KINASE INHIBITORS USEFUL FOR THE TREATMENT OF MYLEOPROLIFIC DISEASES AND OTHER PROLIFERATIVE DISEASES

Abstract

Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant melanomas, solid tumors, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, hepatic cancers, cervical carcinomas, metastasis of primary tumor sites, myeloproliferative diseases, chronic myelogenous leukemia, leukemias, papillary thyroid carcinoma, non-small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colonic cancers, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies, diabetic retinopathy, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, mastocytosis, mast cell leukemia, a disease caused by c-Abl kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, a disease caused by c-Kit kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, a disease caused by c-Met kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, or a disease caused by a Raf kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Provisional Application 60/913,216 filed Apr. 20, 2007. This provisional application is incorporated by reference herein in its entirety.

SEQUENCE LISTING

This application contains a Sequence Listing in both paper and computer readable format in accordance with 37 C.F.R. 1.821 (c) and (e), the contents of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel kinase inhibitors and modulator compounds useful for the treatment of various diseases. More particularly, the invention is concerned with such compounds, kinase/compound adducts, methods of treating diseases, and methods of synthesis of the compounds. Preferrably, the compounds are useful for the modulation of kinase activity of C-Abl c-Kit, the HER family, FGFR, VEGFR, PDGFR, Flt-3, the Raf kinase family and disease causing polymorphs thereof.

BACKGROUND OF THE INVENTION

Several members of the protein kinase family have been clearly implicated in the pathogenesis of various proliferative and myeloproliferative diseases and thus represent important targets for treatment of these diseases. Some of the proliferative diseases relevant to this invention include cancer, rheumatoid arthritis, atherosclerosis, and retinopathies. Important examples of kinases which have been shown to cause or contribute to the pathogensis of these diseases include C-Abl kinase and the oncogenic fusion protein bcr-Abl kinase; c-Kit kinase. FGFR, PDGF receptor kinase; VEGF receptor kinases; Flt-3 kinase, the HER family and the Raf kinase family.

C-Abl kinase is an important non-receptor tyrosine kinase involved in cell signal transduction. This ubiquitously expressed kinase—upon activation by upstream signaling factors including growth factors, oxidative stress, integrin stimulation, and ionizing radiation—localizes to the cell plasma membrane, the cell nucleus, and other cellular compartments including the actin cytoskeleton (Van Etten, Trends Cell Biol. (1999) 9: 179). There are two normal isoforms of Abl kinase: Abl-1A and Abl-1B. The N-terminal half of c-Abl kinase is important for autoinhibition of the kinase domain catalytic activity (Pluk et al, Cell (2002) 108: 247). Details of the mechanistic aspects of this autoinhibition have recently been disclosed (Nagar et al, Cell (2003) 112: 859). The N-terminal myristolyl amino acid residue of Abl-1B has been shown to intramolecularly occupy a hydrophobic pocket formed from alpha-helices in the C-lobe of the kinase domain. Such intramolecular binding induces a novel binding area for intramolecular docking of the SH2 domain and the SH3 domain onto the kinase domain, thereby distorting and inhibiting the catalytic activity of the kinase. Thus, an intricate intramolecular negative regulation of the kinase activity is brought about by these N-terminal regions of c-Abl kinase. An aberrant dysregulated form of c-Abl is formed from a chromosomal translocation event, referred to as the Philadelphia chromosome (P. C. Nowell et al, Science (1960) 132: 1497; J. D. Rowley, Nature (1973) 243: 290). This abnormal chromosomal translocation leads aberrant gene fusion between the Abl kinase gene and the breakpoint cluster region (BCR) gene, thus encoding an aberrant protein called bcr-Abl (G. Q. Daley et al, Science (1990) 247: 824; M. L. Gishizky et al, Proc. Natl. Acad. Sci. USA (1993) 90: 3755; S. Li et al, J. Exp. Med. (1999) 189: 1399). The bcr-Abl fusion protein does not include the regulatory myristolylation site (B. Nagar et al, Cell (2003) 112: 859) and as a result functions as an oncoprotein which causes chronic myeloid leukemia (CML). CML is a malignancy of pluripotent hematopoietic stem cells. The p210 form of bcr-Abl is seen in 95% of patients with CML, and in 20% of patients with acute lymphocytic leukemia and is exemplified by sequences such as e14a2 and e13a2. The corresponding p190 form, exemplified by the sequence e1a2 has also been identified. A p185 form has also been disclosed and has been linked to being causative of up to 10% of patients with acute lymphocytic leukemia. It will be appreciated by one skilled in the art that “p210 form”, “p190 form” and “p185 form” each describe a closely related group of fusion proteins, and that Sequence ID's used herein are merely representative of each form and are not meant to restrict the scope solely to those sequences.

C-KIT (Kit, CD117, stem cell factor receptor) is a 145 kDa transmembrane tyrosine kinase protein that acts as a type-III receptor (Pereira et al. J Carcin. (2005), 4: 19). The c-KIT proto-oncogene, located on chromosome 4q11-21, encodes the c-KIT receptor, whose ligand is the stem cell factor (SCF, steel factor, kit ligand, mast cell growth factor, Morstyn G. et al. Oncology (1994) 51(2):205, Yarden Y, et al. Embo J (1987) 6(11):3341). The receptor has tyrosine-protein kinase activity and binding of the ligands leads to the autophosphorylation of KIT and its association with substrates such as phosphatidylinositol 3-kinase (Pi3K). Tyrosine phosphorylation by protein tyrosine kinases is of particular importance in cellular signalling and can mediate signals for major cellular processes, such as proliferation, differentiation, apoptosis, attachment, and migration. Defects in KIT are a cause of piebaldism, an autosomal dominant genetic developmental abnormality of pigmentation characterized by congenital patches of white skin and hair that lack melanocytes. Gain-of-function mutations of the c-KIT gene and the expression of phosphorylated KIT are found in most gastrointestinal stromal tumors and mastocytosis. Further, almost all gonadal seminomas/dysgerminomas exhibit KIT membranous staining, and several reports have clarified that some (10-25%) have a c-KIT gene mutation (Sakuma, Y. et al. Cancer Sci (2004) 95:9, 716). KIT defects have also been associated with testicular tumors including germ cell tumors (GCT) and testicular germ cell tumors (TGCT).

The role of c-kit expression has been studied in hematologic and solid tumours, such as acute leukemias (Cortes J. et al. Cancer (2003) 97(11):2760) and gastrointestinal stromal tumors (GIST, Fletcher C. D. et al. Hum Pathol (2002) 33(5):459). The clinical importance of c-kit expression in malignant tumors relies on studies with Gleevece (imatinib mesylate, ST1571, Novartis Pharma AG Basel, Switzerland) that specifically inhibits tyrosine kinase receptors (Lefevre G. et al. J Biol Chem (2004) 279(30):31769). Moreover, a clinically relevant breakthrough has been the finding of anti-tumor effects of this compound in GIST, a group of tumors regarded as being generally resistant to conventional chemotherapy (de Silva C M, Reid R: Pathol Oncol Res (2003) 9(1):13-19). GIST most often become Gleevec resistant and molecularly targeted small therapies that target c-KIT mutations remain elusive.

c-MET is a unique receptor tyrosine kinase (RTK) located on chromosome 7p and activated via its natural ligand hepatocyte growth factor. c-MET is found mutated in a variety of solid tumors (Ma P. C. et al, Cancer Metastasis (2003) 22:309). Mutations in the tyrosine kinase domain are associated with hereditary papillary renal cell carcinomas (Schmidt L et al. Nat. Genet. (1997)16:68; Schmidt L, et al. Oncogene (1999) 18:2343), whereas mutations in the sema and juxtamembrane domains are often found in small cell lung cancers (SCLC; Ma P. C. et al. Cancer Res (2003) 63:6272). Many activating mutations are also found in breast cancers (Nakopoulou et al. Histopath (2000) 36(4): 313). The panoply of tumor types for which c-Met mediated growth has been implicated suggests this is a target ideally suited for modulation by specific c-MET small molecule inhibitors.

The TPR-MET oncogene is a transforming variant of the c-MET RTK and was initially identified after treatment of a human osteogenic sarcoma cell line transformed by the chemical carcinogen N-methyl-N-nitro-N-nitrosoguanidine (Park M. et al. Cell (1986) 45:895). The TPR-MET fusion oncoprotein is the result of a chromosomal translocation, placing the TPR3 locus on chromosome 1 upstream of a portion of the c-MAET gene on chromosome 7 encoding only for the cytoplasmic region. Studies suggest that TPR-MET is detectable in experimental cancers (e.g. Yu J. et al. Cancer (2000) 88:1801). Dimerization of the M_r 65.000 TPR-MET oncoprotein through a leucine zipper motif encoded by TPR leads to constitutive activation of the c-MET kinase (Zhen Z. et al. Oncogene (1994) 9:1691). TPR-MET acts to activated wild-type c-MET RTK and can activate crucial cellular growth pathways, including the Ras pathway (Aklilu F. et al. Am J Physiol (1996) 271:E277) and the phosphatidylinositol 3-kinase (PI3K)/AKT pathway (Ponzetto C. et al. Mol Cell Biol (1993) 13:4600). Conversely, in contrast to c-MET RTK, TPR-MET is ligand independent, lacks the CBL binding site in the juxtamembrane region in c-MET, and is mainly cytoplasmic. c-Met immunohistochemical expression seems to be associated with abnormal β-catenin expression, and provides good prognostic and predictive factors in breast cancer patients.

The majority of small molecule kinase inhibitors that have been reported have been shown to bind in one of three ways. Most of the reported inhibitors interact with the ATP binding domain of the active site and exert their effects by competing with ATP for occupancy. Other inhibitors have been shown to bind to a separate hydrophobic region of the protein known as the “DFG-in-conformation” pocket wherein such a binding mode by the inhibitor causes the kinase to adopt the “DFG-out” conformation, and still others have been shown to bind to both the ATP domain and the “DFG-in-conformation” pocket again causing the kinase to adopt the “DGF-out” conformation. Examples specific to inhibitors of Raf kinases can be found in Lowinger et al, Current Pharmaceutical Design (2002) δ: 2269; Dumas, J. et al., Current Opinion in Drug Discovery & Development (2004) 7: 600; Dumas, J. et al, WO 2003068223 A1 (2003); Dumas, J., et al, WO 9932455 A1 (1999), and Wan, P. T. C., et al, Cell (2004) 116: 855.

Physiologically, kinases are regulated by a common activation/deactivation mechanism wherein a specific activation loop sequence of the kinase protein binds into a specific pocket on the same protein which is referred to as the switch control pocket. Such binding occurs when specific amino acid residues of the activation loop are modified for example by phosphorylation, oxidation, or nitrosylation. The binding of the activation loop into the switch pocket results in a conformational change of the protein into its active form (Huse, M. and Kuriyan, J. Cell (109) 275)

SUMMARY OF THE INVENTION

Compounds of the present invention find utility in the treatment of mammalian cancers and especially human cancers including but not limited to malignant, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, cervical carcinomas, metastasis of primary tumor sites, mycloproliferative diseases, leukemias, papillary thyroid carcinoma, non small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colonic cancers, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies, rheumatoid arthritis, asthma, chronic obstructive pulmonary disorder, mastocyclosis, mast cell leukemia, a disease caused by c-Abl kinase, oncogenic forms thereof aberrant fusion proteins thereof and polymorphs thereof, or a disease caused by a laf kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof.

SECTION 1—DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following descriptions refer to various compounds and moieties thereof.

Cycloalkyl refers to monocyclic saturated carbon rings taken from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl and cyclooctanyl;

Aryl refers to monocyclic or fused bicyclic ring systems characterized by delocalized n electrons (aromaticity) shared among the ring carbon atoms of at least one carbocyclic ring; preferred aryl rings are taken from phenyl, naphthyl, tetrahydronaphthyl, indenyl, and indanyl;

Heteroaryl refers to monocyclic or fused bicyclic ring systems characterized by delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms including nitrogen, oxygen, or sulfur of at least one carbocyclic or heterocyclic ring; heteroaryl rings are taken from, but not limited to, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, pyrazolopyridinyl, imidazolonopyridinyl, thiazolopyridinyl, thiazolonopyridinyl, oxazolopyridinyl, oxazolonopyridinyl, isoxazolopyridinyl, isothiazolopyridinyl, triazolopyridinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, imidazolonopyrimidinyl, thiazolopyridiminyl, thiazolonopyrimidinyl, oxazolopyridiminyl, oxazolonopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, triazolopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyrimidinyl, phthalimidyl, plithalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, and benzoxazepinyl;

Heterocyclyl refers to monocyclic rings containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms; heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetraliydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholiniyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;

Poly-aryl refers to two or more monocyclic or fused aryl bicyclic ring systems characterized by delocalized π electrons (aromaticity) shared among the ring carbon atoms of at least one carbocyclic ring wherein the rings contained therein are optionally linked together;

Poly-heteroaryl refers to two or more monocyclic or fused bicyclic systems characterized by delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms including nitrogen, oxygen, or sulfur of at least one carbocyclic or heterocyclic ring wherein the rings contained therein are optionally linked together, wherein at least one of the monocyclic or fused bicyclic rings of the poly-heteroaryl system is taken from heteroaryl as defined broadly above and the other rings are taken from either aryl, heteroaryl, or heterocyclyl as defined broadly above;

Poly-heterocyclyl refers to two or more monocyclic or fused bicyclic ring systems containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms wherein the rings contained therein are optionally linked, wherein at least one of the monocyclic or fused bicyclic rings of the poly-heteroaryl system is taken from heterocyclyl as defined broadly above and the other rings are taken from either aryl, heteroaryl, or heterocyclyl as defined broadly above;

Alkyl refers to straight or branched chain C1-C6alkyls;

Halogen refers to fluorine, chlorine, bromine, and iodine;

Alkoxy refers to —O-(alkyl) wherein alkyl is defined as above;

Alkoxylalkyl refers to -(alkyl)-O-(alkyl) wherein alkyl is defined as above;

Alkoxyl carbonyl refers to —C(O)O-(alkyl) wherein alkyl is defined as above;

CarboxylC1-C₆alkyl refers to —(C₁-C₆alkyl)CO₂H wherein alkyl is defined as above;

Substituted in connection with a moiety refers to the fact that a further substituent may be attached to the moiety to any acceptable location on the moiety.

The term salts embraces pharmaceutically acceptable salts commonly used to form alkali metal salts of free acids and to form addition salts of free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric and galacturonic acid. Suitable pharmaceutically-acceptable salts of free acid-containing compounds of Formula I include metallic salts and organic salts. More preferred metallic salts include, but are not limited to appropriate alkali metal (group Ia) salts, alkaline earth metal (group IIa) salts and other physiological acceptable metals. Such salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from primary amines, secondary amines, tertiary amines and quaternary ammonium salts, including in part, tromethamine, diethylamine, tetra-N-methylammonium, N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.

The term prodrug refers to derivatives of active compounds which revert in vivo into the active form. For example, a carboxylic acid form of an active drug may be esterified to create a prodrug, and the ester is subsequently converted in vivo to revert to the carboxylic acid form. See Ettmayer et. al, J. Med. Chew (2004) 47: 2393 and Lorenzi et. al, J Pharm. Exp. Therapeutics (2005) 883 for reviews.

Structural, chemical and stereochemical definitions are broadly taken from IUPAC recommendations, and more specifically from Glossary of Terms used in Physical Organic Chemistry (IUPAC Recommendations 1994) as summarized by P. Müller, Pure Appl. Chem., 66, 1077-1184 (1994) and Basic Terminology of Stereochemistry (IUPAC Recommendations 1996) as summarized by G. P. Moss Pure and Applied Chemistry, 68. 2193-2222 (1996). Specific definitions are as follows:

Atropisomers are defined as a subclass of conformers which can be isolated as separate chemical species and which arise from restricted rotation about a single bond.

Regioisomers or structural isomers are defined as isomers involving the same atoms in different arrangements.

Enantiomers are defined as one of a pair of molecular entities which are mirror images of each other and non-superimposable.

Diastereomers or diastereoisomers are defined as stereoisomers other than enantiomers. Diastereomers or diastereoisomers are stereoisomers not related as mirror images.

Diastereoisomers are characterized by differences in physical properties, and by some differences in chemical behavior towards achiral as well as chiral reagents.

Tautomerism is defined as isomerism of the general form

G-X-Y=Z=X=Y-Z-G

where the isomers (called tautomers) are readily interconvertible; the atoms connecting the groups X, Y, Z are typically any of C, H, O, or S, and G is a group which becomes an electrofuge or nucleofuge during isomerization. The commonest case, when the electrofuge is H⁺, is also known as “prototropy”.

Tautomers are defined as isomers that arise from tautomerism, independent of whether the isomers are isolable.

1. FIRST ASPECT OF THE INVENTION

Compounds, Methods, Preparations and Adducts

The invention includes compounds of the formula Ia:

wherein Q1 and Q2 are each individually and independently selected from the group consisting of N and CH and wherein at least one of Q1 and Q2 is N;
and wherein the ring containing Q1 and Q2 may be optionally substituted with one or more R20 moieties;
each D is individually taken from the group consisting of C, CH, C—R20, N-Z3, N, O and S, such that the resultant ring is taken from the group consisting of pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxazolyl, and thiadiazolyl;
wherein E is selected from the group consisting of phenyl, pyridyl, and pyrimidinyl;
when Q1 and Q2 are both N, the A ring is selected from the group consisting of cyclopentyl, cyclohexyl, G1, G2, and G3;
when only one of Q1 and Q2 is N, the A ring is selected from the group consisting of cyclopentyl, cyclohexyl. G1, O₂, G0 and G4;
G1 is a heteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl-4-yl, isoxazolyl-5-yl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl;
G2 is a fused bicyclic heteroaryl taken from the group consisting of indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, pyrazolopyridinyl, imidazolonopyridinyl, thiazolopyridinyl, thiazolonopyridinyl, oxazolopyridinyl, oxazolonopyridinyl, isoxazolopyridinyl, isothiazolopyridinyl, triazolopyridinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, imidazolonopyrimidinyl, thiazolopyridiminyl, thiazolonopyrimidinyl, oxazolopyridiminyl, oxazolonopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, triazolopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyrimidinyl, phthalirnidyl, phthalimidinyl, pyrazinylpyndinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cihmolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, phthalazinyl, benzodioxyl, benzisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, and benzoxazepinyl;
G3 is a heterocyclyl taken from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpliolinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;
G4 is selected from the group consisting of phenyl, naphthyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl;
the A ring is substituted with one —(X1-A1) moiety or one A1 moiety, and may be optionally substituted with one or two R2 moieties;
when A is phenyl and E is phenyl, then Z1 cannot be —O(CH₁)_qR5, —(CH₂)_p-G3, or —(CH₂)_pR5;
A1 is selected from the group consisting of phenyl, G1, G3 and 64;
X1 is selected from the group consisting of a direct bond linking the A and A1 rings, —(CH₂)_n(O)_r(CH₂)_n—, —(CH₂)_n(NR3)_r(CH₂)_n—, —(CH₂)_n(S)_r(CH₂)_n—, —(CH₂)_n(C(O))_r(CH₂)_n—, —(CH₂)_n(C(O)NR3)_r(CH₂)_n—, and —(CH₂)_n(SO₂NR3)_r(CH₂)_n—, wherein any of the alkylenes may be straight or branched chain;
when X1 is a direct bond, E is substituted with one or two R16 moieties;
when X1 is not a direct bond, then E is optionally substituted with one or two R16 moieties;
X2 is selected from the group consisting of —O—, —S(CH₂)_n—, —N(R3)(CH₂, —(CH₂)_p—, and wherein the carbon atoms of —(CH₂)_n—, —(CH₂)_p—, of X2 may be further substituted by oxo or one or more C1-C6alkyl moieties;
when A, A1, G1, G2 G3 or G4 has one or more substitutable sp2-hybridized carbon atoms, each respective sp2 hybridized carbon atom may be optionally substituted with a Z1 substituent;
when A, A1, G1, G2 or G3 has one or more substitutable sp3-hybridized carbon atoms, each respective sp3 hybridized carbon atom may be optionally substituted with a Z2 substituent;
when A, A1, G1. G2 or G3 has one or more substitutable nitrogen atoms, each respective nitrogen atom may be optionally substituted with a Z4 substituent;
each Z1 is independently and individually selected from the group consisting of C1-6alkyl, branched C3-C7alkyl, C3-C8cycloalkyl, halogen, fluoroC1-C₆alkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, C1-C6alkoxy, fluoroC1-C6alkoxy wherein the alkyl moiety can be partially or fully fluorinated, —(CH₂)_nOH, oxo. C1-C6alkoxyC1-C6alkyl, (R4)₂N(CH)_n—, (R3)₂N(CH)_n—, (R4)₂N(CH₂)_qN(R4)(CH₂)_n—, (R4)₂N(CH₁)_q—O—(CH₂)_n—, (R3)₂NC(O)—, (R4)₂NC(O)—, (R4)₂NC(O)C₁-C₆alkyl-, —(R4)NC(O)R8, C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl-, (R3)₂NSO₂—, —SOR3, (R4)₂NSO₂—, —N(R4)SO₂R5, —N(R4)SO₂R8, —O(CH₂)_qOC1-C6alkyl, —O(CH₂)_qR5, —SO₂R3, —SOR4, —S(O)₂R5, —(CH₂)_nC(O)R5, —C(O)R8, —C(O)R6, —C(═NOH)R6, —C(—NOR3)R6, —(CH₂)_nN(R4)C(O)R8, —(CH₂)_n-G1, —(CH₂)_n-G4, phenoxy, —(CH₂)_n—O(CH₂)_n-G1, —(CH₂)_pO(CH₂)_n-G4, —N(R3C)(CH₂)_qO-alkyl, —N(R3)(CH₂)_qN(R4)₂, —N(R3)(CH₂)_qR5, —(CH₂)_nN(R3)(CH₂)_n-aryl, —(CH₂)_nN(R3)(CH₂)_n-G1, —(CH₂)_nN(R3)(CH₂)_n-G4, nitro, —(CH₂)_nNHC(O)(CH₂)_nR5, —(CH₂)_nNHS(O)₂(CH₂)_nR5, —(CH₂)_nC(O)NH(CH₂)_qR5, —(CH₂)_nOC(O)R5, —CH(OH)(CH₂)_pR5, —CH(OH)CH(OH)R4, —(CH₂)_nR5, —C(═NH)R5, —C(═NH)N(R4)₂, —C(═NOR3)R5, —C(═NOR3)N(R4)₂, and —NHC(═NH)R8;
in the event that Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C₁-C₆alkyls;
each Z2 is independently and individually selected from the group consisting of aryl, C1-C6alkyl, C3-C8cycloalkyl, branched C3-C7alkyl, hydroxyl, hydroxyC1-C6alkyl-, cyano, (R3)₂N—, (R4)₂N—, (R4)₂NC1-C6alkyl-, (R4)₂NC2-C6alkylN(R4)(CH₂)_n—, (R4)₂NC2—C6alkylO(CH₂)_n—, (R3)₂NC(O)—, (R4)₂NC(O)—, (R4)₂NC(O)—C₁-C₆alkyl-, carboxyl, -carboxyC1-C6alkyl, C1-C6alkoxycarbonyl-, C1-C6alkoxycarbonylC1-C6alkyl-, (R3)₂NSO₂—, (R4)₂NSO₂—, —SO₂R5, —SO₂R8, —(CH₂)_nN(R4)C(O)R8, —C(O)R8, ═O, ═NOH, ═N(OR6), —(CH₂)_n-G1, —(CH₂)_n-G4, —(CH₂)_n—O(CH₂)-G1, —(CH₁)_nO(CH₂)_n-G4, —(CH₂)_nN(R3)(CH₂)_n-aryl, —(CH₂)_nN(R3)(CH₂)_n-G1, —(CH₂)_nN(R3)(CH₂)_n-G4, —(CH₂)_nNHC(O)(CH₂)_nR5, —(CH₂)_nNHS(O)₂(CH₂)_nR5, —(CH₂)_nC(O)NH(CH₂)_qR5, —(CH₂)_nC(O)R5, —(CH₂)_nOC(O)R5, and —(CH₂)_nR5;
in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;
each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8cycloalkyl, fluoroC1-C6alkyl wherein the alkyl moiety can be partially or fully fluorinated, hydroxyC2-C6alkyl-, C1-C6alkoxycarbonyl-, —C(O)R8, R5C(O)(CH₂)_n—, (R4)₂NC(O)—, (R4)₂NC(O)C1-C6alkyl-, R8C(O)N(R4)(CH₂)_q—, (R3)₂NSO₂—, (R4)₂NSO₂—, —(CH₂)_qN(R3)₂, and —(CH₂)_qN(R4)₂;
each Z4 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-7alkyl, hydroxyC2-C6alkyl-, C1-C₆alkoxyC2C6alkyl-, (R4)₂N—C2-C6alkyl-, (R4)₂N—C2-C6alkylN(R4)—C2-C6alkyl-, (R4)₂N—C2-C6alkyl-O—C2-C₆alkyl-(R4)₂NC(O)C1-C6alkyl-, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl-, —C2-C6alkylN(R4)C(O)R8, R8—C(═NR3)—, —SO₂R8, —COR8, —(CH₂)_n-G1, —(CH₂)_n-G4, —(CH₂)_qO(CH₂)_n-G1, —(CH₂)_qO(CH₂)_n-G4, —(CH₂)_qNR3(CH₂)_n-G1, —(CH₂)_nNR3(CH₂)_n-G4, —(CH₂)_qNHC(O)(CH₂)_nR5, —(CH₂)_qC(O)NH(CH₂)_qR5, (CH₂)_qC(O)R5, (CH₂)_qOC(O)R5, —(CH₂)_qR5, —(CH₂)_qNR4(CH₂)_qR5, and (CH₂)_qO(CH₂)_qR5;
in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C₁-C₆alkyls;
each R2 is selected from the group consisting of H, R17-substituted aryl-, R17-substituted G1, R17-substituted G4, C₁-C₆alkyl, branched C3-C8alkyl, R19 substituted C3-C8cycloalkyl-, fluoroC1-C6alkyl- wherein the alkyl is fully or partially fluorinated, halogen, cyano, C1-C6alkoxy-, and fluoroC1-C6alkoxy- wherein the alkyl group is fully or partially fluorinated, hydroxyl substituted C1-C6alkyl-, hydroxyl substituted branched C3-C8alkyl-, cyano substituted C1-C6alkyl-, cyano substituted branched C3-C8alkyl-, (R3)₂NC(O)C1-C6alkyl-, (R10)₂NC(O)C3-C8 branched alkyl-;
wherein each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, and C3-C8cycloalkyl;
each R4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6alkyl-, dihydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-, branched C3-C7alkyl, branched hydroxyC1-C6alkyl-, branched C1-C6alkoxyC1-C6alkyl-, branched dihydroxyC1-C6alkyl-, —(CH₂)_pN(R7)₂, —(CH₂)_pR5, —(CH₂)_pC(O)N(R7)₂, —(CH₂)_nC(O)R5, —(CH₂)_nC(O)OR3, R19 substituted C₃-C₈cycloalkyl-;
each R5 is independently and individually selected from the group consisting of

and wherein the symbol (#4) is the point of attachment to respective R4, R7, R8, Z2, Z3 or Z4 moieties containing a R5 moiety;
each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8cycloalkyl-, phenyl, G1, and G3;
each R7 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl-, dihydroxyC2-C6alkyl-, C1-C6alkoxyC2-C6alkyl-, branched C3-C7alkyl, branched hydroxyC2-C6alkyl-, branched C1-C6alkoxyC2-C6alkyl-, branched dihydroxyC2-C6alkyl-, —(CH₂)_qR5, —(CH₁)_nC(O)R5, —(CH₂)_nC(O)OR3, R19 substituted C3-C8cycloalkyl- and —(CH₂) in R17;
each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroC1-C6alkyl- wherein the alkyl moiety is partially or fully fluorinated, R19 substituted C3-C8cycloalkyl-, phenyl, phenylC1-C6alkyl-, G1, G1-C1-C6alkyl-, G4-(CH2)_n—, OH, C1-C6alkoxy, —N(R3)₂, —N(R4)₂, and R5;
each R10 is independently and individually selected from the group consisting of —CO₂H, —CO₂C1-C6alkyl, —C(O)N(R4)₂, OH, ×C1-C6alkoxy, and —N(R4)₂;
each R16 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8cycloalkyl-, halogen, fluoroC1-C6alkyl- wherein the allyl moiety can be partially or fully fluorinated, cyano, hydroxyl, C1-C6alkoxy, fluoroC1-C6alkoxy- wherein the alkyl moiety can be partially or fully fluorinated, —N(R3)₂, —N(R4)₂, R3 substituted C₂-C₃alkynyl- and nitro;
each R17 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8cycloalkyl-, halogen, fluoroC1-C6alkyl- wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, C1-C6alkoxy, fluoroC1-C6alkoxy- wherein the alkyl moiety can be partially or fully fluorinated, —N(R3)₂, —N(R4)₂, and nitro;
each R19 is independently and individually selected from the group consisting of H, OH and C1-C6alkyl;
each R20 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8cycloalkyl-, halogen, fluoroC1-C6alkyl- wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, C1-C6alkoxy, fluoroC1-C6alkoxy- wherein the alkyl moiety can be partially or fully fluorinated, —N(R3)₂, —N(R4)₂, —N(R3)C(O)R3, —C(O)N(R3)₂ and nitro;
wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl-, and alkoxyalkyl and attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;
k is 0 or 1; n is 0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3; v is 1 or 2; x is 0-2;
stereo-, regioisomers and tautomers of such compounds;
and with the proviso if A1 is G3, imidazolyl or pyrazolyl then X1 is not a direct bond.
1.1 Compounds of Formula Ia which Exemplify Preferred

In a preferred embodiment of compounds of formula Ia, said compounds have preferred

which is selected from the group consisting of

wherein the symbol (**) indicates the point of attachment to the aromatic ring.
1.1.1 Compounds of Formula Ia which Exemplify Preferred E1 and X3 Moieties

In a preferred embodiment of compounds of formula Ia, said compounds have structures of formula Ib

wherein A is any possible isomer of pyrazole.
1.1.2 Compounds of Formula Ib which Exemplify Preferred A, D Ring and R16 Moieties

In a preferred embodiment of compounds of formula Ib, said compounds have structures of formula Ic

1.1.3 Compounds of Formula Ib which Exemplify Preferred A, D Ring and R16 Moieties

In a preferred embodiment of compounds of formula Ib, said compounds have structures of formula Id

1.1.4 Compounds of Formula Ib which Exemplify Preferred A, D Ring and R16 moieties

In a preferred embodiment of compounds of formula Ib, said compounds have structures of formula Ie

1.1.5 Compounds of Formula Ia which Exemplify Preferred A Moieties

In a preferred embodiment of compounds of formula Ia, said compounds have structures of formula If

wherein A is selected from the group consisting of any possible isomer of phenyl, pyridine and pyrimidine.
1.1.6 Compounds of Formula If which Exemplify Preferred A, D Ring and R16 Moieties

In a preferred embodiment of compounds of formula If, said compounds have structures of formula Ig

1.1.7 Compounds of Formula Ig which Exemplify Preferred A, D Ring and R16 Moieties

In a preferred embodiment of compounds of formula If, said compounds have structures of formula Ih

1.1.8 Compounds of Formula If which Exemplify Preferred A, D Ring and R16 Moieties

In a preferred embodiment of compounds of formula If, said compounds have structures of formula Ii

1.1.29 Most Preferred Compounds of Formula Ia

1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)urea, 4-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl ureido)-1H-pyrazol-1-yl)benzyl acetate, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy )phenyl)urea, 1-(3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-cyano-4-fluorophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy phenyl)urea, 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxyophenyl)urea, 1-(1-(4-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, ethyl 3-(3-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)benzoate 1-(3-tert-butyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 3-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)benzoic acid, 1-(3-tert-butyl-1-(4-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-cyanophenyl)-3-ethyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(2-tert-butyl-4-phenylpyrimidin-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-cyano-4-methyl phenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl pyridin-4-yloxy)phenyl)urea, 1-(1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)_3-3-(2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1(1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-methyl-4-phenylpyrimidin-5-yl)urea, 1-(1-(3-cyanophenyl)-3-ethyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-propyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-cyanophenyl)-3-ethyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-isopropyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-cyanophenyl)-3-ethyl-1H-pyrazol-5-yl)-3-(4-(2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)urea, 1-(3-ethyl-1-(4-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1-isopropyl-5-phenyl-1H-pyrazol-4-yl)urea, 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1-isopropyl-3-phenyl-1H-pyrazol-4-yl)urea, 1-(1-ethyl-5-phenyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-ethyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-cyanophenyl)-3-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-(3-cyanophenyl)-1-isopropyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1-(3-fluorophenyl)-3-isopropyl-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)urea, 1-(1,3-diphenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1,3-diphenyl-1H-pyrazol-5-yl)urea, and 1-(5-chloro-2-phenylphenyl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea.

1.2 Methods

1.2a Methods of Protein Modulation

The invention includes methods of modulating kinase activity of a variety of kinases, e.g. C-Abl kinase, ber-Abl kinase, VEGFR-2 kinase mutants, c-Met, the HER family of kinases, FGFR, Flt-3, c-Kit, PDGFRα, PDGFRβ and the Raf family of kinases. The kinases may be wildtype kinases, oncogenic forms thereof, aberrant fusion proteins thereof or polymorphs of any of the foregoing. The method comprises the step of contacting the kinase species with compounds of the invention and especially those set forth in sections section 1. The kinase species may be activated or unactivated, and the species may be modulated by phosphorylations, sulfation, fatty acid acylations glycosylations, nitrosylation, cystinylation (i.e. proximal cysteine residues in the kinase react with each other to form a disulfide bond) or oxidation. The kinase activity may be selected from the group consisting of catalysis of phospho transfer reactions, inhibition of phosphorylation, oxidation or nitrosylation of said kinase by another enzyme, enhancement of dephosphorylation, reduction or denitrosylation of said kinase by another enzyme, kinase cellular localization, and recruitment of other proteins into signaling complexes through modulation of kinase conformation.

1.2b Treatment Methods

The methods of the invention also include treating individuals suffering from a condition selected from the group consisting of cancer, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases or diseases characterized by angiogenesis. These methods comprise administering to such individuals compounds of the invention, and especially those of section 1, said diseases including, but not limited to, solid tumors, malignant melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, kidney cancers, hepatic cancers, cervical carcinomas, metastasis of primary tumor sites, myeloproliferative diseases, chronic myelogenous leukemia, leukemias, papillary thyroid carcinoma, non-small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colonic cancers, ocular diseases characterized by hyperproliferation leading to blindness including various retinopathies, diabetic retinopathy and age-related macular degeneration and hyperosinophilic syndrome, rheumatoid arthritis, asthma, chronic obstructive pulmonary disorder, mastocytosis, mast cell leukemia, a disease caused by c-Abl kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, a disease caused by a c-Kit kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, a disease caused by a c-Met kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof or a disease caused by a Raf kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof. The administration method is not critical, and may be from the group consisting of oral, parenteral, inhalation, and subcutaneous.

1.3 Pharmaceutical Preparations

The compounds of the invention, especially those of Section 1 may form a part of a pharmaceutical composition by combining one or more such compounds with a pharmaceutically acceptable carrier. Additionally, the compositions may include an additive selected from the group consisting of adjuvants, excipients, diluents, and stabilizers.

SECTION 2. SYNTHESIS OF COMPOUNDS OF THE PRESENT INVENTION

The compounds of the invention are available by the procedures and teachings of WO 2006/071940, incorporated by reference, and by the general synthetic methods illustrated in the Schemes below and the accompanying examples.

As indicated in Scheme 1, ureas of general formula 1 can be readily prepared by the union of amines of general formula 2 with isocyanates 3 or isocyanate surrogates 4 (trichloroethyl carbamates) or 5 (isopropenyl carbamates). Preferred conditions for the preparation of compounds of general formula 1 involve heating a solution of 4 or 5 with 2 in the presence of a tertiary base such as diisopropylethylamine, triethylamine or N-methylpyrrolidine in a solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran or 1,4-dioxane at a temperature between 50 and 100° C. for a period of time ranging from 1 hour to 2 days.

As shown in Scheme 2, isocyanates 3 can be prepared from amines A-NH₂ 6 with phosgene, or a phosgene equivalent such as diphosgene, triphosgene, or N,N-dicarbonylimidazole. Trichloroethyl carbamates 4 and isopropenyl carbamates 5 are readily prepared from amines A-NH₂ (6) by acylation with trichloroethyl chloroformate or isopropenyl chloroformate by standard conditions familiar to those skilled in the art. Preferred conditions for the preparation of 4 and 5 include treatment of compound 6 with the appropriate chloroformate in the presence of pyridine in an aprotic solvent such as dichloromethane or in the presence of aqueous hydroxide or carbonate in a biphasic aqueous/ethyl acetate solvent system.

Additionally, compounds of formula 1 can also be prepared from carboxylic acids 7 by the intermediacy of in-situ generated acyl azides (Curtius rearrangement) as indicated in Scheme 3. Preferred conditions for Scheme 3 include the mixing of acid 7 with amine 2 and diphenylphosphoryl azide in a solvent such as 1,4-dioxane or dimethylformamide in the presence of base, such as triethylamine, and raising the temperature of the reaction to about 80-120° C. to affect the Curtius rearrangement.

Many methods exist for the preparation of amines A-NH₂ 6 and acids A-CO₂H 7, depending on the nature of the A-moiety. Many such methods have been described in detail in WO 2006/071940, and are incorporated by reference here. Preferred synthetic methods are outlined in the following Schemes for the non-limiting examples wherein A is a 1-substituted-pyrazole (optionally substituted by EC) or A and A1 are linked by C—C bond.

As illustrated in Scheme 4, A1-substituted, pyrazole amines 10 (a preferred aspect of A-NH2 6, Scheme 2) are available by the condensation of hydrazines 8 and beta-keto nitriles 9. Preferred conditions for this transformation are by heating in ethanolic HCl. Hydrazines 8 are in turn available by the diazotization of amines 11 followed by reduction or, alternately from the hydrolysis of hydrazones 13 obtained by the palladium mediated coupling of benzophenone hydrazone with compounds of formula A1-X 12, wherein X represents a halogen or triflate moiety.

Another preferred method for constructing A1-substituted pyrazoles is illustrated by the general preparation of pyrazole acid 16 (Scheme 5), an aspect of A-CO₂H 7 (Scheme 3). As indicated in Scheme 5, the union of a pyrazole 5-carboxylic ester 14 with A1-X 12, wherein X represents a halide, triflate, or boronic acid suitable for direct transition metal-catalyzed couplings with pyrazoles 14, provides A1-substituted pyrazole esters 15. Preferred conditions for such transformations involve mixing a boronic acid 12 [X=B(OH)₂] and ethyl esters, benzyl esters, or tert-butyl esters 14 in dichloromethane with copper acetate and pyridine in the presence of crushed molecular sieves, with or without heating. The esters 15 in turn can be converted to acids 16 using conditions familiar to those skilled in the art.

A non-limiting illustration of general Scheme 5 is found in Scheme 6, wherein pyrazole ester 17 is combined with boronic acid 18 in the presence of copper(II) acetate and pyridine to provide the N-aryl pyrazole 19. Saponification of ester 19 using lithium hydroxide or other equivalent methods provides acid 20, an example of general intermediate 7, above.

The general synthesis of intermediates useful for the construction of compounds of formula 1 wherein A and A1 are linked by a C—C bond is shown in Scheme 7. In this case, palladium catalyzed reactions (for example. Suzuki or Stille reactions) of A1-X 12 with a complementary component 21 or 22 provides compounds 23 or 94 examples of general intermediates A-NH₂ 6 or A-CO₂H 7, respectively. In this synthetic sequence, the X-groups on the reactants 12 and 21 or 22 are moieties that undergo transition metal catalyzed cross coupling reactions, such as halides or triflates and boronic acids or esters, stannanes, silanes, organozincs or other organometallic moieties known by those skilled in the art to be suitable substrates for such processes. The X-groups in Scheme 7 are complementary moieties for cross coupling processes such that when A1-X 12 is a halide or triflate, A-X 21 or A-X 22 will be a complementary organometallic, such as a stannane or the like or a boronic acid or ester Likewise, if A1-X 12 is an organometallic reagent or a boronic acid or ester, A-X will be a halide or triflate.

Within Scheme 7, it will be understood by those skilled in the art that there are additional synthetic equivalents for the Y-groups of 21 and 22 that can be used interchangeably with NH₂ and CO₂H with the addition of additional transforming steps. For example, the Y group of 21 might also be a protected amino group such as N-Boc or a surrogate amino group such as nitro that would give rise to compounds of formula 23 after acidic hydrolysis or reduction respectively. Similarly, it will be recognized that the Y group of 22 might also be an ester which could be hydrolyzed to an acid of formula 24 by standard synthetic methods.

A non limiting example of Scheme 7 is illustrated by the preparation of compound 28, an example of general intermediate A-CO₂H 7, above. Thus, iodoester 25 can be combined with phenylboronic acid 26 in the presence of a palladium catalyst to provide compound 27. Saponification of ester 27 provides acid 28 an example of general intermediate A-CO₂H 7, above.

By analogy to Schemes 1 and 2 above, it will be recognized by those skilled in the art that the compounds of formula 1 can also be prepared by the union of amines A-NH₂ 6 with isocyanates 29 (Scheme 9). Isocyanates 29 can be prepared from general amines 2 by standard synthetic methods. Suitable methods for example, include reaction of 2 with phosgene, or a phosgene equivalent such as diphosgene, triphosgene, or N,N-dicarbonylimidazole. In addition to the methods above for converting amines 2 into isocynates 299 the isocyanates 29 can also be prepared in situ by the Curtius rearrangement and variants thereof. Those skilled in the art will further recognize that isocycanates 29 need not be isolated, but may be simply generated in situ. Accordingly, acids 30 can be converted to compounds of formula 1 either with or without isolation of 29. Preferred conditions for the direct conversion of acids 30 to compounds of formula 1 involve the mixing of acid 30, amine A-NH, 6, diphenylphosphoryl azide and a suitable base, for example diisopropylethylamine, in an aprotic solvent, for example dioxane. Heating said mixture to a temperature of between 80 and 120° C. provides the compounds of formula 1.

Additionally, compounds of formula 1 can also be prepared from amines 2 by first preparing stable isocyanate equivalents, such as carbamates (Scheme 10). Especially preferred carbamates include trichloroethyl carbamates (31) and isopropenyl carbamates (32) which are readily prepared from amine 2 by acylation with trichloroethyl chloroformate or isopropenyl chloroformate respectively using standard conditions familiar to those skilled in the art. Further reaction of carbamates 31 or 32 with amines A-NH₂ 6 provides compounds of formula 1. Those skilled in the art will further recognize that certain carbamates can also be prepared from acids 30 by Curtius rearrangement and trapping with an alcoholic co-solvent. For example, treatment of acids 30 (Scheme 9) with diphenylphosphoryl azide and trichloroethanol at elevated temperature provide carbamates of formula 31.

Amines 2 useful for the invention can be synthesized according to methods commonly known to those skilled in the art. Amines of general formula 2 contain three rings and can be prepared by the stepwise union of three monocyclic subunits as illustrated in the following non-limiting Schemes. Scheme 11 illustrates one mode of assembly in which an E-containing subunit 33 is combined with the central six-membered-ring-containing subunit 34 to provide the bicyclic intermediate 35. In one aspect of Scheme 11, the “M” moiety of 33 represents a hydrogen atom of a heteroatom on the X2 linker that participates in a nucleophilic aromatic substitution reaction with monocycle 34. Such reactions may be facilitated by the presence of bases (for example, potassium tert-butoxide), thus M may also represent a suitable counterion (for example potassium, sodium, lithium, or cesium) within an alkoxide, sulfide or amide moiety. Alternately, the “M” group can represent a metallic species (for example, copper, boron, tin, zirconium, aluminum, magnesium, lithium, silicon, etc.) on a carbon atom of the X2 moiety that can undergo a transition-metal-mediated coupling with monocycle 34.

The “Y” group of monocyclic species 33 is an amine or an amine surrogate, such as an amine masked by a protecting group (“P” in formula 36), a nitro group, or a carboxy acid or ester that can be used to prepare an amine via known rearrangement. Examples of suitable protecting groups “P” include but are not limited to tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), and acetamide. In the instances wherein the “Y”-group of intermediate 33 is not an amine, the products of Scheme 11 will be amine surrogates such as 36 or 37 that can be converted to amine 2 by a deprotection, reduction or rearrangement (for example, Curtius rearrangement) familiar to those skilled in the art.

In these instances, the “LG” of monocycle 34 represents a moiety that can either be directly displaced in a nucleophilic substitution reaction (with or without additional activation) or can participate in a transition-mediated union with fragment 33. The W group of monocycle 34 or bicycle 35 represents a moiety that allows the attachment of a 5-membered heterocycle. In one aspect, the “W” group represents a halogen atom that will participate in a transition-metal-mediated coupling with a pre-formed heterocyclic reagent (for example a boronic acid or ester, or heteroaryl stannane) to give rise to amine 2. In another aspect, the “W” group of 34 and 35 represents a functional group that can be converted to a five-membered heterocycle by an annulation reaction. Non-limiting examples of such processes would include the conversion of a cyano, formyl, carboxy, acetyl, or alkynyl moiety into a five-membered heterocycle. It will be understood by those skilled in the art that such annulations may in fact be reaction sequences and that the reaction arrows in Scheme 11 may represent either a single reaction or a reaction sequence. Additionally, the “W” group of 35 may represent a leaving group (halogen or triflate) that can be displaced by a nucleophilic nitrogen atom of a pyrazole or triazole ring.

Some non-limiting examples of general Scheme 11 are illustrated in the Schemes below. Scheme 12 illustrates the preparation of pyrazole 42) an example of general amine 2. In Scheme 12, commercially available 3-fluoro-4-aminophenol is reacted with potassium tert-butoxide and 2,4-dichloropyridine 39 to provide chloropyridine 40. The preferred solvent for this transformation is dimethylacetamide at a temperature between 80 and 100° C. Subsequent union of chloropyridine 40 with commercially available pyrazole-4-boronic acid pinacol ester 41 in the presence of a palladium catalyst, preferably palladium tetrakis(triphenylphosphine), provides amine 42.

Scheme 13 illustrates the preparation of amine 48, also an example of general amine 2. In this example, the chloropyridine 43 is representative of general intermediate 34 (Scheme 11) wherein the “W” group of 34 is a tert-butoxycarbonyl moiety. The union of chloropyridine 43 with phenol 38 provides ether 44, an example of general intermediate 35 (Scheme 11). Introduction of a benzylcarbamate (Cbz) protecting group provides compound 45. The ester of 45 can be reduced using diisobutylaluminum hydride to provide aldehyde 46, also an example of general intermediate 35 (Scheme 11). Conversion of aldehyde 46 into isoxazole 47 is accomplished by treatment with tosylmethyl isocyanide and potassium carbonate. Isoxazole 47 is an example of general intermediate 36 (wherein the “Y” group is —NH-Cbz). Hydrogenation of 47 provides amine 48, an example of general amine 2.

Scheme 14 illustrates another general method of preparing amines 2 by first attaching the 5-membered heterocycle to the central 6-membered ring (34). As before, the “LG” of monocycle 34 represents a moiety that can either be directly displaced in a nucleophilic substitution reaction (with or without additional activation) or can participate in a transition-mediated union with fragment 33. The “W” group of monocycle 34 represents a moiety that allows the attachment of a 5-membered heterocycle. In one aspect, the “W” group represents a halogen atom that will participate in a transition-metal-mediated coupling with a pre-formed heterocyclic reagent (for example, a boronic acid or ester, or heteroaryl stannane) to give rise to amine 2. In another aspect, the “W” group of 34 represents a functional group that can be converted to a five-membered heterocycle by an annulation reaction. After conversion of 34 to 49, the “LG” moiety can be replaced with an “X2” linkage to the E-sub-unit to provide the tricylic amine 2, as described above in Scheme 11. Those skilled in the art will recognize that amines 2 may be accessed directly from the union of 49 and 33 or may arise indirectly via the intermediacy of 36 or 37, as described previously.

A specific example of Scheme 14 is illustrated by the preparation of amine 55 in Scheme 15. Thus, commercially available pyrimidine 50, an example of general intermediate 34 undergoes a palladium-catalyzed coupling with the commercially available pyrazole boronate 51 to provide the bicycle 52 an example of general intermediate 49. Oxidation of the sulfide moiety of 52 (The “LG” group of general intermediate 42) with m-chloroperbenzoic acid further activates this moiety toward nucleophilic displacement and gives rise to intermediate 53. Treatment of sulfone 53 with phenol 54 in the presence of a base provides tricylic amine 55, an example of general amine 2. Preferred bases for the later transformation include potassium carbonate and potassium tert-butoxide in polar aprotic solvents such as dimethylformamide or dimethylacetamide.

Additional examples of general amines of formula 2 can be prepared as illustrated in Scheme 16. Thus, by analogy to Scheme 12) the general intermediate 40 can be converted by palladium-mediated Stille-coupling into oxazoles 57 or 59 by reaction with the tributylstannanes 56 (see: Cheng et al. Biorg. Med. Chem Lett., 2006, 2076) or 58 (commercially available, Aldrich). In a similar fashion, commercially available boronic acid 60 (Anichem) can be converted into oxazole 61 via Suzuki reaction employing standard conditions familiar to those skilled in the art. Similarly, isoxazoles 63 and 65 can be obtained by the palladium-catalyzed reaction of 40 with 4-isoxazoleboronic acid pinacol ester 62 (commercially available, Frontier Scientific) or tributylstannane 64 (see: Sakamoto, et al. Tetrahedron, 1991, 5111).

As an extension of Schemes 11, 12 and 16, amines of general formula 2 containing an isothiazole ring can also be prepared by the methods described above. Scheme 17 shows a non-limiting example wherein a palladium-catalyzed Stille reaction of trimethylstannane 66 (see: Wentland, et al. J. Med. Chem., 1993, 1580) with 40 can provide isothiazole 67. In a similar fashion, palladium-catalyzed Suzuki-cross coupling between 40 and the boronate ester 68 (see: Blackaby, et al., U.S. Pat. No. 7,030,128) gives rise to isothiazole amine 69.

Scheme 18 illustrates non-limiting examples of Scheme 11 wherein the “W” group is a leaving group for nucleophilic aromatic substitution. Thus, some amines of general formula 2 in which the 5-membered heterocycle is a nitrogen-linked pyrazole (73)) or triazole (74-77) can be prepared from general intermediate 40 by reaction with pyrazole (70) or triazoles (71 and 72). Preferred conditions for such transformations include the use of polar aprotic solvents such as 1-methyl-2-pyrrolidinone, dimethylacetamide, or dimethylsulfoxide in the presence of non-nucleophilic bases such as potassium carbonate, sodium hydride, 1,8-diaza-bicyclo[5.4.0]undec-7-ene (DBU), and the like. Preferred temperatures for such transformations are from ambient temperature up to about 250° C. and may optionally include the use of microwave irradiation or sonication.

Scheme 19 illustrates the preparation of amine 79, a non-limiting example of a general amine of formula 2 bearing a C-linked 1,2,3-triazole. Conversion of chloropyridine 40 into alkyne 78 can be accomplished by Sonogashira cross-coupling with trimethylsilylacetylene, followed by aqueous hydrolysis of the trimethylsilyl group. Reaction of alkyne 78 with trimethylsilyl azide at elevated temperature affords the triazole 79 after aqueous work-up (see for example, Kallander, et. al, J. Med. Chem. 2005, 5644, and references therein).

Those skilled in the art will recognize that the specific methods disclosed in Schemes 16-19 for the conversion of intermediate 40 to general amine 2 will be applicable to the conversion of intermediate 50 to additional examples of general amine 2 by the sequence of Scheme 15. Additional synthetic methods for the preparation of compounds of formula 1 are found in the following examples.

SECTION 3. EXAMPLES

General method A: To a solution of the starting pyrazole amine (1 eq) in EtOAc were added 2,2,2-trichloroethylchloroformate (1.1 eq) and saturated NaHCO₃ (2-3 eq) at 0° C. After stirring for 3 h at RT, the layers were separated and the aqueous layer extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na₂SO₄) and concentrated under vacuum to yield the crude TROC carbamate of the pyrazole amine.

To the carbamate (1 eq) in DMSO were added diisopropylethylamine (2 eq), the appropriate amine (2 eq) and the mixture was stirred at 60° C. for 16 h or until all the starting carbamate was consumed. Water was added to the mixture and the product was extracted with EtOAc (2×25 mL). The combined organic extracts were washed with brine solution, dried (Na₂SO₄) and concentrated to yield crude product, which was purified by column chromatography to yield the target compound.

General method B: To a suspension of the amine (usually 0.67 mmol) in EtOAc (2 mL) was added aqueous 1N NaOH. The reaction mixture was cooled to 0° C. and treated with isopropenyl chloroformate (0.1 mL, 0.94 mmol) over 30 sec. The reaction mixture was stirred for 15 min at 0° C. and 1 h at RT. The reaction was poured into THF-EtOAc (1:1; 40 mL) and washed with H₂O (2×10 mL) and brine (2×10 mL). The organics were dried (Na₂SO₄), concentrated and the residue purified via column chromatography or recrystallization to provide the target (prop-1-en-2-yl)carbamate. To the carbamate (usually 0.26 mmol) was added the appropriate amine (usually 0.26 mmol) in THF (2 mL) and 1-methylpyrrolidine (catalytic amount) at 60° C. for 18 h. The mixture was diluted with CH₂Cl₂ (2 mL) and hexane (0.5 mL) solution, and stirred for 10 min. The resultant solid was filtered and dried.

General method C: To a stirring solution of the carboxylic acid (0.24 mmol) and TEA (1.2 mmol) in 1,4-dioxane (4.5 mL) at RT was added DPPA (0.29 mmol). After stirring for 0.5 h at RT, the appropriate amine (0.71 mmol) was added and the reaction was stirred with heating at 100° C. for 2 h. The reaction was cooled to RT, diluted with brine (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried (MgSO₄) and concentrated. The residue was purified by chromatography to afford the target compound.

General Method D: To a solution of amine (6.53 mmol) in ethyl acetate (20 mL) at RT was added a solution of sodium bicarbonate (11.90 mmol) in water (20 mL) and isopropenyl chloroformate (9.79=mol). The resultant mixture was stirred for 3 h at RT. The organic layer was separated. The aqueous layer was extracted once with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO₄) and concentrated in vacuo. The residue was used without further purification or purified via recrystallization or chromatography to provide the corresponding prop-1-en-2-yl carbamate.

Example A1

A suspension of 3-fluoro-4-aminophenol (8.0 g, 63.0 mmol) in dimethylacetamide (80 mL) was de-gassed in vacuo and treated with potassium tert-butoxide (7.3 g, 65 mmol). The resultant mixture was stirred at RT for 30 min. 2,4-Dichloropyridine (8 g, 54=mol) was added and the mixture was heated to 80° C. for 12 h. The solvent was removed under reduced pressure to give a residue which was partitioned between water and EtOAc (3×100 mL). The organic layers were washed with saturated brine, dried (MgSO₄), concentrated in vacuo and purified by silica gel column chromatography to give 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-phenylamine (11 g, 86% yield). ¹H NMR (300 MHz, DMSO-d6), δ 8.24 (d. J=5.7 Hz, 1H), 7.00 (dd, J=9.0, 2.7 Hz, 1H), 6.89-6.73 (m, 4H), 5.21 (br s, 2H); MS (ESI) m/z: 239.2 (M+M+).

A solution of 4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine (3 g, 12.6 n-mol), 1-methyl-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (5.2 g, 25.2 mmol), and Na₂CO₃ (2.7 g, 25.2 mmol) in DME (18 mL) and water (6 mL) was sparged with nitrogen for 20 min. Pd(PPh₃)₄ (729 mg, 0.63 mmol) was added and the resulting mixture was heated to 100° C. for 16 h. The solvent was removed under reduced pressure and the crude product was suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo. The residue was purified via silica gel chromatography to give 2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine (2 g, 56% yield). ¹H NMR (300 MHz, DMSO-d₆), δ 8.31 (d, J=5.7 Hz, 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.96 (m, 1H), 6.85-6.72 (m, 2H), 6.56 (m, 1H), 5.15 (s, 2H), 3.84 (s, 3H); MS (ESI) m/z: 285.0 (M+H⁺).

Example A2

A solution of 1,3-difluoro-2-methyl-benzene (15 g, 0.12 mol) in H₂SO₄ (100 mL) was treated drop wise with 65% HNO₃ (11.4 g, 0.12 mol) at −10° C. and the resultant mixture was stirred for about 30 min. The mixture was poured into ice-water and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated in vacuo to give 1,3-difluoro-2-methyl-4-nitro-benzene (16 g, 78% yield) ¹H NMR (400 MHz, CDCl₃): δ 7.80 (m, 1H, 6.95 (m, 1H), 2.30 (s, 3H).

1,3-Difluoro-2-methyl-4-nitro-benzene (16 g, 0.092 mol), benzyl alcohol (10 g, 0.092 mol) and K₂CO₃ (25.3 g, 0.18 mol), were combined in DMF (300 mL) and heated to 100° C. overnight. The mixture was poured into water and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried (Na₂SO₄), concentrated in vacuo and purified by silica gel chromatography to give 1-benzyloxy-3-fluoro-2-methyl-4-nitro-benzene (8 g, 33% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.04 (t, J=8.8 Hz, 1H), 7.30-7.46 (m, 5H), 7.08 (d, J=9.2 Hz, 1H), 5.28 (s, 2H), 2.13 (s, 3H).

Using a procedure analogous to Example A3, 1-benzyloxy-3-fluoro-2-methyl-4-nitro-benzene (8 g, 0.031 mol) was hydrogenated to give 4-amino-3-fluoro-2-methyl-phenol (4.2 g, 96% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 8.61 (s, 1H), 6.36 (m, 2H), 4.28 (s, 2H), 1.96 (s, 3H); MS (ESI) m/z: 142.1 [M+H]⁺.

Potassium tert-butoxide (3.5 g, 31 mmol) was added to a solution of 4-amino-3-fluoro-2-methyl-phenol (4.2 g, 30 mmol) in dimethylacetamide. The mixture was stirred at RT for 30 min. A solution of 2,4-dichloropyridine (4.38 g, 30 mmol) in dimethylacetamide was added and the mixture was heated at 100° C. overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (200 mL) and filtered through silica gel. The filter cake was washed with ethyl acetate and the combined filtrates were concentrated in vacuo and purified by silica gel chromatography to give 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-5-methyl-phenylamine (3.2 g, 42% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.21 (d, J=6.4 Hz, 1H), 6.84 (d, J=2.0 Hz, 1H), 6.81 (dd, J=5.6, 2.4 Hz, 1H), 6.67-6.65 (m, 2H), 5.13 (s, 2H), 1.91 (s, 3H); MS (ESI): m/z 253.2 [M+H]⁺.

Using a procedure analogous to Example A3, 4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (1.0 g, 0.3 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1 g, 4.8 mmol), Na₂CO₃ (0.84 g, 6.6 mmol) and Pd(PPh₃)₄ (0.25 g, 0.2 mmol) were combined to give 2-fluoro-3-methyl-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]-phenylamine (0.74 g, 75% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.27 (d, J=6.4 Hz, 1H), 8.18 (s, 1H), 7.90 (s, 1H), 7.07 (s, 1H), 6.68-6.61 (m, 2H), 6.45 (dd, J=5.6, 2.4 Hz, 1H), 5.06 (s, 2H), 3.82 (s, 3H), 1.95 (s, 3H); MS (ESI) m/z: 299.2 [M+H]⁺.

Example A3

1,2,3-Trifluoro-4-nitro-benzene (30 g, 0.17 mol), benzyl alcohol (18.4 g, 0.17 mol) and K₂CO₃ (35 g, 0.25 mol) were combined in DMF (300 mL) and were stirred at RT for 8 h. Water (300 mL) was added, and the mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine, dried (MgSO₄), concentrated in vacuo and purified by column chromatography on silica gel to give 1-benzyloxy-2,3-difluoro-4-nitro-benzene (16 g, 36% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 8.06 (m, 1H), 7.49-7.30 (m, 6H), 5.37 (s, 2H).

A solution of 1-benzyloxy-2,3-difluoro-4-nitro-benzene (14 g, 52.8 mmol) in MeOH (200 mL) was stirred with Pd/C (10%, 1.4 g, 1.3 mmol) under a hydrogen atmosphere (30 psi) for 2 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to afford 4-amino-2,3-difluorophenol (7 g, 92.1% yield). ¹H NMR (400 MHz, DMSO-d₆): ±9.05 (s, 1H), 6.45 (t, J=8.8 Hz, 1H), 6.34 (t, J=9.2 Hz, 1H), 4.67 (s, 2H); MS (ESI) m/z: 146.1 [M+H]⁺.

4-amino-2,3-difluorophenol (6 g, 41.4 mmol) and potassium tert-butoxide (4.9 g, 43.5 mmol) were suspended in DMAc (200 mL) and stirred at RT for 30 min under Ar atmosphere. 2,4-Dichloropyridine (6.1 g, 41.4 mmol) was added, and the resulting mixture was heated to 70° C. for 8 h. The reaction mixture was filtered, concentrated in vacuo and purified by silica gel chromatography to afford 4-(2-chloro-pyridin-4-yloxy)-2,3-difluoro-phenylamine (7 g, 66% yield). ¹H NMR (400 MHz. DMSO-d₆): δ 8.27 (d, J=6.0 Hz, 1H), 7.05 (s, 1H), 6.95 (m, 1H), 6.92 (m, 1H), 6.62 (m, 1H), 5.60 (s, 2H); MS (ESI) m/z: 257.1 [M+H]⁺.

Nitrogen was bubbled though a solution of 4-(2-chloro-pyridin-4-yloxy)-2,3-difluoro-phenylamine (2 g, 7.8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1.6 g, 7.8 mmol) and Na, CO₃ (1.65 g, 15.6 mmol) in DME (12 mL) and H₂O (4 mL) for 20 min. Pd(PPh₃)₄ (450 mg, 0.4 mmol), was added and then resulting mixture was degassed in vacuo, blanketed with nitrogen and heated to 70° C. for 16 h. The reaction was concentrated to dryness under reduced pressure. The crude product was suspended in water and extracted with EtOAc (3×10 mL). The organic layer was washed with brine, dried (Na₂SO₄), concentrated in vacuo and purified by silica gel chromatography to give 2,3-difluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]-phenylamine (1.3 g, 55% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.40 (d, J=6.0 Hz, 1H), 8.32 (s, 1H), 8.02 (s, 1H), 7.26 (s, 1H), 6.96 (t, J=8.8 Hz, 1H), 6.71-6.68 (m, 2H), 5.62 (s, 2H), 3.92 (s, 3H); MS (ESI) m/z: 303.2 [M+H]⁺.

Example A4

Following the procedure of Lohse, et al. (Synlett. 1999, 1, 45-48), 4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine from Example A1 (0.842 g, 3.53 mmol), 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 4.24 mmol), K₂CO₃ (1.317 g, 9.53 mmol) and Pd(PPh₃)₄ (0.204 g, 0.176 mmol) were combined in DME (4.0 ml)/H₂O (4.80 ml). The headspace was degassed with Ar for 10 min. The reaction was then heated with stirring at 90° C. overnight. The completed reaction was cooled to RT, diluted with EtOAc and filtered through Celite® to remove Pd. The filtrate was washed with brine (2×), dried (MgSO₄), concentrated in vacuo and purified by flash column chromatography (100% hexanes to 100% EtOAc) to afford 2-fluoro-4-(2-(1-propyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine (1.21 g, 110% yield) as a thick oil contaminated with EtOAc but used as obtained. ¹H NMR (400 MHz, DMSO-d₆): δ 8.32-8.31 (m, 1H), 8.27 (s, 1H), 7.95 (brs, 1H), 7.64-7.52 (m, 2H), 7.14 (brs, 1H), 6.98-6.95 (m 1H), 6.84-6.79 (m, 1H), 6.76-6.73 (m, 1H), 6.58-6.56 (m, 1H), 5.17 (s, 2H), 4.05-3.99 (m, 2H), 1.83-1.74 (m, 2H), 0.83-0.79 (m, 3H); MS (ESI) m/z: 313.2 (M+H⁺).

Example A5

Using a procedure analogous to Example A1, 2-fluoro-4-aminophenol (2.6 g, 24 mmol) and 2,4-dichloropyridine (2.88 g, 20 mol) were combined to provide 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (3.2 g, 67% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 8.25 (d, J=5.6 Hz, 1H), 6.99 (m, 1H), 6.90 (m, 2H), 6.50 (d, J=1.6 Hz, 1H), 6.41 (d, J=10.4 Hz, 1H), 5.51 (s, 2H); MS (ESI) m/z: 239.1 (M+H⁺).

Using a procedure analogous to Example A1, 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (3 g, 11.6 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.4 g, 16.4 mmol), Na₂CO₃ (2.7 g, 25.2 mmol) and Pd(Ph₃)₄ (1.5 g, 0.1 eq) were combined to give 3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)aniline (1.1 g, 34% yield). ¹H NMR (400 MHz, DMSO-d₆): 6 (8.31 (d, J=5.6 Hz, 1H), 8.22 (s, 1H), 7.93 (s, 1H), 7.14 (s, 1H), 6.98 (m, 1H), 6.55-6.49 (m, 2H), 6.42 (d, J=7.2 Hz. 1H), 5.44 (s, 2H), 3.86 (s, 3H); MS (ESI) m/z: (M+H⁺): 285.2.

Example A6

Pyrazole-4-boronic acid pinacol ester (0.85 g, 4.38 mmol), powdered K₂CO₃ (1.816 g, 13.14 mmol) and 2-iodopropane (0.547 ml, 5.48 mmol) were combined in MeCN (100 ml) and stirred with heating at 80° C. After 18 h, the reaction was treated with additional 2-iodopropane (0.547 ml, 5.48 mmol) and heating at 80° C. continued. After another 48 h, the reaction was cooled to RT and filtered through a glass frit to remove the solids. The filtrate was concentrated to a residue, which was diluted with EtOAc, filtered again on a glass frit and concentrated. The crude product was purified by flash column chromatography (EtOAc/hexanes) to afford 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.37 g, 36% yield) as a waxy solid. ¹H NMR (400 MHz, DMSO-d₆): δ 7.95 (s, 1H), 7.56 (s, 1H), 4.53-4.46 (m, 1H), 1.39-1.37 (m, 6H), 1.23 (s, 12H); MS (ESI) m/z: 237.3 (M+ H⁺).

Using a procedure analogous to Example A1, 4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine from Example A1 (0.310 g, 1.299 mmol), 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.368 g, 1.559 mmol), K₂CO₃ (0.485 g, 3.51 mmol) and Pd(PPh₃)₄ 0.075 g, 0.065 mmol) were combined and purified by flash column chromatography (EtOAc/CH₂Cl₂) to afford 2-fluoro-4-(2-(1-isopropyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine (0.38 g, 94% yield) as an oil contaminated with EtOAc. ¹H NMR (400 MHz, DMSO-d₆): δ 8.32-8.30 (m, 2H), 7.94 (s, 1H), 7.18-7.17 (m, 1H), 6.98-6.94 (m, 1H), 6.84-6.80 (m, 1H), 6.76-6.75 (m, 1H), 6.57-6.55 (m, 1H), 5.15 (s, 1H), 4.54-4.47 (m, 1H), 1.43-1.41 (m, 6H); MS (ESI) m/z: 313.2 (M+H⁺).

Example A7

Using a procedure analogous to Example A1, 4-(2-chloropyridin-4-yloxy)-2-fluoroaniline from Example A1 (2 g, 8.4 mmol), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.7 g, 16.8 mmol), Na₂CO₃ (1.8 g, 16.8 mmol) and Pd(PPh₃)₄ (0.48 g) were combined to give 4-(2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluoroaniline (2.1 g, 84% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.37 (d, J=6.0 Hz, 1H), 8.33 (s, 1H), 8.00 (s, 1H), 7.21 (s, 1H), 7.02 (dd, J=12.0, 2.8 Hz, 1H), 6.91-6.79 (m, 2H), 6.63 (dd, J=5.6, 2.4 Hz, 1H), 5.22 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 299.1 [M+H]⁺.

Example A8

To a biphasic mixture of Example A2 (1.5 g, 4.96 mmol) in ethyl acetate (20 ml) and water (20.00 ml) was added NaHCO₃ (1.3 g, 15 mmol) and isopropenyl chloroformate (0.6 mL). The reaction was stirred at RT for 1 hour. The organic layer was separated and washed with brine, dried and evaporated to provide prop-1-en-2-yl 2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamate which was used for the next reaction (0.92 g, 48% yield). MS (ESI) m/z: 387.1 (M+H⁺).

Example A9

4-(2-Chloro-pyridin-4-yloxy)-2-fluorophenylamine from Example A1 (0.597 g, 2.5 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.728 g, 3.75 mmol), Cs₂CO₃ (3.10 g, 9.5 mmol) and Pd(PPh₃)₄ (0.289 g, 0.25 mmol) were combined in DMF/H₂O (20 mL). The reaction mixture was degassed, blanketed with N, and heated at 90° C. overnight. The completed reaction was diluted with H₂O (5 mL) and extracted with EtOAc (3×50 mL). The combined organics were washed with brine (20 mL), dried (MgSO₄), concentrated in vacuo and purified by chromatography to afford 4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorobenzenamine (0.56 g, 83% yield) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 13.01 (s, 1H), 8.38 (d, J=5.6 Hz, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.29 (d, J=2.4 Hz, 1H), 7.03 (dd, J=11.6, 2.4 Hz, 1H), 6.89 (t, J=8.8 Hz, 1H), 6.84 (m, J=8.4 Hz, 1H), 6.60 (m, 1H), 5.20 (s, 2H); MS (ESI) m/z: 271.0 (M+H⁺).

Example A10

Methyl chloroformate (77.3 g, 0.82 mol) was added dropwise to a −10° C. solution of 2-chloro-4-fluorophenol (100 g, 0.68 mol) and sodium hydroxide (32.8 g, 0.82 mol) in water (550 mL). After complete addition, the precipitated solid was collected by filtration and washed with water to give 2-chloro-4-fluorophenyl methyl carbonate (110 g, 79% yield), ¹H NMR (300 MHz, DMSO-d₆): δ 7.62 (dd, J=8.1, 2.7 Hz, 1H), 7.50 (dd, J=9.0, 5.4 Hz, 1H), 7.30 (td, J=8.1, 3.0 Hz, 1H), 3.86 (s, 3H); MS (ESI) m/z; 205.2 (M+H⁺).

To a suspension of 2-chloro-4-fluorophenyl methyl carbonate (110 g, 0.54 mol) in conc. H₂SO₄ (50 mL) was slowly added a mixture comprised of conc. H₂SO₄ (40 mL) and fuming H₂SO₃ (40.8 mL, 0.89 mol). The resultant mixture was stirred for 30 min at 0° C. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration and washed with water to give 2-chloro-4-fluoro-5-nitrophenyl methyl carbonate (120 g, 90% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.45 (d, J=7.2 Hz, 1H), 8.12 (d, J=10.8 Hz, 1H), 3.89 (s, 3H); MS (ESI) m/z: 250.1 (M+H⁺).

2-Chloro-4-fluoro-5-nitrophenyl methyl carbonate (120 g 0.48 mol) was combined with a solution of sodium hydroxide (22.7 g, 0.57 mol) in water (300 mL) and the resultant mixture was refluxed for 4 h. The insoluble solids were removed by filtration and the filtrate was acidified with dilute HCl. The precipitated solid was collected by filtration and washed with water to give 2-chloro-4-fluoro-5-nitrophenol (90 g, 98% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 11.18 (s 1H), 8.10 (d, J=10.4 Hz, 1H), 7.62 (d, J=7.2 Hz, 1H); MS (ESI) m/z: 192.1 (M+H⁺).

2-chloro-4-fluoro-5-nitrophenol (85 g, 0.45 mol) and 10% Pd/C (25 g, 0.023 mol) were combined in EtOH and hydrogenated (50 psi) for 12 h. The reaction mixture was filtered. The filtrate was concentrated in vacuo and purified by silica gel chromatography to provide 3-amino-4-fluorophenol (40 g 70%, yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.87 (s, 1H), 6.70 (dd, J=11.2, 8.8 Hz, 1H), 6.14 (dd, J=7.8, 2.4 Hz, 1H), 5.84 (m, 1H), 4.92 (s, 2H); MS (ESI) m/z: 128.2 (M+H⁺).

4-Chloro-2-methylsulfanyl-pyrimidine (1.4 g, 8.8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (2.0 g, 1.1 eq), Na, CO₃ (2.8 g, 3 eq) and Pd(PPh₃)₄ (500 mg, 0.43 mmol) were combined in a solvent comprised of toluene/EtOH/H₂O (4/4/1, 20 mL). The reaction mixture was purged with argon and heated to 100° C. overnight. The reaction was filtered to remove insolubles and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography to provide 4-(1-methyl-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine contaminated with triphenylphoshine oxide (2.0 g, >100% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 8.49 (d, J=5.1 Hz, 1H), 8.46 (s, 1H), 8.12 (s, 1H), 7.38 (d, J=5.1 Hz, 1H), 3.89 (s, 3H), 2.52 (s, 3H).

A solution of 4-(1-methyl-1H-pyrazol-4-yl)-2-methylsulfanyl-pyrimidine (2.0 g crude, 8.8 mmol) in dichloromethane (20 mL) was treated with m-CPBA (3.0 g, 17.4 mmol) portionwise at RT. The reaction was stirred 2 h and was quenched with saturated aqueous NaS₂SO₃ (3 mL). The mixture was partitioned with saturated aq Na₂CO₃ and the organics were washed with brine, dried (Na₂SO₄), and concentrated to provide a mixture (2.0 g) of 2-methanesulfonyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine and 2-methanesulfinyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine with a molar ratio of 1:0.3. ¹H NMR (400 MHz, DMSO-d₆): δ 8.83 (d, J=5.2 Hz, 1H), 8.82 (d, J=5.2 Hz, 0.24H), 8.57 (s, 1H), 8.57 (s, 0.24H), 8.21 (s, 1H), 8.21 (s, 0.23H), 7.80 (d, J=5.6 Hz, 1H), 7.80 (d, J=5.6 Hz, 0.25H), 3.48 (s, 3H), 2.88 (s, 0.7H).

The above mixture of 2-methanesulfonyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine and 2-methanesulfinyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine (1 g, 4.2 mmol), 4-amino-3-fluoro-phenol (1.1 g, 8.6 mmol) and K₂CO₃ (1.2 g, 8.6 mmol) in DMF (10 mL) was heated at 100° C. for 12 h. The reaction was partitioned between H₂O and EtOAc (3×50 mL). The combined organics were dried (Na₂SO4), concentrated in vacuo and chromatographed to 2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)benzenamine (402 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 8.44 (d, J=5.2 Hz, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 7.41 (d, J=5.2 Hz, 1H), 6.98 (t, J=9.6 Hz, 1H), 6.53 (dd, J=5.6, 2.0 Hz, 1H), 6.28 (d, J=8.4 Hz, 1H), 5.25 (br s, 2H), 3.88 (s, 3H). MS (ESI) m/z: 286.2 (M+H⁺).

Example A11

4-Fluoro-2-methyl-phenol (25 g, 0.2 mol) was added to a solution of sodium hydroxide (9.7 g, 0.24 mol) in water (160 mL) and the resultant solution was cooled to 0° C. Methyl chloroformate (24.2 g, 0.26 mol) was added dropwise at 0° C. At the completion of the reaction, the pH was adjusted to pH 8 with saturated aqueous Na₂CO₃ and then mixture was extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with water and brine, dried (MgSO₄) and were concentrated under reduced pressure to provide carbonic acid 4-fluoro-2-methyl-phenyl ester methyl ester (30 g, 82% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 7.22-7.13 (m, 2H), 7.05 (m, 1H), 3.81 (s, 3H), 2.12 (s, 3H).

To a solution of carbonic acid 4-fluoro-2-methyl-phenyl ester methyl ester (15 g, 81.5 mmol) in conc. sulfuric acid (100 mL) at 0° C. was added powdered KNO₃ (8.3 g, 82.2 mmol) in several portions. The reaction mixture was stirred for 1 hour at 0° C. and was then poured into ice water and extracted with ethyl acetate (3×100 mL). The extracts were washed with water and brine, dried (MgSO₄), concentrated in vacuo and purified by silica gel chromatography to provide carbonic acid 4-fluoro-2-methyl-5-nitro-phenyl ester methyl ester (2.0 g, 11% yield). ¹H NMR (300 MHz, DMSO-d₆); δ 8.14 (d, J=6.9, 1H), 7.60 (d, J=12.0 Hz, 1H), 3.86 (s, 3H), 2.25 (s, 3H).

To a solution of aqueous sodium hydroxide (1.2 N, 20 mL, 24 mmol) was added 4-fluoro-2-methyl-5-nitro-phenyl ester methyl ester (2.0 g, 8.7 mmol), then the resultant mixture was refluxed for 2 hours. The reaction was cooled to RT and partitioned between EtOAc and water. The organic layer was washed with water and brine, dried (MgSO₄), and concentrated in vacuo to provide 4-fluoro-2-methyl-5-nitro-phenol (1.4 g, 93% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 10.33 (s, 1H), 7.45 (d, J=6.6, 1H), 7.32 (d, J=12.3 Hz, 1H), 2.19 (s, 3H).

A mixture of 4-fluoro-2-methyl-5-nitro-phenol (1.4 g, 8.2 mmol) and 10% Pd/C (0.3 g, 20%/w) in MeOH (80 mL) was stirred under H₂ (30 psi) for 2 h. The Pd/C was removed by filtration and the filtrate was concentrated to give 5-amino-4-fluoro-2-methyl-phenol (0.68 g, 62% yield). ¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (s, 1H), 6.62 (d, J=12.0 Hz, 1H), 6.21 (d, J=8.1 Hz, 1H), 4.69 (s, 2H), 1.93 (s, 3H).

The mixture of 2-methanesulfonyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine and 2-methanesulfinyl-4-(1-methyl-1H-pyrazol-4-yl)-pyrimidine from Example A10 (1 g, 4.2 mmol), 5-amino-4-fluoro-2-methylphenol (1.2 g, 8.5 mmol) and K₂CO₃ (1.2 g, 8.6 mmol) were combined in DMF (10 mL) using a procedure analogous to Example A10 to provide 2-fluoro-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)benzenamine (420 mg). ¹H NMR (400 MHz, DMSO-d₆): δ 8.42 (d, J=5.2 Hz, 1H), 8.39 (s, 1H), 8.07 (s, 1H), 7.40 (d, J=5.2 Hz, 1H), 6.90 (d. J=9.6 Hz, 1H), 6.47 (d, J=8.4 Hz, 1H), 5.02 (br s. 2H), 3.88 (s, 3H), 1.88 (s, 3H); MS (ESI) m/z: 300.2 (M+H⁺).

Example B1

Phenyl hydrazine and 4,4-dimethyl-3-oxopentanenitrile were combined according to literature procedures to yield 3-t-butyl-1-phenyl-1H-pyrazol-5-amine. See WO 2006/071940.

Example B2

Sodium metal (13.8 g, 0.5 mol) was added portion-wise to ice-cold anhydrous EtOH (700 mL). After complete dissolution of the Na, a mixture of 3-methylbutan-2-one (100 g, 1.16 mol) and oxalic acid diethyl ester (77 ml, 0.5 mol) was added drop-wise. The reaction mixture was stirred in an ice-salt bath and until TLC indicated completion of the reaction. Acetic acid (38.1 ml, 0.5 mol) was added and the mixture was stirred at RT for about 30 min. The reaction mixture was cooled in an ice-salt bath and treated with hydrazine hydrate (29.4 g, 0.5 mol). After complete addition, the mixture was warmed to RT and stirred until judged complete by TLC. The reaction mixture was concentrated under reduced pressure and re-dissolved in EtOAc. The EtOAc solution was washed with NaHCO₃, brine and water, dried (MgSO₄) and concentrated in vacuo. The resultant solid was washed with cold petroleum ether to give ethyl 3-isopropyl-1H-pyrazole-5-carboxylate (90 g, 42% yield, two steps) as an off-white solid. ¹H NMR (3100 MHz, CDCl₃): δ 12.00 (s, 1H), 6.57 (s, 1H), 4.30 (q, J=7.2 Hz, 2H), 3.00 (m, 1H), 1.46 (t, J=7.2 Hz, 3H), 1.28 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 183.3 (M+H⁺).

A mixture of 3-cyanophenylboronic acid (0.423 g, 2.88 mmol), Cu(OAc)₂ (0.498 g, 2.74 mmol) and ethyl 3-isopropyl-1H-pyrazole-5-carboxylate (0.500 g, 2.74 n-mol) in pyridine (4.0 ml) was heated at 80° C. for 4.5 h. The reaction was quenched with H₂O (30 mL) and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO₄) and concentrated. The crude product was purified by chromatography to afford ethyl 1-(3-cyanophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate (0.3267 g, 42% yield) as a white solid. MS (ESI) m/z: 284.0 (M+H⁺)

To a stirrings solution of ethyl 1-(3-cyanophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate (0.3267 g, 1.15 mmol) in 1:1:1 THF/EtOH/H2O (18 ml) at 22° C. was added LiOH.H₂O (0.242 g, 5.765=mol). The reaction was stirred at RT for 4 h. Solvent was removed under reduced pressure. The residue was diluted with H₂O (3 ml) and washed with Et₂O (5 mL). The pH was adjusted to ˜4 with 3M HCl. The aqueous solution was extracted with EtOAc (2×30 mL). The combined organic layers were washed with brine (15 mL), dried (MgSO₄) and concentrated to afford 1-(3-cyanophenyl)-3-isopropyl-1H-pyrazole-5-carboxylic acid (0.275 g, 94% yield) as a white solid. MS (ESI) m/z: 256.0 (M+H⁺).

Example B3

Sodium metal (13.8 g, 0.5 mol) was added portionwise to ice-cold anhydrous EtOH (700 mL). After complete dissolution of the Na, a mixture of 3,3-dimethylbutan-2-one (50 g, 0.5 mol) and oxalic acid diethyl ester (77 ml, 0.5 mol) was added drop-wise. The reaction mixture was stirred in ice-salt bath and until TLC indicated completion of the reaction. Acetic acid (38.1 ml, 0.5 mol) was added and the mixture was stirred at RT for 30 min. The reaction mixture was cooled in an ice-salt bath and treated with hydrazine hydrate (29.4 g, 0.5 mol). After complete addition, the mixture was warmed to RT and stirred until judged complete by TLC. The reaction mixture was concentrated under reduced pressure and re-dissolved in EtOAc. The EtOAc solution was washed with NaHCO₃, brine and water, dried (MgSO₄) and concentrated in vacuo. The resultant solid was washed with cold petroleum ether to give ethyl 3-tert-butyl-1H-pyrazole-5-carboxylate (49 g, 50% yield over two steps) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ 6.65 (s 1H), 4.38 (q, J=6.8 Hz, 2H), 1.39 (t, J=6.8 Hz, 3H), 1.35 (s, 1H); MS (ESI) m/z: 197.2 (M+H⁺).

Following the procedure of Example B5,3-cyanophenylboronic acid (5.0 g, 34 mmol, 1.00 eq), ethyl 3-t-butyl-1H-pyrazole-5-carboxylate (6.68 g 34 mmol, 1.00 eq), Cu(OAc)₂ (6.18 g, 34 mmol, 1.00 eq), 4 Å MS (10 g) and pyridine (34 mmol, 1.00 eq, 2.80 mL) were combined in CH₂Cl₂ (300 mL) to afford ethyl 5-tert-butyl-2-(3-cyano-phenyl)-2H-pyrazole-3-carboxylic acid ethyl ester (3.5 g, 35% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.05 (m, 1H), 7.92 (m, 1H), 7.83 (m, Ht), 7.68 (m. 1H), 7.06 (s, 1H), 4.20 (m, 2H), 1.30 (s, 9H), 1.19 (m, 1H); MS (ESI) m/z: 298.0 [M+H]⁺.

Following the procedure of Example B5, ethyl 3-t-butyl-1-(3-cyanophenyl)-1H-pyrazole-5-carboxylate (3.5 g, 11.8 Phenol, 1.00 eq) and LiOH.H₂O (2.5 g, 60 mmol, 5.00 eq) were combined to provide 5-tert-butyl-2-(3-cyano-phenyl)-2H-pyrazole-3-carboxylic acid (2.9 g, 91% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.02 (m, 1H), 7.89 (m, 1H), 7.82 (m, 1H), 7.66 (t, J=8.0 Hz, 1H), 7.00 (s, 1H), 1.30 (s, 9H); MS (ESI) m/z: 270.2 [M+H]⁺.

Example B4

5-Bromo-2-fluoro-benzonitrile (5 g, 25 mmol), 1-(diphenylmethylene)hydrazine (5 g, 25 mmol), Pd(OAc)₂ (0.2 g, 0.9 mmol), dppf (0.69 g, 1.25 mmol), and Cs₂CO₃ (16 g, 50 mmol) were combined in toluene (500 mL). The resulting mixture was degassed under vacuum, blanketed with nitrogen and then heated to reflux overnight. The cooled reaction mixture was filtered through silica gel, and the filter cake was washed with EtOAc (100 mL). The combined filtrates were concentrated in vacuo to give 5-(2-(diphenylmethylene)hydrazinyl)-2-fluorobenzonitrile (6.7 g, 86% yield). ¹H NMR (300 MHz, DMSO): δ 9.12 (s, 1H), 7.60 (m, 5H), 7.46 (m, 2H), 7.35 (m, 6H).

To a solution of 5-(2-(diphenylmethylene)hydrazinyl)-2-fluorobenzonitrile (3.5 g, 11 mmol) in EtOH (50 mL) was added 4-methyl-3-oxopentanenitrile (1.22 g, 11=mol) and conc HCl (5 mL, 60 mmol). The resulting mixture was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure, the residue poured into water and washed with EtOAc (4×100 mL). The aqueous layer was neutralized with sodium carbonate solution to pH 8, and the resultant suspension was extracted with EtOAc (3×100 mL). The combined organic layers were concentrated in vacuo and purified by silica gel chromatography to provide 5-(5-amino-3-isopropyl-1H-pyrazol-1-yl)-2-fluorobenzonitrile (2.3 g, 86% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.02 (m, 1H), 7.94 (m, 1H), 7.57 (t, J=6.6 Hz, 1H), 5.57 (s, 2H), 5.44 (s, 1H), 2.74 (m, 1H), 1.14 (d, J=6.8 Hz. 6H); MS (ESI) m/z: 245.2 [M+H]⁺.

Example B5

A mixture of 4-cyanophenylboronic acid (5.0 g, 34 mmol, 1.00 eq), ethyl 3-t-butyl-1H-pyrazole-5-carboxylate from Example B3 (6.68 g, 34 mmol), Cu(OAc)₂ (6.18 g, 34 mmol), 4 Å MS (10 g) and pyridine (2.80 mL, 34 mmol) were combined in CH₂Cl₂ (300 mL) and stirred at RT for 48 h open to the air. The solids were removed by filtration and the filtrate was sequentially washed with H₂O, 1M aq HCl, satd aq NaHCO₃, and brine. The organics were dried (MgSO₄) concentrated in vacuo and purified by silica gel chromatography to provide ethyl 3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazole-5-carboxylate (4.0 g, 40% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.98-7.95 (m, 2H), 7.72-7.70 (m, 2H), 7.06 (s, 1H), 4.20 (m, 2H), 1.30 (s, 9H), 1.19 (m, 3H); MS (ESI) m/z: 298.0 [M+H]⁺.

A solution of ethyl 3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazole-5-carboxylate (4.0 g, 13.5 mmol) in a mixed solvent of THF/EtOH/H₂O (100 mL, 1:1:1) was treated with LiOH.H₂O (2.85 g, 68.4 mmol) and the resultant mixture was stirred at ambient temp for 3 h. The reaction mixture was diluted with 1M aq HCl until pH 3 and then the mixture was extracted with EtOAc (2×50 nt). The combined organics were washed with brine, dried (MgSO₄), and concentrated in vacuo to afford 3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazole-5-carboxylic acid (3.3 g, 92%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.95-7.92 (m, 2H), 7.69-7.67 (m, 2H), 7.03 (s, 1H), 1.30 (s, 9H); MS (ESI) m/z: 270.16 [M+H]⁺.

Example B6

To a solution of m-aminobenzoic acid (200 g, a 1.46 mmol) in conc. HCl (200 mL) was added an aqueous solution (250 mL) of NaNO₂ (102 g, 1.46 mmol) at 0° C. and the reaction mixture was stirred for 1 h. A solution of SnCl₂2H₂O (662 g, 2.92 mmol) in conc. HCl (2 L) was then added at 0° C. The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with EtOH and ether to give 3-hydrazinobenzoic acid hydrochloride as a white solid, which was used for the next reaction without further purification. ¹H NMR (400 MHz, DMSO-d₆): δ 10.8 (s, 3H), 8.46 (s, 1H), 7.53 (s, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.37 (m, 1H), 7.21 (d, J=7.6 Hz, 1H).

A mixture of 3-hydrazinobenzoic acid hydrochloride (200 g, 1.06 mol) and 4,4-dimethyl-3-oxopentanenitrile (146 g, 1.167 mol) in EtOH (2 L) was heated at reflux overnight. The reaction solution was evaporated under reduced pressure. The residue was purified by column chromatography to give 3-(5-amino-3-t-butyl-pyrazol-1-yl)-benzoic acid ethyl ester (116 g, 40% yield) as a white solid together with 3-(5-amino-3-t-butyl-pyrazol-1-yl)benzoic acid (93 g, 36% yield). 3-(5-amino-3-t-butyl-pyrazol-1-yl)benzoic acid and ethyl ester. ¹H NMR (400 MHz, DMSO-d₆): δ 8.14 (s, 1H), 7.86-7.80 (m, 2H), 7.57 (t, J=8.0 Hz, 1H), 5.40 (s, 1H), 5.26 (s, 2H), 4.33 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H), 1.20 (s, 9H); MS (ESI) mA: 288.0 [M+H]⁺.

Example B7

Using a procedure analogous to Example B16, ethyl 4-(3-t-butyl-5-amino-1H-pyrazol-1-yl)benzoate (3.67 mmol) was prepared from ethyl 4-hydrazinobenzoate and pivaloylacetonitrile. ¹H NMR (400 MHz, DMSO-d₆): δ 799 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.8 Hz, 2H), 5.43 (s, 1H), 5.38 (br s, 2H), 4.30 (q, J=7.2 Hz, 2H), 1.31 (t, J=7.2 Hz, 3H), 1.20 (s, 9H); MS (ESI) J=288.3 [M+H]⁺.

Example B8

A mixture of ethyl propionate (50 g, 0.49 mol) and acetonitrile (30 mL, 0.59 mol) in THF (50 mL) was added drop-wise to a mixture of NaH (29.4 g, 0.74 mol) in THF (800 mL). After complete addition, the resulting mixture was heated at reflux for 10 h. The reaction was concentrated in vacuo, diluted with water and partitioned with EtOAc (3×400 mL). The organic phase was washed with brine, dried (Na₂SO₄) and concentrated to give 3-oxo-pentanenitrile (39 g, 82% yield). ¹H NMR (400 Hz, DMSO-d6): δ 3.99 (s, 2H), 2.50 (q, J=7.2 Hz, 2H), 0.93 (t, J=7.2 Hz, 3H).

To a suspension of 3-bromo-benzonitrile (25 g, 138 mmol) in toluene (200 mL) was added 1-(diphenylmethylene)hydrazine (30 g, 153 mmol), Pd(OAc)₂ (1 g, 4.46 mmol), dppf (3.5 g, 6.3 mmol), and CsCO₃ (80 g, 245 mmol). The mixture was purged of air, back filled with N₂ and then heated at reflux overnight. The reaction mixture was cooled to RT and filtrated through silica gel. The filter cake was washed with EtOAc (200 mL) and the combined filtrates were concentrated to provide 3-(2-(diphenylmethylene)hydrazinyl)benzonitrile (40 g, 98% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.24 (s, 1H), 7.54-7.59 (m, 5H), 7.42-7.43 (m, 2H), 7.12-7.37 (m, 6H), 7.12 (d, J=6.4 Hz, 1H).

Conc HCl (8 mL, 96 in mmol) was added to a solution of 3-(2-(diphenylmethylene)hydrazinyl)benzonitrile (5.0 g, 16.8 mmol) and -oxo-pentanenitrile (2.5 g, 25.2 mmol) in ethanol (80 mL). The resultant mixture was heated at reflux for 10 h under N₂ atmosphere. The solvent was removed in vacuo and the residue was suspended in water. The alkalinity was adjusted to pH 8 with saturated NaHCO₃ solution, and the mixture was extracted with EtOAc. The combined organics were washed with brine, dried Na₂SO₄), concentrated in vacuo and purified by silica gel chromatography to afford 3-(5-amino-3-ethyl-1H-pyrazol-1-yl)benzonitrile (2 g, 56% yield). ¹H NMR (400 Hz, DMSO-d₆): δ 7.98 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.68 (d. J=7.6 Hz, 1H), 7.61 (t, J=7.6 Hz, 1H), 5.45 (s, 2H), 5.37 (s, 1H), 2.42 (q, J=7.6 Hz, 2H), 1.12 (t, J=7.6 Hz, 3H); MS (ESI) m/z: 213.2[M+H]⁺.

Example B9

In a mixture of saturated sodium bicarbonate:toluene:ethanol (1:2:1) (20 mL) was dissolved methyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate (2.71 g, 11.85 mmol) and phenylboronic acid (2.88 g, 23.7 mmol) and to this was added tetrakis-(triphenylphosphine)palladium(0) (300 mg). The reaction stirred at 75° C., under Ar, overnight. After dilution with ethyl acetate (75 mL) and water (75 mL), the mixture was filtered through Celite® and the organic phase separated. The organic phase was washed with 5% citric acid (75 mL) and brine (75 mL), dried (Na₂SO₄) and evaporated at reduced pressure to give a semi solid/oil. The solid was purified by chromatography (ethyl acetate/Hexanes) to give a clear thick oil, which solidified to a white solid identified as methyl 2-tert-butyl-4-phenylpyrimidine-5-carboxylate (2.58 g, 81% yield). ¹H NMR (300 MHz, DMSO-d₆), δ 1.39 (s, 9H), 3.70 (s, 3H), 7.49-7.52 (m, 3H), 7.61-7.63 (m, 2H), 9.04 (s, 1H); MS (ESI) m/z: 271.3 (M+W).

In a 1:1:1 mixture of methanol:dioxane:water (15 mL) was placed methyl 2-tert-butyl-4-phenylpyrimidine-5-carboxylate (2.58 g, 9.54 mmol) and lithium hydroxide hydrate (1.20 g, 28.6 mmol). The solution was stirred at RT overnight. The mix was diluted with ethyl acetate (70 mL) and washed with 5% citric acid (100 mL). The organic phase washed with brine, dried (Na₂SO₄) and evaporated at reduced pressure to give a white solid, identified as 2-tert-butyl-4-phenylpyrimidine-5-carboxylic acid (2.31 g, 94% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 1.38 (s, 9H), 7.48-7.50 (m, 3H), 7.64-7.67 (m. 2H), 9.01 (s, 1H), 12.75 (s, 1H); MS (ESI) m/z: 257.3 (M+H⁺).

Example B10

A suspension of 5-amino-2-methyl-benzonitrile (3 g, 22.7 mmol) in conc HCl (60 mL) was cooled to 0° C. and treated with a solution of sodium nitrite (1.6 g, 22.7 mmol) in water (10 mL) at such a rate that the reaction temperature never rose above 5′. Stirring was continued for 30 min. To this mixture was added drop-wise a solution of SnCl₂ (10.2 g, 45.4 mmol) in cone HCl (10 mL) also at such a rate that the reaction temperature never rose above 5° C. After the addition, the resulting mixture was stirred at 0° C. for 1 h, and at RT for an additional 1 h. The precipitate was collected by filtration, washed with ethyl ether, and dried in vacuo to provide 5-hydrazinyl-2-methylbenzonitrile hydrochloride (3.6 g, 87% yield), which was used without purification in next step.

A solution of 5-hydrazinyl-2-methylbenzonitrile hydrochloride (3.6 g, 19.7 mmol), 4-methyl-3-oxo-pentanenitrile (2.6 μl, 23.6 mmol), and conc HCl (5 mL, 60 mmol) in EtOH (50 mL) was heated at 80° C. for 8 h under N₂. The solvent was removed in vacuo and the crude solid was washed with ethyl ether. The solid was suspended in H₂O, and the mixture was neutralized with satd NaHCO₃ solution and was extracted with EtOAc. The organic extracts were washed with brine, dried (Na₂SO₄) and concentrated in vacuo to afford 5-(5-amino-3-isopropyl-1H-pyrazol-1-yl)-2-methylbenzonitrile (3.4 g, 72% yield). ¹H NMR (400 Hz, DMSO-d₆): δ 7.92 (d, J=2.4 Hz, 1H), 7.81 (dd, J=8.4, 2.4 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 5.44 (br s, 2H), 5.38 (s, 1H), 2.75 (m, 1H), 2.49 (s, 3H), 1.16 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 241.2 [M+H]⁺.

Example B11

A suspension of 3-(2-(diphenylmethylene)hydrazinyl)benzonitrile from Example B8 (20 g, 67 mmol) in EtOH (500 mL) was treated with cone HCl (5.5 mL, 66 mmol) and 4-methyl-3-oxo-pentanenitrile (11 g, 0.1 mol). The reaction mixture was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure, dissolved in water (300 mL) and washed with EtOAc (3×300 mL). The aqueous layer was neutralized with NaHCO₃ solution to pH=8 and was extracted with EtOAc (2×300 mL). The combined organic layers were washed brine, dried (Na₂SO₄), and evaporated to give 3-(5-amino-3-isopropyl-1H-pyrazol-1-yl)benzonitrile (8.2 g, 54% yield) ¹H-NMR (400 MHz, DMSO-d₆): δ 7.99 (s, 1H), 7.92 (m, 1H), 7.69 (d, J=6.4 Hz 1H), 7.60 (t, J=7.2 Hz, 1H), 5.44 (s, 2H), 5.38 (s, 1H), 2.74 (m, 1H), 1.16 (d, J=7.6 Hz, 6H); MS (ESI) m/z: 227.2 [M+H]⁺.

Example B12

Benzoylacetate (2.88 g, 15.0 mmol) and triethylorthoformate (4.51 g, 30 45 mmol) were stirred into acetic anhydride (10 mL) and warmed to 130° C. for 3 hrs. The reaction was concentrated in vacuo and azeotroped with toluene (2×10 mL) to afford (Z)-ethyl 2-benzoyl-3-ethoxyacrylate.

21% Sodium ethoxide in ethanol (4.86 g, 14.98 mmol) was added to a solution of acetamidine hydrochloride (2.047 g, 14.98 mmol) in ethanol (20 mL) and the reaction was stirred at RT for 15 min. To this was added crude (Z)-ethyl 2-benzoyl-3-ethoxyacrylate (3.72 g, 14.98 mmol) in ethanol (20 mL). After stirring overnight at RT, the reaction was warmed to reflux for 1 hr, cooled to RT and concentrated in vacuo. The residue was diluted with water (50 mL) and acidified with acetic acid (pH˜=3) with formation of a precipate. The mixture was extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with brine, dried (Na₂SO₄) and concentrated in vacuo to give a semi-solid sludge. This was triturated with ether (40 mL), filtered to remove solids and the ether phase concentrated in vacuo to afford ethyl 2-methyl-4-phenylpyrimidine-5-carboxylate (˜70% purity). MS (ESI) m/z: 243.0 (M+H⁺).

A solution of crude ethyl 2-methyl-4-phenylpyrimidine-5-carboxylate (2.46 g, 7.11 mmol) and lithium hydroxide hydrate (1.193 mg, 28.4 mmol) in ethanol:water:dioxane (1:1:1, 24 mL) was stirred at RT overnight. The mixture was diluted with water (40 mL), 1N NaOH (5 mL) and ether (40 mL). The aqueous phase made acidic with 6N HCl (pH˜=3) and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with brine, dried (Na₂SO₄) and concentrated in vacuo to 2-methyl-4-phenylpyrimidine-5-carboxylic acid (1.47 g, 97% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 2.69 (s, 3H), 7.44-7.50 (m, 3H), 7.60 (d, 2H), 8.97 (s, 1H), 13.49 (s, 1H); MS (ESI) m/z: 215.0 (M+H⁺).

Example B13

To a solution of 4-hydrazinobenzoic acid (10 g, 65.8 mmol) in EtOH (200 mL) was added cone. HCl (12 M, 54.8 mL, 658 mmol) and 3-oxo-pentanenitrile from Example B8 (12.7 g, 0.13 mol). The resulting mixture was heated to reflux overnight. The reaction mixture was concentrated in vacuo, the residue was dissolved in water and washed with EtOAc (4×200 mL). The aqueous layer was made alkaline (pH 8) with satd aq NaHCO₃ solution, and was extracted with EtOAc (2×200 mL). The organic extracts were washed with brine, dried (Na₂SO₄) and concentrated in vacuo to give 4-(5-amino-3-ethyl-pyrazol-1-yl)-benzoic acid ethyl ester (9.0 g, 53% yield). ¹H-NMR (400 MHz, DMSO-d₆): δ 7.98 (d, J=7.2 Hz, 2H), 7.73 (d, J=7.2 Hz, 2H), 5.42 (s, 2H), 5.36 (s, 1H), 4.29 (q, J=7.2 Hz, 2H), 2.41 (q, J=7.6 Hz, 2H), 1.30 (t, J=7.2 Hz 3H), 1.11 (t J=7.6 Hz, 3H); MS (ESI) m/z: 260.1 [M+H]⁺.

Example B14

A solution of ethyl 3-oxo-3-phenylpropanoate (3.00 g, 15.61 mmol) and triethylorthoformate (3.89 mL) in acetic anhydride (4.42 mL) was warmed to 120° C. for 4 h and concentrated in vacuo to give (E)-ethyl 2-benzoyl-3-ethoxyacrylate (3.40 g, 88% yield). MS (ESI) m/z: 217.0 (M+H⁺).

A solution of hydrazine hydrate (823 mg, 16.4 mmol) in ethanol (5 mL) was added dropwise to a solution (E)-ethyl 2-benzoyl-3-ethoxyacrylate (3.40 g, 13.7 mmol) in ethanol (20 mL) at 0° C. The mix was allowed to warm to RT, stir for 24 h and then concentrated in vacuo to give a three component mixture. The mixture was dissolved in ethyl acetate (30 mL), washed with 5% citric acid (25 mL), saturated sodium bicarbonate (25 mL) and brine (25 mL), dried Na₂SO₄), concentrated in vacuo and purified by column chromatography (ethyl acetate/hexanes) to give a light yellow solid (1.37 g). LC and LCMS show a 1:1 mix of methyl and ethyl esters. MS (ESI) m/z: 203.0 and 217.0 (M+H⁺).

1N Lithium hexamethyldisilazane (5.09 mL, 5.09 mmol) was added to a solution of the mixture of esters (1.00 g, ˜4.62 mmol) in THF (5 mL) at 0° C. After 0.5 h isopropyliodide (2.58 g, 13.87 mmol) was added and the reaction allowed to slowly warm to RT. After 3 h the reaction was warmed to reflux and stirred overnight. Isopropyliodide (1.5 mL) and cesium carbonate (1 g) were added and warming continued overnight. The reaction is treated with additional isopropyliodide (1.5 mL) and stirred at 80° C. overnight. The reaction is treated with additional isopropyliodide (1.5 mL) and stirred at 80° C. overnight. The reaction is treated with additional isopropyliodide (1.5 mL) and stirred at 80° C. overnight. The reaction is cooled to RT and filtered free of insolubles. The filtrate was diluted with ethyl acetate (50 mL), washed with 5% citric acid (40 mL), saturated sodium bicarbonate (40 mL) and brine (40 mL), dried Na₂SO₄), concentrated in vacuo and purified by column chromatography (ethyl acetate/hexanes) to give ethyl 1-isopropyl-1-phenyl-1-H-pyrazole-4-carboxylate and ethyl 1-isopropyl-5-phenyl-1H-pyrazole-4-carboxylate as a mixture of methyl and ethyl esters (470 mg) as an oil. MS (ESI) m/z: 259.0 and 245.0 (M+H⁺).

A solution of the above esters (470 mg, ˜1.819 mmol) and lithium hydroxide (305 mg, 7.28 mmol) in ethanol:water:dioxane (1:1:1, 6 mL) was warmed to 40° C. and stirred overnight. The reaction was cooled to RT and diluted with water (30 mL) and ether (20 mL). The ether was discarded and the aqueous phase made acidic with 6N HCl (pH˜=2, wet litmus) and extracted with ethyl acetate (2×25 mL). The combined ethyl acetate layers were washed with brine (25 mL), dried (Na₂SO₄) and concentrated in vacuo to give a white solid, 1-isopropyl-3-phenyl-1H-pyrazole-4-carboxylic acid (major isomer) and 1-isopropyl-5-phenyl-1H-pyrazole-4-carboxylic acid (381 mg, 91% yield). ¹H NMR (300 MHz, DMSO-d₆, major isomer): δ 1.50 (d, 6H), 3.38 (s, 3H), 4.61 (hp, 1H), 7.39-7.45 (m, 3H), 7.77-7.79 (m, 2H), 8.38 (s, 1H), 12.21 (s, 1H); MS (ESI) m/z: 231.0 (M+H⁺).

Using General Method C, 1-isopropyl-3-phenyl-1H-pyrazole-4-carboxylic acid and 1-isopropyl-5-phenyl-1H-pyrazole-4-carboxylic acid (381 mg, 1.655 mmol), triethylamine (193 mg, 1.903 mmol), 2,2,2-trichloroethanol (494 mg, 3.31=mol) and DPPA (524 mg, 1.903 mmol) were combined and purified by column chromatography (ethyl acetate/hexanes) to afford 2,2,2-trichloroethyl 1-isopropyl-3-phenyl-1H-pyrazol-4-ylcarbamate (faster elution, 340 mg) as a thick oil, ¹H NMR (300 MHz, DMSO-d₆): δ 1.51 (d, 6H), 4.55 (hp, 1H), 4.95 (s, 2H), 7.35-7.46 (m, 3H), 7.75-7.77 (m, 2H), 7.95 (s, 1H), 9.35 (s, 1H); MS (ESI) m/z: 378.0 (M+H), and 2,2,2-trichloroethyl 1-isopropyl-5-phenyl-1H-pyrazol-4-ylcarbamate (slower elution, 79 mg) as a foam, ¹H NMR (300 MHz, DMSO-d₆): δ 1.40 (d, 6H), 4.42 (hp, 1H), 4.88 (s, 2H), 7.43-7.60 (m, 6H), 9.15 (s, 1H); MS (ESI) m/z: 378.0 (M+H⁺).

Example B15

For the preparation of 2,2,2-trichloroethyl 1-isopropyl-3-phenyl-1H-pyrazol-4-ylcarbamate see Example B14.

Example B16

A slurry of ethyl 3-phenyl-1H-pyrazole-4-carboxylate from Example B14 (1.051 g, 4.86 mmol), powdered potassium carbonate (5.37 g, 38.9 mmol) and ethyl iodide (2.274 g, 14.58 mmol) in acetonitrile (20 mL) was warmed to reflux for 5 h and then cooled to RT. The reaction was filtered and the solids washed with acetonitrile (2×20 mL). The filtrate was concentrated in vacuo and partitioned between ethyl acetate (30 mL) and water (30 mL). The organic phase was washed with brine, dried Na₂SO₄) and concentrated in vacuo to give an oil. LC, LCMS and NMR are consistent with a 2:1 mix of the ethyl isomers (1.066 g, 90% yield). MS (ESI) m/z: 245.0 (M+H⁺).

Using a procedure analogous to Example B14, the 2:1 mix of isomeric esters (1.066 g, 4.36 mmol) and lithium hydroxide (732 mg, 17.45 mmol) were combined to give the carboxylic acids as a 2:1 mixture of the ethyl isomers as a thick oil. LC and LCMS are consistent with assigned structures. MS (ESI) m/z: 217.0 (M+H⁺).

Using General Method C, the mixture of isomeric acids (877 mg, 4.06 mmol), triethylamine (472 mg, 4.66 mmol), 2,2,2-trichloroethanol (1.515 g, 10.14 mmol) and DPPA (1.284 g, 4.66 mmol) were combined and purified by chromatography (ethyl acetate/hexane) to give 2,2,2-trichloroethyl 1-ethyl-3-phenyl-1H-pyrazol-4-ylcarbamate (faster elution, 261 mg, >99% purity), ¹H NMR (300 MHz, DMSO-d₆): δ 1.53 (t, 3H), 4.26 (q, 2H), 5.01 (s, 2H), 7.40-7.52 (m, 3H), 7.81-7.83 (m, 2H), 7.99 (s, 1H), 9.43 (s, 1H); MS (ESI) m/z: 364.0 (M+H⁺), and 2,2,2-trichloroethyl 1-ethyl-5-phenyl-1H-pyrazol-4-ylcarbamate (slower elution. 261 mg, >99% purity), ¹H NMR (300 MHz, DMSO-d₆): δ 1.37 (t, 3H), 4.13 (q, 2H), 4.94 (s, 2H), 7.52-7.64 (m, 6H), 9.24 (s, 1H); MS (ESI) m/z: 364.0 (M+H⁺).

Example B17

For the preparation of 2,2,2-tri chloroethyl 1-ethyl-3-phenyl-1H-pyrazol-4-ylcarbamate see Example B16.

Example B18

A mixture of 3-fluorophenylboronic acid (0.5 g, 3.57 mmol), Cu(OAc)₂ (1.0 g, 5.36 mmol) and ethyl 3-isopropyl-1H-pyrazole-5-carboxylate from Example B2 (0.71 g, 3.93 mmol) was stirred at RT in pyridine (15 mL) for 36 hours. The reaction was diluted with water (40 mL) and extracted with ethyl acetate (3×20 ml). The combined organic layers were washed, dried, concentrated in vacuo and purified by chromatography (ethyl acetate/hexanes) to provide ethyl 1-(3-fluorophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate as a colorless oil (0.42 g, 43% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (m, 1H), 7.40 (m, 1H), 7.31 (m, 2H), 6.98 (s, 1H), 4.20 (q, J=6 Hz, 2H), 3.00 (m, 1H), 1.25 (d, J=6 Hz, 6H), 1.18 (d, J=6 Hz, 3H); m/z: 277.0 (M+H⁺).

A mixture ethyl 1-(3-fluorophenyl)-3-isopropyl-1H-pyrazole-5-carboxylate (0.50 g, 1.8 mmol) and lithium hydroxide monohydrate (0.37 g, 8.8 mmol) was stirred in (THF:ethanol:water-2:1:1, 20 ml) for 1 hr. The volatiles from the reaction mixture were evaporated and the residue diluted with water (50 mL). The solution was acidified with HCl to pH 2 with stirring. The solids were filtered, washed with water and dried to give 1-(3-fluorophenyl)-3-isopropyl-1H-pyrazole-5-carboxylic acid as a white crystalline solid (0.35 g, 78% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.50 (m, 1H), 7.37 (dd, J—10.2, 2.4 Hz, 1H), 7.31-7.25 (m, 2H), 6.92 (s, 1H), 2.96 (m, 1H), 1.24 (d, J=7 Hz, 6H); m/z: 249 (M+H⁺).

Example B19

To a flask charged with KOtBu (4 g, 36 mmol) and ether (100 mL, dry) was added dropwise a mixture of 2-fluorobenzonitrile (2.1 g, 17.5 mmol) and MeCN (0.738 g, 18 mmol) at 0° C. After addition, the mixture was stirred at RT for 2 days. Water was added and the reaction and extracted with ether (3×100 mL). The organic layers were combined, washed with brine, dried (Na₂SO₄) and concentrated in vacuo to afford a yellow oil, which was dissolved in CH₂Cl₂ and the solution was acidified with 3M HCl. After stirring the solution at RT for 2 hours, the solution was extracted with dichloromethane (3×200 mL). The organic layers were combined, washed with brine and dried (Na₂SO₄) and concentrated in vacuo to give 3-(2-fluoro-phenyl)-3-oxo-propionitrile (2 g, 70% yield) as a yellow solid. ¹H NMR (300 MHz, DMSO-d₆): δ 7.99-7.92 (m, 1H), 7.70-7.58 (m, 1H), 7.35-7.14 (m, 2H), 4.09 (m, 2H).

To a solution of 3-(2-fluorophenyl)-3-oxopropanenitrile (0.501 g, 3.07 mmol) in EtOH (5 mL) added methylhydrazine (0.141 g, 3.07 mmol) and Conc. HCl (2 drops) and mixture was stirred at 80° C. for 16 h. Solvents were removed; Sat. NaHCO₃ solution (35 mL) was added and the product was extracted with EtOAc (2×30 mL). The combined organics were washed with brine, dried (Na₂SO₄) and concentrated to afford crude product which was purified column chromatography (methanol/DCM) to afford 3-(2-fluorophenyl)-1-methyl-1H-pyrazol-5-amine as a thick residue (0.3 g, 52% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 7.83 (t, J=7.2 Hz, 1H), 7.19-7.13 (m, 3H), 5.75 (d, J=4.4 Hz, 1H), 5.27 (s, 2H), 3.56 (s, 3H); MS (ESI) m/z: 192.1 (M+H⁺).

Example 1

Using general method B, Example B1 (0.0898 g, 0.30 mmol), THE (1.0 mL), Example A1 (0.0853 g, 0.30 mmol) and 1-methylpyrrolidine (0.00312 mL) were combined and the resultant product purified via column chromatography to yield 1-(3-t-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (0.125 g, 79% yield) as a white foam. ¹H NMR (DMSO-d₆): δ 9.10 (d, J=1.6 Hz, 1H), 8.89 (s, 1H), 8.60-8.57 (m, 2H), 8.28-8.23 (m, 2H), 7.68 (d, J=2.0 Hz, 1H), 7.56-7.49 (m, 3H), 7.44-7.38 (m, 2H), 7.17-7.11 (m, 2H), 6.39 (s, 1H), 3.92 (s, 3H), 2.31 (s, 3H), 1.26 (s, 9H); MS (ESI) m/z: 526.2 (M+H⁺).

Example 2

Using general method C, Example B2 (0.060 g, 0.24 mmol) and Example A1 (0.200 g, 0.71 mmol) were combined and the resultant product purified via column chromatography to yield 1-(1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (0.077 g, 61% yield) as a white solid. ¹H NMR (DMSO-d₆): δ 9.06 (d, J=1.6 Hz, 1H), 8.95 (s, 1H), 8.55-8.54 (m, 2H), 8.22 (s, 1H), 8.18 (t, J=9.2 Hz, 1H), 8.03 (t, J=1.2 Hz, 1H), 7.91-7.86 (m, 2H), 7.73 (t, J=8.0 Hz, 1H), 7.61 (s, 1H), 7.39 (dd, J=11.2, 2.4 Hz, 1H), 7.12-7.07 (m, 2H), 6.38 (s, 1H), 3.90 (s, 3H), 2.89 (m, 1H), 2.29 (s, 3H), 1.22 (d, J=6.4 Hz, 6H); MS (ESI) m/z: 537.3 (M+⁺).

Example 3

Using General Method C, Example B3 (100 mg, 0.370 mmol), triethylamine (43 mg, 0.426=mol), Example A9 (100 mg, 0.370 mmol) and DPPA (117 mg, 0.426 mmol) were combined and purified by chromatography (methanol/ethyl acetate) to give a residue which was treated with 4N HCl/dioxane (0.4 mL) and stirred for 5 min. The solid was collected by filtration and identified as 1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(3-cyanophenyl-1H-pyrazol-5-yl)urea hydrochloride (13 mg, 6% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 1.27 (s, 9H), 6.42 (s, 1H), 7.00-7.12 (m, 2H), 7.38 (d, 1H), 7.50-7.60 (m, 2H), 7.73 (t, 2H), 7.86-7.91 (m, 2H), 8.03 (s, 1H), 8.17 (t, 1H), 8.50-8.53 (m, 2H), 9.01 (s, 1H), 9.10 (s, 1H); MS (ESI) m/z: 537.3 (M+H⁺).

Example 4

Using General Method C, Example B3 (152 mg, 0.563=mol), triethylamine (66 mg, 0.648 mmol), Example A1 (150 mg, 0.563 mmol) and DPPA (178 mg, 0.648 mmol) were combined and purified by column chromatography (methanol/ethyl acetate) to give a white foam. The foam was dissolved in acetonitrile (4 mL), treated with 4N HCl/dioxane (0.3 mL), concentrated in vacuo and lyophilized to afford 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea hydrochloride (129 mg, 41% yield). ¹H NMR (300 MHz, DMSO-d₆); δ 1.27 (s, 9H), 3.92 (s, 3H), 6.41 (s, 1H), 7.12-7.14 (m, 2H), 7.42-7.45 (m, 1H), 7.50-7.60 (m, 1H), 7.70-7.74 (m, 2H), 7.84-7.92 (m, 2H), 8.04 (s, 1H), 8.15-8.20 (m, 1H), 8.49 (s, 1H), 8.52-8.53 (m, 1H), 8.81 (s, 1H), 9.27 (s, 1H), 9.31 (s, 1H); MS (ESI) m/z: 551.2 (M+H⁺).

Example 5

A solution of Example B4 (249 mg, 1.02 mmol) in THF (2 mL) was cooled to −78° C. and treated with a solution of lithium bis(trimethylsilyl)amide (1.0 M in THF) (2.12 mL, 2.12 mmol). The resultant solution was stirred 20 min at −78° C. Isopropenyl chloroformate (0.12 mL, 1.11 mmol) was added rapidly and the reaction was stirred 10 min at −78° C. and quenched by addition of 2 M aq HCl (1.2 mL, 2.4 mmol). The mixture was warmed to RT and partitioned between EtOAc and water. The organics were washed with brine, dried (Na)SO₄) and concentrated in vacuo to provide prop-1-en-2-yl 1-(3-cyano-4-fluorophenyl)-3-isopropyl-1H-pyrazol-5-ylcarbamate (341 mg, 100% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.89 (br s, 1H), 8.04 (dd, J=5.6, 2.8 Hz, 1H), 7.88 (ddd, J=9.2, 4.8, 2.8 Hz, 1H), 7.68 (t, J=9.2 Hz, 1H), 6.30 (s, 1H), 4.70 (br s, 1H), 4.62 (br s, 1H), 2.88 (m, 1H), 1.81 (br s, 3H), 1.21 (d, J=7.2 Hz, 6H); MS (ESI) m/z: 329.0 (M+H⁺).

Prop-1-en-2-yl 1-(3-cyano-4-fluorophenyl)-3-isopropyl-1H-pyrazol-5-ylcarbamate (95 mg, 0.29 mmol), Example A1 (80 mg, 0.298 mmol) and N-methylpyrrolidine (2.5 mg, 0.029 mmol) were combined in THF (2 mL) and heated to 55° C. in a capped flask for 60 h. The reaction mixture was purified by silica gel chromatography and recrystallization (acetone-acetonitrile) to provide 1-(1-(3-cyano-4-fluorophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (49 mg, 30% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.93 (s, 1H), 8.89 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.16 (dd, J=5.8, 2.8 Hz, 1H), 8.09 (t, J=9.1 Hz, 1H), 7.98-7.93 (m, 2H), 7.71 (t, J=9.0 Hz, 1H), 7.26-7.21 (m, 2H), 6.99 (m, 1H), 6.65 (dd, J=5.7, 2.6 Hz, 1H), 6.37 (s, 1H), 3.84 (s, 3H), 2.88 (m, 1H), 1.22 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 555.0 (M+H⁺).

Example 6

Using General Method C, Example B5 (0.100 g, 0.371 mmol), TEA (0.259 mL, 1.857 mmol), DPPA (0.10 mL, 0.464 mmol) and Example A1 (0.211 g, 0.743 mmol) were combined and was purified by chromatography to afford 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (0.116 g, 57% yield) as a white foam. It was converted to corresponding mesylate salt by reacting with MsOH (1.0 eq.). ¹H NMR (400 MHz, DMSO-d₆): δ 9.10 (s, 1H), 9-01 (s, 1H), 8.60-8.57 (m, 2H), 8.27 (s, 1H), 8.18 (t, J=9.6 Hz, 1H), 8.01 (d, J=8.4 Hz, 2H), 7.78 (d, J=8.8 Hz, 2H), 7.68 (d, J=2.0 Hz, 1H), 7.42 (dd, J=11.6, 2.8 Hz, 2H), 7.16-7.10 (m, 2H), 6.44 (s, 1H), 3.92 (s, 3H), 2.32 (s, 3H), 1.28 (s, 9H); MS (ESI) m/z: 551.2 (M+H⁺).

Example 7

Using General Method A, Example B6 (1.50 g, 5.22 mmol) was converted to ethyl 3-(3-tert-butyl-5-((2,2,2-trichloroethoxy)carbonyl)-1H-pyrazol-1-yl)benzoate (2.79 g, 116% yield) as a thick oil. ¹H NMR (300 MHz, DMSO-d₆): δ 1.26 (s, 9H), 1.32 (t, 3H), 4.32 (q, 2H), 4.82 (s, 2H), 6.32 (s, 1H), 7.59-7.63 (m, 1H), 7.72-7.74 (m, 1H), 7.89-7.92 (m, 1H), 8.01 (s, 1H), 10.10 (s, 1H); MS (ESI) m/z: 464.0 (M+H⁺).

Using General Method A, Example A1 (300 mg, 1.055=mol), diisopropylethylamine base (682 mg, 5.28 mmol) and ethyl 3-(3-tert-butyl-5-((2,2,2-trichloroethoxy)carbonyl)-1H-pyrazol-1-yl)benzoate (488 mg, 1.055 mmol) were combined and purified by column chromatography (methanol/ethyl acetate) to afford ethyl 3-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)benzoate (250 mg, 39% yield) as a white foam. ¹H NMR (300 MHz, DMSO-d₆): δ 1.27 (s, 9H), 1.31 (t, 3H), 3.84 (s, 3H), 4.31 (q, 2H), 6.40 (s, 1H), 6.65 (m, 1H), 6.97-7.00 (m, 1H), 7.21 (s, 1H), 7.24 (s, 1H), 6.68 (t, 1H), 7.81-7.84 (m, 1H), 7.95-8.12 (m, 4H), 8.24 (s, 1H), 8.35 (d, 1H), 8.86 (s, 1H), 8.93 (s, 1H); MS (ESI) m/z: 598.2 (M+H⁺).

In tetrahydrofuran (5 mL) was placed ethyl 3-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)benzoate (192 mg, 0.321 mmol) and cooled to ˜0° C. To this was added 1M LiAlH₄/THF (0.321 mL, 0.321 mmol). After 1 hr at ˜0° C. the reaction was carefully quenched with water (10 mL) and diluted with ethyl acetate (20 mL). The organic phase was washed with brine (10 mL), dried (Na₂SO₄) and concentrated in vacuo to give a foam. LC analysis showed starting material. The foam was dissolved in THF (5 mL) and cooled to 0° C. This was treated with 1M LiAlH₄/THF (321 μL) and stirred at ˜0° C. for 1 hr. The reaction was then quenched with water (10 mL), diluted with ethyl acetate (20 mL), washed with brine (10 mL), dried (Na₂SO₄) and concentrated in vacuo to afford 1-(3-tert-butyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (146 mg, 82% yield) as a foam. The foam was dissolved in ethanol (4 mL), treated with p-toluenesulfonic acid (50 mg, 0.263 mmol), concentrated in vacuo, triturated with ether (10 mL) and filtered to give a solid identified as 1-(3-tert-butyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea p-toluenesulfonic acid (133 mg). ¹H NMR (300 MHz, DMSO-d₆): δ 1.26 (s, 9H), 2.27 (s, 3H), 3.90 (s, 3H), 4.58 (s, 2H), 6.38 (s, 1H), 7.07-7.10 (m, 4H), 7.35-7.39 (m, 3H), 7.44-7.48 (m, 4H), 7.55 (br s, 1H), 8.20-8.25 (m, 2H), 8.53-8.55 (m, 2H), 8.87 (s, 1H), 9.07 (s, 1H), OH and SO3H are missing; MS (ESI) m/z: 556.3 (M+H⁺).

Example 8

Using General Method D, Example B7 (0.31 g, 1.079 mmol) was converted to ethyl 4-(3-tert-butyl-5-((prop-1-en-2-yloxy)carbonyl)-1H-pyrazol-1-yl)benzoate (0.35 g, 87% yield) as an off-white solid. ¹H NMR (400 MHz, Acetone-d₆): δ 8.12 (d, J=8.4 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 6.38 (s, 1H), 4.62 (brs, 2H), 4.37 (q, J=7.2 Hz, 2H), 1.96 (brs, 3H), 1.37 (t, J=7.2 Hz, 3H)₅ 1.33 (s, 9H); MS (ESI) m/z: 372.3 (M+H⁺).

To a solution of ethyl 4-(3-tert-butyl-5-((prop-1-en-2-yloxy)carbonyl)-1H-pyrazol-1-yl)benzoate (0.201 g, 0.541 mmol) in THF (2 ml) added Example A1 (0.154 g, 0.541 mmol) and catalytic amount of 1-methylpyrrolidine and the mixture was stirred for 2 h at 60° C. Solvents were removed and the crude product was purified by column chromatography (ethyl acetate/hexanes) to afford ethyl 4-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)benzoate (0.176 g, 54% yield) as a colorless foam. ¹H NMR (400 MHz, DMSO-d₆): δ 8.96 (s, 1H), 8.93 (s, 1H), 8.36 (d, J=5.6 Hz, 1H), 8.25 (s, 1H), 8.10-8.07 (m, 3H), 7.95 (s, 1H), 7.71 (d, J=8.8 Hz, 2H), 7.25-7.71 (m, 2H), 6.98 (dt, J=9.2 Hz, 1.2 Hz, 1H), 6.66 (dd, J=5.6 Hz, 2.4 Hz, 1H), 6.43 (s, 1H), 4.33 (q, J=6.8 Hz, 2H), 3.84 (s, 3H), 1.32 (t. J=6.8 Hz, 3H), 1.27 (s, 9H); MS (ESI) m/z: 598.2 (M+H⁺).

To a solution of ethyl 4-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)benzoate (0.175 g, 0.293 mmol) in THF (2 ml) was added 1M LiAlH₄/THF (0.9 ml. 0.878 mmol) at 0° C. and mixture was stirred for 2 h at RT. Sat. Na₂SO₄ solution was added carefully to quench the reaction mixture and the resulting solution was stirred for 6 h at RT. The quenched mixture was filtered through a Celite® pad, washing with EtOAc (2×3 mL) and the combined filtrate was concentrated in vacuo and purified by column chromatography (methanol/CH₂Cl₂) to afford 1-(3-tert-butyl-1-(4-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (0.086, 53% yield) as a white solid. This was converted to the corresponding tosylate salt. ¹H NMR (400 MHz, DMSO-d₆): δ 9.07 (s, 1H), 8.85 (s, 1H), 8.52-8.49 (m, 2H), 8.24 (t, J=5.2 Hz, 1H), 8.18 (s, 1H), 7.54 (s, 1H), 7.48-7.43 (m, 6H), 7.35 (dd, J=11.6 Hz, 2.4 Hz, 1H), 7.09 (d, J=8.0 Hz, 3H), 7.01 (brs, 1H), 6.38 (s, 1H), 4.56 (s, 2H), 3.89 (s, 3H), 2.27 (s, 3H), 1.26 (s, 9H); MS (ESI) m/z: 556.3 (M+H⁺).

Example 9

Using General Method D, Example B8 (0.250 g, 1.18 mmol) was converted to prop-1-en-2-yl 1-(3-cyanophenyl)-3-ethyl-1H-pyrazol-5-ylcarbamate and purified via recrystallization (hexanes) to isolate a colorless semi-solid (0.350 g, 100% yield) ¹H NMR (400 MHz, DMSO-d₆): δ 9.87(brs, 1H), 7.9-7.65 (m, 4H), 6.26 (s, 1H), 4.61 (m, 2H), 2.53 (q, J=6 Hz, 2H), 1.76 (s, 3H), 1.14 (t, J=6 Hz, 3H); MS (ESI) m/z: 297.0 (M+H⁺).

2,2,2-Trichloroethyl 1-(3-cyanophenyl)-3-ethyl-1H-pyrazol-5-ylcarbamate (0.300 g, 0.774 mmol) was reacted with Example A1 (0.220 g, 0.774 mmol) in presence of N-methylpyrrolidine (0.013 g, 0.155 mmol) in dioxane (5 ml) at 70° C. for 14 hours. The solvent was completely removed and the residue recrystallized (acetonitrile) to provide 1-(1-(3-cyanophenyl)-3-ethyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (0.303 g, 75% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (s, 1H), 8.88 (m, 2H), 8.48 (d. J=9 Hz, 1H), 8.31 (d, J=5.5 Hz, 1H), 8.2 (s, 1H), 8.04 (t, J=9 Hz, 1H), 7.99 (m, 1H), 7.91 (s, 1H), 7.84 (m, 1H), 7.69 (t, J=8 Hz, 1H), 7.19 (dd, J=12.0, 2.6 Hz, 1H), 7.17 (d, J=2.60 Hz, 1H), 6.95 (brd, J=9 Hz, 1H), 6.61 (d, J=5.5, 2.5 Hz, 1H), 6.32 (s, 1H), 3.80 (s, 34H) 2.52 (q, J=6 Hz, 2H), 1.15 (d, J=6 Hz, 3H); MS (ESI) m/z: 523.0 (M+H⁺).

Example 10

Using General Method C, Example B9 (60 mg, 0.23 mmol) and Example A1 (67 mg, 0.23 mmol) in presence of DPPA (57 μL, 0.23 mmol) and (36 μL, 0.23 mmol) were combined and the resultant product purified via column chromatography (EtOAc/hexanes) to afford 1-(2-tert-butyl-4-(pyridin-3-yl)pyrimidin-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (68 mg, 54% yield). ¹H NMR (400 MHz, DMSO-d₆, major isomer): δ 9.05 (s, 1H) 9.02 (brs, 1H), 8.58 (s, 1H), 8.34 (d, J=5.6 Hz, 1H), 8.23 (s, 1H), 8.15 (t, J=9.2 Hz, 1H), 7.94 (s, 1H), 7.74 (m, 2H), 7.53 (m, 3H), 7.22 (dd, J=2.4, and 11.6 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H), 6.99 (m, 1H), 6.65 (dd, J=2.4, and 5.6 Hz, 1H), 3.83 (s, 3H), 1.36 (s, 9H); MS (ESI) m/z: 538.3 (M+H⁺).

Example 11

To a solution of Example B10 (0.15 g, 0.624 mmol) in CH₂Cl₂ (10 mL) were added pyridine (0.102 ml, 1.248 mmol) and 2,2,2-trichloroethyl carbonochloridate (0.103 ml, 0.749 mmol) at 0° C. After stirring for 2 h at RT, 2M HCl was added, the organic layer was separated and aqueous layer was extracted with CH₂Cl₂ (1×20 mL). The combined organics were washed with brine, dried (Na₂SO₄) and concentrated to afford a white foam.

To this foam was added Example A1 (0.177 g, 0.624 mmol), DIPEA (0.081 g, 0.624 mmol) and DMSO (2 mL) and the mixture was heated to 65° C. for 5 h. Water (40 mL) was added and product was extracted with EtOAc (2×35 ml). The combined organics were washed with brine, dried Na₂SO₄) and concentrated to afford crude product which was purified by column chromatography (EtOAc/CH₂Cl₂) to afford 1-(1-(3-cyano-4-methylphenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (71 mg, 20% 2 step yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.96 (s, 1H), 8.88 (s, 1H), 8.38 (d, J=6.0 Hz, 1H), 8.26 (s, 1H), 8.12 (t, J=9.21 Hz, 1H), 7.97 (s 2H), 7.80-7.77 (m, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.27-7.23 (m, 2H), 7.01 (d, J=8.4 Hz, 1H), 6.68 (dd, J=6.0 Hz, 2.0 Hz, 1H), 6.38 (s, 1H), 3.86 (s, 3H), 2.93-2.86 (m, 1H), 2.55 (s, 3H), 1.24 (d, J=6.4 Hz, 6H); MS (ESI) m/z: 551.0 (M+H⁺).

Example 12

Prop-1-en-2-yl 1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-ylcarbamate (63 mg, 0.20 mmol), prepared from Example B11 according to General Method D, Example A2 (57 mg, 0.19 mmol) and N-methylpyrrolidine (1.627 mg, 0.019 mmol) were combined in THF (0.4 mL) and heated to 55° C. overnight. The reaction mixture was purified by chromatography to provide 1-(1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (58 mg, 55% yield. ¹H NMR (400 MHz, DMSO-d₆), δ 8.96 (s, 2H), 8.36 (d, J=5.8 Hz, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 8.00-7.88 (m, 4H), 7.76 (t, J=8.0 Hz, 1H), 7.20 (d, J=1.9 Hz, 1H), 6.97 (d, J=9.2 Hz, 1H), 6.59 (dd, J=5.6, 2.1 Hz, 1H), 6.40 (s, 1H), 3.87 (s, 3H), 2.91 (m, 1H), 2.07 (s, 3H), 1.25 (d, J=7.1 Hz, 6H); MS (ESI) m/z: 551.2 (M+H⁺).

Example 13

A solution of prop-1-en-2-yl 1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-ylcarbamate (73 mg, 0.235 mmol), prepared from Example B111 according to General Method D, Example A3 (68 mg, 0.225 mmol) and N-methylpyrrolidine (1.9 mg, 0.022 mmol) were combined in THF (0.6 mL) and heated to 55° C. overnight. The reaction mixture was purified by chromatography to provide 1-(1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (77 mg, 62% yield). ¹H NMR (400 MHz, DMSO-d₆). δ 9.18 (s, 1H), 8.99 (s, 1H), 8.39 (d, J=5.6 Hz. 1H), 8.29 (s, 1H). 8.05 (m, 1H), 7.99 (s, 1H), 7.94-7.87 (m, 3H), 7.74 (t, J=8.0 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 7.18 (m, 1H), 6.74 (dd, J=5.8, 2.2 Hz, 1H), 6.40 (s, 1H), 3.85 (s, 3H), 2.90 (m, 1H), 1.23 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 555.2 (M+H⁺).

Example 14

Following General Method C, Example B12 (75 mg, 0.352 mmol), triethylamine (41 mg, 0.405 mmol), Example A1 (100 mg, 0.352 mmol) and DPPA (111 mg, 0.405 mmol) were combined and purified by column chromatography (methanol/ethyl acetate) to afford 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-methyl-4-phenylpyrimidin-5-yl)urea (41 mg, 23% yield) as a white foam. ¹H NMR (300 MHz, DMSO-d₆): δ 2.62 (s, 3H), 3.86 (s, 3H), 6.65 (s, 1H), 6.99 (d, 1H), 7.18-7.24 (m, 2H), 7.50-7.53 (m, 3H), 7.66-7.69 (m, 2H), 7.94 (s, 1H), 8.13-8.18 (m, 1H), 8.23 (s, 1H), 8.30-8.35 (m, 1H), 8.55 (br s, 1H), 9.03-9.05 (m, 2H); MS (ESI) m/z: 496.0 (M+H⁺).

Example 15

To a solution of Example B8 (0.300 g, 1.413 mmol) and Troc-Cl (0.233 ml, 1.696 mmol) in EtOAc (7 ml) at 0° C. was added 3M NaOH (0.707 ml, 2.120 mmol). The reaction was stirred at 0° C. for 30 min and then at RT for 2 h. The reaction was treated with satd. NaHCO₃ (2-3 ml) and more Troc-Cl (0.1 ml) and stirred at RT. After 90 min, the layers of the biphasic reaction were separated and the organic layer washed with H₂O (2×), brine (1×), dried (MgSO₄), concentrated in vacuo and purified by flash column chromatography (EtOAc/hexanes) to afford 2,2,2-trichloroethyl 1-(3-cyanophenyl)-3-ethyl-1H-pyrazol-5-ylcarbamate (0.47 g, 86% yield) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆): δ 10.18 (brs, 1H), 7.92 (s, 1H), 7.85-7.82 (m, 2H), 7.70-7.66 (m, 1H), 6.29 (s, 1H), 4.86 (s, 2H), 2.61-2.56 (m, 2H), 1.21-1.18 (m, 3H); MS (ESI) m/z: 387.0 (M+H⁺), 389.0 (M+2+H⁺).

2,2,2-Trichloroethyl 1-(3-cyanophenyl)-3-ethyl-1H-pyrazol-5-ylcarbamate (0.156 g, 0.402 mmol), Example A4 and iPr₇NEt (0.154 ml, 0.885 mmol) were combined in DMSO (4 ml) and stirred with heating at 70° C. After 18 h, the completed reaction was cooled to RT, diluted with brine and extracted with EtOAc (3×). The combined organics were washed with brine (2×), dried (MgSO₄), concentrated in vacuo and purified by reverse phase chromatography to afford 1-(1-(3-cyanophenyl)-S-ethyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-propyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (60 mg, 27% yield) as a white solid following lyophilization. ¹H NMR (400 MHz, DMSO-d₆): δ 9.03 (s, 1H), 8.96 (s, 1H), 8.51 (brs, 2H), 8.18-8.13 (m, 2H), 8.04 (brs, 1H), 7.92-7.87 (m, 2H), 7.87-7.74 (m 1H), 7.52 (brs, 1H), 7.37-7.36 (m, 1H), 7.09-7.07 (m, 1H), 6.96 (brs, 1H), 6.37 (s, 1H), 4.13-4.09 (m, 2H), 2.61-2.55 (m, 2H), 1.83-1.77 (m, 2H), 1.24-1.18 (m, 3H), 0.84-0.81 (m, 3H); MS (ESI) m/z: 551.2 (M+H⁺).

Example 16

A solution of the prop-1-en-2-yl 1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl (90 mg, 0.290 mmol), prepared from of Example B11 using General Method D, Example A5 (78 mg, 0.273 mmol) and N-methylpyrrolidine (2.3 mg, 0.027 mmol) were combined in THF (0.6 mL) and heated to 55° C. for 40 h. The reaction mixture was purified by chromatography and the obtained solid was recrystallized (acetone-hexanes) to provide 1-(1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (93 mg, 63% yield). ¹H NMR (400 MHz, DMSO-d₆). δ 9.40 (s, 1H), 8.71 (s, 1H), 8.40 (d, J=5.6 Hz, 1H), 8.31 (s, 1H), 8.08 (t, J=1.8 Hz, 1H), 8.01 (d, J=0.5 Hz, 1H), 7.96 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 7.92 (dt, J=8.0, 1.2 Hz, 1H), 7.78 (t, J=8.0 Hz, 1H), 7.69 (dd, J=13.3, 2.4 Hz, 1H), 7.34 (t, J=9.1 Hz, 1H), 7.26 (d, J=2.6 Hz, 1H), 7.24 (m, 1H), 6.66 (dd, J=5.8, 2.6 Hz, 1H), 63.4 (s, 1H), 3.90 (s, 3H), 2.96 (m, 1H), 1.29 (d, J=6.9 Hz, 6H); MS (ESI) m/z: 537.3 (M+H⁺).

Example 17

2,2,2-Trichloroethyl 1-(3-cyanophenyl)-3-ethyl-1H-pyrazol-5-ylcarbamate from Example 15 (0.156 g, 0.402 mmol), Example A6 (0.126 g, 0.402 mmol) and iPr₂NEt (0.154 ml, 0.885 mmol) were combined in DMSO (4 ml) and stirred with heating at 70° C. After 18 h, the completed reaction was cooled to RT and purified directly by reverse phase chromatography to afford 1-(1-(3-cyanophenyl)-3-ethyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-isopropyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (87 mg, 39% yield) as a white solid following lyophilization. ¹H NMR (400 MHz, DMSO-d₆): δ 9.10 (brs, 1H), 9.03 (s, 1H), 8.66 (s, 1H), 8.60-8.58 (m, 1H), 8.27-8.20 (m, 2H), 8.10 (brs, 1H), 7.98-7.93 (m. 2H), 7.82-7.80 (m, 1H), 7.66 (s, 1H), 7.45-7.42 (m, 1H), 7.17-7.15 (m, 1H), 7.08-7.07 (m, 1H), 6.43 (s, 1H), 4.63-4.60 (m, 1H) 2.67-2.61)_m, 2H), 1.50-1.49 (m, 6H), 1.28-1.25 (m, 1H); MS (ESI) m/z: 551.2 (M+H⁺).

Example 18

2,2,2-Trichloroethyl 1-(3-cyanophenyl)-3-ethyl-1H-pyrazol-5-ylcarbamate from Example 15 (0.156 g, 0.402 mmol), Example A7 (0.120 g, 0.402 mmol) and iPr₂NEt (0.154 ml, 0.885 mmol) were combined in DMSO (4 ml) and stirred with heating at 70° C. After 18 h, the completed reaction was cooled to RT and the crude product was purified directly by reverse phase chromatography to afford 1-(1-(3-cyanophenyl)-3-ethyl-1H-pyrazol-5-yl)-3-(4-(2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)urea (78 mg, 36% yield) as a white solid following lyophilization. ¹H NMR (400 MHz, DMSO-d₆): δ 9.05 (s, 1H), 8.97 (s, 1H), 8.54-8.51 (m, 2N), 8.19-8.16 (m, 2H), 8.04 (brs, 1H), 7.92-7.87 (m, 2H), 7.76-7.72 (m, 1H), 7.55 (s, 1H), 7.39-7.38 (m, 1H), 7.36-7.35 (m, 1H), 7.00 (brs, 1H), 6.37 (s, 1H), 4.22-4.17 (m, 2H), 2.59-2.53 (m, 2H), 1.41-1.38 (m, 5H), 1.22-1.19 (m, 3H); MS (ESI) m/z: 537.3 (M+H⁺).

Example 19

Using General Method D, Example B13 (0.301 g, 1.161 mmol) was converted to ethyl 4-(3-ethyl-5-((prop-1-en-2-yloxy)carbonyl)-1H-pyrazol-1-yl)benzoate (0.4 g, 100%) as a thick residue. ¹H NMR (400 MHz, DMSO-d₆): δ 9.99 (brs, 1H), 8.12 (d, J=8.4 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 6.35 (s, 1H), 4.72 (brs, 2H), 4.39 (q, J=7.2 Hz, 2H), 2.65 (q, J=7.6 Hz, 2H), 1.87 (brs, 3H), 1.39 (t, J=7.2 Hz, 3H), 1.26 (t, J=7.6 Hz, 3H); MS (ESI) m/z: 344.0 (M+H⁺).

A THF solution of ethyl 4-(3-ethyl-5-(prop-1-en-2-yloxy)carbonyl)-1H-pyrazol-1-yl)benzoate (0.2 g, 0.58 mmol) and Example A1 (0.16 g, 0.58 mmol) in the presence of DBU (a drop) was combined to afford ethyl 4-(3-ethyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)benzoate (0.117 g, 35% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.05 (brs, 2H), 8.46 (d, J=5.6 Hz, 1H), 8.34 (s, 1H), 8.22-8.17 (m, 3H), 8.05 (s, 1H), 7.81 (d, J=8.4 Hz, 2H), 7.35-7.31 (m, 2H), 7.09 (d, J=8.8 Hz, 1H), 6.76 (dd, J=5.6 Hz, 2.4 Hz, 1H), 6.47 (s, 1H), 4.43 (q, J=7.2 Hz, 2H), 3.94 (s, 3N), 2.68 (q, J=7.6 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H), 1.30 (t, J=7.6 Hz, 3H); MS (ESI) m/z. 570.2 (M+N⁺).

Using a procedure analogous to Example 8, ethyl 4-(3-ethyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)benzoate (0.115 g, 0.202 mmol) was converted to 1-(3-ethyl-1-(4-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea (0.096 g, 90% yield) and isolated as a white solid following purification via column chromatography (methanol/CH₂Cl₂). ¹H NMR (400 MHz, DMSO-d₆): δ 9.07 (s, 1H), 8.92 (s, 1H), 8.45 (d, J=5.6 Hz, 1H), 8.33 (s, 1H), 8.24 (t, J=9.2 Hz, 1H), 8.04 (s, 1H), 7.56-7.52 (m, 4H), 7.33-7.29 (m, 2H), 7.09 (dt, J=8.8 Hz, 1.6 Hz, 1H), 6.75 (dd, J=5.6 Hz. 2.4 Hz, 1H), 6.41 (s, 1H), 5.41 (t, J=5.6 Hz, 1H), 4.65 (d, J=5.6 Hz, 2H), 3.93 (s, 3H), 2.64 (q, J=7.6 Hz, 2H), 1.27 (t, J=7.6 Hz, 3H); MS (ESI) m/z: 528.3 (M+H⁺).

Example 20

A solution of Example B14 (79 mg, 0.210 mmol), DIEA (81 mg, 0.629 mmol) and Example A1 (60 mg, 0.210 mmol) in DMSO (2 mL) was warmed to 80° C. overnight and then 110° C. overnight. The reaction was cooled to RT, diluted with water (30 mL) and extracted with ethyl acetate (30 mL). The combined organic phases were washed with brine (30 mL), dried (Na₂SO₄), concentrated in vacuo and purified by column chromatography (ethyl acetate/hexane-methanol/ethyl acetate) to give an impure foam (21 mg). This foam was purified by reverse phase chromatography (acetonitrile/water/0.1% TFA), lyophilized, and dissolved a mixture of water (5 mL), saturated sodium bicarbonate (5 mL) and ethyl acetate (15 mL). The organic phase was separated, washed with brine (10 mL), dried (Na₂SO₄), concentrated in vacuo, dissolved in acetonitrile/water and lyophilized to afford 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1-isopropyl-5-phenyl-1H-pyrazol-4-yl)urea (11 mg, 10% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 1.45 (d, 6H), 3.97 (s, 3H), 4.41 (hp, 1H), 6.77-6.79 (m, 1H), 7.08-7.11 (m, 1H), 7.30-7.34 (m, 2H), 7.53-7.55 (m, 2H), 7.64-7.73 (m, 3H), 7.94 (s, 1H), 8.08 (s, 1H), 8.27 (s, 1H), 8.32-8.37 (m, 2H), 8.47 (d, 1H), 8.84 (s, 1H); MS (ESI) m/z: 512.2 (M+H⁺).

Example 21

In a manner analogous to Example 20, Example B15 (200 mg, 0.531 mmol), DIEA (206 mg, 1.593 mmol) and Example A1 (151 mg, 0.531 mmol) were combined and purified by column chromatography (ethyl acetate/hexane) and reverse phase chromatography (acetonitrile/water/0.1% TFA) to afford 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1-isopropyl-3-phenyl-1H-pyrazol-4-yl)urea (38 mg, 13% yield). ¹H NMR (300 MHz. DMSO-d₆): δ 1.56 (d, 6H), 3.97 (s, 3H), 4.61 (hp, 1H), 6.79 (m, 1H), 7.09-7.12 (m, 1H), 7.33 (s, 1H), 7.34-7.37 (m, 1H), 7.47-7.49 (m, 1H), 7.56-7.60 (m, 2H), 7.76-7.78 (m, 2H), 8.08 (s, 1H), 8.13 (s, 1H), 8.35-8.37 (m, 2H), 8.48 (d, 1H), 8.52 (s, 1H), 9.00 (br s, 1H); MS (EST) m/z: 512.2 (M+H⁺).

Example 22

A solution of Example B16 (261 mg. 0.720 mmol), DIEA (372 mg, 2.88 mmol) and Example A1 (205 mg, 0.720 mmol) in DMSO (5 mL) was warmed to 75° C. and stirred overnight. The mixture was extracted with ethyl acetate (30 mL). The organic phase was washed with brine (30 mL), dried (Na₂SO₄), concentrated in vacuo and purified by column chromatography (methanol/dichloromethane) to give a film. The film was subjected to 4N HCl/dioxane to afford 1-(1-ethyl-5-phenyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea hydrochloride (29 mg, 8% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 1.21 (t, 3H), 3.93 (s, 3H), 3.98 (q, 2H), 7.05-7.08 (m, 2H), 7.35-7.60 (m, 6H), 7.75 (s, 1H), 7.80 (s, 1H), 8.30-8.30 (m, 2H), 8.47 (s, 1H), 8.51 (d, 1H), 8.80 (s, 1H), 8.90 (br s, 1H); MS (ESI) m/z: 498.2 (M+H⁺).

Example 23

A solution of Example B17 (250 mg, 0.689=mol), DIEA (356 mg, 2.76 mmol) and Example A1 (196 mg, 0.689 mmol) in DMSO (5 mL) was warmed to 75° C. and stirred overnight. The temperature was increased to 100° C. and stirring continued overnight. The mixture was cooled to RT and diluted with ethyl acetate (25 mL) and water (25 mL). The organic phase was washed with brine (20 mL), dried (Na₂SO₄), concentrated in vacuo and purified by column chromatography (methanol/dichloromethane) to give a film. The film was subjected to 4N HCl/dioxane to afford 1-(1-ethyl-3-phenyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea hydrochloride (95 mg, 27% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 1.40 (t, 3H), 3.93 (s, 3H), 4.15 (q, 2H), 7.10-7.18 (m, 2H), 7.31-7.48 (m, 4H), 7.62-7.68 (m, 2H), 7.75 (s, 1H), 7.99 (s, 1H), 8.32 (m, 1H), 8.48 (s, 1H), 8.54 (d, 1H), 8.59 (s, 1H), 8.80 (s, 1H), 9.10 (br s, 1H); MS (ESI) m/z: 498.2 (M+H⁺).

Example 24

To a stirring solution of Example B18 (0.09 g, 0.363 mmol) and TEA (0.076 mL, 0.544 mmol) in dioxane (3.0 mL) was added DPPA (0.117 mL, 0.544 mmol). After stirring for 0.5 h at RT, Example A1 (0.103 g, 0.363 mmol) was added and the reaction was heated at 100° C. for 3 h. Water (15 mL) was added to reaction mixture and the resulting precipitate was collected by filtration. The crude product was purified by chromatography to afford 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1-(3-fluorophenyl)-3-isopropyl-1H-pyrazol-5-yl)urea (0.097 g, 50% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d6): δ 9.00 (s, 1H), 8.92 (s, 1H), 8.38 (d, J=5.6 Hz, 1H), 8.27 (s, 1H), 8.14 (t, J=9.2 Hz, 1H), 7.97 (s, 1H), 7.59 (q, J=6.8 Hz, 1H), 7.45-7.41 (m, 2H), 7.31-7.23 (m, 3H), 7.01 (d, J=8.8 Hz, 1H), 6.68 (dd, J=5.6, 2.4 Hz, 1H), 6.38 (s, 1H), 3.86 (s, 3H), 2.90 (m, 1H), 1.24 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 530.2 (M+1K).

Example 25

Using general method B, Example A8 (0.083 g, 0.21 mmol) and Example B19 (0.04 g 0.21 mmol) in presence of N-methylpyrrolidine (cat amount) were combined to afford 1-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)urea as white solid (0.059 g, 53% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.16 (s, 1H), 9.12 (s, 1H), 8.38 (d, J=5.6 Hz, 1H), 8.28 (s, 1H), 8.02-7.98 (m, 2H), 7.90 (t, J=8.0 Hz, 1H), 7.34-7.18 (m, 5H), 6.74 (d, J=5.6 Hz, 1H), 6.65-6.64 (m, 1H), 3.84 (s, 3H), 3.77 (s, 3H); MS (ESI) m/z: 520.1 (M+H⁺).

Example 26

Using General Method C, Example B3 (0.085 g, 0.31 mmol), Example A10 (0.075 g, 0.26 mmol) in presence of triethylamine (0.08 g, 0.79 mmol) and DPPA (0.14 g, 0.52 mmol) were combined to afford 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)urea as a white solid (0.099 g, 68% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 9.06 (d, J=2.0 Hz, 1H), 8.97 (s, 1H), 8.46 (d, J=5.2 Hz, 1H), 8.42 (s, 1H), 8.08 (s, 1H), 8.02 (t, J=2.0 Hz, 1H), 7.96 (dd, J=6.8 Hz, 2.8 Hz, 1H), 7.89-7.84 (m, 2H), 7.72 (t. J=8.0 Hz, 1H), 7.45 (d, J=5.2 Hz, 1H), 7.28 (dd, J=1.8 Hz, 8.8 Hz, 1H), 6.87-6.83 (m, 1H), 6.39 (s, 1H), 3.87 (s, 3H), 1.24 (s, 9H); MS (ESI) m/z: 552.3 (M+H⁺).

Example 27

Using General Method C, Example B3 (0.088 g, 0.32 mmol), Example A11 (0.075 g, 0.25 mmol), triethylamine (0.076 g, 0.75 mmol) and DPPA (0.14 g, 0.5=mol) were combined to afford 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)urea as a white solid (0.108 g, 76% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.96 (d, J=1.6 Hz, 1H), 8.91 (s, 1H), 8.44 (d, J=5.2 Hz, 1H), 8.42 (s, 1H), 8.08 (s, 1H), 8.02 (t, J=1.6 Hz, 1H), 7.88-7.82 (m, 1H), 7.71 (t, J=8.0 Hz, 1H), 7.44 (d, J=4.8 Hz, 1H), 7.21 (d, J=12.0 Hz, 1H), 6.38 (s, 1H), 3.87 (s, 3H), 2.01 (s, 3H), 1.24 (s, 9H); MS (ESI) m/z; 566.3 (M+H⁺).

Using the synthetic procedures and methods described herein and methods known to those skilled in the art, the following compounds were made: 1-(5-chloro-2-phenylphenyl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 4-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)benzyl acetate, 1-(3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(4-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, ethyl 3-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)benzoate, 3-(3-tert-butyl-5-(3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)benzoic acid, 1-(3-ethyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-cyanophenyl)-3-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-(3-cyanophenyl)-1-isopropyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3′-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(1,3-diphenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, and 1-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1,3-diphenyl-1H-pyrazol-5-yl)urea.

Using the synthetic procedures and methods described herein and methods known to those skilled in the art, the following compounds are made:

1-(4-(2(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(4-cyano-3-fluorophenyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-(4-cyano-3-fluorophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(H-pyrazol-4-yl)pyridin-4-yloxy)-3-methylphenyl)-3-(3-tert-butyl-1-(4-cyano-3-fluorophenyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-(4-cyano-3-fluorophenyl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2(2-fluorophenyl)-3-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-3-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-5-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isoxazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-tert-butyl-3-(3-cyanophenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-(3-cyanophenyl)-1-isopropyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-tert-butyl-3-(3-cyanophenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-(3-cyanophenyl)-1-isopropyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-tert-butyl-3-(3-cyanophenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-11H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(5-methyl-1,2,4-thiadiazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(3-methyl-3H-1,2,3-triazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isoxazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isoxazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(4-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(4-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-tert-butyl-3-(3-(hydroxymethyl)phenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(1-tert-butyl-3′-(3-(hydroxymethyl)phenyl)-1H-pyrazol-4-yl)urea, 1-(1-tert-butyl-3-(3-(hydroxymethyl)phenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-3-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(1-tert-butyl-3-(3-(hydroxymethyl)phenyl)-1H-pyrazol-4-yl)urea, 1-(1-tert-butyl-3-(3)hydroxymethylphenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-5-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(1-tert-butyl-3-(3-(hydroxymethyl)phenyl)-1H-pyrazol-4-yl)urea, 1-(1-tert-butyl-3-(3-(hydroxymethyl)phenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(isoxazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)urea, 1-(4-(2-(1H-pyrazol-3-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)urea. 1-(3-tert-butyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isoxazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-(hydroxymethylphenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isoxazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(4-methyloxazol-2-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isoxazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(4H-1,2,4-triazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-isothiazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isothiazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(3-methyl-1H-pyrazol-1-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isothiazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)urea, 1-(1-(4-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)urea, 1-(2-fluoro-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)-3-(1-(4-(hydroxymethyl)phenyl)-3-isopropyl-1H-pyrazol-5-yl)urea, 1-(2-fluoro-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)-3-(1-(3-(hydroxymethyl)phenyl)-3-isopropyl-1H-pyrazol-5-yl)urea, 1-(1-(3-cyano-4-methylphenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)urea, 1-(1-(3-cyano-4-fluorophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-methyl-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl-urea, 1-(1-(3-cyanophenyl)-3-isopropyl-4-pyrazol-5-yl)-3-(2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)urea, 1H-(4-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)urea, 1-(2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)-3-(1-(4-(hydroxymethyl)phenyl)-3-isopropyl-1H-pyrazol-5-yl)urea, 1-(2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)-3-(1-(3-(hydroxymethyl)phenyl)-3-isopropyl-1H-pyrazol-5-yl)urea. 1-(1-(3-cyano-4-methylphenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)urea, 1-(1-(3-cyano-4-fluorophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)urea, 1-(5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylphenyl)-3-(3-tert-butyl-1-(3-cyano-4-methylphenyl)-1H-pyrazol-5-yl)urea, 1-(5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluoro-4-methylphenyl)-3-(3)-tert-butyl-1-(3-cyano-4-fluorophenyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-(3-cyano-4-methylphenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)urea, 1-(5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(3-cyano-4-methylphenyl)-1H-pyrazol-5-yl)urea, 1-(5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(3-cyano-4-fluorophenyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-(3-cyano-4-fluorophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yloxy)phenyl)urea, 1-(1-(3-cyanophenyl)-3-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-cyanophenyl)-3-(1-hydroxyethyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-cyanophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(oxazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(oxazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(4-hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(oxazol-4-yl)pyridin-4-yloxy)phenyl urea, 1-(3-tert-butyl-1-(3-(hydroxymethylphenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(oxazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-benzyl-1-phenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-phenylisoxazol-5-yl)urea, 1-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)urea, 1-(2,3-difluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(5-phenylpyridin-3-yl)urea, 1-(3-tert-butyl-1-(4-cyano-3-fluorophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isothiazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(4-cyano-3-fluorophenyl)-1-(1-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isothiazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(4-cyano-3-fluorophenyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-(4-cyano-3-fluorophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-methylphenyl)-3-(3-tert-butyl-1-(4-cyano-3-fluorophenyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-(4-cyano-3-fluorophenyl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-3-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)urea 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-5-yl)pyridin-4-yloxy)-2-fluorophenyl-3-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isoxazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(4-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-tert-butyl-3-(3-cyanophenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-cyanophenyl)-1-isopropyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-tert-butyl-3-(3-cyanophenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-(3-cyanophenyl)-1-isopropyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yloxy phenyl)urea, 1(1-tert-butyl-3-(3-cyanophenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(3-methyl-4-(2-(1-methyl-1H-pyrazol-5-yl-pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl-3-(3-methyl-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(5-methyl-1,2,4-thiadiazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(4-methyl-4H-1,2,4-triazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(3-methyl-3H-1,2,3-triazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3′-cyanophenyl)-1H-pyrazol-5-yl)-1-(2-fluoro-4-(2-(isoxazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isoxazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(4-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(4-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-tert-butyl-3-(3-(hydroxymethyl)phenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(1-tert-butyl-3-(3-(hydroxymethyl)phenyl)-1H-pyrazol-4-yl)urea, 1-(1-tert-butyl-3-(3-(hydroxymethyl)phenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-3-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(1-tert-butyl-3-(3-(hydroxymethyl)phenyl)-1H-pyrazol-4-yl)urea, 1-(1-tert-butyl-3-(3-(hydroxymethyl)phenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-5-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(1-tert-butyl-3′-(3-(hydroxymethyl)phenyl)-1H-pyrazol-4-yl)urea, 1-(1-tert-butyl-3-(3-(hydroxymethyl)phenyl)-1H-pyrazol-4-yl)-3-(2-fluoro-4-(2-(isoxazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)urea, 1-(4-(2-(1H-pyrazol-3-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl-1-(2-fluoro-4-(2-(isoxazol-4-yl(pyridin-4-yloxy phenyl urea, 1-(3-tert-butyl-1-(3-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isoxazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(4-methyloxazol-2-yl(pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(3-methyl-1,2,4-thiadiazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isoxazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(4-(2-(4H-1,2,4-triazol-4-yl)pyridin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isothiazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isothiazol-3-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(3-methyl-1H-pyrazol-1-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(isothiazol-5-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(4-methyl-2H-1,2,3-triazol-2-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-cyanophenyl)-3-(1-hydroxyethyl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(1-(3-cyanophenyl)-3-(2-hydroxypropan-2-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, 1-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)-3-(2-fluoro-5-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yloxy)phenyl)urea, 1-(5-(2-(1H-pyrazol-4-yl)pyrimidin-4-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1(3-cyanophenyl)-1H-pyrazol-5-yl)urea, 1-(1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(2-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yloxy)phenyl)urea, 1-(5-(2-(1H-pyrazol-4-yl)pyrimidin-4-yloxy)-2-fluorophenyl)-3-(1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)urea, 1-(5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorophenyl)-3-(3-tert-butyl-1-(3-cyanophenyl)-1H-pyrazol-5-yl)urea, 1-(5-(4-(1H-pyrazol-4-yl)pyrimidin-2-yloxy)-2-fluorophenyl)-3-(1-(3-cyanophenyl)-3-isopropyl-1H-pyrazol-5-yl)urea, 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(6-(4-fluorophenoxy)benzo[d]thiazol-2-yl)urea, 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(6-phenoxybenzo[d]thiazol-2-yl)urea, 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(6-phenoxybenzo[d]oxazol-2-yl)urea, 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-phenoxyquinolin-6-yl)urea, 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-oxo-5-phenoxyindolin-3-yl)urea, 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(5-phenoxy-1H-indazol-3-yl)urea, 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(6-phenoxy-1H-indazol-3-yl)urea, 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(6-(4-fluorophenoxy)benzo[d]oxazol-2-yl)urea, 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-(4-fluorophenoxy)quinolin-6-yl)urea, 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(5-(4-fluorophenoxy)-2-oxoindolin-3-yl)urea, 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(5-(4-fluorophenoxy)-1H-indazol-3-yl)urea, 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(6-(4-fluorophenoxy)-1H-indazol-3-yl)urea, 1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-3-(3-(4-fluorophenoxy)phenyl)urea, 1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-3-(3-(4-fluorophenoxy)-5-methylphenyl)urea, 1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-3-(3-chloro-5-(4-fluorophenoxy-phenyl)urea, 1-(4-(2-(1H-pyrazol-4-yl)pyridin-4-yloxy)-3-fluorophenyl)-3-(3-(4-fluorophenoxy)-5-(trifluoromethyl)phenyl)urea, 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-(4-fluorophenoxy)phenyl)urea, 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-(4-fluorophenoxy)-5-methylphenyl)urea, 1-(3-chloro-5-(4-fluorophenoxy)phenyl)-3-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)urea, and 1-(3-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(3-(4-fluorophenoxy)-5-(trifluoromethyl)phenyl)urea.

SECTION 4. BIOLOGICAL DATA

Abl Kinase (SEQ ID NO:1) Assay

Activity of Abl kinase (SEQ ID NO:1) was determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A_340nm) was continuously monitored spectrophometrically. The reaction mixture (100 μl) contained Abl kinase (1 nM. Abl from deCode Genetics), peptide substrate (EAIYAAPFAKKK. 0.2 mM), MgCl₂ (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) in 90 mM Tris buffer containing 0.2% octyl-glucoside and 3.5% DMSO, pH 7.5. Test compounds were incubated with Abl (SEQ ID NO:1) and other reaction reagents at 30° C. for 2 h before ATP (500 μM) was added to start the reaction. The absorption at 340 nm was monitored continuously for 2 hours at 30° C. on Polarstar Optima plate reader (BMG). The reaction rate was calculated using the 1.0 to 2.0 h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound). IC₅₀ values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.

Abl kinase
(SEQ ID NO:1)
GTSMDPSSPNYDKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVK
TLKEDTMEVEEFLKEAAVMKEIKHPNLVQLLGVCTREPPFYIITEFMTYG
NLLDYLRECNRQEVNAVVLLYMATQISSAMEYLEKKNFIHRDLAARNCLV
GENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWTAPESLAYNKFSIKSD
VWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCPEKVYEL
MRACWQWNPSDRPSFAEIHQAFETMFQE

Abl Kinase (SEQ ID NO:2) Assay

Activity of T315I Abl kinase (SEQ ID NO:2) was determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A_340nm) was continuously monitored spectrophometrically. The reaction mixture (100 μl) contained Abl kinase (4.4 nM. M315I Abl from deCode Genetics), peptide substrate (EAIYAAPFAKKK, 0.2 mM), MgCl₂ (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) in 90 mM Tris buffer containing 0.2% octyl-glucoside and 1% DMSO, pH 7.5. Test compounds were incubated with T315I Abl (SEQ ID NO:2) and other reaction reagents at 30° C. for 1 h before ATP (500 μM) was added to start the reaction. The absorption at 340 nm was monitored continuously for 2 hours at 30° C. on Polarstar Optima plate reader (BMG). The reaction rate was calculated using the 1.0 to 2.0 h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound). IC₅₀ values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.

Abl T315I kinase
(SEQ ID NO:2)
GTSMDPSSPNYDKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVE
EFLKEAAVMKEIKHPNLVQLLGVCTREPPFYIIIEFMTYGNLLDYLRECNRQEVNAVVLL
YMATQISSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKF
PIKWTAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERP
EGCPEKVYELMRACWQWNPSDRPSFAEIHQAFETMFQE
BCR-Abl p210-e14a2
(SEQ ID NO:3)
MVDPVGFAEAWKAQFPDSEPPRMELRSVGDIEQELERCKASIRRLEQEVNQERFRMIYLQ
TLLAKEKKSYDRQRWGFRRAAQAPDGASEPRASASRPQPAPADGADPPPAEEPEARPDGE
GSPGKARPGTARRPGAAASGERDDRGPPASVAALRSNFERIRKGHGQPGADAEKPFYVNV
EFHHERGLVKVNDKEVSDRISSLGSQAMQMERKKSQHGAGSSVGDASRPPYRGRSSESSC
GVDGDYEDAELNPRFLKDNLIDANGGSRPPWPPLEYQPYQSIYVGGIMEGEGKGPLLRSQ
STSEQEKRLTWPRRSYSPRSFEDCGGGYTPDCSSNENLTSSEEDFSSGQSSRVSPSPTTY
RMFRDKSRSPSQNSQQSFDSSSPPTPQCHKRHRHCPVVVSEATIVGVRKTGQIWPNDDEG
AFHGDADGSFGTPPGYGCAADRAEEQRRHQDGLPYIDDSPSSSPHLSSKGRGSRDALVSG
ALKSTKASELDLEKGLEMRKWVLSGILASEETYLSHLEALLLPMKPLKAAATTSQPVLTS
QQIETIFFKVPELYEIHKESYDGLFPRVQQWSHQQRVGDLFQKLASQLGVYRAFVDNYGV
AMEMAEKCCQANAQFAEISENLRARSNKDAKDPTTKNSLETLLYKPVDRVTRSTLVLHDL
LKHTPASHPDHPLLQDALRISQNFLSSINEEITPRRQSMTVKKGEHRQLLKDSFMVELVE
GARKLRHVFLFTDLLLCTKLKKQSGGKTQQYDCKWYIPLTDLSFQMVDELEAVPNIPLVP
DEELDALKIKISQIKSDIQREKRANKGSKATERLKKKLSEQESLLLLMSPSMAFRVHSRN
GKSYTFLISSDYERAEWRENIREQQKKCFRSFSLTSVELQMLTNSCVKLQTVHSIPLTIN
KEDDESPGLYGFLNVIVHSATGFKQSSKALQRPVASDFEPQGLSEAARWNSKENLLAGPS
ENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPSNYITPV
NSLEKHSWYHGPVSRNAAEYPLSSGINGSFLVRESESSPSQRSISLRYEGRVYHYRINTA
SDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNYDKWEMER
TDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAAVMKEIKHPNLV
QLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEVNAVVLLYMATQISSAMEYLEKKNF
IHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWTAPESLAYNKFSIK
SDVWAFGVLLWEIATYGMSPYPGIDRSQVYELLEKDYRMKRPEGCPEKVYELMRACWQWN
PSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVTTLLQAPELPTKTRTSRRAA
EHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEGGLNEDERLLPKDKKTNL
FSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDISNGALAFTPLDTADPAKS
PKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATGEEEGGGSSSKRFLRSCSV
SCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKPALPRKRAGENRSDQVTRGT
VTPPPRLVKKNEEAADEVFKDIMESSPGSSPPNLTPKPLRRQVTVAPASGLPHKEEAWKG
SALGTPAAAEPVTPTSKAGSGAPRGTSKGPAEESRVRRHKHSSESPGRDKGKLSKLKPAP
PPPPAASAGKAGGKPSQRPGQEAAGEAVLGAKTKATSLVDAVNSDAAKPSQPAEGLKKPV
LPATPKPHPAKPSGTPISPAPVPLSTLPSASSALAGDQPSSTAFIPLISTRVSLRKTRQP
PERASGAITKGVVLDSTEALCLAISGNSEQMASHSAVLEAGKNLYTFCVSYVDSIQQMRN
KFAFREAINKLENNLRELQICPASAGSGPAATQDFSKLLSSVKEISDIVQR
BCR-Abl p210-e13a2
(SEQ ID NO:4)
MVDPVGFAEAWKAQFPDSEPPRMELRSVGDIEQELERCKASIRRLEQEVNQERFRMIYLQ
TLLAKEKKSYDRQRWGFRRAAQAPDGASEPRASASRPQPAPADGADPPPAEEPEARPDGE
GSPGKARPGTARRPGAAASGERDDRGPPASVAALRSNFERIRKGHGQPGADAEKPFYVNV
EFHHERGLVKVNDKEVSDRISSLGSQAMQMERKKSQHGAGSSVGDASRPPYRGRSSESSC
GVDGDYEDAELNPRFLKDNLIDANGGSRPPWPPLEYQPYQSIYVGGIMEGEGKGPLLRSQ
STSEQEKRLTWPRRSYSPRSFEDCGGGYTPDCSSNENLTSSEEDFSSGQSSRVSPSPTTY
RMFRDKSRSPSQNSQQSFDSSSPPTPQCHKRHRHCPVVVSEATIVGVRKTGQIWPNDDEG
AFHGDADGSFGTPPGYGCAADRAEEQRRHQDGLPYIDDSPSSSPHLSSKGRGSRDALVSG
ALKSTKASELDLEKGLEMRKWVLSGILASEETYLSHLEALLLPMKPLKAAATTSQPVLTS
QQIETIFFKVPELYEIHKESYDGLFPRVQQWSHQQRVGDLFQKLASQLGVYRAFVDNYGV
AMEMAEKCCQANAQFAEISENLRARSNKDAKDPTTKNSLETLLYKPVDRVTRSTLVLHDL
LKHTPASHPDHPLLQDALRISQNFLSSINEEITPRRQSMTVKKGEHRQLLKDSFMVELVE
GARKLRHVFLFTDLLLCTKLKKQSGGKTQQYDCKWYIPLTDLSFQMVDELEAVPNIPLVP
DEELDALKIKISQIKSDIQREKRANKGSKATERLKKKLSEQESLLLLMSPSMAFRVHSRN
GKSYTFLISSDYERAEWRENIREQQKKCFRSFSLTSVELQMLTNSCVKLQTVHSIPLTIN
KEEALQRPVASDFEPQGLSEAARWNSKENLLAGPSENDPNLFVALYDFVASGDNTLSITK
GEKLRVLGYNHNGEWCEAQTKNGQGWVPSNYITPVNSLEKHSWYHGPVSRNAAEYPLSSG
INGSFLVRESESSPSQRSISLRYEGRVYHYRINTASDGKLYVSSESRFNTLAELVHHHST
VADGLITTLHYPAPKRNKPTVYGVSPNYDKWEMERTDITMKHKLGGGQYGEVYEGVWKKY
SLTVAVKTLKEDTMEVEEFLKEAAVMKEIKHPNLVQLLGVCTREPPFYIITEFMTYGNLL
DYLRECNRQEVNAVVLLYMATQISSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGL
SRLMTGDTYTAHAGAKFPIKWTAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGID
RSQVYELLEKDYRMKRPEGCPEKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISD
EVEKELGKQGVRGAVTTLLQAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDH
EPAVSPLLPRKERGPPEGGLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREM
DGQPERRGAGEEEGRDISNGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSP
HLWKKSSTLTSSRLATGEEEGGGSSSKRFLRSCSVSCVPHGAKDTEWRSVTLPRDLQSTG
RQFDSSTFGGHKSEKPALPRKRAGENRSDQVTRGTVTPPPRLVKKNEEAADEVFKDIMES
SPGSSPPNLTPKPLRRQVTVAPASGLPHKEEAWKGSALGTPAAAEPVTPTSKAGSGAPRG
TSKGPAEESRVRRHKHSSESPGRDKGKLSKLKPAPPPPPAASAGKAGGKPSQRPGQEAAG
EAVLGAKTKATSLVDAVNSDAAKPSQPAEGLKKPVLPATPKPHPAKPSGTPISPAPVPLS
TLPSASSALAGDQPSSTAFIPLISTRVSLRKTRQPPERASGAITKGVVLDSTEALCLAIS
GNSEQMASHSAVLEAGKNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPASA
GSGPAATQDFSKLLSSVKEISDIVQR
BCR-Abl p190-e1a2
(SEQ ID NO:5)
MVDPVGFAEAWKAQFPDSEPPRMELRSVGDIEQELERCKASIRRLEQEVNQERFRMIYLQ
TLLAKEKKSYDRQRWGFRRAAQAPDGASEPRASASRPQPAPADGADPPPAEEPEARPDGE
GSPGKARPGTARRPGAAASGERDDRGPPASVAALRSNFERIRKGHGQPGADAEKPFYVNV
EFHHERGLVKVNDKEVSDRISSLGSQAMQMERKKSQHGAGSSVGDASRPPYRGRSSESSC
GVDGDYEDAELNPRFLKDNLIDANGGSRPPWPPLEYQPYQSIYVGGIMEGEGKGPLLRSQ
STSEQEKRLTWPRRSYSPRSFEDCGGGYTPDCSSNENLTSSEEDFSSGQSSRVSPSPTTY
RMFRDKSRSPSQNSQQSFDSSSPPTPQCHKRHRHCPVVVSEATIVGVRKTGQIWPNDDEG
AFHGDAEALQRPVASDFEPQGLSEAARWNSKENLLAGPSENDPNLFVALYDFVASGDNTL
SITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPSNYITPVNSLEKHSWYHGPVSRNAAEYP
LSSGINGSFLVRESESSPSQRSISLRYEGRVYHYRINTASDGKLYVSSESRFNTLAELVH
HHSTVADGLITTLHYPAPKRNKPTVYGVSPNYDKWEMERTDITMKHKLGGGQYGEVYEGV
WKKYSLTVAVKTLKEDTMEVEEFLKEAAVMKEIKHPNLVQLLGVCTREPPFYIITEFMTY
GNLLDYLRECNRQEVNAVVLLYMATQISSAMEYLEKKNFIHRDLAARNCLVGENHLVKVA
DFGLSRLMTGDTYTAHAGAKFPIKWTAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPY
PGIDRSQVYELLEKDYRMKRPEGCPEKVYELMRACWQWNPSDRPSFAEIHQAFETMFQES
SISDEVEKELGKQGVRGAVTTLLQAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESD
PLDHEPAVSPLLPRKERGPPEGGLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSS
FREMDGQPERRGAGEEEGRDISNGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSG
FRSPHLWKKSSTLTSSRLATGEEEGGGSSSKRFLRSCSVSCVPHGAKDTEWRSVTLPRDL
QSTGRQFDSSTFGGHKSEKPALPRKRAGENRSDQVTRGTVTPPPRLVKKNEEAADEVFKD
IMESSPGSSPPNLTPKPLRRQVTVAPASGLPHKEEAWKGSALGTPAAAEPVTPTSKAGSG
APRGTSKGPAEESRVRRHKHSSESPGRDKGKLSKLKPAPPPPPAASAGKAGGKPSQRPGQ
EAAGEAVLGAKTKATSLVDAVNSDAAKPSQPAEGLKKPVLPATPKPHPAKPSGTPISPAP
VPLSTLPSASSALAGDQPSSTAFIPLISTRVSLRKTRQPPERASGAITKGVVLDSTEALC
LAISGNSEQMASHSAVLEAGKNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQIC
PASAGSGPAATQDFSKLLSSVKEISDIVQR
BCR-Abl p210-e14a2 T315I
(SEQ ID NO:6)
MVDPVGFAEAWKAQFPDSEPPRMELRSVGDIEQELERCKASIRRLEQEVNQERFRMIYLQ
TLLAKEKKSYDRQRWGFRRAAQAPDGASEPRASASRPQPAPADGADPPPAEEPEARPDGE
GSPGKARPGTARRPGAAASGERDDRGPPASVAALRSNFERIRKGHGQPGADAEKPFYVNV
EFHHERGLVKVNDKEVSDRISSLGSQAMQMERKKSQHGAGSSVGDASRPPYRGRSSESSC
GVDGDYEDAELNPRFLKDNLIDANGGSRPPWPPLEYQPYQSIYVGGIMEGEGKGPLLRSQ
STSEQEKRLTWPRRSYSPRSFEDCGGGYTPDCSSNENLTSSEEDFSSGQSSRVSPSPTTY
RMFRDKSRSPSQNSQQSFDSSSPPTPQCHKRHRHCPVVVSEATIVGVRKTGQIWPNDDEG
AFHGDADGSFGTPPGYGCAADRAEEQRRHQDGLPYIDDSPSSSPHLSSKGRGSRDALVSG
ALKSTKASELDLEKGLEMRKWVLSGILASEETYLSHLEALLLPMKPLKAAATTSQPVLTS
QQIETIFFKVPELYEIHKESYDGLFPRVQQWSHQQRVGDLFQKLASQLGVYRAFVDNYGV
AMEMAEKCCQANAQFAEISENLRARSNKDAKDPTTKNSLETLLYKPVDRVTRSTLVLHDL
LKHTPASHPDHPLLQDALRISQNFLSSINEEITPRRQSMTVKKGEHRQLLKDSFMVELVE
GARKLRHVFLFTDLLLCTKLKKQSGGKTQQYDCKWYIPLTDLSFQMVDELEAVPNIPLVP
DEELDALKIKISQIKSDIQREKRANKGSKATERLKKKLSEQESLLLLMSPSMAFRVHSRN
GKSYTFLISSDYERAEWRENIREQQKKCFRSFSLTSVELQMLTNSCVKLQTVHSIPLTIN
KEDDESPGLYGFLNVIVHSATGFKQSSKALQRPVASDFEPQGLSEAARWNSKENLLAGPS
ENDPNLFVALYDFVASGDNTLSITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPSNYITPV
NSLEKHSWYHGPVSRNAAEYPLSSGINGSFLVRESESSPSQRSISLRYEGRVYHYRINTA
SDGKLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNYDKWEMER
TDITMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAAVMKEIKHPNLV
QLLGVCTREPPFYIIIEFMTYGNLLDYLRECNRQEVNAVVLLYMATQISSAMEYLEKKNF
IHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFPIKWTAPESLAYNKFSIK
SDVWAFGVLLWEIATYGMSPYPGIDRSQVYELLEKDYRMKRPEGCPEKVYELMRACWQWN
PSDRPSFAEIHQAFETMFQESSISDEVEKELGKQGVRGAVTTLLQAPELPTKTRTSRRAA
EHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEGGLNEDERLLPKDKKTNL
FSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRDISNGALAFTPLDTADPAKS
PKPSNGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATGEEEGGGSSSKRFLRSCSV
SCVPHGAKDTEWRSVTLPRDLQSTGRQFDSSTFGGHKSEKPALPRKRAGENRSDQVTRGT
VTPPPRLVKKNEEAADEVFKDIMESSPGSSPPNLTPKPLRRQVTVAPASGLPHKEEAWKG
SALGTPAAAEPVTPTSKAGSGAPRGTSKGPAEESRVRRHKHSSESPGRDKGKLSKLKPAP
PPPPAASAGKAGGKPSQRPGQEAAGEAVLGAKTKATSLVDAVNSDAAKPSQPAEGLKKPV
LPATPKPHPAKPSGTPISPAPVPLSTLPSASSALAGDQPSSTAFIPLISTRVSLRKTRQP
PERASGAITKGVVLDSTEALCLAISGNSEQMASHSAVLEAGKNLYTFCVSYVDSIQQMRN
KFAFREAINKLENNLRELQICPASAGSGPAATQDFSKLLSSVKEISDIVQR
BCR-Abl p210-e13a2 T315I
(SEQ ID NO:7)
MVDPVGFAEAWKAQFPDSEPPRMELRSVGDIEQELERCKASIRRLEQEVNQERFRMIYLQ
TLLAKEKKSYDRQRWGFRRAAQAPDGASEPRASASRPQPAPADGADPPPAEEPEARPDGE
GSPGKARPGTARRPGAAASGERDDRGPPASVAALRSNFERIRKGHGQPGADAEKPFYVNV
EFHHERGLVKVNDKEVSDRISSLGSQAMQMERKKSQHGAGSSVGDASRPPYRGRSSESSC
GVDGDYEDAELNPRFLKDNLIDANGGSRPPWPPLEYQPYQSIYVGGIMEGEGKGPLLRSQ
STSEQEKRLTWPRRSYSPRSFEDCGGGYTPDCSSNENLTSSEEDFSSGQSSRVSPSPTTY
RMFRDKSRSPSQNSQQSFDSSSPPTPQCHKRHRHCPVVVSEATIVGVRKTGQIWPNDDEG
AFHGDADGSFGTPPGYGCAADRAEEQRRHQDGLPYIDDSPSSSPHLSSKGRGSRDALVSG
ALKSTKASELDLEKGLEMRKWVLSGILASEETYLSHLEALLLPMKPLKAAATTSQPVLTS
QQIETIFFKVPELYEIHKESYDGLFPRVQQWSHQQRVGDLFQKLASQLGVYRAFVDNYGV
AMEMAEKCCQANAQFAEISENLRARSNKDAKDPTTKNSLETLLYKPVDRVTRSTLVLHDL
LKHTPASHPDHPLLQDALRISQNFLSSINEEITPRRQSMTVKKGEHRQLLKDSFMVELVE
GARKLRHVFLFTDLLLCTKLKKQSGGKTQQYDCKWYIPLTDLSFQMVDELEAVPNIPLVP
DEELDALKIKISQIKSDIQREKRANKGSKATERLKKKLSEQESLLLLMSPSMAFRVHSRN
GKSYTFLISSDYERAEWRENIREQQKKCFRSFSLTSVELQMLTNSCVKLQTVHSIPLTIN
KEEALQRPVASDFEPQGLSEAARWNSKENLLAGPSENDPNLFVALYDFVASGDNTLSITK
GEKLRVLGYNHNGEWCEAQTKNGQGWVPSNYITPVNSLEKHSWYHGPVSRNAAEYPLSSG
INGSFLVRESESSPSQRSISLRYEGRVYHYRINTASDGKLYVSSESRFNTLAELVHHHST
VADGLITTLHYPAPKRNKPTVYGVSPNYDKWEMERTDITMKHKLGGGQYGEVYEGVWKKY
SLTVAVKTLKEDTMEVEEFLKEAAVMKEIKHPNLVQLLGVCTREPPFYIIIEFMTYGNLL
DYLRECNRQEVNAVVLLYMATQISSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGL
SRLMTGDTYTAHAGAKFPIKWTAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGID
RSQVYELLEKDYRMKRPEGCPEKVYELMRACWQWNPSDRPSFAEIHQAFETMFQESSISD
EVEKELGKQGVRGAVTTLLQAPELPTKTRTSRAAEHRDTTDVPEMPHISKGQGESDPLDH
EPAVSPLLPRKERGPPEGGLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSSFREM
DGQPERRGAGEEEGRDISNGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSGFRSP
HLWKKSSTLTSSRLATGEEEGGGSSSKRFLRSCSVSCVPHGAKDTEWRSVTLPRDLQSTG
RQFDSSTFGGHKSEKPALPRKRAGENRSDQVTRGTVTPPPRLVKKNEEAADEVFKDIMES
SPGSSPPNLTPKPLRRQVTVAPASGLPHKEEAWKGSALGTPAAAEPVTPTSKAGSGAPRG
TSKGPAEESRVRRHKHSSESPGRDKGKLSKLKPAPPPPPAASAGKAGGKPSQRPGQEAAG
EAVLGAKTKATSLVDAVNSDAAKPSQPAEGLKKPVLPATPKPHPAKPSGTPISPAPVPLS
TLPSASSALAGDQPSSTAFIPLISTRVSLRKTRQPPERASGAITKGVVLDSTEALCLAIS
GNSEQMASHSAVLEAGKNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPASA
GSGPAATQDFSKLLSSVKEISDIVQR
BCR-Abl p190-ela2
(SEQ ID NO:8)
MVDPVGFAEAWKAQFPDSEPPRMELRSVGDIEQELERCKASIRRLEQEVNQERFRMIYLQ
TLLAKEKKSYDRQRWGFRRAAQAPDGASEPRASASRPQPAPADGADPPPAEEPEARPDGE
GSPGKARPGTARRPGAAASGERDDRGPPASVAALRSNFERIRKGHGQPGADAEKPFYVNV
EFHHERGLVKVNDKEVSDRISSLGSQAMQMERKKSQHGAGSSVGDASRPPYRGRSSESSC
GVDGDYEDAELNPRFLKDNLIDANGGSRPPWPPLEYQPYQSIYVGGIMEGEGKGPLLRSQ
STSEQEKRLTWPRRSYSPRSFEDCGGGYTPDCSSNENLTSSEEDFSSGQSSRVSPSPTTY
RMFRDKSRSPSQNSQQSFDSSSPPTPQCHKRHRHCPVVVSEATIVGVRKTGQIWPNDDEG
AFHGDAEALQRPVASDFEPQGLSEAARWNSKENLLAGPSENDPNLFVALYDFVASGDNTL
SITKGEKLRVLGYNHNGEWCEAQTKNGQGWVPSNYITPVNSLEKHSWYHGPVSRNAAEYP
LSSGINGSFLVRESESSPSQRSISLRYEGRVYHYRINTASDGKLYVSSESRFNTLAELVH
HHSTVADGLITTLHYPAPKRNKPTVYGVSPNYDKWEMERTDITMKHKLGGGQYGEVYEGV
WKKYSLTVAVKTLKEDTMEVEEFLKEAAVMKEIKHPNLVQLLGVCTREPPFYIIIEFMTY
GNLLDYLRECNRQEVNAVVLLYMATQISSAMEYLEKKNFIHRDLAARNCLVGENHLVKVA
DFGLSRLMTGDTYTAHAGAKFPIKWTAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPY
PGIDRSQVYELLEKDYRMKRPEGCPEKVYELMRACWQWNPSDRPSFAEIHQAFETMFQES
SISDEVEKELGKQGVRGAVTTLLQAPELPTKTRTSRRAAEHRDTTDVPEMPHSKGQGESD
PLDHEPAVSPLLPRKERGPPEGGLNEDERLLPKDKKTNLFSALIKKKKKTAPTPPKRSSS
FREMDGQPERRGAGEEEGRDISNGALAFTPLDTADPAKSPKPSNGAGVPNGALRESGGSG
FRSPHLWKKSSTLTSSRLATGEEEGGGSSSKRFLRSCSVSCVPHGAKDTEWRSVTLPRDL
QSTGRQFDSSTFGGHKSEKPALPRKRAGENRSDQVTRGTVTPPPRLVKKNEEAADEVFKD
IMESSPGSSPPNLTPKPLRRQVTVAPASGLPHKEEAWKGSALGTPAAAEPVTPTSKAGSG
APRGTSKGPAEESRVRRHKHSSESPGRDKGKLSKLKPAPPPPPAASAGKAGGKPSQRPGQ
EAAGEAVLGAKTKATSLVDAVNSDAAKPSQPAEGLKKPVLPATPKPHPAKPSGTPISPAP
VPLSTLPSASSALAGDQPSSTAFIPLISTRVSLRKTRQPPERASGAITKGVVLDSTEALC
LAISGNSEQMASHSAVLEAGKNLYTFCVSYVDSIQQMRNKFAFREAINKLENNLRELQIC
PASAGSGPAATQDFSKLLSSVKEISDIVQR

C-Kit Kinase (SEQ ID NO:9) Assay

Activity of c-Kit kinase (SEQ ID NO:9) was determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A340 nm) was continuously monitored spectrophometrically. The reaction mixture (1001) contained c-Kit (cKIT residues T544-V976, from ProQinase, 5.4 nM), polyE4Y (1 mg/ml), MgCl2 (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) in 90 mM Tris buffer containing 0.2% octyl-glucoside and 1% DMSO, pH 7.5. Test compounds were incubated with C-Met (SEQ ID NO:9) and other reaction reagents at 22° C. for <2 min before ATP (200 μM) was added to start the reaction. The absorption at 340 nm was monitored continuously for 0.5 hours at 30° C. on Polarstar Optima plate reader (BMG). The reaction rate was calculated using the 0 to 0.5 h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound). IC50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.

c-Kit with N-terminal GST fusion
(SEQ ID NO:9)
LGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPN
LPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVDIRYG
VSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFML
YDALDVVLYMDPMCLDAFPKLVCFKKRIEAIPQIDKYLKSSKYIWPLQGW
QATFGGGDHPPKSDLVPRHNQTSLYKKAGSAAAVLEENLYFQGTYKYLQK
PMYEVQWKVVEEINGNNYVYIDPTQLPYDHKWEFPRNRLSFGKTLGAGAF
GKVVEATAYGLIKSDAAMTVAVKMLKPSAHLTEREALMSELKVLSYLGNH
MNIVNLLGACTIGGPTLVITEYCCYGDLLNFLRRKRDSFICSKQEDHAEA
ALYKNLLHSKESSCSDSTNEYMDMKPGVSYVVPTKADKRRSVRIGSYIER
DVTPAIMEDDELALDLEDLLSFSYQVAKGMAFLASKNCIHRDLAARNILL
THGRITKICDFGLARDIKNDSNYVVKGNARLPVKWMAPESIFNCVYTFES
DVWSYGIFLWELFSLGSSPYPGMPVDSKFYKMIKEGFRMLSPEHAPAEMY
DIMKTCWDADPLKRPTFKQIVQLIEKQISESTNHIYSNLANCSPNRQKPV
VDHSVRINSVGSTASSSQPLLVHDDV

C-Met Kinase (SEQ ID NO:10) Assay

Activity of C-Met kinase (SEQ ID NO:10) was determined by following the production of ADP from the kinase reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A340 nm) was continuously monitored spectrophometrically. The reaction mixture (100 μl) contained C-Met (c-Met residues; 956-1390, from Invitrogen, catalogue #PV3143, 6 nM), polyE4Y (1 mg/ml), MgCl2 (10 mM), pyruvate kinase (4 units), lactate dehydrogenase (0.7 units), phosphoenol pyruvate (1 mM), and NADH (0.28 mM) in 90 mM Tris buffer containing 0.25 mM DTT, 0.2% octyl-glucoside and 1% DMSO, pH 7.5. Test compounds were incubated with C-Met (SEQ ID NO:10) and other reaction reagents at 22° C. for 0.5 h before ATP (100 μM) was added to start the reaction. The absorption at 340 n=was monitored continuously for 2 hours at 30° C. on Polarstar Optima plate reader (BMG). The reaction rate was calculated using the 1.0 to 2.0 h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound). IC50 values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.

cMet Kinase
(SEQ ID NO:10)
MSYYHHHHHHDYDIPTTENLYFQGAMLVPRGSPWIPFTMKKRKQIKDLGS
ELVRYDARVHTPHLDRLVSARSVSPTTEMVSNESVDYRATFPEDQFPNSS
QNGSCRQVQYPLTDMSPILTSGDSDISSPLLQNTVHIDLSALNPELVQAV
QHVVIGPSSLIVHFNEVIGRGHFGCVYHGTLLDNDGKKIHCAVKSLNRIT
DIGEVSQFLTEGIIMKDFSHPNVLSLLGICLRSEGSPLVVLPYMKHGDLR
NFIRNETHNPTVKDLIGFGLQVAKGMKYLASKKFVHRDLAARNCMLDEKF
TVKVADFGLARDMYDKEYYSVHNKTGAKLPVKWMALESLQTQKFTTKSDV
WSFGVLLWELMTRGAPPYPDVNTFDITVYLLQGRRLLQPEYCPDPLYEVM
LKCWHPKAEMRPSFSELVSRISAIFSTFIGEHYVHVNATYVNVKCVAPYP
SLLSSEDNADDEVDTRPASFWETS

B-Raf(V600E) Kinase Assay

The activity of B-Raf(V600E) kinase (SEQ ID NO:11) was determined by following the formation of ADP from the reaction through coupling with the pyruvate kinase/lactate dehydrogenase system (e.g., Schindler, et al. Science (2000) 289, 1938-1942). In this assay, the oxidation of NADH (thus the decrease at A_340nm) was continuously monitored spectrophotometrically. The reaction mixture (100 μl) contained B-Raf(V600E) kinase (0.34 nM nominal concentration, SEQ ID NO:11), unphosphorylated, full-length MEK1 (42 nM, SEQ ID NO:12), MgCl₂ (13 mM), pyruvate kinase (3.5 units), lactate dehydrogenase (5.5 units), phosphoenolpyruvate (1 mM), and NADH (0.28 mM), in 60 mM Tris buffer, containing 0.13% octyl-glucoside and 3.5% DMSO concentration at pH 7.5. The test compounds were incubated with the reaction mixture at 30° C. for 1 h. The reaction was initiated by adding ATP (0.2 mM, final concentration). The absorption at 340 nm was continuously monitored for 3 h at 30° C. on a Polarstar Optima plate reader (BMG). The reaction rate was calculated using the 0.5 h to 1.5 h time frame. Percent inhibition was obtained by comparison of reaction rate with that of a control (i.e. with no test compound). IC₅₀ values were calculated from a series of percent inhibition values determined at a range of inhibitor concentrations using software routines as implemented in the GraphPad Prism software package.

BRaf V600E kinase
(SEQ ID NO:11)
MDRGSHHHHHHGSEDRNRMKTLGRRDSSDDWEIPDGQITVGQRIGSGSFG
TVYKGKWHGDVAVKMLNVTAPTPQQLQAFKNEVGVLRKTRHVNILLFMGY
STKPQLAIVTQWCEGSSLYHHLHIIETKFEMIKLIDIARQTAQGMDYLHA
KSIIHRDLKSNNIFLHEDLTVKIGDFGLATEKSRWSGSHQFEQLSGSILW
MAPEVIRMQDKNPYSFQSDVYAFGIVLYELMTGQLPYSNINNRDQIIFMV
GRGYLSPDLSKVRSNCPKAMKRLMAECLKKKRDERPLFPQILASIELLAR
SLPKIHR
MEK1 kinase
(SEQ ID NO:12)
MELKDDDFEKISELGAGNGGVVFKVSHKPSGLVMARKLIHLEIKPAIRNQ
IIRELQVLHECNSPYIVGFYGAFYSDGEISICMEHMDGGSLDQVLKKAGR
IPEQILGKVSIAVIKGLTYLREKHKIMHRDVKPSNILVNSRGEIKLCDFG
VSGQLIDSMANSFVGTRSYMSPERLQGTHYSVQSDIWSMGLSLVEMAVGR
YPIPPPDAKELELMFGCQVEGDAAETPPRPRTPGRPLSSYGMDSRPPMAI
FELLDYIVNEPPPKLPSGVFSLEFQDFVNKCLIKNPAERADLKQLMVHAF
IKRSDAEEVDFAGWLCSTIGLNQPSTPTHAAGV

TABLE 1
Biological Data Summary.
Biochemical IC50 values of compounds of Formula I.
	Abl	Abl T315l	c-Kit	c-Met
Exam-	Enzyme	Enzyme	Enzyme	Enzyme	B-Raf V600E
ple	Assay	Assay	Assay	Assay	Enzyme Assay
1	+++	+++	n/a	+++	n/a
2	+++	+++	+++	+++	+++
3	+++	+++	n/a	+++	+++
4	+++	+++	n/a	+++	+++
5	+++	+++	+++	++	+++
6	+++	+++	n/a	+++	+++
7	+++	+++	n/a	+++	+++
8	+++	+++	n/a	+++	+++
9	+++	+++	+++	++	++
10	+++	‡	n/a	+	++
11	+++	+++	n/a	+++	+++
12	+++	+++	+++	+++	+++
13	+++	+++	+++	+++	+++
14	+++	‡	n/a	+	‡
15	+++	n/a	n/a	++	++
16	+++	+++	n/a	+++	+++
17	+++	+++	+++	++	+
18	+++	n/a	n/a	++	++
19	+++	+++	+++	++	++
20	+++	n/a	n/a	n/a	+
21	+++	+++	+++	++	++
22	++	n/a	n/a	n/a	+
23	+++	n/a	n/a	n/a	+
24	+++	+++	n/a	+++	+++
25	+++	+++	n/a	++	++
26	n/a	n/a	n/a	n/a	n/a
27	n/a	n/a	n/a	n/a	n/a
+++ = <0.1 μM; ++ = <1.0 μM; + = <10 μM; ‡ < 100 μM; n/a = not available

The biochemical IC₅₀ values of other compounds disclosed herein are at least 10 μM against Abl enzyme.

Cell Culture

BaF3 cells (parental or transfected with the following: wild type p210 BCR-Abl and T315I p210 BCR-Abl was obtained from Professor Richard Van Etten (New England Medical Center, Boston, Mass.). Briefly, cells were grown in RPMI 1640 supplemented with 10% characterized fetal bovine serum (HyClone, Logan, Utah) at 37 degrees Celsius, 5% CO₂, 95% humidity. Cells were allowed to expand until reaching 80% saturation at which point they were subcultured or harvested for assay use.

Cell Proliferation Assay

A serial dilution of test compound was dispensed into a 96 well black clear bottom plate (Corning, Corning, N.Y.). For each cell line, three thousand cells were added per well in complete growth medium. Plates were incubated for 72 hours at 37 degrees Celsius, 5% CO₂, 95% humidity. At the end of the incubation period Cell Titer Blue (Promega, Madison, Wis.) was added to each well and an additional 4.5 hour incubation at 37 degrees Celsius, 5% CO₂, 95% humidity was performed. Plates were then read on a BMG Fluostar Optima (BMG, Durham, N.C.) using an excitation of 544 nM and an emission of 612 nM. Data was analyzed using Prism software (Graphpad, San Diego, Calif.) to calculate IC50's.

TABLE 2
Biological Data Summary. Whole Cell Antiproliferation
IC50 values of compounds of Formula I.
		Ba/F3 p210 T315I
	Ba/F3 p210 whole cell	whole cell proliferation
Example	proliferation assay	assay
1	+++	+++
2	+++	+++
3	+++	+++
4	+++	+++
5	+++	+++
6	+++	+++
7	+++	+++
8	+++	+++
9	+++	+++
10	+++	+++
11	+++	+++
12	+++	+++
13	+++	+++
14	+++	+++
15	+++	+++
16	+++	+++
17	+++	+++
18	+++	+++
19	+++	+++
20	+++	++
21	+++	+++
22	n/a	n/a
23	n/a	n/a
24	+++	+++
25	++	+
26	n/a	n/a
27	n/a	n/a
+++ = <0.1 μM;
++ = <1.0 μM;
+ = <10 μM;
‡ <100 μM;
n/a = not available

Claims

1. Compounds of the formula Ia stereo-, regioisomers and tautomers of such compounds; and with the proviso if A1 is G3, imidazolyl or pyrazolyl then X1 is not a direct bond.

wherein Q1 and Q2 are each individually and independently selected from the group consisting of N and CH and wherein at least one of Q1 and Q2 is N;

and wherein the ring containing Q1 and Q2 may be optionally substituted with one or more R20 moieties;

each D is individually taken from the group consisting of C, CH, C—R20, N-Z3, N, O and S, such that the resultant ring is taken from the group consisting of pyrazolyl, triazolyl, isoxazolyl, isothiazolyl, oxazolyl, and thiadiazolyl;

wherein E is selected from the group consisting of phenyl, pyridyl, and pyrimidinyl;

when Q1 and Q2 are both N, the A ring is selected from the group consisting of cyclopentyl, cyclohexyl, G1, G2, and G3;

when only one of Q1 and Q2 is N, the A ring is selected from the group consisting of cyclopentyl, cyclohexyl, G1, G2, G3 and G4;

G1 is a heteroaryl taken from the group consisting of pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl-4-yl, isoxazolyl-5-yl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, and tetrazolyl;

G2 is a fused bicyclic heteroaryl taken from the group consisting of indolyl, indolinyl, isoindolyl, isoindolinyl, indazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzothiazolonyl, benzoxazolyl, benzoxazolonyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzimidazolonyl, benztriazolyl, imidazopyridinyl, pyrazolopyridinyl, imidazolonopyridinyl, thiazolopyridinyl, thiazolonopyridinyl, oxazolopyridinyl, oxazolonopyridinyl, isoxazolopyridinyl, isothiazolopyridinyl, triazolopyridinyl, imidazopyrimidinyl, pyrazolopyrimidinyl, imidazolonopyrimidinyl, thiazolopyridiminyl, thiazolonopyrimidinyl, oxazolopyridiminyl, oxazolonopyrimidinyl, isoxazolopyrimidinyl, isothiazolopyrimidinyl, triazolopyrimidinyl, dihydropurinonyl, pyrrolopyrimidinyl, purinyl, pyrazolopyrimidinyl, phthalimidyl, phthalimidinyl, pyrazinylpyridinyl, pyridinopyrimidinyl, pyrimidinopyrimidinyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, plithalazinyl, benzodioxyl, benizisothiazoline-1,1,3-trionyl, dihydroquinolinyl, tetrahydroquinolinyl, dihydroisoquinolyl, tetrahydroisoquinolinyl, benzoazepinyl, benzodiazepinyl, benzoxapinyl, and benzoxazepinyl;

G3 is a heterocyclyl taken from the group consisting of oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, imidazolonyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholiniyl, tiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl;

G4 is selected from the group consisting of phenyl, naphthyl, pyrazinyl, pyridazinyl, triazinyl, pyridinyl, and pyrimidinyl;

the A ring is substituted with one —(X1-A1) moiety or one A1 moiety, and may be optionally substituted with one or two R2 moieties;

when A is phenyl and E is phenyl, then Z1 cannot be —O(CH2)qR5, —(CH2)p-G33, or —(CH2)pR5;

A1 is selected from the group consisting of phenyl, G1, G3 and G4;

X1 is selected from the group consisting of a direct bond linking the A and A1 rings, —(CH2)n)(O)r(CH2)n—, —(CH2)nNR3)r(CH2)n—, —(CH2)n(S)r(CH2)n—, —(CH2)n(C(O))r(CH2)n—, —(CH2)n(C(O)NR3)r(CH2)n—, and —(CH2)n(SO2NR3)r(CH2)n—, wherein any of the alkylenes may be straight or branched chain;

when X1 is a direct bond, E is substituted with one or two R16 moieties;

when X1 is not a direct bond, then E is optionally substituted with one or two R16 moieties;

X2 is selected from the group consisting of —O—, —S(CH2)n—, —N(R3)(CH2)n—, —(CH2)p—, and wherein the carbon atoms of —(CH2)n—, —(CH2)p—, of X2 may be further substituted by oxo or one or more C1-C6alkyl moieties;

when A, A1, G1, G2 G3 or G4 has one or more substitutable sp2-hybridized carbon atoms, each respective sp2 hybridized carbon atom may be optionally substituted with a Z1 substituent;

when A, A1, G1, G2 or G3 has one or more substitutable sp3-hybridized carbon atoms, each respective sp3 hybridized carbon atom may be optionally substituted with a Z2 substituent;

when A, A1, G1, G2 or G3 has one or more substitutable nitrogen atoms, each respective nitrogen atom may be optionally substituted with a Z4 substituent;

each Z1 is independently and individually selected from the group consisting of C1-6alkyl, branched C3-C7alkyl, C3-C8cycloalkyl, halogen, fluoroC1-C6alkyl wherein the alkyl moiety can be partially or fully fluorinated, cyano, C1-C6alkoxy, fluoroC1-C6alkoxy wherein the alkyl moiety can be partially or fully fluorinated, —(CH2)nOH, oxo, C1-C6alkoxyC1-C6alkyl, (R4)2N(CH)n—, (R3)2N(CH)n—, (R4)2N(CH2)qN(R4)(CH2)n—, (R4)2N(CH2)q—O—(CH2)n—, (R3)2NC(O)—, (R4)2NC(O)—, (R4)2NC(O)C1-C6alkyl-, —(R4)NC(O)R8, C1-C6alkoxycarbonyl-, -carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl-, (R3)2NSO2—, —SOR3, (R4)2NSO2—, —N(R4)SO2R5, —N(R4)SO2R8, —O(CH2)qOC1-C6alkyl, —O(CH2)qR5, —SO2R3, —SOR4, —S(O)2R5, —(CH2)nC(O)R5, —C(O)R8, —C(O)R6, —C(═NOH)R6, —C(═NOR3)R6, —(CH2)nN(R4)C(O)R8, —(CH2)n-G1, —(CH2)n-G4, phenoxy, —(CH2)nO(CH2)n-G1, —(CH2)pO(CH2)n-G4, —N(R3)(CH2)qO-alkyl, —N(R3)(CH2)qN(R4)2, —N(R3)(CH2)qR5, —(CH2)nN(R3)(CH2)n-aryl, —(CH2)nN(R3)(CH2)n—G1, —(CH2)nN(R3)(CH2)n-G4, nitro, —(CH2)nNHC(O)(CH2)nR5, —(CH2)nNHS(O)2(CH2)nR5, —(CH2)nC(O)NH(CH2)qR5, —(CH2)nOC(O)R5, —CH(OH)(CH2)pR5, —CH(OH)CH(OH)R4, —(CH2)nR5, —C(═NH)R5, —C(═NH)N(R4)2, —C(═NOR3)R5, —C(═NOR3)N(R4)2, and —NHC(═NH)R8;

in the event mat Z1 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;

each Z2 is independently and individually selected from the group consisting of aryl, C1-C6alkyl, C3-C8cycloalkyl, branched C3-C7alkyl, hydroxyl, hydroxyC1-C6alkyl-, cyano, (R3)2N—, (R4)2N—, (R4)2NC1-C6alkyl-, (R4)2NC2-C6alkylN(R4)(CH2)n—, (R4)2NC2-C6alkylO(CH2)n—, (R3)2NC(O)—, (R4)2NC(O)—, (R4)2NC(O)—C1-C6alkyl-, carboxyl, -carboxyC1-C6alkyl, C1-C6alkoxycarbonyl-, C1-C6alkoxycarbonylC1-C6alkyl-, (R3)2NSO2—, (R4)2NSO2—, —SO2R5, —SO2R8, —(CH2)nN(R4)C(O)R8, —C(O)R8, ═O, ═NOH, ═N(OR6), —(CH2)n-G1, —(CH2)n-G4, —(CH2)nO(CH2)n-G1, —(CH2)nO(CH2)n-G4, —(CH2)nN(R3)(CH2)n-aryl, —(CH2)nN(R3)(CH2)n-G1, —(CH2)nN(R3)(CH2)n-G4, —(CH2)nNHC(O)(CH2)nR5, —(CH2)nNHS(O)2(CH2)nR5, —(CH2)nC(O)NH(CH2)qR5, —(CH2)nC(O)R5, —(CH2)nOC(O)R5, and —(CH2)nR5;

in the event that Z2 contains an alkyl or alkylene moiety, such moieties may be ether substituted with one or more C1-C6alkyls;

each Z3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, C3-C8cycloalkyl, fluoroC1-C6alkyl wherein the alkyl moiety can be partially or fully fluorinated, hydroxyC2-C6alkyl-, C1-C6alkoxycarbonyl-, —C(O)R8, R5C(O)(CH2)n—, (R4)2NC(O)—, (R4)2NC(O)C1-C6alkyl-, R8C(O)N(R4)(CH2)q—, (R3)2NSO2—, (R4)2NSO2—, —(CH2)qN(R3)2, and —(CH2)qN(R4)2;

each Z4 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-7alkyl, hydroxyC2-C6alkyl-, C1-C6alkoxyC2-C6alkyl-, (R4)2N—C2-C6alkyl-, (R4)2N—C2-C6alkylN(R4)-C2-C6alkyl-, (R4)2N—C2-C6alkyl-O—C2-C6alkyl-(R4)2NC(O)C1-C6alkyl-, carboxyC1-C6alkyl, C1-C6alkoxycarbonylC1-C6alkyl-, —C2-C6alkylN(R4)C(O)R8, R8-C(═NR3)—, —SO2R8, —COR8, —(CH2)n-G1, —(CH2)n-G4, —(CH2)qO(CH2)n-G1, —(CH2)qO(CH2)n-G4, —(CH2)qNR1(CH2)n-G1, —(CH2)qNR3(CH2)n-G4, —(CH2)qNHC(O)(CH2)nR5, —(CH2)qC(O)NH(CH2)qR5, —(CH2)qC(O)R5, —(CH2)qOC(O)R5. (CH2)qR5, —(CH2)qNR4(CH2)qR5, and —(CH2)qO(CH2)qR5;

in the event that Z4 contains an alkyl or alkylene moiety, such moieties may be further substituted with one or more C1-C6alkyls;

each R2 is selected from the group consisting of H, R17-substituted aryl-, R17-substituted G1, R17-substituted G4, C1-C6alkyl, branched C3-C8alkyl, R19 substituted C3-C8cycloalkyl-, fluoroC1-C6alkyl- wherein the alkyl is fully or partially fluorinated, halogen, cyano, C1-C6alkoxy-, and fluoroC1-C6alkoxy- wherein the alkyl group is fully or partially fluorinated, hydroxyl substituted C1-C6alkyl-, hydroxyl substituted branched C3-C8alkyl-, cyano substituted C1-C6alkyl-, cyano substituted branched C3-C8alkyl-, (R3)2NC(O)C1-C6alkyl-, (R3)2NC(O)C3-C8 branched alkyl-;

wherein each R3 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, and C3-C8cycloalkyl;

each R4 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC1-C6alkyl-, dihydroxyC1-C6alkyl-, C1-C6alkoxyC1-C6alkyl-, branched C3-C7alkyl, branched hydroxyC1-C6alkyl-, branched C1-C6alkoxyC1-C6alkyl-, branched dihydroxyC1-C6alkyl-, —(CH2)pN(R7)2, —(CH2)pR5, —(CH2)pC(O)N(R7)2, —(CH2)nC(O)R5, —(CH2)2C(O)OR3, R19 substituted C3-C8cycloalkyl-;

each R5 is independently and individually selected from the group consisting of

and wherein the symbol (##) is the point of attachment to respective R4, R7, R8, Z2, Z3 or Z4 moieties containing a R5 moiety;

each R6 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8cycloalkyl-, phenyl, G1, and G3;

each R7 is independently and individually selected from the group consisting of H, C1-C6alkyl, hydroxyC2-C6alkyl-, dihydroxyC2-C6alkyl-, C1-C6alkoxyC2-C6alkyl-, branched C3-C7alkyl, branched hydroxyC2-C6alkyl-, branched C1-C6alkoxyC2-C6alkyl-, branched dihydroxyC2-C6alkyl-, —(CH2)qR5, —(CH2)nC(O)R5, —(CH2)nC(O)OR3, R19 substituted C3-C8cycloalkyl- and —(CH2)nR17;

each R8 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, fluoroC1-C6alkyl- wherein the alkyl moiety is partially or fully fluorinated, R19 substituted C3-C8cycloalkyl-, phenyl, phenylC1-C6alkyl-, G1, G1-C1-C6alkyl-, G4-(CH2)n—, OH, C1-C6alkoxy, —N(R3)2, —N(R4)2, and R5;

each R10 is independently and individually selected from the group consisting of —CO2H, —CO2C1-C6alkyl, —C(O)N(R4)2, OH, C1-C6alkoxy, and —N(R4)2;

each R16 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8cycloalkyl-, halogen, fluoroC1-C6alkyl- wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, C1-C6alkoxy, fluoroC1-C6alkoxy- wherein the alkyl moiety can be partially or fully fluorinated, —N(R3)2, —N(R4)2, R3 substituted C2-C3alkynyl- and nitro;

each R17 is independently and individually selected from the group consisting of H, C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8cycloalkyl-, halogen, fluoroC1-C6alkyl- wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, C1-C6alkoxy, fluoroC1-C6alkoxy- wherein the alkyl moiety can be partially or fully fluorinated, —N(R3)2, —N(R4)2, and nitro;

each R19 is independently and individually selected from the group consisting of H, OH and C1-C6alkyl;

each R20 is independently and individually selected from the group consisting of C1-C6alkyl, branched C3-C7alkyl, R19 substituted C3-C8cycloalkyl-, halogen, fluoroC1-C6allyl- wherein the alkyl moiety can be partially or fully fluorinated, cyano, hydroxyl, C1-C6alkoxy, fluoroC1-C6alkoxy- wherein the alkyl moiety can be partially or fully fluorinated, —N(R3)2, —N(R4)2, —N(R3)C(O)R3, —C(O)N(R3)2 and nitro;

wherein two R4 moieties independently and individually taken from the group consisting of C1-C6alkyl, branched C3-C6alkyl, hydroxyalkyl-, and alkoxyalkyl and attached to the same nitrogen heteroatom may cyclize to form a C3-C7 heterocyclyl ring;

k is 0 or 1; n is 0-6; p is 1-4; q is 2-6; r is 0 or 1; t is 1-3; v is 1 or 2; x is 0-2;

2. Compounds of claim 1 wherein is selected from the group consisting of wherein the symbol (**) indicates the point of attachment to the aromatic ring.

3. Compounds of claim 2 having formula Ib wherein A is any possible isomer of pyrazole.

4. Compounds of claim 3 having formula Ic

5. Compounds of claim 3 having formula Id

6. Compounds of claim 3 having formula Ie

7. Compounds of claim 2 having the formula If wherein A is selected from the group consisting of any possible isomer of phenyl, pyridine and pyrimidine.

8. Compounds of claim 7 having formula Ig

9. Compounds of claim 7 having formula Ih

10. Compounds of claim 7 having formula Ii

11. A method of treating mammalian disease wherein the disease etiology or progression is at least partially mediated by the kinase activity of c-Abl kinase, bcr-Abl kinase, Flt-3 kinase, VEGFR-2 kinase mutants, c-Met, HER-1. HER-2, HER-3, HER-4, FGFR, c-Kit, Raf kinase, PDGFRα kinase and PDGFR, kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs of any of the foregoing, comprising the step of administering to the mammal a compound of claim 1.

12. A method of claim 11 wherein said kinase is selected from the group consisting of bcr-Abl fusion protein kinases p210, bcr-Abl fusion protein kinases p190, bcr-Abl fusion protein kinases bearing the T315I gatekeeper mutant in the Abl kinase domain of p210, bcr-Abl fusion protein kinases bearing the T315I gatekeeper mutant in the Abl kinase domain of p190, and other bcr-Abl polymorphs of any of the foregoing kinases.

13. The method of claim 12, wherein said bcr-Abl fusion protein kinases p210 having SEQ ID NO:3 & SEQ ID NO:4, wherein said bcr-Abl fusion protein kinase p190 has SEQ ID NO:5, wherein said bcr-Abl fusion protein kinases p210 bearing the TB315I mutation in the Abl kinase domain has SEQ ID NO:6 & SEQ ID NO:7, and wherein said bcr-Abl fusion protein kinase p190 bearing the T315I mutation in the Abl kinase domain has SEQ ID NO:8.

14. A method of claim 11 wherein said kinase is selected from the group consisting of cKit protein kinase, PDGFR-alpha kinase, and any fusion protein, mutation and polymorphs of any of the foregoing.

15. A method of claim 11 wherein said kinase is selected from the group consisting of B-Raf V600E protein kinase, and any fusion protein, mutation and polymorphs of any of the foregoing.

16. A method of claim 11 wherein said kinase is selected from the group consisting of c-Met protein kinase, and any fusion protein, mutation and polymorphs of any of the foregoing.

17. A pharmaceutical composition comprising a compound of claim 1, together with a pharmaceutically acceptable carrier, optionally containing an additive selected from the croup including adjuvants, excipients, diluents, and stabilizers.

18. A method of treating an individual suffering from a condition selected from the group consisting of cancer, hyperproliferative diseases, metabolic diseases, neurodegenerative diseases, or diseases characterized by angiogenesis, such as solid tumors, melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breast cancers, renal cancers, hepatic cancers, cervical carcinomas, metastasis of primary tumor sites, myeloproliferative diseases, chronic myelogenous leukemia, leukemias, papillary thyroid carcinoma, non-small cell lung cancer, mesothelioma, hypereosinophilic syndrome, gastrointestinal stromal tumors, colonic cancers, ocular diseases characterized by hyperproliferation leading to blindness including retinopathies, diabetic retinopathy, age-related macular degeneration and hypereosinophilic syndrome, rheumatoid arthritis, asthma, chronic obstructive pulmonary, mastocytosis, mast cell leukemia, or disease a disease caused by c-Kit kinase, oncogenic forms thereof, aberrant fusion proteins thereof and polymorphs thereof, comprising the step of administering to such individual a compound of claim 1.

19. The method of claim 18, said compound being administered by a method selected from the group consisting of oral, parenteral, inhalation, and subcutaneous.