-nitro-benzoate (478 mg) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=345.0[M+1]⁺.

Step E. 6-Morpholino-5-nitro-1,1-dioxo-benzothiophen-3-one

A mixture of methyl 2-methylsulfonyl-4-morpholino-5-nitro-benzoate (574.0 mg, 1.67 mmol) in N,N-Dimethylformamide (15 mL) was treated with sodium hydride (60% wt with mineral oil, 100 mg, 2.5 mmol) at 0° C. The mixture was stirred at 25° C. for 4 h. Water was added slowly and the pH was adjusted to 3 using 1N HCl. The aqueous layer was extracted with ethyl acetate (70 mL). The organic layer was concentrated to afford 6-morpholino-5-nitro-1,1-dioxo-benzothiophen-3-one (560 mg) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=313.0[M+1]⁺.

Step F. 2,2-Dimethyl-6-morpholino-5-nitro-1,1-dioxo-benzothiophen-3-one

A mixture of 6-morpholino-5-nitro-1,1-dioxo-benzothiophen-3-one (560.0 mg, 1.79 mmol) iodomethane (1272.6 mg, 8.97 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1362.79 mg, 8.97 mmol) in N,N-dimethylformamide (10 mL) was stirred at 40° C. in a sealed tube for 16 h. Water was added and the aqueous layer was extracted with ethyl acetate (70 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:5) as eluting solvents to afford 2,2-dimethyl-6-morpholino-5-nitro-1,1-dioxo-benzothiophen-3-one (250 mg, 33%) as yellow solid. MS (ESI): m/z=341.1 [M+1]⁺.

Step G. 2,2-Dimethyl-6-morpholino-5-nitro-1,1-dioxo-3H-benzothiophen-3-ol

A mixture of 2,2-dimethyl-6-morpholino-5-nitro-1,1-dioxo-benzothiophen-3-one (200.0 mg, 0.47 mmol) in methyl alcohol (30 mL) was treated with sodium borohydride (53.59 mg, 1.41 mmol) The mixture was stirred at 25° C. for 3 h. The mixture was quenched with water and ethyl acetate (30 mL) was added. The organic layer was separated, dried over sodium sulfate and concentrated to afford 2,2-dimethyl-6-morpholino-5-nitro-1,1-dioxo-3H-benzothiophen-3-ol (150 mg) as a brown solid, which was used directly to next step without further purification. MS (ESI): m/z=343.1 [M+1]⁺.

Step H. 2,2-Dimethyl-6-morpholino-5-nitro-3H-benzothiophene 1,1-dioxide

A mixture of 2,2-dimethyl-6-morpholino-5-nitro-1,1-dioxo-3H-benzothiophen-3-ol (150.0 mg, 0.44 mmol) triethylsilane (2.0 mL, 12.52 mmol) in trifluoroacetic acid (8 mL, 107.7 mmol) was stirred at 50° C. for 16 h. The mixture was concentrated and purified by silica gel chromatography using ethyl acetate:petroleum ether (1:5 to 1:3) as eluting solvents to afford 2,2-dimethyl-6-morpholino-5-nitro-3H-benzothiophene 1,1-dioxide (88 mg, 62%) as a yellow solid. MS (ESI): m/z=327.0 [M+1]⁺.

Step I. 2,2-Dimethyl-6-morpholino-1,1-dioxo-3H-benzothiophen-5-amine

A mixture of 2,2-dimethyl-6-morpholino-5-nitro-3H-benzothiophene 1,1-dioxide (78.0 mg, 0.24 mmol) and 10 wt % palladium on carbon (20.0 mg, 0.24 mmol) in methyl alcohol (20 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. The reaction was filtered through celite and concentrated under reduced pressure to afford 2,2-dimethyl-6-morpholino-1,1-dioxo-3H-benzothiophen-5-amine (60 mg) as a pink solid, which was used directly to next step without further purification. MS (ESI): m/z=297.2 [M+1]⁺.

Step J. N-[2,2-Dimethyl-6-(morpholin-4-yl)-1,1-dioxo-2,3-dihydro-benzothiophen-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 2,2-dimethyl-6-morpholino-1,1-dioxo-3H-benzothiophen-5-amine (50.0 mg, 0.17 mmol), pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (Example 3, Step B) (153.16 mg, 0.84 mmol), and potassium carbonate (879.55 mg, 1.69 mmol) in toluene (10 mL) was stirred at 110° C. for 14 h. Ethyl acetate (10 mL) and water were added. The organic layer was separated, dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC (Gilson 281, Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-55%; B: 10 M ammonium bicarbonate in water) to afford N-(2,2-dimethyl-6-morpholino-1,1-dioxo-3H-benzothiophen-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 40%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 9.42 (dd, J=1.6, 7.2 Hz, 1H), 9.00 (dd, J=1.6, 4.4 Hz, 1H), 8.76 (s, 1H), 8.63 (s, 1H), 7.70 (s, 1H), 7.39 (dd, J=4.4, 7.2 Hz, 1H), 3.88-3.90 (m, 4H), 3.15 (s, 2H), 2.92-2.95 (m, 4H), 1.38 (s, 6H). MS (ESI): m/z=442.1 [M+1]⁺.

Examples 119 and 120. N—((S)-2-(hydroxymethyl)-2-methyl-6-((1R,4R)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and N—((R)-2-(hydroxymethyl)-2-methyl-6-((1R,4R)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N—((S)-2-(hydroxymethyl)-2-methyl-6-((1R,4R)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and N—((R)-2-(hydroxymethyl)-2-methyl-6-((1R,4R)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (3.8 mg, 3%) (4.9 mg, 4%) were isolated as yellow solids with absolute stereochemistry assigned arbitrarily using a method similar to Examples 78 and 79.

Example 119, Peak 1: ¹H NMR (400 MHz, DMSO-d₆): δ9.74 (s, 1H), 9.37 (dd, J=1.6, 6.8 Hz, 1H), 8.85 (dd, J=1.6, 4.0 Hz, 1H), 8.69 (s, 1H)), 7.80 (s, 1H), 7.33 (dd, J=4.0, 6.8 Hz, 1H), 6.48 (s, 1H), 5.04 (t, J=6.0 Hz, 1H), 3.93 (s, 1H), 3.51 (s, 1H), 3.45-3.41 (m, 2H), 3.32-3.25 (m, 3H), 3.16 (d, J=16.0 Hz, 1H), 3.07-3.04 (m, 1H), 2.92-2.88 (m, 2H), 2.78 (d, J=15.6 Hz, 1H), 1.89-1.76 (m, 2H), 1.34 (s, 3H). MS (ESI): m/z=503.3 [M+1]⁺.

Example 120, Peak 2: ¹H NMR (400 MHz, DMSO-d₆): δ9.72 (s, 1H), 9.37 (dd, J=1.6, 6.8 Hz, 1H), 8.85 (dd, J=1.6, 4.0 Hz, 1H), 8.68 (s, 1H)), 7.78 (s, 1H), 7.33 (dd, J=4.0, 6.8 Hz, 1H), 6.47 (s, 1H), 5.04 (t, J=6.0 Hz, 1H), 3.93 (s, 1H), 3.50 (s, 1H), 3.45-3.41 (m, 2H), 3.32-3.25 (m, 3H), 3.16 (d, J=16.0 Hz, 1H), 3.07-3.04 (m, 1H), 2.92-2.88 (m, 2H), 2.78 (d, J=15.6 Hz, 1H), 1.89-1.76 (m, 2H), 1.34 (s, 3H). MS (ESI): m/z=503.3 [M+1]⁺.

Examples 121 and 122. (S)—N-(6-(4,4-Difluoropiperidin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)—N-(6-(4,4-difluoropiperidin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(S)—N-(6-(4,4-Difluoropiperidin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)—N-(6-(4,4-difluoropiperidin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide were isolated as white solids with absolute stereochemistry assigned arbitrarily using a method similar to Examples 78 and 79.

Example 121, Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 9.38 (dd, J=7.0, 1.6 Hz, 1H), 8.75 (dd, J=4.2, 1.7 Hz, 1H), 8.69 (s, 1H), 8.32 (d, J=1.0 Hz, 1H), 7.37 (dd, J=7.0, 4.2 Hz, 1H), 6.73 (s, 1H), 5.03 (t, J=5.8 Hz, 1H), 3.42 (h, J=5.8 Hz, 2H), 3.20 (dd, J=15.8, 1.2 Hz, 1H), 2.93 (t, J=5.5 Hz, 4H), 2.83 (dd, J=15.6, 1.2 Hz, 1H), 2.31-2.17 (m, 5H), 1.34 (s, 3H). MS (ESI): m/z=444.2 [M+1]⁺.

Example 122, Peak 2: ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 9.38 (dd, J=7.0, 1.6 Hz, 1H), 8.75 (dd, J=4.2, 1.7 Hz, 1H), 8.69 (s, 1H), 8.32 (d, J=1.0 Hz, 1H), 7.37 (dd, J=7.0, 4.2 Hz, 1H), 6.73 (s, 1H), 5.07-5.00 (m, 1H), 3.44 (h, J=5.5 Hz, 7H), 3.39 (d, J=1.2 Hz, 0H), 3.24-3.17 (m, 1H), 2.93 (t, J=5.6 Hz, 4H), 2.87-2.78 (m, 1H), 2.32-2.17 (m, 4H), 1.34 (s, 3H). MS (ESI): m/z=444.2 [M+1]⁺.

Examples 123 and 124. N—((S)-6-((1R,4R)-5-(2,2-Difluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and N—((R)-6-((1R,4R)-5-(2,2-difluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N—((S)-6-((1R,4R)-5-(2,2-Difluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and N—((R)-6-((1R,4R)-5-(2,2-difluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide were isolated as white solids with absolute stereochemistry assigned arbitrarily using a method similar to Examples 78 and 79.

Example 123, Peak 1: ¹H NMR (400 MHz, DMSO-d₆): δ: 9.72 (s, 1H), 9.37 (dd, J=1.6, 7.2 Hz, 1H), 8.86 (dd, J=2.0, 4.4 Hz, 1H), 8.68 (s, 1H), 7.78 (s, 1H), 7.33 (dd, J=4.4, 6.8 Hz, 1H), 6.45 (s, 1H), 5.99 (tt, J=4.4, 56.0 Hz, 1H), 5.04 (t, J=6.0 Hz, 1H), 3.90 (s, 1H), 3.49-3.32 (m, 2H), 3.31-3.26 (m, 1H), 3.16 (d, J=15.6 Hz, 1H), 3.10-3.00 (m, 1H), 2.97-2.81 (m, 4H), 2.78 (d, J=15.6 Hz, 1H), 1.88-1.72 (m, 2H), 1.34 (s, 3H). MS (ESI): m/z=485.2 [M+1]⁺.

Example 124, Peak 2: ¹H NMR (400 MHz, DMSO-d₆): δ: 9.74 (s, 1H), 9.37 (dd, J=1.6, 7.2 Hz, 1H), 8.86 (dd, J=1.6, 4.0 Hz, 1H), 8.68 (s, 1H), 7.80 (s, 1H), 7.33 (dd, J=4.4, 6.8 Hz, 1H), 6.47 (s, 1H), 6.00 (tt, J=4.0, 56.0 Hz, 1H), 5.04 (t, J=5.6 Hz, 1H), 3.90 (s, 1H), 3.48-3.38 (m, 3H), 3.15 (d, J=15.6 Hz, 1H), 3.06-2.99 (m, 1H), 2.97-2.82 (m, 4H), 2.78 (d, J=15.6 Hz, 1H), 1.88-1.72 (m, 2H), 1.34 (s, 3H). MS (ESI): m/z=485.2 [M+1]⁺.

Examples 125 and 126. (R)—N-(2-(Hydroxymethyl)-2-methyl-6-(2-oxa-8-azaspiro[4.5]decan-8-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(hydroxymethyl)-2-methyl-6-(2-oxa-8-azaspiro[4.5]decan-8-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)—N-(2-(Hydroxymethyl)-2-methyl-6-(2-oxa-8-azaspiro[4.5]decan-8-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(hydroxymethyl)-2-methyl-6-(2-oxa-8-azaspiro[4.5]decan-8-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide were isolated as white solids with absolute stereochemistry assigned arbitrarily using a method similar to Examples 78 and 79.

Example 125, Peak 1: ¹H NMR (400 MHz, DMSO-d₆): δ 10.46 (s, 1H), 9.36 (dd, J=1.6, 7.0 Hz, 1H), 8.83 (dd, J=1.6, 4.2 Hz, 1H), 8.68 (s, 1H), 8.30 (s, 1H), 7.34 (dd, J=4.2, 7.0 Hz, 1H), 6.70 (s, 1H), 5.04 (t, J=5.8 Hz, 1H), 3.77 (t, J=7.1 Hz, 2H), 3.57 (s, 2H), 3.43 (t, J=5.6 Hz, 2H), 3.19 (d, J=15.8 Hz, 1H), 2.84-2.72 (m, 5H), 1.84-1.72 (m, 6H), 1.34 (s, 3H). MS (ESI): m/z=464.2 [M+1]⁺.

Example 126, Peak 2: ¹H NMR (400 MHz, DMSO-d₆): δ 10.46 (s, 1H), 9.36 (dd, J=1.6, 7.0 Hz, 1H), 8.83 (dd, J=1.6, 4.2 Hz, 1H), 8.68 (s, 1H), 8.30 (s, 1H), 7.34 (dd, J=4.2, 7.0 Hz, 1H), 6.70 (s, 1H), 5.04 (t, J=5.8 Hz, 1H), 3.77 (t, J=7.1 Hz, 2H), 3.57 (s, 2H), 3.43 (t, J=5.6 Hz, 2H), 3.19 (d, J=15.8 Hz, 1H), 2.84-2.72 (m, 5H), 1.84-1.72 (m, 6H), 1.34 (s, 3H). MS (ESI): m/z=464.3 [M+1]⁺.

Examples 127 and 128. (R)—N-(2-(Hydroxymethyl)-2-methyl-6-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(hydroxymethyl)-2-methyl-6-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)—N-(2-(Hydroxymethyl)-2-methyl-6-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(hydroxymethyl)-2-methyl-6-(4-methylpiperazin-1-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide were isolated as white solids with absolute stereochemistry assigned arbitrarily using a method similar to Examples 78 and 79.

Example 127, Peak 1: ¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 8.83 (dd, J=1.2, 6.8 Hz, 1H), 8.80-8.75 (m, 2H), 8.44 (s, 1H), 7.07 (dd, J=4.0, 6.8 Hz, 1H), 6.69 (s, 1H), 3.71-3.61 (m, 2H), 3.25 (d, J=15.6 Hz, 1H), 3.06-2.88 (m, 5H), 2.8-2.63 (m, 4H), 2.44 (s, 3H), 1.46 (s, 3H). MS (ESI): m/z=439.2 [M+1]⁺.

Example 128, Peak 2: ¹H NMR (400 MHz, CDCl₃) δ 10.44 (s, 1H), 8.83 (d, J=6.8 Hz, 1H), 8.80-8.75 (m, 2H), 8.44 (s, 1H), 7.07 (dd, J=4.0, 7.2 Hz, 1H), 6.70 (s, 1H), 3.71-3.61 (m, 2H), 3.25 (d, J=15.6 Hz, 1H), 3.06-2.88 (m, 5H), 2.8-2.63 (m, 4H), 2.41 (s, 3H), 1.46 (s, 3H). MS (ESI): m/z=439.2 [M+1]⁺.

Examples 129 and 130. (R)—N-(2-(Hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)—N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide were isolated as white solids with absolute stereochemistry assigned arbitrarily using a method similar to Examples 78 and 79.

Example 129, Peak 1: ¹H NMR (400 MHz, CDCl₃) δ 10.48 (s, 1H), 8.80 (d, J=7.2 Hz, 1H), 8.79-8.76 (m, 2H), 8.45 (s, 1H), 7.02 (dd, J=4.0, 7.2 Hz, 1H), 6.67 (s, 1H), 3.69-3.60 (m, 4H), 3.23 (d, J=15.6 Hz, 1H), 3.10 (d, J=11.6 Hz, 2H), 2.94 (d, J=15.6 Hz, 1H), 2.68 (t, J=10.8 Hz, 2H), 1.91 (t, J=6.4 Hz, 1H), 1.83-1.65 (m, 5H) 1.46 (s, 3H). MS (ESI): m/z=438.2[M+1]⁺.

Example 130, Peak 2: ¹H NMR (400 MHz, CDCl₃) δ 10.50 (s, 1H), 8.80 (d, J=7.2 Hz, 1H), 8.79-8.75 (m, 2H), 8.45 (s, 1H), 7.02 (dd, J=6.8 Hz, 1H), 6.67 (s, 1H), 3.70-3.66 (m, 4H), 3.23 (d, J=15.6 Hz, 1H), 3.10 (d, J=11.6 Hz, 2H), 2.94 (d, J=15.6 Hz, 1H), 2.68 (t, J=10.8 Hz, 2H), 1.90 (t, J=6.4 Hz, 1H), 1.83-1.65 (m, 5H), 1.46 (s, 3H). MS (ESI): m/z=438.2 [M+1]⁺.

Example 131. N-[6-[4-(2, 2-Difluoroethyl) piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]-6-fluoro-pyrazolo[1, 5-a]pyrimidine-3-carboxamide

The title compound was made in a manner analogous to Examples 54 and 55 to give N-[6-[4-(2, 2-difluoroethyl) piperazin-1-yl]-2-(hydroxymethyl)-2-methyl-3H-benzofuran-5-yl]-6-fluoro-pyrazolo[1, 5-a]pyrimidine-3-carboxamide. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.24 (s, 1H), 9.83 (dd, J=4.8, 2.4 Hz, 1H), 9.15 (d, J=2.4 Hz, 1H), 8.70 (s, 1H), 8.27 (s, 1H), 6.70 (s, 1H), 6.20 (tt, J=56, 4.0 Hz, 1H), 5.04 (t, J=5.6 Hz, 1H), 3.44-3.41 (m, 2H), 3.19 (d, J=15.2 Hz, 1H), 2.89-2.78 (m, 11H), 1.34 (s, 3H). LCMS (ESI): m/z=491.1 [M+H]⁺.

Examples 132 and 133. (S)—N-(6-(4-(2,2-Difluoroethyl)piperazin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)—N-(6-(4-(2,2-Difluoroethyl)piperazin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide

(S)—N-(6-(4-(2,2-Difluoroethyl)piperazin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)—N-(6-(4-(2,2-Difluoroethyl)piperazin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxamide were resolved in a manner analogous to Examples 163 and 164 with absolute stereochemistry assigned arbitrarily.

Example 132. Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 10.24 (s, 1H), 9.83 (dd, J=4.4, 2.4 Hz, 1H), 9.16 (d, J=2.4 Hz, 1H), 8.71 (s, 1H), 8.27 (s, 1H), 6.70 (s, 1H), 6.35-6.05 (m, 1H), 5.06 (br s, 1H), 3.50-3.40 (m, 2H), 3.19 (d, J=15.6 Hz, 1H), 2.95-2.70 (m, 11H), 1.34 (s, 3H). MS (ESI): m/z=491.2 [M+1]⁺.

Example 133. Peak 2: ¹H NMR (400 MHz, DMSO-d₆) δ 10.24 (s, 1H), 9.83 (dd, J=4.4, 2.4 Hz, 1H), 9.16 (d, J=2.8 Hz, 1H), 8.71 (s, 1H), 8.27 (s, 1H), 6.70 (s, 1H), 6.34-6.06 (m, 1H), 5.05 (t, J=5.6 Hz, 1H), 3.50-3.40 (m, 2H), 3.25-3.10 (m, 1H), 3.00-2.70 (m, 11H), 1.34 (s, 3H). MS (ESI): m/z=491.2 [M+1]⁺.

Examples 134 and 135. (R)—N-(2-isopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-isopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-(2-isopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 150), 116.3 mg, 0.276 mmol) was resolved by chiral preparatory SFC to afford (R)—N-(2-isopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (35.3 mg, 30%) and (S)—N-(2-isopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (42.0 mg, 36%) as light yellow solids with absolute stereochemistry assigned arbitrarily.

Example 134 Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 9.37 (dd, J=7.0, 1.7 Hz, 1H), 8.94 (dd, J=4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.30 (s, 1H), 7.34 (dd, J=7.0, 4.2 Hz, 1H), 6.72 (s, 1H), 3.87-3.79 (m, 4H), 3.13 (dd, J=15.9, 1.3 Hz, 1H), 2.86-2.77 (m, 5H), 1.94 (h, J=6.8 Hz, 1H), 1.28 (s, 3H), 0.93 (dd, J=20.3, 6.8 Hz, 6H). MS (ESI): m/z=422.2 [M+1]⁺.

Example 135 Peak 2: ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 9.37 (dd, J=7.0, 1.6 Hz, 1H), 8.94 (dd, J=4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.30 (s, 1H), 7.34 (dd, J=7.0, 4.1 Hz, 1H), 6.72 (s, 1H), 3.87-3.80 (m, 4H), 3.13 (dd, J=15.7, 1.4 Hz, 1H), 2.86-2.77 (m, 5H), 1.94 (h, J=6.8 Hz, 1H), 1.28 (s, 3H), 0.93 (dd, J=20.3, 6.8 Hz, 6H). MS (ESI): m/z=422.2 [M+1]⁺.

Example 136. N-(6-Methyl-2-morpholino-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. Ethyl 2-[4-[2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]piperazin-1-yl]acetate

Ethyl 2-[4-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)piperazin-1-yl]acetate (Example 134 Step C; 200 mg, 0.60 mmol) in pyridine (10 ml) was treated with pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (120 mg, 0.66 mmol) and stirred at 25° C. for 4 h. The reaction was concentrated and purified by silica gel chromatography (eluting gradient 0-10% methanol:dichloromethane) to afford ethyl 2-[4-[2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]piperazin-1-yl]acetate (280 mg, 98% yield) as a brown solid. LCMS (ESI): m/z=479.0 [M+H]⁺

Step B. N-[2,2-Dimethyl-6-[4-[2-(methylamino)-2-oxo-ethyl]piperazin-1-yl]-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Ethyl 2-[4-[2,2-Dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]piperazin-1-yl]acetate (280 mg, 0.59 mmol) was treated with 2M methylamine in tetrahydrofuran (10 ml, 20 mmol) was stirred at 100° C. for 36 h under autoclave, concentrated and purified by preparatory TLC (eluent: 10% methanol in dichloromethane) to afford N-[2,2-dimethyl-6-[4-[2-(methylamino)-2-oxo-ethyl]piperazin-1-yl]-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (93.6 mg, 33% yield) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) 10.42 (s, 1H), 9.40-9.35 (m, 1H), 8.97-8.95 (m, 1H), 8.67 (s, 1H), 8.33 (s, 1H), 7.75-7.74 (m, 1H), 7.36 (dd, J=7.2, 4.4 Hz, 1H), 6.67 (s, 1H), 3.04 (s, 2H), 3.00 (s, 2H), 2.85-2.84 (m, 4H), 2.72-2.68 (m, 4H), 2.64 (d, J=4.8 Hz, 3H), 1.41 (s, 6H). LCMS (ESI) m/z: 464.1 [M+H]⁺.

Example 137. N-[6-[4-(2-Hydroxy-1,1-dimethyl-ethyl)piperazin-1-yl]-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. tert-Butyl 4-(2-ethoxy-1,1-dimethyl-2-oxo-ethyl)piperazine-1-carboxylate

A mixture of tert-butyl 1-piperazinecarboxylate (3.0 g, 20.08 mmol), ethyl 2-bromoisobutyrate (5.9 g, 30.12 mmol) and potassium carbonate (5.6 g, 40.16 mmol) in acetonitrile (40 ml) was stirred at 80° C. for 15 h under nitrogen. The mixture was filtered, the filtrate was concentrated and the residue was purified by silica gel chromatography (eluent 15% ethyl acetate:petroleum ether) to give tert-butyl 4-(2-ethoxy-1,1-dimethyl-2-oxo-ethyl)piperazine-1-carboxylate (2.8 g, 47% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ 4.20-4.16 (m, 2H), 3.43-3.41 (m, 4H), 2.55-2.53 (m, 4H), 1.46 (s, 9H), 1.45-1.26 (m, 9H).

Step B. Ethyl 2-methyl-2-piperazin-1-yl-propanoate dihydrochloride

tert-Butyl 4-(2-ethoxy-1,1-dimethyl-2-oxo-ethyl)piperazine-1-carboxylate (1.0 g, 3.33 mmol) in 1,4-dioxane (10 ml) was treated with hydrochloric acid (0.83 ml, 3.32 mmol), stirred at 15° C. for 15 h and concentrated to afford ethyl 2-methyl-2-piperazin-1-yl-propanoate dihydrochloride (700 mg, 77% yield) as a yellow oil which was use directly without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 9.62 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 3.50-3.25 (m, 8H), 1.52 (s, 6H), 1.26 (t, J=7.2 Hz, 3H).

Step C. Ethyl 2-[4-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)piperazin-1-yl]-2-methyl-propanoate

6-Chloro-2,2-dimethyl-5-nitro-3H-benzofuran (100 mg, 0.44 mmol) in acetonitrile (10 ml) was treated with potassium carbonate (182 mg, 1.32 mmol) and ethyl 2-methyl-2-piperazin-1-yl-propanoate dihydrochloride (180 mg, 0.66 mmol) and stirred at 100° C. for 16 h. The mixture was filtered, concentrated and purified by silica gel chromatography (eluting gradient 0-20% ethyl acetate:petroleum ether) to afford ethyl 2-[4-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)piperazin-1-yl]-2-methyl-propanoate (150 mg, 87% yield) as a yellow oil. LCMS (ESI): m/z=392.1 [M+H]⁺.

Step D. 2-[4-(2,2-Dimethyl-5-nitro-3H-benzofuran-6-yl)piperazin-1-yl]-2-methyl-propan-1-ol

To a solution of ethyl 2-[4-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)piperazin-1-yl]-2-methyl-propanoate (150 mg, 0.38 mmol) in methyl alcohol (5 ml) and tetrahydrofuran (10 ml) was added lithium borohydride (17 mg, 0.77 mmol). After being stirred at 40° C. for 16 h, the reaction was diluted with water (1 ml) and extracted with dichloromethane (20 ml×3). The combined organic phases were washed with brine (20 ml×2), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (eluting gradient 0-50% ethyl acetate:petroleum ether) to afford 2-[4-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)piperazin-1-yl]-2-methyl-propan-1-ol (80 mg, 60% yield) as a yellow oil. LCMS (ESI): m/z=350.3 [M+H]⁺.

Step E. 2-[4-(5-Amino-2,2-dimethyl-3H-benzofuran-6-yl)piperazin-1-yl]-2-methyl-propan-1-ol

2-[4-(2,2-Dimethyl-5-nitro-3H-benzofuran-6-yl)piperazin-1-yl]-2-methyl-propan-1-ol (80 mg, 0.23 mmol) in methanol (10 ml) was treated with 10% of palladium on carbon (24 mg, 0.02 mmol) and stirred at 25° C. for 2 h under hydrogen (15 psi). The reaction was filtered and the filtrate was concentrated to afford 2-[4-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)piperazin-1-yl]-2-methyl-propan-1-ol (53 mg, 73% yield) as a yellow oil, which was used directly without further purification.

Step F. N-[6-[4-(2-Hydroxy-1,1-dimethyl-ethyl)piperazin-1-yl]-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-[6-[4-(2-Hydroxy-1,1-dimethyl-ethyl)piperazin-1-yl]-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (30 mg, 39% yield) was made in a manner analogous to Example 136 and isolated as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.32 (s, 1H), 8.84-8.80 (m, 2H), 8.69 (dd, J=4.0, 1.6 Hz, 1H), 8.36 (s, 1H), 7.05 (dd, J=6.8, 4.0 Hz, 1H), 6.64 (s, 1H), 3.38 (s, 2H), 3.04 (s, 2H), 3.00-2.90 (m, 4H), 2.85-2.75 (m, 4H), 1.49 (s, 6H), 1.10 (s, 6H). LCMS (ESI) m/z: 465.1 [M+H]⁺.

Example 138. N-(2-Isopropyl-6-morpholino-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 6-Chloro-2-isopropyl-5-nitroisoindolin-1-one

To a solution of methyl 2-(bromomethyl)-5-chloro-4-nitrobenzoate (prepared following protocol from WO 2013/079505) (130 mg, 0.42 mmol) in methanol (4.2 mL) was added trimethylamine (0.071 mL, 0.51 mmol) and isopropylamine (0.043 mL, 0.51 mmol). The reaction mixture was heated at 70° C. for 6 h, cooled to ambient temperature, and diluted with isopropyl acetate and 1N HCl. The layers were separated and the aqueous layer was washed with isopropyl acetate (2×). The combined organic layers were dried over sodium sulfate and carried on without further purification.

Step B. 2-Isopropyl-6-morpholino-5-nitroisoindolin-1-one

A solution of 6-chloro-2-isopropyl-5-nitroisoindolin-1-one (88 mg, 0.35 mmol), morpholine (0.036 mL, 0.42 mmol), diisopropylamine (0.12 mL, 0.69 mmol) in DMSO (1 mL) was heated at 90° C. for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with isopropyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and absorbed onto celite to be purified by silica gel chromatography (0% to 100% isopropyl acetate in heptanes) to afford 2-isopropyl-6-morpholino-5-nitroisoindolin-1-one (17 mg, 16%) as an orange oil. ¹H NMR (400 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.64 (s, 1H), 4.67 (p, J=6.8 Hz, 1H), 4.36 (s, 2H), 3.88-3.79 (m, 4H), 3.12-3.02 (m, 4H), 1.31 (d, J=6.8 Hz, 6H).

Step C. 5-Amino-2-isopropyl-6-morpholinoisoindolin-1-one

2-Isopropyl-6-morpholino-5-nitroisoindolin-1-one (17 mg, 0.056 mmol) was brought up in ethanol (0.35 mL) and water (0.035 mL) and treated with tin(II) chloride dehydrate (42 mg, 0.22 mmol) and heated to 65° C. for 5 h. DCM (0.75 mL) and 2M NaOH (aq) (0.37 mL) were added and the mixture was passed through a hydrophobic frit. The solvent was removed in vacuo to give the desired product as a yellow solid. The crude material was carried on without further purification. MS (ESI): m/z=276.1 [M+1]⁺.

Step D. N-(2-Isopropyl-6-morpholino-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution of 5-amino-2-isopropyl-6-morpholino-isoindolin-1-one (19 mg, 0.069 mmol), pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (19 mg, 0.10 mmol), 4-dimethylaminopyridine (2 mg, 0.014 mmol), and diisopropylethylamine (0.036 mL, 0.21 mmol) in DCE (1 mL) was stirred at ambient temperature for 18 h. The reaction was concentrated under reduced pressure and purified by reverse phase HPLC to afford N-(2-isopropyl-6-morpholino-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (6.8 mg, 24%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H), 9.41 (dd, J=7.0, 1.6 Hz, 1H), 9.00 (dd, J=4.2, 1.6 Hz, 1H), 8.76 (d, J=3.8 Hz, 2H), 7.56 (s, 1H), 7.39 (dd, J=7.0, 4.2 Hz, 1H), 4.42 (d, J=5.3 Hz, 3H), 3.94-3.83 (m, 4H), 2.96-2.85 (m, 4H), 1.23 (d, J=6.8 Hz, 6H). MS (ESI): m/z=421.2 [M+1]⁺.

Example 139. (R)—N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)—N-(2-(2-Fluoro-3-hydroxy-3-methylbutyl)-6-morpholino-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (44 mg, 32%) was prepared following the procedure described for Example 138 using (R)-4-amino-3-fluoro-2-methylbutan-2-ol (WO 2014/074675). ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H), 9.41 (dd, J=7.0, 1.6 Hz, 1H), 9.00 (dd, J=4.2, 1.6 Hz, 1H), 8.76 (d, J=2.4 Hz, 2H), 7.59 (s, 1H), 7.39 (dd, J=7.0, 4.2 Hz, 1H), 4.90 (s, 1H), 4.55 (s, 3H), 4.05-3.85 (m, 5H), 3.70 (td, J=15.9, 9.3 Hz, 1H), 2.99-2.85 (m, 4H), 1.24-1.12 (m, 6H). MS (ESI): m/z=483.2 [M+1]⁺.

Example 140. N-(2-Methyl-6-morpholino-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-(2-Methyl-6-morpholino-1-oxoisoindolin-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (55 mg, 17%) was prepared following the procedure described for Example 138. ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 9.40 (dd, J=7.0, 1.6 Hz, 1H), 8.99 (dd, J=4.2, 1.6 Hz, 1H), 8.74 (d, J=4.6 Hz, 2H), 7.56 (s, 1H), 7.38 (dd, J=7.0, 4.2 Hz, 1H), 4.45 (s, 2H), 3.94-3.84 (m, 4H), 3.07 (s, 3H), 2.97-2.86 (m, 4H). MS (ESI): m/z=393.1 [M+1]⁺.

Example 141. N-(2-(Hydroxymethyl)-2-methyl-7-morpholinochroman-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 2-((tert-Butyldimethylsilyloxy)methyl)-7-chloro-2-methylchroman-4-one

A mixture of 1-(4-chloro-2-hydroxyphenyl)ethanone (513.0 mg, 3.01 mmol) pyrrolidine (0.5 mL, 6.01 mmol) and 1-(tert-butyldimethylsilyloxy)propan-2-one (849.56 mg, 4.51 mmol) in methyl alcohol (10 mL) was stirred at reflux for 16 h. After concentration, the residue was purified on silica gel chromatography using ethyl acetate:petroleum ether (5:95) as eluting solvents to afford 2-[[tert-butyl(dimethyl)silyl]oxymethyl]-7-chloro-2-methyl-chroman-4-one (685 mg, 57%) as an orange oil. MS (ESI): m/z=341.1 [M+1]⁺.

Step B. 2-((tert-Butyldimethylsilyloxy)methyl)-7-chloro-2-methylchroman-4-ol

To a solution of 2-[[tert-butyl(dimethyl)silyl]oxymethyl]-7-chloro-2-methyl-chroman-4-one (102.0 mg, 0.30 mmol) in methyl alcohol (15 mL) was added sodium borohydride (34.11 mg, 0.90 mmol). The mixture was stirred at 25° C. for 3 h. Water and ethyl acetate (30 mL) was added. The organic layer was separated, dried sodium sulfate and concentrated to afford 2-[[tert-butyl(dimethyl)silyl]oxymethyl]-7-chloro-2-methyl-chroman-4-ol (101 mg, crude) as a yellow oil, which was used directly to next step without further purification. MS (ESI): m/z=365.2 [M+23]⁺.

Step C. (7-Chloro-2-methylchroman-2-yl)methanol

A mixture of 2-[[tert-butyl(dimethyl)silyl]oxymethyl]-7-chloro-2-methyl-chroman-4-ol (513 mg, 1.5 mmol) and triethylsilane (6.85 mL, 42.75 mmol) in trifluoroacetic acid (25 mL) was stirred at 50° C. overnight. Saturated sodium bicarbonate solution was added until pH=7.0. The aqueous phase was extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford (7-chloro-2-methyl-chroman-2-yl)methanol (115 mg, crude) as a yellow oil, which was used directly to next step without further purification. ¹H NMR (400 MHz, CDCl₃): δ 6.98 (d, J=8.0 Hz, 1H), 8.87-8.80 (m, 2H), 4.43-4.32 (m, 2H), 2.82-2.70 (m, 2H), 2.02-1.92 (m, 1H), 1.87-1.79 (m, 1H), 1.36 (s, 3H).

Step D. (7-Chloro-2-methylchroman-2-yl)methyl benzoate

A mixture of (7-chloro-2-methyl-chroman-2-yl)methanol (115 mg, 0.54 mmol), benzoyl chloride (91 mg, 0.65 mmol) and triethylamine (164 mg, 1.62 mmol) in dichloromethane (10 mL) was stirred overnight. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:20 to 1:10) as eluting solvents to afford (7-chloro-2-methylchroman-2-yl)methyl benzoate (130 mg, 76%) as a yellow oil. MS (ESI): m/z=317.2 [M+1]⁺.

Step E. (7-Chloro-2-methyl-6-nitrochroman-2-yl)methyl benzoate

To a solution of (7-Chloro-2-methylchroman-2-yl)methyl benzoate (130 mg, 0.41 mmol) in dichloromethane (5 mL) was added fuming nitric acid (1 mL) drop wise. Water and ethyl acetate (20 mL) was added. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford (7-Chloro-2-methyl-6-nitrochroman-2-yl)methyl benzoate (110 mg, crude) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=362.1 [M+1]⁺.

Step F. (2-Methyl-7-morpholino-6-nitro-chroman-2-yl)methyl benzoate

A mixture of morpholine (5. mL, 57.16 mmol) and (7-chloro-2-methyl-6-nitro-chroman-2-yl)methylbenzoate (110.0 mg, 0.3 mmol) was stirred at 100° C. overnight. The reaction was concentrated to dryness to afford (2-methyl-7-morpholino-6-nitro-chroman-2-yl)methyl benzoate (115 mg, crude) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=413.2 [M+1]⁺.

Step G. (2-Methyl-7-morpholino-6-nitro-chroman-2-yl)methanol

A solution of (2-methyl-7-morpholino-6-nitro-chroman-2-yl)methyl benzoate (94.0 mg, 0.23 mmol) in methyl alcohol (10 mL) at 0° C. was added sodium methanolate (36.92 mg, 0.68 mmol). The mixture was stirred for 1 h at room temperature. The solvent was removed under reduced pressure. The residue was dissolved by dichloromethane (25 mL) and saturated ammonium chloride solution was added. The organic layer was washed with water, brine, dried over sodium sulfate and concentrated to afford (2-methyl-7-morpholino-6-nitro-chroman-2-yl)methanol (137 mg, crude) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=309.1 [M+1]⁺.

Step H. (6-Amino-2-methyl-7-morpholino-chroman-2-yl)methanol

A mixture of palladium on carbon (20 mg) and (2-methyl-7-morpholino-6-nitro-chroman-2-yl)methanol (131.19 mg, 0.43 mmol) in methyl alcohol (10 mL) was stirred at room temperature under hydrogen atomsphere for 30 min. After filtration and concentration, it was afforded (6-amino-2-methyl-7-morpholino-chroman-2-yl)methanol (79 mg, 60%) as a light yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=279.1 [M+1]⁺.

Step I. N-[2-(Hydroxymethyl)-2-methyl-7-morpholino-chroman-6-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (46.3 mg, 0.28 mmol), diisopropylethylamine (73.36 mg, 0.57 mmol) and (7-azabenzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (162.77 mg, 0.31 mmol) in N,N-dimethylformamide (2 mL) was stirred at 0° C. Then (6-amino-2-methyl-7-morpholino-chroman-2-yl)methanol (79.0 mg, 0.28 mmol) in N,N-dimethylformamide (1 mL) was added. The mixture was stirred at room temperature for 2 h. The crude was purified by reverse phase chromatography (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile, 25-75%; B: 10 mM ammonium bicarbonate in water) to afford N-[2-(hydroxymethyl)-2-methyl-7-morpholino-chroman-6-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (55 mg, 46%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 10.41 (s, 1H), 8.83 (dd, J=1.6, 6.8 Hz, 1H), 8.79-8.76 (m, 2H), 8.37 (s, 1H), 7.06 (dd, J=4.0, 7.2 Hz, 1H), 6.68 (s, 1H), 3.98-3.92 (m, 4H), 3.69-3.60 (m, 2H), 2.96-2.89 (m, 4H), 2.89-2.76 (m, 2H), 2.08-1.98 (m, 1H), 1.89 (t, J=6.4 Hz, 1H), 1.77-1.70 (m, 1H), 1.29 (s, 3H). MS (ESI): m/z=424.2 [M+1]⁺.

Example 142. N-(6-Morpholinospiro[3H-benzofuran-2,4′-piperidine]-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. tert-Butyl 4-[(2,4-difluorophenyl)methyl]-4-hydroxy-piperidine-1-carboxylate

To a solution of magnesium (2400 mg, 100 mmol) and iodine (180 mg, 0.71 mmol) in diethyl ether (25 mL) at reflux was added 1-(bromomethyl)-2,4-difluorobenzene (8200.0 mg, 39.61 mmol) slowly and stirred for 30 min. To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (6500.0 mg, 32.62 mmol) in diethyl ether (200 mL) was added Grignard reagent at −78° C. and the reaction was stirred room temperature for 2 h. Water and EtOAc (200 mL) was added. The organic layer was separated and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:4 to 1:2) to afford tert-butyl 4-[(2,4-difluorophenyl)methyl]-4-hydroxy-piperidine-1-carboxylate (9500 mg, 73%) as a white solid. MS (ESI): m/z=350.1 [M+23]⁺.

Step B. tert-Butyl 6-fluorospiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate

A mixture of tert-butyl 4-[(2,4-difluorophenyl)methyl]-4-hydroxy-piperidine-1-carboxylate (491.0 mg, 1.5 mmol) and potassium tert-butanolate (420.74 mg, 3.75 mmol) in tetrahydrofuran (30 mL) was stirred at 65° C. for 3 h. Water was added. The aqueous layer was extracted with ethyl acetate (60 mL). The organic layer was dried over sodium sulfate and concentrated to afford tert-butyl 6-fluorospiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate (409 mg, crude) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=252.2 [M−55]⁺.

Step C. 6-Fluorospiro[3H-benzofuran-2,4′-piperidine]

To a solution of tert-butyl 6-fluorospiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate (270.0 mg, 0.88 mmol) in dichloromethane (9 mL), was added trifluoroacetic acid (1 mL). The reaction solution was stirred for 2 h at room temperature. Saturated sodium bicarbonate solution was added until pH=7.0. The aqueous layer was extracted twice with 20 mL of dichloromethane. The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After removal of the solvent, it was afforded 6-fluorospiro[3H-benzofuran-2,4′-piperidine] (189 mg, crude) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=208.2 [M+1]⁺.

Step D. 6-Fluoro-5-nitro-spiro[3H-benzofuran-2,4′-piperidine]

To a solution of 6-fluorospiro[3H-benzofuran-2,4′-piperidine] (171.0 mg, 0.8300 mmol) in dichloromethane (10 ml) was added concentrated nitric acid (0.5 mL, 8 mmol). The reaction was stirred at 25° C. for 1 h. Water was added. Then saturated sodium bicarbonate was added until pH=7.0. The aqueous was extracted with dichloromethane (50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 6-fluoro-5-nitro-spiro[3H-benzofuran-2,4′-piperidine] (135 mg, crude) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=253.2 [M+1]⁺.

Step E. tert-Butyl 6-fluoro-5-nitro-spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate

A mixture of 6-fluoro-5-nitro-spiro[3H-benzofuran-2,4′-piperidine] (135.0 mg, 0.54 mmol), triethylamine (108.31 mg, 1.07 mmol) and di-tert-butyl dicarbonate (80.28 mg, 0.80 mmol) was stirred at room temperature for 2 h. Then the reaction was concentrated in vacuo to obtained tert-butyl 6-fluoro-5-nitro-spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate (with 7a impurity) (270 mg, crude) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=297.1 [M−55]⁺.

Step F. tert-Butyl 6-morpholino-5-nitro-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate

A mixture of tert-butyl 6-fluoro-5-nitro-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate (270.0 mg, 0.38 mmol), morpholine (66.76 mg, 0.77 mmol) and potassium carbonate (132.09 mg, 0.96 mmol) in acetonitrile (6 mL) was stirred at room temperature overnight. Then to the reaction was added water and the aqueous layer was extracted twice with 20 mL of ethyl acetate. The combined organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After removal of solvents, the residue was purified on silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford tert-butyl 6-morpholino-5-nitro-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate (73 mg, 42%) as a yellow oil. MS (ESI): m/z=420.3 [M+1]⁺.

Step G. tert-Butyl 5-amino-6-morpholino-spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate

A mixture of palladium on carbon (20.0 mg, 10% wt) and tert-butyl 6-morpholino-5-nitro-spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate (73.0 mg, 0.17 mmol) in methylalcohol (10 mL) was stirred at room temperature under hydrogen atmosphere for 2 h. After filtration and concentration under reduced pressure, it was afforded tert-butyl 5-amino-6-morpholino-spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate (61 mg, 79%) as a yellow solid. MS (ESI): m/z=390.2 [M+1]⁺.

Step H. tert-Butyl 5-amino-6-morpholino-spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (25.55 mg, 0.16 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (89.82 mg, 0.17 mmol) and N-ethyl-N-isopropylpropan-2-amine (60.72 mg, 0.47 mmol) in N,N-dimethylformanide (2 mL) was stirred at 0° C. Then tert-butyl 5-amino-6-morpholino-spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate (61.0 mg, 0.16 mmol) in N,N-dimethylformanide (1 mL) was added and the reaction was stirred at room temperature for 2 h. The crude was purified by reverse phase chromatography (Gilson 281-G, Phenomenex, Gemini C18, 21.2×100 mm. 5 um, 110 A, A:acetonitrile 55-70%; B: 0.05% formic acid in water) to afford tert-butyl 6-morpholino-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate (73 mg, 87%) as a yellow solid. MS (ESI): m/z=535.3 [M+1]⁺.

Step I. N-(6-morpholinospiro[3H-benzofuran-2,4′-piperidine]-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of tert-butyl 6-morpholino-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate (73.0 mg, 0.14 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (0.5 mL). The reaction solution was stirred for 2 h at room temperature. To the reaction solution, an aqueous saturated sodium bicarbonate was added until pH=7.0. The aqueous layer was extracted twice with 20 mL of dichloromethane. The combined organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After concentration, the residue was purified by reverse phase chromatography (Gilson 281-G, Phenomenex, Gemini C18, 21.2×100 mm. 5 um, 110 A, A:acetonitrile, 55-70%; B: 0.05% formic acid in water) to afford N-(6-morpholinospiro[3H-benzofuran-2,4′-piperidine]-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (29 mg, 49%) as a yellow solid. ¹H NMR (400 MHz, MeOD-d₄) δ 9.03 (dd, J=1.6, 7.2 Hz, 1H), 8.82 (dd, J=1.6, 4.0 Hz, 1H), 8.56 (s, 1H), 8.41 (s, 1H), 8.20 (s, 1H), 7.19 (dd, J=4.0, 7.2 Hz, 1H), 6.69 (s, 1H), 3.87-3.80 (m, 4H), 3.31-3.20 (m, 4H), 3.04 (s, 1H), 2.82-2.76 (m, 4H), 2.10-2.02 (m, 2H), 1.98-1.88 (m, 2H). MS (ESI): m/z=435.3 [M+1]⁺.

Example 143. N-(7-Cyano-2,2-dimethyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 2-Chloro-6-(2-methylallyloxy)benzonitrile

A mixture of 2-chloro-6-hydroxy-benzonitrile (500.0 mg, 3.26 mmol), 3-bromo-2-methylpropene (0.39 mL, 3.91 mmol) and potassium carbonate (898.6 mg, 6.51 mmol) in acetonitrile (10 mL) was stirred at 25° C. overnight. The solid was filtered off, the filtrate was concentrated and purified by silica gel chromatography using petroleum ether:ethyl acetate (100:1) to afford 2-chloro-6-(2-methylallyloxy)benzonitrile (699.0 mg, 98%) as a light oil. MS (ESI): m/z=208.1 [M+1]⁺.

Step B. 6-Chloro-2-hydroxy-3-(2-methylallyl)benzonitrile

A mixture of 2-chloro-6-(2-methylallyloxy)benzonitrile (100.0 mg, 0.48 mmol) in N,N-dimethylformamide (3 mL) was stirred at 220° C. under microwave condition for 2 h. Water was added. The aqueous phase was extracted with ethyl acetate (20 mL). The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated to afford 6-chloro-2-hydroxy-3-(2-methylallyl)benzonitrile (70 mg, 70%) as a light oil. (ESI): m/z=208.2 [M+1]⁺.

Step C. 6-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-carbonitrile

To a mixture of 6-chloro-2-hydroxy-3-(2-methylallyl)benzonitrile (200.0 mg, 0.96 mmol) in dichloromethane (10 mL) was added 3-chloroperoxybenzoic acid (292.3 mg, 1.44 mmol) at 0° C. The mixture was stirred at 25° C. overnight. Water and dichloromethane (20 mL) was added. The organic layer was washed by saturated sodium bicarbonate, brine and dried over sodium sulfate. After concentration, it was afforded 6-chloro-2,2-dimethyl-3H-benzofuran-7-carbonitrile (200.0 mg, crude) as a colorless oil, which was used to next step without further purification. MS (ESI): m/z=208.1 [M+1]⁺.

Step D. 6-Chloro-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-7-carbonitrile

A mixture of 6-chloro-2,2-dimethyl-3H-benzofuran-7-carbonitrile (200.0 mg, 0.96 mmol) in dichloromethane (10 mL) was added fuming nitric acid (0.5 mL) drop wise at 25° C. The mixture was stirred at 25° C. for 30 min. The mixture was poured into ice water. The aqueous layer was extracted with ethyl acetate (30 mL). The organic layer was dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:9) to afford 6-chloro-2,2-dimethyl-5-nitro-3H-benzofuran-7-carbonitrile (200.0 mg, 74%) as a light grey solid. MS (ESI): m/z=253.1 [M+1]⁺.

Step E. 2,2-Dimethyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-7-carbonitrile

A mixture of 6-chloro-2,2-dimethyl-5-nitro-3H-benzofuran-7-carbonitrile (100.0 mg, 0.40 mmol) in morpholine (2 mL) in a sealed vial was stirred at 110° C. overnight. The mixture was concentrated and the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:2) to afford 2,2-dimethyl-6-morpholino-5-nitro-3H-benzofuran-7-carbonitrile (100 mg, 79%) as a yellow oil. MS (ESI): m/z=304.2 [M+1]⁺.

Step F. 5-Amino-2,2-dimethyl-6-morpholino-2,3-dihydrobenzofuran-7-carbonitrile

A mixture of 2,2-dimethyl-6-morpholino-5-nitro-3H-benzofuran-7-carbonitrile (80.0 mg, 0.26 mmol) and palladium on carbon (8 mg, 10% wt) in methanol (10 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. After filtration and concentration under reduced pressure, it was afforded 5-amino-2,2-dimethyl-6-morpholino-3H-benzofuran-7-carbonitrile (70.0 mg, crude) as a green oil, which was used directly to next step without further purification. MS (ESI): m/z=274.1[M+1]⁺.

Step G. N-(7-Cyano-2,2-dimethyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (41.8 mg, 0.26 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (133.4 mg, 0.26 mmol) and N-ethyl-N-isopropylpropan-2-amine (99.1 mg, 0.77 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 30 min. 5-Amino-2,2-dimethyl-6-morpholino-3H-benzofuran-7-carbonitrile (70.0 mg, 0.26 mmol) was added. The resulting mixture was stirred at room temperature overnight. Water and ethyl acetate (30 mL) was added. The organic layer was separated the organic layer was washed with brine and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (10:1) and then further purified by preparative HPLC(Column: Xbridge 21.2*250 mm c18, 10 um; A:acetonitrile, 25-75%; B:10 mM ammonium bicarbonatein water) to afford N-(7-cyano-2,2-dimethyl-6-morpholino-3H-benzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (28 mg, 26%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 10.65 (s, 1H), 8.85 (d, J=7.2 Hz, 1H), 8.82-8.77 (m, 2H), 8.73 (s, 1H), 7.13-7.08 (m, 1H), 4.05-3.95 (m, 4H), 3.73-2.70 (m, 6H), 1.54 (s, 6H). MS (ESI): m/z=419.2[M+1]⁺.

Example 144. N-(2-(Difluoromethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. Methyl 2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carboxylate

A mixture of 6-fluoro-2-methyl-5-nitro-3H-benzofuran-2-carboxylate (Intermediate 3, step D) (300.0 mg, 1.18 mmol) in morpholine (2 mL) in a sealed tube was stirred at 80° C. overnight. The mixture was concentrated and the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:6) as eluting solvents to afford methyl 2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-carboxylate (329.0 mg, 83%) as yellow oil. MS (ESI): m/z=323.1 [M+1]⁺.

Step B. 2-Methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-carbaldehyde

To a mixture of methyl 2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-carboxylate (315.0 mg, 0.89 mmol) in dichloromethane (10 mL) was added diisobutyl aluminium hydride (1.33 mL, 1.33 mmol) drop wise at −78° C. over 5 min. Then the mixture was stirred at −78° C. for 2 h. The mixture was quenched with sodium sulfate decahydrate. The reaction was filtered and the filtrate was concentrated and the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:6) as eluting solvents to afford 2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-carbaldehyde (163.0 mg, 56%) as a yellow solid. (ESI): m/z=293.1 [M+1]⁺.

Step C. 4-(2-(Difluoromethyl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine

To a mixture of 2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-carbaldehyde (163.0 mg, 0.56 mmol) in dichloromethane (10 mL) was added drop wise diethylaminosulfurtrifluoride (561.8 mg, 2.79 mmol) at −78° C. The mixture was stirred at −78° C. overnight, concentrated and purified by silica gel chromatography using ethyl acetate:petroleum ether (1:9) as eluting solvents to afford 4-[2-(difluoromethyl)-2-methyl-5-nitro-3H-benzofuran-6-yl]morpholine (77.0 mg, 42%) as a yellow solid. (ESI): m/z=315.1 [M+1]⁺.

Step D. 2-(Difluoromethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine

A mixture of 4-[2-(difluoromethyl)-2-methyl-5-nitro-3H-benzofuran-6-yl]morpholine (77.0 mg, 0.25 mmol) and palladium on carbon (15 mg, 15% wt) in methyl alcohol (5 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(difluoromethyl)-2-methyl-6-morpholino-3H-benzofuran-5-amine (55.0 mg, crude) as a colorless oil, which was used to next step without purification further. (ESI): m/z=285.1 [M+1]⁺.

Step E. N-(2-(Difluoromethyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)-6-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 2-(difluoromethyl)-2-methyl-6-morpholino-3H-benzofuran-5-amine (55.0 mg, 0.19 mmol), 6-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Example 7, step A) (34.27 mg, 0.19 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (100.9 mg, 0.19 mmol) and N-ethyl-N-isopropylpropan-2-amine (75.0 mg, 0.58 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature overnight. Water and ethyl acetate (30 mL) were added and the organic layer was separated. The organic layer was washed with brine and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (10:1) as eluting solvents to afford N-[2-(difluoromethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]-6-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide (38.0 mg, 44%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.40 (s, 1H), 9.24 (s, 1H), 8.87 (s, 1H) 8.60 (s, 1H), 8.36 (s, 1H), 6.85 (s, 1H), 6.18 (t, J=54.8 Hz, 1H), 3.88-3.82 (m, 4H), 3.36 (d, J=17.2 Hz, 1H), 3.06 (d, J=16.4 Hz, 1H), 2.86-2.79 (m, 4H), 2.44 (s, 3H) 1.46 (s, 3H). MS (ESI): m/z=444.1[M+1]⁺.

Example 145. [1-[2,2-Dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]-4-piperidyl]methyl diethyl phosphate

Step A. [1-(2,2-Dimethyl-5-nitro-3H-benzofuran-6-yl)-4-piperidyl]methyl diethyl phosphate

To a solution of [1-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-4-piperidyl]methanol (Example 4, Step A) (270 mg, 0.85 mmol), iodine (22 mg, 0.09 mmol) and diethyl phosphate (141 mg, 1.02 mmol) in dichloromethane (10 mL) was added hydrogen peroxide (0.31 mL, 4.26 mmol) then the mixture was stirred at 20° C. for 20 h. Water and dichloromethane (50 mL) was added and the aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1 to 2:1) as eluting solvents to afford[1-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-4-piperidyl]methyl diethyl phosphate (113 mg, 23%) as a yellow solid. MS (ESI): m/z=443.1 [M+1]⁺.

Step B. [1-(5-Amino-2,2-dimethyl-3H-benzofuran-6-yl)-4-piperidyl]methyl diethyl phosphate

A mixture of [1-(2,2-dimethyl-5-nitro-3H-benzofuran-6-yl)-4-piperidyl]methyl diethyl phosphate (113 mg, 0.19 mmol), iron powder (54 mg, 0.96 mmol) and ammonium chloride (52 mg, 0.96 mmol) in ethanol (5 mL) and water (0.5 mL), was heated at 60° C. for 2 h. After filtration, water and dichloromethane (50 mL) was added. The aqueous phase was extracted with dichloromethane (2×50 mL). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford[1-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)-4-piperidyl]methyl diethyl phosphate (79 mg, crude) as a brown solid, which was used directly to next step without further purification. MS (ESI): m/z=413.3 [M+1]⁺.

Step C. [1-[2,2-Dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]-4-piperidyl]methyl diethyl phosphate

A mixture of [1-(5-amino-2,2-dimethyl-3H-benzofuran-6-yl)-4-piperidyl]methyl diethyl phosphate (79 mg, 0.14 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (27 mg, 0.17 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (78 mg, 0.21 mmol) and diisopropylethylamine (53 mg, 0.41 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 1 h. The mixture was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A: acetonitrile 25-55%; B: 10 mM ammonium bicarbonate in water) to afford[1-[2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-6-yl]-4-piperidyl]methyl diethyl phosphate (7 mg, 9%) as yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 10.51 (s, 1H), 8.85 (dd, J=1.6, 4.0 Hz, 1H), 8.79-8.76 (m, 2H), 8.44 (s, 1H), 7.10 (dd, J=1.6, 7.2 Hz, 1H), 6.63 (s, 1H), 4.14 (q, J=7.2 Hz, 4H), 4.01-4.00 (m, 2H), 3.11 (d, J=11.6 Hz, 2H), 3.03 (s, 2H), 2.69-2.64 (m, 2H), 1.87-1.77 (m, 5H), 1.48 (s, 6H), 1.35 (t, J=6.8 Hz, 6H). MS (ESI): m/z=558.3 [M+1]⁺.

Example 146. N-(1-methyl-6′-morpholino-3′H-spiro[azetidine-3,2′-benzofuran]-5′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. tert-Butyl 3-[(2,4-Difluorophenyl)methyl]-3-hydroxy-azetidine-1-carboxylate

To the mixture of magnesium powder (2.0 g, 81.51 mmol) and iodine (6.1 g, 24.15 mmol) in diethyl ether (40 mL) at 40° C. was added 2,4-difluorobenzylbromide (5.0 g, 24.15 mmol) dropwise. The reaction was stirred for 30 min. To a solution of 1-Boc-3-azetidinoe (4.1 g, 24.15 mmol) in diethyl ether (40 mL) was added Grignard reagent at −78° C. and the reaction was stirred at room temperature for 2 h. Saturated ammonium chloride solution was added. The aqueous layer was extracted with ethyl acetate (40 mL) twice. The combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford tert-butyl 3-[(2,4-difluorophenyl)methyl]-3-hydroxy-azetidine-1-carboxylate (4 g, crude) as a colorless oil, which was used directly to next step without further purification. MS (ESI): m/z=244.1 [M−56]⁺.

Step B. tert-Butyl 6-fluorospiro[3H-benzofuran-2,3′-azetidine]-1′-carboxylate

The mixture of potassium tert-butylate (3.7 g, 33.41 mmol) and tert-butyl 3-[(2,4-difluorophenyl)methyl]-3-hydroxy-azetidine-1-carboxylate (4.0 g, 13.36 mmol) in tetrahydrofuran (75 mL) was stirred at 65° C. overnight. After cooling to room temperature, water was added. The aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase Combiflash (A: acetonitrile 30%-50%; B: 0.1% wt ammonium bicarbonate in water) to afford tert-butyl 6-fluorospiro[3H-benzofuran-2,3′-azetidine]-1′-carboxylate (350 mg, 19%) as an orange oil. MS (ESI): m/z=224.1 [M−56]t

Step C. 6-Fluorospiro[3H-benzofuran-2,3′-azetidine]

A mixture of tert-butyl 6-fluorospiro[3H-benzofuran-2,3′-azetidine]-1′-carboxylate (350 mg, 1.25 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (40 mL) at room temperature was stirred overnight. Ammonia (30% wt in methanol, 10 mL) was slowly added. After concentration under reduced pressure, it was afforded 6-fluorospiro[3H-benzofuran-2,3′-azetidine] (400.0 mg, crude) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=180.1 [M+1]⁺.

Step D. 6-Fluoro-1′-methyl-spiro[3H-benzofuran-2,3′-azetidine]

To a solution of 6-fluorospiro[3H-benzofuran-2,3′-azetidine] (100.0 mg, 0.56 mmol) in methyl alcohol (4 mL) was added formaldehyde (30% wt in water, 1.1 g, 13.8 mmol) then the mixture was stirred at 25° C. for 30 min. To the mixture was added sodium cyanoborohydride (70.0 mg, 1.12 mmol). The reaction was stirred at 25° C. for 1 h. Water was added and the crude was purified by reverse phase combiflash (A: acetonitrile 23%-30%; B: 0.1% wt ammonium bicarbonate in water) to afford 6-fluoro-1′-methyl-Spiro[3H-benzofuran-2,3′-azetidine](108 mg, 99%) as a yellow solid. MS (ESI): m/z=194.1 [M+1]⁺.

Step E. 6-Fluoro-1′-methyl-5-nitro-spiro[3H-benzofuran-2,3′-azetidine]

A mixture of 6-fluoro-1′-methyl-spiro[3H-benzofuran-2,3′-azetidine] (90.0 mg, 0.4700 mmol) in dichloromethane (10 mL) was added drop wise fuming nitric acid (0.3 mL, 4.66 mmol) at 25° C. The mixture was stirred at 25° C. for 30 min and poured into ice water. 5M Sodium hydroxide was added until pH=10.0. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 6-fluoro-1′-methyl-5-nitro-spiro[3H-benzofuran-2,3′-azetidine] (85 mg, 77%) as a yellow solid. ¹H NMR (400 MHz, MeOD-d₄): 7.90-7.88 (d, J=8.0 Hz, 1H), 6.70-6.67 (d, J=11.6 Hz, 1H), 3.52-3.46 (m, 4H), 3.39 (s, 2H), 2.35 (s, 3H). MS (ESI): m/z=239.1 [M+1]⁺.

Step F. 1′-Methyl-6-morpholino-5-nitro-spiro[3H-benzofuran-2,3′-azetidine]

A solution of 6-fluoro-1′-methyl-5-nitro-spiro[3H-benzofuran-2,3′-azetidine] (116.0 mg, 0.49 mmol) in morpholine (426.0 mg, 4.9 mmol), was stirred at 110° C. for 3 h, then removed the solvents under reduced pressure to get the residue and used in next step directly without further purification. MS (ESI): m/z=306.1 [M+1]⁺.

Step G. 1′-Methyl-6-morpholino-spiro[3H-benzofuran-2,3′-azetidine]-5-amine

To a solution of 1′-methyl-6-morpholino-5-nitro-spiro[3H-benzofuran-2,3′-azetidine] (90.0 mg, 0.29 mmol) in methyl alcohol (10 mL) was added palladium on carbon (20.0 mg, 10% wt). The mixture was stirred at 25° C. for 2 h under hydrogen atmosphere. After filtration and concentration, it was afforded 1′-methyl-6-morpholino-spiro[3H-benzofuran-2,3′-azetidine]-5-amine (65 mg, 82%) as a brown oil. MS (ESI): m/z=276.2 [M+1]⁺.

Step H. N-(1′-Methyl-6-morpholino-spiro[3H-benzofuran-2,3′-azetidine]-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 1′-methyl-6-morpholino-spiro[3H-benzofuran-2,3′-azetidine]-5-amine (30.0 mg, 0.11 mmol) in N,N-dimethylformamide (3 mL) was added pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (23.0 mg, 0.14 mmol), N,N-diisopropylethylamine (42.0 mg, 0.33 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-te-tramethyluronium hexafluorophosphate (83.0 mg, 0.22 mmol). The mixture was stirred at 25° C. for 3 h. Water was added. The aqueous layer was extracted with ethyl acetate (20 mL). The organic layer was washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC (A:acetonitrile 25-55%; B: 0.05% wt formic acid in water) to afford N-(1′-methyl-6-morpholino-spiro[3H-benzofuran-2,3′-azetidine]-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20 mg, 44%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.46 (s, 1H), 9.37 (dd, J=1.6, 6.8 Hz, 1H), 8.95 (dd, J=1.6, 4.0 Hz, 1H), 8.68 (s, 1H), 8.34 (s, 1H), 7.35 (dd, J=4.0, 6.8 Hz, 1H), 6.80 (s, 1H), 3.84 (t, J=8.8 Hz, 4H), 3.46-3.42 (m, 4H), 3.27-3.25 (m, 2H), 2.86-2.76 (m, 4H), 2.31 (s, 3H). MS (ESI): m/z=421.3 [M+1]⁺.

Example 147. N-(1-(2,2-Difluoroethyl)-6′-morpholino-3′H-spiro[azetidine-3,2′-benzofuran]-5′-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 1′-(2,2-Difluoroethyl)-6-fluoro-spiro[3H-benzofuran-2,3′-azetidine]

A mixture of 6-fluorospiro[3H-benzofuran-2,3′-azetidine] (Example 146, Step C) (185.0 mg, 1.03 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (265.0 mg, 1.24 mmol) and potassium carbonate (442.0 mg, 3.2 mmol) in acetonitrile (10 mL) was stirred at 25° C. overnight. After filtration and concentration, it was afforded 1′-(2,2-difluoroethyl)-6-fluoro-spiro[3H-benzofuran-2,3′-azetidine] (170 mg, crude) as white solid, which was used directly to next step without further purification. MS (ESI): m/z=244.1 [M+1]⁺.

Step B. 1′-(2,2-Difluoroethyl)-6-fluoro-5-nitro-spiro[3H-benzofuran-2,3′-azetidine]

A mixture of 1′-(2,2-difluoroethyl)-6-fluoro-spiro[3H-benzofuran-2,3′-azetidine] (113.0 mg, 0.47 mmol) in dichloromethane (10 mL) was added drop wise fuming nitric acid (0.3 mL, 4.66 mmol) at 25° C. The mixture was stirred at 25° C. for 30 min. The mixture was poured into ice water. 5N sodium hydroxide was added until pH=10.0. The aqueous layer was extracted with dichloromethane (40 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 1′-(2,2-difluoroethyl)-6-fluoro-5-nitro-spiro[3H-benzofuran-2,3′-azetidine] (165 mg crude) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=289.1 [M+1]⁺.

Step C. 1-(2,2-Difluoroethyl)-6′-morpholino-5′-nitro-3′H-spiro[azetidine-3,2′-benzofuran]

A solution of 1′-(2,2-difluoroethyl)-6-fluoro-5-nitro-spiro[3H-benzofuran-2,3′-azetidine] (120.0 mg, 0.42 mmol) in morpholine (426.0 mg, 4.9 mmol) was stirred at 110° C. for 3 h. After concentration, it was afforded 1-(2,2-difluoroethyl)-6′-morpholino-5′-nitro-3′H-spiro[azetidine-3,2′-benzofuran] (90 mg, crude) as a yellow oil, which was used to the next step directly without further purification. MS (ESI): m/z=356.2 [M+1]⁺.

Step D. 1′-(2,2-Difluoroethyl)-6-morpholino-spiro[3H-benzofuran-2,3′-azetidine]-5-amine

To a solution of 1′-(2,2-difluoroethyl)-6-morpholino-5-nitro-spiro[3H-benzofuran-2,3′-azetidine](90.0 mg, 0.25 mmol) in methyl alcohol (10 mL) was added palladium on carbon (20.0 mg, 10% wt). The mixture was stirred at 25° C. for 2 h under hydrogen atmosphere. After filtration and concentration, it was afforded 1′-(2,2-difluoroethyl)-6-morpholino-spiro[3H-benzofuran-2,3′-azetidine]-5-amine (50 mg, crude) as a brown oil, which was used to the next step directly without further purification. MS (ESI): m/z=326.2 [M+1]⁺.

Step E. N-[1′-(2,2-Difluoroethyl)-6-morpholino-spiro[3H-benzofuran-2,3′-azetidine]-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (26.0 mg, 0.16 mmol) in N,N-dimethylformamide (3 mL) was added 1′-(2,2-difluoroethyl)-6-morpholino-spiro[3H-benzofuran-2,3′-azetidine]-5-amine (40.0 mg, 0.1200 mmol), N,N-diisopropylethylamine (47.0 mg, 0.37 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (93.0 mg, 0.25 mmol). The mixture was stirred at 25° C. for 3 h. Water and ethyl acetate (20 mL) was added and the organic layer was washed with water, brine and concentrated. The residue was purified by preparative HPLC (A:acetonitrile 25-55%; B: 0.05% wt formic acid in water) to afford N-[1′-(2,2-difluoroethyl)-6-morpholino-spiro[3H-benzofuran-2,3′-azetidine]-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (16.0 mg, 0.034 mmol, 28%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.45 (s, 1H), 9.37 (dd, J=1.6, 6.8 Hz, 1H), 8.95 (dd, J=1.6, 4.4 Hz, 1H), 8.68 (s, 1H), 8.35 (s, 1H), 7.34 (dd, J=4.4, 6.8 Hz, 1H), 6.80 (s, 1H), 6.15-5.87 (m, 1H), 3.85-3.83 (m, 4H), 3.57-3.44 (m, 6H), 2.95-2.86 (m, 2H), 2.82-2.80 (m, 4H). MS (ESI): m/z=471.1 [M+1]⁺.

Example 148. N-[6-Morpholino-1′-(2,2,2-trifluoroethyl)spiro[3H-benzofuran-2,3′-azetidine]-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was made in a manner analogous to Example 147 to give N-[6-Morpholino-1′-(2,2,2-trifluoroethyl)spiro[3H-benzofuran-2,3′-azetidine]-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (72 mg, 25%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.46 (s, 1H), 9.37 (dd, J=1.6, 6.8 Hz, 1H), 8.95 (dd, J=1.6, 4.4 Hz, 1H), 8.68 (s, 1H), 7.34 (dd, J=4.4, 6.8 Hz, 1H), 6.81 (s, 1H), 3.85-3.83 (m, 4H), 3.64-3.57 (m, 6H), 3.16 (s, 2H), 2.82-2.80 (m, 4H). MS (ESI): m/z=489.2 [M+1]⁺.

Example 149. N-(6-(4-(2,2-difluoroethyl)-1,4-diazepan-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. tert-Butyl 4-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-1,4-diazepane-1-carboxylate

A mixture of 6-fluoro-2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran (Example 3, Step F) (210 mg, 0.99 mmol), tert-butyl 1,4-diazepane-1-carboxylate (219 mg, 1.09 mmol) and potassium carbonate (412 mg, 2.98 mmol) in acetonitrile (10 mL) was stirred at 80° C. for 2 h. After removal of the solvents under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:9 to 1:1) as eluting solvents to afford tert-butyl 4-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-1,4-diazepane-1-carboxylate (260 mg, 63%) as a yellow solid. MS (ESI): m/z=392.2 [M+1]⁺.

Step B. 1-(2,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-1,4-diazepane

A mixture of tert-butyl 4-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-1,4-diazepane-1-carboxylate (260 mg, 0.66 mmol) and trifluoroacetic acid (1 mL) in dichloromethane (3 mL), was stirred at 25° C. for 2 h. After removal of solvents under reduced pressure, it was afforded 1-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-1,4-diazepane trifluoroacetic acid salt (180 mg, crude) as a yellow solid, which was used directly to next step without further purification.

MS (ESI): m/z=291.2 [M+1]⁺.

Step C. 1-(2,2-Difluoroethyl)-4-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-1,4-diazepane

A mixture of 1-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-1,4-diazepane trifluoroacetic acid salt (180 mg, 0.61 mmol), 2,2-difluoroethyl trifluoromethanesulfonate (132 mg, 0.61 mmol) and potassium carbonate (257 mg, 1.85 mmol) in acetonitrile (10 mL) was stirred at 80° C. for 16 h. After filtration and removal of the solvents under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:9 to 1:1) as eluting solvents to afford 1-(2,2-difluoroethyl)-4-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-1,4-diazepane (150 mg, 64%) as a yellow solid. MS (ESI): m/z=356.2 [M+1]⁺.

Step D. 6-(4-(2,2-Difluoroethyl)-1,4-diazepan-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-amine

A mixture of 1-(2,2-difluoroethyl)-4-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-1,4-diazepane (150 mg, 0.42 mmol) and palladium on carbon (20 mg, 10% wt) in methanol (3 mL) was stirred at 25° C. under hydrogen atmosphere for 2 hours. After filtration and concentration, it was afforded 6-(4-(2,2-difluoroethyl)-1,4-diazepan-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-amine (120 mg, crude) as a brown oil, which was used directly to next step without further purification. MS (ESI): m/z=326.3 [M+1]⁺.

Step E. N-(6-(4-(2,2-Difluoroethyl)-1,4-diazepan-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 6-(4-(2,2-difluoroethyl)-1,4-diazepan-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-amine (120 mg, 0.36 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (60 mg, 0.36 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (210 mg, 0.55 mmol) and diisopropylethylamine (95 mg, 0.73 mmol) in N,N-dimethylformamide (3 mL) was stirred at 60° C. for 3 h. The crude was purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um; A:acetonitrile 25-55%; B: 10 mM ammonium bicarbonate in water) to afford N-(6-(4-(2,2-difluoroethyl)-1,4-diazepan-1-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (22 mg, 12%) as a yellow solid. ¹H NMR (400 MHz, MeOD-d₄): δ 9.17 (d, J=6.0 Hz, 1H), 8.95 (d, J=2.8 Hz, 1H), 8.70 (s, 1H), 8.06 (s, 1H), 7.31 (dd, J=6.0, 2.8 Hz, 1H), 6.73 (s, 1H), 6.27-6.54 (tt, J=1.2, 53.2 Hz 1H), 3.77-3.89 (m, 6H), 3.45 (s, 2H), 3.23 (t, J=5.6 Hz 2H), 3.05 (s, 2H), 2.21-2.27 (m, 2H), 1.48 (s, 6H). MS (ESI): m/z=471.3 [M+1]⁺.

Example 150. N-(2-Isopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 1-(2,4-Difluorophenyl)-2,3-dimethylbutan-2-ol

A mixture of magnesium (2.2 g, 92.88 mmol) and iodine (59 mg, 0.23 mmol) in diethyl ether (80 mL) at 40° C. under nitrogen atmosphere was slowly added 2,4-difluorobenenzyl bromide (4.2 g, 20.31 mmol) and stirred for 2 h. To a solution of 3-methyl-2-butanone (2 g, 23.22 mmol) in diethyl ether (100 mL) at −78° C. under nitrogen atmosphere was added Grignard reagent and the reaction was stirred at room temperature for 2 h. Saturated ammonium chloride solution and ethyl acetate (200 mL) was added. The organic layer was separated, washed with water, brine and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:10) as eluting solvents to afford 1-(2,4-difluorophenyl)-2,3-dimethyl-butan-2-ol (3.4 g, 65%) as a yellow oil. MS (ESI): m/z=197.2 [M 17]⁺.

Step B. 6-Fluoro-2-isopropyl-2-methyl-2,3-dihydrobenzofuran

A mixture of 1-(2,4-difluorophenyl)-2,3-dimethyl-butan-2-ol (428 mg, 2 mmol) and tetrahydrofuran (50 mL) at 0° C. was added potassium tert-butylate (1.12 g, 9.99 mmol). The reaction was stirred for 16 h. The aqueous layer was extracted with ethyl acetate (100 mL) and the organics were washed with saturated brine solution. The organics were then separated and dried over sodium sulfate before concentration to dryness. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:20) as eluting solvents to afford 6-fluoro-2-isopropyl-2-methyl-3H-benzofuran (350 mg, 90%) as a yellow oil. MS (ESI): m/z=217.1 [M+23]⁺.

Step C. 6-Fluoro-2-isopropyl-2-methyl-5-nitro-2,3-dihydrobenzofuran

To a solution of 6-fluoro-2-isopropyl-2-methyl-3H-benzofuran (350 mg, 1.8 mmol) in dichloromethane (30 mL) at 0° C. was added fuming nitric acid (2 mL). Water and dichloromethane (30 mL) were added and the organics were then separated and dried over sodium sulfate before concentration to dryness. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:5) as eluting solvents to afford 6-fluoro-2-isopropyl-2-methyl-5-nitro-2,3-dihydrobenzofuran (220 mg, 51%) as a yellow oil. MS (ESI): m/z=240.1 [M+1]⁺.

Step D. 4-(2-Isopropyl-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine

A mixture of 6-fluoro-2-isopropyl-2-methyl-5-nitro-3H-benzofuran (220 mg, 0.92 mmol), morphline (88 mg, 1.01 mmol) and potassium carbonate (254 mg, 1.84 mmol) in acetonitrile (15 mL) was stirred at 25° C. for 16 h. Water was added and the aqueous layer was extracted with ethyl acetate (30 mL). The organic layer was washed with brine and dried over sodium sulfate before concentration to dryness. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1) as eluting solvents to afford 4-(2-isopropyl-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine (250 mg, 85%) as a yellow solid. MS (ESI): m/z=307.2 [M+1]⁺.

Step E. 2-Isopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine

A mixture of palladium on carbon (80.0 mg, 10% wt) and 4-(2-isopropyl-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine (250 mg, 0.78 mmol) in methanol (15 mL) was stirred at 25° C. under hydrogen atmosphere for 2 h. After filtration and concentration under reduced pressure, it was afforded 2-isopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine (200 mg, 89%) as a white oil. MS (ESI): m/z=277.3 [M+1]⁺.

Step F. N-(2-Isopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (130 mg, 0.80 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (464 mg, 0.87 mmol), ethyldiisopropylamine (347 mg, 2.16 mmol) 2-isopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine (200 mg, 0.72 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature overnight. After concentration, the residue was purified by preparative HPLC (A: acetonitrile 25-45%; 0.05% wt formic acid in water) to afford N-(2-isopropyl-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (125 mg, 41%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.46 (s, 1H), 8.83 (dd, J=1.6, 7.2 Hz, 1H), 8.79 (s, 1H), 8.76 (dd, J=1.6, 4.0 Hz, 1H), 8.40 (s, 1H), 7.06 (dd, J=4.0, 7.2 Hz, 1H), 6.65 (s, 1H), 4.00-3.89 (m, 4H), 3.16 (d, J=11.6 Hz, 1H), 2.93-2.87 (m, 4H), 2.83 (d, J=11.6 Hz, 1H), 2.08-1.95 (m, 2H), 1.01 (d, J=6.8, 3H), 0.96 (d, J=6.8 Hz, 6H). MS (ESI): m/z=422.2 [M+1]⁺.

Example 151. N-(6-(4-(2-Hydroxy-2-methylpropyl)piperazin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 2-Methyl-1-(piperazin-1-yl)propan-2-ol

Piperazine (6.88 g, 80 mmol) was dissolved in ethanol (40 mL). 1-Chloro-2-methyl-2-propanol (2.18 g, 20 mmol) was added. The mixture was stirred at 110° C. for 6 h. After the mixture was left to cool to room temperature, the solvent was evaporated. Ethyl acetate (40 mL) was added and the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure to afford 2-methyl-1-piperazin-1-yl-propan-2-ol (4.1 g, crude) as a white solid, which was used directly to the next step without purification. MS (ESI): m/z=159.3 [M+1]⁺.

Step B. 1-(4-(2-(Hydroxymethyl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)piperazin-1-yl)-2-methylpropan-2-ol

A mixture of (6-fluoro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (Intermediate 3) (300 mg, 1.32 mmol), 2-methyl-1-(piperazin-1-yl)propan-2-ol (1.44 g, 6.6 mmol) and potassium carbonate (365 mg, 2.64 mmol) in acetonitrile (10 mL) was stirred at 25° C. for 16 h. Water was added and the aqueous layer was extracted with ethyl acetate (20 mL) and the organic was washed with brine and dried over sodium sulfate before concentration to dryness. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:2) as eluting solvents to afford 1-(4-(2-(hydroxymethyl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)piperazin-1-yl)-2-methylpropan-2-ol (100 mg, 18%) as a yellow solid. MS (ESI): m/z=366.3 [M+1]⁺.

Step C. 1-(4-(5-Amino-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-6-yl)piperazin-1-yl)-2-methylpropan-2-ol

A mixture of palladium on carbon (30 mg, 10% wt) and 1-(4-(2-(hydroxymethyl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)piperazin-1-yl)-2-methylpropan-2-ol (100 mg, 0.27 mmol) in methanol (10 mL) was stirred at 25° C. under hydrogen atmosphere for 2 h. After filtration and concentration under reduced pressure, it was afforded 1-(4-(5-amino-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-6-yl)piperazin-1-yl)-2-methylpropan-2-ol (60 mg, crude) as a white oil, which was used directly to next step without further purification. MS (ESI): m/z=336.1 [M+1]⁺.

Step D. N-(6-(4-(2-Hydroxy-2-methylpropyl)piperazin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 1-(4-(5-amino-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-6-yl)piperazin-1-yl)-2-methylpropan-2-ol (60 mg, 0.18 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (113 mg, 0.21 mmol), ethyldiisopropylamine (68 mg, 0.54 mmol) and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (32 mg, 0.21 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature overnight. After concentration, the residue was purified by preparative HPLC (A: acetonitrile 25-45%; B: 0.05% wt formic acid in water) to afford N-(6-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 58%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.39 (s, 1H), 8.86-8.75 (m, 3H), 8.43 (s, 1H), 8.17 (s, 1H), 7.08 (dd, J=4.0, 6.8 Hz, 1H), 6.68 (s, 1H), 5.33 (s, 1H), 3.69-3.61 (m, 2H), 3.25 (d, J=16.0 Hz, 1H), 3.08-2.90 (m, 8H), 2.58-2.50 (m, 2H), 1.46 (s, 3H), 1.26 (s, 6H). MS (ESI): m/z=481.2 [M+1]⁺.

Example 152. N-(1′-Methyl-6-morpholino-3H-spiro[benzofuran-2,4′-piperidine]-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. tert-Butyl 4-[(2,4-difluorophenyl)methyl]-4-hydroxy-piperidine-1-carboxylate

To a solution of magnesium (2400 mg, 100 mmol) and iodine (180 mg, 0.71 mmol) in diethyl ether (25 mL) at reflux was added 1-(bromomethyl)-2,4-difluorobenzene (8200.0 mg, 39.61 mmol) slowly and stirred for 30 min. To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (6500.0 mg, 32.62 mmol) in diethyl ether (200 mL) was added Grignard reagent and stirred at 78° C. then room temperature for 2 h. Water and EtOAc (200 mL) was added. The organic layer was separated and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using petroleum ether:ethyl acetate (4:1 to 2:1) as eluting solvents to afford tert-butyl 4-[(2,4-difluorophenyl)methyl]-4-hydroxy-piperidine-1-carboxylate (9500 mg, 73%) as a white solid. MS (ESI): m/z=350.1[M+23]⁺.

Step B. tert-Butyl 6-fluoro-3H-spiro[benzofuran-2,4′-piperidine]-1′-carboxylate

A mixture of tert-butyl 4-[(2,4-difluorophenyl)methyl]-4-hydroxy-piperidine-1-(818.0 mg, 2.5 mmol) and potassium tert-butanolate (700.95 mg, 6.25 mmol) in tetrahydrofuran (50 mL) was stirred at 65° C. for 3 h. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated to dryness to afford tert-butyl 6-fluorospiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate (644 mg, crude) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=252.2 [M−55]⁺.

Step C. 6-Fluorospiro[3H-benzofuran-2,4′-piperidine]

To a solution of tert-butyl 6-fluorospiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate (644.0 mg, 2.1 mmol) in dichloromethane (20 mL), was added trifluoroacetic acid (2 mL). The reaction solution was stirred for 2 h at room temperature. To the reaction was added saturated sodium hydrogen carbonate (20 mL). The aqueous layer was extracted twice with 20 mL of dichloromethane. The combined organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent, it was afforded 6-fluorospiro[3H-benzofuran-2,4′-piperidine] (429 mg, crude) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=208.2 [M+1]⁺.

Step D. 6-Fluoro-1′-methyl-3H-spiro[benzofuran-2,4′-piperidine]

To a solution of 6-fluorospiro[3H-benzofuran-2,4′-piperidine] (429.0 mg, 1.51 mmol) in methyl alcohol (40 mL) was added formaldehyde (28% wt in water, 1.5 mL) at room temperature. The reaction solution was stirred for 30 min at room temperature. Sodium borohydride (574.22 mg, 15.11 mmol) was added slowly and the reaction was stirred for 2 h at room temperature. To the reaction solution saturated ammonium chloride (200 mL) was added and the aqueous layer was extracted twice with 200 mL of ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After concentration, it was afforded 6-fluoro-1′-methyl-spiro[3H-benzofuran-2,4′-piperidine] (402 mg, crude) as a yellow oil, which was used directly to next step without further purification. MS (ESI): m/z=222.2 [M+1]⁺.

Step E. 6-Fluoro-1′-methyl-5-nitro-3H-spiro[benzofuran-2,4′-piperidine]

To a solution of 6-fluoro-1′-methyl-spiro[3H-benzofuran-2,4′-piperidine] (402.0 mg, 1.82 mmol) in dichloromethane (30 mL) was added fuming nitric acid (1.7 mL, 27.25 mmol) slowly. The mixture was stirred at room temperature for 30 min. Water (50 mL) was added. Sodium bicarbonate was added until pH=7 was reached and the aqueous layer was extracted with dichloromethane (50 mL). The organic layer was dried over sodium sulfate and concentrated to afford 6-fluoro-1′-methyl-5-nitro-3H-spiro[benzofuran-2,4′-piperidine] (399 mg, crude) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=267.1 [M−55]⁺.

Step F. 1′-Methyl-6-morpholino-5-nitro-3H-spiro[benzofuran-2,4′-piperidine]

A mixture of 6-fluoro-1′-methyl-5-nitro-spiro[3H-benzofuran-2,4′-piperidine] (399.0 mg, 1.5 mmol), morpholine (195.82 mg, 2.25 mmol) and potassium carbonate (516.64 mg, 3.75 mmol) in acetonitrile (10 mL) was stirred at 25° C. overnight. Water was added and the aqueous layer was extracted twice with 20 mL of ethyl acetate. The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, it was afforded 1′-methyl-6-morpholino-5-nitro-3H-spiro[benzofuran-2,4′-piperidine] (467 mg, crude) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=334.2 [M+1]⁺.

Step G. 1′-Methyl-6-morpholino-3H-spiro[benzofuran-2,4′-piperidin]-5-amine

A mixture of 10 wt % palladium on carbon (70.0 mg) and 1′-methyl-6-morpholino-5-nitro-3H-spiro[benzofuran-2,4′-piperidine] (467.0 mg, 1.4 mmol) in methyl alcohol (40 mL) was stirred at room temperature under a hydrogen atmosphere for 2 h. After filtration and concentration under reduced pressure, it was afforded 1′-methyl-6-morpholino-3H-spiro[benzofuran-2,4′-piperidin]-5-amine (419 mg, crude) as a brown solid, which was used directly to next step without further purification. MS (ESI): m/z=304.3 [M+1]⁺.

Step H. N-(1′-Methyl-6-morpholino-3H-spiro[benzofuran-2,4′-piperidine]-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (109.69 mg, 0.6700 mmol), (3-hydroxy-3H-1,2,3-triazolo[4,5-b]pyridinato-O)tri-1-pyrrolidinylphosphonium hexafluorophosphate (385.62 mg, 0.74 mmol) and N-ethyl-N-isopropylpropan-2-amine (260.7 mg, 2.02 mmol) in N,N-dimethylformanide (5 mL) at 0° C. was added 1′-methyl-6-morpholino-spiro[3H-benzofuran-2,4′-piperidine]-5-amine (204.0 mg, 0.6700 mmol) in N,N-dimethylformanide (2 mL) and the reaction was stirred at room temperature overnight. The crude was purified by reverse phase chromatography (Xbridge Prep C18 10 um OBD, 19*250 mm, A: acetonitrile 30-60%; B: 0.01% wt ammonium hydroxide and 10 mM ammonium carbonate in water) to afford N-(1′-methyl-6-morpholino-3H-spiro[benzofuran-2,4′-piperidine]-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (121 mg, 40%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.46 (s, 1H), 8.83 (dd, J=1.6, 6.8 Hz, 1H), 8.78 (s, 1H), 8.77 (dd, J=1.6, 4.4 Hz, 1H), 8.43 (s, 1H), 7.06 (dd, J=4.4, 7.2 Hz, 1H), 6.69 (s, 1H), 3.99-3.91 (m, 4H), 3.02 (s, 2H), 2.94-2.88 (m, 4H), 2.66-2.44 (m, 4H), 2.35 (s, 3H), 2.05-1.95 (m, 2H), 1.89-1.79 (m, 2H). MS (ESI): m/z=449.3 [M+1]⁺.

Example 153 and 154. (R)—N-(2-(hydroxymethyl)-6-morpholino-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(hydroxymethyl)-6-morpholino-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. Methyl 2-(2,4-difluorobenzyl)-3,3,3-trifluoro-2-hydroxypropanoate

To a solution of magnesium powder (3290.81 mg, 137.12 mmol) and iodine (243.76 mg, 0.96 mmol) in diethyl ether (50 mL) at reflux was added 2,4-difluorobenzyl bromide (11291.0 mg, 54.54 mmol) drop wise and stirred for 30 min. This Grignard solution was then added to a solution of methyl 3,3,3-trifluoro-2-oxopropanoate (8567.5 mg, 54.92 mmol) in diethyl ether (200 mL) at −78° C. and stirred for 30 min followed by room temperature for 2 h. Saturated ammonium chloride solution and ethyl acetate (200 mL) was added. The organic phase was separated and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:20 to 1:10) as eluting solvents to afford methyl 3-(2,4-difluorophenyl)-2-hydroxy-2-methyl-propanoate (9.7 g, 63%) as a yellow oil. MS (ESI): m/z=307.1 [M+23]⁺.

Step B. 2-(2,4-Difluorobenzyl)-3,3,3-trifluoro-2-hydroxypropanoic acid

A mixture of methyl methyl 2-(2,4-difluorobenzyl)-3,3,3-trifluoro-2-hydroxypropanoate (9.7 g, 34.13 mmol) and potassium hydroxide (5.73 g, 102.4 mmol) in methyl alcohol (100 mL) and water (50 mL) was stirred at 50° C. for 2 h. After cooling to room temperature, 1N hydrochloric acid was added until pH=3.0. The aqueous phase was extracted with ethyl acetate (200 mL). The organic layer was separated, dried over sodium sulfate and concentrated to afford 2-(2,4-difluorobenzyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (9.2 g, crude) as a white solid, which was used directly to next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.29 (m, 1H), 6.85-6.77 (m, 2H), 3.45 (d, J=16.0 Hz, 1H), 3.20 (d, J=16.0 Hz, 1H).

Step C. 6-Fluoro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylic acid

To a mixture of 2-(2,4-difluorobenzyl)-3,3,3-trifluoro-2-hydroxypropanoic acid (3.6 g, 13.33 mmol) in N,N-dimethylformamide (5 mL) and toluene (20 mL) was added sodium hydride (1.06 g, 26.65 mmol) at room temperature. The mixture was stirred at 110° C. overnight. After cooling to room temperature, 1N hydrochloric acid was added until pH=3.0. The aqueous phase was extracted with ethyl acetate (50 mL). The organic layer was separated, dried over sodium sulfate and concentrated to afford 6-fluoro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylic acid (3.3 g, crude) as a brown solid, which was used directly to next step without further purification. MS (ESI): m/z=273.1 [M+23]⁺.

Step D. Methyl 6-fluoro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate

To a mixture of 6-fluoro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylic acid (500 mg, 2.0 mmol) and cesium carbonate (1.3 g, 4.0 mmol) in N,N-dimethylformamide (10 mL) was added methyl iodide (570 mg, 4.0 mmol). The mixture was stirred at room temperature overnight. Water was added and the aqueous phase was extracted with ethyl acetate (50 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford methyl 6-fluoro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate (500 mg, crude), which was used directly to next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.12-7.09 (m, 1H), 6.70-6.66 (m, 2H), 3.89 (s, 3H), 3.68 (d, J=16.0 Hz, 1H), 3.62 (d, J=16.0 Hz, 1H).

Step E. Methyl 6-fluoro-5-nitro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate

To a mixture of methyl methyl 6-fluoro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate (3.8 g, 8.77 mmol) in dichloromethane (20 mL) was added fuming nitric acid (4.0 mL). The mixture was stirred at room temperature for 1 h. The mixture was poured into ice water and the aqueous phase was extracted with ethyl acetate (50 mL). The organic phase was separated, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether from 1:20 to 1:5 as eluting solvents to afford methyl 6-fluoro-5-nitro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate (2.6 g, 96%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J=7.2 Hz, 1H), 6.86 (d, J=10.4 Hz, 1H), 3.93 (s, 3H), 3.76 (d, J=15.6 Hz, 1H), 3.70 (d, J=15.6 Hz, 1H). MS (ESI): m/z=310.0 [M+1]⁺.

Step F. Methyl 6-morpholino-5-nitro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate

A mixture of morpholine (108 mg, 1.25 mmol), 6-fluoro-5-nitro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate (350 mg, 1.13 mmol) and cesium carbonate (738 mg, 2.26 mmol) in acetonitrile (20 mL) was stirred at room temperature for 3 h. Water was added and the aqueous phase was extracted with ethyl acetate (40 mL). The organic layer was separated, dried over sodium sulfate and concentrated to afford methyl 6-morpholino-5-nitro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate (400 mg, 84%) as a yellow oil. MS (ESI): m/z=377.1 [M+1]⁺.

Step G. (6-Morpholino-5-nitro-2-(trifluoromethyl)-2,3-Dihydrobenzofuran-2-yl)methanol

To a mixture of methyl 6-morpholino-5-nitro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-2-carboxylate (400 mg, 1.06 mmol) in tetrahydrofuran (20 mL) and ethanol (5 mL) was added sodium borohydride (121.19 mg, 3.19 mmol) and lithium chloride (134 mg, 3.19 mmol) at 0° C. The mixture was stirred at room temperature for 2 h. Saturated ammonium chloride solution and ethyl acetate (50 mL) was added. The organic layer was separated, dried over sodium sulfate and concentrated to afford (6-morpholino-5-nitro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-2-yl)methanol (370 mg, crude) as a yellow solid, which was used directly to next step without further purification. MS (ESI): m/z=349.1 [M+1]⁺.

Step H. (5-Amino-6-morpholino-2-(trifluoromethyl)-2,3-Dihydrobenzofuran-2-yl)methanol

A mixture of palladium on carbon (60 mg, 10% wt) and (6-morpholino-5-nitro-2-(trifluoromethyl)-2,3-dihydrobenzofuran-2-yl)methanol (370 mg, 1.06 mmol) in methyl alcohol (30 mL) was stirred at room temperature under hydrogen atmosphere for 2 h. After filtration and concentration under reduced pressure, it was afforded (5-amino-6-morpholino-2-(trifluoromethyl)-2,3-dihydrobenzofuran-2-yl)methanol (50 mg, crude) as a dark solid, which was used directly to next step without further purification. MS (ESI): m/z=319.1 [M+1]⁺.

Step I. (R)—N-(2-(hydroxymethyl)-6-morpholino-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(hydroxymethyl)-6-morpholino-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of [5-amino-6-morpholino-2-(trifluoromethyl)-3H-benzofuran-2-yl]methanol (310 mg, 0.97 mmol), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (167 mg, 1.02 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (558 mg, 1.07 mmol) and N-ethyl-N-isopropylpropan-2-amine (354 mg, 2.92 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. Water was added and the aqueous phase was extracted with ethyl acetate (20 mL). The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (9:1) to afford 250 mg racemic product as a yellow solid. The product was resolved by chiral preparatory SFC (Column: OJ 4.6*250 mm, Sum (Decial), Mobile phase: CO₂/MeOH (0.2% Methanol Ammonia)=65/35) to afford N-[(2R)-2-(hydroxymethyl)-6-morpholino-2-(trifluoromethyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-2-(Hydroxymethyl)-6-morpholino-2-(trifluoromethyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (105 mg, 22%) (100 mg, 21%) as light yellow solids with absolute stereochemistry assigned arbitrarily.

Example 153, Peak 1: ¹H NMR (400 MHz, CDCl₃) δ 10.49 (s, 1H), 8.84 (dd, J=1.6, 7.2 Hz, 1H), 8.78 (s, 1H), 8.76 (dd, J=4.0, 6.4 Hz, 1H), 8.49 (s, 1H), 7.08 (dd, J=1.6, 4.0 Hz, 1H), 6.77 (s, 1H), 4.07 (d, J=12.4 Hz, 1H), 3.96-3.93 (m, 4H), 3.86 (d, J=12.4 Hz, 1H), 3.53 (d, J=16.4 Hz, 1H), 3.42 (d, J=16.4 Hz, 1H), 2.92-2.89 (m, 4H). MS (ESI): m/z=464.2 [M+1]⁺.

Example 154, Peak2: ¹H NMR (400 MHz, CDCl₃) δ 10.49 (s, 1H), 8.84 (dd, J=1.6, 7.2 Hz, 1H), 8.78 (s, 1H), 8.76 (dd, J=4.0, 6.4 Hz, 1H), 8.49 (s, 1H), 7.08 (dd, J=1.6, 4.0 Hz, 1H), 6.77 (s, 1H), 4.07 (d, J=12.4 Hz, 1H), 3.96-3.93 (m, 4H), 3.86 (d, J=12.4 Hz, 1H), 3.53 (d, J=16.4 Hz, 1H), 3.42 (d, J=16.4 Hz, 1H), 2.92-2.89 (m, 4H). MS (ESI): m/z=464.2 [M+1]⁺.

Examples 155 and 156. (R)—N-(2-((difluoromethoxy)methyl)-2-Methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-((difluoromethoxy)methyl)-2-Methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (2-Methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol

A mixture of morpholine (230 mg, 2.64 mmol), (6-fluoro-2-methyl-5-nitro-3H-benzofuran-2-yl)methanol (Intermediate 3) (300 mg, 1.32 mmol) and potassium carbonate (364 mg, 2.64 mmol) in acetonitrile (20 mL) was stirred at room temperature for 3 h. Water was added and the mixture was extracted with ethyl acetate (40 mL). The organic layer was concentrated to afford (2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (420 mg, crude) as a yellow oil, which was used directly to next step without further purification. MS (ESI): m/z=295.1 [M+1]⁺.

Step B. 4-(2-((Difluoromethoxy)methyl)-2-Methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine

To a mixture of (2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-yl)methanol (180 mg, 0.61 mmol) and copper iodide (34 mg, 0.24 mmol) in acetonitrile (20 mL) was added difluoro(fluorosulfonyl)acetic acid (218 mg, 1.22 mmol) at 50° C. The mixture was stirred 50° C. for 1 h. The mixture was concentrated and purified by silica gel chromatography using ethyl acetate:petroleum ether (3:20) to afford 4-(2-((difluoromethoxy)methyl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine (70 mg, 31%) as a yellow oil. MS (ESI): m/z=345.1 [M+1]⁺.

Step C. 2-((Difluoromethoxy)methyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine

A mixture of palladium on carbon (20 mg, 10% wt) and 4-(2-((difluoromethoxy)methyl)-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)morpholine (70 mg, 0.2 mmol) in methanol (15 mL) was stirred at room temperature under hydrogen atmosphere for 1 h. After filtration and concentration under reduced pressure, it was afforded 2-((difluoromethoxy)methyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine (60 mg, crude) as a green oil, which was used directly to next step without further purification. MS (ESI): m/z=315.1[M+1]⁺.

Step D. (R)—N-(2-((difluoromethoxy)methyl)-2-Methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-((difluoromethoxy)methyl)-2-Methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (80 mg, 0.5 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (324 mg, 0.62 mmol), N-ethyl-N-isopropylpropan-2-amine (150 mg, 1.24 mmol) and 2-((difluoromethoxy)methyl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-amine (140 mg, 0.42 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. Water was added and the aqueous phase was extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (3:1) as eluting solvents to afford N-(2-(hydroxymethyl)-2,7-dimethyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (140 mg, 73%) as a yellow solid. The product was resolved by chiral preparatory SFC (Column: AD 20*250 mm, 5 um (Dacel), Mobile phase: CO₂/MEOH{0.5% Ammonia (7M methanol)}=70/30) to afford N-[(2R)-2-(difluoromethoxymethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-2-(difluoromethoxymethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (50 mg, 53%) (45 mg, 47%) as yellow solids with absolute stereochemistry assigned arbitrarily.

Example 155, Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.36 (dd, J=1.5, 6.8 Hz, 1H), 8.94 (dd, J=1.6, 4.0 Hz, 1H), 8.68 (s, 1H), 8.32 (s, 1H), 7.35 (dd, J=4.0, 7.2 Hz, 1H), 6.73 (t, J=75.2 Hz, 1H), 6.77 (s, 1H), 3.94 (s, 2H), 3.85-3.83 (m, 4H), 3.18 (d, J=15.6 Hz, 1H), 2.97 (d, J=15.6 Hz, 1H), 2.83-2.81 (m, 4H), 1.42 (s, 3H). MS (ESI): m/z=460.2[M+1]⁺.

Example 156, Peak 2: ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 9.36 (dd, J=1.5, 6.8 Hz, 1H), 8.94 (dd, J=1.6, 4.0 Hz, 1H), 8.68 (s, 1H), 8.32 (s, 1H), 7.35 (dd, J=4.0, 7.2 Hz, 1H), 6.73 (t, J=75.2 Hz, 1H), 6.77 (s, 1H), 3.94 (s, 2H), 3.85-3.83 (m, 4H), 3.18 (d, J=15.6 Hz, 1H), 2.97 (d, J=15.6 Hz, 1H), 2.83-2.81 (m, 4H), 1.42 (s, 3H). MS (ESI): m/z=460.2[M+1]⁺.

Examples 157 and 158. (R)—N-(2-(2-Hydroxypropan-2-yl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(2-Hydroxypropan-2-yl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a] pyrimidine-3-carboxamide

Step A. 2-(6-Fluoro-2-methyl-2,3-dihydrobenzofuran-2-yl)propan-2-ol

To a solution of methyl 6-fluoro-2-methyl-3H-benzofuran-2-carboxylate (877 mg, 4.17 mmol) in anhydrous tetrahydrofuran (20 mL) was added drop-wise methylmagnesium bromide (3 M in ditheyl ether, 4.17 mL, 12.52 mmol) under N₂ atmosphere at −78° C. The mixture was stirred at −78° C. for 1 h. The mixture was quenched with saturated ammonium chloride solution. Ethyl acetate (50 mL) was added. The organic layer was separated, dried over sodium sulfate and concentrated to afford 2-(6-fluoro-2-methyl-2,3-dihydrobenzofuran-2-yl)propan-2-ol (800 mg, crude) as a colorless oil, which was used directly to next step without further purification. MS (ESI): m/z=193.1 [M−17]⁺.

Step B. 2-(6-Fluoro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)propan-2-ol

A mixture of 2-(6-fluoro-2-methyl-2,3-dihydrobenzofuran-2-yl)propan-2-ol (400 mg, 1.9 mmol) in dichloromethane (15 mL) was added concentrated nitric acid (60-70% wt, 0.5 mL). The mixture was stirred at room temperature for 1 h. The mixture was poured into ice water and extracted with dichloromethane (30 mL). The organic layer was separated, dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography ethyl acetate:petroleum ether (1:4) as eluting solvents to afford 2-(6-fluoro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)propan-2-ol (320 mg, 59%) as a brown oil. ¹H NMR (400 MHz, CDCl₃) δ 7.94 (d, J=7.8 Hz, 1H), 6.61 (d, J=12.8 Hz, 1H), 3.54 (d, J=15.6 Hz, 1H), 2.82 (d, J=15.6 Hz, 1H), 1.38 (s, 3H), 1.24 (s, 6H).

Step C. 2-(2-Methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-yl)propan-2-ol

A mixture of morpholine (218 mg, 2.51 mmol), 2-(6-fluoro-2-methyl-5-nitro-2,3-dihydrobenzofuran-2-yl)propan-2-ol (320 mg, 1.25 mmol) and potassium carbonate (346 mg, 2.51 mmol) in acetonitrile (20 mL) was stirred at room temperature for 3 h. Water was added and the aqueous phase was extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate and concentrated to afford 2-(2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-yl)propan-2-ol (318 mg, crude) as a yellow oil, which was used directly to next step without further purification. MS (ESI): m/z=323.2 [M+1]⁺.

Step D. 2-(5-Amino-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)propan-2-ol

A mixture of palladium on carbon (100 mg, 10% wt) and 2-(2-methyl-6-morpholino-5-nitro-2,3-dihydrobenzofuran-2-yl)propan-2-ol (300 mg, 0.93 mmol) in methanol (30 mL) was stirred at room temperature under hydrogen atmosphere for 1 h. After filtration and concentration under reduced pressure, it was afforded 2-(5-amino-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)propan-2-ol (280 mg, crude) as a green oil, which was used directly to next step without further purification. MS (ESI): m/z=293.2[M+1]⁺.

Step E. (R)—N-(2-(2-Hydroxypropan-2-yl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(2-Hydroxypropan-2-yl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (174 mg, 1.07 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (695 mg, 1.33 mmol), N-ethyl-N-isopropylpropan-2-amine (323 mg, 2.67 mmol) and 2-(5-amino-2-methyl-6-morpholino-2,3-dihydrobenzofuran-2-yl)propan-2-ol (260 mg, 0.89 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The crude reaction was purified by preparative HPLC (Gilson 281, Xbridge 21.2*250 mm c18, 10 um; A:acetonitrile, 25-55%, B: 10 M ammonium bicarbonatein water) to afford N-(2-(2-hydroxypropan-2-yl)-2-methyl-6-morpholino-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg) as a yellow solid. The product was resolved by chiral preparatory SFC (Column: AD 20*250 mm, 5 um (Dacel), Mobile phase: CO₂/MEOH{0.5% Ammonia (7M methanol)}=70/30) to afford N-[(2R)-2-(1-hydroxy-1-methyl-ethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-2-(1-hydroxy-1-methyl-ethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (45 mg, 45%) (50 mg, 50%) as yellow solids with absolute stereochemistry assigned arbitrarily.

Example 157, Peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 9.37 (dd, J=7.2, 1.6 Hz, 1H), 8.94 (dd, J=4.0, 1.6 Hz, 1H), 8.68 (s. 1H), 8.29 (s, 1H), 7.34 (dd, J=7.2, 4.0 Hz, 1H), 6.71 (s, 1H), 4.53 (s, 1H), 3.85-3.83 (m, 4H), 3.46 (d, J=16.0 Hz, 1H), 2.83-2.81 (m, 4H), 2.73 (d, J=16.0 Hz, 1H), 1.32 (s, 3H), 1.17 (d, J=5.2 Hz, 6H). MS (ESI): m/z=438.3[M+1]⁺.

Example 158, Peak 2: ¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 9.37 (dd, J=7.2, 1.6 Hz, 1H), 8.94 (dd, J=4.0, 1.6 Hz, 1H), 8.68 (s. 1H), 8.29 (s, 1H), 7.34 (dd, J=7.2, 4.0 Hz, 1H), 6.71 (s, 1H), 4.53 (s, 1H), 3.85-3.83 (m, 4H), 3.46 (d, J=16.0 Hz, 1H), 2.83-2.81 (m, 4H), 2.73 (d, J=16.0 Hz, 1H), 1.32 (s, 3H), 1.17 (d, J=5.2 Hz, 6H). MS (ESI): m/z=438.3[M+1]⁺.

Examples 159 and 160. (R)—N-(2-Cyclopropyl-6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-Cyclopropyl-6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 2-Cyclopropyl-1-(2,4-difluorophenyl)propan-2-ol

To a mixture of 1-(2,4-difluorophenyl)propan-2-one (prepared by similar method as Example 14, step B) (900.0 mg, 5.29 mmol) in tetrahydrofuran (20 mL) was added drop-wise cyclopropylmagnesium bromide (0.5 M in tetrahydrofuran, 10.58 mL, 5.29 mmol) at −78° C. under nitrogen atmosphere. The mixture was stirred at room temperature for 1 h. The reaction was quenched by addition of saturated ammonium chloride (20 mL). The mixture was extracted with ethyl acetate (50 mL) twice. The combined organic layers were washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified on silica gel chromatography using ethyl acetate:petroleum ether (1:10) as eluting solvents to afford 2-cyclopropyl-1-(2,4-difluorophenyl)propan-2-ol (800.0 mg, 68%) as a light yellow foam. MS (ESI): m/z=195.1 [M−17]+.

Step B. 2-Cyclopropyl-6-fluoro-2-methyl-2,3-dihydrobenzofuran

A mixture of 2-cyclopropyl-1-(2,4-difluorophenyl)propan-2-ol (600.0 mg, 2.83 mmol) and tert-butoxypotassium (1268.9 mg, 11.31 mmol) in tetrahydrofuran (10 mL) was stirred at 65° C. for 3 h. After cooling to room temperature, water and ethyl acetate (20 mL) was added. The organic layer was separated and dried over sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:10) as eluting solvents to afford 2-cyclopropyl-6-fluoro-2-methyl-3H-benzofuran (460.0 mg, 80%) as a colorless oil. MS (ESI): m/z=193.1 [M+H]⁺.

Step C. 2-Cyclopropyl-6-fluoro-2-methyl-5-nitro-2,3-dihydrobenzofuran

To a solution of 2-cyclopropyl-6-fluoro-2-methyl-3H-benzofuran (460.0 mg, 2.39 mmol) in dichloromethane (20 mL) at 0° C. was slowly added fuming nitric acid (0.5 mL) and stirred for 15 min. The mixture was poured into ice water and the organic layer was separated and dried over hydrous sodium sulfate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:15) as eluting solvents to afford 2-cyclopropyl-6-fluoro-2-methyl-5-nitro-3H-benzofuran (450.0 mg, 75%) as an orange solid. MS (ESI): m/z=238.1 [M+1]⁺.

Step D. 1-(2-Cyclopropyl-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-4-(2,2-difluoroethyl)piperazine

A mixture of 2-cyclopropyl-6-fluoro-2-methyl-5-nitro-3H-benzofuran (220.0 mg, 0.93 mmol), 1-(2,2-difluoroethyl)piperazine dihydrochloride (310.3 mg, 1.39 mmol) and cesium carbonate (906.5 mg, 2.78 mmol) in acetonitrile (5 mL) was stirred at 60° C. overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:2) to afford 1-(2-cyclopropyl-2-methyl-5-nitro-3H-benzofuran-6-yl)-4-(2,2-difluoroethyl)piperazine (300.0 mg, 84%) as a yellow solid. MS (ESI): m/z=368.2 [M+1]⁺.

Step E. 2-Cyclopropyl-6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-amine

A mixture of 1-(2-cyclopropyl-2-methyl-5-nitro-3H-benzofuran-6-yl)-4-(2,2-difluoroethyl)piperazine (150.0 mg, 0.41 mmol) and palladium on carbon (15.0 mg, 10% wt) in methanol (5 mL) was stirred at 25° C. under hydrogen atmosphere for 2 h. After filtration, the filtrate was concentrated under reduced pressure to afford 2-cyclopropyl-6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2-methyl-3H-benzofuran-5-amine (100.0 mg, crude) as a colorless oil, which was used directly to next step without further purification. MS (ESI): m/z=338.3 [M+1]⁺.

Step F. (R)—N-(2-Cyclopropyl-6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-Cyclopropyl-6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 2-cyclopropyl-6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2-methyl-3H-benzofuran-5-amine (240.0 mg, 0.71 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (370.9 mg, 0.71 mmol) and N-ethyl-N-isopropylpropan-2-amine (275.8 mg, 2.13 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 30 min. Pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (116.0 mg, 0.71 mmol) was then added. The resulting mixture was stirred at room temperature overnight. Water and ethyl acetate (30 mL) was added and the organic layer was separated and dried over sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (10:1) and then resolved by chiral pre-HPLC(Column: AS-H 20*250 mm, 5 um (Dacel), Mobile phase: Hexane (0.1% DEA)/Ethanol(0.1% DEA)=80/20) to afford N-[(2R)-2-cyclopropyl-6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-2-cyclopropyl-6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (40 mg, 12%) (55 mg, 16%) as yellow solids with absolute stereochemistry assigned arbitrarily.

Example 159, Peak 1: ¹H NMR (400 MHz, DMSO-d₆): δ 10.38 (s, 1H), 9.35 (d, J=6.8 Hz, 1H), 8.94 (d, J=2.8 Hz, 1H), 8.67 (s, 1H), 8.29 (s, 1H), 7.35 (dd, J=4.0, 6.8 Hz, 1H), 6.68 (s, 1H), 6.19 (tt, J=4.0, 56.0 Hz, 1H), 2.98 (q, J=15.6, 32.0 Hz, 2H), 2.91-2.73 (m, 10H), 1.36 (s, 3H), 1.25-1.16 (m, 1H), 0.46-0.40 (m, 3H) 0.31-0.27 (m, 1H). MS (ESI): m/z=483.3[M+1]⁺.

Example 160, Peak 2: ¹H NMR (400 MHz, DMSO-d₆): δ 10.38 (s, 1H), 9.35 (d, J=6.8 Hz, 1H), 8.94 (d, J=2.8 Hz, 1H), 8.67 (s, 1H), 8.29 (s, 1H), 7.35 (dd, J=4.0, 6.8 Hz, 1H), 6.68 (s, 1H), 6.19 (tt, J=4.0, 56.0 Hz, 1H), 2.98 (q, J=15.6, 32.0 Hz, 2H), 2.91-2.73 (m, 10H), 1.36 (s, 3H), 1.25-1.16 (m, 1H), 0.46-0.40 (m, 3H) 0.31-0.27 (m, 1H). MS (ESI): m/z=483.3[M+1]⁺.

Examples 161 and 162. (R)—N-(2-Cyclopropyl-6-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-Cyclopropyl-6-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. (1-(2,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-4-fluoropiperidin-4-yl)methanol 2,2,2-trifluoroacetic acid salt

A mixture of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (300 mg, 1.29 mmol in trifluoroacetic acid (1 mL) and dichloromethane (2 mL) was stirred 20° C. for 1 h. The mixture was concentration under reduced pressure to afford (4-fluoropiperidin-4-yl)methanol 2,2,2-trifluoroacetic acid salt (300 mg, 1.21 mmol, crude) as a colorless oil, which was used directly to the next step without purification. MS (ESI): m/z=134.1 [M+1]⁺.

Step B. (1-(2-Cyclopropyl-2-methyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-4-fluoropiperidin-4-yl)methanol

A mixture of 2-cyclopropyl-6-fluoro-2-methyl-5-nitro-3H-benzofuran (Examples 159 and 160, step C) (110.0 mg, 0.46 mmol), (4-fluoro-4-piperidyl)methanol and potassium carbonate (192.3 mg, 1.39 mmol) in acetonitrile (5 mL) was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated under vacuum and the residue was purified on silica gel chromatography using ethyl acetate:petroleum ether (1:5) as eluting solvents to afford[1-(2-cyclopropyl-2-methyl-5-nitro-3H-benzofuran-6-yl)-4-fluoro-4-piperidyl]methanol (130.0 mg, 76%) as a yellow solid. MS (ESI): m/z=351.2 [M+1]⁺.

Step F. (1-(5-Amino-2-cyclopropyl-2-methyl-2,3-dihydrobenzofuran-6-yl)-4-fluoropiperidin-4-yl)methanol

A mixture of [1-(2-cyclopropyl-2-methyl-5-nitro-3H-benzofuran-6-yl)-4-fluoro-4-piperidyl]methanol (130.0 mg, 0.37 mmol) and palladium on carbon (13 mg, 10% wt) in methyl alcohol (5 mL) was stirred at 25° C. under hydrogen atmosphere for 1 h. After filtration, the filtrate was concentrated under reduced pressure to afford[1-(5-amino-2-cyclopropyl-2-methyl-3H-benzofuran-6-yl)-4-fluoro-4-piperidyl]methanol (100.0 mg, crude) as a colorless oil, which was used in the next step without further purification. MS (ESI): m/z=321.2 [M+1]⁺.

Step G. (R)—N-(2-Cyclopropyl-6-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-Cyclopropyl-6-(4-fluoro-4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of [1-(5-amino-2-cyclopropyl-2-methyl-3H-benzofuran-6-yl)-4-fluoro-4-piperidyl]methanol (100.0 mg, 0.3100 mmol), pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (56.7 mg, 0.31 mmol), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (162.7 mg, 0.31 mmol) and N-ethyl-N-isopropylpropan-2-amine (121.0 mg, 0.94 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature overnight. Water and ethyl acetate (30 mL) were added and the organic layer was separated. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the mixture was concentrated and purified by silica gel chromatography using ethyl acetate:petroleum ether (10:1) and resolved by chiral preparative HPLC(Column CE-4, Mobile Phase: n-Hexane (0.1% DEA):EtOH (0.1% DEA)=70:30, Flow rate: 50 mL/min) to afford N-[(2S)-2-cyclopropyl-6-[4-fluoro-4-(hydroxymethyl)-1-piperidyl]-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2R)-2-cyclopropyl-6-[4-fluoro-4-(hydroxymethyl)-1-piperidyl]-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (36.0 mg, 25%; 25.0 mg, 17%) as yellow solids with absolute stereochemistry assigned arbitrarily.

Example 161, Peak 1: ¹H NMR (400 MHz, DMSO-d₆): δ 10.41 (s, 1H), 9.36 (dd, J=1.6, 7.2 Hz, 1H), 8.88 (dd, J=1.2, 4.0 Hz, 1H), 8.68 (s, 1H), 8.32 (s, 1H), 7.33 (dd, J=4.0, 7.2 Hz, 1H), 6.68 (s, 1H), 5.15 (t, J=6.0 Hz, 1H), 3.53 (dd, J=6.0, 18.0 Hz, 2H), 2.99 (q, J=16.0, 31.6 Hz, 2H), 2.92-2.78 (m, 4H), 2.15-1.95 (m, 2H), 1.91-1.75 (m, 2H), 1.37 (s, 3H), 1.27-1.16 (m, 1H), 0.46-0.36 (m, 3H) 0.33-0.26 (m, 1H). MS (ESI): m/z=466.2[M+1]⁺.

Example 162, Peak 2: ¹H NMR (400 MHz, DMSO-d₆): δ 10.41 (s, 1H), 9.36 (dd, J=1.6, 7.2 Hz, 1H), 8.88 (dd, J=1.2, 4.0 Hz, 1H), 8.68 (s, 1H), 8.32 (s, 1H), 7.33 (dd, J=4.4, 7.2 Hz, 1H), 6.68 (s, 1H), 5.15 (t, J=6.0 Hz, 1H), 3.52 (dd, J=6.0, 18.0 Hz, 2H), 2.99 (q, J=16.0, 31.6 Hz, 2H), 2.92-2.78 (m, 4H), 2.14-1.94 (m, 2H), 1.91-1.79 (m, 2H), 1.36 (s, 3H), 1.27-1.17 (m, 1H), 0.46-0.36 (m, 3H) 0.33-0.26 (m, 1H). MS (ESI): m/z=466.2[M+1]⁺.

Examples 163 and 164. (R)-6-Chloro-N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)-6-Chloro-N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5a]pyrimidine-3-carboxamide

Step A. 6-Chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A mixture of 5-amino-1H-pyrazole-4-carboxylic acid (100.0 mg, 0.79 mmol) and 2-chloromalonaldehyde (84.0 mg, 0.79 mmol) in acetic acid (1 mL) and 0.3 mL ethanol was stirred for 2 h at 60° C. After filtration, the wet cake was washed with methanol and dried in vacuo to afford 6-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (80 mg, crude) as a white solid, which was used directly to next step without further purification. MS (ESI): m/z=179.9 [M−17]⁺.

Step B. [1-[2-(Hydroxymethyl)-2-methyl-5-nitro-3H-benzofuran-6-yl]-4-piperidyl]methanol

A mixture of (6-fluoro-2-methyl-5-nitro-3H-benzofuran-2-yl)methanol (Intermediate 3) (285 mg, 1.22 mmol) and 4-piperidinylmethanol (211 mg, 1.83 mmol) in acetonitrile (5 mL), was stirred at 20° C. for 2 h. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using ethyl acetate:petroleum ether (from 1:1 to 2:1) as eluting solvents to afford[1-[2-(hydroxymethyl)-2-methyl-5-nitro-3H-benzofuran-6-yl]-4-piperidyl]methanol (360 mg, 91%) as a yellow oil. MS (ESI): m/z=323.1 [M+1]⁺.

Step C. [1-[5-Amino-2-(hydroxymethyl)-2-methyl-3H-benzofuran-6-yl]-4-piperidyl]methanol

A mixture of [1-[2-(hydroxymethyl)-2-methyl-5-nitro-3H-benzofuran-6-yl]-4-piperidyl]methanol (120 mg, 0.37 mmol) and palladium on carbon (20 mg, 10% wt) in methanol (10 mL) was stirred at 20° C. under hydrogen atmosphere for 2 hours. After filtration and concentration under reduced pressure, [1-[5-amino-2-(hydroxymethyl)-2-methyl-3H-benzofuran-6-yl]-4-piperidyl]methanol (87 mg) was afforded as a brown solid, which was used directly to next step without further purification. MS (ESI): m/z=293.2 [M+1]⁺.

Step D. (R)-6-Chloro-N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)-6-Chloro-N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of [1-[5-amino-2-(hydroxymethyl)-2-methyl-3H-benzofuran-6-yl]-4-piperidyl]methanol (87 mg, 0.30 mmol), 6-chloropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (70 mg, 0.36 mmol), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (170 mg, 0.45 mmol) and diisopropylethylamine (115 mg, 0.89 mmol) in N,N-dimethylformamide (5 mL) was stirred at 20° C. for 2 h. The mixture was purified by silica gel chromatography using ethyl acetate:petroleum ether (1:1 to 2:1) as eluting solvents to afford 6-chloro-N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (120 mg, 81%) as a yellow solid. The product was resolved by chiral SFC (SFC-80 (Thar, Waters), AD 20*250 mm, 5 um (Dacel), mobile phase: CO₂/MEOH{0.5% Ammonia (7M methanol)}=60/40) to afford (S)-6-chloro-N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)-6-chloro-N-(2-(hydroxymethyl)-6-(4-(hydroxymethyl)piperidin-1-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (43.1 mg, 72%) (28.9 mg, 48%) as yellow solids with absolute stereochemistry assigned arbitrarily.

Example 163, Peak 1: ¹H NMR (400 MHz, DMSO-d₆): δ 10.39 (s, 1H), 9.81-9.80 (m, 1H), 8.98-8.97 (m, 1H), 8.69 (s, 1H), 8.31 (s, 1H), 6.67 (s, 1H), 5.02 (t, J=5.6 Hz, 1H), 4.64 (t, J=4.8 Hz, 1H), 3.45-3.39 (m, 4H), 3.20-3.17 (m, 1H), 2.91-2.89 (m, 2H), 2.83-2.79 (m, 1H), 2.66-2.60 (m, 2H), 1.67-1.63 (m, 4H), 1.51-1.48 (m, 1H), 1.33 (s, 3H). MS (ESI): m/z=472.2 [M+1]⁺.

Example 164, Peak 2: ¹H NMR (400 MHz, DMSO-d₆): δ 10.39 (s, 1H), 9.81 (d, J=2.0 Hz, 1H), 8.98 (d, J=2.0 Hz, 1H), 8.69 (s, 1H), 8.31 (s, 1H), 6.67 (s, 1H), 5.02 (t, J=5.6 Hz, 1H), 4.64 (t, J=4.8 Hz, 1H), 3.45-3.39 (m, 4H), 3.20-3.17 (m, 1H), 2.91-2.89 (m, 2H), 2.83-2.79 (m, 1H), 2.66-2.60 (m, 2H), 1.67-1.63 (m, 4H), 1.51-1.48 (m, 1H), 1.33 (s, 3H). MS (ESI): m/z=472.2 [M+1]⁺.

TABLE 5
The following examples were made in a manner similar to that for Examples 163 and
164.
Ex.	Name	Structure	NMR, MS
165, 166	(S)-6-Chloro-N-(2- (hydroxymethyl)-2- methyl-6-morpholino- 2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide and (R)-6- Chloro-N-(2- (hydroxymethyl)-2- methyl-6-morpholino- 2,3-dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 165, Peak 1: 1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.87 (d, J = 2.4 Hz, 1H), 8.77 (s, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.43 (s, 1H), 6.68 (s, 1H), 3.97-3.94 (m, 4H), 3.67 (s, 2H), 3.25 (d, J = 16.0 Hz, 1H), 2.94 (d, J = 15.6 Hz, 1H), 2.92-2.89 (m, 4H), 1.46 (s, 3H). MS (ESI): m/z = 444.1 [M + 1]+.
			Example 166, Peak 2: 1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.87 (d, J = 2.4 Hz, 1H), 8.77 (s, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.43 (s, 1H), 6.68 (s, 1H), 3.95-3.93 (m, 4H), 3.67 (s, 2H), 3.25 (d, J = 16.0 Hz, 1H), 2.94 (d, J = 15.2 Hz, 1H), 2.92-2.89 (m, 4H), 1.46 (s, 3H). MS (ESI): m/z = 444.1 [M + 1]+.
167	6-Chloro-N-(2,2- dimethyl-6-(2-oxa-8- azaspiro[4.5]decan-8- yl)-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3) δ 10.30 (s, 1H), 8.86 (d, J = 2.0 Hz, 1H), 8.77 (s, 1H), 8.54 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 6.64 (s, 1H), 3.91 (t, J = 7.2 Hz, 2H), 3.65 (s, 2H), 3.03 (s, 2H), 2.86- 2.84 (m, 4H), 1.85 (t, J = 7.2 Hz, 2H), 1.85-1.81 (m, 4H), 1.48 (s, 6H). MS (ESI): m/z = 482.1 [M + 1]+.
168	N-(6-(4-(2,2- Difluoroethyl)piperazin- 1-yl)-2- (hydroxymethyl)-2- methyl-2,3- dihydrobenzofuran-5- yl)-6- methylpyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.18 (s, 1H), 9.82 (d, J = 2.0 Hz, 1H), 8.96 (d, J = 2.0 Hz, 1H), 8.70 (s, 1H), 8.26 (s, 1H),6.70(s, 1H), 6.20 (tt, J = 56.0, 4.4 Hz, 1H) , 5.05 (t, J = 5.6 Hz, 1H), 3.45-3.41 (m, 2H), 3.20 (d, J = 16.4 Hz, 1H), 2.88-2.78 (m, 11H), 1.33 (s, 3H). LCMS (ESI): m/z = 507.0 [M + H]+.
169 and 170	(S)-6-Chloro-N-(6-(4- (2,2- difluoroethyl)piperazin- 1-yl)-2- (hydroxymethyl)-2- methyl-2,3- dihydrobenzofuran-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide and (R)-6- Chloro-N-(6-(4-(2,2- difluoroethyl)piperazin- 1-yl)-2- (hydroxymethyl)-2-		Example 169 Peak 1: 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.78 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H), 6.68 (s, 1H), 6.15-5.80 (m, 1H), 3.68-3.67 (m, 2H), 3.25-3.23 (m, 1H), 2.95 -2.84 (m, 11H), 1.92 (t, J = 6.4 Hz, 1H), 1.47 (s, 3H). LCMS (ESI): m/z = 507.2 [M + H]+.
	methyl-2,3-
	dihydrobenzofuran-5-
	yl)pyrazolo[1,5-
	a]pyrimidine-3-
	carboxamide (absolute
	stereochemistry
	assigned arbitrarily)
			Example 170 Peak 2: 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 8.88 (d, J = 2.0 Hz, 1H), 8.78 (s, 1H), 8.65 (d, J = 2.0 Hz, 1H), 8.40 (s, 1H), 6.68 (s, 1H), 6.15-5.80 (m, 1H), 3.69- 3.66 (m, 2H), 3.25-3.23 (m, 1H), 2.95-2.84 (m, 11H), 2.00 (t, J = 6.4 Hz, 1H), 1.47 (s, 3H). LCMS (ESI): m/z = 507.2 [M + H]+.

Examples 171 and 172. (R)—N-(2-(Hydroxymethyl)-2-methyl-6-(trifluoromethoxy)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(2-(hydroxymethyl)-2-methyl-6-(trifluoromethoxy)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compounds were made in a manner analogous to Example 70 to give N-(2-(hydroxymethyl)-2-methyl-6-(trifluoromethoxy)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide which was resolved via Chiral SFC to afford N-[(2R)-2-(hydroxymethyl)-2-methyl-6-(trifluoromethoxy)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (73.9 mg, 38.1% yield) and N-[(2S)-2-(hydroxymethyl)-2-methyl-6-(trifluoromethoxy)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (73.4 mg, 37.9% yield) as light yellow solids. Stereochemistry was arbitrarily assigned based on peak elution.

Example 171 peak 1: ¹H NMR (400 MHz, dimethyl sulfoxide-d₆): δ 10.23 (s, 1H), 9.40 (dd, J=1.6, 7.2 Hz, 1H), 8.83 (dd, J=1.6, 4.4 Hz, 1H), 8.72 (s, 1H), 8.28 (s, 1H), 7.34 (dd, J=4.4, 7.2 Hz 1H), 6.86 (s, 1H), 5.11 (t, J=5.6 Hz, 1H), 3.53-3.40 (m, 2H), 3.28 (d, J=16.4 Hz, 1H), 2.92 (d, J=16.4 Hz, 1H), 1.37 (s, 3H). ¹⁹F NMR (400 MHz, DMSO-d₆) δ−57.24 (s, 3F). MS (ESI): m/z=409.1 [M+1]⁺.

Example 172 peak 2: ¹H NMR (400 MHz, dimethyl sulfoxide-d₆): δ 10.23 (s, 1H), 9.40 (dd, J=1.6, 6.8 Hz, 1H), 8.83 (dd, J=1.6, 4.0 Hz, 1H), 8.72 (s, 1H), 8.28 (s, 1H), 7.34 (dd, J=4.0, 6.8 Hz 1H), 6.85 (s, 1H), 5.11 (t, J=5.6 Hz, 1H), 3.53-3.40 (m, 2H), 3.28 (d, J=16.4 Hz, 1H), 2.92 (d, J=16.4 Hz, 1H), 1.37 (s, 3H). ¹⁹F NMR (400 MHz, DMSO-d₆) δ−57.24 (s, 3F). MS (ESI): m/z=409.1 [M+1]⁺.

Example 173. N-[6-Morpholino-1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 6-Chloro-5-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one

To methyl 2-(bromomethyl)-5-chloro-4-nitro-benzoate (preparation 5, WO 2013079505 (150 mg, 0.49 mmol) in methanol (5 ml) was added triethylamine (0.081 ml, 0.58 mmol) and 2,2,2-trifluoroethylamine (0.047 ml, 0.58 mmol). The reaction was heated to 70° C. for 18 h, concentrated and purified by silica gel chromatography (eluting gradient 0-20% methanol:dichloromethane) to afford 6-chloro-5-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one (90 mg, 63%). LCMS (ESI) m/z:295.0 [M+H]⁺.

Step B. 6-Morpholino-5-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one

A solution of 6-chloro-5-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one (90 mg, 0.31 mmol), morpholine (0.032 ml, 0.37 mmol), N,N-diisopropylethylamine (0.100 ml, 0.61 mmol) in dimethyl sulfoxide (1.5 ml) was heated at 80° C. for 18 h. The reaction was cooled to rt then diluted with water and extracted with isopropyl acetate (3×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product purified by silica gel chromatography (eluting gradient 0-20% methanol:dichloromethane) to afford 6-morpholino-5-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one (87 mg, 82%). LCMS (ESI) m/z:346.0 [M+H]⁺.

Step C. 5-Amino-6-morpholino-2-(2,2,2-trifluoroethyl)isoindolin-1-one

To solution of 6-morpholino-5-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one (60 mg, 0.17 mmol) in ethanol (3.5 ml) and water (1.0 ml) was added iron (48 mg, 0.87 mmol) and ammonium chloride (37 mg, 0.69 mmol). The reaction mixture was heated to 50° C. for 6 h. The reaction mixture was cooled to rt then filtered through celite and concentrated. The crude product was purified by silica gel chromatography (eluting gradient 0-20% methanol:dichloromethane) to afford 5-amino-6-morpholino-2-(2,2,2-trifluoroethyl)isoindolin-1-one (40 mg, 73%). LCMS (ESI) m/z:316.0 [M+H]+.

Step D. N-[6-morpholino-1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 5-amino-6-morpholino-2-(2,2,2-trifluoroethyl)isoindolin-1-one (50 mg, 0.16 mmol) and pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (60 mg, 0.32 mmol) in 1,2-dichloroethane (2.00 ml) was added triethylamine (0.090 ml, 0.63 mmol). The reaction mixture was stirred at 70° C. for 18 h. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was dried with sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (eluting gradient 0-20% methanol:dichloromethane) followed by reverse-phase HPLC to afford N-[6-morpholino-1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (14 mg, 19%). ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.94 (s, 1H), 9.43 (dd, J=7.0, 1.5 Hz, 1H), 9.01 (dd, J=4.3, 1.6 Hz, 1H), 8.80 (s, 1H), 8.77 (s, 1H), 7.66 (s, 1H), 7.40 (dd, J=7.0, 4.2 Hz, 1H), 4.62 (s, 2H), 4.38 (q, J=9.7 Hz, 2H), 3.90 (t, J=4.4 Hz, 4H), 2.93 (t, J=4.5 Hz, 4H). LCMS (ESI) m/z: 461.1 [M+H]+.

TABLE 6
The following examples were made in a manner similar to that for Example 173:
Ex.	Name	Structure	NMR, MS
174	N-[2-(2,2- difluoroethyl)-6- morpholino-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.93 (s, 1H), 9.43 (dd, J = 7.0, 1.6 Hz, 1H), 9.01 (dd, J = 4.2, 1.6 Hz, 1H), 8.77 (d, J = 2.9 Hz, 2H), 7.63 (s, 1H), 7.40 (dd, J = 7.0, 4.2 Hz, 1H), 6.29 (tt, J = 55.2,3.6 Hz, 1H), 4.58 (s, 2H), 4.09-3.76 (m, 6H), 3.01-2.84 (m, 4H). LCMS (ESI) m/z: 443.1 [M + H]+.
175	N-[2-(3- hydroxy-3- methyl-butyl)-6- morpholino-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.89 (s, 1H), 9.41 (dd, J = 7.0, 1.6 Hz, 1H), 9.00 (dd, J = 4.2, 1.6 Hz, 1H), 8.75 (d, J = 2.4 Hz, 2H), 7.56 (s, 1H), 7.39 (dd, J = 7.0, 4.2 Hz, 1H), 4.46 (s, 2H), 4.34 (s, 1H), 3.94-3.86 (m, 4H), 3.64- 3.54 (m, 2H), 2.96-2.87 (m, 4H), 1.73-1.63 (m, 2H), 1.15 (s, 6H). LCMS (ESI) m/z: 465.2 [M + H]+.
176	N-[2-(2- hydroxy-2- methyl-propyl)- 6-morpholino-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.90 (s, 1H), 9.42 (dd, J = 7.0, 1.6 Hz, 1H), 9.01 (dd, J = 4.2, 1.6 Hz, 1H), 8.77 (s, 1H), 8.74 (s, 1H), 7.59 (s, 1H), 7.39 (dd, J = 7.0, 4.2 Hz, 1H), 4.69 (s, 1H), 4.64 (s, 2H), 3.94-3.85 (m, 4H), 3.47-3.41 (m, 2H), 2.96- 2.86 (m, 4H), 1.11 (s, 6H). LCMS (ESI) m/z: 451.2 [M + H]+
177	N-[6-[4-(2- amino-2-oxo- ethyl)piperazin- 1-yl]-1-oxo-2- tetrahydropyran- 4-yl-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 10.89 (s, 1H), 9.40 (dd, J = 7.0, 1.6 Hz, 1H), 9.03 (dd, J = 4.2, 1.6 Hz, 1H), 8.78 (s, 1H), 8.75 (s, 1H), 7.58 (s, 1H), 7.39 (dd, J = 7.0, 4.2 Hz, 1H), 7.29 (s, 1H), 7.19 (s, 1H), 4.47 (s, 2H), 4.32-4.19 (m, 1H), 4.01-3.91 (m, 2H), 3.50-3.41 (m, 2H), 3.06 (s, 2H), 2.95 (dd, J = 5.5, 3.5 Hz, 4H), 2.83-2.75 (m, 4H), 1.83 (qd, J = 12.3, 4.5 Hz, 2H), 1.71-1.61 (m, 2H).
			LCMS (ESI) m/z: 519.2
			[M + H]+
178	N-[2-(2- methoxyethyl)- 6-morpholino-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 10.89 (s, 1H), 9.41 (dd, J = 7.0,1.6 Hz, 1H), 9.00 (dd, J = 4.2, 1.6 Hz, 1H), 8.75 (d, J = 3.3 Hz, 2H), 7.58 (d, J = 0.5 Hz, 1H), 7.39 (dd, J = 7.0, 4.2 Hz, 1H), 4.53-4.47 (m, 2H), 3.93-3.87 (m, 4H), 3.70-3.64 (m, 2H), 3.56 (td, J = 5.4, 0.7 Hz, 2H), 3.27 (s, 3H), 2.95-2.88 (m, 4H). LCMS (ESI) m/z: 437.2 [M + H]+
179	N-[2-(2- hydroxyethyl)-6- morpholino-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		LCMS (ESI) m/z: 423.1 [M + H]+
180	N-[2-(1-methyl- 4-piperidyl)-6- morpholino-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 10.90 (s, 1H), 9.41 (dd, J = 7.0, 1.6 Hz, 1H), 9.00 (dd, J = 4.2, 1.6 Hz, 1H), 8.76 (d, J = 2.8 Hz, 2H), 7.57 (s, 1H), 7.39 (dd, J = 7.0, 4.3 Hz, 1H), 4.45 (s, 2H), 4.03-3.86 (m, 5H), 2.96-2.82 (m, 6H), 2.19 (s, 3H), 2.00 (td, J = 11.9, 2.3 Hz, 2H), 1.81 (qd, J = 12.2, 3.8 Hz, 2H), 1.72- 1.60 (m, 2H). LCMS (ESI) m/z: 476.2 [M + H]+
181	N-[2-(4- hydroxycyclo- hexyl)-6- morpholino-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 10.89 (s, 1H), 9.41 (dd, J = 7.0, 1.6 Hz, 1H), 8.99 (dd, J = 4.3, 1.7 Hz, 1H), 8.75 (d, J = 1.3 Hz, 2H), 7.56 (s, 1H), 7.38 (dd, J = 7.0, 4.2 Hz, 1H), 4.62 (d, J = 4.4 Hz, 1H), 4.41 (s, 2H), 4.03-3.85 (m, 5H), 3.42 (dd, J = 10.5, 4.7 Hz, 1H), 2.94-2.86 (m, 4H), 1.91 (d, J = 13.5 Hz, 2H), 1.77-1.55 (m, 4H), 1.39- 1.25 (m, 2H). LCMS (ESI) m/z: 477.2 [M + H]+

TABLE 7
The following examples were made in a manner similar to that for Example 4:
Ex.	Name	Structure	NMR, MS
182	N-[2,2-dimethyl- 6-[(1S,5R)-6- (methylcarba- moyl)-3- azabicyclo[3.1.0] hexan-3-yl]-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 9.58 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 8.90 (dd, J = 4.3, 1.7 Hz, 1H), 8.67 (s, 1H), 8.01 (d, J = 0.9 Hz, 1H),7.73 (d, J = 4.7 Hz, 1H), 7.34 (dd, J = 7.0,4.3 Hz, 1H), 6.60 (s, 1H), 3.43-3.38 (m, 2H), 3.12- 3.05 (m, 2H), 3.00-2.93 (m, 2H), 2.58 (d, J = 4.6 Hz, 3H), 2.17 (t, J = 3.0 Hz, 1H), 1.94- 1.87 (m, 2H), 1.40 (s, 6H). LCMS (ESI) m/z: 447.2 [M + H]+.
183	N-[2,2-dimethyl- 6-[4-2- (methylamino)- 2-oxo-ethyl]-1- piperidyl]-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.44 (s, 1H), 9.37 (dd, J = 7.0, 1.6 Hz, 1H), 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.32 (d, J = 1.0 Hz, 1H), 7.78 (d, J = 4.8 Hz, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 6.68 (s, 1H), 3.02-2.96 (m, 2H), 2.94-2.84 (m, 2H), 2.69- 2.56 (m, 5H), 2.11 (d, J = 6.9 Hz, 2H), 1.81 (s, 1H), 1.69 (d, J = 12.1 Hz, 2H), 1.62- 1.48 (m, 2H), 1.41 (s, 6H). LCMS (ESI) m/z: 463.3 [M + H]+.
184	N-[6-(4- carbamoyl-4- methyl-1- piperidyl)-2,2- dimethyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.43 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 8.90 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.32 (d, J = 1.0 Hz, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 7.18 (s, 1H), 6.90 (s, 1H), 6.63 (s, 1H), 3.02-2.96 (m, 2H), 2.87-2.76 (m, 2H), 2.73-2.62 (m, 2H), 2.21 (m, 2H), 1.67-1.56 (m, 2H), 1.41 (s, 6H), 1.21 (s, 3H). LCMS (ESI) m/z: 449.2 [M + H]+.
185	N-[6-(4- hydroxyazepan- 1-yl)-2,2- dimethyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.45 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.93 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.26 (d, J = 1.0 Hz, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 6.64 (s, 1H), 4.54 (d, J = 3.7 Hz, 1H), 3.98-3.87 (m, 1H), 3.03-2.80 (m, 6H), 2.04 (m, 1H), 1.99-1.80 (m, 3H), 1.80-1.57 (m, 2H), 1.40 (s, 6H). LCMS (ESI) m/z: 422.2 [M + H]+.
186	N-[6-[(1S,5R)-6- carbamoyl-3- azabicyclo[3.1.0] hexan-3-yl]-2,2- dimethyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 9.58 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.98 (dd, J = 4.3, 1.7 Hz, 1H), 8.68 (s, 1H), 8.01 (d, J = 1.0 Hz, 1H), 7.39- 7.29 (m, 2H), 6.78 (s, 1H), 6.60 (s, 1H), 3.44-3.38 (m, 2H), 3.11-3.03 (m, 2H), 2.97 (d, J = 1.1 Hz, 2H), 2.20 (t, J = 3.0 Hz, 1H), 1.90 m, 2H), 1.41 (s, 6H). LCMS (ESI) m/z: 433.2 [M + H]+.
187	N-[6-[4-(2- amino-2-oxo- ethyl)piperazin- 1-yl]-2,2- dimethyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.42 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.97 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.33 (s, 1H), 7.35 (dd, J = 7.0, 4.2 Hz, 1H), 7.19 (d, J = 29.3 Hz, 2H), 6.68 (s, 1H), 3.01 (m, 4H), 2.85 (m, 4H), 2.73 (m, 4H), 1.41 (s, 6H). LCMS (ESI) m/z: 450.2 [M + H]+.
188	N-[2,2-dimethyl- 6-[3-(3- methylimidazol- 4-yl)pyrrolidin- 1-yl]-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.00 (s, 1H), 9.35 (dd, J = 7.0, 1.6 Hz, 1H), 8.82 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.00 (d, J = 1.0 Hz, 1H), 7.48 (dd, J = 1.1, 0.5 Hz, 1H), 7.30 (dd, J = 7.0, 4.2 Hz, 1H), 6.74 (t, J = 0.9 Hz, 1H), 6.63 (s, 1H), 3.55 (s, 3H), 3.53- 3.43 (m, 2H), 3.16-3.05 (m, 2H), 3.03-2.94 (m, 2H), 2.39 (m, 1H), 2.02-1.89 (m, 1H), 1.41 (s, 6H). LCMS (ESI) m/z: 458.2 [M + H]+.
189	N-[6-(5,7- dihydropyrrolo[3, 4-b]pyridin-6- yl)-2,2-dimethyl- 3H-benzofuran- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.38 (s, 1H), 9.29 (dd, J = 7.0, 1.6 Hz, 1H), 8.67 (s, 1H), 8.45 (ddt, J = 5.0, 1.4, 0.7 Hz, 1H), 8.14 (d, J = 1.0 Hz, 1H), 7.83 (dd, J = 4.2, 1.7 Hz, 1H), 7.76-7.72 (m, 1H), 7.36- 7.27 (m, 1H), 7.16 (dd, J = 7.0, 4.2 Hz, 1H), 6.91 (s, 1H), 4.52 (s, 2H), 4.48 (s, 2H), 3.02 (s, 2H), 1.43 (s, 6H). LCMS (ESI) m/z: 427.2 [M + H]+.
190	N-[2,2-dimethyl- 6-[3-(1H- pyrazol-5-yl)-1- piperidyl]-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 12.40 (s, 1H), 10.53 (s, 1H), 9.37 (dd, J = 7.0,1.6 Hz, 1H), 8.89 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (s, 1H), 8.33 (s, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 6.70 (s, 1H), 6.04 (s, 1H), 3.12 (m, 1H), 3.00 (s, 2H), 2.93 (m, 1H), 2.67 (s, 2H), 2.16 (m, 1H), 2.05-1.89 (m, 1H), 1.87-1.76 (m, 1H), 1.52 (m, 1H), 1.41 (d, J = 3.2 Hz, 6H). LCMS (ESI) m/z: 458.2 [M + H]+.
191	N-[6- (1,3,3a,4,6,6a- hexahydrofuro[3, 4-c]pyrrol-5-yl)- 2,2-dimethyl- 3H-benzofuran- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.02 (s, 1H), 9.37 (dd, J = 7.0, 1.6 Hz, 1H), 8.85 (dd, J = 4.2, 1.6 Hz, 1H), 8.69 (s, 1H), 8.15 (d, J = 1.0 Hz, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 6.67 (s, 1H), 3.83-3.76 (m, 2H), 3.60-3.53 (m, 2H), 3.15-3.08 (m, 2H), 3.02- 2.98 (m, 2H), 2.96-2.87 (m, 2H), 2.73 (dd, J = 9.2, 3.1 Hz, 2H), 1.42 (s, 6H). LCMS (ESI) m/z: 420.2 [M + H]+.
192	N-[2,2-dimethyl- 6-[3-(1H- pyrazol-3- yl)pyrrolidin-1- yl]-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 12.52 (d, J = 70.2 Hz, 1H), 10.04 (s, 1H), 9.35 (dd, J = 7.0,1.6 Hz, 1H), 8.77 (s, 1H), 8.67 (s, 1H), 8.01 (s, 1H), 7.58 (s, 1H), 7.30 (dd, J = 7.0, 4.2 Hz, 1H), 6.60 (s, 1H), 6.13 (s, 1H), 3.68-3.51 (m, 1H), 3.48-3.40 (m, 1H), 3.30-3.22 (m, 1H), 3.20- 3.07 (m, 2H), 2.98 (s, 2H), 2.35 (m, 1H), 2.07 (m, 1H), 1.41 (s, 6H). LCMS (ESI) m/z: 444.2 [M + H]+.
193	N-[6-(5,5- difluoro-2- azabicyclo[2.2.1] heptan-2-yl)-2,2- dimethyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 9.82 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 7.91 (d, J = 1.1 Hz, 1H), 7.32 (dd, J = 7.0, 4.2 Hz, 1H), 6.48 (s, 1H), 3.93 (s, 1H), 3.39-3.34 (m, 1H), 3.17-3.08 (m, 1H), 2.97 (d, J = 1.1 Hz, 2H), 2.81 (s, 1H), 2.35-2.19 (m, 1H), 2.06 (d, J = 11.4 Hz, 2H), 1.88 (d, J = 10.5 Hz, 1H), 1.41 (s, 6H). LCMS (ESI) m/z: 440.2 [M + H]+.
194	N-[2,2-dimethyl- 6-(6-oxa-2- azaspiro[3.5] nonan-2-yl)-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 9.37 (dd, J = 7.0,1.6 Hz, 1H), 9.25 (s, 1H), 8.87 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 7.58 (d, J = 1.0 Hz, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 6.15 (s, 1H), 3.67 (s, 2H), 3.60 (d, J = 7.1 Hz, 2H), 3.49-3.40 (m, 4H), 2.93 (d, J = 1.0 Hz, 2H), 1.74 (t, J = 6.0 Hz, 2H), 1.40 (s, 8H). LCMS (ESI) m/z: 434.2 [M + H]+.
195	N-[2,2-dimethyl- 6-[3- (trifluoromethyl) pyrrolidin-1-yl]- 3H-benzofuran- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.03 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.83 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.12 (d, J = 1.0 Hz, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 6.66 (s, 1H), 3.42-3.34 (m, 1H), 3.14-3.01 (m, 3H), 2.99 (d, J = 1.1 Hz, 2H), 2.24 (m, 1H), 2.02 (m, 1H), 1.41 (d, J = 1.0 Hz, 6H). LCMS (ESI) m/z: 446.2 [M + H]+.
196	N-(6-(3,3- difluoropiperidin- 1-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.35 (s, 1H), 9.35 (dd, J = 7.0, 1.6 Hz, 1H), 8.78 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.39-8.18 (m, 1H), 7.32 (dd, J = 7.0, 4.2 Hz, 1H), 6.73 (s, 1H), 3.23-3.09 (m, 2H), 3.06-2.88 (m, 2H), 2.80-2.66 (m, 2H), 2.17- 1.95 (m, 2H), 1.95-1.79 (m, 2H), 1.41 (s, 6H). (ESI): m/z = 428.2 [M + 1]+.
197	N-(6-((3aR,6aS)- 5,5- difluorohexahy- drocyclopenta[c] pyrrol-2(1H)-yl)- 2,2-dimethyl- 2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 9.83 (s, 1H), 9.37 (dd, J = 7.0, 1.6 Hz, 1H), 8.78 (dd, J = 4.2, 1.5 Hz, 1H), 8.69 (s, 1H), 7.95 (s, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 6.62 (s, 1H), 3.12-3.01 (m, 2H), 2.99 (s, 2H), 2.84 (d, J = 7.8 Hz, 4H), 2.32-2.14 (m, 2H), 2.10- 1.83 (m, 2H), 1.42 (s, 6H). (ESI): m/z = 454.2 [M + 1]+.
198	N-(6-(2- (methoxymethyl) morpholino)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.41 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.89 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.30 (s, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 6.69 (s, 1H), 4.02-3.77 (m, 3H), 3.45-3.27 (m, 2H), 3.17 (s, 3H), 3.00 (s, 2H), 2.91-2.70 (m, 3H), 2.60-2.51 (m, 1H), 1.41 (s, 6H). (ESI): m/z = 438.2 [M + 1]+.
199	N-(6-(6,6- difluoro-3- azabicyclo[3.2.0] heptan-3-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 9.58 (s, 1H), 9.35 (dd, J = 7.0, 1.7 Hz, 1H), 8.75 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (s, 1H), 7.83 (s, 1H), 7.31 (dd, J = 7.0, 4.2 Hz, 1H), 6.67 (s, 1H), 3.44-3.20 (m, 3H), 3.17 (d, J = 9.0 Hz, 1H), 2.99 (s, 2H), 2.84 (dd, J = 10.4, 7.6 Hz, 1H), 2.79-2.53 (m, 3H), 1.42 (s, 6H). (ESI): m/z = 440.2 [M + 1]+.
200	N-(6-((3aR,6aS)- 4,4- difluorohexahy- drocyclopenta[c] pyrrol-2(1H)-yl)- 2,2-dimethyl- 2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 9.78 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.83 (dd, J = 4.3, 1.6 Hz, 1H), 8.68 (s, 1H), 7.93 (s, 1H), 7.31 (dd, J = 7.0, 4.2 Hz, 1H), 6.64 (s, 1H), 3.14 (t, J = 8.0 Hz, 1H), 3.10- 3.01 (m, 2H), 2.99 (s, 2H), 2.95-2.77 (m, 4H), 2.47- 2.20 (m, 1H), 2.10-1.91 (m, 1H), 1.91-1.75 (m, 1H), 1.68-1.50 (m, 1H), 1.41 (s, 6H). (ESI): m/z = 454.2 [M + 1]+.
201	N-(6-(2- (hydroxymethyl) pyrrolidin-1-yl)- 2,2-dimethyl- 2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.54 (s, 1H), 9.35 (dd, J = 7.0, 1.6 Hz, 1H), 8.82 (dd, J = 4.2, 1.7 Hz, 1H), 8.66 (s, 1H), 8.27 (d, J = 1.0 Hz, 1H), 7.30 (dd, J = 7.0, 4.2 Hz, 1H), 6.76 (s, 1H), 4.33 (t, J = 5.5 Hz, 1H), 3.55-3.39 (m, 1H), 3.39-3.10 (m, 3H), 3.00 (s, 2H), 2.77-2.60 (m, 1H), 2.26-2.05 (m, 1H), 2.05- 1.74 (m, 2H), 1.41 (s, 6H). (ESI): m/z = 408.2 [M + 1]+.
202	N-(6-(3-(1H- imidazol-2- yl)piperidin-1- yl)-2,2-dimethyl- 2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 11.67 (s, 1H), 10.56 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.90 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.36 (s, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 6.92 (s, 1H), 6.70 (s, 1H), 3.36-3.23 (m, 1H), 3.16 (d, J = 11.7 Hz, 1H), 3.00 (s, 2H), 2.92 (d, J = 11.3 Hz, 1H), 2.78 (t, J = 11.0 Hz, 1H), 2.65 (td, J = 11.4, 2.6 Hz, 1H), 2.18 (d, J = 11.9 Hz, 1H), 1.96 (d, J = 11.9 Hz, 1H), 1.83 (s, 1H), 1.72-1.57 (m, 1H), 1.41 (d, J = 3.7 Hz, 6H). (ESI): m/z = 458.2 [M + 1]+.
203	N-(6-((3R,4S)- 3,4- difluoropyrrolidin- 1-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 9.92 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 8.84 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 7.95 (s, 1H), 7.32 (dd, J = 7.0, 4.2 Hz, 1H), 6.59 (s, 1H), 5.52-5.36 (m, 1H), 5.36- 5.18 (m, 1H), 3.67-3.46 (m, 2H), 3.31 (s, 2H), 2.98 (s, 2H), 1.41 (s, 6H). (ESI): m/z = 414.2 [M + 1]+.
204	N-(6-(5,5- difluoro-2- azaspiro[3.3]hep- tan-2-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 9.37 (dd, J = 7.0, 1.6 Hz, 1H), 9.22 (s, 1H), 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (s, 1H), 7.46 (s, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 6.15 (s, 1H), 4.07 (d, J = 8.1 Hz, 2H), 3.68 (d, J = 8.0 Hz, 2H), 2.93 (s, 2H), 2.48-2.31 (m, 2H), 1.93 (t, J = 8.5 Hz, 2H). (ESI): m/z = 440.2 [M + 1]+.
205	N-(6-((4- cyanobenzyl) (methyl)amino)- 2,2-dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.47 (s, 1H), 9.37 (dd, J = 7.0, 1.7 Hz, 1H), 8.77 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.30-8.14 (m, 1H), 7.87-7.70 (m, 2H), 7.67 (d, J = 8.3 Hz, 2H), 7.34 (dd, J = 7.0,4.2 Hz, 1H), 6.77 (s, 1H), 4.23 (s, 2H), 2.98 (s, 2H), 2.56 (s, 3H), 1.40 (s, 6H). (ESI): m/z = 453.2 [M + 1]+.
206	N-(6-(4-(1H- imidazol-1- yl)piperidin-1- yl)-2,2-dimethyl- 2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.30 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.81 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.24 (s, 1H), 7.85-7.66 (m, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 7.28 (t, J = 1.3 Hz, 1H), 6.95 (t, J = 1.1 Hz, 1H), 6.71 (s, 1H), 4.33-4.11 (m, 1H), 3.07 (d, J = 11.8 Hz, 2H), 3.01 (s, 2H), 2.93-2.74 (m, 2H), 2.25-2.04 (m, 4H), 1.42 (s, 6H). (ESI): m/z = 458.2 [M + 1]+.
207	N-(6-(4,4- difluoroazepan- 1-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.42 (s, 1H), 9.38 (dd, J = 7.0, 1.6 Hz, 1H), 8.75 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (s, 1H), 8.29 (s, 1H), 7.37 (dd, J = 7.0, 4.2 Hz, 1H), 6.73 (s, 1H), 3.11-3.02 (m, 2H), 2.99 (s, 2H), 2.97-2.90 (m, 2H), 2.55-2.40 (m, 2H), 2.39-2.20 (m, 2H), 1.90- 1.78 (m, 2H), 1.41 (s, 6H). (ESI): m/z = 442.2 [M + 1]+.
208	N-(6- ((1R,5S,6r)-6- carbamoyl-3- azabicyclo[3.1.0] hexan-3-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 9.58 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.01 (s, 1H), 7.37-7.29 (m, 2H), 6.78 (s, 1H), 6.60 (s, IH), 3.41 (d, J = 9.3 Hz, 2H), 3.08 (d, J = 9.3 Hz, 1H), 2.97 (s, 2H), 2.20 (t, J = 3.0 Hz, 1H), 1.92-1.87 (m, 2H), 1.41 (s, 6H). (ESI): m/z = 433.2 [M + 1]+.
209	N-(6-(4- hydroxyazepan- 1-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.45 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 8.93 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.26 (s, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 6.64 (s, 1H), 4.54 (d, J = 3.7 Hz, 1H), 3.98-3.86 (m, 1H), 3.05- 2.89 (m, 4H), 2.89-2.78 (m, 1H), 2.10-1.99 (m, 1H), 1.98-1.81 (m, 2H), 1.81- 1.65 (m, 1H), 1.64 (s, 1H), 1.40 (d, J = 1.5 Hz, 6H). (ESI): m/z = 422.2 [M + 1]+.
210	N-(6-(4- carbamoyl-4- methylpiperidin- 1-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.43 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 8.89 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.32 (s, 1H), 7.33 (dd, J = 7.0, 4.1 Hz, 1H), 7.18 (s, 1H), 6.89 (s, 1H), 6.63 (s, 1H), 2.99 (s, 2H), 2.87-2.76 (m, 2H), 2.72-2.62 (m, 2H), 2.26-2.16 (m, 2H), 1.67- 1.56 (m, 2H), 1.41 (s, 6H), 1.21 (s, 3H). (ESI): m/z = 449.2 [M + 1]+.
211	N-(2,2-dimethyl- 6-(4-(2- (methylamino)- 2- oxoethyl)piperidin- 1-yl)-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.43 (s, 1H), 9.37 (dd, J = 7.0, 1.7 Hz, 1H), 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.38-8.26 (m, 1H), 7.78 (q, J = 5.5, 5.0 Hz, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 6.68 (s, 1H), 2.99 (s, 2H), 2.93-2.84 (m, 2H), 2.69- 2.60 (m, 2H), 2.58 (d, J = 4.6 Hz, 3H), 2.11 (d, J = 7.0 Hz, 2H), 1.88-1.73 (m, 1H), 1.69 (d, J = 12.6 Hz, 2H), 1.62-1.48 (m, 2H), 1.40 (s, 6H). (ESI): m/z = 463.3 [M + 1]+.
212	N-(2,2-dimethyl- 6-((1R,5S,6r)-6- (methylcarba- moyl)-3- azabicyclo[3.1.0] hexan-3-yl)-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 9.58 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.90 (dd, J = 4.3, 1.7 Hz, 1H), 8.67 (s, 1H), 8.08-7.90 (m, 1H), 7.73 (q, J = 4.5 Hz, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 6.60 (s, 1H), 3.40 (d, J = 9.2 Hz, 2H), 3.08 (d, J = 9.1 Hz, 2H), 2.97 (s, 2H), 2.58 (d, J = 4.6 Hz, 3H), 2.17 (t, J = 3.0 Hz, 1H), 1.97- 1.84 (m, 2H), 1.40 (s, 6H). (ESI): m/z = 447.2 [M + 1]+.
213	N-(2,2-dimethyl- 6-(3-oxo-2,8- diazaspiro[4.5] decan-8-yl)-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3-		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.46 (s, 1H), 9.35 (dd, J = 7.0, 1.6 Hz, 1H), 8.84 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.34-8.28 (m, 1H), 7.58 (s, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 6.73 (s, 1H), 3.21-3.12 (m, 2H), 3.04- 2.95 (m, 2H), 2.84-2.70 (m, 4H), 2.17 (s, 2H), 1.80 (d, J = 6.4 Hz, 4H), 1.41 (s, 6H). (ESI): m/z = 461.2 [M + 1]+.
214	N-(2,2-dimethyl- 6-(pyrrolidin-1- yl)-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.13 (s, 1H), 9.37 (dd, J = 7.0, 1.6 Hz, 1H), 8.85 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (s, 1H), 8.08 (s, 1H), 7.31 (dd, J = 7.0, 4.2 Hz, 1H), 6.59 (s, 1H), 3.00 (m, 4H), 2.98 (s, 2H), 1.98- 1.86 (m, 4H), 1.41 (s, 6H). MS (ESI): m/z = 378.2 [M + 1]+.
215	N-(6-(6- (hydroxymethyl)- 3- azabicyclo[3.1.0] hexan-3-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 9.69 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 8.98 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.12 (d, J = 1.0 Hz, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 6.63 (s, 1H), 4.54 (s, 1H), 3.33 (m, 2H), 3.26 (d, J = 8.7 Hz, 2H), 2.99-2.95 (m, 2H), 2.97 (s, 2H), 1.92 (m, 1H), 1.42 (m, 2H), 1.40 (s, 6H). MS (ESI): m/z = 420.2 [M + 1]+.
216	N-(6-(4- cyanopiperidin- 1-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.37 (s, 1H), 9.38 (dd, J = 7.0, 1.6 Hz, 1H), 8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.69 (s, 1H), 8.32 (d, J = 1.2 Hz, 1H), 7.38 (dd, J = 7.0, 4.2 Hz, 1H), 6.66 (s, 1H), 3.09 (m, 1H), 3.00 (s, 2H), 2.90 (m, 2H), 2.77 (m, 2H), 2.12 (m, 2H), 1.99 (m, 2H), 1.41 (s, 6H). MS (ESI): m/z = 417.2 [M + 1]+.
217	N-(6-(3,3- difluoropyrrolidin- 1-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.24 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.79 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.22 (d, J = 1.0 Hz, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 6.73 (s, 1H), 3.48 (t, J = 13.1 Hz, 2H), 3.25-3.14 (m, 2H), 3.00 (s, 2H), 2.49 (m, 2H), 1.41 (s, 6H). MS (ESI): m/z = 414.1 [M + 1]+.
218	N-(2,2-dimethyl- 6-(4- (trifluoromethyl) piperidin-1-yl)- 2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.34 (s, 1H), 9.37 (dd, J = 7.0, 1.6 Hz, 1H), 8.72 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.31 (d, J = 1.0 Hz, 1H), 7.38 (dd, J = 7.0, 4.2 Hz, 1H), 6.66 (s, 1H), 3.05-2.95 (m, 5H), 2.72 (m, 2H), 1.98- 1.77 (m, 4H), 1.41 (s, 6H). MS (ESI): m/z = 460.2 [M + 1]+.
219	N-(6-(4- isobutyrylpiper- azin-1-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.48 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.87 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.32 (d, J = 1.0 Hz, 1H), 7.32 (dd, J = 7.0, 4.2 Hz, 1H), 6.70 (s, 1H), 3.73 (s, 4H), 3.00 (s, 2H), 2.91 (p, J = 6.7 Hz, 1H), 2.78 (m, 4H), 1.41 (s, 6H), 1.03 (d, J = 6.7 Hz, 6H). MS (ESI): m/z = 463.2 [M + 1]+.
220	N-(6-(4-acetyl- 1,4-diazepan-1- yl)-2,2-dimethyl- 2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.39 (s, 1H), 9.36 (dt, J = 7.0, 1.5 Hz, 1H), 8.87 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (d, J = 1.5 Hz, 1H), 8.33-8.19 (m, 1H), 7.32 (ddd, J = 7.0, 4.2, 1.1 Hz, 1H), 6.67 (d, J = 20.9 Hz, 1H), 3.76-3.59 (m, 4H), 3.06-2.98 (m, 3H), 2.94 (m, 3H), 1.99 (m, 5H), 1.41 (s, 6H). MS (ESI): m/z = 449.2 [M + 1]+.
221	N-(2,2-dimethyl- 6-(3-oxo-2,8- diazaspiro[4.5] decan-8-yl)-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 10.46 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.84 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.32 (s, 1H), 7.67-7.51 (m, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 6.73 (s, 1H), 3.17 (s, 2H), 3.05-2.95 (s, 2H), 2.84- 2.70 (m, 4H), 2.18 (s, 2H), 1.80 (m, 4H), 1.41 (s, 6H). MS (ESI): m/z = 461.2 [M + 1]+.
222 and 223	(R)-N-(2,2- dimethyl-6-(2- oxa-7- azaspiro[4.4]no- nan-7-yl)-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide and (S)-N-(2,2- dimethyl-6-(2- oxa-7- azaspiro[4.4] nonan-7-yl)-2,3- dihydrobenzo-		Example 222 Peak 1: 1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 9.80 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.83 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 7.98 (d, J = 1.1 Hz, 1H), 7.32 (dd, J = 7.0, 4.2 Hz, 1H), 6.56 (s, 1H), 3.82- 3.70 (m, 2H), 3.70-3.57 (m, 2H), 3.19-3.06 (m, 2H), 3.05 (s, 2H), 2.97 (d, J = 1.3 Hz, 2H), 2.05-1.87 (m, 4H), 1.41 (s, 6H). MS (ESI): m/z = 434 [M + 1]+.
	furan-5-
	yl)pyrazolo[1,5-
	a]pyrimidine-3-
	carboxamide
	(stereochemistry
	assigned
	arbitrarily)
			Example 223, Peak 2: 1H NMR (400 MHz, dimethyl sulfoxide- d6) δ 9.80 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.83 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 7.98 (t, J = 0.9 Hz, 1H), 7.32 (dd, J = 7.0, 4.2 Hz, 1H), 6.56 (s, 1H), 3.82- 3.70 (m, 2H), 3.70-3.57 (m, 2H), 3.19-3.06 (m, 2H), 3.05 (s, 2H), 2.97 (d, J = 1.1 Hz, 2H), 2.03-1.87 (m, 4H), 1.41 (s, 6H). MS (ESI): m/z = 434 [M + 1]+.
224	N-[6-(6- hydroxy-4- methyl-1,4- diazepan-1-yl)- 2,2-dimethyl- 3H-benzofuran- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, Methanol-d4) δ 9.05 (d, J = 6.6 Hz, 1H), 8.83 (d, J = 3.7 Hz, 1H), 8.57 (s, 1H), 8.43 (d, J = 30.3 Hz, 1H), 7.86 (s, 1H), 7.23-7.15 (m, 1H), 6.61 (s, 1H), 4.22-4.15 (m, 1H), 3.63 (d, J = 12.7 Hz, 1H), 3.41 (td, J = 14.8, 14.4, 6.1 Hz, 3H), 3.29 (dd, J = 13.3, 3.9 Hz, 1H), 3.18 (m, 2H), 3.11 (dd, J = 13.4, 3.5 Hz, 1H), 2.93 (s, 2H), 2.77 (s, 3H), 1.35 (s, 6H). MS (ESI): m/z = 437.3 [M + 1]+.
225	N-(6-(4-(2- (Isopropylamino)- 2- oxoethyl)piper- azin-1-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.41 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.98 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.33 (d, J = 0.9 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.35 (dd, J = 7.0, 4.2 Hz, 1H), 6.71 (s, 1H), 3.99- 3.81 (m, 1H), 3.05-2.95 (m, 4H), 2.90-2.81 (m, 4H), 2.72 (d, J = 5.1 Hz, 4H), 1.41 (s, 6H), 1.08 (d, J = 6.6 Hz, 6H). (ESI): m/z = 492.2 [M + 1]+.
226	N-(6-(4-(1- Amino-2- methyl-1- oxopropan-2- yl)piperazin-1- yl)-2,2-dimethyl- 2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.34 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.26 (s, 1H), 7.37 (dd, J = 7.1, 4.2 Hz, 1H), 7.16 (d, J = 3.4 Hz, 1H), 7.02 (d, J = 3.0 Hz, 1H), 6.66 (s, 1H), 3.00 (s, 2H), 2.86 (t, J = 4.6 Hz, 4H), 2.67 (d, J = 4.7 Hz, 4H), 1.41 (s, 6H), 1.15 (s, 6H). (ESI): m/z = 478.2 [M + 1]+.
227	N-(6-((3R,5S)-4- (2-Amino-2- oxoethyl)-3,5- dimethylpiperazin- 1-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		(ESI): m/z = 478.2 [M + 1]+.
228	N-(2,2- Dimethyl-6-(4- (2-morpholino- 2- oxoethyl)piper- azin-1-yl)-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.38 (s, 1H), 9.37 (dd, J = 6.9, 1.6 Hz, 1H), 8.97 (dd, J = 4.3, 1.7 Hz, 1H), 8.67 (s, 1H), 8.31 (s, 1H), 7.37 (dd, J = 7.0, 4.2 Hz, 1H), 6.69 (s, 1H), 3.57 (d, J = 22.3 Hz, 7H), 3.45 (t, J = 4.7 Hz, 2H), 3.29 (s, 2H), 3.00 (s, 2H), 2.82 (t, J = 4.7 Hz, 4H), 2.70 (d, J = 4.9 Hz, 5H), 2.54 (dd, J = 8.1, 4.2 Hz, 1H), 1.41 (s, 6H). (ESI): m/z = 520.2 [M + 1]+.
229	N-(2,2- Dimethyl-6-(3- (2- methylpyrimidin- 4-yl)pyrrolidin- 1-yl)-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.05 (s, 1H), 9.35 (dd, J = 7.0, 1.5 Hz, 1H), 8.73 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.52 (d, J = 5.2 Hz, 1H), 8.03 (s, 1H), 7.34- 7.24 (m, 2H), 6.64 (s, 1H), 3.64 (p, J = 7.9 Hz, 1H), 3.47-3.32 (m, 2H), 3.36- 3.13 (m, 3H), 2.99 (s, 2H), 2.47-2.34 (m, 1H), 2.27- 2.13 (m, 1H), 1.42 (s, 6H). (ESI): m/z = 470.2 [M + 1]+.
230	N-(2,2- Dimethyl-6-(4- ((tetrahydrofuran- 2- yl)methyl)pipera- zin-1-yl)-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.41 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.91 (dd, J = 4.1, 1.6 Hz, 1H), 8.67 (s, 1H), 8.31 (s, 1H), 7.37 (dd, J = 7.0, 4.1 Hz, 1H), 6.69 (s, 1H), 4.02-3.91 (m, 1H), 3.81-3.70 (m, 1H), 3.61 (td, J = 7.8, 6.3 Hz, 1H), 2.99 (s, 2H), 2.84-2.73 (m, 6H), 2.66 (s, 2H), 2.01- 1.79 (m, 2H), 1.84-1.70
			(m, 2H), 1.57-1.43 (m,
			1H), 1.41 (s, 6H). MS (ESI):
			m/z = 477.2 [M + 1]+.
231	N-(6-(4-(2-(1H- Imidazol-1- yl)ethyl)piperazin- 1-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.39 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 8.92 (dd, J = 4.3, 1.7 Hz, 1H), 8.68 (s, 1H), 8.30 (s, 1H), 7.65 (s, 1H), 7.35 (dd, J = 7.0, 4.2 Hz, 1H), 7.21 (d, J = 1.2 Hz, 1H), 6.87 (d, J = 1.0 Hz, 1H), 6.70 (s, 1H), 4.11 (t, J = 6.6 Hz, 2H), 3.00 (s, 2H), 2.82 (t, J = 4.7 Hz, 4H), 2.74 (t, J = 6.6 Hz, 2H), 2.70 (s, 5H), 1.41 (s, 6H). MS (ESI): m/z = 487.2 [M + 1]+.
232	N-(6-(4-(2- (Dimethylamino)- 2- oxoethyl)pipera- zin-1-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.39 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 8.99 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.32 (s, 1H), 7.37 (dd, J = 7.0, 4.2 Hz, 1H), 6.69 (s, 1H), 5.75 (s, 2H), 3.28 (d, J = 9.9 Hz, 3H), 3.06 (s, 3H), 3.00 (s, 2H), 2.82 (d, J = 4.9 Hz, 7H), 2.72 (d, J = 4.5 Hz, 4H), 1.41 (s, 6H). MS (ESI): m/z = 478.2 [M + 1]+.
233	N-(6-(5,6- Dihydroimidazo [1,2-a]pyrazin- 7(8H)-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.73 (s, 1H), 9.28 (dd, J = 7.0, 1.6 Hz, 1H), 8.65 (s, 1H), 8.40 (s, 1H), 7.70 (dd, J = 4.1, 1.6 Hz, 1H), 7.25 (d, J = 1.2 Hz, 1H), 7.17 (dd, J = 7.0, 4.1 Hz, 1H), 6.92 (d, J = 1.2 Hz, 1H), 6.84 (s, 1H), 4.19 (t, J = 5.3 Hz, 2H), 4.00 (s, 2H), 3.43-3.35 (m, 2H), 3.04 (s, 2H), 1.43 (s, 6H). MS (ESI): m/z = 430.2 [M + 1]+.
234	N-(6- (Hexahydro-5H- furo[2,3- c]pyrrol-5-yl)- 2,2-dimethyl- 2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 9.80 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.85 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (s, 1H), 7.95 (s, 1H), 7.31 (dd, J = 7.0, 4.2 Hz, 1H), 6.58 (s, 1H), 4.57 (ddd, J = 8.0, 5.9, 2.9 Hz, 1H), 3.87 (q, J = 7.5 Hz, 1H), 3.72-3.57 (m, 1H), 3.13-3.02 (m, 2H), 3.00-2.81 (m, 3H), 2.07 (s, 2H), 1.90 (dq, J = 12.2, 7.6 Hz, 1H), 1.74-1.62 (m, 1H), 1.41 (s, 6H). MS (ESI): m/z = 420.2 [M + 1]+.
235	N-(6-(4-(1,3,4- Oxadiazol-2- yl)piperidin-1- yl)-2,2-dimethyl- 2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.49 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 9.20 (s, 1H), 8.85 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.36 (s, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 6.70 (s, 1H), 3.27- 3.15 (m, 1H), 3.01 (s, 3H), 3.01-2.95 (m, 1H), 2.84 (td, J = 11.2, 3.1 Hz, 2H), 2.25-2.05 (m, 4H), 1.42 (s, 6H). MS (ESI): m/z = 460.2 [M + 1]+.
236	N-(6-(3- Carbamoylpyrrol- idin-1-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.16 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 8.90 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.11 (s, 1H), 7.37- 7.28 (m, 2H), 6.85 (s, 1H), 6.59 (s, 1H), 3.28 (d, J = 7.7 Hz, 1H), 3.16-2.93 (m, 3H), 2.98 (s, 2H), 2.11 (q, J = 7.1 Hz, 2H), 1.41 (s, 6H). MS (ESI): m/z = 421.2 [M + 1]+.
237	N-(6-(9- Hydroxy-3-oxa- 7- azabicyclo[3.3.1] nonan-7-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1:0.38 diastereomeric ratio. Resonances from the minor diastereomer are indicated with partial integrals. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 9.52 (s, 1H), 9.43 (s, 0.35 H), 9.31-9.23 (m, 1.47 H), 8.80-8.71 (m, 1.45 H), 8.68 (m, J = 2.7 Hz, 1.38 H), 7.92 (s, 1H), 7.83 (s, 0.33 H), 7.30-7.21 (m, 1.46 H), 6.64 (s, 1H), 6.59 (s, 0.36 H), 5.07-4.99 (m, 1.44 H), 3.95-3.88 (m,
			3H), 3.81-3.73 (m, 1H),
			3.52 (d, J = 11.3 Hz, 1H),
			3.44 (s, 1H), 3.42 (s, 1H),
			3.15-3.01 (m, 5H), 2.98 (s,
			3H), 2.78 (d, J = 10.5 Hz,
			1H), 1.65-1.55 (m, 3H),
			1.41 (s, 8H). MS (ESI):
			m/z = 450.2 [M + 1]+.
238	N-(2,2- Dimethyl-6- (1,4,6,7- tetrahydro-5H- imidazo[4,5- c]pyridin-5-yl)- 2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 11.99-11.57 (m, 1H), 11.00- 10.63 (m, 1H), 9.27 (d, J = 7.0 Hz, 1H), 8.64 (s, 1H), 8.44-8.33 (m, 1H), 7.84- 7.61 (m, 1H), 7.50 (s, 1H), 7.17 (dd, J = 7.0, 4.2 Hz, 1H), 6.88-6.62 (m, 1H), 3.83 (d, J = 24.2 Hz, 2H), 3.27-3.13 (m, 2H), 3.02 (s, 2H), 2.86-2.68 (m, 2H), 1.42 (s, 6H). MS (ESI): m/z = 430.2 [M + 1]+.
239	N-(6-(7- Methoxy-2- azabicyclo[2.2.1] heptan-2-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1:0.39 diastereomeric ratio. Resonances from the minor diastereomer are indicated with partial integrals. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.06 (s, 0.39 H), 9.73 (s, 1H), 9.37 (m, 1.38 H), 8.94-8.87 (m, 1.43 H), 8.71 (s, 0.30 H), 8.67 (s, 1H), 8.18 (s, 0.4 H), 7.82 (s, 1H), 7.38-7.29 (m, 1.39 H), 6.94 (s, 0.33 H), 6.48 (s, 1H), 3.99 (s, 1H), 3.74- 3.68 (m, 1H), 3.23 (s, 5H),
			3.05 (s, 1H), 3.03 (s, 1H),
			2.95 (s, 2H), 2.34 (s, 1H),
			1.81-1.62 (m, 3H), 1.48-
			1.38 (m, 10H). MS (ESI):
			m/z = 434.2 [M + 1]+.
240	N-(6-(2- Azabicyclo[3.1.0] hexan-2-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1:0.12 diastereomeric ratio. Resonances from the minor diastereomer are indicated with partial integrals. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.06 (s, 0.12 H), 10.01 (s, 1H), 9.39 (dd, J = 6.9, 1.5 Hz, 0.12 H), 9.35 (dd, J = 7.0, 1.7 Hz, 1H), 8.91 (dd, J = 4.3, 1.6 Hz, 0.12 H), 8.87 (dd, J = 4.3, 1.6 Hz, 1H), 8.71 (s, 0.12 H), 8.67 (s, 1H), 8.18 (s, 0.12 H), 8.13 (s, 1H), 7.34
			(dd, J = 7.0, 4.2 Hz, 0.12 H),
			7.30 (dd, J = 7.0, 4.2 Hz,
			1H), 6.94 (s, 0.12 H), 6.87
			(s, 1H), 3.45 (t, J = 8.9 Hz,
			1H), 3.30 (t, J = 13.1 Hz,
			1H), 3.05 (s, 0H), 2.99 (s,
			2H), 2.93 (td, J = 5.8, 2.6
			Hz, 1H), 2.34-2.24 (m,
			1H), 2.19-2.05 (m, 1H),
			1.94 (dd, J = 11.8, 6.8 Hz,
			1H), 1.60-1.50 (m, 1H),
			1.41 (d, J = 4.7 Hz, 7H),
			1.01-0.92 (m, 1H), 0.48
			(dt, J = 8.3, 5.6 Hz, 1H). MS
			(ESI): m/z = 390.2 [M + 1]+.
241	N-(2,2- Dimethyl-6-(3- sulfamoylpyrroli- din-1-yl)-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.17 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 8.90 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.18 (s, 1H), 7.33 (dd, J = 7.0, 4.3 Hz, 1H), 6.94 (s, 2H), 6.69 (s, 1H), 3.92- 3.80 (m, 1H), 3.52 (dd, J = 10.1, 8.4 Hz, 1H), 3.33- 3.03 (m, 4H), 3.00 (s, 2H), 2.37-2.27 (m, 2H), 1.42 (s, 6H). MS (ESI): m/z = 457.1 [M + 1]+.
242	N-(6-(4-(2- (Cyclopropyl- amino)-2- oxoethyl)pipera- zin-1-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		MS (ESI): m/z = 490.2 [M + 1]+.
243	N-(2,2- Dimethyl-6-(4- (2-oxo-2- (pyrrolidin-1- yl)ethyl)pipera- zin-1-yl)-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.41 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 9.02 (dd, J = 4.3, 1.7 Hz, 1H), 8.68 (s, 1H), 8.32 (s, 1H), 7.36 (dd, J = 7.0, 4.2 Hz, 1H), 6.70 (s, 1H), 3.52 (t, J = 6.7 Hz, 2H), 3.44-3.26 (m, 2H, buried under H2O peak), 3.23 (s, 2H), 3.00 (s, 2H), 2.86- 2.72 (m, 8H), 1.94-1.82 (m, 2H), 1.83-1.71 (m, 2H), 1.42 (s, 6H). MS (ESI): m/z = 504.2 [M + 1]+.
244	N-(6-(4-(1- (Cyclopropyl- amino)-1- oxopropan-2- yl)piperazin-1- yl)-2,2-dimethyl- 2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.41 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 9.00 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.33 (s, 1H),7.85 (d, J = 4.6 Hz, 1H), 7.37 (dd, J = 7.0, 4.2 Hz, 1H), 6.69 (s, 1H), 3.08 (q, J = 6.8 Hz, 1H), 2.99 (s, 2H), 2.84- 2.66 (m, 9H), 1.41 (s, 6H), 1.14 (d, J = 6.9 Hz, 3H), 0.69-0.58 (m, 2H), 0.49- 0.34 (m, 2H). MS (ESI): m/z = 504.2 [M + 1]+.
245	N-(2,2- Dimethyl-6-(4- (2,2,2-trifluoro- 1- hydroxyethyl) piperidin-1-yl)- 2,3-dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.51 (s, 1H), 9.35 (dd, J = 7.0, 1.7 Hz, 1H), 8.99 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.37 (s, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 6.69 (s, 1H), 6.38 (d, J = 2.6 Hz, 1H), 3.94 (s, 1H), 2.99 (s, 2H), 2.95 (d, J = 11.4 Hz, 2H), 2.74-2.59 (m, 2H), 1.98- 1.83 (m, 2H), 1.80-1.72 (m, 2H), 1.66 (d, J = 12.3 Hz, 1H), 1.41 (s, 6H). MS (ESI): m/z = 490.2 [M + 1]+.
246	N-(6-(4,6- dihydropyrrolo[3, 4-c]pyrazol- 5(1H)-yl)-2,2- dimethyl-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 12.54 (s, 1H), 10.45 (s, 1H), 9.31 (dd, J = 7.0, 1.7 Hz, 1H), 8.66 (s, 1H), 8.10 (dd, J = 4.1, 1.5 Hz, 1H), 8.06 (s, 1H), 7.51 (s, 1H), 7.21 (dd, J = 7.0, 4.2 Hz, 1H), 6.85 (s, 1H), 4.27 (s, 4H), 3.00 (s, 2H), 1.43 (s, 6H). MS (ESI): m/z = 416.2 [M + 1]+.
247	N-(2,2-dimethyl- 6-(3-methyl-4,6- dihydropyrrolo[3, 4-c]pyrazol- 5(1H)-yl)-2,3- dihydrobenzo- furan-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 12.19 (s, 1H), 10.43 (s, 1H), 9.31 (dd, J = 7.0, 1.7 Hz, 1H), 8.66 (s, 1H), 8.13 (dd, J = 4.2, 1.7 Hz, 1H), 8.08 (s, 1H), 7.23 (dd, J = 7.0, 4.2 Hz, 1H), 6.82 (s, 1H), 4.20 (d, J = 12.3 Hz, 4H), 3.00 (s, 2H), 2.19 (s, 3H), 1.42 (s, 6H). MS (ESI): m/z = 430.2 [M + 1]+.

Example 248. N-(6-(2-(2,2-Difluoroethyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. tert-Butyl 7-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

To a mixture of 6-bromo-2,2-dimethyl-5-nitro-3H-benzofuran (Intermediate 4; 200 mg, 0.74 mmol), and cesium carbonate (790 mg, 2.43 mmol) in acetonitrile (2.23 ml) was added tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate and oxalic acid (256 mg, 0.809 mmol). The mixture was heated at 60° C. for 16 h, cooled to room temperature, and diluted with water and isopropyl acetate. The aqueous phase was isolated and extracted with isopropyl acetate (3×). The combined organic phases were dried over anhydrous sodium sulfate, filtered and purified by flash column chromatography (eluting gradient 0-100% isopropyl acetate:heptanes) to afford the title compound (177 mg, 0.424 mmol, 58% yield) as a bright yellow solid. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 7.82 (s, 1H), 6.54 (s, 1H), 3.58 (s, 5H), 2.99 (s, 2H), 2.90-2.82 (m, 4H), 1.82-1.73 (m, 4H), 1.43 (s, 6H), 1.38 (s, 9H).

Step B. 7-(2,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-2,7-diazaspiro[3.5]nonane

tert-butyl 7-(2,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (176 mg, 0.422 mmol) was dissolved in dichloromethane (3.3 ml) and treated with trifluoroacetic acid (1.3 ml). After 10 min, the solvent was removed under reduced pressure. The product was taken on without further purification.

Step C. 2-(2,2-Difluoroethyl)-7-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-2,7-diazaspiro[3.5]nonane

7-(2,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-2,7-diazaspiro[3.5]nonane (67 mg, 0.21 mmol) was dissolved in dichloromethane (8 ml) and slowly treated with collidine (0.61 ml, 4.6 mmol) followed by 2,2-difluoroethyl trifluoromethanesulfonate (0.044 ml, 0.32 mmol). After 18 h, methanol (5 ml) and potassium carbonate were added. The reaction mixture stirred vigorously for 4 h at ambient temperature and then was diluted with water and isopropyl acetate. The aqueous phase was isolated and extracted with isopropyl acetate (3×). The combined organic phases were dried over anhydrous sodium sulfate, filtered and purified by column chromatography (eluting gradient 0-100% isopropyl acetate:heptanes) to afford 2-(2,2-difluoroethyl)-7-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-2,7-diazaspiro[3.5]nonane (61 mg, 0.16 mmol) as a yellow solid. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 7.81 (s, 1H), 6.54 (s, 1H), 5.93 (tt, J=55.9, 4.3 Hz, 1H), 3.08 (s, 4H), 2.98 (s, 2H), 2.85 (m, 4H), 2.82 (d, J=4.3 Hz, 2H), 1.82-1.72 (m, 4H), 1.43 (s, 6H).

Step D. 6-(2-(2,2-Difluoroethyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-amine

A mixture of 2-(2,2-difluoroethyl)-7-(2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)-2,7-diazaspiro[3.5]nonane (61 mg, 0.16 mmol), iron (77 mg, 1.4 mmol), and ammonium chloride (74 mg, 1.4 mmol) in ethanol (6 ml) and water (2 ml) was stirred at 80° C. for 30 min. The mixture was filtered through celite and a small plug of silica to afford 6-(2-(2,2-difluoroethyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-amine (0.16 mmol) which was used without further purification. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 6.50 (s, 1H), 6.28 (s, 1H), 4.16 (s, 2H), 3.32-3.15 (m, 254H), 3.08 (s, 4H), 2.82 (s, 5H), 2.69-2.65 (m, 1H), 2.61 (s, 4H), 1.78 (t, J=5.3 Hz, 4H), 1.33 (s, 6H).

Step E. N-(6-(2-(2,2-Difluoroethyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (20.3 mg, 0.124 mmol) in dimethylformamide (2 ml) at 0° C. under a nitrogen atmosphere was added (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (62 mg, 0.119 mmol) followed by 2,4,6-trimethylpyridine (0.119 mmol). 6-[2-(2,2-Difluoroethyl)-2,7-diazaspiro[3.5]nonan-7-yl]-2,2-dimethyl-3H-benzofuran-5-amine (38 mg, 0.11 mmol) was then introduced and the reaction mixture was warmed to room temperature. After 16 h, the mixture was filtered through a plug of silica and concentrated in vacuo. The residue was purified by reverse phase HPLC to afford the title compound (2.3 mg, 0.047 mmol, 44% yield). ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.46 (s, 1H), 9.35 (dd, J=7.0, 1.6 Hz, 1H), 8.74 (dd, J=4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.32 (d, J=1.0 Hz, 1H), 7.32 (dd, J=7.0, 4.2 Hz, 1H), 6.65 (s, 1H), 5.95 (tt, J=55.9, 4.2 Hz, 1H), 3.15 (s, 4H), 2.99 (s, 2H), 2.84 (td, J=16.1, 4.3 Hz, 2H), 2.75-2.63 (m, 4H), 1.92 (m, 4H), 1.40 (s, 6H). MS (ESI): m/z=497.2 [M+1]⁺.

Example 249. N-(2,2-dimethyl-6-(2-(2,2,2-trifluoroethyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was made in a manner analogous to Example 248, replacing 2,2-difluoroethyl trifluoromethanesulfonate with 2,2,2-trifluoroethyl trifluoromethanesulfonate (Step C), to give N-(2,2-dimethyl-6-(2-(2,2,2-trifluoroethyl)-2,7-diazaspiro[3.5]nonan-7-yl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (26 mg, 62% yield) as an orange crystalline solid. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.46 (s, 1H), 9.35 (dd, J=7.0, 1.6 Hz, 1H), 8.75 (dd, J=4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.32 (d, J=0.9 Hz, 1H), 7.32 (dd, J=7.0, 4.2 Hz, 1H), 6.65 (s, 1H), 3.26-3.16 (m, 6H), 2.99 (s, 2H), 2.77-2.63 (m, 4H), 1.98-1.88 (m, 4H), 1.40 (s, 6H). MS (ESI): m/z=515.2 [M+1]⁺.

Example 250. N-[2-(2-Hydroxy-1,1-dimethyl-ethyl)-6-morpholino-1-oxo-isoindolin-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step 1: Ethyl 5-fluoro-2-methyl-4-nitro-benzoate

To a solution of 1-bromo-5-fluoro-2-methyl-4-nitrobenzene (5.0 g, 21.36 mmol) and triethylamine (50 ml, 360.71 mmol) in ethanol (100 ml) was added bis(triphenylphosphine) palladium(II) dichloride (1.5 g, 2.14 mmol). The reaction was stirred at 70° C. for 16 h under carbon monoxide (50 psi). The reaction was filtered through celite and the filtrate was concentrated to dryness. The residue was purified by flash column chromatography (eluent 10% ethyl acetate:petroleum ether) to give ethyl 5-fluoro-2-methyl-4-nitro-benzoate (2.0 g, 41% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, J=7.2 Hz, 1H), 7.82 (d, J=11.6 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 2.63 (s, 3H), 1.42 (t, J=7.2 Hz, 3H).

Step 2: Ethyl 2-(bromomethyl)-5-fluoro-4-nitro-benzoate

To a solution of ethyl 5-fluoro-2-methyl-4-nitro-benzoate (200 mg, 0.88 mmol) in carbon tetrachloride (5 ml) was added benzoyl peroxide (43 mg, 0.18 mmol) and N-bromosuccinimide (313 mg, 1.76 mmol). The mixture was stirred at 100° C. for 16 h under nitrogen. The reaction was concentrated to dryness and the crude reaction was purified by flash column chromatography (eluent 20% ethyl acetate:petroleum ether) to afford ethyl 2-(bromomethyl)-5-fluoro-4-nitro-benzoate (110 mg, 41% yield) as a yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 8.18 (d, J=6.4 Hz, 1H), 7.90 (d, J=10.8 Hz, 1H), 4.92 (s, 2H), 4.50 (q, J=7.2 Hz, 2H), 1.49 (t, J=7.2 Hz, 3H).

Step 3: 6-Fluoro-2-(2-hydroxy-1,1-dimethyl-ethyl)-5-nitro-isoindolin-1-one

To a solution of ethyl 2-(bromomethyl)-5-fluoro-4-nitro-benzoate (110 mg, 0.36 mmol) in methanol (3 ml) was added 2-amino-2-methyl-1-propanol (64 mg, 0.72 mmol) and triethylamine (73 mg, 0.72 mmol). The mixture was stirred at 70° C. for 6 h. The mixture was concentrated and purified by preparatory TLC (50% ethyl acetate in petroleum ether) to afford 6-fluoro-2-(2-hydroxy-1,1-dimethyl-ethyl)-5-nitro-isoindolin-1-one (60 mg, 62% yield) as a yellow solid. ¹HNMR (400 MHz, CDCl₃) δ 8.12 (d, J=6.4 Hz, 1H), 7.70 (d, J=9.2 Hz, 1H), 4.58 (s, 2H), 4.17 (t, J=6.8 Hz, 1H), 3.94 (d, J=6.8 Hz, 2H), 1.49 (s, 6H).

Step 4: 2-(2-Hydroxy-1,1-dimethyl-ethyl)-6-morpholino-5-nitro-isoindolin-1-one

To a solution of 6-fluoro-2-(2-hydroxy-1,1-dimethyl-ethyl)-5-nitro-isoindolin-1-one (240 mg, 0.89 mmol) in dimethyl sulfoxide (4 ml) was added morpholine (156 mg, 1.79 mmol) and N, N-diisopropylethylamine (231 mg, 1.79 mmol). The mixture was stirred at 90° C. for 3 h. The mixture was concentrated and purified by preparatory TLC (50% ethyl acetate in petroleum ether) to afford 2-(2-hydroxy-1,1-dimethyl-ethyl)-6-morpholino-5-nitro-isoindolin-1-one (245 mg, 82% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.60 (s, 1H), 4.59 (t, J=6.8 Hz, 1H), 4.51 (s, 2H), 3.91 (d, J=6.8 Hz, 2H), 3.87 (t, J=4.4 Hz, 4H), 3.10 (t, J=4.4 Hz, 4H), 1.47 (s, 6H). LCMS (ESI): m/z=336.1 [M+H]⁺.

Step 5: 5-Amino-2-(2-hydroxy-1,1-dimethyl-ethyl)-6-morpholino-isoindolin-1-one

To a solution of 2-(2-hydroxy-1,1-dimethyl-ethyl)-6-morpholino-5-nitro-isoindolin-1-one (245 mg, 0.73 mmol) in ethanol (5 ml) and water (1 ml) was added iron (204 mg, 3.65 mmol) and ammonium chloride (195 mg, 3.65 mmol). The reaction was stirred at 80° C. for 2 h. The reaction was filtered and the filtrate was concentrated. The crude material was diluted with water (10 ml) and extracted with ethyl acetate (20 ml×3). The combined organic phases were washed with brine (20 ml), dried over sodium sulfate and concentrated to give 5-amino-2-(2-hydroxy-1,1-dimethyl-ethyl)-6-morpholino-isoindolin-1-one (210 mg, 94% yield) as a pale yellow solid. LCMS (ESI): m/z=305.9 [M+H]⁺.

Step 6: N-[2-(2-Hydroxy-1,1-dimethyl-ethyl)-6-morpholino-1-oxo-isoindolin-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 5-amino-2-(2-hydroxy-1,1-dimethyl-ethyl)-6-morpholino-isoindolin-1-one (210 mg, 0.69 mmol), N,N-diisopropylethylamine (267 mg, 2.06 mmol) and 4-dimethyl aminopyridine (17 mg, 0.14 mmol) in 1,2-dichloroethane (8 ml) was added pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (200 mg, 1.10 mmol). The reaction mixture was stirred at 35° C. for 16 h. The reaction was concentrated and purified by reverse phase HPLC (20-50% acetonitrile in water with 0.05% ammonia hydroxide) to give N-[2-(2-hydroxy-1,1-dimethyl-ethyl)-6-morpholino-1-oxo-isoindolin-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (60.8 mg, 19% yield) as pale yellow solid. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.89 (s, 1H), 9.41 (d, J=5.6 Hz, 1H), 9.00 (d, J=2.8 Hz, 1H), 8.76 (s, 1H), 8.70 (s, 1H), 7.50 (s, 1H), 7.40 (dd, J=7.2, 4.0 Hz, 1H), 4.95 (t, J=5.6 Hz, 1H), 4.57 (s, 2H), 3.92-3.86 (m, 4H), 3.69 (d, J=6.0 Hz, 2H), 2.92-2.85 (m, 4H), 1.43 (s, 6H). LCMS (ESI): m/z=451.1 [M+H]⁺.

TABLE 8
The following examples were made in a manner similar to that for Example 250.
Ex.	Name	Structure	NMR, MS
251	N-[6- Morpholino-2- (oxetan-3-yl)-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.92 (s, 1H), 9.41 (d, J = 6.4 Hz, 1H), 8.99 (s, 1H), 8.81- 8.72 (m, 2H), 7.59 (s, 1H), 7.39 (m, 1H), 5.41 (t, J = 6.8 Hz, 1H), 4.92-4.84 (m, 2H), 4.83-4.73 (m, 4H), 3.95- 3.85 (m, 4H), 2.96-2.86 (m, 4H). LCMS (ESI): m/z = 435.2 [M + H]+.
252	N-[6- Morpholino-2- [2-(oxetan-3- yl)ethyl]-1-oxo- isoindolin-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3) δ 10.93 (s, 1H), 8.81-8.82 (m, 4H), 7.72 (s, 1H), 7.17- 7.09 (m, 1H), 4.82 (t, J = 6.8 Hz, 2H), 4.43 (t, J = 6.4 Hz, 2H), 4.37 (s, 2H), 4.08-4.96 (m, 4H), 3.58 (t, J = 7.2 Hz, 2H), 3.18-2.91 (m, 5H), 2.13- 2.03 (m, 2H). LCMS (ESI): m/z = 463.1 [M + H]+.
253	N-(2- (Cyanomethyl)- 6-morpholino-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6): δ 10.92 (s, 1H), 9.42-9.40 (m, 1H), 9.00-8.99 (m, 1H), 8.80 (s, 1H), 8.76 (s, 1H), 7.64 (s, 1H), 7.40-7.38 (m, 1H), 4.71 (s, 2H), 4.57 (s, 2H), 3.90 (t, J = 4.4 Hz, 4H), 2.92 (t, J = 4.4 Hz, 4H). LCMS (ESI): m/z = 417.9 [M + H]+.
254	N-(6- Morpholino-1- oxo-2- tetrahydrofuran- 3-yl-isoindolin- 5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3) δ 10.92 (s, 1H), 8.87-8.81 (m, 4H), 7.72 (s, 1H), 7.11 (dd, J = 6.8, 4.0 Hz, 1H), 5.15 (d, J = 4.0 Hz, 1H), 4.49- 4.37 (m, 2H), 4.16-4.12 (m, 1H), 4.00 (s, 4H), 3.89-3.83 (m, 3H), 2.99 (s, 4H), 2.43- 2.34 (m, 1H), 2.04-2.02 (m, 1H). LCMS (ESI): m/z = 448.9 [M + H]+.
255	N-(6- Morpholino-1- oxo-2- tetrahydropyran- 4-yl-isoindolin- 5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3) δ 10.93 (s, 1H), 8.88-8.83 (m, 4H), 7.74 (s, 1H), 7.13 (dd, J = 6.4,4.0 Hz, 1H), 4.55- 4.46 (m, 1H), 4.38 (s, 2H), 4.15-4.05 (m, 2H), 4.06- 3.96 (m, 4H), 3.59 (t, J = 11.2 Hz, 2H), 3.05-2.95 (m, 4H), 1.94-1.77 (m, 4H). LCMS (ESI): m/z = 463.0 [M + H]+.
256	N-(6-Methyl-2- morpholino-7- oxo-6,7- dihydro-H- pyrrolo[3,4- b]pyridin-3- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3) δ 10.92 (s, 1H), 8.88-8.82 (m, 4H), 7.72 (s, 1H), 7.12 (dd, J = 6.8, 4.0 Hz, 1H), 4.40 (s, 2H), 4.02 (t, J = 4.4 Hz, 4H), 3.71-3.67 (m, 2H), 3.25 (s, 3H), 3.01 (t, J = 4.4 Hz, 4H), 1.87-1.83 (m, 4H), 1.25 (s, 6H). LCMS (ESI): m/z = 479.2 [M + H]+.
257	N-[6- Morpholino-1- oxo-2- (tetrahydropyran- 2- ylmethyl) isoindolin-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3) δ 10.92 (s, 1H), 8.88-8.82 (m, 4H), 7.74 (s, 1H), 7.14 (dd, J = 6.8, 4.0 Hz, 1H), 4.66- 4.47 (m, 2H), 4.01-3.97 (m, 5H), 3.81-3.39 (m, 4H), 3.00-2.99 (m, 4H), 1.86- 1.67 (m, 2H), 1.55-1.49 (m, 3H), 1.37-1.31 (m, 1H). LCMS (ESI): m/z = 477.3 [M + H]+.
258	N-[6-[4-(2,2- Difluoroethyl) piperazin-1-yl]-2- [(2R)-2-fluoro- 3-hydroxy-3- methyl-butyl]-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3) δ 10.82 (s, 1H), 8.90-8.75 (m, 4H), 7.73 (s, 1H), 7.14 (s, 1H), 6.14-5.83 (m, 1H), 4.65- 4.42 (m, 3H), 4.28-4.10 (m, 1H), 3.75-3.60 (m, 1H), 3.12-2.84 (m, 9H), 2.48- 2.40 (m, 1H), 1.34 (s, 6H). LCMS (ESI): m/z = 546.2 [M + H]+.
259 and 260	N-[2-[(2R)-2- Fluoro-3- hydroxy-3- methyl-butyl]-1- oxo-6-[4-[(1S)- 2,2,2-trifluoro-1- hydroxy-ethyl]- 1- piperidyl] isoindolin-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide and N-[2-[(2R)-2- fluoro-3- hydroxy-3- methyl-butyl]-1- oxo-6-[4-[(1R)- 2,2,2-trifluoro- 1-hydroxy- ethyl]-1- piperidyl] isoindolin-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 259, Peak 1: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.95 (s, 1H), 9.39 (d, J = 6.8 Hz, 1H), 9.06 (d, J = 3.6 Hz, 1H), 8.79 (s, 1H), 8.74 (s, 1H), 7.58 (s, 1H), 7.37 (dd, J = 6.8, 4.0 Hz, 1H), 6.43 (s, 1H), 4.89 (s, 1H), 4.59-4.35 (m, 3H), 4.05-3.85 (m, 2H), 3.73-3.65 (m, 1H), 3.08- 2.96 (m, 2H), 2.88-2.73 (m, 2H), 2.03-1.69 (m, 5H), 1.25- 1.10 (m, 6H). LCMS (ESI): m/z = 579.1 [M + H]+. Example 260, Peak 2: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.95 (s, 1H), 9.39 (d, J = 6.8 Hz, 1H), 9.06 (d, J = 3.6 Hz, 1H), 8.79 (s, 1H), 8.74 (s, 1H), 7.59 (s, 1H), 7.37 (dd, J = 6.8, 4.4 Hz, 1H), 6.43 (s, 1H), 4.89 (s, 1H), 4.61-4.31 (m, 3H), 4.05-3.83 (m, 2H), 3.73-3.65 (m, 1H), 3.08- 2.96 (m, 2H), 2.88-2.73 (m, 2H), 2.03-1.69 (m, 5H), 1.25- 1.10 (m, 6H). LCMS (ESI): m/z = 579.1 [M + H]+.
261	N-[6-(3,3- Difluoropyrrolidin- 1-yl)-2-[(2R)- 2-fluoro-3- hydroxy-3- methyl-butyl]-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.77 (s, 1H), 9.40 (dd, J = 7.0, 1.6 Hz, 1H), 8.84 (dd, J = 4.3, 1.6 Hz, 1H), 8.75 (s, 1H), 8.74 (s, 1H), 7.65 (s, 1H), 7.38 (dd, J = 7.0, 4.2 Hz, 1H), 4.90 (s, 1H), 4.61-4.34 (m, 3H), 3.94 (ddd, J = 38.5, 15.0, 1.9 Hz, 1H), 3.78-3.66 (m, 1H), 3.61 (t, J = 12.9 Hz, 2H), 2.59 (dq, J = 15.3, 8.0, 7.4 Hz, 2H), 1.18 (dd, J = 4.4, 1.6 Hz, 6H). LCMS (ESI): m/z = 503.2 [M + H]+.
262	N-2-[(3- Hydroxycyclobutyl) methyl]-6- morpholino-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.89 (s, 1H), 9.41 (dd, J = 7.0, 1.6 Hz, 1H), 9.00 (dd, J = 4.3, 1.6 Hz, 1H), 8.75 (d, J = 4.6 Hz, 2H), 7.57 (s, 1H), 7.39 (dd, J = 7.0, 4.2 Hz, 1H), 4.99 (d, J = 6.1 Hz, 1H), 4.44 (s, 2H), 4.33-4.21 (m, 1H), 3.95-3.85 (m, 4H), 3.55 (d, J = 8.0 Hz, 2H), 2.95-2.87 (m, 4H), 2.08-1.87 (m, 4H). LCMS (ESI): m/z = 463.2 [M + H]+.
263	N-[6-[4- (Hydroxymethyl)- 1-piperidyl]-1- oxo-2-(2,2,2- trifluoroethyl) isoindolin-5- yl]pyrazolo[1,5- a]pyrazine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.98 (s, 1H), 9.40 (dd, J = 7.0, 1.6 Hz, 1H), 8.96 (dd, J = 4.2, 1.6 Hz, 1H), 8.81 (s, 1H), 8.76 (s, 1H), 7.64 (s, 1H), 7.38 (dd, J = 7.0, 4.2 Hz, 1H), 4.60 (s, 3H), 4.36 (q, J = 9.7 Hz, 2H), 3.44 (t, J = 5.3 Hz, 2H), 3.01 (d, J = 11.3 Hz, 2H), 2.77 (dd, J = 12.1, 9.9 Hz, 2H), 1.83-1.73 (m, 2H), 1.66 (m, 3H). LCMS (ESI): m/z = 489.1 [M + H]+.
264	N-[2-[(2R)-2- Fluoro-3- hydroxy-3- methyl-butyl]-6- morpholino-1- oxo-isoindolin- 5-yl]-6-methyl- pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.84 (s, 1H), 9.27 (dd, J = 2.1, 1.1 Hz, 1H), 8.92 (d, J = 2.0 Hz, 1H), 8.76 (s, 1H), 8.67 (s, 1H), 7.58 (s, 1H), 4.90 (s, 1H), 4.63-4.35 (m, 3H), 3.91 (dd, J = 5.8, 3.2 Hz, 5H), 3.70 (td, J = 15.6, 9.4 Hz, 1H), 2.97-2.85 (m, 4H), 2.46 (d, J = 1.1 Hz, 3H), 1.22- 1.13. LCMS (ESI): m/z = 497.2 [M + H]+. (m, 6H).
265	N-[6-[4-(2- Amino-2-oxo- ethyl)piperazin- 1-yl]-1-oxo-2- (2,2,2- trifluoroethyl) isoindolin-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.92 (s, 1H), 9.44-9.33 (m, 1H), 9.04 (dd, J = 4.3, 1.6 Hz, 1H), 8.82 (s, 1H), 8.76 (s, 1H), 7.64 (s, 1H), 7.40 (dd, J = 7.0, 4.2 Hz, 1H), 7.24 (d, J = 43.2 Hz, 2H), 4.61 (s, 2H), 4.37 (q, J = 9.6 Hz, 2H), 3.06 (s, 2H), 2.96 (t, J = 4.7 Hz, 4H), 2.80 (t, J = 4.4 Hz, 4H). LCMS (ESI): m/z = 517.1 [M + H]+.
266	N-[6-[4-(2,2- Difluoroethyl) piperazin-1-yl]-1- oxo-2-(2,2,2- trifluoroethyl) isoindolin-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.86 (s, 1H), 9.41 (dd, J = 7.0, 1.6 Hz, 1H), 9.01 (dd, J = 4.2, 1.6 Hz, 1H), 8.80 (s, 1H), 8.76 (s, 1H), 7.62 (s, 1H), 7.40 (dd, J = 7.0, 4.2 Hz, 1H), 6.22 (t, J = 4.4 Hz, 1H), 4.60 (s, 2H), 4.37 (q, J = 9.6 Hz, 2H), 2.99-2.81 (m, 10H). LCMS (ESI): m/z = 524.1 [M + H]+.
267	N-[2-(3- hydroxy-2,2- Dimethyl- propyl)-6- morpholino-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.90 (s, 1H), 9.41 (ddd, J = 7.0, 1.7, 0.8 Hz, 1H), 9.00 (dt, J = 4.2, 1.1 Hz, 1H), 8.79- 8.71 (m, 2H), 7.59 (s, 1H), 7.39 (dd, J = 7.0, 4.2 Hz, 1H), 4.75 (t, J = 5.8 Hz, 1H), 4.57 (s, 2H), 3.90 (t, J = 4.4 Hz, 4H), 3.36 (tdd, J = 2.5, 1.6, 0.9 Hz, 2H), 3.16 (d, J = 5.8 Hz, 2H), 2.96-2.87 (m, 4H). LCMS (ESI): m/z = 465.2 [M + H]+.
268	N-[2-[[3- (Hydroxymethyl) oxetan-3- yl]methyl]-6- morpholino-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.91 (s, 1H), 9.41 (dd, J = 7.0, 1.6 Hz, 1H), 9.00 (dd, J = 4.3, 1.6 Hz, 1H), 8.75 (d, J = 5.8 Hz, 2H), 7.59 (s, 1H), 7.39 (dd, J = 7.0, 4.2 Hz, 1H), 4.94 (t, J = 5.3 Hz, 1H), 4.52 (s, 2H), 4.49 (d, J = 6.0 Hz, 2H), 4.35 (d, J = 6.0 Hz, 2H), 3.90 (t, J = 4.5 Hz, 4H), 3.80 (s, 2H), 3.57 (d, J = 5.3 Hz, 2H), 2.95-2.88 (m, 4H). LCMS (ESI): m/z = 479.2 [M + H]+.
269	6-Bromo-N-[2- [(2R)-2-fluoro- 3-hydroxy-3- methyl-butyl]-6- morpholino-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.69 (s, 1H), 9.91 (d, J = 2.0 Hz, 1H), 9.06 (d, J = 2.1 Hz, 1H), 8.75 (s, 1H), 8.73 (s, 1H), 7.59 (s, 1H), 4.90 (s, 1H), 4.62-4.51 (m, 2H), 4.51-4.34 (m, 1H), 3.88 (m, 5H), 3.70 (m, 1H), 2.91 (m, 4H), 1.18 (dd, J = 4.6, 1.6 Hz, 6H). LCMS (ESI): m/z = 561.1 [M + H]+.
270	N-[2-(2,2- Difluoro-3- hydroxy-3- methyl-butyl)-6- morpholino-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.91 (s, 1H), 9.41 (dt, J = 7.0, 1.2 Hz, 1H), 9.00 (dd, J = 4.3, 1.6 Hz, 1H), 8.77 (d, J = 6.8 Hz, 2H), 7.62 (s, 1H), 7.39 (dd, J = 7.0, 4.2 Hz, 1H), 5.43 (s, 1H), 4.59 (s, 2H), 4.12 (t, J = 17.0 Hz, 2H), 3.95- 3.85 (m, 4H), 2.93 (m, 4H), 1.25 (s, 6H). LCMS (ESI): m/z = 501.2 [M + H]+.
271	6-Chloro-N-[2- [(2R)-2-fluoro- 3-hydroxy-3- methyl-butyl]-6- morpholino-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.70 (s, 1H), 9.86 (d, J = 2.3 Hz, 1H), 9.05 (d, J = 2.2 Hz, 1H), 8.78 (s, 1H), 8.73 (s, 1H), 7.59 (s, 1H), 4.90 (s, 1H), 4.58-4.35 (m, 3H), 3.93-3.84 (m, 5H), 3.70 (m, 1H), 2.95-2.88 (m, 4H), 1.18 (dd, J = 4.4, 1.6 Hz, 6H). LCMS (ESI): m/z = 517.1 [M + H]+.
272	N-[6-[4-(2- Amino-2-oxo- ethyl)piperazin- 1-yl]-2- isopropyl-1-oxo- isoindolin-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.89 (s, 1H), 9.43-9.35 (m, 1H), 9.03 (dd, J = 4.3, 1.6 Hz, 1H), 8.78 (s, 1H), 8.75 (s, 1H), 7.56 (s, 1H), 7.39 (dd, J = 7.0, 4.2 Hz, 1H), 7.30 (s, 1H), 7.18 (s, 1H), 4.48-4.35 (m, 3H), 3.06 (s, 2H), 2.98- 2.90 (m, 4H), 2.85-2.80 (m, 4H), 1.23 (d, J = 6.7 Hz, 6H). LCMS (ESI): m/z = 477.2 [M + H]+.
273	N-[2-(2,2- Difluoro-3- hydroxy- propyl)-6- morpholino-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.92 (s, 1H), 9.41 (dd, J = 7.0, 1.6 Hz, 1H), 9.00 (dd, J = 4.2, 1.6 Hz, 1H), 8.77 (d, J = 6.5 Hz, 2H), 7.63 (s, 1H), 7.39 (dd, J = 7.0, 4.2 Hz, 1H), 5.61 (t, J = 6.2 Hz, 1H), 4.59 (s, 2H), 4.02 (t, J = 15.5 Hz, 2H), 3.92-3.88 (m, 4H), 3.68 (td, J = 13.6, 6.3 Hz, 2H), 2.97-2.88 (m, 4H). LCMS (ESI): m/z = 473.1 [M + H]+.
274	(R)-N-(6-(4- cyanopiperidin- 1-yl)-2-(2- fluoro-3- hydroxy-3- methylbutyl)-1- oxoisoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.86 (s, 1H), 9.43 (dd, J = 7.0, 1.6 Hz, 1H), 8.91 (dd, J = 4.2, 1.6 Hz, 1H), 8.77 (d, J = 1.7 Hz, 2H), 7.56 (s, 1H), 7.44 (dd, J = 7.0, 4.2 Hz, 1H), 4.90 (s, 1H), 4.63-4.46 (m, 2H), 4.50-4.39 (m, 2H), 3.99 (m, 1H), 3.70 (m, 1H), 3.16 (s, 1H), 3.04-2.94 (m, 2H), 2.90 (m, 2H), 2.17 (m, 2H), 2.07 (m, 2H), 1.22-1.13 (m, 6H). LCMS (ESI) m/z: 506.2 [M + H]+.
275 and 276	N-(6- morpholino-1- oxo-2- (tetrahydrofuran- 3-yl)isoindolin- 5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 276, Peak 1: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.90 (s, 1H), 9.41 (dd, J = 7.0, 1.6 Hz, 1H), 9.00 (dd, J = 4.2, 1.6 Hz, 1H), 8.76 (s, 2H), 7.58 (s, 1H), 7.39 (dd, J = 7.0, 4.2 Hz, 1H), 4.90 (m, 1H), 4.50 (s, 2H), 3.99 (m, 1H), 3.94-3.85 (m, 4H), 3.87-3.66 (m, 3H), 2.96- 2.87 (m, 4H), 2.24 (m, 1H), 2.14-1.92 (m, 1H). MS (ESI): m/z = 449.2 [M + 1]+. Example 275, Peak 2: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.90 (s, 1H), 9.41 (dd, J = 7.0, 1.6 Hz, 1H), 9.00 (dd, J = 4.2, 1.6 Hz, 1H), 8.76 (s, 2H), 7.58 (s, 1H), 7.39 (dd, J = 7.0, 4.2 Hz, 1H), 4.90 (m, 1H), 4.50 (s, 2H), 3.99 (m, 1H), 3.94-3.86 (m, 4H), 3.84-3.67 (m, 3H), 2.96- 2.85 (m, 4H), 2.30-2.17 (m, 1H), 2.11-1.95 (m, 1H). MS (ESI): m/z = 449.2 [M + 1]+.
277 and 278	N-(6- morpholino-1- oxo-2- ((tetrahydro-2H- pyran-2- yl)methyl) isoindolin-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 278, Peak 1: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.88 (s, 1H), 9.40 (dd, J = 7.0, 1.6 Hz, 1H), 8.99 (dd, J = 4.2, 1.6 Hz, 1H), 8.75 (s, 1H), 8.73 (s, 1H), 7.57 (s, 1H), 7.38 (dd, J = 7.0, 4.2 Hz, 1H), 4.52 (s, 2H), 3.97-3.80 (m, 5H), 3.61- 3.45 (m, 3H), 3.35 (m, 1H), 2.97-2.84 (m, 4H), 1.84- 1.71 (m, 1H), 1.57 (m, 1H), 1.45 (m, 3H), 1.20 (m, 1H). MS (ESI): m/z = 477.2 [M + 1]+. Example 277, Peak 2: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.89 (s, 1H), 9.40 (dd, J = 7.0, 1.6 Hz, 1H), 9.00 (dd, J = 4.2, 1.6 Hz, 1H), 8.75 (s, 1H), 8.73 (s, 1H), 7.57 (s, 1H), 7.39 (dd, J = 7.0, 4.2 Hz, 1H), 4.52 (s, 2H), 3.97-3.81 (m, 5H), 3.62- 3.47 (m, 3H), 3.35 (m, 1H), 2.97-2.82 (m, 4H), 1.77 (m, 1H), 1.63-1.52 (m, 1H), 1.52-1.38 (m, 3H), 1.28- 1.10 (m, 1H). MS (ESI): m/z = 477.2 [M + 1]+.
279	N-[6-[4-(2,2- Difluoroethyl) piperazin-1-yl]-2- (3-hydroxy-3- methyl-butyl)-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3) δ 10.82 (s, 1H), 8.88-8.86 (m, 1H), 8.83-8.82 (m, 2H), 8.80-8.78 (m, 1H), 7.71 (s, 1H), 7.13 (dd, J = 6.8, 4.0 Hz, 1H), 6.12-5.83 (m, 1H), 4.41 (s, 2H), 3.78 (t, J = 7.2 Hz, 2H), 3.03-3.01 (m, 4H), 2.93-2.87 (m, 6H), 1.84 (t, J = 7.2 Hz, 2H), 1.30 (s, 6H). LCMS (ESI): m/z = 528.3 [M + H]+.
280	N-[6-[4-(2- Amino-2-oxo- ethyl)piperazin- 1-yl]-2-(3- hydroxy-3- methyl-butyl)-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 10.87 (s, 1H), 9.39 (dd, J = 7.2, 2.0 Hz, 1H), 9.03- 9.01 (m, 1H), 8.75 (s, 1H), 8.74 (s, 1H), 7.54 (s, 1H), 7.39 (dd, J = 7.2, 4.4 Hz, 1H), 7.30 (s, 1H), 7.20 (s, 1H), 4.45 (s, 2H), 4.35 (s, 1H), 3.58 (t, J = 8.0 Hz, 2H), 3.05 (s, 2H), 2.99-2.89 (m, 4H), 2.84-2.74 (m, 4H), 1.68 (t, J = 8.0 Hz, 2H), 1.15 (s, 6H). LCMS (ESI): m/z = 521.3 [M + H]+.
281	N-[6-[4-(2- Amino-2-oxo- ethyl)piperazin- 1-yl]-2-(1- methyl-4- piperidyl)-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 10.89 (s, 1H), 9.40 (d, J = 7.2 Hz, 1H), 9.05-9.00 (m, 1H), 8.78 (s, 1H), 8.75 (s, 1H), 7.56 (s, 1H), 7.39 (dd, J = 7.2, 4.0 Hz, 1H), 7.31 (s, 1H), 7.21 (s, 1H), 4.44 (s, 2H), 3.99-3.90 (m, 1H), 3.06 (s, 2H), 2.96-2.92 (m, 2H), 2.90-2.82 (m, 2H), 2.81- 2.75 (m, 2H), 2.69-2.65 (m, 2H), 2.34-2.31 (m, 2H), 2.19 (s, 3H), 2.02-1.95 (m, 2H), 1.85-1.75 (m, 2H), 1.70- 1.65 (m, 2H). LCMS (ESI): m/z = 532.3 [M + H]+.
282 and 283	N-[6-[4-[(1S)- 2,2-Difluoro-1- hydroxy-ethyl]- 1-piperidyl]-2- [(2R)-2-fluoro- 3-hydroxy-3- methyl-butyl]-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide and N-[6-[4- [(1R)-2,2- difluoro-1- hydroxy-ethyl]- 1-piperidyl]-2- [(2R)-2-fluoro- 3-hydroxy-3- methyl-butyl]-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 282, Peak 1: 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.40-9.35 (m, 1H), 9.10-9.05 (m, 1H), 8.78 (s, 1H), 8.74 (s, 1H), 7.58 (s, 1H), 7.36 (dd, J = 6.8, 4.4 Hz, 1H), 6.00 (td, J = 55.6, 4.4 Hz, 1H), 4.91 (br s, 1H), 4.65-4.29 (m, 3H), 4.04-3.55 (m, 3H), 3.07- 2.95 (m, 2H), 2.86-2.70 (m, 2H), 2.04-1.86 (m, 2H), 1.84-1.63 (m, 3H), 1.18 (s, 3H), 1.17 (s, 3H). LCMS (ESI): m/z = 561.1 [M + H]+. Example 283, Peak 2: 1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.40-9.35 (m, 1H), 9.10-9.05 (m, 1H), 8.78 (s, 1H), 8.74 (s, 1H), 7.58 (s, 1H), 7.36 (dd, J = 6.8, 4.4 Hz, 1H), 6.00 (td, J = 55.6, 4.4 Hz, 1H), 4.93 (br s, 1H), 4.65-4.29 (m, 3H), 4.04-3.55 (m, 3H), 3.07- 2.95 (m, 2H), 2.86-2.70 (m, 2H), 2.04-1.86 (m, 2H), 1.84-1.63 (m, 3H), 1.18 (s, 3H), 1.17 (s, 3H). LCMS (ESI): m/z = 561.1 [M + H]+.
284	N-[6-[4-(2,2- Difluoroethyl) piperazin-1-yl]-2- [(2R)-2-fluoro- 3-hydroxy-3- methyl-butyl]-1- oxo-isoindolin- 5-yl]-6-methyl- pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 10.75 (s, 1H), 9.27 (s, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.74 (s, 1H), 8.66 (s, 1H), 7.55 (s, 1H), 6.38-6.08 (m, 1H), 4.91 (s, 1H), 4.54-4.37 (m, 3H), 4.00-3.87 (m, 1H), 3.74-3.64 (m, 1H), 2.98- 2.86 (m, 10H), 2.46 (s, 3H), 1.18 (s, 3H), 1.17 (s, 3H). LCMS (ESI): m/z = 560.1 [M + H]+.
285	6-Chloro-N-[6- [4-(2,2- difluoroethyl) piperazin-1-yl]-2- [(2R)-2-fluoro- 3-hydroxy-3- methyl-butyl]-1- oxo-isoindolin- 5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 10.61 (s, 1H), 9.87 (d, J = 2.0 Hz, 1H), 9.01 (d, J = 2.4 Hz, 1H), 8.78 (s, 1H), 8.71 (s, 1H), 7.56 (s, 1H), 6.37-6.09 (m, 1H), 4.91 (s, 1H), 4.54- 4.52 (m, 2H), 4.39-4.32 (m, 1H), 4.00-3.86 (m, 1H), 3.75- 3.65 (m, 1H), 2.94-2.85 (m, 10H), 1.18 (s, 3H), 1.17 (s, 3H). LCMS (ESI): m/z = 580.1 [M + H]+.

Example 286. N3-[2-[(2R)-2-Fluoro-3-hydroxy-3-methyl-butyl]-6-morpholino-1-oxo-isoindolin-5-yl]pyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide

A solution of 6-bromo-N-[2-[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]-6-morpholino-1-oxo-isoindolin-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 269; 80 mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium(0) (13.5 mg, 0.014 mmol), 1,1′-bis(diphenylphosphino)ferrocene (16.0 mg, 0.029 mmol) and zinc cyanide (37 mg, 0.31 mmol) in N,N-dimethylformamide (1.5 ml) was purged with nitrogen and stirred at 120° C. for 30 min. The reaction was quenched with water and extracted with ethyl acetate. The organic phase was isolated, dried with sodium sulfate, filtered, concentrated and purified by silica gel chromatography (eluting gradient 0%-20% methanol:dichloromethane) followed by reverse-phase HPLC to afford N3-[2-[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]-6-morpholino-1-oxo-isoindolin-5-yl]pyrazolo[1,5-a]pyrimidine-3,6-dicarboxamide (2.6 mg, 4%). ¹H NMR (400 MHz, dimethyl sulfoxide-d6) δ 11.00 (s, 1H), 10.09 (s 1H), 8.96 (1H), 8.76 (s, 1H), 8.71 (s, 1H), 4.90 (s, 1H), 4.61-4.46 (m, 3H), 4.34-4.40 (m, 1H), 4.04-3.86 (m, 5H), 2.96-2.89 (m, 4H), 1.39-1.18 (m, 6H). LCMS (ESI) m/z:526.2 [M+H]⁺.

Example 287. N-(2-Isopropyl-6-morpholino-1, 1-dioxo-3H-1,2-benzothiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 5-Chloro-2-methyl-4-nitro-benzenesulfonyl chloride

To a chilled and well-stirred solution of acetic acid (1.84 ml, 32.15 mmol) and hydrochloric acid (10 ml, 120 mmol) was added 5-chloro-2-methyl-4-nitrophenylamine (6.0 g, 32.15 mmol) in small portions at −5° C., then sodium nitrite (2.9 g, 41.80 mmol) in water (6 ml) was added drop-wise to the mixture and stirred for 3 h at −5° C. to afford the solution of diazonium salt. In a separate vessel, concentrated hydrochloric acid (10 ml) was added drop-wise to sodium sulfite (18.7 g, 180.06 mmol) to afford sulfur dioxide which was bubbled into acetic acid (10 ml) to afford the solution of sulfur dioxide in acetic acid. Cuprous chloride (637 mg, 6.43 mmol) was added to the resulting solution. The solution of diazonium salt was added drop-wise to the solution of sulfur dioxide in acetic acid at −5° C. After the addition, the mixture was stirred at −5° C. for further 3 h. Water (50 ml) was added to the mixture which was extracted with dichloromethane (150 ml×3). The combined organic phases were washed with brine (150 ml×3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by flash column (eluent 0-10% ethyl acetate:petroleum ether) to afford 5-chloro-2-methyl-4-nitro-benzenesulfonyl chloride (4.5 g, 52% yield) as yellow solid. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 7.92 (s, 1H), 7.90 (s, 1H), 2.57 (s, 3H).

Step B. 5-Chloro-N-isopropyl-2-methyl-4-nitro-benzenesulfonamide

To a solution of 5-chloro-2-methyl-4-nitro-benzenesulfonyl chloride (2.0 g, 7.4 mmol) and N,N-diisopropylethylamine (1.9 g, 14.8 mmol) in N,N-dimethylformamide (10 ml) was added isopropylamine (525 mg, 8.88 mmol). The mixture was stirred at 20° C. for 30 min, poured into water (50 ml) and extracted with ethyl acetate (150 ml×3). The combined organic phases were washed with brine (150 ml×3), dried over anhydrous sodium sulfate and concentrated to dryness. The residual was purified by flash column (eluting gradient 0-20% ethyl acetate:petroleum ether) to afford 5-chloro-N-isopropyl-2-methyl-4-nitro-benzenesulfonamide (1.8 g, 83% yield) as yellow solid. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.18-8.15 (m, 2H), 8.06 (s, 1H), 3.34-3.31 (m, 1H), 2.67 (s, 3H), 0.99-0.98 (d, J=6.0 Hz, 6H).

Step C. 2-(Bromomethyl)-5-chloro-N-isopropyl-4-nitro-benzenesulfonamide

To a solution of 5-chloro-N-isopropyl-2-methyl-4-nitro-benzenesulfonamide (350 mg, 1.20 mmol) in acetonitrile (10 ml) was added azobisisobutyronitrile (20 mg, 0.12 mmol) and N-bromosuccinimide (234 mg, 1.32 mmol) under nitrogen atmosphere. The mixture was stirred at 70° C. for 16 h and then concentrated. The crude product was purified by flash column (eluting gradient 0-20% ethyl acetate:petroleum ether) to afford 2-(bromomethyl)-5-chloro-N-isopropyl-4-nitro-benzenesulfonamide (80 mg, 18% yield) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (s, 1H), 8.05 (s, 1H), 4.97 (s, 2H), 3.63-3.50 (m, 1H), 1.18 (d, J=6.4 Hz, 6H).

Step D. 6-Chloro-2-isopropyl-5-nitro-3H-1,2-benzothiazole 1,1-dioxide

To a solution of 2-(bromomethyl)-5-chloro-N-isopropyl-4-nitro-benzenesulfonamide (240 mg, 0.64 mmol) in N,N-dimethylformamide (10 ml) were added cesium carbonate (420 mg, 1.30 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 30 min. The reaction mixture was poured into ice water (20 ml) and extracted with dichloromethane (20 ml×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The crude material was purified by flash column (eluting gradient 0-10% methanol:dichloromethane) to afford 6-chloro-2-isopropyl-5-nitro-3H-1,2-benzothiazole 1,1-dioxide (160 mg, 85% yield) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 1H), 7.88 (s, 1H), 4.43 (s, 2H), 4.18-4.09 (m, 1H), 1.41 (d, J=6.4 Hz, 6H).

Step E. 2-Isopropyl-6-morpholino-5-nitro-3H-1,2-benzothiazole 1,1-dioxide

To a solution of 6-chloro-2-isopropyl-5-nitro-3H-1,2-benzothiazole 1,1-dioxide (160 mg, 0.56 mmol) in dimethyl sulfoxide (4 ml) was added N,N-diisopropylethylamine (72 mg, 0.56 mmol) was added morpholine (72 mg, 0.82 mmol). The mixture was stirred at 90° C. for 1 h. The reaction mixture was concentrated and purified by preparatory TLC (eluent: 20% ethyl acetate:petroleum ether) to afford 2-isopropyl-6-morpholino-5-nitro-3H-1,2-benzothiazole 1,1-dioxide (160 mg, 85% yield) as white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.75 (s, 1H), 7.53 (s, 1H), 4.36 (s, 2H), 4.10-4.07 (m, 1H), 3.86 (t, J=4.4 Hz, 4H), 3.10-3.08 (t, J=4.4 Hz, 4H), 1.40 (d, J=6.4 Hz, 6H).

Step F. 2-Isopropyl-6-morpholino-1,1-dioxo-3H-1,2-benzothiazol-5-amine

To a solution of 2-isopropyl-6-morpholino-5-nitro-3H-1, 2-benzothiazole 1,1-dioxide (160 mg, 0.46 mmol) in ethanol (5 ml) and water (1 ml) was added iron (130 mg, 2.34 mmol) and ammonium chloride (63 mg, 1.17 mmol). The mixture was stirred at 80° C. for 2 h. The mixture was filtered and the filtrate was concentrated. The residue was diluted with water (20 ml) and extracted with ethyl acetate (20 ml×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to afford 2-isopropyl-6-morpholino-1,1-dioxo-3H-1,2-benzothiazol-5-amine (140 mg) as a yellow solid, which was used without further purification. LCMS (ESI): m/z=312.1 [M+H]⁺.

Step G. N-(2-Isopropyl-6-morpholino-1,1-dioxo-3H-1,2-benzothiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 2-isopropyl-6-morpholino-1,1-dioxo-3H-1,2-benzothiazol-5-amine (124 mg, 0.40 mmol) and pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (65 mg, 0.40 mmol) in pyridine (4 ml) was added phosphorus oxychloride (0.18 ml, 1.99 mmol). The reaction was stirred at 25° C. for 5 min. The reaction mixture was quenched with saturated sodium bicarbonate solution (10 ml) at 0° C. and extracted with ethyl acetate (20 ml×3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC (23-53% acetonitrile in water with 0.225% formic acid) to give N-(2-isopropyl-6-morpholino-1,1-dioxo-3H-1,2-benzothiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (71.3 mg, 39% yield) as white solid. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.91 (s, 1H), 9.42-9.40 (m, 1H), 9.01-9.00 (m, 1H), 8.76-8.74 (m, 2H), 7.78 (s, 1H), 7.41-7.38 (dd, J=7.2, 4.4 Hz, 1H), 4.45 (s, 2H), 3.90 (t, J=6.4 Hz, 4H), 3.60-3.30 (m, 1H), 2.94-2.92 (m, 4H), 1.29 (d, J=6.8 Hz, 6H). LCMS (ESI): m/z=457.0 [M+H]⁺.

Example 288. N-[2-(2-Hydroxy-2-methyl-propyl)-6-morpholino-1,1-dioxo-3H-1,2-benzothiazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was made in a manner analogous to Example 287 to give N-[2-(2-hydroxy-2-methyl-propyl)-6-morpholino-1,1-dioxo-3H-1,2-benzothiazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (67 mg, 19% yield) as a white solid. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.90 (s, 1H), 9.43-9.41 (m, 1H), 9.01-8.99 (m, 1H), 8.77-8.75 (m, 1H), 8.70-8.69 (m, 1H), 7.83 (s, 1H), 7.41-7.38 (m, 1H), 4.65 (s, 1H), 4.58 (s, 2H), 3.95-3.85 (m, 4H), 3.07 (s, 2H), 2.95-2.90 (m, 4H), 1.19 (s, 6H). LCMS (ESI): m/z=487.1 [M+H]⁺.

Example 289. N-[2-[(2R)-2-Fluoro-3-hydroxy-3-methyl-butyl]-6-morpholino-1,1-dioxo-3H-1,2-benzothiazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was made in a manner analogous to Example 287 to give N-[2-[(2R)-2-fluoro-3-hydroxy-3-methyl-butyl]-6-morpholino-1,1-dioxo-3H-1,2-benzothiazol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 10.88 (s, 1H), 8.89-8.81 (m, 4H), 7.66 (s, 1H), 7.15 (dd, J=7.2, 4.4 Hz, 1H), 4.72-4.58 (m, 2H), 4.44-4.40 (m, 1H), 4.03 (t, J=4.4 Hz, 4H), 3.92-3.80 (m, 1H), 3.48-3.42 (m, 1H), 3.01 (t, J=4.4 Hz, 4H), 1.35 (s, 6H). LCMS (ESI): m/z=519.2 [M+H]⁺.

Example 290. Diethyl ((2-methyl-6-morpholino-5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2,3-dihydrobenzofuran-2-yl)methyl) phosphate

N-[2-(hydroxymethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (142 mg, 0.35 mmol) was dissolved in tetrahydrofuran (2.6 ml) and treated with trimethylamine (0.07 ml, 0.52 mmol), diethyl chlorophosphate (0.06 ml, 0.38 mmol), and 4-dimethylaminopyridine (47 mg, 0.38 mmol). Dichloromethane (2 ml) was added and the reaction mixture was heated at 50° C. Additional diethyl chlorophosphate (0.55 ml, 3.82 mmol) and trimethylamine (0.73 ml, 5.22 mmol) were added and the reaction was allowed to stir at 50° C. for 2 wk. The reaction mixture was cooled to ambient temperature and diluted with dichloromethane, water, and brine. The aqueous phase was isolated and extracted into dichloromethane (3×). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. The crude residue was purified via HPLC to afford the title compound (29 mg, 0.053 mmol). ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.44 (s, 1H), 9.37 (dd, J=7.0, 1.6 Hz, 1H), 8.95 (dd, J=4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.33 (d, J=1.0 Hz, 1H), 7.34 (dd, J=7.0, 4.2 Hz, 1H), 6.76 (s, 1H), 4.03 (d, J=5.7 Hz, 2H), 4.01-3.93 (m, 4H), 3.84 (m, 4H), 3.26-3.16 (m, 1H), 3.05-2.92 (m, 1H), 2.86-2.75 (m, 4H), 1.42 (s, 3H), 1.20 (tdd, J=7.1, 2.8, 0.9 Hz, 6H). MS (ESI): m/z=546.2 [M+1]⁺.

Example 291. (R)—N-(2,2-Dimethyl-6-(pyrrolidin-2-ylmethoxy)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. tert-Butyl 2-(((2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)oxy)methyl)pyrrolidine-1-carboxylate

A mixture of tert-butyl (2R)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (395 mg, 1.92 mmol), potassium tert-butoxide (249 mg, 2.20 mmol), and 6-chloro-2,2-dimethyl-5-nitro-3H-benzofuran (250 mg, 1.10 mmol) in dioxane (6.1 ml) was stirred at 40° C. for 36 h. The reaction mixture was diluted with water and isopropyl acetate. The aqueous phase was isolated and extracted with isopropyl acetate (3×). The combined organic phases were dried over anhydrous sodium sulfate, filtered and purified by flash column chromatography (eluting gradient 0-50% isopropyl acetate:heptanes) to afford the title compound (196 mg, 0.498 mmol, 45% yield) as an orange-yellow viscous oil. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 7.84 (s, 1H), 6.75 (s, 1H), 4.13 (d, J=4.0 Hz, 2H), 4.08-3.94 (m, 2H), 3.27 (m, 2H), 3.00 (d, J=0.9 Hz, 2H), 2.02-1.85 (m, 2H), 1.76 (s, 1H), 1.45 (s, 6H), 1.39 (s, 9H).

Step B. tert-Butyl (R)-2-(((5-amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)oxy)methyl)pyrrolidine-1-carboxylate

A mixture of tert-butyl (R)-2-(((2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran-6-yl)oxy)methyl)pyrrolidine-1-carboxylate (180 mg, 0.456 mmol), iron (535 mg, 9.58 mmol), and ammonium chloride (512 mg, 9.58 mmol) in ethanol (13 ml) and water (2.5 ml) was stirred at 80° C. for 30 min. The mixture was filtered through celite and a small plug of silica to afford tert-butyl (R)-2-(((5-amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)oxy)methyl)pyrrolidine-1-carboxylate (139 mg, 0.385 mmol) which was carried on without further purification.

Step C. tert-Butyl 2-(((2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2,3-dihydrobenzofuran-6-yl)oxy)methyl)pyrrolidine-1-carboxylate

tert-Butyl (R)-2-(((5-amino-2,2-dimethyl-2,3-dihydrobenzofuran-6-yl)oxy)methyl)pyrrolidine-1-carboxylate (139 mg, 0.385 mmol), pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (105 mg, 0.578 mmol), and dimethylaminopyridine (9.5 mg, 0.077 mmol) were dissolved in dichloroethane (3 ml) and treated with N,N-diisopropylethylamine (0.20 ml, 1.16 mmol) and stirred for 16 h at room temperature. The reaction mixture was absorbed onto celite and purified via flash column chromatography (eluting gradient 0-100% isopropyl acetate:heptanes) to provide tert-butyl (R)-2-(((2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2,3-dihydrobenzofuran-6-yl)oxy)methyl)pyrrolidine-1-carboxylate (130 mg, 0.257 mmol, 67% yield).

Step D. (R)—N-(2,2-Dimethyl-6-(pyrrolidin-2-ylmethoxy)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

tert-Butyl (R)-2-(((2,2-dimethyl-5-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2,3-dihydrobenzofuran-6-yl)oxy)methyl)pyrrolidine-1-carboxylate (130 mg, 0.256 mmol) was dissolved in dichloromethane (2 ml) and treated with trifluoroacetic acid (0.25 ml). After 90 min, the solvent was removed and the material was purified by reverse phase HPLC to afford (R)—N-(2,2-dimethyl-6-(pyrrolidin-2-ylmethoxy)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (45 mg, 0.11 mmol). ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.12 (s, 1H), 9.37 (dd, J=7.0, 1.6 Hz, 1H), 8.81 (dd, J=4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.25 (s, 1H), 7.34 (dd, J=7.0, 4.2 Hz, 1H), 6.54 (s, 1H), 3.88 (d, J=6.4 Hz, 2H), 3.65-3.51 (m, 1H), 2.97 (s, 2H), 2.85 (t, J=6.7 Hz, 2H), 2.03-1.86 (m, 1H), 1.79-1.61 (m, 2H), 1.61-1.46 (m, 1H), 1.41 (s, 6H).). MS (ESI): m/z=408.2 [M+1]⁺

Example 292. (R)—N-(6-((1-(2,2-Difluoroethyl)pyrrolidin-2-yl)methoxy)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(R)—N-(2,2-Dimethyl-6-(pyrrolidin-2-ylmethoxy)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 291, 52 mg, 0.128 mmol) was dissolved in dimethylformamide (2 ml) and treated with triethylamine (0.45 ml, 3.20 mmol) followed by 2,2-difluoroethyl trifluoromethanesulfonate (0.021 ml, 0.154 mmol) and heated at 60° C. for 16 h. Additional triethylamine (0.45 ml, 3.20 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (0.021 ml, 0.154 mmol) were added and continued to stir at 60° C. for 4 h. The reaction mixture was concentrated in vacuo and purified by reverse phase HPLC to afford the title compound (24 mg, 0.05 mmol, 60% yield) as a solid. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.02 (s, 1H), 9.37 (dd, J=7.0, 1.6 Hz, 1H), 8.85 (dd, J=4.3, 1.6 Hz, 1H), 8.67 (s, 1H), 8.23 (s, 1H), 7.34 (dd, J=7.0, 4.2 Hz, 1H), 6.58 (s, 1H), 5.99 (tt, J=56.2, 4.4 Hz, 1H), 4.08 (dd, J=9.4, 5.1 Hz, 1H), 3.81 (dd, J=9.3, 7.2 Hz, 1H), 3.18 (m, 1H), 3.11 (m, 1H), 2.98 (s, 2H), 2.82 (qd, J=14.3, 4.8 Hz, 1H), 2.47 (m, 1H), 2.11-2.00 (m, 1H), 1.74 (m, 3H), 1.42 (s, 6H), 1.24 (s, 1H). MS (ESI): m/z=472.2 [M+1]⁺.

TABLE 9
The following examples were made in a manner similar to that for Example 64:
Ex.	Name	Structure	NMR, MS
293	N-(6- (((1S,3S,5S)-2-(2,2- difluoroethyl)-2- azabicyclo[3.1.0] hexan-3- yl)methoxy)- 2,2-dimethyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 9.98 (s, 1H), 9.37 (dd, J = 7.0, 1.6 Hz, 1H), 8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.19 (d, J = 1.1 Hz, 1H), 7.35 (dd, J = 7.0, 4.2 Hz, 1H), 6.57 (s, 1H), 5.97 (tt, J = 56.2, 4.3 Hz, 1H), 4.00 (dd, J = 9.3, 5.9 Hz, 1H), 3.89-3.80 (m, 1H), 3.70 (dd, J = 9.4, 6.6 Hz, 1H), 3.23-3.11 (m, 2H), 2.97 (s, 2H), 2.67 (td, J = 6.3, 2.4 Hz, 1H), 2.42 (m, 1H), 1.66- 1.60 (m, 1H), 1.51-1.43 (m, 1H), 1.41 (s, 6H), 0.57 (m, 1H), 0.32 (m, 1H). MS (ESI): m/z = 484.2 [M + 1]+.
294	N-(6- (((1R,5S,6R)-3-(2,2- difluoroethyl)-3- azabicyclo[3.1.0] hexan-6- yl)methoxy)- 2,2-dimethyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.27 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.75 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.27 (d, J = 1.1 Hz, 1H), 7.26 (dd, J = 7.0, 4.1 Hz, 1H), 6.50 (s, 1H), 6.12 (tt, J = 55.8, 4.2 Hz, 1H), 3.90 (d, J = 6.9 Hz, 2H), 3.05 (d, J = 8.7 Hz, 2H), 2.97 (s, 2H), 2.86 (td, J = 16.2, 4.2 Hz, 2H), 2.49- 2.45 (m, 2H), 1.71 (m, 1H), 1.52 (m, 2H), 1.41 (s, 6H). MS (ESI): m/z = 484.2 [M + 1]+.
295	N-(6- (((1R,5S,6R)-3- azabicyclo[3.1.0] hexan-6- yl)methoxy)- 2,2-dimethyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.13 (s, 1H), 9.37 (dd, J = 7.0, 1.6 Hz, 1H), 8.88 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.23 (s, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 6.52 (s, 1H), 3.96 (d, J = 6.9 Hz, 2H), 2.97 (s,2H), 2.85 (d, J = 11.1 Hz, 2H), 2.78-2.66 (m, 2H), 1.49 (m, 2H), 1.41 (s, 6H), 1.29 (m, 1H). MS (ESI): m/z = 420.2 [M + 1]+.
296	N-(2,2- Dimethyl-6- ((tetrahydrofuran- 3-yl)methoxy)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		MS (ESI): m/z = 409.2 [M + 1]+.
297	N-(2,2- Dimethyl-6- (pyridin-3- ylmethoxy)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.09 (s, 1H), 9.35 (dd, J = 7.0, 1.6 Hz, 1H), 8.91 (d, J = 2.5 Hz, 1H), 8.66 (s, 1H), 8.62 (dd, J = 4.9, 1.6 Hz, 1H), 8.40 (dd, J = 4.3, 1.6 Hz, 1H), 8.31 (s, 1H), 7.99 (dt, J = 8.0, 2.1 Hz, 1H), 7.49 (dd, J = 7.7, 4.8 Hz, 1H), 7.30 (dd, J = 7.0, 4.3 Hz, 1H), 6.77 (s, 1H), 5.25 (s, 2H), 3.00 (s, 2H), 1.43 (s, 6H). MS (ESI): m/z = 416.1
			[M + 1]+.
298	N-(6-(Cyclopropyl- methoxy)-2,2- dimethyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.31 (s, 1H), 9.37 (dd, J = 7.1, 1.6 Hz, 1H), 8.85 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.29 (s, 1H), 7.31 (dd, J = 7.0, 4.2 Hz, 1H), 6.52 (s, 1H), 3.91 (d, J = 6.8 Hz, 2H), 2.97 (s, 2H), 1.41 (s, 6H), 1.37 (dd, J = 8.2, 4.3 Hz, 1H), 0.64 (dt, J = 8.0, 2.9 Hz, 2H), 0.47-0.35 (m, 2H). MS (ESI): m/z = 379.1 [M + 1]+.
299	N-(2,2- Dimethyl-6-((3- methyloxetan-3- yl)methoxy)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 9.89 (s, 1H), 9.37 (dd, J = 7.0, 1.5 Hz, 1H), 8.83 (dd, J = 4.3, 1.7 Hz, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 7.32 (dd, J = 7.0, 4.2 Hz, 1H), 6.63 (s, 1H), 4.56 (d, J = 5.8 Hz, 2H), 4.39 (d, J = 5.8 Hz, 2H), 4.17 (s, 2H), 2.98 (s, 2H), 1.53 (s, 3H), 1.42 (s, 6H). MS (ESI): m/z = 409.1 [M + 1]+.
300	N-(2,2- Dimethyl-6-((1- methyl-1H- pyrazol-4- yl)methoxy)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- arboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.16 (s, 1H), 9.35 (dd, J = 7.0, 1.7 Hz, 1H), 8.65 (s, 1H), 8.32-8.25 (m, 2H), 7.85 (s, 1H), 7.64 (s, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 6.71 (s, 1H), 5.02 (s, 2H), 3.87 (s, 3H), 2.98 (s, 2H), 1.42 (s, 6H). MS (ESI): m/z = 419.1 [M + 1]+.
301	N-(2,2-Dimethyl-6- (pyridin-4- ylmethoxy)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		MS (ESI): m/z = 416.1 [M + 1]+.
302	N-(6-(2,2- Difluoroethoxy)- 2,2-dimethyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.30 (s, 1H), 9.38 (dd, J = 7.0, 1.7 Hz, 1H), 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 6.66 (s, 1H), 6.54 (t, J = 3.7 Hz, 1H), 4.41 (td, J = 14.2, 3.7 Hz, 2H), 2.99 (s, 2H), 1.42 (s, 6H). MS (ESI): m/z = 389.1 [M + 1]+.
303	2,2-Dimethyl-6- [1-(1-methylpyrazol- 4-yl)ethoxy]- 3H-benzofuran- 5-amine		1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 8.80 (dd, J = 6.8, 1.6 Hz, 1H), 8.75 (s, 1H), 8.54 (dd, J = 4.4, 1.6 Hz, 1H), 8.40 (s, 1H), 7.57 (s, 1H), 7.34 (s, 1H), 7.01 (dd, J = 6.8, 4.0 Hz, 1H), 6.45 (s, 1H), 5.41 (q, J = 6.4 Hz, 1H), 3.84 (s, 3H), 3.01 (s, 2H), 1.75 (d, J = 6.4 Hz, 3H), 1.47 (s, 6H). LCMS (ESI): m/z = 455.0 [M + H]+.
304	N-(2,2- Dimethyl-6-((1- methylpiperidin- 3-yl)oxy)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3) δ 10.17 (s., 1H), 8.82 (d, J = 7.2 Hz, 1H), 8.76 (s, 1H), 8.68 (s., 1H), 8.41 (s, 1H), 7.04 (dd, J = 6.8, 4.0 Hz, 1H), 6.49 (s, 1H), 4.38 (m, 1H), 3.16- 3.14 (m 1H), 3.02 (s, 2H), 2.74-2.72 (m, 1H), 2.32 (s, 3H), 2.28-2.23 (m, 2H), 2.05- 2.01 (m, 1H), 1.87-1.85 (m, 1H), 1.78-1.55 (m, 2H), 1.49 (s, 6H). LCMS (ESI): m/z = 422.1 [M + H]+.
305 and 306	R)-N-(2,2- Dimethyl-6-((2- oxo piperidin-4- yl)methoxy)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide and (S)-N-(2,2- Dimethyl-6-((2- oxo piperidin-4- yl)methoxy)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 305, Peak 1: 1HNMR (400 MHz,CDCl3) δ 9.85 (s, 1H), 8.86-8.77 (m, 3H), 8.36 (s, 1H), 7.04 (dd, J = 6.4, 4.0 Hz, 1H), 6.40 (s, 1H), 5.76 (s, 1H), 4.07-4.04 (m, 1H), 3.92 (dd, J = 8.8, 6.4 Hz, 1H), 3.44-3.40 (m, 2H), 3.03 (s, 2H), 2.95-2.91 (m, 1H), 2.61-2.50 (m, 2H), 2.06-1.94 (m, 1H), 1.91- 1.80 (m, 1H), 1.49 (s, 6H). LCMS (ESI): m/z = 436.2 [M + H]+. Example 306, Peak 1: 1HNMR(400 MHz, CDCl3) δ 9.84 (s, 1H), 8.85-8.77 (m, 3H), 8.36 (s, 1H), 7.04 (dd, J = 6.8, 4.0 Hz, 1H), 6.40 (s, 1H), 5.76 (s, 1H), 4.07-4.04 (m, 1H), 3.92 (dd, J = 8.8, 6.4 Hz, 1H), 3.44-3.40 (m, 2H), 3.03 (s, 2H), 2.95-2.91 (m, 1H), 2.61-2.50 (m, 2H), 2.06-1.94 (m, 1H), 1.91- 1.80 (m, 1H), 1.49 (s, 6H). LCMS (ESI): m/z = 436.2 [M + H]+.
307 and 308	N-[2,2- Dimethyl-6- [[(3R)-5- oxopyrrolidin-3- yl]methoxy]-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide and N-[2,2-Dimethyl-6- [[3S)-5-oxo pyrrolidin-3- yl]methoxy]-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 308, Peak 1: 1H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 8.82-8.71 (m, 3H), 8.32 (s, 1H), 7.05 (dd, J = 7.2, 4.8 Hz, 1H), 6.41 (s, 1H), 5.53 (s, 1H), 4.11-4.06 (m, 2H), 3.64-3.59 (m, 1H), 3.43-3.39 (m, 1H), 3.06- 3.04 (m, 1H), 3.03 (s, 2H), 2.58 (d, J = 8..8 Hz, 2H), 1.49 (s, 6H). LCMS (ESI): m/z = 422.2 [M + H]+. Example 307, Peak 2: 1H NMR (400 MHz, CDCl3) δ 9.85 (s, 1H), 8.82-8.71 (m, 3H), 8.31 (s, 1H), 7.05 (dd, J = 6.8, 4.4 Hz, 1H), 6.41 (s, 1H), 5.54 (s, 1H), 4.10-4.05 (m, 2H), 3.64-3.59 (m, 1H), 3.43-3.39 (m, 1H), 3.06- 3.04 (m, 1H), 3.03 (s, 2H), 2.58 (d, J = 8.8 Hz, 2H), 1.49 (s, 6H). LCMS (ESI): m/z = 422.2 [M + H]+.
309	N-(2,2- Dimethyl-6- (piperidin-4- ylmethoxy)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.03 (s, 1H) , 9.40 (d, J = 6.0 Hz, 1H), 8.85-8.75 (m, 2H), 8.65 (s, 1H), 8.23 (s, 1H), 7.40 (dd, J = 7.2, 4.0 Hz, 1H), 6.60 (s, 1H), 3.96 (d, J = 6.8 Hz, 2H), 3.30-3.25 (m, 2H), 2.97-2.92 (m, 4H), 2.30-2.15 (m, 2H), 2.10- 2.00 (m, 2H), 1.55-1.45 (m, 2H), 1.41 (s, 6H). LCMS (ESI): m/z = 422.3 [M + H]+.
310 and 311	(S)-N-(6-(2,2- difluoroethoxy)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide and (R)-N-(6-(2,2- difluoroethoxy)- 2-(hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 310, Peak 1: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.27 (s, 1H), 9.36 (dd, J = 7.0, 1.5 Hz, 1H), 8.83 (dd, J = 4.2, 1.5 Hz, 1H), 8.67 (s, 1H), 8.28 (s, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 6.70-6.33 (m, 2H), 5.04 (t, J = 5.8 Hz, 1H), 4.40 (td, J = 14.5, 3.2 Hz, 2H), 3.43 (m, 2H), 3.19 (d, J = 15.6 Hz, 1H), 2.82 (d, J = 15.5 Hz, 1H), 1.35 (s, 3H).MS (ESI): m/z = 405.1 [M + 1]+. Example 311, Peak 2: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.27 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.83 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.28 (s, 1H), 7.33 (dd, J = 7.0, 4.2 Hz, 1H), 6.70-6.31 (m, 2H), 5.04 (t, J = 5.7 Hz, 1H),4.40 (td, J = 14.2, 3.0 Hz, 2H), 3.44 (m, 2H), 3.19 (d, J = 15.7 Hz, 1H), 2.82 (d, J = 15.6 Hz, 1H), 1.35 (s, 3H). MS (ESI): m/z = 405.1 [M + 1]+.
312 and 313	N-[(2S)-6-(cis-4- Hydroxycyclo- hexoxy)-2-(1- hydroxy-1- methyl-ethyl)-2- methyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide and N-[(2R)-6-(cis- 4-Hydroxycyclo- hexoxy)-2-(1- hydroxy-1- methyl-ethyl)-2- methyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 312, Peak 1: 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.40-9.35 (m, 1H), 9.00-8.95 (m, 1H), 8.67 (s, 1H), 8.14 (s, 1H), 7.35- 7.32 (m, 1H), 6.50 (s, 1H), 4.67 (s, 1H), 4.63 (d, J = 3.2 Hz, 1H), 4.55-4.50 (m, 1H), 3.65-3.60 (m, 1H), 2.67- 2.66 (m, 1H), 2.52-2.51 (m, 1H), 1.99-1.96 (m, 2H), 1.81- 1.73 (m, 2H), 1.69-1.59 3H), 1.16 (s, 3H). LCMS (ESI): m/z = 467.0 [M + H] Example 313, Peak 2: 1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.40-9.35 (m, 1H), 9.00-8.95 (m, 1H), 8.67 (s, 1H), 8.14 (s, 1H), 7.35- 7.32 (m, 1H), 6.50 (s, 1H), 4.67 (s, 1H), 4.63 (d, J = 3.2 Hz, 1H), 4.55-4.50 (m, 1H), 3.65-3.60 (m, 1H), 2.67- 2.66 (m, 1H), 2.52-2.51 (m, 1H), 1.99-1.96 (m, 2H), 1.78- 1.64 (m, 6H), 1.24 (s, 3H), 1.23 (s. 3H), 1.16 (s, 3H). LCMS (ESI): m/z = 467.0 [M + H]+.
314 and 315	N-[(2S)-6- (trans-4- Hydroxycyclo- hexoxy)-2-(1- hydroxy-1- methyl-ethyl)-2- methyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide and N-[(2R)-6- (trans-4- Hydroxycyclohexoxy)- 2-(1-hydroxy-1- methyl-ethyl)-2- methyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 314, Peak 1: 1H NMR (400 MHz, DMSO- d6) δ 10.18 (s, 1H), 9.36 (d, J = 6.8 Hz, 1H), 8.82 (dd, J = 4.0, 1.6 Hz, 1H), 8.65 (s, 1H), 8.14 (s, 1H), 7.33-7.30 (m, 1H), 6.52 (s, 1H), 4.67 (s, 1H), 4.58 (d, J = 4.0 Hz, 1H), 4.39-4.36 (m, 1H), 3.60- 3.58 (m, 1H), 2.67-2.66 (m, 1H), 2.52-2.51 (m, 1H), 2.07- 2.04 (m, 2H), 1.93-1.86 (m, 2H), 1.58-1.53 (m, 2H), 1.41-1.35 (m, 2H), 1.24 (s, 3H), 1.23 (s, 3H), 1.16 (s, 3H). LCMS (ESI): m/z = 467.0 [M + H]+. Example 315, Peak 2: 1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.40-9.35 (m, 1H), 8.82 (dd, J = 4.4, 2.0 Hz, 1H), 8.65 (s, 1H), 8.14 (s, 1H), 7.33-7.30 (m, 1H), 6.52 (s, 1H), 4.67 (s, 1H), 4.58 (s, 1H), 4.39-4.36 (m, 1H), 3.60-3.50 (m, 1H), 2.67- 2.66 (m, 1H), 2.52-2.51 (m, 1H), 2.07-2.04 (m, 2H), 1.92- 1.88 (m, 2H), 1.57-1.56 (m, 2H), 1.38-1.35 (m, 2H), 1.24 (s, 3H), 1.23 (s, 3H), 1.16 (s, 3H). LCMS (ESI): m/z = 467.2 [M + H]+.

TABLE 10
The following examples were made in a manner similar to that for Example 6:
Ex.	Name	Structure	NMR, MS
316 and 317	(R)-N-(2- (hydroxymethyl)-6-(4- (hydroxymethyl) piperidin-1-yl)-2- (trifluoromethyl)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide and (S)-N-(2- (hydroxymethyl)-6- (4-(hydroxymethyl) piperidin-1-yl)-2- (trifluoromethyl)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 316, Peak 1: 1H NMR (400 MHz, Chloroform-d) δ 10.44 (s, 1H), 8.77-8.66 (m, 3H), 8.41 (s, 1H), 6.96 (dd, J = 7.0, 4.1 Hz, 1H), 6.69 (s, 1H), 3.99 (d, J = 12.3 Hz, 1H), 3.79 (d, J = 12.4 Hz, 1H), 3.56 (d, J = 4.9 Hz, 2H), 3.38 (q, J = 16.2 Hz, 2H), 3.02 (t, J = 10.6 Hz, 2H), 2.60 (dd, J = 11.7, 9.2 Hz, 2H), 2.34-1.90 (m, 1H), 1.79-1.62 (m, 4H), 1.30-1.11 (m, 2H). (ESI): m/z = 492.2 [M + 1]+. Example 317, Peak 2: 1H NMR (400 MHz, Chloroform-d) δ 10.52 (s, 1H), 8.86-8.75 (m, 3H), 8.50 (s, 1H), 7.03 (dd, J = 7.0, 4.2 Hz, 1H), 6.77 (s, 1H), 4.07 (d, J = 12.4 Hz, 1H), 3.85 (d, J = 12.4 Hz, 1H), 3.64 (d, J = 4.9 Hz, 2H), 3.55-3.37 (m, 2H), 3.21-2.97 (m, 2H), 2.67 (q, J = 10.0 Hz, 2H), 2.29-
			1.87 (m, 2H), 1.75 (d, J =
			29.5 Hz, 3H), 1.37-1.20
			(m, 2H). (ESI): m/z = 492.2
			[M + 1]+.
318 and 319	(R)-N-(6-(4- fluoro-4- (hydroxymethyl) piperidin-1-yl)-2- (hydroxymethyl)-2- (trifluoromethyl)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide and (S)-N-(6-(4- fluoro-4- (hydroxymethyl) piperidin-1-yl)-2- (hydroxymethyl)-2- (trifluoromethyl)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 318, Peak 1: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.46 (s, 1H), 9.37 (dt, J = 7.0, 1.0 Hz, 1H), 8.89 (dd, J = 4.3, 1.5 Hz, 1H), 8.70 (s, 1H), 8.42 (s, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 6.92 (s, 1H), 5.57 (t, J = 6.1 Hz, 1H), 5.16 (t, J = 5.9 Hz, 1H), 3.76 (qd, J = 12.1, 6.1 Hz, 2H), 3.60-3.45 (m, 3H), 3.37 (s, 1H), 2.87 (q, J = 9.4, 8.8 Hz, 4H), 2.06 (dt, J = 35.2, 11.3 Hz, 2H), 1.86 (t, J = 12.3 Hz, 2H). (ESI): m/z = 510.2 [M + 1]+. Example 319, Peak 2: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.44 (s, 1H), 9.34 (d, J = 7.0 Hz, 1H), 8.88 (dd, J = 4.2, 1.5 Hz, 1H), 8.68 (s, 1H), 8.40 (s, 1H), 7.32 (dd, J = 7.0, 4.2 Hz, 1H), 6.90 (s, 1H), 5.66- 5.56 (m, 1H), 5.22-5.10 (m, 1H), 3.76 (qd, J = 12.1, 6.1 Hz, 2H), 3.53 (dd, J = 17.6, 6.2 Hz, 3H), 3.34 (d, J = 16.6 Hz, 1H), 2.94-2.79
			(m, 4H), 2.15-1.95 (m,
			2H), 1.90-1.81 (m, 2H).
			(ESI): m/z = 510.2 [M + 1]+.
320 and 321	(R)-N-(2- (hydroxymethyl)- 2-methyl-6-(1- oxo-2,7- diazaspiro[3.5] nonan-7-yl)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide and (S)-N-(2- (hydroxymethyl)- 2-methyl-6-(1- oxo-2,7- diazaspiro[3.5] nonan-7-yl)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 320, Peak 1: 1H NMR (400 MHz, Chloroform-d) δ 10.69 (s, 1H), 9.15(s, 1H), 8.80 (dd, J = 7.1, 1.7 Hz, 1H), 8.77 (s, 1H), 8.56 (s, 1H), 7.11 (dd, J = 7.0, 4.1 Hz, 1H), 6.62 (s, 1H), 5.68 (s, 1H), 3.66 (d, J = 6.3 Hz, 2H), 3.33 (s, 2H), 3.24 (d, J = 15.6 Hz, 1H), 3.13-3.04 (m, 2H), 2.94 (d, J = 15.5 Hz, 1H), 2.69 (t, J = 11.6 Hz, 2H), 2.52 (td, J = 12.6, 4.1 Hz, 2H), 1.92 (dd, J = 9.5, 5.0 Hz, 3H), 1.46 (s, 3H). (ESI): m/z = 463.2 [M + 1]+. Example 321, Peak 2: 1H NMR (400 MHz, Chloroform-d) δ 10.69 (s, 1H), 9.14 (s, 1H), 8.84- 8.73 (m, 2H), 8.56 (s, 1H), 7.11 (dd, J = 7.0, 4.1 Hz, 1H), 6.62 (s, 1H), 5.68 (s, 1H), 3.66 (d, J = 6.0 Hz, 2H), 3.34 (s, 2H), 3.24 (d, J = 15.6 Hz, 1H), 3.08 (d, J = 11.8 Hz, 2H), 2.94 (d, J = 15.6 Hz, 1H), 2.70 (dd, J = 12.8, 10.5 Hz, 2H), 2.57- 2.45 (m, 2H), 1.91 (d, J = 13.5 Hz, 3H), 1.46 (s, 3H). (ESI): m/z = 463.2 [M + 1]+.
322	N-(2- (hydroxymethyl)-6- (6-(hydroxymethyl)- 3-azabicyclo[3.1.0] hexan-3-yl)-2- methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, Chloroform-d) δ 9.67 (s, 1H), 8.85 (d, J = 4.1 Hz, 1H), 8.76-8.68 (m, 2H), 8.17 (s, 1H), 6.99 (dd, J = 7.0, 4.2 Hz, 1H), 6.55 (s, 1H), 3.59 (s, 2H), 3.46 (d, J = 7.3 Hz, 2H), 3.34 (t, J = 8.1 Hz, 2H), 3.15 (d, J = 15.5 Hz, 1H), 2.96 (t, J = 8.9 Hz, 2H), 2.85 (d, J = 15.4 Hz, 1H), 1.38 (s, 5H), 1.31- 1.15 (m, 3H). (ESI): m/z = 436.2 [M + 1]+.
323 and 324	N-[(2S)-2- (Hydroxymethyl)- 6-[4-(1- hydroxy-1- methyl-ethyl)-1- piperidyl]-2- methyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide and N-[(2R)-2- (Hydroxymethyl)- 6-[4-(1-hydroxy- 1-methyl-ethyl)-1- piperidyl]-2- methyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 323, Peak 1: 1HNMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 8.85-8.75 (m, 3H), 8.43 (s, 1H), 7.00 (dd, J = 7.2, 4.0 Hz, 1H), 6.66 (s, 1H), 3.75-3.65 (m, 2H), 3.24 (d, J = 16.0 Hz, 1H), 3.20- 3.10 (m, 1H), 2.94 (d, J = 16.0 Hz, 1H), 2.66-2.60 (m, 2H), 1.90-1.70 (m, 5H), 1.47 (s, 3H), 1.27 (s, 6H). LCMS (ESI): m/z = 466.2 [M + H]+. Example 324, Peak 2: 1HNMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 8.84-8.77 (m, 3H), 8.42 (s, 1H), 7.00 (dd, J = 7.2, 4.0 Hz, 1H), 6.66 (s, 1H), 3.67 (s, 2H), 3.24 (d, J = 16.0 Hz, 1H), 3.20-3.10 (m, 1H), 2.94 (d, J = 16.0 Hz, 1H), 2.65-2.62 (m, 2H), 1.90- 1.70 (m, 5H), 1.47 (s, 3H), 1.26 (s, 6H). LCMS (ESI): m/z = 466.2 [M + H]+.
325	N-(6-(4-(2,2- Difluoroethyl) piperazin-1-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)-6- methylpyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.31 (s, 1H), 9.22 (s, 1H), 8.82 (d, J = 1.6 Hz, 1H), 8.59 (s, 1H), 8.27 (s, 1H), 6.69 (s, 1H), 6.33-6.04 (m, 1H), 5.04 (t, J = 6.0 Hz, 1H), 3.42 (t, J = 5.2Hz, 1H), 3.32-3.17 (m, 2H), 2.88-2.84 (m, 2H), 2.84- 2.79 (m, 8H), 2.44 (s, 3H), 1.33 (s, 3H). LCMS (ESI): m/z = 487.5 [M + H]+
326 and 327	(S)-N-(6-(4-(2,2- Difluoroethyl) piperazin-1-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)-6- methylpyrazolo[1,5- a]pyrimidine-3- carboxamide and (R)-N-(6-(4- (2,2-Difluoroethyl) piperazin-1-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)-6- methylpyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 326, Peak 1: 1H NMR (400 MHz, CD3OD) δ 8.93 (s, 1H), 8.79 (d, J = 1.6 Hz, 1H), 8.57 (s, 1H), 8.18 (s, 1H), 6.69 (s, 1H), 6.18- 5.88 (m, 1H), 3.62-3.57 (m, 2H), 3.24 (d, J = 16.0 Hz, 1H), 2.93-2.85 (m, 11H), 2.50 (s, 3H), 1.42 (s, 3H). MS (ESI): m/z = 487.1 [M + 1]+. Example 327, Peak 2: 1H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H), 8.78 (s, 1H), 8.56 (s, 1H), 8.18 (s, 1H), 6.68 (s, 1H), 6.17-5.87 (m, 1H), 3.62-3.57 (m, 2H), 3.24 (d, J = 16.0 Hz, 1H), 2.93- 2.85 (m, 11H), 2.50 (s, 3H), 1.42 (s, 3H). MS (ESI): m/z = 487.1 [M + 1]+.
328	N-(6-(4-Fluoro-4- (hydroxymethyl) piperidin-1-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)-6- methylpyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) 10.41 (s, 1H), 9.22 (s, 1H), 8.81 (d, J = 2.0 Hz, 1H), 8.59 (s, 1H), 8.31 (s, 1H), 6.68 (s, 1H), 5.22 (t, J = 6.4 Hz, 1H), 5.04 (t, J = 6.4 Hz, 1H), 3.55-3.50 (m, 2H), 3.44-3.41 (m, 2H), 3.19 (d, J = 16.0 Hz, 1H), 2.87-2.80 (m, 5H), 2.40 (s, 3H), 2.17-2.02 (m, 2H), 1.82 (t, 5.2 Hz, 2H), 1.34 (s, 3H). LCMS (ESI): m/z = 470.1 [M + H]+.
329, 330, 331 and 332	N-((R)-6-((R)-4- hydroxy-4- methylazepan-1- yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide, N- (R)-6-((S)-4- hydroxy-4- methylazepan-1-yl)- 2-(hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide, N- (S)-6-((R)-4- hydroxy-4- methylazepan-1-yl)- 2-(hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide and N-((S)-6- ((S)-4-hydroxy- 4-methylazepan-1- yl)-2-		Example 329, Peak 4: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.50 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.95 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 7.35 (dd, J = 7.0, 4.2 Hz, 1H), 6.64 (s, 1H), 5.02 (t, J = 5.8 Hz, 1H), 4.29 (s, 1H), 3.42 (m, 2H), 3.22-3.14 (m, 1H), 3.13- 3.03 (m, 1H), 2.94-2.75 (m, 4H), 2.07-1.86 (m, 3H), 1.85-1.69 (m, 2H), 1.62-1.49 (m, 1H), 1.33 (s, 3H), 1.18 (s, 3H). MS (ESI): m/z = 452.2 [M + 1]+. Example 330, Peak 3: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.50 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.95 (dd, J = 4.2, 1.6 Hz, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 7.35 (dd, J = 7.0, 4.2 Hz, 1H), 6.64 (s, 1H), 5.02 (t, J = 5.8 Hz, 1H), 4.29 (s, 1H), 3.42 (m, 2H), 3.18 (d, J = 15.9 Hz, 1H), 3.07 (m, 1H), 2.95-2.73 (m, 4H), 2.09-1.86 (m, 3H), 1.85-1.70 (m, 2H), 1.63-1.47 (m, 1H), 1.34 (s,
	(hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute and relative stereochemistry assigned arbitrarily)		3H), 1.18 (s, 3H). MS (ESI): m/z = 452.2 [M + 1]+. Example 331, Peak 2: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.50 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.95 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 7.35 (dd, J = 7.0, 4.2 Hz, 1H), 6.64 (s, 1H), 5.02 (t, J = 5.8 Hz, 1H), 4.29 (s, 1H), 3.49-3.35 (m, 2H), 3.18 (d, J = 16.1 Hz, 1H), 3.07 (m, 1H), 2.95- 2.73 (m, 4H), 2.06-1.87 (m, 3H), 1.85-1.70 (m, 2H), 1.60-1.48 (m, 1H), 1.34 (s, 3H), 1.18 (s, 3H). MS (ESI): m/z = 452.2 [M + 1]+. Example 332, Peak 1: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.50 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.95 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 7.35 (dd, J = 7.0, 4.2 Hz, 1H), 6.64 (s, 1H), 5.02 (t, J = 5.8 Hz, 1H), 4.29 (s, 1H), 3.42 (m, 2H), 3.18 (d, J = 16.2 Hz, 1H), 3.14-2.98 (m, 1H), 2.95-
			2.73 (m, 4H), 2.10-1.85
			(m, 3H), 1.85-1.68 (m,
			2H), 1.62-1.47 (m, 1H),
			1.33 (s, 3H), 1.18 (s,
			3H). MS (ESI): m/z = 452.2
			[M + 1]+.
333 and 334	(R)-N-(6-(4-(2- amino-2- oxoethyl)piperidin- 1-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide and (S)-N-(6-(4- (2-amino-2- oxoethyl)piperidin- 1-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 333, Peak 1: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.43 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.88 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 7.33 (m, 2H), 6.79 (s, 1H), 6.67 (s, 1H), 5.02 (t, J = 5.8 Hz, 1H), 3.42 (m, 2H), 3.19 (d, J = 16.0 Hz, 1H), 2.90 (d, J = 11.1 Hz, 2H), 2.82 (d, J = 15.9 Hz, 1H), 2.64 (t, J = 11.3 Hz, 2H), 2.14-2.04 (m, 2H), 1.89-1.77 (m, 1H), 1.73 (m, 2H), 1.64-1.49 (m, 2H), 1.34 (s, 3H). MS (ESI): m/z = 465.2 [M + 1]+. Example 334, Peak 2: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.43 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.88 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 7.33 (m, 2H), 6.79 (s, 1H), 6.67 (s, 1H), 5.02 (t, J = 5.8 Hz, 1H), 3.42 (m, 2H), 3.19 (d, J = 16.0 Hz, 1H), 2.90 (d, J = 11.1
			Hz, 2H), 2.82 (d, J = 15.9
			Hz, 1H), 2.64 (t, J = 11.3 Hz,
			2H), 2.10 (m, 2H), 1.87-
			1.77 (m, 1H), 1.73 (m, 2H),
			1.67-1.46 (m, 2H), 1.34 (s,
			3H). MS (ESI): m/z = 465.2
			[M + 1]+.
335 and 336	(R)-N-(6-(4- cyanopiperidin- 1-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide and (S)-N-(6-(4- cyanopiperidin- l-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 336, Peak 1: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.37 (s, 1H), 9.38 (dd, J = 7.0, 1.6 Hz, 1H), 8.86 (dd, J = 4.2,1.7 Hz, 1H), 8.69 (s, 1H), 8.30 (d, J = 1.0 Hz, 1H), 7.38 (dd, J = 7.0, 4.2 Hz, 1H), 6.65 (s, 1H), 5.09- 4.96 (m, 1H), 3.49-3.36 (m, 2H), 3.20 (d, J = 16.8 Hz, 1H), 3.09 (m, 1H), 2.96- 2.86 (m, 2H), 2.86-2.79 (m, 1H), 2.76 (m, 2H), 2.17- 2.07 (m, 2H), 2.00 (m, 2H), 1.34 (s, 3H). MS (ESI): m/z = 433.2 [M + 1]+. Example 335, Peak 2: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.37 (s, 1H), 9.38 (dd, J = 7.0, 1.7 Hz, 1H), 8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.69 (s, 1H), 8.30 (s, 1H), 7.38 (dd, J = 7.0, 4.2 Hz, 1H), 6.65 (s, 1H), 5.07-4.98 (m, 1H), 3.42 (m, 2H), 3.20 (d, J = 16.8 Hz, 1H), 3.09 (m, 1H), 2.97-2.87 (m, 2H), 2.87-
			2.71 (m, 3H), 2.18-2.06
			(m, 2H), 2.00 (m, 2H), 1.34
			(s, 3H). MS (ESI): m/z =
			433.2 [M + 1]+.
337, 338, 339 and 340	N-((R)-6-((R)-4- hydroxyazepan- 1-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide, N- ((R)-6-((S)-4- hydroxyazepan- l-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide, N- (S)-6-((R)-4- hydroxyazepan- l-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide and N-((S)-6- ((S)-4- hydroxyazepan-		Example 337, Peak 1: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.45 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 8.93 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 6.63 (s, 1H), 5.06-4.97 (m, 1H), 4.54 (d, J = 3.7 Hz, 1H), 3.92 (m, 1H), 3.52-3.37 (m, 2H), 3.18 (d, J = 16.5 Hz, 1H), 3.03-2.75 (m, 5H), 2.10-2.00 (m, 1H), 1.99- 1.79 (m, 3H), 1.81-1.70 (m, 1H), 1.69-1.58 (m, 1H), 1.34 (s, 3H). MS (ESI): m/z = 438.2 [M + 1]+. Example 338, Peak 2: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.45 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 8.93 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 6.63 (s, 1H), 5.06-4.96 (m, 1H), 4.54 (d, J = 3.7 Hz, 1H), 4.00-3.85 (m, 1H),3.48- 3.36 (m, 2H), 3.23-3.13 (m, 1H), 3.04-2.77 (m,
	1-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute and relative stereochemistry assigned arbitrarily)		5H), 2.05 (m, 1H), 1.98- 1.81 (m, 3H), 1.81-1.71 (m, 1H), 1.72-1.58 (m, 1H), 1.33 (s, 3H). MS (ESI): m/z = 433.2 [M + 1]+. Example 339, Peak 3: 1H NMR (400 MHz, DMSO- d6) δ 10.45 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 8.93 (dd, J = 4.2, 1.7 Hz, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 7.34 (dd, J = 7.0, 4.2 Hz, 1H), 6.63 (s, 1H), 5.02 (t, J = 5.8 Hz, 1H), 4.54 (d, J = 3.7 Hz, 1H), 3.92 (m, 1H), 3.51- 3.37 (m, 2H),3.18(d, J = 16.2 Hz, 1H), 3.06-2.90 (m, 3H), 2.87 (m, 1H), 2.85- 2.75 (m, 1H), 2.12-1.99 (m, 1H), 1.99-1.81 (m, 3H), 1.81-1.69 (m, 1H), 1.69-1.57 (m, 1H), 1.34 (s, 3H). MS (ESI): m/z = 438.2 [M + 1]+. Example 340, Peak 4: 1H NMR (400 MHz, DMSO- d6) δ 10.45 (s, 1H), 9.36 (dd, J = 7.0, 1.6 Hz, 1H), 8.93 (dd, J = 4.2, 1.6 Hz, 1H),
			8.67 (s, 1H), 8.24 (s, 1H),
			7.34 (dd, J = 7.0, 4.2 Hz,
			1H), 6.63 (s, 1H), 5.02 (t, J =
			5.8 Hz, 1H), 4.54 (d, J = 3.6
			Hz, 1H), 3.92 (m, 1H), 3.42
			(m, 2H), 3.18 (d, J = 16.1
			Hz, 1H), 3.05-2.85 (m,
			3H), 2.85-2.75 (m, 1H),
			2.11-1.99 (m, 1H), 1.99-
			1.81 (m, 3H), 1.81-1.55
			(m, 2H), 1.33 (s, 3H). MS
			(ESI): m/z = 438.2 [M + 1]+.
341 and 342	N-[(2R)-6-[4-(1- hydroxycyclopropyl)- l-piperidyl]-2- (hydroxymethyl)- 2-methyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide and N-[(2S)-6-[4-(1- hydroxycyclopropyl)- 1-piperidyl]-2- (hydroxymethyl)- 2-methyl-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 341, Peak 1: 1H NMR (400 MHz, CDCl3) δ 10.57 (s, 1H), 8.95-8.90 (m, 1H), 8.78-8.77 (m, 2H), 8.48 (s, 1H), 6.99 (dd, J = 6.8, 4.0 Hz, 1H), 6.65 (s, 1H), 3.66 (d, J = 6.0 Hz, 2H), 3.22 (d, J = 16.0 Hz, 1H), 3.15-3.12 (m, 2H), 2.93 (d, J = 16.0 Hz, 1H), 2.66-2.60 (m, 2H), 2.08-2.06 (m, 2H), 1.88 (t, J = 6.0 Hz, 1H), 1.80-1.78 (m, 3H), 1.46 (s, 3H), 1.02-0.99 (m, 1H), 0.79 (t, J = 6.0 Hz, 2H), 0.53 (t, J = 5.6 Hz, 2H). LCMS (ESI): m/z = 464.0 [M + H]+. Example 342, Peak 2: 1HNMR (400 MHz, CDCl3) δ 10.50 (s, 1H), 8.90-8.85 (m, 1H), 8.75-8.65 (m, 2H), 8.41 (s, 1H), 6.92 (dd, J = 6.8, 4.0 Hz, 1H), 6.58 (s, 1H), 3.60- 3.55 (m, 2H), 3.16 (d, J = 15.6 Hz, 1H), 3.10-3.00 (m, 2H), 2.86 (d, J = 15.6 Hz, 1H), 2.60-2.54 (m, 2H), 2.02-1.98 (m, 2H), 1.90- 1.70 (m, 4H), 1.39 (s, 3H), 0.95-0.85 (m, 1H), 0.73 (t, J =
			6.0 Hz, 2H), 0.46 (t, J = 5.6
			Hz, 2H). LCMS (ESI): m/z =
			464.1 [M + H]+.
343	N-[2- (Hydroxymethyl)- 2-methyl-6-(4- propanoyl-1- piperidyl)-3H- benzofuran-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3): δ 10.62 (s, 1H), 9.05-9.00 (m, 1H), 8.80-8.75 (m, 2H), 8.53 (s, 1H), 7.10 (dd, J = 7.2, 4.0 Hz, 1H), 6.64 (s, 1H), 3.66 (s, 2H), 3.23 (d, J = 15.2 Hz, 1H), 3.12-3.09 (m, 2H), 2.93 (d, J = 15.6 Hz, 1H), 2.69-2.61 (m, 2H), 2.56 (q, J = 7.2 Hz, 2H), 2.12-2.09 (m, 2H), 1.87-1.83 (m, 2H), 1.46 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H). LCMS (ESI): m/z = 486.2 [M + Na]+.
344 and 345	N-(6-(4-(1H- imidazol-1- yl)piperidin-1-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 344, Peak 1: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.30 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 8.82 (dd, J = 4.2, 1.7 Hz, 1H), 8.68 (s, 1H), 8.23 (s, 1H), 7.77 (s, 1H), 7.35 (dd, J = 7.0, 4.2 Hz, 1H), 7.28 (t, J = 1.2 Hz, 1H), 6.95 (s, 1H), 6.70 (s, 1H), 5.11-4.94 (m, 1H), 4.22 (m, 1H), 3.51-3.39 (m, 2H), 3.25-3.16 (m, 1H), 3.11-3.00 (m, 2H), 2.93-2.77 (m, 3H), 2.21- 2.10 (m, 4H), 1.35 (s, 3H). MS (ESI): m/z = 474.2 [M + 1]+. Example 345, Peak 2: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.30 (s, 1H), 9.36 (dd, J = 7.0, 1.7 Hz, 1H), 8.82 (dt, J = 4.2, 1.4 Hz, 1H), 8.68 (s, 1H), 8.23 (s, 1H), 7.77 (s, 1H), 7.39-7.31 (m, 1H), 7.28 (q, J = 1.4 Hz, 1H), 6.95 (t, J = 1.0 Hz, 1H), 6.70 (s, 1H), 5.09-4.95 (m, 1H), 4.30-4.17 (m, 1H), 3.52-
			3.39 (m, 2H), 3.25-3.17
			(m, 1H), 3.14-3.00 (m,
			2H), 2.92-2.77 (m, 3H),
			2.23-2.07 (m, 4H), 1.35
			(s, 3H). MS (ESI): m/z =
			474.1 [M + 1]+.
346 and 347	(S)-N-(6-(4- fluoro-4- (hydroxymethyl) piperidin-1-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide and (R)-N-(6-(4- fluoro-4- (hydroxymethyl) piperidin-1-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 346, Peak 1: 1H NMR (400 MHz, DMSO- d6) δ 10.41 (s, 1H), 9.22 (dd, J = 2.1, 1.2 Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.59 (s, 1H), 8.31 (s, 1H), 6.68 (s, 1H), 5.20 (t, J = 5.8 Hz, 1H), 5.09-4.96 (m, 1H), 3.53 (dd, J = 15.8, 5.8 Hz, 2H), 3.42 (m, 2H), 3.24-3.15 (m, 1H), 2.95- 2.76 (m, 5H), 2.40 (d, J = 1.1 Hz, 3H), 2.20-1.99 (m, 2H), 1.82 (t, J = 12.1 Hz, 2H), 1.34 (s, 3H). LCMS (ESI): m/z = 470.2 [M + H]+. Example 347, Peak 2: 1H NMR (400 MHz, DMSO- d6) δ 10.41 (s, 1H), 9.22 (dt, J = 2.1, 1.1 Hz, 1H), 8.82 (dd, J = 2.1, 0.5 Hz, 1H), 8.59 (s, 1H), 8.31 (d, J = 0.9 Hz, 1H), 6.68 (s, 1H), 5.20 (t, J = 5.8 Hz, 1H), 5.07-4.98 (m, 1H), 3.53 (dd, J = 15.8, 5.9 Hz, 2H), 3.48-3.36 (m, 2H),
			3.24-3.14 (m, 1H), 2.94-
			2.76 (m, 5H), 2.44-2.36
			(m, 3H), 2.09 (m, 2H),
			1.82 (t, J = 12.1 Hz, 2H),
			1.34 (s, 3H).
			LCMS (ESI): m/z = 470.2
			[M + H]+.
348 and 349	N-((R)-6- ((1R,5S,6S)-6- carbamoyl-3- azabicyclo[3.1.0] hexan-3-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide and N-((S)-6- ((1R,5S,6R)-6- carbamoyl-3- azabicyclo[3.1.0] hexan-3-yl)-2- (hydroxymethyl)- 2-methyl-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 348, Peak 1: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 9.32-9.28 (m, 2H), 8.84-8.80 (m, 1H), 8.77 (s, 1H), 7.44 (s, 1H), 7.32 (s, 1H), 7.26 (dd, J = 7.0, 4.2 Hz, 1H), 6.69(s, 1H), 6.41 (s, 1H), 5.04- 4.98 (m, 1H), 3.57 (d, J = 8.6 Hz, 2H), 3.46-3.38 (m, 2H), 3.20 (d, J = 8.6 Hz, 2H), 3.12 (d, J = 16.2 Hz, 1H), 2.74 (d, J = 16.0 Hz, 1H), 1.85-1.78 (m, 2H), 1.58 (t, J = 8.0 Hz, 1H), 1.33 (s, 3H).MS (ESI): m/z = 449.1 [M + 1]+. Example 349, Peak 2: 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 9.32-9.28 (m, 2H), 8.83 (d, J = 1.7 Hz, 1H), 8.77 (s, 1H), 7.44 (s, 1H), 7.32 (s, 1H), 7.26 (dd, J = 7.0, 4.2 Hz, 1H), 6.69 (s, 1H), 6.41 (s, 1H), 5.04-4.98 (m, 1H), 3.57 (d, J = 9.1 Hz, 2H), 3.47- 3.37 (m, 2H), 3.24-3.16 (m, 3H), 3.12 (d, J = 16.2 Hz, 1H), 2.74 (d, J = 16.1
			Hz, 1H), 1.85-1.78 (m,
			2H), 1.58 (t, J = 8.0 Hz,
			1H), 1.33 (s, 3H). MS
			(ESI): m/z = 449.1 [M + 1]+.
350 and 351	N-(2- (hydroxymethyl)- 2-methyl-6-((1- methyl-1H- pyrazol-4- yl)methoxy)-2,3- dihydrobenzofuran- 5-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide and N-(3-hydroxy-3- methyl-7-((1- methyl-1H- pyrazol-4- yl)methoxy)chroman- 6-yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide (absolute stereochemistry assigned arbitrarily)		Example 350, Peak 2: 1H NMR (400 MHz, DMSO- d6) δ 10.13 (s, 1H), 9.33 (dd, J = 7.0, 1.7 Hz, 1H), 8.64 (s, 1H), 8.32 (dd, J = 4.2, 1.7 Hz, 1H), 8.25 (s, 1H), 7.84 (s, 1H), 7.62 (d, J = 0.6 Hz, 1H), 7.32 (dd, J = 7.0, 4.2 Hz, 1H), 6.68 (s, 1H), 5.06-5.00 (m, 3H), 3.86 (s, 3H), 3.50-3.39 (m, 2H), 3.17 (d, J = 15.7 Hz, 1H), 2.80 (d, J = 15.8 Hz, 1H), 1.35 (s, 3H). MS (ESI): m/z = 435.1 [M + 1]+. Example 351, Peak 1: 1H NMR (400 MHz, DMSO- d6) δ 10.13 (s, 1H), 9.33 (dd, J = 7.0, 1.7 Hz, 1H), 8.64 (s, 1H), 8.32 (dd, J = 4.2, 1.7 Hz, 1H), 8.25 (s, 1H), 7.84 (s, 1H), 7.68- 7.52 (m, 1H), 7.32 (dd, J = 7.0, 4.2 Hz, 1H), 6.68 (s, 1H), 5.03 (m, 3H), 3.86 (s, 3H), 3.52-3.39 (m, 2H), 3.17 (d, J = 16.0 Hz, 1H), 2.80 (d, J = 15.9 Hz, 1H), 1.35 (s, 3H). MS (ESI): m/z = 435.1 [M + 1]+.

Example 352. N-(6-(4-(2,2-Difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. tert-Butyl 4-(2,2-difluoro-1-hydroxyethyl)piperidine-1-carboxylate

To a solution of tert-butyl 4-formyl-1-piperidinecarboxylate (1 g, 4.69 mmol) in tetrahydrofuran (20 ml) was added difluoromethyl trimethylsilane (0.82 g, 6.56 mmol) and 1M tetrabutyl ammoniumfluoride (0.47 ml, 0.47 mmol) in tetrahydrofuran. The mixture was stirred at 17° C. for 15 h under nitrogen atmosphere. The reaction was concentrated under reduced pressure to give tert-butyl 4-(2,2-difluoro-1-hydroxy-ethyl)piperidine-1-carboxylate (1.4 g, 100% yield) as a light yellow oil, which was used directly without further purification. ¹H NMR (400 MHz, CDCl₃): δ 5.76 (td, J=50.8, 4.4 Hz, 1H), 4.25-4.10 (m, 2H), 3.61-3.52 (m, 1H), 2.75-2.60 (m, 2H), 1.81-1.74 (m, 2H), 1.65-1.62 (m, 2H), 1.46 (s, 9H), 1.41-1.37 (m, 1H),

Step B. 2,2-Difluoro-1-(piperidin-4-yl)ethanol hydrochloride

To a solution of tert-butyl 4-(2,2-difluoro-1-hydroxy-ethyl)piperidine-1-carboxylate (1.19 g, 4.49 mmol) in ethyl acetate (10 ml) was added hydrochloric acid (11 ml, 4 M, 45.33 mmol) in ethyl acetate. The mixture was stirred at 17° C. for 40 min and concentrated under reduced pressure to give 2,2-difluoro-1-(4-piperidyl)ethanol hydrochloride (900 mg, 99% yield) as a colorless oil, which used directly without further purification.

Step C. N-(6-(4-(2,2-Difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was made in a manner analogous to Example 6, Steps A through C to afford N-(6-(4-(2,2-Difluoro-1-hydroxyethyl)piperidin-1-yl)-2-(hydroxymethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.12 g, 53% yield over 3 steps). ¹H NMR (400 MHz, CD₃OD): δ 9.08-9.04 (m, 2H), 8.63 (s, 1H), 8.27 (s, 1H), 7.22-7.20 (dd, J=7.6, 4.4 Hz, 1H), 6.68 (s, 1H), 5.95 (td, J=41.6, 4.8 Hz, 1H), 3.62-3.58 (m, 3H), 3.23 (d, J=16.0 Hz, 1H), 3.04-3.01 (m, 2H), 2.90 (d, J=16.0 Hz, 1H), 2.71-2.67 (m, 2H), 2.10-1.95 (m, 2H), 1.78-1.63 (m, 3H), 1.42 (s, 3H). LCMS (ESI): m/z=488.1 [M+H]⁺.

Example 353. N-[6-[4-Fluoro-4-(hydroxymethyl)-1-piperidyl]-2-(1-hydroxy-1-methyl-ethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (308303452)

The title compound was made in a manner analogous to Examples 157 and 158 to afford N-[6-[4-fluoro-4-(hydroxymethyl)-1-piperidyl]-2-(1-hydroxy-1-methyl-ethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (63 mg, 29% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 10.43 (s, 1H), 8.87-8.74 (m, 2H), 8.68 (m, 1H), 8.44 (s, 1H), 7.03 (m, 1H), 6.71 (s, 1H), 3.73 (d, J=18.8 Hz, 2H), 3.51 (d, J=15.6 Hz, 1H), 3.07-2.90 (m, 4H), 2.80 (d, J=15.2 Hz, 1H), 2.17-1.97 (m, 4H), 1.42 (s, 3H), 1.37 (s, 3H), 1.26 (s, 3H). LCMS (ESI): m/z=484.0 [M+H]⁺.

Example 354 and 355. (S)—N-(6-(4-(Hydroxymethyl)piperidin-1-yl)-2-(2-hydroxypropan-2-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)—N-(6-(4-(Hydroxymethyl)piperidin-1-yl)-2-(2-hydroxypropan-2-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compounds were made in a manner analogous to Examples 157 and 158 to afford (S)—N-(6-(4-(Hydroxymethyl)piperidin-1-yl)-2-(2-hydroxypropan-2-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (R)—N-(6-(4-(Hydroxymethyl)piperidin-1-yl)-2-(2-hydroxypropan-2-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (absolute stereochemistry assigned arbitrarily).

Example 354, Peak 1: ¹H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.47 (s, 1H), 9.36-9.35 (d, J=5.2 Hz, 1H), 8.90-8.88 (m, 1H), 8.67 (s, 1H), 8.30 (s, 1H), 7.34-7.31 (dd J=4.4, 7.2 Hz, 1H), 6.68 (s, 1H), 4.55 (t, J=5.6 Hz, 1H), 4.50 (s, 1H), 3.44 (d, J=16.0 Hz, 1H), 3.40-3.38 (m, 2H), 2.94-2.91 (m, 2H), 2.71 (d, J=16.0 Hz, 1H), 2.66-2.60 (m, 2H), 1.72-1.70 (m, 2H), 1.59-1.56 (m, 3H), 1.31 (s, 3H), 1.16 (d, J=4.0 Hz, 6H). LCMS (ESI): m/z=466.1 [M+H]⁺.

Example 355, Peak 2: ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.48 (s, 1H), 9.37-9.35 (d, J=6.8 Hz, 1H), 8.90-8.89 (m, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 7.35-7.32 (m, 1H), 6.69 (s, 1H), 4.56 (t, J=5.6 Hz, 1H), 4.51 (s, 1H), 3.45 (d, J=16.0 Hz, 1H), 3.40-3.38 (m, 2H), 2.94-2.92 (m, 2H), 2.71 (d, J=16.0 Hz, 1H), 2.66-2.61 (m, 2H), 1.73-1.70 (m, 2H), 1.59-1.53 (m, 3H), 1.32 (s, 3H), 1.16 (d, J=3.2 Hz, 6H). LCMS (ESI): m/z=466.1 [M+H]⁺.

Example 356. N-(6-Methyl-2-morpholino-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was made in a manner analogous to Examples 157 and 158 to afford N-[6-[4-(2-amino-2-oxo-ethyl) piperazin-1-yl]-2-(1-hydroxy-1-methyl-ethyl)-2-methyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (64.5 mg, 27% yield) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): 10.37 (s, 1H), 8.85 (dd, J=7.2, 2.0 Hz, 1H), 8.79 (s, 1H), 8.73-8.71 (m, 1H), 8.42 (s, 1H), 7.09-7.07 (m, 2H), 6.67 (s, 1H), 5.48 (s, 1H), 3.51 (d, J=15.6 Hz, 1H), 3.13 (s, 2H), 2.97-2.96 (m, 4H), 2.83-2.79 (m, 5H), 1.43 (s, 3H), 1.37 (s, 3H), 1.26 (s, 3H). LCMS (ESI): m/z=494.0 [M+H]⁺.

Example 357. N-(6-(1-(2-Hydroxyethyl)piperidin-4-yl)-2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-[2,2-Dimethyl-6-(4-piperidyl)-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Example 62, Step D, 50.8 mg, 0.13 mmol) was brought up in acetonitrile (1.3 ml, 24.7 mmol) and treated with trimethylamine (0.45 ml, 3.24 mmol) followed by iodoethanol (29 mg, 0.169 mmol) and heated at 60° C. for 72 h. The reaction mixture was then concentrated and purified by reverse phase HPLC to give N-[6-[1-(2-hydroxyethyl)-4-piperidyl]-2,2-dimethyl-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (13.8 mg, 24% yield) as a solid. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 9.61 (s, 1H), 9.39 (dd, J=7.0, 1.6 Hz, 1H), 8.87 (dd, J=4.3, 1.6 Hz, 1H), 8.68 (s, 1H), 7.74 (s, 1H), 6.65 (s, 1H), 4.36 (s, 1H), 3.51 (t, J=6.4 Hz, 2H), 3.00 (s, 2H), 2.98 (m, 2H), 2.88-2.75 (m, 1H), 2.40 (t, J=6.4 Hz, 2H), 2.15-2.00 (m, 2H), 1.82-1.57 (m, 4H), 1.42 (s, 6H). MS (ESI): m/z=436.2 [M+1]⁺.

Example 358. N-(3-Hydroxy-2,2-dimethyl-5-morpholino-2,3-dihydrobenzofuran-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 1-Chloro-4-((2-methylallyl)oxy)-2-nitrobenzene

Cesium carbonate (3.58 g, 11.0 mmol) was added portion-wise to a solution of 4-chloro-3-nitrophenol (1.74 g, 10.0 mmol) in N,N-dimethylformamide (25 ml) followed by addition of 3-bromo-2-methyl-prop-1-ene (1.62 g, 12.0 mmol). The mixture was stirred for 3 h and filtered. The filtrate was concentrated in vacuo and the residue partitioned between water and ethyl acetate. The organic phase was isolated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting gradient 0-20% isopropyl acetate:heptane) to afford 1-chloro-4-((2-methylallyl)oxy)-2-nitrobenzene (2.00 g, 88% yield) as a light yellow oil. MS (ESI): m/z=226[M−1]⁻.

Step B. 4-(4-((2-Methylallyl)oxy)-2-nitrophenyl)morpholine

A mixture of 1-chloro-4-(2-methylallyloxy)-2-nitro-benzene (2.00 g, 8.8 mmol) and morpholine (23 ml, 263 mmol) was heated in a sealed vial at 100° C. for 36 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl ether and 5% aqueous citric acid. The organic phase was isolated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting gradient 0-20% isopropyl acetate:heptane) to afford 4-(4-((2-methylallyl)oxy)-2-nitrophenyl)morpholine (2.11 g, 78% yield) as a yellow oil. MS (ESI): m/z=279[M+1]⁺.

Step C. 5-((2-Methylallyl)oxy)-2-morpholinoaniline

Iron (7.62 g, 136.5 mmol) was added portion-wise over a period of 1 h to a mixture of 4-[4-(2-methylallyloxy)-2-nitro-phenyl]morpholine (2.11 g, 6.82 mmol) and saturated aqueous ammonium chloride (12 ml) in methanol (40 ml) at 65° C. After 30 min, the reaction was cooled to room temperature, filtered through Celite and the precipitate was washed with methanol. The filtrate was concentrated and the residue partitioned between water and ethyl acetate. The organic phase was isolated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting gradient 0-4% methanol:dichloromethane) to afford 5-((2-methylallyl)oxy)-2-morpholinoaniline (1.06 g, 62% yield) as a light red oil. MS (ESI): m/z=249[M+1]⁺.

Step D. 5-Amino-2-(2-methylallyl)-4-morpholinophenol

A mixture of 5-(2-methylallyloxy)-2-morpholino-aniline (500 mg, 2.01 mmol) in dimethylformamide (6 ml) was subjected to a microwave heating at 180° C. for 12 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl ether and water. The organic phase was isolated, washed with water (3*20 ml) and brine, dried over magnesium sulfate and concentrated to afford 5-amino-2-(2-methylallyl)-4-morpholinophenol (498 mg, 100% yield) MS (ESI): m/z=249[M+1]⁺.

Step E. 2,2-Dimethyl-5-morpholino-2,3-dihydrobenzofuran-6-amine

Potassium tert-butoxide (450 mg, 4.0 mmol) was added portion-wise to a solution of 5-amino-2-(2-methylallyl)-4-morpholino-phenol in tetrahydrofuran (25 ml) at 5° C. The mixture was then heated in a sealed vial at 60° C. for 2 h. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and 1% aqueous citric acid. The organic phase was isolated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting gradient 0-4% methanol:dichloromethane) to afford 2,2-dimethyl-5-morpholino-2,3-dihydrobenzofuran-6-amine (234 mg, 45%) as a colorless solid. ¹H NMR (400 MHz, Chloroform-d) δ 6.83 (t, J=1.0 Hz, 1H), 6.17 (s, 1H), 4.02 (s, 2H), 3.82 (dd, J=5.7, 3.4 Hz, 4H), 2.92-2.88 (m, 2H), 2.86-2.80 (m, 4H), 1.44 (s, 6H). MS (ESI): m/z=249[M+1]⁺.

Step F. N-(2,2-Dimethyl-5-morpholino-2,3-dihydrobenzofuran-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 2,2-dimethyl-5-morpholino-3H-benzofuran-6-amine (234 mg, 0.90 mmol), pyrazolo[1,5-a]pyrimidine-3-carbonyl chloride hydrochloride (254 mg, 1.17 mmol), N,N-diisopropylethylamine (0.47 ml, 2.68 mmol) and 4-dimethylaminopyridine (22 mg, 0.18 mmol) in pyridine (6 ml) was subjected to a microwave heating at 110° C. for 30 min. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was isolated, washed with aqueous saturated citric acid, aqueous saturated sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting gradient 0-100% isopropyl acetate:heptane) to afford N-(2,2-dimethyl-5-morpholino-2,3-dihydrobenzofuran-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (309 mg, 88%) as a light yellow solid. MS (ESI): m/z=394[M+1]⁺.

Step G. 2,2-Dimethyl-5-morpholino-6-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2,3-dihydrobenzofuran-3-yl acetate

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (196 mg, 0.86 mmol) was added portion-wise to a solution of N-(2,2-dimethyl-5-morpholino-3H-benzofuran-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (309 mg, 0.786 mmol) in acetic acid (12 ml). The mixture was stirred for 3 h, concentrated in vacuo and the residue partitioned between ethyl acetate and 1 M aqueous sodium carbonate. The organic phase was isolated, washed with aqueous sodium carbonate, water and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluting gradient 0-60% isopropyl acetate:heptane) to afford 2,2-dimethyl-5-morpholino-6-(pyrazolo[1,5-a]pyrimidine-3-carboxamido)-2,3-dihydrobenzofuran-3-yl acetate (290 mg, 82%). MS (ESI): m/z=452[M+1]⁺.

Step H. N-(3-Hydroxy-2,2-dimethyl-5-morpholino-2,3-dihydrobenzofuran-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of [2,2-dimethyl-5-morpholino-6-(pyrazolo[1,5-a]pyrimidine-3-carbonylamino)-3H-benzofuran-3-yl]acetate (280 mg, 0.62 mmol) and lithium hydroxide (1M in water, 1.55 mmol) was stirred in a mixture of methanol and tetrahydrofuran (4:1) for 4 h. The mixture was concentrated and the residue partitioned between ethyl acetate and 1% aqueous citric acid. The organic phase was isolated and concentrated to afford N-(3-hydroxy-2,2-dimethyl-5-morpholino-2,3-dihydrobenzofuran-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (162 mg, 62%) as a colorless solid. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.83 (s, 1H), 9.38 (dd, J=7.0, 1.6 Hz, 1H), 8.96 (dd, J=4.3, 1.6 Hz, 1H), 8.72 (s, 1H), 7.98 (s, 1H), 7.38-7.35 (m, 1H), 7.34 (s, 1H), 5.41 (d, J=6.7 Hz, 1H), 4.66 (d, J=6.7 Hz, 1H), 3.88 (t, J=4.7 Hz, 4H), 2.90-2.77 (m, 4H), 1.35 (s, 3H), 1.28 (s, 3H). MS (ESI): m/z=410[M+1]⁺.

Example 359. N-(2,2-dimethyl-5-morpholino-3-oxo-2,3-dihydrobenzofuran-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Dess-Martin periodinane (179 mg, 0.42 mmol) was added portion-wise to a solution of N-(3-hydroxy-2,2-dimethyl-5-morpholino-3H-benzofuran-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (115 mg, 0.28 mmol) in dichloromethane (30 ml). The mixture was stirred for 3 h. The mixture was filtered through celite, the filtrate concentrated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was isolated, washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluent 100% isopropyl acetate) followed by recrystallisation from acetonitrile to afford N-(2,2-dimethyl-5-morpholino-3-oxo-2,3-dihydrobenzofuran-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (26 mg, 22%) as a colorless solid. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 11.17 (s, 1H), 9.42 (dd, J=7.0, 1.6 Hz, 1H), 9.00 (dd, J=4.2, 1.6 Hz, 1H), 8.79 (s, 1H), 8.38 (s, 1H), 7.59 (s, 1H), 7.40 (dd, J=7.0, 4.2 Hz, 1H), 3.90 (t, J=4.5 Hz, 4H), 2.95-2.83 (m, 4H), 1.40 (s, 6H). MS (ESI): m/z=408[M+1]⁺.

Examples 360 and 361. (R)—N-(6-(4-(2,2-Difluoroethyl)piperazin-1-yl)-2-(2-hydroxypropan-2-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(6-(4-(2,2-Difluoroethyl)piperazin-1-yl)-2-(2-hydroxypropan-2-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compounds were made in a manner analogous to Example 157 and 158 to give (R)—N-(6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2-(2-hydroxypropan-2-yl)-2-methyl-2, 3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2-(2-hydroxypropan-2-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with absolute stereochemistry assigned arbitrarily.

Example 360, Peak 1: ¹H NMR (400 MHz, Chloroform-d) δ 10.37 (s, 1H), 8.87-8.81 (m, 1H), 8.79 (s, 1H), 8.74-8.69 (m, 1H), 8.40 (s, 1H), 7.08 (dd, J=7.0, 4.2 Hz, 1H), 6.67 (s, 1H), 5.96 (tt, J=55.9, 4.3 Hz, 1H), 3.50 (d, J=15.5 Hz, 1H), 3.01-2.78 (m, 11H), 2.01 (s, 1H), 1.41 (s, 3H), 1.37 (s, 3H), 1.25 (s, 3H). (ESI): m/z=501.2 [M+1]⁺.

Example 361, Peak 2: ¹H NMR (400 MHz, Chloroform-d) δ 10.37 (s, 1H), 8.87-8.81 (m, 1H), 8.79 (s, 1H), 8.75-8.70 (m, 1H), 8.40 (s, 1H), 7.08 (dd, J=7.0, 4.2 Hz, 1H), 6.67 (s, 1H), 5.96 (tt, J=55.9, 4.3 Hz, 1H), 3.50 (d, J=15.5 Hz, 1H), 2.99-2.76 (m, 12H), 1.41 (s, 3H), 1.37 (s, 3H), 1.25 (s, 3H). (ESI): m/z=501.2 [M+1]⁺.

Example 362. N-(6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2-((difluoromethoxy)methyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was made in a manner analogous to Example 155 and 156 to give N-(6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2-((difluoromethoxy)methyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. ¹H NMR (400 MHz, Methanol-d₄) δ 9.15 (d, J=7.0 Hz, 1H), 8.95 (d, J=4.1 Hz, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.31 (dd, J=7.0, 4.2 Hz, 1H), 6.74 (s, 1H), 3.94 (s, 2H), 3.34-3.19 (m, 2H), 3.18 (d, J=3.5 Hz, 1H), 3.12 (s, 5H), 3.07-2.97 (m, 5H), 1.50 (s, 3H), 1.31 (s, 1H). (ESI): m/z=523.2 [M+1]⁺.

Example 363. N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(2-hydroxypropan-2-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was made in a manner analogous to Example 157 and 158 to give N-(6-(4-(hydroxymethyl)piperidin-1-yl)-2-(2-hydroxypropan-2-yl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. ¹H NMR (400 MHz, Chloroform-d) δ 10.50 (s, 1H), 8.84-8.73 (m, 3H), 8.44 (s, 1H), 7.02 (dd, J=7.0, 4.1 Hz, 1H), 6.67 (s, 1H), 3.63 (t, J=4.9 Hz, 2H), 3.50 (d, J=15.4 Hz, 1H), 3.11 (d, J=11.4 Hz, 2H), 2.79 (d, J=15.4 Hz, 1H), 2.68 (dt, J=11.4, 8.4 Hz, 2H), 2.06 (s, 1H), 1.79 (s, 3H), 1.51 (t, J=5.4 Hz, 1H), 1.41 (s, 3H), 1.36 (s, 3H), 1.25 (s, 3H). (ESI): m/z=466.2 [M+1]⁺.

Example 364. N-(6-(4-(2,2-Difluoroethyl)piperazin-1-yl)-2-(difluoromethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compound was made in a manner analogous to Examples 50 and 51 to give N-(6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2-(difluoromethyl)-2-methyl-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. ¹H NMR (400 MHz, Chloroform-d) δ 10.38 (s, 1H), 8.84 (d, J=7.0 Hz, 1H), 8.79 (s, 1H), 8.73 (d, J=4.1 Hz, 1H), 8.43 (s, 1H), 7.08 (dd, J=7.0, 4.1 Hz, 1H), 6.71 (s, 1H), 5.85 (dt, J=82.7, 55.8 Hz, 2H), 3.43 (d, J=16.2 Hz, 1H), 3.08-2.80 (m, 11H), 1.54 (s, 3H). (ESI): m/z=493.2 [M+1]⁺.

Examples 365 and 366. (R)—N-(6-(4-(2,2-Difluoroethyl)piperazin-1-yl)-2-(hydroxymethyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(6-(4-(2,2-Difluoroethyl)piperazin-1-yl)-2-(hydroxymethyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compounds were made in a manner analogous to Example 153 and 154 to give (R)—N-(6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2-(hydroxymethyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide and (S)—N-(6-(4-(2,2-difluoroethyl)piperazin-1-yl)-2-(hydroxymethyl)-2-(trifluoromethyl)-2,3-dihydrobenzofuran-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide with absolute stereochemistry assigned arbitrarily.

Example 365, Peak 1: ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.43 (s, 1H), 9.36 (d, J=7.0 Hz, 1H), 8.94 (d, J=4.1 Hz, 1H), 8.68 (s, 1H), 8.39 (s, 1H), 7.35 (dd, J=7.0, 4.2 Hz, 1H), 6.92 (s, 1H), 6.19 (tt, J=55.7, 4.4 Hz, 1H), 5.59 (t, J=6.0 Hz, 1H), 3.76 (qd, J=12.1, 6.0 Hz, 2H), 3.49 (d, J=16.6 Hz, 1H), 3.32 (s, 1H), 2.89-2.72 (m, 10H). (ESI): m/z=527.2 [M+1]⁺.

Example 366, Peak 2: ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.43 (s, 1H), 9.35 (d, J=7.0 Hz, 1H), 8.94 (d, J=4.1 Hz, 1H), 8.67 (s, 1H), 8.39 (s, 1H), 7.34 (dd, J=7.0, 4.1 Hz, 1H), 6.91 (s, 1H), 6.19 (tt, J=55.6, 4.2 Hz, 1H), 5.59 (t, J=6.1 Hz, 1H), 3.75 (qd, J=12.1, 5.8 Hz, 2H), 3.49 (d, J=16.6 Hz, 1H), 3.32 (s, 1H), 2.94-2.72 (m, 10H). (ESI): m/z=527.2 [M+1]⁺.

Example 367 and 368. N-[(2R)-2-(2,2-difluoroethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-2-(2,2-difluoroethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 2-Fluoro-4-(2-methylallyloxy)-1-nitro-benzene

To a solution of 3-fluoro-4-nitrophenol (20.6 g, 131.2 mmol) in acetonitrile was added 3-bromo-2-methylpropene (15.6 ml, 183.7 mmol) and potassium carbonate (25.4 g, 183.7 mmol). The reaction mixture was stirred at 55° C. for 13 h and then cooled to room temperature and maintained there with stirring overnight. The mixture was diluted with isopropyl acetate and washed with water. The aqueous phase was isolated and extracted with isopropyl acetate. The combined organic phases were dried over sodium sulfate, filtered and purified by column chromatography (eluting gradient 0-25% isopropyl acetate:heptanes) to give the title compound as a white crystalline solid (26.0 g, 94% yield). ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 8.15 (t, J=9.2 Hz, 1H), 7.20 (dd, J=13.7, 2.7 Hz, 1H), 7.00 (ddd, J=9.3, 2.7, 1.1 Hz, 1H), 5.11-5.04 (m, 1H), 5.01 (d, J=1.5 Hz, 1H), 4.66 (s, 2H), 1.81-1.73 (m, 3H).

Step B. 4-[5-(2-Methylallyloxy)-2-nitro-phenyl]morpholine

To a mixture of 2-fluoro-4-(2-methylallyloxy)-1-nitro-benzene (26.0 g, 123.2 mmol), and potassium carbonate (56.2 g, 406.6 mmol) in dimethyl sulfoxide (186.7 ml, 2600 mmol) was added morpholine (10.7 ml, 123.20 mmol) and the mixture was heated to 100° C. After 40 min, the reaction was cooled to room temperature and diluted with water and ethyl acetate. The organic phase was isolated and washed with saturated aqueous sodium bicarbonate. The aqueous phase was then extracted with ethyl acetate (3×). The combined organic phases were washed brine, dried over sodium sulfate, filtered, concentrated and purified by column chromatography (eluting gradient 0-50% isopropyl acetate:heptanes) to give the title product as a bright yellow-orange crystalline solid (32.3 g, 94% yield). ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 7.92 (d, J=9.0 Hz, 1H), 6.72-6.66 (m, 2H), 5.13-5.04 (m, 1H), 5.00 (s, 1H), 4.60 (s, 2H), 3.77-3.64 (m, 4H), 3.07-2.91 (m, 4H), 1.78 (s, 3H).

Step C. 2-(2-Methylallyl)-5-morpholino-4-nitro-phenol

A solution of 4-[5-(2-methylallyloxy)-2-nitro-phenyl]morpholine (375 mg, 1.35 mmol) was heated in dimethylformamide (2 ml) at 220° C. for 60 min. The reaction was cooled to room temperature and diluted with isopropyl acetate and brine. The aqueous phase was isolated and extracted with isopropyl acetate (3×). The combined organic phases were dried over sodium sulfate, filtered and and purified by column chromatography (eluting gradient 0-50% isopropyl acetate:heptanes) to give the desired product (44.1 mg, 11.8% yield) along with recovered starting material and undesired regioisomers. ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.73 (s, 1H), 7.74 (s, 1H), 6.59 (s, 1H), 4.84-4.73 (m, 1H), 4.64 (dd, J=2.2, 0.9 Hz, 1H), 3.79-3.64 (m, 5H), 3.20 (s, 2H), 2.97-2.88 (m, 5H), 1.66 (s, 3H).

Step D. 1-(2-Hydroxy-4-morpholino-5-nitro-phenyl)propan-2-one

To a solution of 2-(2-Methylallyl)-5-morpholino-4-nitro-phenol (283.5 mg, 1.02 mmol) in water (0.08 M) and dioxane (0.03 M) was added osmium tetroxide (0.08 M in tert-butyl alcohol, 0.6 ml, 0.05 mmol) followed by sodium periodate (435.8 mg, 2.04 mmol). The suspension was stirred overnight at room temperature, poured into water and extracted with dichloromethane. The organic phase was isolated, dried over sodium sulfate, concentrated and purified by column chromatography (eluting gradient 0-100% isopropyl acetate:heptanes) to give the desired product (135.2 mg, 47% yield). ¹H NMR (400 MHz, Chloroform-d) δ 8.26 (s, 1H), 7.78 (s, 1H), 6.60 (s, 1H), 3.88-3.81 (m, 4H), 3.73 (s, 2H), 3.08-2.97 (m, 4H), 2.35 (s, 3H).

Step E. Methyl 2-(2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-yl)acetate

A mixture of 1-(2-hydroxy-4-morpholino-5-nitro-phenyl)propan-2-one (1.7 g, 6.07 mmol) methyl(triphenylphosphoranylidine)acetate (2.13 g, 6.37 mmol) in chloroform (100 ml) was stirred at 60° C. for 2 h. Triethylamine (6 ml) was added and the mixture was stirred at 60° C. for 12 h. The reaction was then concentrated and purified by column chromatography (eluent 3% ethyl acetate:petroleum ether) to afford methyl 2-(2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-yl)acetate (1.6 g, 78% yield) as a yellow solid. (ESI): m/z=337.1 [M+1]⁺.

Step F. 2-(2-Methyl-6-morpholino-5-nitro-3H-benzofuran-2-yl)acetaldehyde

To a mixture of diisobutylaluminium hydride (2.01 ml, 2.01 mmol) in dichloromethane (10 ml) was added methyl 2-(2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-yl)acetate (450.0 mg, 1.34 mmol) drop-wise at −78° C. over 5 min and the reaction was maintained there for 2 h. The mixture was quenched with sodium sulfate decahydrate, filtered, concentrated and purified by column chromatography (eluent 15% ethyl acetate:petroleum ether) to afford 2-(2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-yl)acetaldehyde (450 mg, 99% yield) as a yellow solid. (ESI): m/z=307.1 [M+1]⁺.

Step G. 4-[2-(2,2-Difluoroethyl)-2-methyl-5-nitro-3H-benzofuran-6-yl]morpholine

A mixture of diethylaminosulfur trifluoride (1.48 g, 7.35 mmol) in dichloromethane (30 ml) was added drop-wise to 2-(2-methyl-6-morpholino-5-nitro-3H-benzofuran-2-yl)acetaldehyde (450.0 mg, 1.47 mmol) at −78° C. and the reaction was maintained there for 30 min followed by room temperature for 12 h. The mixture was concentrated and purified by column chromatography (eluent 15% ethyl acetate:petroleum ether) to afford 4-[2-(2,2-difluoroethyl)-2-methyl-5-nitro-3H-benzofuran-6-yl]morpholine (320 mg, 63% yield) as a yellow solid. (ESI): m/z=329.1 [M+1]⁺.

Step H. 2-(2,2-Difluoroethyl)-2-methyl-6-morpholino-3H-benzofuran-5-amine

The title compound was made in a manner analogous to Example 2, Step B to afford 2-(2,2-difluoroethyl)-2-methyl-6-morpholino-3H-benzofuran-5-amine (245 mg, 84% yield) as a colorless oil. (ESI): m/z=299.1 [M+1]⁺.

Examples 367 and 368. N-[(2R)-2-(2,2-difluoroethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide and N-[(2S)-2-(2,2-difluoroethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

The title compounds were made in a manner analogous to Examples 29 and 30 to give N-[(2R)-2-(2,2-difluoroethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (130 mg, 36% yield) and N-[(2S)-2-(2,2-difluoroethyl)-2-methyl-6-morpholino-3H-benzofuran-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (120 mg, 33% yield) as yellow solids.

Example 367, Peak 1: ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.44 (s, 1H), 9.36 (d, J=7.0 Hz, 1H), 8.93 (d, J=4.1 Hz, 1H), 8.67 (s, 1H), 8.32 (s, 1H), 7.34 (dd, J=7.0, 4.2 Hz, 1H), 6.76 (s, 1H), 3.83 (t, J=4.2 Hz, 4H), 3.20 (d, J=15.8 Hz, 1H), 3.00 (d, J=15.8 Hz, 1H), 2.81 (t, J=4.3 Hz, 4H), 2.50 (s, 1H), 2.35 (td, J=17.4, 4.6 Hz, 2H), 1.44 (s, 3H). MS (ESI): m/z=444.2 [M+1]⁺. MS (ESI): m/z=299.1 [M+1]⁺.

Example 368, Peak 2: ¹H NMR (400 MHz, dimethyl sulfoxide-d₆) δ 10.45 (s, 1H), 9.38 (dd, J=7.0, 1.4 Hz, 1H), 8.95 (dd, J=4.2, 1.4 Hz, 1H), 8.69 (s, 1H), 8.33 (s, 1H), 7.35 (dd, J=7.0, 4.2 Hz, 1H), 6.77 (s, 1H), 3.83 (t, J=4.2 Hz, 4H), 3.34 (s, 2H), 3.21 (d, J=15.8 Hz, 1H), 3.01 (d, J=15.8 Hz, 1H), 2.82 (t, J=4.5 Hz, 4H), 2.36 (td, J=17.4, 4.7 Hz, 1H), 1.45 (s, 3H). MS (ESI): m/z=299.1 [M+1]⁺.

Example 369. N-[1′-(2-Hydroxyethyl)-6-morpholino-spiro[3H-benzofuran-2,4′-piperidine]-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. 2-(6-Fluorospiro[3H-benzofurn-2,4′-piperidine]-1′-yl)ethanol

To a solution of 6-fluorospiro[3H-benzofuran-2,4′-piperidine (Example 142, Step C; 414.0 mg, 2 mmol) in acetonitrile (15 ml) was added potassium carbonate (689.2 mg, 4.99 mmol) and 2-bromoethanol (374.5 mg, 3 mmol). The reaction was stirred at 45° C. for 12 h, cooled to room temperature, filtered and concentrated to give 2-(6-fluorospiro[3H-benzofuran-2,4′-piperidine]-1′-yl)ethanol (561 mg, quant.) as a yellow solid. MS (ESI): m/z=252.1 [M+1]⁺.

Step B. 2-(6-Fluoro-5-nitro-spiro[3H-benzofurn-2,4′-piperidine]-1′-yl)ethanol

To a solution of 2-(6-fluorospiro[3H-benzofuran-2,4′-piperidine]-1′-yl)ethanol (510.0 mg, 2 mmol) in dichloromethane (9 ml) was added fuming nitric acid (1 ml, 16 mmol) and the reaction was stirred for 2 h. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×). The combined organic phases were isolated, washed with brine, dried over magnesium sulfate and concentrated to give 2-(6-fluoro-5-nitro-spiro[3H-benzofurn-2,4′-piperidine]-1′-yl)ethanol (374 mg, 35% yield) as a yellow oil. MS (ESI): m/z=297.1 [M+1]⁺.

Step C. 2-(6-Morpholino-5-nitro-spiro[3H-benzofuran-2,4′-piperidine]-1′-yl)ethanol

A mixture of potassium carbonate (435.2 mg, 3.16 mmol), morpholine (0.33 ml, 3.79 mmol) and 2-(6-fluoro-5-nitro-spiro[3H-benzofuran-2,4′-piperidine]-1′-yl)ethanol (374.0 mg, 1.26 mmol) in acetonitrile (10 ml) was stirred for 2 h. The reaction was diluted with water and extracted with ethyl acetate (2×). The combined organic phases were isolated, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (eluent 1:10 methanol:dichloromethane) to afford 2-(6-morpholino-5-nitro-spiro[3H-benzofuran-2,4′-piperidine]-1′-yl)ethanol (214 mg, 47% yield) as an orange solid. MS (ESI): m/z=364.2 [M+1]⁺.

Step D. 2-(5-Amino-6-morpholino-spiro[3H-benzofuran-2,4′-piperidine]-1′-yl)ethanol

The title compound was made in a manner analogous to Example 2, Step B to afford 2-(5-amino-6-morpholino-spiro[3H-benzofuran-2,4′-piperidine]-1′-yl)ethanol (160 mg, 64% yield) as a yellow oil. (ESI): m/z=334.2 [M+1]⁺.

Step E. 2-(5-Amino-6-morpholino-spiro[3H-benzofuran-2,4′-piperidine]-1′-yl)ethanol

The title compound was made in a manner analogous to Example 1, Step C to afford 2 N-[1′-(2-hydroxyethyl)-6-morpholino-spiro[3H-benzofuran-2,4′-piperidine]-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (91 mg, 40% yield) as a yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 10.47 (s, 1H), 8.87-8.74 (m, 3H), 8.43 (s, 1H), 7.07 (dd, J=7.0, 4.1 Hz, 1H), 6.69 (s, 1H), 3.95 (t, J=4.5 Hz, 4H), 3.64 (t, J=5.4 Hz, 2H), 3.02 (s, 2H), 2.92 (t, J=4.6 Hz, 4H), 2.74-2.57 (m, 4H), 2.00 (dt, J=13.3, 4.3 Hz, 2H), 1.83 (ddd, J=13.2, 8.8, 4.7 Hz, 2H), 1.61 (s, 2H). (ESI): m/z=479.2 [M+1]⁺.

TABLE 11
The following examples were made in a manner similar to that for Example 152:
Ex.	Name	Structure	NMR, MS
370	N-[1′-(2,2- difluoroethyl)-6- morpholino- spiro[3H- benzofuran-2,4′- piperidine]-5- yl]pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, Chloroform-d) δ 10.47 (s, 1H), 8.87-8.74 (m, 3H), 8.43 (s, 1H), 7.07 (dd, J = 7.0, 4.1 Hz, 1H), 6.68 (s, 1H), 5.91 (tt, J = 56.1, 4.3 Hz, 1H), 3.95 (t, J = 4.5 Hz, 4H), 3.01 (s, 2H), 2.92 (t, J = 4.5 Hz, 4H), 2.88-2.65 (m, 6H), 1.99 (dt, J = 13.1, 3.7 Hz, 2H), 1.84 (ddd, J = 13.5, 9.3, 4.2 Hz, 2H). MS (ESI): m/z = 499.2 [M + 1]+.
371	N-(6-(4- (Hydroxymethyl) piperidin-1-yl)- 1′-methyl-3H- spiro[benzofuran- 2,4′-piperidin]- 5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, Chloroform-d) δ 10.51 (s, 1H), 8.88-8.73 (m, 3H), 8.43 (s, 1H), 7.02 (dd, J = 7.0, 4.3 Hz, 1H), 6.69 (s, 1H), 3.71-3.56 (m, 2H), 3.10 (d, J = 11.4 Hz, 2H), 3.01 (s, 2H), 2.76-2.42 (m, 6H), 2.34 (s, 3H), 2.00 (d, J = 13.2 Hz, 3H), 1.90-1.67 (m, 6H). (ESI): m/z = 477.2 [M + 1]+.
372	N-(1′-isopropyl- 6-morpholino- spiro[3H- benzofuran-2,4′- piperidine]-5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 10.47 (d, J = 4.8 Hz, 1H), 9.39 (dd, J = 7.0, 1.6 Hz, 1H), 8.95 (dd, J = 4.1, 1.7 Hz, 1H), 8.69 (d, J = 2.1 Hz, 1H), 8.37 (s, 1H), 7.36 (dd, J = 7.0, 4.2 Hz, 1H), 6.81 (d, J = 2.6 Hz, 1H), 3.84 (t, J = 4.4 Hz, 4H), 3.50-3.36 (m, 4H), 3.21-3.06 (m, 3H), 2.82 (t, J = 4.5 Hz, 4H), 2.08 (dt, J = 50.5, 14.3 Hz, 4H), 1.30 (dd, J = 6.6, 3.6 Hz, 6H). (ESI): m/z = 477.3 [M + 1]+.
373	N-(6-(4-(2- Amino-2- oxoethyl) piperazin-1-yl)- 1′-methyl-3H- spiro[benzofuran- 2,4′-piperidin]- 5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 10.42 (s, 1H), 9.40-9.35 (m, 1H), 9.00-8.95 (m, 1H), 8.67 (s, 1H), 8.34 (s, 1H), 7.35 (dd, J = 6.8, 4.0 Hz, 1H), 7.23 (s, 1H), 7.17 (s, 1H), 6.72 (s, 1H), 3.03-3.00 (m, 4H), 2.84-2.83 (m, 4H), 2.74-2.72 (m, 4H), 2.69-2.60 (m, 4H), 2.32 (s, 3H), 1.86- 1.78 (m, 4H). LCMS (ESI) m/z: 505.2 [M + H]+.
374	N-(1′-Acetyl-6- (4-(2-amino-2- oxoethyl)piperazin- 1-yl)-3H- spiro[benzofuran- 2,4′-piperidin]- 5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, DMSO- d6) δ 10.43 (s, 1H), 9.40-9.35 (m, 1H), 9.00-8.95 (m, 1H), 8.68 (s, 1H), 8.36 (s, 1H), 7.35(dd, J = 6.8, 4.0 Hz, 1H), 7.22 (s, 1H), 7.17 (s, 1H), 6.75 (s, 1H), 3.78-3.73 (m, 1H), 3.54-3.41 (m, 2H), 3.38-3.32 (m, 1H), 3.04-3.01 (m, 4H), 2.85 (s, 4H), 2.74- 2.72 (m, 4H), 2.03 (s, 3H), 1.86-1.66 (m, 4H). LCMS (ESI): m/z = 533.2 [M + H]+.
375	N-(6-(4-(2- (Cyclopropylamino)- 2- oxoethyl)piperazin- 1-yl)-3H- spiro[benzofuran- 2,4′-piperidin]- 5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.90-8.85 (m, 1H), 8.78 (s, 1H), 8.75-8.70 (m, 1H), 8.41 (s, 1H), 7.17 (s, 1H), 7.07 (dd, J = 6.8, 4.0 Hz, 1H), 6.68 (s, 1H), 3.17-3.12 (m, 4H), 3.08 (s, 2H), 3.03- 2.94 (m, 6H), 2.78-2.74 (m, 5H), 1.93-1.92 (m, 2H), 1.83-1.80 (m, 2H), 0.84-0.81 (m, 2H), 0.55-0.50 (m, 2H). LCMS (ESI): m/z = 531.3 [M + H]+.
376	N-(6-(4-(2- (Cyclopropylamino)- 2- oxoethyl)piperazin- 1-yl)-1′- methyl-3H- spiro[benzofuran- 2,4′-piperidin]- 5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.84-8.82 (m, 1H), 8.78 (s, 1H), 8.72- 8.70 (m, 1H), 8.41 (s, 1H), 7.17 (s, 1H), 7.01 (dd, J = 6.4, 4.0 Hz, 1H), 6.68 (s, 1H), 3.08 (s, 2H), 3.02 (s, 2H), 2.94-2.92 (m, 4H), 2.76- 2.74 (m, 5H), 2.65-2.61 (m, 3H), 2.37 (s, 3H), 2.04-2.02 (m, 2H), 2.00-1.98 (m, 2H), 0.84-0.82 (m, 2H), 0.55- 0.50 (m, 2H). LCMS (ESI): m/z = 545.3 [M + H]+.
377	N-(6-(2,2- Difluoroethoxy)- 3H- spiro[benzofuran- 2,4′-piperidin]- 5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz,DMSO- d6) δ 10.32 (s, 1H), 9.40-9.35 (m, 1H), 8.85-8.75 (m, 2H), 8.67 (s, 1H), 8.35 (s, 1H), 7.34 (dd, J = 7.2, 4.0 Hz, 1H), 6.75 (s, 1H), 6.67-6.40 (m, 1H), 4.46-4.37 (m, 2H), 3.32- 3.15 (m, 4H), 3.11 (s, 2H), 2.05-1.95 (m, 4H). LCMS (ESI): m/z = 430.1 [M + H]+.
378	N-(6-(2,2- difluoroethoxy)- 1′-methyl-3H- spiro[benzofuran- 2,4′-piperidin]- 5- yl)pyrazolo[1,5- a]pyrimidine-3- carboxamide		1H NMR (400 MHz,CDCl3) δ 10.24 (s, 1H), 8.84-8.80 (m, 1H), 8.75 (s, 1H), 8.70 (dd, J = 4.0, 1.6 Hz, 1H), 8.42 (s, 1H), 7.04 (dd, J = 6.8, 4.0 Hz, 1H), 6.42 (s, 1H), 6.40-6.10 (m, 1H), 4.30-4.22 (m, 2H), 3.01 (s, 2H), 2.58-2.53 (m, 4H), 2.35 (s, 3H), 2.02-2.00 (m, 2H), 1.99-1.68 (m, 2H). LCMS (ESI): m/z = 444.2 [M + H]+.

Example 379. N-[6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2,2-dimethyl-3H-benzofuran-5-yl]-6-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Step A. Ethyl 6-[(4-methoxyphenyl)methyl-methyl-amino]pyrazolo[1,5-a]pyrimidine-3-carboxylate

A mixture of ethyl 6-bromopyrazolo[1,5-a]pyrimidine-3-carboxylate (1.5 g, 5.55 mmol), N-(4-methoxybenzyl)-N-methylamine (1.67 g, 11.04 mmol) and N,N-diisopropylethylamine (2.75 ml, 16.63 mmol) in ethanol (25 ml) was stirred at 85° C. for 96 h. The mixture was concentrated to dryness and the residue was purified by column chromatography (eluent 50% ethyl acetate:petroleum ether) to afford ethyl 6-[(4-methoxyphenyl)methyl-methyl-amino]pyrazolo[1,5-a]pyrimidine-3-carboxylate (1120 mg, 57.5% yield) as a yellow solid. (ESI): m/z=341.2 [M+1]⁺.

Step B. 6-[(4-Methoxyphenyl)methyl-methyl-amino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A mixture of ethyl 6-[(4-methoxyphenyl)methyl-methyl-amino]pyrazolo[1,5-a]pyrimidine-3-carboxylate (50 mg, 0.15 mmol) and lithium hydroxide hydrate (7.0 mg, 0.17 mmol) in tetrahydrofuran (1 ml), methanol (1 ml) and water (1 ml) was stirred in a sealed tube at 100° C. under microwave irradiation for 45 min. The mixture will neutralized with 2N HCl and concentrated to dryness to afford 6-[(4-methoxyphenyl)methyl-methyl-amino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 98% yield) as a yellow solid. (ESI): m/z=313.1 [M+1]⁺.

Step C. N-[6-[4-(2,2-Difluoroethyl)piperazin-1-yl]-2,2-dimethyl-3H-benzofuran-5-yl]-6-[(4-methoxyphenyl)methyl-methyl-amino]pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2,2-dimethyl-3H-benzofuran-5-amine (120.0 mg, 0.39 mmol), 6-[(4-methoxyphenyl)methyl-methyl-amino]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (150.0 mg, 0.48 mmol), HATU (300.0 mg, 0.79 mmol) and N,N-diisopropylethylamine (0.3 ml, 1.72 mmol) in N,N-dimethylformamide (2 ml) was stirred for 12 h. The reaction was then purified by preparative HPLC (Xbridge 21.2*250 mm c18, 10 um acetonitrile 50-70% (10 mM ammonium bicarbonate) in water) to afford N-[6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2,2-dimethyl-3H-benzofuran-5-yl]-6-[(4-methoxyphenyl)methyl-methyl-amino]pyrazolo[1,5-a]pyrimidine-3-carboxamide (96 mg, 41% yield).

Step D. N-[6-[4-(2,2-difluoroethyl)piperazin-1-yl]-2,2-dimethyl-3H-benzofuran-5-yl]-6-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

N-[6-[4-(2,2-difluoroethyl)piperazin