HETEROARYL COMPOUNDS AND THEIR USE AS THERAPEUTIC DRUGS
The present invention provides heterocyclic compounds, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt, which are capable of modulating the activity of Mer receptor tyrosine kinase (MERTK). This invention also provides pharmaceutical compositions thereof, methods to prepare the said compounds, and the use of such compounds as a medicament. The present invention is directed to MERTK inhibitory compounds with marked potency, thereby having an outstanding potential for a pharmaceutical intervention of cancer and any other diseases related to MERTK dysregulation.
This application claims the benefit of priority under U.S.C. §119(e) to U.S. Provisional Patent Application Ser. No. 62/212,520 filed Aug. 31, 2015, which is incorporated herein by reference.
TECHNICAL FIELDThe present invention relates to novel heterocyclic compounds having Mer kinase inhibitory activity, a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof, the use for preparing pharmaceutical compositions, pharmaceutical compositions comprising the same, methods of treating diseases using these compositions.
BACKGROUND ARTTransmembrane receptor tyrosine kinases (RTKs) comprise an evolutionarily conserved family of structurally related proteins. The gene Mer is a member of the Tyro3/Axl/Mer (TAM) receptor kinase family and a proto-oncogene. Its abnormal expression and activation is found in conjunction with human cancers such as pituitary adenomas, mantle cell lymphomas, and T-cell acute lymphoblastic leukemia.
The ATP-binding site is similar for all protein kinases. For this reason, it is challenging to find an inhibitor that is specific for the Mer. Compound-52, a 2,6,9-trisubstituted purine that occupies the ATP-binding site, was actually the first molecule that was found to be successful in inhibiting Mer (J Struct Biol. 2009 February; 165(2): 88-96). This inhibitor has, however, limited potency and lack of selectivity. Lately, several compounds have been unveiled mostly by modifying Compound-52 including UNC-569, UNC-1062, and UNC-2025 (ACS Med Chem Lett. 2012 Feb. 9; 3(2):129-134, Eur J Med Chem. 2013 July; 65:83-93, J Med Chem. 2014 Aug. 28; 57(16):7031-41).
It is an object of the invention to provide reagents and methods of regulating a receptor tyrosine kinase Mer. This and other objects of the invention are provided by one or more of the embodiments described below.
DISCLOSURE Technical ProblemSeveral Mer kinase inhibitors have been previously described, but they have different moieties onto the scaffold from the present invention. Highly potent and selective Mer kinase inhibitors based on aminopyridine or aminopyrimidine scaffolds are described.
The present invention relates to compounds capable of inhibiting the activity of Mer, which compounds are useful for the prevention and/or the treatment of cancer and other immune-related diseases such as infection and sepsis.
Technical Solution Novel Mer Kinase InhibitorsThe present invention relates to a heterocyclic compound represented by the following Formula I, a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof:
wherein:
X is CR7, or N;
Y is CHR8, NR8, or O;
Z is CH2, CH2O, C(═O), C(═O)O, C(═O)NH, NR8, NHC(═O), O or O(C═O);
R1 is H, halogen, C1-3 alkyl, NHR8 or OR8;
R2 is H, halogen, C1-4 alkyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl or -L-aryl, which C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl or -L-aryl may optionally be substituted with one or more R9;
R3 is H, halogen, CN, C1-3 alkyl, cycloalkenyl, C2-6 alkenyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl which aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl may optionally be substituted with one or more R9;
R4 and R5 each independently is H, C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C(═O) R6, C1-2 alkylaryl, aryl; or
R4 and R5 may be combined with each other to form a 3-7 membered cyclic ring or heterocyclic ring containing 1 or 2 of NR8, O or S, and the cyclic or heterocyclic ring may optionally be substituted with 1 or 2 halogen(s), C1-4 alkyl or C1-4 alkoxy;
R5′ is H or R5 and R5′ may be combined with each other to form carbonyl;
R6 is H, C1-4 alkyl, C1-6 alkoxy, —NR15R16, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl, C1-2 alkylbiaryl, -L-aryl or -L-biaryl, which C1-4 alkyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl, C1-2 alkylbiaryl, -L-aryl or -L-biaryl, may optionally be substituted with one or more R9;
R7 is H, halogen or C1-3 alkyl;
R8 is H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkylaryl or C(═O)R10 which C1-6 alkyl or C1-3 alkylaryl may optionally be substituted with one or more R9;
when Z is NR8, R8 and R6 may be combined with each other to form a 3-7 membered heterocyclic ring comprising 1 to 2 N or 0 to 2 O heteroatoms;
R9 is halogen, hydroxyl, —CN, —NO2, —COOH, —(C═O)H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —NR15R16, -L-NR15R16, -L-COOR17, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl which C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl may substituted with halogen, hydroxyl, —CN, —NR15R16, C1-6 alkyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, aryl, heterocyclyl, -L-heterocyclyl, or —(CH2)l—C(═O)—NR15R16;
R10 is C1-3 alkyl or C1-3 alkylaryl;
R15 and R16 each independently is H, C1-6 alkyl, C3-10 cycloalkyl or SO2R17;
R17 is H, C1-3alkyl or C1-3 alkylaryl;
L is C1-3 alkyl, C1-3 alkylO, C2-6 alkynyl, C3-10 cycloalkyl, —(CH2)l—C(═O)—(CH2)m—, C(═O)O, —(CH2)l—C(═O)NH—(CH2)m—, —(CH2)l—NHC(═O)—(CH2)m—, —(CH2)l—NH—(CH2)m, —NH—C(═O)—CR15R16—NH—C(═O)—, NHC(═O), O, O(C═O)S, S(═O), or SO2; and
l and m each independently is an integer of 0 to 2.
In accordance with a second embodiment of the present invention, there are provided the heterocyclic compound represented formula I is represented by the following Formula Ia:
wherein:
X is CH, or N;
Y is NR8, or O;
W is CH2, (CH2)2, NR11, or O;
Z is CH2, CH2O, C(═O), C(═O)O, C(═O)NH, NR8, NHC(═O), O or O(C═O);
R3 is H, halogen, CN, C1-3 alkyl, cycloalkenyl, C2-6 alkenyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl which aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl may optionally be substituted with one or more R9,
R6 is H, C1-4 alkyl, C1-6 alkoxy, —NR15R16, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl, C1-2 alkylbiaryl, -L-aryl or -L-biaryl, which C1-4 alkyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl, C1-2 alkylbiaryl, -L-aryl or -L-biaryl, may optionally be substituted with one or more R9;
R8 is H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkylaryl or C(═O)R10 which C1-6 alkyl or C1-3 alkylaryl may optionally be substituted with one or more R9;
when Z is Me, R8 and R6 may be combined with each other to form a 3-7 membered heterocyclic ring comprising 1 to 2 N or 0 to 2 O heteroatoms;
R9 is halogen, hydroxyl, —CN, —NO2, —COOH, —(C═O)H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —NR15R16, -L-NR15R16, -L-COOR17, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl which C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl may substituted with halogen, hydroxyl, —CN, —NR15R16, C1-6 alkyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, aryl, heterocyclyl, -L-heterocyclyl, or —(CH2)l—C(═O)—NR15R16;
R10 is C1-3 alkyl or C1-3 alkylaryl;
R11 is H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkylaryl or C(═O)R10 which C1-6 alkyl or C1-3 alkylaryl may optionally be substituted with one or more R9;
R15 and R16 each independently is H, C1-6 alkyl, C3-10 cycloalkyl or SO2R17;
R17 is H, C1-3 alkyl or C1-3 alkylaryl;
R18 to R21 are the same as or different from each other, and are each independently H or halogen; or
R18 and R19; or R20 and R21 may be combined with each other to form a 3-7 membered cyclic ring or heterocyclic ring containing 1 or 2 of Me, O or S, and the cyclic or heterocyclic ring may optionally be substituted with 1 or 2 halogen(s), C1-4 alkyl or C1-4 alkoxy;
L is C1-3 alkyl, C1-3 alkylO, C2-6 alkynyl, C3-10 cycloalkyl, —(CH2)l—C(═O)—(CH2)m—, C(═O)O, —(CH2)l—C(═O)NH—(CH2)m—, —(CH2)l—NHC(═O)—(CH2)m—, —(CH2)l—NH—(CH2)m—, NR8, —NH—C(═O)—CR15R16—NH—C(═O)—NHC(═O)—, O, O(C═O)S, S, S(═O), or SO2; and
l and m each independently is an integer of 0 to 2.
In accordance with a third embodiment of the present invention, there are provided the heterocyclic compound represented formula I is represented by the following Formula Ib:
wherein:
X is CH, or N;
W is CH2, NR11, or O;
V1 and V2 each independently is CR13R13′, NR13 or O;
-
- at least one of V1 and V2 is CR13R13′;
X1 to X5 are the same as or different from each other, and are each independently CR14 or N;
at least one of X1 to X5 is CR14;
R3 is H, halogen, CN, C1-3 alkyl, cycloalkenyl, C2-6 alkenyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl which aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl may optionally be substituted with one or more R9;
R9 is halogen, hydroxyl, —CN, —NO2, —COOH, —(C═O)H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —NR15R16, -L-NR15R16, -L-COOR′7, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl which C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl may substituted with halogen, hydroxyl, —CN, —NR15R16, C1-6 alkyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, aryl, heterocyclyl, -L-heterocyclyl, or —(CH2)l—C(═O)—NR15R16;
R10 is C1-3 alkyl or C1-3 alkylaryl;
R11 is H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkylaryl or C(═O)R10 which C1-6 alkyl or C1-3 alkylaryl may optionally be substituted with one or more R9;
R13 and R13′ each independently is H, C1-3 alkyl, C2-3 hydroxyalkyl;
each R14 is independently selected from H, halogen, hydroxyl, —CN, —NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —NR15R16, -L-alkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl which C1-6 alkyl, aryl, heteroaryl, heterocyclyl may optionally be substituted with one or more R9; or adjacent groups among a plurality of R14s are bonded to each other to form a 3-7 membered cyclic ring or heterocyclic ring containing 1 or 2 of NR11 O or S, and the cyclic or heterocyclic ring may optionally be substituted with 1 or 2 halogen(s), C1-4 alkyl or C1-4 alkoxy;
R15 and R16 each independently is H, C1-6 alkyl, C3-10 cycloalkyl or SO2R17;
R17 is H, C1-3 alkyl or C1-3 alkylaryl;
L is C1-3 alkyl, C1-3 alkylO, C2-6 alkynyl, C3-10 cycloalkyl, —(CH2)l—C(═O)—(CH2)m—, C(═O)O, —(CH2)l—C(═O)NH—(CH2)m—, —(CH2)l—NHC(═O)—(CH2)m—, —(CH2)l—NH—(CH2)m, NR8, —NH—C(═O)—CR15R16—NH—C(═O)—, NHC(═O), O, O(C═O)S, S, S(═O), or SO2; and
l and m each independently is an integer of 0 to 2.
In the present disclosure, a halogen may be fluorine, chlorine, bromine or iodine.
In the present disclosure, the alkyl may be straight or branched, and the number of carbon atoms thereof is not particularly limited, but is preferably 1 to 6. Specific examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, a hexyl group, and the like, or a branched chain thereof, but are not limited thereto.
In the present disclosure, the cycloalkyl is not particularly limited, but has preferably 3 to 10 carbon atoms. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, a norbornyl group, an adamantly group, and the like, but are not limited thereto.
In the present disclosure, the alkoxy may be straight, branched, or cyclic. The number of carbon atoms of the alkoxy group is not particularly limited, but is preferably 1 to 6. Specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and the like, but are not limited thereto.
In the present disclosure, the alkenyl may be straight or branched, and the number of carbon atoms thereof is not particularly limited, but is preferably 2 to 6. Specific examples thereof include vinyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 3-methyl-1-butenyl, 1,3-butadienyl, and the like, but are not limited thereto.
In the present disclosure, the aryl may be monocyclic, or polycyclic and the number of carbon atoms is not particularly limited, but is preferably 6 to 60. Specific examples of the aryl group include a monocyclic aromatic group, such as a phenyl group and a polycyclic aromatic group, such as a naphthyl group, an anthracenyl group, a phenanthrenyl group, a pyrenyl group, a perylenyl group, a tetracenyl group, a chrysenyl group, a fluorenyl group, an acenaphthacenyl group, a triphenylene group, and a fluoranthene group, and the like, but are not limited thereto.
In the present disclosure, the biaryl may two or more monocyclics and/or polycyclics linked each other.
In the present disclosure, the aryl in the alkylaryl and biaryl is the same as the above-described examples of the aryl group.
In the present disclosure, a heterocyclic or a heteroaryl including one or more hetero atom, for example, a heterocyclic group including one or more of O, N, S, Si, Se and the like. Examples of the heterocyclic group include a thiophene group, a furan group, a pyrrole group, an imidazole group, a thiazole group, an oxazole group, an oxadiazole group, a triazole group, a pyridyl group, a bipyridyl group, a triazine group, an acridyl group, a pyridazine group, a pyrrolidine group, a morpholine group, a piperazin group, a piperidine group, a tetrahydrofuran group, a pyrazole group, a quinolinyl group, an isoquinoline group, an indole group, a carbazole group, a benzoxazole group, a benzimidazole group, a benzothiazole group, a benzocarbazole group, a benzothiophene group, a dibenzothiophene group, a benzofuranyl group, a phenanthroline group, a dibenzofuranyl group, and the like, but are not limited thereto.
In the present disclosure, the “adjacent” group may mean a substituent substituted with an atom directly linked to an atom in which the corresponding substituent is substituted, a substituent disposed sterically closest to the corresponding substituent, or another substituent substituted with an atom in which the corresponding substituent is substituted. For example, two substituents substituted at the ortho position in a benzene ring and two substituents substituted with the same carbon in an aliphatic ring may be interpreted as groups “adjacent” to each other.
In the present disclosure, the cyclic ring or heterocyclic ring formed by binding two or more R14s comprises cycloalkyl, cycloalkenyl, aryl, heterocycle, heteroaryl. In accordance with a forth embodiment of the present invention, there are provided the heterocyclic compound represented formula I is represented by any one of the following compounds.
Pharmaceutical Compositions Comprising of Novel Mer Kinase Inhibitors
The present invention provides pharmaceutical compositions comprising the heterocyclic compounds, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof together with pharmaceutically acceptable carriers.
The carriers that are used in the present invention may be those that are conventionally used in the art, and examples thereof include, but are not limited to, sugar, starch, microcrystalline cellulose, lactose (lactose hydrate), glucose, di-mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, anhydrous dibasic calcium phosphate, or mixtures thereof.
Further, according to another embodiment of the present invention, the pharmaceutical compositions may contain additives such as binders, disintegrants, lubricants, pH-adjusting agents, antioxidants, and the like.
Examples of the binders that may be used in the present invention include, but are not limited to, starch, microcrystalline cellulose, highly dispersed silica, mannitol, di-mannitol, sucrose, lactose hydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymer (copovidone), hypromellose, hydroxypropyl cellulose, natural gum, synthetic gum, copovidone, gelatin, or mixtures thereof.
Examples of the disintegrants that may be used in the present invention include, but are not limited to, starches or modified starches such as sodium starch glyconate, maize starch, potato starch or pregelatinized starch; clays such as bentonite, montmorillonite, or veegum; celluloses such as microcrystalline cellulose, hydroxypropylcellulose or carboxymethylcellulose; algins such as sodium alginate or alginic acid; crosslinked celluloses such as croscarmellose sodium; gums such as guar gum or xanthan gum; crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); effervescent formulations such as sodium bicarbonate or citric acid; or mixtures thereof.
Examples of the lubricants that may be used in the present invention include, but are not limited to, talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, colloidal silicon dioxide, or mixtures thereof.
Examples of the pH-adjusting agents that may be used in the present invention include, but are not limited to, acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium etherate, malic acid, succinic acid, tartaric acid, fumaric acid or citric acid, and basifying agents such as precipitated calcium carbonate, ammonia water, meglumine, sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate, or tribasic calcium phosphate.
Examples of the antioxidants that may be used in the present invention include, but are not limited to, dibutyl hydroxytoluene, butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyrosulfite, and the like.
The present invention provides the pharmaceutical compositions comprise, as active ingredients, the heterocyclic compounds, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof and are used for prevention or treatment of a disease which is influenced by inhibition of Mer kinase.
The present invention provides the disease which is influenced by inhibition of Mer kinase is cancer or immune-related diseases.
The cancer is selected from the group consisting of: glioma, gliosarcoma, anaplastic astrocytoma, medulloblastoma, lung cancer, small cell lung carcinoma, cervical carcinoma, colon cancer, rectal cancer, chordoma, throat cancer, Kaposi's sarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, colorectal cancer, endometrium cancer, ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, hepatic carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, testicular tumor, Wilms' tumor, Ewing's tumor, bladder carcinoma, angiosarcoma, endotheliosarcoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland sarcoma, papillary sarcoma, papillary adenosarcoma, cystadenosarcoma, bronchogenic carcinoma, medullary carcinoma, mastocytoma, mesotheliorma, synovioma, melanoma, leiomyosarcoma, rhabdomyosarcoma, neuroblastoma, retinoblastoma, oligodentroglioma, acoustic neuroma, hemangioblastoma, meningioma, pinealoma, ependymoma, craniopharyngioma, epithelial carcinoma, embryonal carcinoma, squamous cell carcinoma, base cell carcinoma, fibrosarcoma, myxoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, leukemia and metastatic lesions secondary to these primary tumors.
The immune-related disease is selected from the group consisting of infection and sepsis.
The term “treatment” is used to refer to both prevention of diseases and treatment of pre-existing conditions.
The therapeutic amount varies according to the specific disease and can be determined by the person skilled in the art without undue effort.
In addition, the subject in the prevention or treatment method of the present invention includes mammals, particularly humans.
The dose varies depending on the specific compound used, the specific disease, the patient status, etc. A therapeutic dose is typically sufficient considerably to reduce the undesired cell population in the target tissue while the viability of the patient is maintained. The treatment is generally continued until a considerable reduction has occurred, for example an at least about 50% reduction in the cell burden, and may be continued until essentially no more undesired cells are detected in the body.
Method for Prevention or Treatment of Immune-Related Diseases or Cancer
The present invention provides a method of treating or preventing immune-related diseases or cancer, the method comprising administering to a mammals including humans in need thereof compositions comprising, as active ingredients, the heterocyclic compounds, isomers thereof or pharmaceutically acceptable salts thereof.
The composition that is used in the inventive method for preventing or treating immune-related diseases or cancer includes the pharmaceutical composition described in the specification
The present invention provides use of compositions comprising, as active ingredients, the heterocyclic compounds, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof for preparation of medicaments for preventing or treating cancer or immune-related diseases.
Methods for Preparing of Novel Mer Kinase Inhibitors
The compounds of this invention can be prepared in accordance with one or more of schemes discussed below.
These methods can be used either directly or with obvious variations to trained chemists to prepare key intermediates and certain compounds of this invention.
Suitable synthetic sequences are readily selected per specific structures of this invention, but within the art known to individuals practicing organic synthesis, such as methods summarized in available chemistry data bases, as in CAS Scifinder and Elesevier Reaxys. Based on these general methods, the enablement for making the compounds of this invention is straightforward and can be practiced within a common professional knowledge. Some general synthetic methods to prepare the compounds of this invention are illustrated below in Schemes 1-2 (non-limiting, for illustration only).
One general approach to the compounds of this invention is illustrated in general
a) NBS, CH3CN, H2O; b) R1—B(OH)2 or its pinacol ester, Pd(PPh3)4, aq. K3PO4, Dioxane, heat; c) NaOH, MeOH, heat; d) HATU, TEA, DMF
Another general approach to the compounds of this invention is illustrated in general
a) NaOH, MeOH, heat; b) HATU, TEA, DMF; c) R1—B(OH)2 or its pinacol ester, Pd(PPh3)4, aq. K3PO4, Dioxane, heat
Advantageous EffectsNovel heterocyclic compounds according to the present invention, a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof exhibit the effect of effectively inhibiting Mer kinase.
Novel heterocyclic compounds according to the present invention, a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt can be used for the prevention or treatment of cancer or immune-related disease.
MODE FOR INVENTIONBased on the studies conducted and the results obtained so far, it is believed that the following compounds (numbered 1 to 458), including isomers, mixtures of isomer as well as pharmaceutically acceptable salts and solvates thereof, are particularly interesting.
General Synthetic Methods ExamplesEmbodiments of the present invention are described in the following examples, which are meant to illustrate and not limit the scope of this invention. Common abbreviations well known to those with ordinary skills in the synthetic art used throughout.
All chemical reagents were commercially available. Flash column chromatography means silica gel chromatography unless specified otherwise, which was performed on Teledyne Combiflash-RF200 System. 1H NMR spectra (δ, ppm) are recorded on 400 MHz or 600 MHz instrument. Mass spectroscopy data for a positive ionization method are provided. Preparative HPLC was performed on Agilent technologies G1361A.
Example 1 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideScheme for the preparation of the Compound of Example 1:
To a mixture of methyl 2-amino-5-bromonicotinate (1.5 g, 6.5 mmol) and 1-Methylpyrazole-4-boronic acid pinacol ester (1.76 g, 8.5 mmol) in 24 ml of 1,4-dioxane was added 8 ml of aq. 2N K3PO4 followed by Pd(PPh3)4 (370 mg, 0.32 mmol). The reaction mixture was heated at 100° C. for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO4 and concentrated under vacuum. The crude product was purified by silicagel column chromatography to give 1.25 g of off-white solid.
1H NMR (400 MHz, CD3OD) δ 3.90 (s, 3H), 3.91 (s, 3H), 7.74 (s, 1H), 7.91 (s, 1H), 8.29 (d, J=2.4 Hz, 1H), 8.35 (d, J=2.4 Hz, 1H);
MS (ESI, m/z): 233.1 [M+H]+
Intermediate 2To a suspension of intermediate 1 (1.2 g, 5.17 mmol) in 26 ml of MeOH was added 2N NaOH (4.3 ml, 8.63 mmol) and the mixture was heated at 65° C. for 1 hr, cooled to room temperature, neutralized (4.3 ml of 2N HCl), and the resulting precipitate was filtered, washed with MeOH, and dried to give 0.97 g of off-white solid.
1H NMR (600 MHz, DMSO-d6) δ ppm 3.82 (s, 3H), 5.73 (s, 2H), 7.77 (s, 1H), 8.05 (s, 1H), 8.13 (d, J=2.4 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H); MS (ESI, m/z): 219.1 [M+H]+
Example 1 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideTo a mixture of intermediate 2 (43 mg, 0.2 mmol) and triethylamine (24 mg, 0.24 mmol) in 2 ml of DMF was added HATU (91 mg, 0.24 mmol) followed by (1S,2S)-2-(benzyloxy)cyclopentan-1-amine (38 mg, 0.2 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 46 mg of the title compound.
1H NMR (600 MHz, CD3OD) δ ppm 1.57-1.69 (m, 1H) 1.72-1.86 (m, 3H) 1.90-2.08 (m, 1H) 2.11-2.21 (m, 1H) 3.93 (s, 3H) 3.96 (dt, J=6.75, 4.26 Hz, 1H) 4.39 (td, J=7.34, 4.11 Hz, 1H) 4.61 (s, 2H) 7.13-7.24 (m, 1H) 7.27 (t, J=7.46 Hz, 2H) 7.32 (d, J=7.04 Hz, 2H) 7.79-7.90 (m, 1H) 8.00 (s, 1H) 8.23 (d, J=1.76 Hz, 1H) 8.46 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 392.2 [M+H]+
Example 2 2-amino-N-(1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1-pyrazol-4-yl)nicotinamideUsing (1R,2R)-2-(benzyloxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 392.2 [M+H]+
Example 3 2-amino-N-(trans-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-2-(benzyloxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 392.2 [M+H]+
Example 4 2-amino-N-((1R,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1R,2S)-2-(benzyloxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 392.2 [M+H]+
Example 5 2-amino-N-(cis-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing cis-2-(benzyloxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 392.2 [M+H]+
Example 6 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(1S,2S)-2-((2-methylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((2-methylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 406.2 [M+H]+
Example 7 2-amino-N-(1S,2S)-2-((3-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3-ethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 420.2 [M+H]+
Example 8 2-amino-N-(1S,2S)-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((4-ethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 420.2 [M+H]+
Example 9 2-amino-N-(trans-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-2-((4-ethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 420.2 [M+H]+
Example 10 2-amino-N-((1S,2S)-2-((4-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((4-isopropylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 434.3 [M+H]+
Example 11 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((2,3-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 420.2 [M+H]+
Example 12 2-amino-N-((1R,2R)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1R,2R)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 420.2 [M+H]+
Example 13 2-amino-N-(trans-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 420.2 [M+H]+
Example 14 2-amino-N-((1S,2S)-2-((2,3-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((2,3-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 420.2 [M+H]+
Example 15 2-amino-N-((1S,2S)-2-((2,6-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((2,6-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 420.2 [M+H]+
Example 16 2-amino-N-((1S,2S)-2-((2,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((2,5-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 420.2 [M+H]+
Example 17 2-amino-N-((1S,2S)-2-((3,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3,5-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 420.2 [M+H]+
Example 18 2-amino-N-((1S,2S)-2-((2,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((2,4-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 420.2 [M+H]+
Example 19 2-amino-N-((1S,2S)-2-((4-ethyl-3-methylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((4-ethyl-3-methylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 434.3 [M+H]+
Example 20 2-amino-N-((1S,2S)-2-((3,4-diethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3,4-diethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 448.3 [M+H]+
Example 21 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 434.3 [M+H]+
Example 22 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-propylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3-propylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 434.3 [M+H]+
Example 23 2-amino-N-((1S,2S)-2-((3-cyclopentylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3-cyclopentylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 460.3 [M+H]+
Example 24 2-amino-N-((1S,2S)-2-((3-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3-isopropylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 434.3 [M+H]+
Example 25 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(prop-1-en-2-yl)benzyl)oxy)cyclopentyl)nicotinamideUsing (1 S,2 S)-2-((3-(prop-1-en-2-yl)benzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 432.2 [M+H]+
Example 26 2-amino-N-((1S,2S)-2-((3-cyclopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3-cyclopropylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 432.2 [M+H]+
Example 27 2-amino-N-((1S,2S)-2-((3-cyclobutylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3-cyclobutylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 446.3 [M+H]+
Example 28 2-amino-N-((1S,2S)-2-((3-ethynylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3-ethynylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 416.2 [M+H]+
Example 29 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(trifluoromethyl)benzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((4-(trifluoromethyl)benzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 460.2 [M+H]+
Example 30 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-nitrobenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2 S)-2-((3-nitrobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 437.2 [M+H]+
Example 31 2-amino-N-((1S,2S)-2-((3-cyanobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)benzonitrile, the title compound was obtained as described for the example 1.
1H NMR (400 MHz, CD3OD) δ ppm 1.58-1.70 (m, 1H) 1.73-1.90 (m, 3H) 1.95-2.07 (m, 1H) 2.11-2.22 (m, 1H) 3.88-3.98 (m, 4H) 4.36-4.44 (m, 1H) 4.61-4.72 (m, 2H) 7.43-7.51 (m, 1H) 7.57 (br d, J=7.43 Hz, 1H) 7.63 (br d, J=7.43 Hz, 1H) 7.70 (s, 1H) 7.85 (s, 1H) 7.99 (s, 1H) 8.23 (d, J=1.96 Hz, 1H) 8.45 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 417.2 [M+H]+
Example 32 2-amino-N-((1S,2S)-2-((3-hydroxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3-hydroxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 408.2 [M+H]+
Example 33 2-amino-N-((1S,2S)-2-((3-methyloxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3-methyloxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
1H NMR (400 MHz, CD3OD) δ ppm 1.54-1.65 (m, 1H) 1.68-1.88 (m, 3H) 1.95-2.07 (m, 1H) 2.09-2.22 (m, 1H) 3.65-3.74 (m, 3H) 3.88-3.98 (m, 4H) 4.33-4.43 (m, 1H) 4.51-4.66 (m, 2H) 6.74 (dd, J=8.41, 1.76 Hz, 1H) 6.83-6.93 (m, 2H) 7.12-7.22 (m, 1H) 7.85 (s, 1H) 7.99 (s, 1H) 8.22 (d, J=1.96 Hz, 1H) 8.45 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 422.2 [M+H]+
Example 34 2-amino-N-((1R,2R)-2-((3-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1R,2R)-2-((3-methoxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 422.2 [M+H]+
Example 35 2-amino-N-((1S,2S)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((4-methoxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 422.2 [M+H]+
Example 36 2-amino-N-((1R,2R)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1R,2R)-2-((4-methoxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 422.2 [M+H]+
Example 37 2-amino-N-(trans-2-((3,5-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-2-((3,5-dimethoxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 452.2 [M+H]+
Example 38 2-amino-N-((1S,2S)-2-((2,3-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((2,3-dimethoxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 452.2 [M+H]+
Example 39 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-phenoxybenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3-phenoxybenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 484.2 [M+H]+
Example 40 2-amino-N-((1S,2S)-2-(benzo[d][1,3]dioxol-5-yl-methoxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-(benzo[d][1,3]dioxol-5-ylmethoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 436.2 [M+H]+
Example 41 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(methylthio)benzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((4-(methylthio)benzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 438.2 [M+H]+
Example 42 methyl 3-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)benzoateUsing methyl 3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)benzoate, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 450.2 [M+H]+
Example 43 2-amino-N-((1S,2S)-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3-chlorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
1H NMR (400 MHz, CD3OD) δ ppm 1.62 (br dd, J=13.50, 6.46 Hz, 1H) 1.72-1.87 (m, 3H) 1.94-2.05 (m, 1H) 2.16 (br d, J=6.65 Hz, 1H) 3.89-3.97 (m, 4H) 4.38 (br d, J=4.70 Hz, 1H) 4.55-4.66 (m, 2H) 7.20 (br s, 1H) 7.22-7.28 (m, 2H) 7.34 (s, 1H) 7.85 (s, 1H) 7.99 (s, 1H) 8.22 (d, J=2.35 Hz, 1H) 8.44 (br d, J=2.35 Hz, 1H); MS (ESI, m/z): 426.2 [M+H]+
Example 44 2-amino-N-(trans-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-2-((3-chlorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 426.2 [M+H]+
Example 45 2-amino-N-(trans-2-((4-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-2-((4-chlorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 426.2 [M+H]+
Example 46 2-amino-N-(trans-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-2-((3,4-dichlorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 460.1 [M+H]+
Example 47 2-amino-N-(trans-2-((2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-2-((2-fluorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 410.2 [M+H]+
Example 48 2-amino-N-((1S,2S)-2-((3-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3-fluorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
1H NMR (400 MHz, CD3OD) δ ppm 1.63 (dq, J=13.69, 7.17 Hz, 1H) 1.70-1.88 (m, 3H) 1.93-2.06 (m, 1H) 2.15 (dt, J=13.69, 6.85 Hz, 1H) 3.87-4.00 (m, 4H) 4.34-4.42 (m, 1H) 4.62 (s, 2H) 6.92 (td, J=8.61, 1.96 Hz, 1H) 7.03-7.16 (m, 2H) 7.27 (dd, J=8.02, 6.06 Hz, 1H) 7.85 (s, 1H) 8.00 (s, 1H) 8.22 (d, J=1.96 Hz, 1H) 8.49 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 410.2 [M+H]+
Example 49 2-amino-N-(trans-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 488.1/490.1 [M+H]+
Example 50 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-2-((2,4,5-trifluorobenzyl)oxy)cyclopentyl)nicotinamideUsing trans-2-((2,4,5-trifluorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 446.2 [M+H]+
Example 51 2-amino-N-((1S,2S)-2-((3-bromobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3-bromobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 470.1/472.1 [M+H]+
Example 52 2-amino-N-(trans-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 488.1/490.1 [M+H]+
Example 53 2-amino-N-((1R,2R)-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1R,2R)-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 488.1/490.1 [M+H]+
Example 54 2-amino-N-((1S,2S)-2-(1-(4-bromophenyl)ethoxy)cyclopentyl)-5-(1-methyl-M-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-(1-(4-bromophenyl)ethoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 484.1/486.1 [M+H]+
Example 55 methyl (3-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)benzoyl)glycinateUsing methyl (3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)benzoyl)glycinate, the title compound was obtained as described for the example 1.
1H NMR (400 MHz, CD3OD) δ ppm 1.58-1.70 (m, 1H) 1.73-1.90 (m, 3H) 1.95-2.07 (m, 1H) 2.11-2.22 (m, 1H) 3.88-3.98 (m, 4H) 4.36-4.44 (m, 1H) 4.61-4.72 (m, 2H) 7.43-7.51 (m, 1H) 7.57 (br d, J=7.43 Hz, 1H) 7.63 (br d, J=7.43 Hz, 1H) 7.70 (s, 1H) 7.85 (s, 1H) 7.99 (s, 1H) 8.23 (d, J=1.96 Hz, 1H) 8.45 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 507.2[M+H]+
Example 56 2-amino-N-((1S,2S)-2-((3-((2-hydroxyethyl)carbamoyl)benzyl)-oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing methyl (3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)-N-(2-hydroxyethyl)-benzamide, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 479.2[M+H]+
Example 57 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-4-carboxamido)benzyl)oxy)cyclopentyl)nicotinamideUsing tert-butyl 4-((3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)phenyl)carbamoyl)-piperidine-1-carboxylate, the title compound was obtained as described for the example 1 and following deprotection with TFA.
MS (ESI, m/z): 518.3[M+H]+
Example 58 2-amino-N-((1S,2S)-2-((3-((S)-2-aminopropanamido)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing tert-butyl ((S)-1-((3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)carbamate, the title compound was obtained as described for the example 1 and following deprotection with TFA.
MS (ESI, m/z): 478.3[M+H]+
Example 59 N-((1S,2S)-2-((3-((S)-2-acetamidopropanamido)benzyl)oxy)-cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (S)-2-acetamido-N-(3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)phenyl)-propanamide, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 520.3[M+H]+
Example 60 2-amino-N-((1S,2S)-2-((3-(3-aminopropanamido)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing tert-butyl (3-((3-((((1S,2S)-2-aminocyclopentyl)oxy)methyl)phenyl)amino)-3-oxopropyl)carbamate, the title compound was obtained as described for the example 1 and following deprotection with TFA.
MS (ESI, m/z): 478.3[M+H]+
Example 61 N-((1S,2S)-2-((3-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 459.2 [M+H]+
Example 62 N-((1S,2S)-2-((4-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((4-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 459.2 [M+H]+
Example 63 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(naphthalen-2-ylmethoxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-(naphthalen-2-ylmethoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 442.2 [M+H]+
Example 64 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(quinolin-8-ylmethoxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-(quinolin-8-ylmethoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 443.2 [M+H]+
Example 65 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((2′,3′,4′,5′-tetrahydro-[1,1′-biphenyl]-4-yl)methoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
1H NMR (400 MHz, CD3OD) δ ppm 1.62 (br d, J=5.87 Hz, 2H) 1.67-1.87 (m, 5H) 1.93-2.09 (m, 2H) 2.14 (br s, 3H) 2.28 (br s, 2H) 3.92 (s, 3H) 4.37 (br d, J=5.48 Hz, 1H) 4.49-4.65 (m, 2H) 6.00 (br s, 1H) 7.18-7.30 (m, 2H) 7.54 (br s, 1H) 7.59-7.69 (m, 1H) 7.84 (s, 1H) 7.98 (s, 1H) 8.23 (s, 1H) 8.38 (s, 1H);
MS (ESI, m/z): 472.3 [M+H]+
Example 66 N-(trans-2-([1,1′-biphenyl]-2-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-2-([1,1′-biphenyl]-2-ylmethoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 468.2 [M+H]+
Example 67 N-((1S,2S)-2-([1,1′-biphenyl]-3-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-([1,1′-biphenyl]-3-ylmethoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 468.2 [M+H]+
Example 68 N-((1S,2S)-2-([1,1′-biphenyl]-4-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-3-([1,1′-biphenyl]-4-ylmethoxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
1H NMR (400 MHz, CD3OD) δ ppm 1.59 (br d, J=1.17 Hz, 1H) 1.79 (br s, 3H) 1.97 (br s, 1H) 2.11-2.21 (m, 1H) 3.62 (s, 2H) 3.87 (s, 3H) 3.97 (br s, 1H) 4.39 (br s, 1H) 4.65 (br d, J=13.69 Hz, 2H) 7.34-7.42 (m, 2H) 7.50 (br t, J=7.43 Hz, 2H) 7.80 (s, 1H) 7.90 (s, 1H) 8.17 (br s, 1H) 8.29-8.34 (m, 1H); MS (ESI, m/z): 468.2 [M+H]+
Example 69 2-amino-N-((1S,2S)-2-hydroxycyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-aminocyclopentan-1-ol, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 302.2 [M+H]+
Example 70 2-amino-N-(cis-2-hydroxycyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing cis-2-aminocyclopentan-1-ol, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 302.2 [M+H]+
Example 71 N-((1S,2S)-2-(benzyloxy)cyclopentyl)-2-(ethylamino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 2-(ethylamino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinic acid, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 420.2 [M+H]+
Example 72 N-((1S,2S)-2-(benzyloxy)cyclopentyl)-2-((3,4-dimethylbenzyl-)amino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 2-((3,4-dimethylbenzyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)nicotinic acid, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 510.3 [M+H]+
Example 73 2-amino-N-((6R,7S)-6-(benzyloxy)-1,4-dioxaspiro[4.4]nonan-7-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (6R,7S)-6-(benzyloxy)-1,4-dioxaspiro[4.4]nonan-7-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 450.2 [M+H]+
Example 74 2-amino-N-(trans-2-(benzyloxy)cyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-2-(benzyloxy)cyclohexan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 406.2 [M+H]+
Example 75 2-amino-N-((1S,2S)-2-(benzyloxy)cyclohexyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-(benzyloxy)cyclohexan-1-amine, the title compound was obtained as described for the example 1.
1H NMR (400 MHz, CD3OD) δ ppm 1.28-1.47 (m, 4H) 1.77 (br s, 1H) 1.83 (br s, 1H) 1.97 (s, 1H) 2.29 (br s, 1H) 3.38 (br d, J=9.39 Hz, 1H) 3.92 (s, 3H) 3.99 (br d, J=10.17 Hz, 1H) 4.41-4.47 (m, 1H) 4.68 (br d, J=12.13 Hz, 1H) 7.13 (dt, J=14.57, 6.99 Hz, 3H) 7.25 (br d, J=7.43 Hz, 2H) 7.77 (s, 1H) 7.89 (s, 1H) 8.21 (s, 1H) 8.25 (br s, 1H); MS (ESI, m/z): 406.2 [M+H]+
Example 76 2-amino-N-(trans-2-(benzyl(methyl)amino)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-N1-benzyl-N1-methylcyclopentane-1,2-diamine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 405.2 [M+H]+
Example 77 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(1S,2S)-2-(phenoxymethyl)cyclopentyl)nicotinamideUsing (1S,2S)-2-(phenoxymethyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 392.2 [M+H]+
Example 78 2-amino-N-((1S,2S)-2-((3,4-dimethylphenoxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylphenoxy)methyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 420.2 [M+H]+
Example 79 2-amino-N-(trans-2,2-difluoro-5-(phenoxymethyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (trans-2,2-difluoro-5-(phenoxymethyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 428.2 [M+H]+
Example 80 2-amino-N-((1S,2S)-2-(((2,3-dihydro-1H-inden-5-yl)oxy)-methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-(((2,3-dihydro-1H-inden-5-yl)oxy)methyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 432.2 [M+H]+
Example 81 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4,5-trimethylphenoxy)methyl)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4,5-trimethylphenoxy)methyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 434.3 [M+H]+
Example 82 2-amino-N-((1S,2S)-2-((3-(dimethylamino)phenoxy)-methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 3-(((1S,2S)-2-aminocyclopentyl)methoxy)-N,N-dimethylaniline, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 435.2 [M+H]+
Example 83 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-1-carbonyl)phenoxy)methyl)cyclopentyl)nicotinamideUsing (3-(((1S,2S)-2-aminocyclopentyl)methoxy)phenyl)(piperidin-1-yl)methanone, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 503.3 [M+H]+
Example 84 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-phenoxyphenoxy)methyl)cyclopentyl)nicotinamideUsing (1S,2S)-2-((4-phenoxyphenoxy)methyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 484.2 [M+H]+
Example 85 2-amino-N-((1S,2S)-2-((benzyloxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((benzyloxy)methyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 406.2 [M+H]+
Example 86 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)oxy)methyl)cyclopentyl)nicotinamideUsing (1S,2S)-2-(((4′-(4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)oxy)methyl)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
1H NMR (600 MHz, CD3OD) δ ppm 1.56-1.65 (m, 1H) 1.67-1.75 (m, 1H) 1.79 (br d, J=6.46 Hz, 1H) 1.85 (br d, J=8.80 Hz, 1H) 2.03-2.12 (m, 1H) 2.16 (br dd, J=12.91, 5.87 Hz, 1H) 2.43-2.51 (m, 1H) 2.84 (s, 3H) 3.75 (s, 2H) 3.89 (s, 3H) 4.10 (d, J=5.87 Hz, 2H) 4.30-4.38 (m, 1H) 6.96 (d, J=8.80 Hz, 2H) 7.38 (br d, J=8.22 Hz, 2H) 7.50 (dd, J=16.43, 8.22 Hz, 4H) 7.86 (s, 1H) 7.98 (s, 1H) 8.21 (d, J=2.35 Hz, 1H) 8.51 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 580.3 [M+H]+
Example 87 (1S,2S)-2-(benzyloxy)cyclopentyl 2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinateUsing (1S,2S)-2-(benzyloxy)cyclopentan-1-ol, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 393.2 [M+H]+
Example 88 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2-phenethylcyclopentyl)nicotinamideUsing (1S,2R)-2-phenethylcyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 390.2 [M+H]+
Example 89 2-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-4-(benzyloxy)tetrahydrofuran-3-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 394.2 [M+H]+
Example 90 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-morpholinotetrahydrofuran-3-yl)nicotinamideUsing trans-4-morpholinotetrahydrofuran-3-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 373.2 [M+H]+
Example 91 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-(pyrrolidin-1-yl)tetrahydrofuran-3-yl)nicotinamideUsing trans-4-(pyrrolidin-1-yl)tetrahydrofuran-3-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 357.2 [M+H]+
Example 92 2-amino-N-(cis-4-hydroxytetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing cis-4-aminotetrahydrofuran-3-ol, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 304.1 [M+H]+
Example 93 2-amino-N-(4-(benzyloxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-4-(benzyloxy)-1-methylpyrrolidin-3-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 407.2 [M+H]+
Example 94 2-amino-N-(trans-4-(benzyloxy)-1-isopropylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-4-(benzyloxy)-1-isopropylpyrrolidin-3-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 435.2 [M+H]+
Example 95 (R)-2-amino-N-(2-(benzyloxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (R)-2-(benzyloxy)propan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 366.2 [M+H]+
Example 96 (S)-2-amino-N-(2-(benzyloxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (S)-2-(benzyloxy)propan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 366.2 [M+H]+
Example 97 (S)-2-amino-N-(1-(benzyloxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (S)-1-(benzyloxy)propan-2-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 366.2 [M+H]+
Example 98 (R)-2-amino-N-(1-(benzyloxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (R)-1-(benzyloxy)propan-2-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 366.2 [M+H]+
Example 99 2-amino-N-(1-(benzyloxy)-2-methylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 1-(benzyloxy)-2-methylpropan-2-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 380.2 [M+H]+
Example 100 (R)-2-amino-N-(1-((3,4-dimethylbenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (R)-1-((3,4-dimethylbenzyl)oxy)propan-2-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 394.2 [M+H]+
Example 101 (S)-2-amino-N-(2-((3,4-dimethylbenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (S)-2-((3,4-dimethylbenzyl)oxy)propan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 394.2 [M+H]+
Example 102 (R)-2-amino-N-(1-((4-chlorobenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (R)-1-((4-chlorobenzyl)oxy)propan-2-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 400.2 [M+H]+
Example 103 (S)-2-amino-N-(2-((4-chlorobenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (S)-2-((4-chlorobenzyl)oxy)propan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 400.2 [M+H]+
Example 104 (R)-2-amino-N-(1-((3,4-dichlorobenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (R)-1-((3,4-dichlorolbenzyl)oxy)propan-2-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 434.1 [M+H]+
Example 105 (S)-2-amino-N-(2-((3,4-dichlorobenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (S)-2-((3,4-dichlorobenzyl)oxy)propan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 419.1 [M+H]+
Example 106 (R)-2-amino-N-(1-((3-methoxybenzyl)oxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (R)-1-((3-methoxybenzyl)oxy)propan-2-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 396.2 [M+H]+
Example 107 (S)-2-amino-N-(2-((3-methoxybenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (S)-2-((3-methoxybenzyl)oxy)propan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 396.2 [M+H]+
Example 108 (R)-2-amino-N-(1-(benzyloxy)butan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (R)-1-(benzyloxy)butan-2-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 380.2 [M+H]+
Example 109 (S)-2-amino-N-(1-(benzyloxy)-3-methylbutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (S)-1-(benzyloxy)-3-methylbutan-2-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 394.2 [M+H]+
Example 110 (R)-2-amino-N-(1-(benzyloxy)-3-methylbutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (R)-1-(benzyloxy)-3-methylbutan-2-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 394.2 [M+H]+
Example 111 (S)-2-amino-N-(1-(benzyloxy)-4-methylpentan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (S)-1-(benzyloxy)-4-methylpentan-2-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 408.2 [M+H]+
Example 112 (R)-2-amino-N-(1-(benzyloxy)-4-methylpentan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (R)-1-(benzyloxy)-4-methylpentan-2-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 408.2 [M+H]+
Example 113 (R)-2-amino-N-(2-(benzyloxy)-1-cyclohexylethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (R)-2-(benzyloxy)-1-cyclohexylethan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 434.3 [M+H]+
Example 114 (R)-2-amino-N-(1-cyclohexyl-2-hydroxyethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (R)-2-amino-2-cyclohexylethan-1-ol, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 344.3 [M+H]+
Example 115 (S)-2-amino-N-(2-(benzyloxy)-1-phenylethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (S)-2-(benzyloxy)-1-phenylethan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 428.2 [M+H]+
Example 116 (R)-2-amino-N-(2-(benzyloxy)-1-phenylethyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (R)-2-(benzyloxy)-1-phenylethan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 428.2 [M+H]+
Example 117 (S)-2-amino-N-(1-(benzyloxy)-3-phenylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (S)-1-(benzyloxy)-3-phenylpropan-2-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 442.2 [M+H]+
Example 118 (R)-2-amino-N-(1-(benzyloxy)-3-phenylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (R)-1-(benzyloxy)-3-phenylpropan-2-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 442.2 [M+H]+
Example 119 (R)-2-amino-N-(1-(cyclobutylmethoxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (R)-1-(cyclobutylmethoxy)propan-2-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 344.2 [M+H]+
Example 120 methyl N-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-O-benzyl-L-serinateUsing methyl O-benzyl-L-serinate, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 410.2 [M+H]+
Example 121 methyl N-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-O-benzyl-L-threoninateUsing methyl O-benzyl-L-threoninate, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 424.2 [M+H]+
Example 122 2-amino-N-((2S,3R)-3-(benzyloxy)-1-(methylamino)-1-oxobutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (2S,3R)-2-amino-3-(benzyloxy)-N-methylbutanamide, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 423.2 [M+H]+
Example 123 2-amino-N-((2S,3R)-3-(benzyloxy)-1-oxo-1-(propylamino)butan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (2S,3R)-2-amino-3-(benzyloxy)-N-propylbutanamide, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 451.2 [M+H]+
Example 124 2-amino-N-((2S,3R)-3-(benzyloxy)-1-(cyclopentylamino)-1-oxobutan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (2S,3R)-2-amino-3-(benzyloxy)-N-cyclopentylbutanamide, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 477.3 [M+H]+
Example 125 2-amino-N-((2S,3R)-3-(benzyloxy)-1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (2S,3R)-2-amino-3-(benzyloxy)-1-(pyrrolidin-1-yl)butan-1-one, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 463.2 [M+H]+
Example 126 benzyl (2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-alaninateUsing benzyl L-alaninate, the title compound was obtained as described for the example 1.
1H NMR (400 MHz, CD3OD) δ ppm 1.51 (d, J=7.43 Hz, 3H) 3.92 (s, 3H) 4.64 (d, J=7.43 Hz, 1H) 5.12-5.25 (m, 2H) 7.21-7.42 (m, 5H) 7.84 (s, 1H) 7.96-8.00 (m, 1H) 8.21-8.27 (m, 1H) 8.54 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 380.2 [M+H]+
Example 127 benzyl (2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-valinateUsing benzyl L-valinate, the title compound was obtained as described for the example 1.
1H NMR (400 MHz, CD3OD) δ ppm 1.00 (dd, J=9.19, 6.85 Hz, 6H) 2.16-2.36 (m, 1H) 4.46-4.55 (m, 1H) 5.10-5.30 (m, 2H) 7.22-7.41 (m, 5H) 7.84 (d, J=0.78 Hz, 1H) 7.98 (s, 1H) 8.24 (d, J=1.96 Hz, 1H) 8.48 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 408.2 [M+H]+
Example 128 benzyl (2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-serinateUsing benzyl L-serinate, the title compound was obtained as described for the example 1.
1H NMR (400 MHz, CD3OD) δ ppm 3.94-4.07 (m, 2H) 4.78 (dd, J=5.48, 4.30 Hz, 1H) 5.21 (s, 2H) 7.23-7.43 (m, 5H) 7.86 (d, J=0.78 Hz, 1H) 8.01 (s, 1H) 8.24 (d, J=1.96 Hz, 1H) 8.64 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 396.2 [M+H]+
Example 129 3-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamideUsing 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid and (1S,2S)-2-(benzyloxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 393.2 [M+H]+
Example 130 3-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamideUsing 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid and (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 421.2 [M+H]+
Example 131 (S)-3-amino-6-(1-methyl-1H-pyrazol-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazine-2-carboxamideUsing 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid and (S)-1,2,3,4-tetrahydronaphthalen-1-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 349.2 [M+H]+
Example 132 3-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamideUsing 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid and trans-4-(benzyloxy)tetrahydrofuran-3-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 395.2 [M+H]+
Example 133 3-amino-N-(cis-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxamideUsing 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid and cis-4-(benzyloxy)tetrahydrofuran-3-amine, the title compound was obtained as described for the example 1.
MS (ESI, m/z): 395.2 [M+H]+
Example 134 2-amino-N-((1S,2S)-2-((3′-amino-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideScheme for the preparation of the Compound of Example 134:
To a solution of methyl 2-amino-5-bromonicotinate (560 mg, 2.42 mmol) in 10 ml of MeOH was added 2N NaOH (2 ml, 4 mmol) and the mixture was heated at 65° C. for 1 hr, cooled to room temperature, neutralized (2 ml of 2N HCl), and the resulting precipitate was filtered, washed with MeOH, and dried to give 0.35 g of white solid.
1H NMR (400 MHz, CD3OD) δ ppm 8.17 (d, J=2.4 Hz, 1H), 8.23 (d, J=2.4 Hz, 1H); MS (ESI, m/z): 217.0 [M+H]+
Intermediate 2To a mixture of intermediate 3 (4.48 g, 20.6 mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (5.5 g, 26.8 mmol) in 100 ml of 1,4-dioxane/water (3/1) was added K2CO3 (8.5 g, 61.9 mmol) followed by Pd(PPh3)4 (1.19 g, 1.03 mmol). The reaction mixture was heated at 100° C. for 3 hrs, cooled to room temperature, and partitioned between water and EtOAc. Water layer was separated and adjusted to pH value between 4 and 5. The precipitate was collected by filtration and dried to afford 4 g of the title compound. The crude product was used for the next step without further purification.
1H NMR (600 MHz, DMSO-d6) δ ppm 3.82 (s, 3H), 5.73 (s, 2H), 7.77 (s, 1H), 8.05 (s, 1H), 8.13 (d, J=2.4 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H); MS (ESI, m/z): 219.1 [M+H]+
Intermediate 4To a mixture of intermediate 2 (350 mg, 1.60 mmol) and triethylamine (0.34 ml, 2.41 mmol) in 4 ml of DMF was added HATU (732 mg, 1.92 mmol) followed by (1S,2S)-2-((4-bromobenzyl)oxy)cyclopentan-1-amine (475 mg, 1.76 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified through silicagel column chromatography to give 650 mg of off-white solid.
1H NMR (600 MHz, CD3OD) δ ppm 1.59-1.69 (m, 1H) 1.72-1.78 (m, 1H) 1.78-1.86 (m, 2H) 1.96-2.07 (m, 1H) 2.16 (dq, J=13.50, 6.85 Hz, 1H) 3.94 (s, 3H) 3.95 (br d, J=1.76 Hz, 1H) 4.33-4.42 (m, 1H) 4.53-4.62 (m, 2H) 7.25 (m, J=8.22 Hz, 2H) 7.41 (m, J=8.22 Hz, 2H) 7.87 (s, 1H) 8.01 (s, 1H) 8.22 (d, J=1.76 Hz, 1H) 8.52 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 470.1/472.1 [M+H]+
Example 134 2-amino-N-((1S,2S)-2-((3′-amino-[1,1′-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideTo a mixture of intermediate 4 (33 mg, 0.07 mmol) and (3-aminophenyl)boronic acid (11 mg, 0.08 mmol) in 0.4 ml of 1,4-dioxane/water (3/1) was added K2CO3 (29 mg, 0.21 mmol) followed by Pd(PPh3)4 (4 mg, 0.003 mmol). The reaction mixture was heated at 100° C. for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO4 and concentrated under vacuum. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 30 mg of the title compound.
1H NMR (400 MHz, CD3OD) δ ppm 1.60-1.69 (m, 1H) 1.73-1.90 (m, 3H) 2.05 (br d, J=7.04 Hz, 1H) 2.17 (s, 1H) 3.89 (s, 3H) 4.00 (br d, J=4.30 Hz, 1H) 4.36-4.46 (m, 2H) 4.67 (s, 2H) 7.24 (br d, J=7.43 Hz, 1H) 7.42-7.59 (m, 7H) 7.84 (s, 1H) 7.97 (s, 1H) 8.20 (d, J=2.35 Hz, 1H) 8.48 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 483.2 [M+H]+
Example 135 2-amino-N-((1S,2S)-2-((4′-amino-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-aminophenyl)boronic acid, the title compound was obtained as described for the example 134.
MS (ESI, m/z): 483.2 [M+H]+
Example 136 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(methylamino)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing (4-(methylamino)phenyl)boronic acid, the title compound was obtained as described for the example 134.
1H NMR (400 MHz, CD3OD) δ ppm 1.64 (br d, J=5.87 Hz, 1H) 1.73-1.94 (m, 3H) 2.05 (br s, 1H) 2.17 (br s, 1H) 3.55 (br t, J=11.15 Hz, 3H) 3.90 (s, 3H) 4.00 (br s, 1H) 4.43 (s, 4H) 4.67 (s, 2H) 7.45 (br d, J=8.22 Hz, 2H) 7.55 (br d, J=7.83 Hz, 2H) 7.60 (br d, J=7.83 Hz, 2H) 7.71 (br d, J=7.83 Hz, 2H) 7.85 (s, 1H) 7.98 (s, 1H) 8.21 (s, 1H) 8.52 (s, 1H);
MS (ESI, m/z): 497.3 [M+H]+
Example 137 2-amino-N-((1S,2S)-2-((4′-(dimethylamino)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-(dimethylamino)phenyl)boronic acid, the title compound was obtained as described for the example 134.
MS (ESI, m/z): 511.3 [M+H]+
Example 138 2-amino-N-((1S,2S)-2-((4′-((dimethylamino)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing ((4-((dimethylamino)methyl)phenyl)boronic acid, the title compound was obtained as described for the example 134.
1H NMR (400 MHz, CD3OD) δ ppm 1.55-1.68 (m, 1H) 1.80 (br s, 3H) 2.04 (br d, J=7.43 Hz, 1H) 2.15 (br s, 1H) 3.49 (br s, 3H) 3.62 (br s, 3H) 3.75 (br s, 2H) 3.89 (s, 3H) 3.97 (br s, 1H) 4.39 (br s, 1H) 4.62 (br d, J=12.91 Hz, 1H) 4.66-4.73 (m, 1H) 7.44 (br t, J=9.19 Hz, 4H) 7.56 (br d, J=8.22 Hz, 2H) 7.62 (br d, J=7.83 Hz, 2H) 7.82 (s, 1H) 7.94 (s, 1H) 8.16 (s, 1H) 8.42 (s, 1H); MS (ESI, m/z): 525.3 [M+H]+
Example 139 2-amino-N-((1S,2S)-2-((3′-amino-2′-methyl-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (3-amino-2-methylphenyl)boronic acid, the title compound was obtained as described for the example 134.
MS (ESI, m/z): 497.2 [M+H]+
Example 140 2-amino-N-((1S,2S)-2-((3′-hydroxy-[1,1′-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (3-hydroxyphenyl)boronic acid, the title compound was obtained as described for the example 134.
1H NMR (400 MHz, CD3OD) δ ppm 1.61 (br d, J=7.43 Hz, 1H) 1.72-1.86 (m, 3H) 1.95-2.08 (m, 1H) 2.09-2.20 (m, 1H) 3.87 (s, 3H) 3.97 (br s, 1H) 4.40 (br d, J=18.00 Hz, 1H) 4.56-4.71 (m, 2H) 6.70-6.75 (m, 1H) 6.90 (br s, 1H) 6.95 (br d, J=7.83 Hz, 1H) 7.14-7.21 (m, 1H) 7.32-7.41 (m, 2H) 7.42-7.50 (m, 2H) 7.78-7.83 (m, 1H) 7.88-7.93 (m, 1H) 8.16 (br d, J=1.96 Hz, 1H) 8.36 (br d, J=2.35 Hz, 1H); MS (ESI, m/z): 484.2 [M+H]+
Example 141 2-amino-N-((1S,2S)-2-((3′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (3-(hydroxymethyl)phenyl)boronic acid, the title compound was obtained as described for the example 134.
MS (ESI, m/z): 498.2 [M+H]+
Example 142 2-amino-N-((1S,2S)-2-((4′-(hydroxymethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing ((4-(hydroxymethyl)phenyl)boronic acid, the title compound was obtained as described for the example 134.
MS (ESI, m/z): 498.2 [M+H]+
Example 143 2-amino-N-(1S,2S)-2-((3′-(aminomethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (3-(aminomethyl)phenyl)boronic acid, the title compound was obtained as described for the example 134.
1H NMR (600 MHz, CD3OD) δ ppm 1.54-1.67 (m, 1H) 1.71-1.90 (m, 3H) 2.03 (br dd, J=12.33, 7.04 Hz, 1H) 2.11-2.21 (m, 1H) 3.88 (s, 3H) 3.96-4.03 (m, 1H) 4.16 (s, 2H) 4.35-4.47 (m, 1H) 4.67 (s, 2H) 7.40 (br d, J=7.63 Hz, 1H) 7.44 (d, J=8.22 Hz, 1H) 7.49 (br t, J=7.63 Hz, 2H) 7.58 (d, J=7.63 Hz, 1H) 7.59-7.62 (m, 2H) 7.61 (br d, J=7.63 Hz, 1H) 7.66 (s, 1H) 7.80 (s, 1H) 7.92 (s, 1H) 8.21 (d, J=2.35 Hz, 1H) 8.29 (br s, 1H); MS (ESI, m/z): 497.3 [M+H]+
Example 144 2-amino-N-(1S,2S)-2-((4′-(aminomethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-(aminomethyl)phenyl)boronic acid, the title compound was obtained as described for the example 134.
1H NMR (600 MHz, CD3OD) δ ppm 1.64 (br dd, J=14.09, 7.04 Hz, 1H) 1.72-1.90 (m, 3H) 2.03 (br dd, J=13.21, 6.16 Hz, 1H) 2.14-2.23 (m, 1H) 3.90 (s, 3H) 4.01 (br d, J=7.04 Hz, 1H) 4.14 (s, 2H) 4.40-4.45 (m, 1H) 4.63-4.70 (m, 2H) 7.43 (d, J=8.22 Hz, 2H) 7.49 (d, J=7.63 Hz, 2H) 7.57 (d, J=7.63 Hz, 2H) 7.65 (d, J=8.22 Hz, 2H) 7.85 (s, 1H) 7.97 (s, 1H) 8.21 (d, J=1.76 Hz, 1H) 8.49 (br s, 1H); MS (ESI, m/z): 497.3 [M+H]+
Example 145 2-amino-N-((1S,2S)-2-((4′-(2-aminoethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-(2-aminoethyl)phenyl)boronic acid, the title compound was obtained as described for the example 134.
MS (ESI, m/z): 511.3 [M+H]+
Example 146 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing (4-(4-methylpiperazin-1-yl)phenyl)boronic acid, the title compound was obtained as described for the example 134.
MS (ESI, m/z): 566.3 [M+H]+
Example 147 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(piperazin-1-yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamideUsing (6-(piperazin-1-yl)pyridin-3-yl)boronic acid, the title compound was obtained as described for the example 134.
1H NMR (400 MHz, CD3OD) δ ppm 1.64 (br d, J=7.83 Hz, 1H) 1.81 (br d, J=7.83 Hz, 3H) 2.04 (br s, 1H) 2.18 (br s, 1H) 3.32-3.40 (m, 4H) 3.84 (br s, 4H) 3.90 (s, 3H) 3.98 (br s, 1H) 4.40 (br s, 1H) 4.65 (s, 2H) 6.98-7.02 (m, 1H) 7.41 (br d, J=7.04 Hz, 2H) 7.50 (br d, J=7.83 Hz, 2H) 7.83-7.89 (m, 2H) 7.96 (s, 1H) 8.20 (s, 1H) 8.35 (s, 1H) 8.48 (s, 1H);
MS (ESI, m/z): 553.3 [M+H]+
Example 148 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamideUsing (6-(4-methylpiperazin-1-yl)pyridin-3-yl)boronic acid, the title compound was obtained as described for the example 134.
1H NMR (600 MHz, CD3OD) δ ppm 1.58-1.66 (m, 1H) 1.73-1.87 (m, 3H) 2.04 (dq, J=13.72, 6.77 Hz, 1H) 2.16 (dt, J=13.35, 6.53 Hz, 1H) 2.96 (s, 3H) 3.90 (s, 3H) 3.96-4.01 (m, 1H) 4.37-4.45 (m, 1H) 4.60-4.69 (m, 2H) 6.99 (d, J=8.80 Hz, 1H) 7.41 (d, J=8.22 Hz, 2H) 7.50 (d, J=8.22 Hz, 2H) 7.83 (s, 1H) 7.85 (d, J=2.35 Hz, 1H) 7.96 (s, 1H) 8.20 (d, J=2.35 Hz, 1H) 8.36 (d, J=2.35 Hz, 1H) 8.45 (s, 1H); MS (ESI, m/z): 567.3 [M+H]+
Example 149 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-(piperazin-1-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing (3-(piperazin-1-yl)phenyl)boronic acid, the title compound was obtained as described for the example 134.
1H NMR (400 MHz, CD3OD) δ ppm 1.62 (br d, J=5.87 Hz, 2H) 1.81 (br d, J=6.65 Hz, 3H) 1.96-2.07 (m, 1H) 2.17 (br s, 1H) 3.40 (br dd, J=19.95, 5.87 Hz, 8H) 3.88 (s, 3H) 4.00 (br s, 1H) 4.40 (br s, 1H) 4.65 (s, 2H) 6.99 (br d, J=7.43 Hz, 1H) 7.10 (br d, J=6.65 Hz, 1H) 7.16 (s, 1H) 7.32 (t, J=7.60 Hz, 1H) 7.40 (d, J=7.83 Hz, 2H) 7.53 (d, J=8.61 Hz, 2H) 7.84 (s, 1H) 7.95 (s, 1H) 8.19 (s, 1H) 8.46 (s, 1H);
MS (ESI, m/z): 552.3 [M+H]+
Example 150 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-(4-methylpiperazin-1-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing (3-(4-methylpiperazin-1-yl)phenyl)boronic acid, the title compound was obtained as described for the example 134.
1H NMR (600 MHz, CD3OD) δ ppm 1.66 (s, 1H) 1.73-1.88 (m, 3H) 1.99-2.08 (m, 1H) 2.17 (br dd, J=13.50, 5.87 Hz, 1H) 2.97 (s, 3H) 3.06 (br s, 2H) 3.60 (br s, 2H) 3.88 (s, 3H) 3.96-4.03 (m, 1H) 4.41 (br d, J=4.70 Hz, 1H) 4.61-4.70 (m, 2H) 6.99 (br d, J=8.80 Hz, 1H) 7.10 (br d, J=7.63 Hz, 1H) 7.16 (s, 1H) 7.32 (t, J=7.92 Hz, 1H) 7.41 (d, J=8.22 Hz, 2H) 7.53 (d, J=8.22 Hz, 2H) 7.82 (s, 1H) 7.93 (s, 1H) 8.19 (d, J=1.76 Hz, 1H) 8.35-8.41 (m, 1H); MS (ESI, m/z): 566.3 [M+H]+
Example 151 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing (3-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 134.
1H NMR (400 MHz, CD3OD) δ ppm 1.65 (br dd, J=13.30, 6.26 Hz, 1H) 1.76-1.90 (m, 3H) 1.99-2.10 (m, 1H) 2.18 (br dd, J=14.09, 6.65 Hz, 1H) 2.85 (s, 3H) 3.78 (s, 2H) 3.91 (s, 3H) 4.02 (br s, 1H) 4.43 (br dd, J=10.96, 7.83 Hz, 1H) 4.68 (s, 2H) 7.34 (br d, J=7.43 Hz, 1H) 7.38-7.45 (m, 3H) 7.51 (br d, J=7.83 Hz, 1H) 7.54-7.60 (m, 3H) 7.86 (s, 1H) 7.99 (s, 1H) 8.21 (d, J=1.96 Hz, 1H) 8.51 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 579.3 [M+H]+
Example 152 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(morpholine-4-carbonyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing (4-(morpholine-4-carbonyl)phenyl)boronic acid, the title compound was obtained as described for the example 134.
MS (ESI, m/z): 581.3 [M+H]+
Example 153 2-amino-N-((1S,2S)-2-((4′-ethyl-[1,1′-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-ethylphenyl)boronic acid, the title compound was obtained as described for the example 134.
1H NMR (600 MHz, CD3OD) δ ppm 1.24 (t, J=7.63 Hz, 3H) 1.55-1.67 (m, 1H) 1.73-1.86 (m, 3H) 2.01-2.08 (m, 1H) 2.16 (br dd, J=13.21, 5.58 Hz, 1H) 2.66 (q, J=7.63 Hz, 2H) 3.87 (s, 3H) 3.93-3.99 (m, 1H) 4.38-4.42 (m, 1H) 4.61 (d, J=12.91 Hz, 1H) 4.65-4.71 (m, 1H) 7.21 (d, J=7.63 Hz, 2H) 7.38 (d, J=8.22 Hz, 2H) 7.41 (d, J=8.22 Hz, 2H) 7.50 (d, J=8.22 Hz, 2H) 7.82 (s, 1H) 7.91 (s, 1H) 8.16 (d, J=1.76 Hz, 1H) 8.42 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 496.3 [M+H]+
Example 154 2-amino-N-((1S,2S)-2-((4′-(cyanomethyl)-[1,1′-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-(cyanomethyl)phenyl)boronic acid, the title compound was obtained as described for the example 134.
MS (ESI, m/z): 507.2 [M+H]+
Example 155 2-amino-N-((1S,2S)-2-((4′-carbamoyl-[1,1′-biphenyl]-4-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-carbamoylphenyl)boronic acid, the title compound was obtained as described for the example 134.
1H NMR (600 MHz, CD3OD) δ ppm 1.62 (s, 1H) 1.70-1.88 (m, 3H) 2.05 (s, 1H) 2.16 (td, J=13.06, 7.92 Hz, 1H) 3.88 (s, 3H) 3.98 (br d, J=6.46 Hz, 1H) 4.40 (br d, J=4.70 Hz, 1H) 4.63 (d, J=12.33 Hz, 1H) 4.70 (d, J=12.91 Hz, 1H) 7.44 (d, J=8.22 Hz, 2H) 7.58 (d, J=8.22 Hz, 2H) 7.61 (d, J=8.80 Hz, 2H) 7.81 (s, 1H) 7.89 (d, J=8.22 Hz, 2H) 7.92 (s, 1H) 8.17 (d, J=2.35 Hz, 1H) 8.38 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 511.2 [M+H]+
Example 156 2-amino-N-((1S,2S)-2-((3-fluoro-4′-((4-methylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideUsing (1S,2S)-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentan-1-amine and 4-(4-methylpiperazino)methylphenylboronic acid pinacol ester, the title compound was obtained as described for the example 134.
1H NMR (400 MHz, CD3OD) δ ppm 1.64 (br dd, J=13.30, 7.04 Hz, 1H) 1.74-1.92 (m, 3H) 2.04 (br dd, J=12.72, 6.06 Hz, 1H) 2.17 (br dd, J=13.50, 6.46 Hz, 1H) 2.91 (s, 3H) 3.25 (br s, 4H) 3.47 (br s, 4H) 3.90 (s, 3H) 3.96-4.08 (m, 1H) 4.12 (s, 2H) 4.34-4.45 (m, 1H) 4.64-4.78 (m, 2H) 5.47 (s, 1H) 7.32 (br d, J=11.35 Hz, 1H) 7.40 (br d, J=7.83 Hz, 1H) 7.47-7.57 (m, 3H) 7.62 (br d, J=7.83 Hz, 2H) 7.85 (s, 1H) 7.99 (s, 1H) 8.18 (s, 1H) 8.55 (s, 1H); MS (ESI, m/z): 598.4 [M+H]+
Example 157 2-amino-N-((1S,2S)-2-((3-fluoro-4′-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideUsing (1S,2S)-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentan-1-amine and (4-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 134.
MS (ESI, m/z): 626.4 [M+H]+
Example 158 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-methoxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((4-bromo-2-(trifluoromethyl)benzyl)oxy)cyclopentan-1-amine and 4-(4-methylpiperazino)methylphenylboronic acid pinacol ester, the title compound was obtained as described for the example 134.
1H NMR (400 MHz, CD3OD) δ ppm 1.69 (dt, J=13.89, 6.75 Hz, 1H) 1.77-1.93 (m, 3H) 2.01-2.12 (m, 1H) 2.13-2.30 (m, 1H) 2.87 (s, 3H) 3.75 (s, 2H) 3.92 (s, 3H) 4.00-4.08 (m, 1H) 4.45 (br dd, J=11.54, 7.24 Hz, 1H) 7.47 (d, J=8.22 Hz, 2H) 7.62 (m, J=8.22 Hz, 2H) 7.81-7.84 (m, 2H) 7.86 (d, J=5.09 Hz, 2H) 8.00 (s, 1H) 8.23 (d, J=1.96 Hz, 1H) 8.56 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 648.3[M+H]+
Example 159 2-amino-N-((1S,2S)-2-((2-chloro-4′-((4-methylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl) methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideUsing (1S,2S)-2-((4-bromo-3-chlorobenzyl)oxy)cyclopentan-1-amine and 4-(4-methylpiperazino)methylphenylboronic acid pinacol ester, the title compound was obtained as described for the example 134.
1H NMR (600 MHz, CD3OD) δ ppm 1.65 (br dd, J=13.50, 7.04 Hz, 1H) 1.74-1.89 (m, 3H) 1.97-2.11 (m, 1H) 2.15-2.22 (m, 1H) 2.85 (s, 3H) 3.72 (s, 2H) 3.92 (s, 3H) 3.98 (dt, J=6.46, 4.11 Hz, 1H) 4.42 (td, J=7.34, 4.11 Hz, 1H) 4.66 (d, J=2.35 Hz, 2H) 7.27 (d, J=7.63 Hz, 1H) 7.30-7.37 (m, 3H) 7.40 (d, J=8.22 Hz, 2H) 7.47 (d, J=1.17 Hz, 1H) 7.86 (s, 1H) 7.99 (s, 1H) 8.22 (d, J=2.35 Hz, 1H) 8.49 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 614.3[M+H]+
Example 160 2-amino-N-((1S,2S)-2-((3-fluoro-4′-((cis-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentan-1-amine and (4-((cis-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 134.
MS (ESI, m/z): 656.4 [M+H]+
Example 161 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 4-(2-(4-methylpiperazino)ethyl)phenylboronic acid pinacol ester, the title compound was obtained as described for the example 134.
1H NMR (600 MHz, CD3OD) δ ppm 1.63 (br dd, J=13.79, 6.75 Hz, 1H) 1.74-1.87 (m, 3H) 2.00-2.11 (m, 1H) 2.11-2.23 (m, 1H) 2.79-2.96 (m, 2H) 3.02 (br s, 2H) 3.24 (s, 2H) 3.41 (br s, 4H) 3.89 (s, 3H) 3.97-4.03 (m, 1H) 4.41 (br s, 1H) 4.61-4.71 (m, 2H) 7.31 (br d, J=8.22 Hz, 2H) 7.40 (d, J=7.63 Hz, 2H) 7.50 (br d, J=8.22 Hz, 2H) 7.51-7.57 (m, 2H) 7.84 (br d, J=2.93 Hz, 1H) 7.96 (s, 1H) 8.16-8.21 (m, 1H) 8.50 (br d, J=4.70 Hz, 1H);
MS (ESI, m/z): 594.4 [M+H]+
Example 162 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamideUsing tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate, the title compound was obtained as described for the example 134 and following deprotection with TFA.
1H NMR (400 MHz, CD3OD) δ ppm 1.62 (br s, 1H) 1.80 (br d, J=6.65 Hz, 3H) 2.03 (br s, 1H) 2.15 (br s, 1H) 2.28 (br d, J=13.69 Hz, 4H) 3.14-3.25 (m, 2H) 3.56 (br d, J=11.35 Hz, 2H) 3.90 (s, 3H) 3.97 (br s, 1H) 4.39 (br s, 1H) 4.53 (br s, 1H) 4.60 (s, 2H) 7.32 (br d, J=7.83 Hz, 2H) 7.47 (br d, J=7.83 Hz, 2H) 7.79 (s, 1H) 7.85 (s, 1H) 7.97 (br s, 2H) 8.20 (br s, 1H) 8.48 (s, 1H);
MS (ESI, m/z): 541.3 [M+H]+
Example 163 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamideUsing (1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-piperidine, the title compound was obtained as described for the example 134.
1H NMR (600 MHz, CD3OD) δ ppm 1.57-1.66 (m, 1H) 1.72-1.87 (m, 3H) 2.03 (br dd, J=12.62, 6.75 Hz, 1H) 2.17 (br s, 1H) 2.24-2.42 (m, 4H) 2.94 (s, 3H) 3.19-3.27 (m, 2H) 3.48 (br s, 1H) 3.90 (s, 3H) 3.98 (br d, J=6.46 Hz, 1H) 4.36-4.45 (m, 1H) 4.46-4.55 (m, 1H) 4.57-4.64 (m, 2H) 7.33 (br d, J=8.22 Hz, 2H) 7.47 (br d, J=8.22 Hz, 2H) 7.79 (br s, 1H) 7.84 (s, 1H) 7.97 (d, J=5.87 Hz, 2H) 8.20 (br d, J=1.76 Hz, 1H) 8.47 (s, 1H); MS (ESI, m/z): 555.3 [M+H]+
Example 164 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing (1S,2R)-2-((4-bromobenzyl)oxy)cyclopentan-1-amine and (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 134.
1H NMR (600 MHz, CD3OD) δ ppm 1.58-1.69 (m, 1H) 1.82-1.97 (m, 4H) 2.00-2.07 (m, 1H) 2.83-2.90 (m, 3H) 3.79 (s, 3H) 3.80-3.87 (m, 2H) 4.11-4.18 (m, 1H) 4.36-4.43 (m, 1H) 4.45 (d, J=11.74 Hz, 1H) 4.67 (d, J=11.74 Hz, 1H) 7.38 (d, J=8.22 Hz, 2H) 7.40-7.44 (m, 2H) 7.46 (d, J=8.22 Hz, 2H) 7.49 (d, J=8.22 Hz, 2H) 7.78 (s, 1H) 7.83 (s, 1H) 8.12-8.19 (m, 1H) 8.44 (s, 1H); MS (ESI, m/z): 580.3 [M+H]+
Example 165 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1R,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing (1R,2S)-2-((4-bromobenzyl)oxy)cyclopentan-1-amine and (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 134.
1H NMR (600 MHz, CD3OD) δ ppm 1.60-1.70 (m, 1H) 1.81-1.98 (m, 4H) 2.00-2.09 (m, 1H) 2.87 (s, 3H) 3.79 (s, 3H) 3.80-3.85 (m, 2H) 4.15 (d, J=4.70 Hz, 1H) 4.36-4.42 (m, 1H) 4.45 (d, J=11.74 Hz, 1H) 4.67 (d, J=12.33 Hz, 1H) 7.38 (d, J=8.22 Hz, 2H) 7.42 (d, J=7.04 Hz, 2H) 7.46 (d, J=8.22 Hz, 2H) 7.48-7.50 (m, 2H) 7.78 (s, 1H) 7.83 (s, 1H) 8.15 (d, J=1.76 Hz, 1H) 8.44 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 580.3 [M+H]+
Example 166 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclohexyl)nicotinamideUsing (1S,2S)-2-((4-bromobenzyl)oxy)cyclohexan-1-amine and (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 134.
1H NMR (600 MHz, CD3OD) δ ppm 1.43 (br s, 4H) 1.97-2.07 (m, 2H) 2.18 (br s, 2H) 2.32 (s, 3H) 3.40-3.48 (m, 1H) 3.58 (s, 2H) 3.80-3.89 (m, 1H) 3.90 (s, 3H) 4.61 (s, 2H) 7.41 (dd, J=14.09, 8.22 Hz, 4H) 7.55-7.62 (m, 4H) 7.78 (s, 1H) 7.89 (s, 1H) 8.03 (d, J=1.76 Hz, 1H) 8.23 (br s, 1H); MS (ESI, m/z): 594.4 [M+H]+
Example 167 2-amino-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 2-aminonicotinic acid and (4-(2-(4-methylpiperazin-1-yl)propan-2-yl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 134.
1H NMR (400 MHz, CD3OD) δ ppm 1.47 (s, 6H) 1.55-1.70 (m, 1H) 1.82 (br d, J=7.04 Hz, 3H) 2.03 (br s, 1H) 2.12-2.25 (m, 1H) 2.86 (s, 3H) 4.00 (br s, 1H) 4.40 (br s, 1H) 4.66 (s, 2H) 6.90-6.99 (m, 1H) 7.38-7.46 (m, 2H) 7.59 (br dd, J=10.96, 7.83 Hz, 6H) 8.01 (d, J=5.09 Hz, 1H) 8.33 (d, J=7.83 Hz, 1H); MS (ESI, m/z): 528.3 [M+H]+
Example 168 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 2-aminonicotinic acid, (1S,2S)-2-((4-bromo-2-(trifluoromethyl)benzyl)oxy)cyclopentan-1-amine and 4-(4-methylpiperazino)methylphenylboronic acid pinacol ester, the title compound was obtained as described for the example 134.
1H NMR (400 MHz, CD3OD) δ ppm 1.66 (dt, J=13.60, 6.70 Hz, 1H) 1.78-1.93 (m, 3H) 1.97-2.12 (m, 1H) 2.13-2.26 (m, 1H) 2.87 (s, 3H) 3.77 (s, 2H) 4.00-4.05 (m, 1H) 4.43 (br dd, J=10.76, 7.63 Hz, 1H) 6.98 (dd, J=7.43, 6.26 Hz, 1H) 7.48 (d, J=8.22 Hz, 2H) 7.65 (d, J=8.22 Hz, 2H) 7.77-7.93 (m, 3H) 8.02 (br dd, J=6.26, 1.57 Hz, 1H) 8.37 (dd, J=7.43, 1.57 Hz, 1H):
MS (ESI, m/z): 568.3[M+H]+
Example 169 amino-N-((1S,2S)-2-((3′-hydroxy-[1,1′-biphenyl]-3-yl)methoxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideScheme for the preparation of the Compound of Example 169:
To a mixture of intermediate 2 (350 mg, 1.60 mmol) and triethylamine (0.34 ml, 2.41 mmol) in 4 ml of DMF was added HATU (732 mg, 1.92 mmol) followed by (1S,2S)-2-((3-bromobenzyl)oxy)cyclopentan-1-amine (475 mg, 1.76 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified through silicagel column chromatography to give 680 mg of off-white solid.
1H NMR (400 MHz, CD3OD) δ ppm 1.58-1.69 (m, 1H) 1.72-1.88 (m, 3H) 1.96-2.08 (m, 1H) 2.16 (td, J=13.35, 7.92 Hz, 1H) 3.86-4.00 (m, 3H) 4.39 (td, J=7.48, 4.40 Hz, 1H) 4.60 (q, J=12.72 Hz, 2H) 7.20 (t, J=7.92 Hz, 1H) 7.29 (d, J=7.63 Hz, 1H) 7.35 (d, J=7.63 Hz, 1H) 7.50 (s, 1H) 7.45-7.53 (m, 1H) 7.86 (s, 1H) 8.00 (s, 1H) 8.23 (d, J=2.35 Hz, 1H) 8.46 (d, J=1.76 Hz, 1H):
MS (ESI, m/z): 470.1/472.1 [M+H]+
Example 169 2-amino-N-((1S,2S)-2-((3′-hydroxy-[1,1′-biphenyl]-3-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideTo a mixture of intermediate 5 (33 mg, 0.07 mmol) and (3-hydroxyphenyl)boronic acid (11 mg, 0.08 mmol) in 0.4 ml of 1,4-dioxane/water (3/1) was added K2CO3 (29 mg, 0.21 mmol) followed by Pd(PPh3)4 (4 mg, 0.003 mmol). The reaction mixture was heated at 100° C. for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO4 and concentrated under vacuum. The crude residue was dissolved with 0.5 ml of CH2Cl2/TFA (10/1) and the mixture was stirred for 2 hrs. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 27 mg of the title compound.
1H NMR (600 MHz, CD3OD) δ ppm 1.62 (br dd, J=12.62, 6.75 Hz, 1H) 1.81 (br d, J=4.70 Hz, 3H) 2.03 (br d, J=11.74 Hz, 1H) 2.16 (br s, 1H) 3.92 (s, 3H) 3.94-4.01 (m, 1H) 4.43 (br s, 1H) 4.64-4.74 (m, 2H) 7.13 (br d, J=6.46 Hz, 2H) 7.34-7.43 (m, 3H) 7.47 (br d, J=7.63 Hz, 2H) 7.58-7.62 (m, 1H) 7.81 (s, 1H) 7.96 (s, 1H) 8.17 (br d, J=1.76 Hz, 1H) 8.36 (br d, J=2.35 Hz, 1H); MS (ESI, m/z): 484.2 [M+H]+
Example 170 2-amino-N-((1S,2S)-2-((3′-amino-[1,1′-biphenyl]-3-yl)methoxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (3-aminophenyl)boronic acid, the title compound was obtained as described for the example 169.
MS (ESI, m/z): 483.2 [M+H]+
Example 171 2-amino-N-((1S,2S)-2-((3′-(hydroxymethyl)-[1,1′-biphenyl]-3-yl)-methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (3-(hydroxymethyl)phenyl)boronic acid, the title compound was obtained as described for the example 169.
MS (ESI, m/z): 498.2 [M+H]+
Example 172 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideScheme for the preparation of the Compound of Example 172:
To a mixture of intermediate 4 (33 mg, 0.07 mmol) and (4-formylphenyl)boronic acid (12 mg, 0.08 mmol) in 0.4 ml of 1,4-dioxane/water (3/1) was added K2CO3 (29 mg, 0.21 mmol) followed by Pd(PPh3)4 (4 mg, 0.003 mmol). The reaction mixture was heated at 100° C. for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO4. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 30 mg of the title compound.
1H NMR (400 MHz, CDCl3) δ ppm 1.52-1.62 (m, 1H) 1.74-1.85 (m, 3H) 1.85-1.93 (m, 1H) 1.97-2.06 (m, 1H) 2.27 (br dd, J=13.30, 5.48 Hz, 1H) 3.87 (s, 3H) 3.97-4.03 (m, 1H) 4.36-4.46 (m, 1H) 4.69 (s, 2H) 6.90 (br s, 1H) 7.12 (br s, 1H) 7.16-7.19 (m, 1H) 7.43-7.48 (m, 2H) 7.50 (s, 1H) 7.54-7.60 (m, 2H) 7.68 (m, J=8.22 Hz, 2H) 7.79 (s, 1H) 7.90 (m, J=8.22 Hz, 2H) 7.98 (s, 1H) 10.02 (s, 1H); MS (ESI, m/z): 496.2 [M+H]+
Example 172 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideTo intermediate 6 (30 mg, 0.06 mmol) in 0.4 ml of dichloroethane was added 1-methylpiperazine (12 mg, 0.12 mmol) followed by NaBH(OAc)3 (26 mg, 0.18 mmol). The mixture was stirred at room temperature for 4 hr and then water was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 27 mg of the title compound.
1H NMR (400 MHz, CD3OD) δ ppm 1.52-1.67 (m, 1H) 1.69-1.86 (m, 3H) 2.01 (br dd, J=12.52, 5.87 Hz, 1H) 2.08-2.21 (m, 1H) 2.28 (s, 3H) 2.51 (br s, 8H) 3.54 (s, 2H) 3.84 (s, 3H) 3.91-3.99 (m, 1H) 4.40 (br d, J=4.70 Hz, 1H) 4.64 (br d, J=3.13 Hz, 2H) 7.34 (br d, J=7.83 Hz, 2H) 7.39 (br d, J=8.22 Hz, 2H) 7.47 (br d, J=7.83 Hz, 1H) 7.50 (br d, J=7.83 Hz, 2H) 7.73 (s, 1H) 7.81 (s, 1H) 7.96 (s, 1H) 8.23 (s, 1H); MS (ESI, m/z): 580.3 [M+H]+
Example 173 2-amino-N-((1S,2S)-2-((4′-(((2-hydroxyethyl)amino)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 2-aminoethan-1-ol, the title compound was obtained as described for the example 172.
1H NMR (600 MHz, CD3OD) δ ppm 1.59-1.69 (m, 1H) 1.74-1.88 (m, 3H) 1.99-2.11 (m, 1H) 2.18 (td, J=12.91, 7.04 Hz, 1H) 3.11-3.12 (m, 1H) 3.11-3.16 (m, 1H) 3.77-3.86 (m, 2H) 3.90 (s, 3H) 3.93 (br d, J=5.87 Hz, 1H) 3.97-4.05 (m, 1H) 4.26 (s, 2H) 4.39-4.48 (m, 1H) 4.67 (s, 2H) 7.44 (d, J=8.22 Hz, 2H) 7.53 (m, J=8.22 Hz, 2H) 7.55-7.62 (m, 2H) 7.66 (d, J=8.22 Hz, 2H) 7.85 (s, 1H) 7.97 (s, 1H) 8.20 (s, 1H) 8.49 (br s, 1H);
MS (ESI, m/z): 541.3 [M+H]+
Example 174 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing morpholine, the title compound was obtained as described for the example 172.
1H NMR (600 MHz, CD3OD) δ ppm 1.57-1.69 (m, 1H) 1.74-1.90 (m, 3H) 2.04 (s, 1H) 2.14-2.23 (m, 1H) 2.19 (br d, J=7.63 Hz, 1H) 3.31-3.46 (m, 2H) 3.90 (s, 3H) 3.99-4.03 (m, 1H) 4.39 (s, 2H) 4.42 (br d, J=5.28 Hz, 1H) 4.67 (d, J=3.52 Hz, 2H) 7.45 (d, J=8.22 Hz, 2H) 7.56 (d, J=8.22 Hz, 2H) 7.59 (d, J=8.22 Hz, 2H) 7.71 (d, J=7.63 Hz, 2H) 7.85 (s, 1H) 7.98 (s, 1H) 8.21 (d, J=1.76 Hz, 1H) 8.49 (br s, 1H);
MS (ESI, m/z): 567.3 [M+H]+
Example 175 2-amino-N-((1S,2S)-2-((4′-((4-(3,3-difluoropiperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 3,3-difluoropiperidine, the title compound was obtained as described for the example 172.
MS (ESI, m/z): 601.3 [M+H]+
Example 176 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 4-methylpiperidine, the title compound was obtained as described for the example 172.
MS (ESI, m/z): 579.3 [M+H]+
Example 177 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(piperazin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing piperazine, the title compound was obtained as described for the example 172.
1H NMR (600 MHz, CD3OD) δ ppm 1.63 (br dd, J=13.50, 7.04 Hz, 1H) 1.73-1.88 (m, 3H) 2.00-2.08 (m, 1H) 2.13-2.22 (m, 1H) 2.96 (br s, 4H) 3.32 (br d, J=9.98 Hz, 4H) 3.50 (s, 1H) 3.84-3.89 (m, 2H) 3.90 (s, 3H) 4.00 (br s, 1H) 4.38-4.44 (m, 1H) 4.66 (d, J=2.93 Hz, 2H) 7.38-7.47 (m, 4H) 7.52-7.60 (m, 4H) 7.85 (s, 1H) 7.97 (s, 1H) 8.19 (d, J=2.35 Hz, 1H) 8.50 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 566.3 [M+H]+
Example 178 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-phenylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 1-phenylpiperazine, the title compound was obtained as described for the example 172.
1H NMR (600 MHz, CD3OD) δ ppm 1.61-1.69 (m, 1H) 1.76-1.87 (m, 3H) 2.00-2.07 (m, 1H) 2.15-2.23 (m, 1H) 3.90 (s, 3H) 3.98-4.04 (m, 1H) 4.39-4.44 (m, 1H) 4.45 (s, 2H) 4.68 (s, 2H) 6.92 (t, J=7.34 Hz, 1H) 7.00 (d, J=8.22 Hz, 2H) 7.27 (t, J=7.92 Hz, 2H) 7.45 (d, J=8.22 Hz, 2H) 7.60 (dd, J=9.68, 8.51 Hz, 4H) 7.72 (br d, J=8.22 Hz, 2H) 7.85 (s, 1H) 7.98 (s, 1H) 8.21 (d, J=1.76 Hz, 1H) 8.51 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 642.4 [M+H]+
Example 179 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamideUsing 4-(pyrrolidin-1-yl)piperidine, the title compound was obtained as described for the example 172.
1H NMR (600 MHz, CD3OD) δ ppm 1.60-1.69 (m, 1H) 1.74-1.88 (m, 3H) 1.96-2.23 (m, 8H) 2.43 (br d, J=13.50 Hz, 2H) 3.06-3.21 (m, 4H) 3.44 (br s, 2H) 3.66 (br d, J=12.91 Hz, 4H) 3.90 (s, 3H) 3.99-4.03 (m, 1H) 4.37 (s, 2H) 4.39-4.45 (m, 1H) 4.67 (s, 2H) 7.41-7.48 (m, 2H) 7.51-7.57 (m, 2H) 7.58 (d, J=8.22 Hz, 2H) 7.68 (br d, J=8.22 Hz, 2H) 7.85 (s, 1H) 7.98 (s, 1H) 8.20 (d, J=2.35 Hz, 1H) 8.50 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 634.4 [M+H]+
Example 180 2-amino-N-((1S,2S)-2-((4′-((4-hydroxypiperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing piperidin-4-ol, the title compound was obtained as described for the example 172.
1H NMR (600 MHz, CD3OD) δ ppm 1.59-1.68 (m, 1H) 1.74-1.87 (m, 3H) 1.92 (br s, 1H) 2.03 (dt, J=13.35, 6.53 Hz, 1H) 2.10-2.23 (m, 1H) 3.07 (br s, 1H) 3.51 (br d, J=10.56 Hz, 1H) 3.82 (br s, 1H) 3.89-3.92 (m, 3H) 3.98-4.03 (m, 1H) 4.08 (br s, 1H) 4.34 (br s, 2H) 4.39-4.45 (m, 1H) 4.67 (s, 2H) 7.45 (d, J=8.22 Hz, 2H) 7.54 (br s, 2H) 7.57-7.61 (m, 2H) 7.59 (d, J=8.22 Hz, 2H) 7.69 (br d, J=8.22 Hz, 2H) 7.85 (s, 1H) 7.99 (s, 1H) 8.21 (s, 1H) 8.52 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 581.3 [M+H]+
Example 181 2-amino-N-((1S,2S)-2-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideUsing 2-(piperazin-1-yl)ethan-1-ol, the title compound was obtained as described for the example 172.
1H NMR (600 MHz, CD3OD) δ ppm 1.64 (br dd, J=13.50, 7.04 Hz, 1H) 1.76-1.86 (m, 3H) 2.00-2.08 (m, 1H) 2.14-2.22 (m, 1H) 3.19 (br s, 2H) 3.82-3.85 (m, 2H) 3.90 (s, 3H) 3.98-4.02 (m, 1H) 4.39-4.44 (m, 1H) 4.66 (s, 2H) 7.40-7.47 (m, 4H) 7.53-7.61 (m, 4H) 7.85 (s, 1H) 7.97 (s, 1H) 8.20 (d, J=2.35 Hz, 1H) 8.52 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 610.3 [M+H]+
Example 182 2-amino-N-((1S,2S)-2-((4′-((4-(2-hydroxy-2-methylpropyl)-piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 2-methyl-1-(piperazin-1-yl)propan-2-ol, the title compound was obtained as described for the example 172.
MS (ESI, m/z): 638.4 [M+H]+
Example 183 2-amino-N-((1S,2S)-2-((4′-((4-ethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 1-ethylpiperazine, the title compound was obtained as described for the example 172.
1H NMR (600 MHz, CD3OD) δ ppm 1.32 (t, J=7.34 Hz, 3H) 1.59-1.68 (m, 1H) 1.74-1.88 (m, 3H) 2.04 (dq, J=13.50, 6.85 Hz, 1H) 2.13-2.21 (m, 1H) 3.18 (br d, J=7.63 Hz, 2H) 3.78-3.87 (m, 2H) 3.90 (s, 3H) 3.98-4.02 (m, 1H) 4.38-4.44 (m, 1H) 4.66 (d, J=1.76 Hz, 2H) 7.38-7.46 (m, 4H) 7.51-7.60 (m, 4H) 7.85 (s, 1H) 7.97 (s, 1H) 8.19 (d, J=2.35 Hz, 1H) 8.51 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 594.4 [M+H]+
Example 184 2-amino-N-((1S,2S)-2-((4′-((4-cyclopropylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 1-cyclopropylpiperazine, the title compound was obtained as described for the example 172.
MS (ESI, m/z): 606.4 [M+H]+
Example 185 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(((R)-3-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing tert-butyl(R)-2-methylpiperazine-1-carboxylate, the title compound was obtained as described for the example 172 and following deprotection with TFA.
MS (ESI, m/z): 580.3 [M+H]+
Example 186 2-amino-N-((1S,2S)-2-((4′-(((R)-3,4-dimethylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideUsing (R)-1,2-dimethylpiperazine, the title compound was obtained as described for the example 172.
MS (ESI, m/z): 594.4 [M+H]+
Example 187 2-amino-N-((1S,2S)-2-((4′-(((R)-2,4-dimethylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideUsing (R)-1,3-dimethylpiperazine, the title compound was obtained as described for the example 172.
1H NMR (400 MHz, CD3OD) δ ppm 1.34 (br d, J=5.09 Hz, 3H) 1.63 (br dd, J=15.06, 6.46 Hz, 1H) 1.81 (br d, J=7.43 Hz, 3H) 2.03 (br d, J=6.26 Hz, 1H) 2.18 (s, 1H) 2.55 (br s, 1H) 2.82 (s, 3H) 2.92 (br s, 1H) 3.02 (br d, J=12.52 Hz, 1H) 3.89 (s, 3H) 4.00 (br s, 1H) 4.30 (br d, J=11.35 Hz, 1H) 4.42 (br s, 1H) 4.65 (s, 2H) 7.41 (br d, J=7.43 Hz, 4H) 7.54 (br dd, J=7.63, 3.33 Hz, 4H) 7.84 (s, 1H) 7.96 (s, 1H) 8.19 (s, 1H) 8.50 (s, 1H);
MS (ESI, m/z): 594.4 [M+H]+
Example 188 2-amino-N-((1S,2S)-2-((4′-((3-ethyl-4-methylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideUsing 2-ethyl-1-methylpiperazine, the title compound was obtained as described for the example 172.
1H NMR (400 MHz, CD3OD) δ ppm 0.96 (br t, J=7.24 Hz, 3H) 1.62 (br d, J=14.48 Hz, 3H) 1.81 (br d, J=7.43 Hz, 3H) 1.92 (br s, 1H) 2.04 (br s, 1H) 2.16 (br d, J=7.04 Hz, 1H) 2.87 (s, 3H) 3.20 (br d, J=14.09 Hz, 1H) 3.45 (br d, J=13.30 Hz, 1H) 3.70 (br d, J=13.30 Hz, 1H) 3.81 (br d, J=12.91 Hz, 1H) 3.89 (s, 3H) 3.99 (br s, 1H) 4.42 (br s, 1H) 4.65 (s, 2H) 7.41 (br d, J=8.22 Hz, 4H) 7.55 (br d, J=7.43 Hz, 4H) 7.85 (s, 1H) 7.97 (s, 1H) 8.19 (s, 1H) 8.51 (s, 1H);
MS (ESI, m/z): 608.4 [M+H]+
Example 189 2-amino-N-((1S,2S)-2-((4′-((cis-3,5-dimethylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideUsing tert-butyl cis-2,6-dimethylpiperazine-1-carboxylate, the title compound was obtained as described for the example 172 and following deprotection with TFA.
1H NMR (400 MHz, CD3OD) δ ppm 1.27 (br d, J=6.26 Hz, 6H) 1.64 (br d, J=5.87 Hz, 1H) 1.81 (br d, J=7.04 Hz, 3H) 1.96-2.24 (m, 3H) 3.09 (d, J=12.91 Hz, 2H) 3.62 (br s, 5H) 3.68 (s, 3H) 3.89 (s, 3H) 4.00 (br s, 1H) 4.37-4.45 (m, 1H) 4.65 (s, 2H) 7.34-7.46 (m, 4H) 7.53 (br d, J=7.43 Hz, 4H) 7.83 (s, 1H) 7.95 (s, 1H) 8.20 (s, 1H) 8.45 (s, 1H);
MS (ESI, m/z): 594.4 [M+H]+
Example 190 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((cis-3,4,5-trimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamideUsing cis-1,2,6-trimethylpiperazine, the title compound was obtained as described for the example 172.
1H NMR (600 MHz, CD3OD) δ ppm 1.30 (br d, J=6.46 Hz, 6H) 1.64 (br dd, J=13.50, 7.04 Hz, 1H) 1.74-1.90 (m, 3H) 2.00-2.09 (m, 1H) 2.18 (br dd, J=12.91, 5.87 Hz, 1H) 2.30 (br d, J=12.91 Hz, 3H) 3.22 (br s, 3H) 3.45 (br s, 2H) 3.84 (br d, J=19.37 Hz, 2H) 3.90 (s, 3H) 3.97-4.03 (m, 1H) 4.38-4.45 (m, 1H) 4.66 (s, 2H) 4.69 (s, 1H) 7.42 (br d, J=7.63 Hz, 4H) 7.49-7.62 (m, 4H) 7.85 (s, 1H) 7.97 (s, 1H) 8.20 (d, J=2.35 Hz, 1H) 8.52 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 608.4 [M+H]+
Example 191 2-amino-N-((1S,2S)-2-((4′-((trans-2,5-dimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing trans-2,5-dimethylpiperazine, the title compound was obtained as described for the example 172.
MS (ESI, m/z): 594.4 [M+H]+
Example 192 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(((2R,5S)-2,4,5-trimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing trans-1,2,5-trimethylpiperazine, the title compound was obtained as described for the example 172.
MS (ESI, m/z): 608.4 [M+H]+
Example 193 2-amino-N-((1S,2S)-2-((4′-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing N,N-Dimethyl-3-pyrrolidinamine, the title compound was obtained as described for the example 172.
MS (ESI, m/z): 594.4 [M+H]+
Example 194 3-amino-6-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)pyrazine-2-carboxamideUsing 3-amino-6-(1-methyl-1H-pyrazol-4-yl)pyrazine-2-carboxylic acid, the title compound was obtained as described for the example 172.
1H NMR (600 MHz, CD3OD) δ ppm 1.60-1.69 (m, 1H) 1.70-1.78 (m, 1H) 1.78-1.87 (m, 2H) 2.03-2.20 (m, 3H) 2.88 (d, J=1.76 Hz, 3H) 3.00 (br s, 4H) 3.34 (br d, J=11.74 Hz, 3H) 3.85 (s, 3H) 3.91 (br d, J=11.74 Hz, 2H) 3.99-4.06 (m, 1H) 4.33-4.40 (m, 1H) 4.59-4.70 (m, 2H) 7.38 (d, J=8.22 Hz, 2H) 7.42 (br d, J=8.22 Hz, 2H) 7.47 (d, J=8.22 Hz, 2H) 7.52 (br d, J=8.22 Hz, 2H) 7.99 (s, 1H) 8.12 (s, 1H) 8.41 (s, 1H);
MS (ESI, m/z): 581.3 [M+H]+
Example 195 2-amino-N-((1S,2S)-2-((3′-fluoro-4′-((4-methylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideUsing (3-fluoro-4-formylphenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172.
1H NMR (400 MHz, CD3OD) δ ppm 1.63 (br dd, J=13.69, 7.04 Hz, 1H) 1.72-1.90 (m, 3H) 1.96-2.09 (m, 1H) 2.10-2.23 (m, 1H) 2.90 (s, 3H) 3.05-3.27 (m, 4H) 3.34-3.51 (m, 4H) 3.89 (s, 3H) 3.94-4.01 (m, 1H) 4.07 (s, 2H) 4.34-4.47 (m, 1H) 4.60-4.73 (m, 2H) 5.47 (s, 1H) 7.35 (br d, J=11.35 Hz, 1H) 7.42 (br d, J=7.83 Hz, 3H) 7.50 (br t, J=7.83 Hz, 1H) 7.55 (d, J=8.22 Hz, 2H) 7.83 (s, 1H) 7.97 (s, 1H) 8.17 (d, J=1.96 Hz, 1H) 8.50 (d, J=1.96 Hz, 1H);
MS (ESI, m/z): 598.7 [M+H]+
Example 196 2-amino-N-((1S,2S)-2-((3′,5′-difluoro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing ((3,5-difluoro-4-formylphenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172.
1H NMR (400 MHz, CD3OD) δ ppm 1.63 (br dd, J=13.30, 7.04 Hz, 1H) 1.71-1.91 (m, 3H) 2.03 (br dd, J=12.91, 5.48 Hz, 1H) 2.12-2.23 (m, 1H) 2.87 (s, 3H) 2.94 (br d, J=18.00 Hz, 3H) 3.32 (br s, 4H) 3.90 (s, 3H) 3.99 (br s, 1H) 4.40 (br d, J=3.91 Hz, 1H) 4.62-4.77 (m, 2H) 7.24 (br d, J=8.61 Hz, 2H) 7.44 (m, J=7.83 Hz, 2H) 7.57 (m, J=7.83 Hz, 2H) 7.83 (s, 1H) 7.98 (s, 1H) 8.19 (s, 1H) 8.50 (s, 1H);
MS (ESI, m/z): 616.8 [M+H]+
Example 197 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)-cyclopentyl)nicotinamideUsing (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172.
1H NMR (400 MHz, CD3OD) δ ppm 1.59-1.71 (m, 1H) 1.75-1.89 (m, 3H) 1.99-2.10 (m, 1H) 2.13-2.25 (m, 1H) 2.91 (s, 3H) 3.47 (br d, J=1.57 Hz, 2H) 3.81 (s, 2H) 3.91 (s, 3H) 4.02 (br d, J=4.30 Hz, 1H) 4.39-4.46 (m, 1H) 4.69 (s, 2H) 7.47 (m, J=8.22 Hz, 2H) 7.60 (m, J=8.22 Hz, 2H) 7.83 (d, J=8.22 Hz, 4H) 7.98 (s, 1H) 8.21 (d, J=1.96 Hz, 1H) 8.50 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 648.32 [M+H]+
Example 198 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-methyl-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamideUsing (4-formyl-3-methylphenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172.
1H NMR (400 MHz, CD3OD) δ ppm 1.64 (br dd, J=13.11, 6.85 Hz, 2H) 1.72-1.90 (m, 3H) 1.82 (br s, 1H) 1.94-2.09 (m, 2H) 2.10-2.24 (m, 2H) 2.43 (s, 1H) 2.88 (s, 3H) 3.29-3.31 (m, 11H) 3.69 (s, 1H) 3.90 (s, 2H) 3.93-3.96 (m, 1H) 4.01 (br d, J=4.70 Hz, 1H) 4.16 (s, 1H) 4.37-4.47 (m, 1H) 4.66 (d, J=3.13 Hz, 1H) 7.37-7.43 (m, 2H) 7.51-7.55 (m, 1H) 7.52-7.59 (m, 1H) 7.85 (d, J=0.78 Hz, 1H) 7.96 (s, 1H) 8.19 (d, J=1.96 Hz, 1H) 8.49 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 594.4 [M+H]+
Example 199 2-amino-N-((1S,2S)-2-((3′-hydroxy-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-formyl-3-hydroxyphenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172.
1H NMR (400 MHz, CD3OD) δ ppm 1.64 (br dd, J=12.72, 6.85 Hz, 1H) 1.74-1.90 (m, 3H) 2.05 (br s, 1H) 2.12-2.26 (m, 1H) 2.82 (d, J=3.13 Hz, 3H) 3.13 (br s, 5H) 3.91 (s, 3H) 4.01 (br d, J=6.26 Hz, 1H) 4.05 (s, 1H) 4.08 (s, 1H) 4.38-4.46 (m, 1H) 4.66 (s, 2H) 7.05 (s, 1H) 7.28 (br d, J=8.61 Hz, 1H) 7.25-7.34 (m, 1H) 7.32 (br d, J=7.83 Hz, 1H) 7.41 (d, J=8.22 Hz, 2H) 7.52 (d, J=8.22 Hz, 2H) 7.54-7.59 (m, 1H) 7.85 (s, 1H) 7.97 (s, 1H) 8.20 (d, J=2.35 Hz, 1H) 8.48 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 596.3 [M+H]+
Example 200 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3′-nitro-[1,1′-biphenyl]-4-yl)methoxy)-cyclopentyl)nicotinamideUsing (4-formyl-3-nitrophenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172.
1H NMR (400 MHz, CD3OD) δ ppm 1.64 (dt, J=13.89, 7.14 Hz, 1H) 1.74-1.91 (m, 3H) 2.00-2.10 (m, 1H) 2.13-2.24 (m, 1H) 2.88 (s, 3H) 3.35-3.39 (m, 2H) 3.91 (s, 3H) 3.92-3.95 (m, 2H) 3.99-4.03 (m, 1H) 4.39-4.47 (m, 1H) 4.69 (d, J=3.13 Hz, 2H) 7.48 (d, J=8.22 Hz, 2H) 7.60-7.65 (m, 4H) 7.83 (s, 1H) 7.97 (s, 1H) 8.02 (d, J=1.96 Hz, 1H) 8.21 (d, J=2.35 Hz, 1H) 8.48 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 625.3 [M+H]+
Example 201 2-amino-N-((1S,2S)-2-((3′-methoxy-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-formyl-3-methoxyphenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172.
1H NMR (400 MHz, CD3OD) δ ppm 1.65 (br dd, J=13.50, 6.46 Hz, 1H) 1.74-1.91 (m, 3H) 1.99-2.10 (m, 1H) 2.19 (br d, J=6.65 Hz, 1H) 2.81 (s, 3H) 3.91 (s, 3H) 3.92 (s, 3H) 3.98-4.07 (m, 1H) 4.43 (br d, J=3.52 Hz, 1H) 4.68 (s, 2H) 7.15-7.24 (m, 2H) 7.37-7.47 (m, 3H) 7.59 (d, J=8.22 Hz, 2H) 7.86 (s, 1H) 7.98 (s, 1H) 8.21 (d, J=1.96 Hz, 1H) 8.51 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 610.3 [M+H]+
Example 202 2-amino-N-((1S,2S)-2-((2′-chloro-4′-((4-methylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideUsing (2-chloro-4-formylphenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172.
MS (ESI, m/z): 614.3 [M+H]+
Example 203 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-((4-methylpiperazin-1-yl)methyl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamideUsing ((6-formylpyridin-3-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 172.
1H NMR (400 MHz, CD3OD) δ ppm 1.65 (dt, J=13.60, 7.09 Hz, 1H) 1.74-1.90 (m, 3H) 2.05 (br dd, J=13.11, 6.46 Hz, 1H) 2.13-2.26 (m, 1H) 2.90 (s, 3H) 3.91-3.94 (m, 3H) 3.99-4.06 (m, 1H) 4.43 (br dd, J=11.93, 6.85 Hz, 1H) 7.52 (d, J=8.22 Hz, 2H) 7.64-7.68 (m, 2H) 7.72 (br dd, J=12.33, 8.41 Hz, 2H) 7.85 (s, 1H) 7.99 (s, 1H) 8.22 (d, J=2.35 Hz, 1H) 8.51 (d, J=1.96 Hz, 1H) 8.82 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 581.3 [M+H]+
Example 204 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-yl)benzyl)oxy)cyclopentyl)nicotinamideUsing (5-formylpyridin-2-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 172.
1H NMR (400 MHz, CD3OD) δ ppm 1.66 (td, J=14.09, 7.04 Hz, 1H) 1.76-1.92 (m, 3H) 1.98-2.11 (m, 1H) 2.19 (br s, 1H) 2.90 (s, 3H) 3.64 (s, 1H) 3.76 (s, 3H) 3.98-4.07 (m, 1H) 4.38-4.48 (m, 1H) 7.52 (d, J=8.22 Hz, 2H) 7.84 (s, 1H) 7.90 (dd, J=8.41, 1.76 Hz, 3H) 7.98 (s, 1H) 8.02 (br d, J=8.61 Hz, 1H) 8.21 (d, J=1.96 Hz, 1H) 8.50 (d, J=1.96 Hz, 1H) 8.60 (s, 1H);
MS (ESI, m/z): 581.3 [M+H]+
Example 205 2-amino-N-((1S,2S)-2-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester and 2-(piperazin-1-yl)ethan-1-ol, the title compound was obtained as described for the example 11′)
1H NMR (400 MHz, CD3OD) δ ppm 1.57-1.72 (m, 1H) 1.75-1.90 (m, 3H) 2.04 (dt, J=12.81, 6.70 Hz, 1H) 2.13-2.26 (m, 1H) 3.82 (s, 2H) 3.86-3.90 (m, 2H) 3.91 (s, 3H) 3.97-4.05 (m, 1H) 4.43 (br dd, J=11.93, 6.46 Hz, 1H) 4.69 (s, 2H) 7.48 (d, J=8.22 Hz, 2H) 7.60 (d, J=8.22 Hz, 2H) 7.81-7.87 (m, 3H) 7.99 (s, 1H) 8.22 (d, J=2.35 Hz, 1H) 8.51 (d, J=1.96 Hz, 1H);
MS (ESI, m/z): 678.3[M+H]+
Example 206 2-amino-N-((1S,2S)-2-((2′-chloro-4′-((4-(2-hydroxyethyl)-piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (2-chloro-4-formylphenyl)boronic acid pinacol ester and 2-(piperazin-1-yl)ethan-1-ol, the title compound was obtained as described for the example 172.
MS (ESI, m/z): 644.3 [M+H]+
Example 207 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 2-aminonicotinic acid and (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 172.
1H NMR (400 MHz, CD3OD) δ ppm 1.53-1.69 (m, 1H) 1.76-1.89 (m, 3H) 2.01 (s, 1H) 2.18 (br dd, J=13.30, 5.87 Hz, 1H) 2.48 (br s, 2H) 2.91 (s, 3H) 3.82 (s, 2H) 3.99 (br d, J=4.30 Hz, 1H) 4.40 (br d, J=5.09 Hz, 1H) 4.68 (d, J=4.30 Hz, 2H) 6.95 (dd, J=7.43, 6.26 Hz, 1H) 7.47 (d, J=8.22 Hz, 2H) 7.62 (d, J=8.22 Hz, 2H) 7.84-7.92 (m, 3H) 7.98-8.05 (m, 1H) 8.32 (dd, J=7.43, 1.56 Hz, 1H);
MS (ESI, m/z): 568.3 [M+H]+
Example 208 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideScheme for the preparation of the Compound of Example 208:
To a mixture of intermediate 4 (100 mg, 0.21 mmol) and (4-acetylphenyl)boronic acid (52 mg, 0.32 mmol) in 1.2 ml of 1,4-dioxane/water (3/1) was added K2CO3 (88 mg, 0.64 mmol) followed by Pd(PPh3)4 (12 mg, 0.01 mmol). The reaction mixture was heated at 100° C. for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO4. After concentration under vacuum, the crude product was purified by silicagel column chromatography to give 80 mg of off-white solid
1H NMR (600 MHz, CD3OD) δ ppm 1.62 (br dd, J=13.21, 7.34 Hz, 1H) 1.74-1.88 (m, 3H) 2.05 (br dd, J=12.62, 7.34 Hz, 1H) 2.17 (br dd, J=13.21, 5.58 Hz, 1H) 2.62 (s, 3H) 3.89 (s, 3H) 3.96-4.01 (m, 1H) 4.38-4.45 (m, 1H) 4.61-4.73 (m, 2H) 7.45 (d, J=8.22 Hz, 2H) 7.60 (d, J=8.22 Hz, 2H) 7.66 (d, J=8.22 Hz, 2H) 7.82 (s, 1H) 7.94 (s, 1H) 8.01 (d, J=8.22 Hz, 2H) 8.18 (d, J=1.76 Hz, 1H) 8.44 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 510.8[M+H]+
Example 208 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′41-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideTo a mixture of intermediate 7 (30 mg, 0.06 mmol) in 0.4 ml of methanol was added 1-methylpiperazine (14 μl, 0.12 mmol) followed by NaBH3CN (11 mg, 0.18 mmol). The mixture was stirred at room temperature for 4 hr and then water was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 17 mg of the title compound.
1H NMR (600 MHz, CD3OD) δ ppm 1.40 (d, J=6.46 Hz, 3H) 1.59 (br dd, J=13.21, 7.34 Hz, 1H) 1.73-1.85 (m, 3H) 1.98-2.05 (m, 1H) 2.15 (br dd, J=13.21, 5.58 Hz, 1H) 2.31 (s, 3H) 2.35-2.77 (m, 8H) 3.41-3.48 (m, 1H) 3.86 (s, 3H) 3.90-3.99 (m, 1H) 4.37-4.44 (m, 1H) 4.61-4.70 (m, 2H) 7.34 (d, J=7.63 Hz, 2H) 7.39 (br d, J=7.63 Hz, 2H) 7.48 (br d, J=7.63 Hz, 2H) 7.50 (br d, J=8.22 Hz, 2H) 7.74 (s, 1H) 7.82 (d, J=2.93 Hz, 1H) 7.96 (s, 1H) 8.22-8.26 (m, 1H);
MS (ESI, m/z): 594.7 [M+H]+
Example 209 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(1-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)-cyclopentyl)nicotinamideUsing (2S,6R)-1,2,6-trimethylpiperazine, title compound was obtained as described for the example 208.
MS (ESI, m/z): 622.4 [M+H]+
Example 210 2-amino-N-((1S,2S)-2-((4′41-(4-(2-hydroxyethyl)piperazin-1-yl)-ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideUsing 1-(2-hydroxyethyl)piperazine, title compound was obtained as described for the example 208.
1H NMR (600 MHz, CD3OD) δ ppm 1.64 (br dd, J=13.50, 7.04 Hz, 1H) 1.69 (d, J=7.04 Hz, 3H) 1.75-1.88 (m, 3H) 2.00-2.08 (m, 1H) 2.18 (br dd, J=13.50, 5.87 Hz, 1H) 3.16-3.23 (m, 2H) 3.23-3.27 (m, 2H) 3.53 (br s, 4H) 3.84 (br t, J=4.99 Hz, 2H) 3.90 (s, 3H) 3.98-4.03 (m, 1H) 4.25 (br d, J=7.04 Hz, 1H) 4.38-4.45 (m, 1H) 4.64-4.70 (m, 2H) 7.43 (d, J=7.63 Hz, 2H) 7.51 (m, J=8.22 Hz, 2H) 7.56 (m, J=8.22 Hz, 2H) 7.64 (d, J=8.22 Hz, 2H) 7.85 (s, 1H) 7.98 (s, 1H) 8.19 (s, 1H) 8.53 (s, 1H);
MS (ESI, m/z): 624.4 [M+H]+
Example 211 2-amino-N-((1S,2S)-2-((4′-((1-((3S,5R)-4-(2-hydroxyethyl)-3,5-dimethylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 2-(cis-2,6-dimethylpiperazin-1-yl)ethan-1-ol, title compound was obtained as described for the example 208.
MS (ESI, m/z): 652.4 [M+H]+
Example 212 2-amino-N-((1S,2S)-2-((3′,5′-difluoro-4′-(1-(4-(2-hydroxyethyl)-piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-acetyl-3,5-difluorophenyl)boronic acid pinacol ester and 2-(piperazin-1-yl)ethan-1-ol, the title compound was obtained as described for the example 208.
MS (ESI, m/z): 660.32 [M+H]+
Scheme for the preparation of the intermediate 9:
A mixture of (S)-1-(4-Bromophenyl)ethylamine (300 mg, 1.50 mmol) and (N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide (533 mg, 1.80 mmol) in 3 ml of DIPEA was heated at 120° C. for 24 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO4. After concentration under vacuum, the crude product was purified by silicagel column chromatography to give 500 mg of off-white solid
1H NMR (600 MHz, DMSO-d6) δ ppm 1.16 (d, J=6.46 Hz, 3H) 2.27-2.33 (m, 2H) 2.39 (s, 5H) 2.78 (br s, 4H) 3.37-3.44 (m, 1H) 7.16 (d, J=7.87 Hz, 2H) 7.43 (t, J=7.59 Hz, 4H) 7.55-7.60 (m, 2H):
MS (ESI, m/z): 423.1/425.2[M+H]+
Intermediate 9 (S)-1-(1-(4-bromophenyl)ethyl)piperazineIntermediate 8 (0.5 g, 1.1 mmol) in 5 ml of HBr in AcOH was stirred at room temperature for 24 hrs. After concentration under vacuum, the crude product was diluted with EtOAC and the solid was collected by filtration to give 0.5 g of off-white solid
1H NMR (600 MHz, DMSO-d6) δ ppm 1.63 (br s, 3H) 3.40 (br s, 1H) 3.47-3.72 (br s, 8H) 7.54 (br s, 2H) 7.69 (br d, J=7.63 Hz, 2H);
MS (ESI, m/z): 269.1/271.4 [M+H]+
Intermediate 10 (R)-1-(1-(4-bromophenyl)ethyl)piperazineUsing (R)-1-(4-Bromophenyl)ethylamine, the title compound was obtained as described for the intermediate 9.
MS (ESI, m/z): 269.1/271.4 [M+H]+
Intermediate 11 1-(1-(4-bromophenyl)cyclopropyl)piperazineUsing 1-(4-Bromophenyl)cyclopropan-1-amine, the title compound was obtained as described for the intermediate 9.
MS (ESI, m/z): 281.1/283.4 [M+H]+
Intermediate 12 1-(2-(4-bromophenyl)propan-2-yl)piperazineUsing 2-(4-Bromophenyl)propan-2-amine, the title compound was obtained as described for the intermediate 9.
MS (ESI, m/z): 283.1/285.4 [M+H]+
Example 213 and 214Scheme for the preparation of the Compounds of Example 213 and 214;
To a mixture of intermediate 4 (0.56 g, 1.19 mmol) and bis(pinacalato)diboron (0.6 g, 2.38 mmol) in 6 ml of 1,4-dioxane was added KOAc (0.35 g, 3.57 mmol) followed by Pd(PPh3)4 (69 mg, 0.06 mmol). The reaction mixture was heated at 110° C. for 5 hrs, cooled to room temperature, and partitioned between water and EtOAc, dried over anhydrous MgSO4. After concentration under vacuum, the crude product was purified by silicagel column chromatography to give 0.5 g of light yellow solid
1H NMR (400 MHz, CD3OD) δ ppm 1.19 (s, 6H) 1.30 (s, 6H) 1.60 (br dd, J=13.30, 7.04 Hz, 1H) 1.68-1.88 (m, 3H) 1.93-2.06 (m, 1H) 2.15 (br dd, J=13.11, 6.06 Hz, 1H) 3.90 (s, 3H) 3.92-3.99 (m, 1H) 4.32-4.44 (m, 1H) 4.64 (s, 2H) 7.33 (m, J=7.83 Hz, 2H) 7.66 (m, J=7.83 Hz, 2H) 7.75 (s, 1H) 7.85 (s, 1H) 7.97 (d, J=1.96 Hz, 1H) 8.20-8.30 (m, 1H);
MS (ESI, m/z): 518.3 [M+H]+
Example 213 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((R)-1-(piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideTo a mixture of intermediate 13 (150 mg, 0.29 mmol) and intermediate 10 (100 mg, 0.29 mmol) in 1.5 ml of 1,4-dioxane/water (3/1) was added K2CO3 (120 mg, 0.87 mmol) followed by Pd(PPh3)4 (17 mg, 0.01 mmol). The reaction mixture was heated at 100° C. for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO4. After concentration under vacuum, the crude product was purified by silicagel column chromatography to give 130 mg of off-white solid
1H NMR (600 MHz, CD3OD) δ ppm 1.40 (d, J=6.46 Hz, 3H) 1.54-1.63 (m, 1H) 1.73-1.86 (m, 3H) 1.98-2.05 (m, 1H) 2.12-2.19 (m, 1H) 2.40 (br s, 2H) 2.82 (t, J=4.99 Hz, 4H) 3.40 (q, J=6.46 Hz, 1H) 3.86 (s, 3H) 3.95 (dt, J=6.90, 4.48 Hz, 1H) 4.41 (td, J=7.63, 4.70 Hz, 1H) 4.61-4.70 (m, 2H) 5.48 (s, 1H) 7.33 (d, J=8.22 Hz, 2H) 7.39 (d, J=8.22 Hz, 2H) 7.44-7.49 (m, 2H) 7.49-7.55 (m, 2H) 7.74 (s, 1H) 7.83 (s, 1H) 7.97 (d, J=2.35 Hz, 1H) 8.23 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 580.6[M+H]+
Example 214 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((R)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideTo compound 213 (20 mg, 0.03 mmol) in 0.2 ml of 1,2-dichloroethane was added formaldehyde (0.005 ml, 0.06 mmol) followed by NaBH(OAc)3 (13 mg, 0.09 mmol). The mixture was stirred at room temperature for 1 hr and then water was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 15 mg of the title compound.
1H NMR (600 MHz, CD3OD) δ ppm 1.64 (dd, J=13.50, 7.04 Hz, 1H) 1.71 (d, J=7.04 Hz, 3H) 1.75-1.88 (m, 3H) 2.00-2.10 (m, 1H) 2.12-2.23 (m, 1H) 2.91 (s, 3H) 3.20-3.28 (m, 2H) 3.52 (br s, 4H) 3.90 (s, 3H) 4.00 (dt, J=6.46, 4.40 Hz, 1H) 4.32 (q, J=6.65 Hz, 1H) 4.42 (td, J=7.34, 4.11 Hz, 1H) 4.63-4.71 (m, 2H) 7.43 (d, J=8.22 Hz, 2H) 7.52 (d, J=8.22 Hz, 2H) 7.56 (d, J=8.22 Hz, 2H) 7.64 (d, J=8.22 Hz, 2H) 7.85 (s, 1H) 7.98 (s, 1H) 8.20 (d, J=1.76 Hz, 1H) 8.53 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 594.8 [M+H]+
Example 215 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing intermediate 9, the title compound was obtained as described for the example 214.
1H NMR (600 MHz, CD3OD) δ ppm 1.51 (d, J=7.04 Hz, 3H) 1.64 (br dd, J=13.21, 6.75 Hz, 1H) 1.76-1.85 (m, 3H) 2.01-2.06 (m, 1H) 2.14 (s, 1H) 2.15-2.20 (m, 1H) 2.84 (s, 3H) 3.82 (br d, J=6.46 Hz, 1H) 3.90 (s, 3H) 3.98-4.02 (m, 1H) 4.42 (br dd, J=6.75, 3.23 Hz, 1H) 4.66 (s, 2H) 7.42 (dd, J=8.22, 1.76 Hz, 4H) 7.54-7.59 (m, 4H) 7.86 (s, 1H) 7.98 (s, 1H) 8.20 (d, J=2.35 Hz, 1H) 8.53 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 594.8 [M+H]+
Example 216 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′(1-(4-methylpiperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamideUsing intermediate 11, the title compound was obtained as described for the example 214.
1H NMR (600 MHz, CD3OD) δ ppm 0.85-0.88 (m, 1H) 0.89-0.92 (m, 1H) 0.99-1.01 (m, 1H) 1.01-1.04 (m, 1H) 1.64 (br dd, J=13.50, 6.46 Hz, 1H) 1.75-1.88 (m, 3H) 2.01-2.07 (m, 1H) 2.16-2.24 (m, 2H) 2.79 (d, J=1.76 Hz, 3H) 3.00 (br s, 2H) 3.15-3.21 (m, 2H) 3.34-3.43 (m, 4H) 3.90 (s, 3H) 4.00 (dt, J=6.46, 4.11 Hz, 1H) 4.42 (td, J=7.34, 4.70 Hz, 1H) 4.66 (s, 2H) 7.26 (d, J=8.31 Hz, 2H) 7.37-7.40 (m, 2H) 7.40-7.43 (m, 2H) 7.49-7.52 (m, 1H) 7.86 (s, 1H) 7.98 (s, 1H) 8.20 (d, J=1.76 Hz, 1H) 8.54 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 606.3 [M+H]+
Example 217 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-nicotinamideUsing intermediate 12, the title compound was obtained as described for the example 214.
1H NMR (400 MHz, CD3OD) δ ppm 1.49 (s, 5H) 1.60-1.61 (m, 1H) 1.60-1.66 (m, 1H) 1.80-1.88 (m, 3H) 2.02-2.08 (m, 1H) 2.17 (br s, 1H) 2.87 (s, 3H) 3.90 (s, 3H) 4.02 (br s, 1H) 4.40-4.47 (m, 1H) 4.67 (s, 2H) 7.42 (d, J=8.22 Hz, 2H) 7.51-7.58 (m, 4H) 7.58-7.62 (m, 2H) 7.85 (d, J=0.78 Hz, 1H) 7.98 (s, 1H) 8.20 (d, J=2.35 Hz, 1H) 8.51 (d, J=1.96 Hz, 1H);
MS (ESI, m/z): 608.2 [M+H]+
Example 218 2-amino-N-((1S,2S)-2-((4′-((R)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideScheme for the preparation of the Compound of Example 218;
To a mixture of compound 213 (20 mg, 0.03 mmol) and K2CO3 (14 mg, 0.1 mmol) in 0.3 ml of methanol was added 2-bromothanol (4 μl, 0.05 mmol). The reaction mixture was stirred at room temperature for 3 hrs, After concentration under vacuum, the crude product was purified by HPLC to give 10 mg of off-white solid
1H NMR (600 MHz, CD3OD) δ ppm 1.60-1.71 (m, 1H) 1.75 (d, J=7.04 Hz, 3H) 1.76-1.85 (m, 3H) 2.00-2.09 (m, 1H) 2.14-2.23 (m, 1H) 3.33-3.44 (m, 2H) 3.56-3.73 (m, 4H) 3.83-3.87 (m, 2H) 3.90 (s, 3H) 4.00 (dt, J=6.60, 4.33 Hz, 1H) 4.38-4.45 (m, 2H) 4.64-4.70 (m, 2H) 7.43 (d, J=8.22 Hz, 2H) 7.54 (d, J=8.22 Hz, 2H) 7.56-7.61 (m, 2H) 7.64-7.71 (m, 2H) 7.85 (s, 1H) 7.98 (s, 1H) 8.20 (d, J=1.76 Hz, 1H) 8.53 (s, 1H);
MS (ESI, m/z): 624.8 [M+H]+
Example 219 2-amino-N-((1S,2S)-2-((4′-((S)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideUsing intermediate 9, the title compound was obtained as described for the example 213 and 218.
1H NMR (600 MHz, CD3OD) δ ppm 1.58 (d, J=7.04 Hz, 3H) 1.64 (br dd, J=13.21, 6.75 Hz, 1H) 1.72-1.87 (m, 3H) 2.00-2.07 (m, 1H) 2.15-2.23 (m, 1H) 2.99 (br s, 2H) 3.17-3.22 (m, 3H) 3.35-3.44 (m, 4H) 3.80-3.85 (m, 3H) 3.90 (s, 3H) 3.96-4.03 (m, 2H) 4.42 (td, J=7.34, 4.11 Hz, 1H) 4.66 (s, 2H) 7.42 (d, J=8.22 Hz, 2H) 7.46 (d, J=8.22 Hz, 2H) 7.55-7.57 (m, 2H) 7.60 (d, J=8.22 Hz, 2H) 7.86 (s, 1H) 7.98 (s, 1H) 8.20 (d, J=2.35 Hz, 1H) 8.52 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 624.8 [M+H]+
Example 220 2-amino-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing intermediate 11, the title compound was obtained as described for the example 213 and 218.
1H NMR (600 MHz, CD3OD) δ ppm 0.85-0.88 (m, 1H) 0.91-0.94 (m, 1H) 1.00-1.03 (m, 1H) 1.05-1.07 (m, 1H) 1.64 (dd, J=13.21, 6.75 Hz, 1H) 1.74-1.86 (m, 2H) 1.99-2.07 (m, 1H) 2.15-2.21 (m, 1H) 3.13-3.18 (m, 3H) 3.76-3.81 (m, 2H) 3.90 (s, 3H) 3.97-4.04 (m, 1H) 4.39-4.45 (m, 1H) 4.61-4.71 (m, 2H) 7.25-7.28 (m, 1H) 7.35-7.43 (m, 3H) 7.49-7.58 (m, 4H) 7.85 (s, 1H) 7.98 (s, 1H) 8.19 (d, J=1.76 Hz, 1H) 8.53 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 636.5 [M+H]+
Example 221 2-amino-N-((1S,2S)-2-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing intermediate 12, the title compound was obtained as described for the example 213 and 218.
1H NMR (400 MHz, CD3OD) δ ppm 1.35-1.44 (m, 6H) 1.60 (br dd, J=12.91, 7.43 Hz, 1H) 1.73-1.89 (m, 3H) 2.03 (br dd, J=13.50, 6.46 Hz, 1H) 2.11-2.21 (m, 1H) 2.48-2.62 (m, 9H) 3.67 (t, J=6.06 Hz, 2H) 3.86 (s, 3H) 3.96 (dt, J=6.95, 4.55 Hz, 1H) 4.36-4.46 (m, 1H) 4.59-4.72 (m, 2H) 7.40 (d, J=7.83 Hz, 2H) 7.43-7.49 (m, 2H) 7.53 (dd, J=12.72, 8.41 Hz, 4H) 7.75 (s, 1H) 7.83 (s, 1H) 7.97 (d, J=2.35 Hz, 1H) 8.24 (d, J=1.96 Hz, 1H);
MS (ESI, m/z): 624.8 [M+H]+
Example 222 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideScheme for the preparation of the Compound of Example 222:
Using 6-fluoropyridine-3-boronic acid, the title compound was obtained as described for the intermediate 2.
1H NMR (600 MHz, DMSO-d6) δ ppm 7.20 (dd, J=8.51, 2.64 Hz, 1H) 8.20 (td, J=8.22, 2.35 Hz, 1H) 8.27 (d, J=2.93 Hz, 1H) 8.45 (d, J=2.93 Hz, 1H) 8.48 (d, J=2.35 Hz, 1H);
MS (ESI+) m/z 234.1 [M+H]+
Intermediate 15Using intermediate 14, the title compound was obtained as described for the intermediate 4.
1H NMR (400 MHz, CD3OD) δ ppm 1.60 (br dd, J=13.30, 7.04 Hz, 1H) 1.71-1.84 (m, 3H) 2.00 (br dd, J=13.30, 6.26 Hz, 1H) 2.10-2.21 (m, 1H) 3.92 (dt, J=6.55, 4.35 Hz, 1H) 4.39 (td, J=7.34, 4.50 Hz, 1H) 4.58 (s, 2H) 7.15 (dd, J=8.41, 2.54 Hz, 1H) 7.26 (d, J=8.22 Hz, 2H) 7.38-7.43 (m, 2H) 8.08 (d, J=2.35 Hz, 1H) 8.12-8.21 (m, 1H) 8.35 (d, J=2.35 Hz, 1H) 8.43 (d, J=2.35 Hz, 1H);
MS (ESI+) m/z 485.2/487.3 [M+H]+
Intermediate 16Using intermediate 15, the title compound was obtained as described for the intermediate 13.
1H NMR (600 MHz, CD3OD) δ ppm 1.18 (s, 12H) 1.58 (br dd, J=13.21, 7.34 Hz, 1H) 1.69-1.84 (m, 3H) 1.96-2.03 (m, 1H) 2.15 (br d, J=7.63 Hz, 1H) 3.93 (br d, J=6.46 Hz, 1H) 4.39 (br d, J=4.70 Hz, 1H) 4.63 (s, 2H) 7.13 (dd, J=8.51, 2.64 Hz, 1H) 7.32 (d, J=7.63 Hz, 2H) 7.49-7.57 (m, 1H) 7.64 (d, J=7.63 Hz, 2H) 8.07 (d, J=2.35 Hz, 1H) 8.10-8.18 (m, 1H) 8.33 (d, J=1.76 Hz, 1H) 8.41 (d, J=2.35 Hz, 1H);
MS (ESI+) m/z 533.3 [M+H]+
Intermediate 17Using intermediate 16, the title compound was obtained as described for the compound 213.
1H NMR (400 MHz, CD3OD) δ ppm 1.61 (d, J=6.65 Hz, 3H) 1.64 (br s, 1H) 1.77-1.86 (m, 3H) 2.02-2.08 (m, 1H) 2.16-2.22 (m, 1H) 3.02 (br s, 2H) 3.13 (br s, 2H) 3.32-3.40 (m, 4H) 3.97-4.02 (m, 2H) 4.05 (br d, J=6.26 Hz, 1H) 4.41-4.46 (m, 1H) 4.67 (d, J=3.91 Hz, 2H) 7.16 (br dd, J=8.41, 2.54 Hz, 1H) 7.43 (br d, J=8.22 Hz, 2H) 7.48 (d, J=8.22 Hz, 2H) 7.55 (d, J=7.83 Hz, 2H) 7.60 (d, J=7.83 Hz, 2H) 8.19 (td, J=8.02, 2.74 Hz, 1H) 8.35 (d, J=2.35 Hz, 1H) 8.47 (br d, J=2.74 Hz, 1H) 8.52 (d, J=2.35 Hz, 1H);
MS (ESI+) m/z 595.3 [M+H]+
Example 222 6-amino-6′-fluoro-N-((1S,2S)-2-(4′-((S)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideUsing intermediate 17, the title compound was obtained as described for the example 214.
1H NMR (400 MHz, CD3OD) δ ppm 1.57 (d, J=6.65 Hz, 3H) 1.63 (br dd, J=13.50, 6.85 Hz, 1H) 1.72-1.89 (m, 3H) 2.00-2.08 (m, 1H) 2.14-2.23 (m, 1H) 2.87 (s, 3H) 3.90-3.97 (m, 1H) 3.97-4.05 (m, 1H) 4.40-4.47 (m, 1H) 4.63-4.71 (m, 2H) 7.16 (dd, J=8.61, 2.74 Hz, 1H) 7.32-7.50 (m, 4H) 7.55 (br d, J=8.22 Hz, 2H) 7.58 (br d, J=8.22 Hz, 2H) 8.19 (ddd, J=8.61, 7.43, 2.74 Hz, 1H) 8.35 (d, J=2.35 Hz, 1H) 8.48 (d, J=2.74 Hz, 1H) 8.56 (d, J=2.35 Hz, 1H);
MS (ESI+) m/z 609.3 [M+H]+
Example 223 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-((R)-1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideUsing intermediate 10, the title compound was obtained as described for the example 222.
1H NMR (400 MHz, CD3OD) δ ppm 1.49 (d, J=7.04 Hz, 3H) 1.63 (br d, J=6.65 Hz, 1H) 1.84 (br d, J=15.65 Hz, 3H) 2.06 (br s, 1H) 2.19 (br d, J=8.61 Hz, 1H) 2.84 (s, 3H) 3.74 (br d, J=6.26 Hz, 1H) 4.00 (br s, 1H) 4.43 (br s, 1H) 4.67 (d, J=3.13 Hz, 2H) 7.15 (br dd, J=9.00, 2.74 Hz, 1H) 7.42 (dd, J=7.83, 3.52 Hz, 4H) 7.54 (br dd, J=7.83, 5.09 Hz, 4H) 8.15-8.22 (m, 1H) 8.35 (br d, J=2.35 Hz, 1H) 8.46 (s, 1H) 8.50 (br d, J=1.96 Hz, 1H);
MS (ESI+) m/z 609.4 [M+H]+
Example 224 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideUsing intermediate 11, the title compound was obtained as described for the example 222.
1H NMR (400 MHz, CD3OD) δ ppm 0.91-0.95 (m, 2H) 1.01-1.06 (m, 2H) 1.64 (br dd, J=13.21, 6.75 Hz, 1H) 1.76-1.85 (m, 3H) 2.01-2.06 (m, 1H) 2.14 (s, 1H) 2.15-2.20 (m, 1H) 2.80 (s, 3H) 3.34 (s, 2H) 3.99 (br d, J=4.30 Hz, 1H) 4.43 (br d, J=4.70 Hz, 1H) 4.67 (d, J=3.52 Hz, 2H) 7.12-7.16 (m, 1H) 7.40 (dd, J=14.28, 8.41 Hz, 4H) 7.52 (br dd, J=8.22, 3.91 Hz, 4H) 8.18 (s, 1H) 8.35 (d, J=2.35 Hz, 1H) 8.42 (d, J=2.35 Hz, 1H) 8.45 (s, 1H);
MS (ESI+) m/z 621.5 [M+H]+
Example 225 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideUsing intermediate 12, the title compound was obtained as described for the example 222.
MS (ESI+) m/z 623.3 [M+H]+
Example 226 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-((S)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideScheme for the preparation of the Compound of Example 226:
Using intermediate 17, the title compound was obtained as described for the example 218.
1H NMR (400 MHz, CD3OD) δ ppm 1.58-1.68 (m, 4H) 1.77-1.87 (m, 3H) 2.02-2.09 (m, 1H) 2.15-2.23 (m, 1H) 3.13 (br s, 2H) 3.17-3.26 (m, 2H) 3.46 (br s, 4H) 3.77 (br s, 1H) 3.82-3.87 (m, 2H) 4.02 (br d, J=4.70 Hz, 2H) 4.11 (br d, J=6.26 Hz, 1H) 4.44 (br dd, J=11.74, 7.43 Hz, 1H) 4.67 (d, J=2.74 Hz, 2H) 7.17 (dd, J=8.61, 2.74 Hz, 1 H) 7.43 (d, J=8.22 Hz, 2H) 7.49 (d, J=8.22 Hz, 2H) 7.56 (d, J=8.22 Hz, 2H) 7.62 (d, J=8.61 Hz, 2H) 8.20 (td, J=8.02, 2.74 Hz, 1H) 8.36 (d, J=2.35 Hz, 1H) 8.48 (br d, J=2.74 Hz, 1H) 8.57 (d, J=1.96 Hz, 1H);
MS (ESI+) m/z 639.4 [M+H]+
Example 227 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-((R)-1-(4-(2-hydroxyethyl)-piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideUsing intermediate 10, the title compound was obtained as described for the example 226.
MS (ESI+) m/z 639.1 [M+H]+
Example 228 6-amino-6′-fluoro-N-al S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)-piperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideUsing intermediate 11, the title compound was obtained as described for the example 226.
MS (ESI+) m/z 651.6 [M+H]+
Example 229 6-amino-6′-fluoro-N-(1S,2S)-2-((4′-(2-(4-(2-hydroxyethyl)-piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideUsing intermediate 12, the title compound was obtained as described for the example 226.
MS (ESI+) m/z 653.4 [M+H]+
Example 230 6-amino-5′-fluoro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideScheme for the preparation of the Compound of Example 230:
Using (1S,2S)-2-((4-bromobenzyl)oxy)cyclopentan-1-amine, the title compound was obtained as described for the intermediate 7.
1H NMR (600 MHz, CD3OD) δ ppm 1.58-1.65 (m, 1H) 1.74-1.85 (m, 3H) 2.01-2.08 (m, 1H) 2.12-2.18 (m, 1H) 2.60 (s, 3H) 3.41-3.48 (m, 1H) 3.92 (q, J=5.87 Hz, 1H) 4.45-4.55 (m, 2H) 7.27 (d, J=8.22 Hz, 2H) 7.43-7.50 (m, 3H) 7.65 (d, J=8.22 Hz, 1 H) 7.73 (d, J=8.22 Hz, 1H) 8.03 (d, J=8.22 Hz, 1H);
MS (ESI+) m/z 310.1 [M+H]+
Intermediate 19Using intermediate 18, the title compound was obtained as described for the intermediate 4.
1H NMR (600 MHz, CDCl3) δ ppm 1.45-1.54 (m, 1H) 1.71-1.82 (m, 2H) 1.84-1.92 (m, 1H) 1.92-2.02 (m, 1H) 2.23-2.33 (m, 1H) 2.63 (s, 3H) 3.81-3.91 (m, 1H) 4.29-4.44 (m, 1H) 4.63-4.75 (m, 2H) 5.90 (br d, J=6.46 Hz, 1H) 6.35 (br s, 2H) 7.44 (d, J=8.22 Hz, 2H) 7.56-7.62 (m, 3H) 7.66 (d, J=8.22 Hz, 2H) 8.01 (d, J=8.22 Hz, 2H) 8.15 (d, J=1.76 Hz, 1H); MS (ESI+) m/z 508.1/510.2 [M+H]+
Intermediate 20To intermediate 19 (300 mg, 0.59 mmol) in 3 ml of THF was added 1-methylpiperazine (0.13 ml, 1.18 mmol) followed by Ti(OiPr)4 (0.7 ml, 2.36 mmol). The mixture was stirred at 60° C. for 4 hr and then NaBH3CN (0.11 g, 1.18 mmol) was added. The mixture was stirred for 1 h and extracted with EtOAc, washed with brine, dried over MgSO4. After concentration under vacuum, the crude product was purified by silicagel column chromatography to give 200 mg of off-white solid.
1H NMR (600 MHz, CD3OD) δ ppm 1.55-1.61 (m, 1H) 1.64 (d, J=7.04 Hz, 3H) 1.72-1.84 (m, 3H) 1.97-2.05 (m, 1H) 2.09-2.17 (m, 1H) 2.88 (s, 3H) 3.11 (br s, 2H) 3.36-3.49 (m, 4H) 3.95 (dt, J=6.75, 4.26 Hz, 1H) 4.14 (br d, J=6.46 Hz, 1H) 4.35 (td, J=7.34, 4.70 Hz, 1H) 4.61-4.68 (m, 2H) 7.42 (d, J=8.22 Hz, 2H) 7.50 (d, J=8.22 Hz, 2H) 7.57 (d, J=8.22 Hz, 2H) 7.65 (d, J=8.22 Hz, 2H) 8.13 (d, J=2.35 Hz, 1H) 8.20 (d, J=2.35 Hz, 1H);
MS (ESI+) m/z 592.2/594.3 [M+H]+
Example 230 6-amino-5′-fluoro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideUsing intermediate 20 and 5-fluoropyridine-3-boronic acid, the title compound was obtained as described for the intermediate 14.
1H NMR (600 MHz, CD3OD) δ ppm 1.54 (d, J=7.04 Hz, 3H) 1.63 (br dd, J=13.21, 6.75 Hz, 1H) 1.77-1.86 (m, 3H) 2.04 (br dd, J=12.91, 7.04 Hz, 1H) 2.16-2.23 (m, 1H) 2.85 (s, 3H) 3.88 (br d, J=7.04 Hz, 1H) 3.97-4.03 (m, 1H) 4.43 (br d, J=4.70 Hz, 1H) 4.64-4.70 (m, 2H) 7.42 (br dd, J=8.22, 4.11 Hz, 4H) 7.53 (br d, J=8.22 Hz, 2H) 7.56 (br d, J=8.22 Hz, 2H) 7.96 (br d, J=9.39 Hz, 1H) 8.42 (s, 1H) 8.50 (d, J=2.35 Hz, 1H) 8.56 (s, 1H) 8.70 (br s, 1H);
MS (ESI+) m/z 609.3 [M+H]+
Example 231 2-amino-5-chloro-N-((1S,2S)-2-((4′-((1-(4-methylpiperazin-1-yl)-ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 2-amino-5-chloronicotinic acid, the title compound was obtained as described for the synthesis of intermediate 20.
1H NMR (400 MHz, CD3OD) δ ppm 1.60 (dt, J=13.60, 7.09 Hz, 1H) 1.66 (d, J=6.65 Hz, 3H) 1.73-1.87 (m, 3H) 1.98-2.06 (m, 1H) 2.10-2.20 (m, 1H) 2.90 (s, 2H) 3.15 (br s, 2H) 3.45 (br s, 4H) 3.96 (dt, J=6.65, 4.30 Hz, 1H) 4.18 (q, J=6.65 Hz, 1H) 4.37 (td, J=7.24, 4.30 Hz, 1H) 4.61-4.71 (m, 2H) 7.43 (m, J=8.22 Hz, 2H) 7.52 (d, J=8.22 Hz, 2H) 7.59 (d, J=8.22 Hz, 2H) 7.67 (m, J=8.22 Hz, 2H) 8.09 (d, J=2.74 Hz, 1H) 8.14 (d, J=2.74 Hz, 1H);
MS (ESI+) m/z 548.3 [M+H]+
Example 232 2-amino-5-fluoro-N-((1S,2S)-2-((4′41-(4-methylpiperazin-1-yl)-ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 2-amino-5-fluoronicotinic acid, the title compound was obtained as described for the synthesis of intermediate 20.
MS (ESI, m/z): 532.3 [M+H]+
Example 233 2-amino-5-cyano-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)-ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 2-amino-5-cyanonicotinic acid, the title compound was obtained as described for the synthesis of intermediate 20.
MS (ESI, m/z): 539.3 [M+H]+
Example 234 2-amino-6-chloro-N-((1S,2S)-2-((4′-((1-(4-methylpiperazin-1-yl)-ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 2-amino-6-chloronicotinic acid, the title compound was obtained as described for the synthesis of intermediate 20.
1H NMR (400 MHz, CD3OD) δ ppm 1.56 (br dd, J=13.11, 7.24 Hz, 1H) 1.66 (d, J=7.04 Hz, 3H) 1.70-1.85 (m, 3H) 2.01 (br dd, J=13.11, 6.46 Hz, 1H) 2.07-2.19 (m, 2H) 2.90 (s, 3H) 3.09-3.21 (m, 2H) 3.39-3.58 (m, 4H) 3.87-3.96 (m, 1H) 4.19 (br d, J=6.65 Hz, 1H) 4.35 (br d, J=4.70 Hz, 1H) 4.57-4.73 (m, 2H) 6.56 (d, J=7.83 Hz, 1H) 7.42 (m, J=8.22 Hz, 2H) 7.52 (d, J=8.22 Hz, 2H) 7.56 (d, J=8.22 Hz, 2H) 7.66 (m, J=8.22 Hz, 2H) 7.73 (d, J=8.22 Hz, 1H);
MS (ESI, m/z): 548.3 [M+H]+
Example 235 2-amino-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 2-aminonicotinic acid, the title compound was obtained as described for the synthesis of intermediate 20.
1H NMR (600 MHz, CD3OD) δ ppm 1.58-1.64 (m, 1H) 1.66 (d, J=7.04 Hz, 3H) 1.74-1.85 (m, 3H) 1.97-2.05 (m, 1H) 2.13-2.20 (m, 1H) 2.89 (s, 3H) 3.02-3.27 (m, 4H) 3.46 (br s, 4H) 3.93-4.00 (m, 1H) 4.20 (q, J=6.46 Hz, 1H) 4.35-4.42 (m, 1H) 4.65 (s, 2H) 6.95 (t, J=6.75 Hz, 1H) 7.43 (d, J=8.22 Hz, 2H) 7.52 (m, J=8.22 Hz, 2H) 7.58 (m, J=8.22 Hz, 2H) 7.67 (d, J=8.22 Hz, 2H) 7.99 (dd, J=6.46, 1.17 Hz, 1H) 8.33 (dd, J=7.34, 1.47 Hz, 1H);
MS (ESI, m/z): 514.3 [M+H]+
Example 236 6-amino-5′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)-piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideScheme for the preparation of the Compound of Example 236:
Using 1-(2-hydroxyethyl)piperazine, the title compound was obtained as described for the intermediate 20.
1H NMR (600 MHz, CD3OD) δ ppm 1.42 (d, J=6.46 Hz, 2H) 1.51-1.58 (m, 1H) 1.71-1.81 (m, 3H) 1.97-2.04 (m, 1H) 2.08-2.15 (m, 1H) 2.61 (br s, 2H) 3.47 (br d, J=5.28 Hz, 1H) 3.67 (t, J=5.87 Hz, 2H) 3.91 (dt, J=6.46, 4.70 Hz, 1H) 4.35 (td, J=7.34, 4.70 Hz, 1H) 4.59-4.67 (m, 2H) 7.37 (br d, J=8.22 Hz, 2H) 7.39 (br d, J=8.22 Hz, 2H) 7.54 (d, J=7.63 Hz, 4H) 7.90 (d, J=2.35 Hz, 1H) 8.05 (d, J=2.35 Hz, 1H);
MS (ESI+) m/z 622.2/624.2 [M+H]+
Example 236 6-amino-5′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideUsing intermediate 21, the title compound was obtained as described for the example 230.
1H NMR (400 MHz, CD3OD) δ ppm 1.63 (br dd, J=13.89, 6.85 Hz, 1H) 1.72 (br d, J=6.65 Hz, 3H) 1.76-1.87 (m, 3H) 2.04 (br dd, J=12.72, 6.46 Hz, 1H) 2.13-2.23 (m, 1H) 3.52-3.68 (m, 4H) 3.84 (br t, J=4.89 Hz, 2H) 4.00 (br d, J=3.91 Hz, 1H) 4.35 (br d, J=6.65 Hz, 1H) 4.39-4.49 (m, 2H) 4.61-4.73 (m, 2H) 7.43 (br d, J=7.83 Hz, 2H) 7.53 (br t, J=9.39 Hz, 4H) 7.63 (br d, J=8.22 Hz, 2H) 7.98 (br d, J=9.78 Hz, 1H) 8.43 (s, 1H) 8.52 (s, 1H) 8.61 (s, 1H) 8.71 (s, 1H);
MS (ESI+) m/z 639.3 [M+H]+
Example 237 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)-piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideUsing 6-fluoropyridine-3-boronic acid, the title compound was obtained as described for the example 236.
1H NMR (400 MHz, CD3OD) δ ppm 1.62 (br dd, J=13.30, 6.65 Hz, 1H) 1.68 (br d, J=7.04 Hz, 3H) 1.81 (br d, J=7.43 Hz, 3H) 1.98-2.08 (m, 1H) 2.12-2.23 (m, 1H) 3.17-3.28 (m, 4H) 3.53 (br s, 4H) 3.84 (br d, J=4.30 Hz, 2H) 3.99 (br s, 1H) 4.25 (br d, J=7.04 Hz, 1H) 4.42 (br d, J=4.70 Hz, 1H) 4.62-4.72 (m, 2H) 7.16 (br d, J=7.83 Hz, 1H) 7.42 (br d, J=7.83 Hz, 2H) 7.47-7.59 (m, 4H) 7.62 (br d, J=7.83 Hz, 2H) 8.19 (br t, J=8.02 Hz, 1H) 8.34 (s, 1H) 8.47 (br s, 1H) 8.56 (s, 1H);
MS (ESI+) m/z 639.3 [M+H]+
Example 238 6-amino-2′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)-piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideUsing 2-fluoropyridine-3-boronic acid, the title compound was obtained as described for the example 236.
MS (ESI+) m/z 639.3 [M+H]+
Example 239 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((1-methylpiperidin-4-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideScheme for the preparation of the Compound of Example 239:
Using 4-(4-(1-trifluoroacetylpiperidino)methyl)phenylboronic acid pinacol ester, the title compound was obtained as described for the example 134.
1H NMR (600 MHz, CD3OD) δ ppm 1.39-1.48 (m, 2H) 1.63 (br dd, J=13.50, 7.04 Hz, 1H) 1.76-1.86 (m, 4H) 1.86-1.95 (m, 3H) 2.04 (br dd, J=13.21, 6.75 Hz, 1H) 2.18 (br dd, J=13.50, 5.87 Hz, 1H) 2.64 (br d, J=6.46 Hz, 2H) 2.90-2.98 (m, 2H) 3.33 (s, 3H) 3.36 (br d, J=12.33 Hz, 3H) 3.89 (s, 3H) 3.97-4.03 (m, 1H) 4.37-4.45 (m, 1H) 4.63-4.70 (m, 2H) 7.23 (br d, J=8.22 Hz, 2H) 7.40 (d, J=8.22 Hz, 2H) 7.48 (d, J=8.22 Hz, 2H) 7.52 (d, J=8.22 Hz, 2H) 7.85 (s, 1H) 7.97 (s, 1H) 8.19 (d, J=1.76 Hz, 1H) 8.51 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 564.8 [M+H]+
Example 239 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((l-methylpiperidin-4-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing intermediate 22 and formaldehyde, the title compound was obtained as described for the example 214.
1H NMR (600 MHz, CD3OD) δ ppm 1.42-1.54 (m, 2H) 1.63 (br dd, J=13.50, 7.04 Hz, 1H) 1.75-1.88 (m, 4H) 1.92 (br d, J=14.67 Hz, 2H) 2.00-2.08 (m, 1H) 2.17 (br dd, J=13.50, 5.87 Hz, 1H) 2.64 (br d, J=7.04 Hz, 2H) 2.82 (s, 3H) 2.89-2.98 (m, 2H) 3.47 (br d, J=12.33 Hz, 2H) 3.89 (s, 3H) 3.94-4.05 (m, 1H) 4.36-4.46 (m, 1H) 4.61-4.69 (m, 2H) 7.22 (d, J=8.22 Hz, 2H) 7.39 (br d, J=8.22 Hz, 2H) 7.47 (br d, J=8.22 Hz, 2H) 7.51 (br d, J=8.22 Hz, 2H) 7.84 (s, 1H) 7.96 (s, 1H) 8.18 (d, J=1.76 Hz, 1H) 8.49 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 579.8 [M+H]+
Example 240 2-amino-N-((1S,2S)-2-((4′-((1-(2-hydroxyethyl)piperidin-4-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideScheme for the preparation of the Compound of Example 240:
To a mixture of intermediate 22 (30 mg, 0.05 mmol) and K2CO3 (22 mg, 0.16 mmol) in 0.4 ml of DMF was added 2-bromoethanol (6 μl, 0.08 mmol). The mixture was stirred at room temperature for 4 hr and then water was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 27 mg of the title compound.
1H NMR (600 MHz, CD3OD) δ ppm 1.26 (br d, J=13.50 Hz, 2H) 1.56-1.74 (m, 4H) 1.74-1.89 (m, 4H) 2.04 (br dd, J=13.21, 6.16 Hz, 1H) 2.20 (br dd, J=13.50, 7.04 Hz, 1H) 2.64 (br d, J=7.04 Hz, 2H) 2.77 (br t, J=12.62 Hz, 2H) 3.05-3.13 (m, 2H) 3.47 (br d, J=12.33 Hz, 2H) 3.75-3.81 (m, 2H) 3.92 (s, 3H) 4.01-4.07 (m, 1H) 4.40-4.47 (m, 1H) 4.62-4.72 (m, 2H) 7.10 (br d, J=7.63 Hz, 1H) 7.20-7.26 (m, 3H) 7.27-7.33 (m, 2H) 7.41 (br d, J=7.63 Hz, 2H) 7.87-7.90 (m, 1H) 7.88 (s, 1H) 8.03 (s, 1H) 8.23 (d, J=1.76 Hz, 1H) 8.60 (br s, 1H);
MS (ESI, m/z): 609.8 [M+H]+
Example 241 methyl 2-(4-((4′-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamido)cyclopentyl)oxy)methyl)-[1,1′-biphenyl]-4-yl)methyl)piperidin-1-yl)-acetateUsing intermediate 22 and methyl bromoacetate, the title compound was obtained as described for the example 240.
1H NMR (600 MHz, CD3OD) δ ppm 1.32 (br s, 2H) 1.61-1.71 (m, 4H) 1.79-1.89 (m, 4H) 2.01-2.06 (m, 1H) 2.20 (br dd, J=13.79, 6.75 Hz, 1H) 2.66 (br s, 2H) 2.85 (br s, 2H) 3.49 (br s, 2H) 3.79 (s, 3H) 3.92 (s, 3H) 4.01 (br s, 2H) 4.02-4.06 (m, 1H) 4.44 (br dd, J=11.15, 7.04 Hz, 1H) 4.63-4.73 (m, 2H) 7.11 (br d, J=7.63 Hz, 1H) 7.23-7.30 (m, 4H) 7.41 (br d, J=8.22 Hz, 2H) 7.88 (s, 1H) 8.02-8.04 (m, 1H) 8.23 (d, J=1.76 Hz, 1H) 8.60 (s, 1H);
MS (ESI, m/z): 637.7 [M+H]+
Example 242 2-amino-N-((1S,2S)-2-((4′-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideUsing intermediate 22 and bromoacetamide, the title compound was obtained as described for the example 240.
MS (ESI, m/z): 622.8 [M+H]+
Example 243 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(3-(4-methylpiperazin-1-yl)propyl)benzyl)oxy)cyclopentyl)nicotinamideScheme for the preparation of the Compound of Example 243
A mixture of intermediate 4 (300 mg, 0.64 mmol), Pd(dba)2 (7 mg, 0.01 mmol), P(t-bu)3 (8 mg, 0.04 mmol) in DMF (3 ml) was degassed with nitrogen and TEA (0.133 ml, 0.96 mmol), allyl alcohol (0.11 ml, 1.28 mmol) were added. The mixture was heated at 100° C. for 1 h. After cooling, the mixture was partitioned between EA and water. The organic layer was separated and washed with water, brine dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with Et2O-hexane mixtures as eluents to give 150 mg of off-white solid.
1H NMR (600 MHz, CD3OD) δ ppm 1.64 (br dd, J=13.21, 6.75 Hz, 1H) 1.75 (br d, J=7.63 Hz, 1H) 1.79-1.85 (m, 2H) 1.94-2.04 (m, 3H) 2.16 (br d, J=6.46 Hz, 1H) 2.64 (br t, J=7.63 Hz, 2H) 2.89 (s, 3H) 3.02-3.07 (m, 2H) 3.40 (br s, 2H) 3.46 (br s, 4H) 3.93 (s, 3H) 3.96-4.00 (m, 1H) 4.36-4.42 (m, 1H) 4.54-4.65 (m, 3H) 7.16 (d, J=8.22 Hz, 2H) 7.27 (d, J=8.22 Hz, 2H) 7.84-7.89 (m, 1H) 8.03 (s, 1H) 8.23 (d, J=1.76 Hz, 1H) 8.56 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 532.5 [M+H]+
Example 243 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(3-(4-methylpiperazin-1-yl)propyl)benzyl)oxy)cyclopentyl)nicotinamideUsing intermediate 23, the title compound was obtained as described for the example 172.
1H NMR (600 MHz, CD3OD) δ ppm 1.64 (br dd, J=13.21, 6.75 Hz, 1H) 1.75 (br d, J=7.63 Hz, 1H) 1.79-1.85 (m, 2H) 1.94-2.04 (m, 3H) 2.16 (br d, J=6.46 Hz, 1H) 2.64 (br t, J=7.63 Hz, 2H) 2.89 (s, 3H) 3.02-3.07 (m, 2H) 3.40 (br s, 2H) 3.46 (br s, 4H) 3.93 (s, 3H) 3.96-4.00 (m, 1H) 4.36-4.42 (m, 1H) 4.54-4.65 (m, 3H) 7.16 (d, J=8.22 Hz, 2H) 7.27 (d, J=8.22 Hz, 2H) 7.84-7.89 (m, 1H) 8.03 (s, 1H) 8.23 (d, J=1.76 Hz, 1H) 8.56 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 532.4 [M+H]+
Example 244 2-amino-N-((1S,2S)-2-((4-(3-(dimethylamino)propyl)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing intermediate 23 and dimethylamine (50% in THF), the title compound was obtained as described for the example 243.
1H NMR (600 MHz, CD3OD) δ ppm 1.63-1.68 (m, 1H) 1.73-1.78 (m, 1H) 1.80-1.83 (m, 3H) 1.96-2.05 (m, 3H) 2.17 (br d, J=6.46 Hz, 1H) 2.65 (br t, J=7.63 Hz, 2H) 2.84 (s, 6H) 3.06-3.14 (m, 2H) 3.94 (s, 3H) 3.98 (br s, 1H) 4.39 (br s, 1H) 4.55-4.67 (m, 3H) 7.18 (br d, J=7.63 Hz, 2H) 7.29 (br d, J=7.63 Hz, 2H) 7.87-7.89 (m, 1H) 8.04 (s, 1H) 8.23 (d, J=1.76 Hz, 1H) 8.57 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 477.5 [M+H]+
Example 245 2-amino-N-((1S,2S)-2-((4′-(2-(dimethylamino)ethoxy)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-M-pyrazol-4-yl)nicotinamideScheme for the preparation of the Compound of Example 245
To a mixture of intermediate 4 (300 mg, 0.64 mmol) and (4-hydroxyphenyl)boronic acid (132 mg, 0.96 mmol) in 4 ml of 1,4-dioxane/water (3/1) was added K2CO3 (264 mg, 1.91 mmol) followed by Pd(PPh3)4 (37 mg, 0.03 mmol). The reaction mixture was heated at 100° C. for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO4 and concentrated under vacuum. After concentration under vacuum, the crude material was purified by flash chromatography on silica gel with DCM-MeOH mixtures as eluents to give 250 mg of off-white solid.
1H NMR (600 MHz, CD3OD) δ ppm 1.60 (br dd, J=13.21, 7.34 Hz, 1H) 1.74-1.87 (m, 3H) 2.04 (br dd, J=12.62, 7.34 Hz, 1H) 2.10-2.20 (m, 1H) 3.88 (s, 3H) 3.92-4.00 (m, 1H) 4.35-4.44 (m, 1H) 4.57 (d, J=12.33 Hz, 1H) 4.66 (d, J=12.33 Hz, 2H) 6.78 (m, J=8.22 Hz, 2H) 7.33 (t, J=9.10 Hz, 4H) 7.43 (m, J=8.22 Hz, 2H) 7.82 (s, 1H) 7.91 (s, 1H) 8.15 (d, J=2.35 Hz, 1H) 8.43 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 484.3 [M+H]+
Example 245 2-amino-N-((1S,2S)-2-((4′-(2-(dimethylamino)ethoxy)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-M-pyrazol-4-yl)nicotinamideA mixture of intermediate 24 (30 mg, 0.06 mmol) and K2CO3 (43 mg, 0.31 mmol) was heated at 60° C. for 12 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO4 and concentrated under vacuum. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 30 mg of the title compound
1H NMR (400 MHz, CD3OD) δ ppm 1.57-1.68 (m, 1H) 1.81 (br d, J=7.83 Hz, 3H) 2.01 (br d, J=19.56 Hz, 1H) 2.16 (br d, J=12.91 Hz, 1H) 2.99 (s, 6H) 3.61 (br s, 2H) 3.89 (s, 3H) 3.99 (br s, 1H) 4.37 (br d, J=3.52 Hz, 3H) 4.64 (s, 2H) 7.05 (br d, J=8.22 Hz, 2H) 7.38 (br d, J=7.83 Hz, 2H) 7.50 (br t, J=7.43 Hz, 3H) 7.84 (s, 1H) 7.96 (s, 1H) 8.19 (br s, 1H) 8.48 (s, 1H);
MS (ESI, m/z): 555.4 [M+H]+
Example 246 2-amino-N-((1S,2S)-2-((4′-(3-(dimethylamino)propoxy)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-M-pyrazol-4-yl)nicotinamideUsing (3-chloropropyl)dimethylamine, title compound was obtained as described for the example 245.
1H NMR (600 MHz, CD3OD) δ ppm 1.62 (br dd, J=13.21, 7.34 Hz, 1H) 1.73-1.86 (m, 3H) 2.04 (br dd, J=12.91, 7.63 Hz, 1H) 2.16 (br dd, J=13.21, 6.16 Hz, 1H) 2.19-2.28 (m, 2H) 2.94 (s, 6H) 3.32-3.41 (m, 2H) 3.88 (s, 3H) 3.93-4.05 (m, 1H) 4.13 (t, J=5.87 Hz, 2H) 4.36-4.43 (m, 1H) 4.58-4.68 (m, 2H) 6.97 (d, J=8.80 Hz, 2H) 7.37 (d, J=8.22 Hz, 2H) 7.46 (t, J=8.51 Hz, 4H) 7.82 (s, 1H) 7.93 (s, 1H) 8.17 (d, J=2.35 Hz, 1H) 8.43 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 569.4 [M+H]+
Example 247 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((1-methylpiperidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 4-bromo-1-methylpiperidine, title compound was obtained as described for the example 245.
MS (ESI, m/z): 581.5 [M+H]+
Example 248 2-amino-N-((1S,2S)-2-((4-(3-(dimethylamino)prop-1-yn-1-yl)benzyl)oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideScheme for the preparation of the Compound of Example 248
A mixture of intermediate 4 (40 mg, 0.09 mmol), Pd(dba)2 (1 mg, 2 mol %), P(t-bu)3 (1 mg, 6 mol %) in DMF (3 ml) was degassed with nitrogen and TEA (0.018 ml, 0.13 mmol), N,N-dimethylpropargylamine (0.016 ml, 0.17 mmol) were added. The mixture was heated at 100° C. for 12 hrs. After cooling, the mixture was partitioned between EA and water. The organic layer was separated and washed with water, brine dried over MgSO4 and concentrated in vacuo. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 10 mg of the title compound.
1H NMR (400 MHz, CD3OD) δ ppm 1.63 (s, 2H) 1.78 (br dd, J=14.28, 6.85 Hz, 2H) 1.99 (br dd, J=12.91, 6.65 Hz, 1H) 2.09-2.18 (m, 1H) 2.35 (s, 3H) 3.12-3.18 (m, 1H) 3.32-3.34 (m, 4H) 3.42-3.50 (m, 2H) 3.58 (br d, J=7.04 Hz, 1H) 3.90 (s, 3H) 4.32-4.42 (m, 1H) 4.61 (s, 2H) 7.27-7.40 (m, 4H) 7.76 (s, 1H) 7.87 (s, 1H) 7.98 (s, 1H) 8.24 (s, 1H);
MS (ESI, m/z): 473.4 [M+H]+
Example 249 2-amino-N-((1S,2S)-2-((4-(4-hydroxybut-1-yn-1-yl)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 3-butyn-1-ol, title compound was obtained as described for the example 248.
1H NMR (600 MHz, CD3OD) δ ppm 1.62 (br dd, J=13.21, 7.34 Hz, 1H) 1.70-1.77 (m, 1H) 1.77-1.84 (m, 3H) 2.01 (br dd, J=12.62, 7.34 Hz, 1H) 2.15 (br dd, J=13.21, 6.16 Hz, 1H) 2.57 (t, J=6.75 Hz, 2H) 3.69 (t, J=6.75 Hz, 2H) 3.94 (s, 3H) 4.32-4.40 (m, 1H) 4.54-4.63 (m, 2H) 7.23-7.31 (m, 4H) 7.87 (s, 1H) 8.01 (s, 1H) 8.23 (d, J=2.35 Hz, 1H) 8.50 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 460.6 [M+H]+
Example 250 2-amino-N-((1S,2S)-2-((4-(5-hydroxypent-1-yn-1-yl)-benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 4-pentyn-1-ol, title compound was obtained as described for the example 248.
1H NMR (600 MHz, CD3OD) δ ppm 1.62 (br dd, J=12.91, 7.04 Hz, 1H) 1.69-1.78 (m, 3H) 1.78-1.86 (m, 2H) 2.01 (br dd, J=12.91, 7.63 Hz, 1H) 2.16 (br d, J=5.87 Hz, 1H) 2.45 (t, J=7.04 Hz, 2H) 3.66 (t, J=6.46 Hz, 2H) 3.88-4.00 (m, 4H) 4.31-4.41 (m, 1H) 4.51-4.65 (m, 2H) 7.26 (s, 4H) 7.87 (s, 1H) 8.01 (s, 1H) 8.23 (d, J=1.76 Hz, 1H) 8.51 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 474.2 [M+H]+
Example 251 2-amino-N-((1S,2S)-2-((4-(6-hydroxyhex-1-yn-1-yl)benzyl)oxy)-cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 5-hexyn-1-ol, title compound was obtained as described for the example 248.
1H NMR (600 MHz, CD3OD) δ ppm 0.00-0.00 (m, 1H) 1.54-1.69 (m, 8H) 1.72-1.78 (m, 1H) 1.78-1.86 (m, 3H) 1.91 (br d, J=7.63 Hz, 1H) 1.97-2.05 (m, 1H) 2.12-2.20 (m, 1H) 2.24-2.30 (m, 2H) 2.32 (br d, J=3.52 Hz, 1H) 2.40 (t, J=7.04 Hz, 1H) 2.45 (t, J=6.75 Hz, 1H) 2.43-2.43 (m, 1H) 3.55 (t, J=6.46 Hz, 2H) 3.56-3.60 (m, 1H) 3.94 (d, J=1.17 Hz, 3H) 4.35-4.41 (m, 2H) 4.43 (t, J=6.46 Hz, 1H) 4.54-4.65 (m, 2H) 4.68-4.68 (m, 1H) 4.69-4.69 (m, 1H) 7.26 (d, J=7.04 Hz, 3H) 7.87 (s, 1H) 8.01 (s, 1H) 8.19-8.26 (m, 1H) 8.48-8.53 (m, 1H);
MS (ESI, m/z): 488.3 [M+H]+
Example 252 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(4-(4-methylpiperazin-1-yl)but-1-yn-1-yl)benzyl)oxy)cyclopentyl)nicotinamideScheme for the preparation of the Compound of Example 252
To a mixture of compound 249 (30 mg, 0.07 mmol) and triethylamine (27 μL, 0.2 mmol) in DCM (0.3 mL) was added methanesulfonyl chloride (12 μL, 0.16 mmol). The mixture was stirred at room temperature for 2 hrs. After completion of conversion, the volatile was removed under reduced pressure. The crude residue was diluted with EtOH (0.3 mL) and 1-methylpiperazine (16 μL, 0.13 mmol) was added. The mixture was refluxed for 2 hrs. After cooling, the crude residue was purified by preparative HPLC to afford 20 mg of the title compound.
1H NMR (600 MHz, CD3OD) δ ppm 1.63 (br dd, J=13.21, 6.75 Hz, 1H) 1.75 (br d, J=5.28 Hz, 1H) 1.80-1.84 (m, 2H) 1.98-2.02 (m, 1H) 2.16 (br dd, J=13.79, 6.75 Hz, 1H) 2.78 (br s, 2H) 2.89-2.93 (m, 3H) 3.44 (br s, 4H) 3.55 (br s, 2H) 3.94 (s, 3H) 3.95-3.99 (m, 1H) 4.38 (br dd, J=11.15, 7.04 Hz, 1H) 4.60 (s, 2H) 7.26-7.35 (m, 4H) 7.88 (s, 1H) 8.02 (s, 1H) 8.23 (d, J=2.35 Hz, 1H) 8.55 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 542.5 [M+H]+
Example 253 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamideScheme for the preparation of the Compound of Example 253:
To a mixture of intermediate 3 (300 mg, 1.38 mmol) and triethylamine (168 mg, 1.66 mmol) in 7 ml of DMF was added HATU (524 mg, 1.66 mmol) followed by (1S,2S)-2-(benzyloxy)cyclopentan-1-amine (263 mg, 1.38 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified through silicagel column chromatography to give 326 mg of off-white solid.
1H NMR (400 MHz, CDCl3) δ ppm 1.47 (dt, J=13.99, 6.90 Hz, 1H) 1.72-1.82 (m, 2H) 1.83-1.92 (m, 1H) 1.92-2.01 (m, 2H) 2.22-2.34 (m, 1H) 3.79-3.88 (m, 1H) 4.32 (dd, J=7.04, 4.70 Hz, 1H) 4.56-4.68 (m, 2H) 5.81 (br d, J=6.65 Hz, 1H) 6.35 (br s, 2H) 7.26-7.38 (m, 4H) 7.53 (d, J=2.35 Hz, 1H) 8.17 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 390.2/392.2 [M+H]+
Example 253 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamideTo a mixture of intermediate 25 (40 mg, 0.1 mmol) and (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester (51 mg, 0.16 mmol) in 1 ml of 1,4-dioxane was added 0.15 ml of aq. 2N K3PO4 followed by Pd(PPh3)4 (8 mg, 0.007 mmol). The reaction mixture was heated at 100° C. for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO4 and concentrated under vacuum. The crude residue was purified by preparative HPLC to afford 23 mg of the title compound.
1H NMR (400 MHz, METHANOL-d4) δ ppm 1.57 (br dd, J=13.30, 7.04 Hz, 1H) 1.66-1.87 (m, 3H) 1.97 (dt, J=13.01, 6.60 Hz, 1H) 2.13 (br dd, J=13.11, 6.85 Hz, 1H) 2.95 (s, 3H) 3.44-3.62 (m, 4H) 3.87-3.97 (m, 1H) 4.17 (s, 2H) 4.31-4.39 (m, 1H) 4.60 (s, 2H) 6.25 (d, J=9.00 Hz, 1H) 7.21-7.35 (m, 5H) 7.43 (d, J=8.22 Hz, 2H) 7.58 (d, J=8.61 Hz, 2H) 8.08 (d, J=9.00 Hz, 1H);
MS (ESI, m/z): 500.3 [M+H]+
Example 254 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamideUsing (1-(piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 201.
MS (ESI, m/z): 461.3 [M+H]+
Example 255 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamideUsing (1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 475.3 [M+H]+
Example 256 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamideUsing (1-(1-ethylpiperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 489.3 [M+H]+
Example 257 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl) nicotinamideUsing (1-(1-isopropylpiperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 503.3 [M+H]+
Example 258 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamideUsing (1-(1-(pyrrolidin-3-ylmethyl)piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 544.3 [M+H]+
Example 259 2-amino-N-((1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamideUsing (1R,2R)-2-(benzyloxy)cyclopentan-1-amine and (1-(piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 461.3 [M+H]+
Example 260 2-amino-N-((1S,2S)-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamideUsing (1S,2S)-2-((3,4-dichlorobenzyl)oxy)cyclopentan-1-amine and (1-(piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 529.2 [M+H]+
Example 261 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (3-(hydroxymethyl)-1-methyl-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 422.2 [M+H]+
Example 262 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(((2-hydroxyethyl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (3-(((2-hydroxyethyl)amino)methyl)-1-methyl-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 465.3 [M+H]+
Example 263 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((3-hydroxypiperidin-1-yl)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (3-((3-hydroxypiperidin-1-yl)methyl)-1-methyl-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 505.3 [M+H]+
Example 264 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-cyanophenyl)-nicotinamideUsing (4-cyanophenyl)boronic acid, the title compound was obtained as described for the example 253.
1H NMR (400 MHz, CDCl3) δ 1.59 (m, 2H) 1.85 (m, 4H) 2.10 (m, 2H) 2.24 (m, 1H) 4.17 (br d, J=7.04 Hz, 1H) 4.28 (br d, J=7.04 Hz, 1H) 4.43-4.54 (m, 1H) 4.56-4.67 (m, 2H) 7.13-7.19 (m, 1H) 7.13-7.19 (m, 1H) 7.13-7.19 (m, 2H) 7.19-7.24 (m, 2H) 7.35 (br d, J=7.43 Hz, 2H) 7.64 (m, J=8.22 Hz, 2H) 7.73 (m, J=8.22 Hz, 2H) 7.80 (s, 1H) 7.85-7.91 (m, 1H) 8.27 (s, 1H) 8.58 (br s, 2H) 11.76-11.97 (m, 2H); MS (ESI, m/z): 413.2 [M+H]+
Example 265 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-cyanophenyl)-nicotinamideUsing (3-cyanophenyl)boronic acid, the title compound was obtained as described for the example 253.
1H NMR (400 MHz, CDCl3) □□1.54-1.70 (m, 2H) 1.70-1.95 (m, 4H) 2.07 (br s, 2H) 2.23 (br s, 2H) 4.08 (br d, J=5.87 Hz, 1H) 4.33 (br s, 1H) 4.61 (q, J=11.74 Hz, 2H) 7.14-7.20 (m, 1H) 7.20-7.29 (m, 2H) 7.29-7.38 (m, 2H) 7.53-7.63 (m, 1H) 7.70 (br d, J=7.43 Hz, 1H) 7.75 (br d, J=7.43 Hz, 1H) 7.87 (s, 1H) 7.91 (s, 1H) 8.26 (s, 1H) 8.87 (br s, 2H) 11.40-11.54 (m, 1H);
MS (ESI, m/z): 413.2 [M+H]+
Example 266 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-(cyanomethyl)phenyl)nicotinamideUsing (4-(cyanomethyl)phenyl)boronic acid, the title compound was obtained as described for the example 253.
1H NMR (400 MHz, CDCl3) □□1.54-1.64 (m, 1H) 1.70 (br s, 1H) 1.83 (br s, 2H) 1.97-2.05 (m, 2H) 3.11 (br s, 1H) 3.79 (s, 2H) 4.35 (br s, 1H) 4.64 (s, 2H) 7.14 (br s, 1H) 7.18-7.24 (m, 3H) 7.39 (br t, J=7.83 Hz, 2H) 7.55 (br d, J=7.83 Hz, 1H) 7.59 (s, 1H) 8.00 (br s, 1H) 8.34 (s, 1H) 8.55-8.67 (m, 1H);
MS (ESI, m/z): 427.2 [M+H]+
Example 267 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-phenoxyphenyl)nicotinamideUsing (4-phenoxyphenyl)boronic acid, the title compound was obtained as described for the example 253.
1H NMR (400 MHz, CDCl3) □1.23 (m, 2H) 1.56 (m, 2H) 1.75 (m, 4H) 2.07 (br s, 2H) 2.24 (br s, 2H) 4.12 (br d, J=5.87 Hz, 1H) 4.29 (br s, 1H) 4.56-4.66 (m, 2H) 7.04 (br t, J=6.85 Hz, 3H) 7.17 (br d, J=7.43 Hz, 1H) 7.22-7.26 (m, 4H) 7.30-7.39 (m, 3H) 7.39-7.44 (m, 2H) 7.50 (s, 1H) 7.74 (s, 1H) 8.18 (s, 1H) 8.45 (br s, 2H) 11.28 (br s, 1H);
MS (ESI, m/z): 480.2 [M+H]+
Example 268 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamideUsing (3-((1-methylpiperidin-4-yl)carbamoyl)phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 528.3 [M+H]+
Example 269 6-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6′-(hydroxymethyl)-[3,3′-b]pyridinel-5-carboxamideUsing (6-(hydroxymethyl)pyridin-3-yl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 420.2 [M+H]+
Example 270 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 514.3 [M+H]+
Example 271 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamideUsing (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and (4-methyl piperazin-1-yl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 528.3 [M+H]+
Example 272 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamideUsing (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and (4-(pyrrolidin-1-yl)piperidin-1-yl)(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 582.3 [M+H]+
Example 273 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and 1-methyl-4-(3-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)benzyl)piperazine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 514.3 [M+H]+
Example 274 2-amino-5-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-methylpiperazine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 532.3 [M+H]+
Example 275 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and 4-(pyrrolidin-1-yl)-1-(4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)benzyl)piperidine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 568.4 [M+H]+
Example 276 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamideUsing (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and (4-methylpiperazin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 528.3 [M+H]+
Example 277 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamideUsing (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and (4-(pyrrolidin-1-yl)piperidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 582.3 [M+H]+
Example 278 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-((1-methylpiperidin-4-yl)amino)-2-oxoethyl)phenyl)nicotinamideUsing (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and N-(1-methylpiperidin-4-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 556.3 [M+H]+
Example 279 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-methylpiperazin-1-yl)acetyl)phenyl)nicotinamideUsing (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and 2-(4-methylpiperazin-1-yl)-1-(4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenyl)ethan-1-one, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 542.3 [M+H]+
Example 280 2-amino-5-(3-fluoro-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)-methyl)phenyl)-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamide(1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-(pyrrolidin-1-yl)piperidine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 586.4 [M+H]+
Example 281 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamideUsing (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and (4-(4-methylpiperazin-1-yl)piperidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-methanone, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 611.4 [M+H]+
Example 282 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(piperazin-1-ylmethyl)phenyl)nicotinamideUsing (1S,2S)-2-((3-methylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 500.3 [M+H]+
Example 283 2-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamideUsing (1S,2S)-2-((4-methylbenzyl)oxy)cyclopentan-1-amine and (4-methylpiperazin-1-yl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 528.3 [M+H]+
Example 284 2-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamideUsing (1 S,2 S)-2-((4-methylbenzyl)oxy)cyclopentan-1-amine and (4-(pyrrolidin-1-yl)piperidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenyl)methanone, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 582.3 [M+H]+
Example 285 2-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (1,5-dimethyl-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 434.3 [M+H]+
Example 286 2-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (1,3-dimethyl-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 434.3 [M+H]+
Example 287 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(2-hydroxypropan-2-yl)-4-methylthiazol-5-yl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-(2-hydroxypropan-2-yl)-4-methylthiazol-5-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 495.2 [M+H]+
Example 288 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(3-hydroxytetrahydrofuran-3-yl)-4-methylthiazol-5-yl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-(3-hydroxytetrahydrofuran-3-yl)-4-methylthiazol-5-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 523.2 [M+H]+
Example 289 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 528.3 [M+H]+
Example 290 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(4-methylpiperazin-1-yl)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethan-1-one, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 556.3 [M+H]+
Example 291 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(morpholinomethyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 515.3 [M+H]+
Example 292 2-amino-5-(4-((dimethylamino)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-((dimethyl-amino)methyl)phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 473.3 [M+H]+
Example 293 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)nicotinamideUsing (1 S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazin-1-yl)ethan-1-ol, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 558.3 [M+H]+
Example 294 6-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-2′-methoxy-[3,3′-bipyridine]-5-carboxamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-methoxy-pyridin-3-yl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 447.2 [M+H]+
Example 295 2-amino-5-(4-(dimethylamino)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-(dimethyl-amino)phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 459.3 [M+H]+
Example 296 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-hydroxyphenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-hydroxy-phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 432.2 [M+H]+
Example 297 2-amino-5-(3-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)-oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-amino-phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 431.2 [M+H]+
Example 298 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(methylsulfonamido)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-(methyl-sulfonamido)phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 509.2 [M+H]+
Example 299 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(hydroxymethyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-(hydroxy-methyl)phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 446.2 [M+H]+
Example 300 2-amino-5-(3-(aminomethyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-(amino-methyl)phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 445.3 [M+H]+
Example 301 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(3-hydroxypropyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-(3-hydroxy-propyl)phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 474.3 [M+H]+
Example 302 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((1r,4S)-4-hydroxycyclohexyl)amino)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (1r,4r)-4-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)amino)cyclohexan-1-ol, the title compound was obtained as described for the example 253
MS (ESI, m/z): 543.3 [M+H]+
Example 303 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(((1-methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-amine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 542.3 [M+H]+
Example 304 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((S)-piperidin-3-yl)amino)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (S)-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-3-amine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 528.3 [M+H]+
Example 305 3-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)-5-hydroxybenzoic acidUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 3-borono-5-hydroxybenzoic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 476.2 [M+H]+
Example 306 4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)-2-methylbenzoic acidUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 4-borono-2-methylbenzoic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 474.2 [M+H]+
Example 307 2-amino-5-(4-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)-oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-amino-phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 431.2 [M+H]+
Example 308 3-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)benzoic acidUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 3-boronobenzoic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 460.2 [M+H]+
Example 309 3-amino-5-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)-cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acidUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 3-amino-5-boronobenzoic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 475.2 [M+H]+
Example 310 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-methyl-5-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamideUsing (1S,2 S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-methyl-3-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 610.4 [M+H]+
Example 311 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4-(4-methylpiperazine-1-carbonyl)phenyl)nicotinamideUsing (1S,2 S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-methyl-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)phenyl)(4-methylpiperazin-1-yl)methanone, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 556.3 [M+H]+
Example 312 2-amino-5-(3-amino-5-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 611.4 [M+H]+
Example 313 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-(hydroxymethyl)phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 446.2 [M+H]+
Example 314 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-formylphenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-formyl-phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 444.2 [M+H]+
Example 315 4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-carbamoyl)pyridin-3-yl)benzoic acidUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 4-boronobenzoic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 460.2 [M+H]+
Example 316 3-(4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)-cyclopentyl)carbamoyl)pyridin-3-yl)phenyl)propanoic acidUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 3-(4-boronophenyl)propanoic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 488.3 [M+H]+
Example 317 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-hydroxyphenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-hydroxyphenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 432.22 [M+H]+
Example 318 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamideUsing (1S,2S)-2-(3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and N-(1-methylpiperidin-4-yl)-4-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 556.3 [M+H]+
Example 319 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(dimethylcarbamoyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-(dimethyl-carbamoyl)phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 487.3 [M+H]+
Example 320 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((1-methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-amine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 542.3 [M+H]+
Example 321 6-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6′-(hydroxymethyl)-[3,3′-bipyridine]-5-carboxamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (6-(hydroxy-methyl)pyridin-3-yl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 447.2 [M+H]+
Example 322 2-amino-4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)-cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acidUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 2-amino-4-boronobenzoic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 475.2 [M+H]+
Example 323 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)-3-methoxyphenyl)nicotinamideUsing (1S,2 S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 476.3 [M+H]+
Example 324 2-amino-N-(1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4-(hydroxymethyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-fluoro-4-(hydroxymethyl)phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 464.2 [M+H]+
Example 325 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-4-(pyrrolidin-1-yl)piperidine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 600.4 [M+H]+
Example 326 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(1-hydroxyethyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-(1-hydroxyethyl)phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 460.3 [M+H]+
Example 327 2-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 542.3 [M+H]+
Example 328 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-hydroxypiperidin-1-yl)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-ol, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 529.3 [M+H]+
Example 329 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((((1-methylpiperidin-4-yl)methyl)amino)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(1-methylpiperidin-4-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)methanamine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 556.4 [M+H]+
Example 330 2-amino-N-((1S,2S)-2-(3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 610.4 [M+H]+
Example 331 2-amino-5-(3-amino-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-amino-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 611.4 [M+H]+
Example 332 2-amino-5-(3-amino-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 2-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 597.4 [M+H]+
Example 333 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)-3-methylphenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 460.3 [M+H]+
Example 334 2-amino-5-(3-chlorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)-oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-chloro-phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 450 [M+H]+
Example 335 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(m-tolyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and m-tolylboronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 430.2 [M+H]+
Example 336 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3,5-dimethylphenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3,5-dimethylphenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 444.3 [M+H]+
Example 337 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-morpholinopyrrolidin-1-yl)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 4-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-yl)morpholine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 584.4 [M+1-1]
Example 338 2-amino-5-(4-((4-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-4-amine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 528.3 [M+H]+
Example 339 2-amino-5-(4-((3-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-3-amine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 528.3 [M+H]+
Example 340 2-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 514.3 [M+H]+
Example 341 2-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3-fluorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 532.3 [M+H]+
Example 342 2-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3,5-difluorophenyl)-N-(1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1 S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 550.3 [M+H]+
Example 343 2-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and N,N-dimethyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 542.3 [M+H]+
Example 344 2-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-4-methoxyphenyl)-N-(1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-N,N-dimethylpyrrolidin-3-amine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 572.4 [M+H]+
Example 345 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxyazetidin-1-yl)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)azetidin-3-ol, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 501.3 [M+H]+
Example 346 2-amino-5-(4-(((R)-3-(dimethylamino)pyrrolidin-1-yl)methyl)-phenyl)-N-(1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1 S,2 S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (R)—N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 542.3 [M+H]+
Example 347 2-amino-5-(4-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (S)—N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 542.3 [M+H]+
Example 348 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-ol, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 515.3 [M+H]+
Example 349 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((S)-3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-ol, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 515.3 [M+H]+
Example 350 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxypiperidin-1-yl)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperidin-3-ol, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 529.3 [M+H]+
Example 351 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-hydroxyphenyl)nicotinamideUsing (1 S,2 S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-hydroxy-phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 432.2 [M+H]+
Example 352 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-hydroxy-3-methoxyphenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (4-hydroxy-3-methoxyphenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 462.23 [M+H]+
Example 353 2-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3,4-dimethoxy-phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 476.3 [M+H]+
Example 354 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(pyrrolidin-1-yl)phenyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and (3-(pyrrolidin-1-yl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 253
MS (ESI, m/z): 485.3 [M+H]+
Example 355 2-amino-5-(5-amino-1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentan-1-amine and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-5-amine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 435.2 [M+H]+
Example 356 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxymethyl)phenyl)nicotinamideUsing (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine and (4-(hydroxy-methyl)phenyl)boronic acid, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 460.3 [M+H]+
Example 357 2-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)nicotinamideUsing (1S,2 S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine and N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-amine, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 556.4 [M+H]+
Example 358 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamideUsing (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-3-ol, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 529.3 [M+H]+
Example 359 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(piperazin-1-yl)propan-2-yl)phenyl)nicotinamideUsing (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine and 1-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)piperazine, the title compound was obtained as described for the example 253.
1H NMR (400 MHz, CD3OD) δ ppm 1.11 (t, J=7.63 Hz, 3H) 1.50 (s, 6H) 1.58-1.67 (m, 1H) 1.70-1.88 (m, 3H) 1.98-2.06 (m, 1H) 2.10-2.17 (m, 1H) 2.17 (s, 3H) 2.49-2.57 (q, J=7.63 Hz, 2H) 2.84 (br s, 4H) 3.24 (t, J=4.70 Hz, 4H) 3.91-4.00 (m, 1H) 4.40 (br d, J=4.70 Hz, 1H) 4.49-4.61 (m, 2H) 6.98-7.05 (m, 2H) 7.09 (s, 1H) 7.64-7.80 (m, 4H) 8.31 (d, J=2.35 Hz, 1H) 8.57 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 556.4 [M+H]+
Example 360 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)phenyl)nicotinamideUsing (1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentan-1-amine and 2-(4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-yl)piperazin-1-yl)ethan-1-ol, the title compound was obtained as described for the example 253.
1H NMR (400 MHz, CD3OD) δ ppm 1.11 (t, J=7.43 Hz, 3H) 1.57 (s, 3H) 1.61-1.64 (m, 1H) 1.64 (s, 3H) 1.69-1.89 (m, 3H) 2.01 (br dd, J=13.11, 6.06 Hz, 1H) 2.10-2.29 (m, 4H) 2.53 (q, J=7.56 Hz, 2H) 2.88-3.13 (m, 4H) 3.22-3.28 (m, 1H) 3.33-3.39 (m, 2H) 3.43 (br s, 2H) 3.83-3.90 (m, 1H) 3.92-4.00 (m, 1H) 4.35-4.45 (m, 1H) 4.47-4.62 (m, 2H) 6.95-7.07 (m, 2H) 7.09 (s, 1H) 7.65-7.84 (m, 4H) 8.29-8.36 (m, 1H) 8.56-8.64 (m, 1H);
MS (ESI, m/z): 600.3 [M+H]+
Example 361 3-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyrazine-2-carboxamideUsing 3-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-bromopyrazine-2-carboxamide and (1-(piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 462.3 [M+H]+
Example 362 (S)-3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazine-2-carboxamideUsing (S)-3-amino-6-bromo-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazine-2-carboxamide and (1-(piperidin-4-yl)-1H-pyrazol-4-yl)boronic acid pinacol ester, the title compound was obtained as described for the example 253.
MS (ESI, m/z): 418.2 [M+H]+
Example 363 2-amino-5-(4-fluorophenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideScheme for the preparation of the Compound of Example 363:
To a solution of trans-(1S,2S)-2-Aminocyclopentanol hydrochloride (8.0 mmol) in DMF (5 ml) was added 1M potassium tert-butoxide in THF (20 ml) at room temperature. The mixture was allowed to stir for 30 min. After being allowed to stir for 30 min, 4-bromobenzyl bromide (9.6 mmol) was added to the mixture, and then allowed to stir for additional 2 h at room temperature. The reaction mixture was then quenched with water and extracted with EtOAc. The separated organic layer was dried over MgSO4, filtered and concentrated in vacuo. The concentrated residue was used in the next step without further purification.
1H NMR (600 MHz, CDCl3) δ ppm 1.29-1.35 (m, 1H) 1.57-1.65 (m, 1H) 1.65-1.77 (m, 2H) 1.96 (br dd, J=12.62, 6.75 Hz, 2H) 3.20-3.27 (m, 1H) 3.51 (br d, J=5.28 Hz, 1H) 4.40-4.46 (m, 1H) 4.46-4.54 (m, 1H) 7.21 (br t, J=7.63 Hz, 2H) 7.40-7.48 (m, 2H); MS (ESI+) m/z 270 [M+H]+
Intermediate 27To a solution of intermediate 26 (0.851 mmol) in 1,4-dioxane (4 ml) and water (1 ml) was added 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine (0.851 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0851 mmol) and potassium carbonate (0.851 mmol). The mixture was heated to 100° C. and allowed to stir for overnight. After being cooled to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The separated organic layer was dried over MgSO4, filtered and concentrated in vacuo. The concentrated residue was purified by flash column chromatography to afford the desired compound (265 mg, 0.7 mmol).
1H NMR (600 MHz, CD3OD) δ ppm 1.36-1.45 (m, 1H) 1.63-1.78 (m, 3H) 1.97-2.07 (m, 2H) 2.26 (s, 3H) 2.30-2.71 (br s, 8H) 3.24 (td, J=7.48, 4.99 Hz, 1H) 3.55 (s, 2H) 3.67-3.74 (m, 1H) 4.53 (d, J=11.74 Hz, 1H) 4.60 (d, J=11.74 Hz, 1H) 7.38 (d, J=8.22 Hz, 2H) 7.42 (d, J=8.22 Hz, 2H) 7.55-7.58 (m, 2H) 7.58-7.61 (m, 2H);
MS (ESI+) m/z 380 [M+H]+
Intermediate 28To a solution of intermediate 27 (0.685 mmol) and 2-amino-5-bromonicotinic acid (0.685 mmol) in N,N-dimethylformamide (5 mL) was added diisopropylethylamine (3.425 mmol) and HATU (1.027 mmol) at room temperature. The reaction mixture was allowed to stir for overnight, concentrated in vacuo, diluted with EtOAc and washed with brine. The separated organic layer was dried over MgSO4, filtered and concentrated in vacuo. The concentrated residue was purified by flash column chromatography to afford the desired compound (0.653 mmol) as a pale yellow oil.
1H NMR (600 MHz, CD3OD) δ ppm 1.49-1.57 (m, 1H) 1.68-1.78 (m, 3H) 1.95-2.01 (m, 1H) 2.07-2.13 (m, 1H) 2.41 (s, 3H) 2.49-2.79 (br s, 8H) 3.56 (s, 2H) 3.91 (dt, J=6.90, 4.48 Hz, 1H) 4.34 (td, J=7.48, 4.40 Hz, 1H) 4.57-4.65 (m, 2H) 7.35 (br d, J=8.22 Hz, 2H) 7.37 (br d, J=8.22 Hz, 2H) 7.52 (d, J=7.63 Hz, 4H) 7.90 (d, J=2.35 Hz, 1H) 8.04 (d, J=2.35 Hz, 1H);
MS (ESI+) m/z 579 [M+H]+
Example 363 2-amino-5-(4-fluorophenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideTo a solution of intermediate 28 (0.076 mmol) in 1,4-dioxane (4 ml) and water (1 ml) was added (4-fluorophenyl)boronic acid (0.076 mmol), tetrakis(triphenylphosphine)-palladium(0) (0.0076 mmol) and potassium carbonate (0.076 mmol). The mixture was heated to 100° C. and allowed to stir for overnight. After being cooled to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL). The separated organic layer was dried over MgSO4, filtered and concentrated in vacuo. The concentrated residue was purified by preparative HPLC to afford the compound of Example 363.
1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.23 (s, 1H), 7.64-7.47 (m, 8H), 7.42 (d, 2H), 7.17 (t, 2H), 4.66 (qd, 2H), 4.45-4.39 (m, 1H), 4.25 (s, 1H), 4.09-3.90 (m, 1H), 3.62 (s, 1H), 3.53 (br s, 2H), 3.39 (br s, 2H), 2.94 (s, 3H), 2.19-2.12 (m, 1H), 2.05-1.97 (m, 1H), 1.83-1.75 (m, 3H), 1.66-1.57 (m, 1H); MS (ESI+) m/z 594 [M+H]+
Example 364 2-amino-5-(3,4-difluorophenyl)-N-(1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 3,4-difluorophenylboronic acid, the title compound was obtained as described for the example 363.
1H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.26 (s, 1H), 7.71-7.52 (m, 8H), 7.42-7.33 (m, 3H), 4.65 (qd, 2H), 4.41 (m, 1H), 4.32 (s, 2H), 3.98 (m, 1H), 3.57 (br s, 2H), 3.48 (br s, 2H), 2.94 (s, 3H), 2.18-2.05 (m, 1H), 2.04-1.99 (m, 1H), 1.81-1.73 (m, 3H), 1.66-1.59 (m, 1H);
MS (ESI+) m/z 612 [M+H]+
Example 365 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(trifluoromethyl)phenyl)nicotinamideUsing 4-trifluoromethylphenylboronic acid, the title compound was obtained as described for the example 363.
1H NMR (400 MHz, CD3OD) δ 8.65 (s, 1H), 8.36 (s, 1H), 7.83 (d, J=8.0 Hz, 2H), 7.75 (d, J=12.0 Hz, 2H), 7.62 (d, J=8.0 Hz, 2H), 7.54-7.50 (m, 4H), 7.42 (d, J=8.0 Hz, 2H), 4.69-4.62 (qd, 2H), 4.44-4.39 (m, 1H), 4.27 (s, 2H), 4.02-4.00 (m, 1H), 3.54 (br s, 2H), 3.42 (br s, 2H), 2.94 (s, 3H), 2.21-2.05 (m, 1H), 2.05-1.97 (m, 1H), 1.87-1.76 (m, 3H), 1.68-1.59 (m, 1H);
MS (ESI+) m/z 644 [M+H]+
Example 366 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamideUsing 1-methyl-4-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]-piperidine, the title compound was obtained as described for the example 363.
1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.63 (d, J=8.0 Hz, 2H), 7.57-7.50 (m, 4H), 7.42 (d, J=8.0 Hz, 2H), 4.66 (s, 2H), 4.59-4.53 (m, 1H), 4.43-4.38 (m, 1H), 4.25 (s, 2H), 4.12-4.01 (m, 2H), 3.69-3.66 (d, 2H), 3.53 (br s, 2H), 3.39 (br s, 2H), 3.25-3.20 (m, 1H), 2.93 (s, 3H), 2.92 (s, 3H), 2.41-2.33 (m, 4H), 2.19-1.97 (m, 2H), 1.84-1.76 (m, 3H), 1.69-1.60 (m, 1H);
MS (ESI+) m/z 663 [M+H]+
Example 367 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)-nicotinamideUsing 4-(4-Methylpiperazin-1-yl)phenylboronic acid, the title compound was obtained as described for the example 363.
1H NMR (400 MHz, CD3OD) δ 8.59 (s, 1H), 8.18 (s, 1H), 7.64-7.50 (m, 8H), 7.43 (d, J=8.0 Hz, 2H), 7.11 (d, J=8.0 Hz, 2H), 4.66 (s, 2H), 4.43-4.39 (m, 1H), 4.25 (s, 2H), 4.03-4.00 (m, 1H), 3.92 (d, J=1.2 Hz, 2H), 3.62 (d, J=1.2 Hz, 2H), 3.52 (br s, 2H), 3.39 (br s, 2H), 3.26-3.20 (m, 2H), 3.12-3.06 (m, 2H), 2.96 (s, 3H), 2.93 (s, 3H), 2.18-2.13 (m, 1H), 2.05-1.92 (m, 1H), 1.83-1.76 (m, 3H), 1.66-1.59 (m, 1H);
MS (ESI+) m/z 674 [M+H]+
Example 368 2-amino-N-((1S,2S)-2-(4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamideUsing 4-((4-methylpiperazin-1-yl)methyl)phenylboronic acid, the title compound was obtained as described for the example 363.
1H NMR (400 MHz, CD3OD) δ 8.66 (s, 1H), 8.29 (s, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.65-7.52 (m, 8H), 7.43 (d, J=8.0 Hz, 2H), 4.66 (s, 2H), 4.42 (m, 1H), 4.31 (s, 2H), 4.21 (s, 2H), 4.02 (m, 1H), 3.53 (br, 8H), 3.46 (br, 4H), 3.29 (br, 4H), 2.94 (s, 3H), 2.93 (s, 3H), 2.23-2.10 (m, 1H), 2.04-1.98 (m, 1H), 1.88-1.75 (m, 3H), 1.67-1.60 (m, 1H);
MS (ESI+) m/z 688 [M+H]+
Example 369 2-amino-5-(4-(hydroxymethyl)phenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 4-(Hydroxymethyl)phenylboronic acid, the title compound was obtained as described for the example 363.
1HNMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 8.26 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.61-7.53 (m, 5H), 7.46-7.41 (m, 6H), 4.66 (s, 2H), 4.64 (s, 2H), 4.42 (m, 1H), 3.99 (m, 1H), 3.91 (s, 2H), 3.35 (br s, 2H), 3.00 (br s, 2H), 2.88 (s, 3H), 2.22-2.10 (m, 1H), 2.04 (m, 1H), 1.85-1.74 (m, 3H), 1.63 (m, 1H); MS (ESI+) m/z 606 [M+H]+
Example 370 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(m-tolyl)nicotinamideUsing 3-tolylboronic acid, the title compound was obtained as described for the example 363.
1H NMR (400 MHz, CD3OD) δ 8.62 (s, 1H), 8.23 (s, 1H), 7.72-7.32 (m, 11H), 7.24 (d, J=8.0 Hz, 1H), 4.66 (s, 2H), 4.41 (m, 1H), 4.06 (s, 2H), 4.00 (m, 1H), 3.43 (br s, 2H), 3.17 (br s, 2H), 2.90 (s, 3H), 2.39 (s, 3H), 2.18 (m, 1H), 2.04 (m, 1H), 1.89-1.75 (m, 3H), 1.65-1.60 (m, 1H);
MS (ESI+) m/z 590 [M+H]+
Example 371 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-phenylnicotinamideUsing phenylboronic acid, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 576 [M+H]+
Example 372 2-amino-5-(4-hydroxyphenyl)-N-(1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 4-hydroxyphenylboronic acid, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 592 [M+H]+
Example 373 2-amino-5-(4-chloro-3-fluorophenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 4-chloro-3-fluorophenylboronic acid, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 629 [M+H]+
Example 374 2-amino-5-methyl-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing trimethylboroxine, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 514 [M+H]+
Example 375 6-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideUsing 3-pyridylboronic acid, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 577 [M+H]+
Example 376 2-amino-5-(4-methoxyphenyl)-N-(1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 4-methoxyphenylboronic acid, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 606 [M+H]+
Example 377 6-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,4′-bipyridine]-5-carboxamideUsing 4-pyridylboronic acid, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 577 [M+H]+
Example 378 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)-nicotinamideUsing (4-((4-methylpiperidin-1-yl)methyl)phenyl)boronic acid, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 687 [M+H]+
Example 379 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-(morpholinomethyl)phenyl)nicotinamideUsing (4-(morpholinomethyl)phenyl)boronic acid, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 675 [M+H]+
Example 380 2-amino-N-((1S,2S)-2-(4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)nicotinamideUsing 1-(Tetrahydro-pyran-4-yl)-1H-pyrazole-4-boronic acid pinacol ester, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 650 [M+H]+
Example 381 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-morpholinophenyl)nicotinamideUsing 4-morpholinophenylboronic acid, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 661 [M+H]+
Example 382 2-amino-5-(cyclohex-1-en-1-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 1-cyclohexenylboronic acid, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 580 [M+H]+
Example 383 2-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamideUsing 3,4-dimethoxyphenylboronic acid, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 636 [M+H]+
Example 384 6-amino-2′,6′-difluoro-N-(1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,4′-bipyridine]-5-carboxamideUsing 2,6-difluoropyridine-4-boronic acid, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 613 [M+H]+
Example 385 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(4-methylthiophen-3-yl)nicotinamideUsing 4-Methyl-3-thienylboronic acid, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 596 [M+H]+
Example 386 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamideUsing 6-fluoro-3-pyridinylboronic acid, the title compound was obtained as described for the example 363.
MS (ESI+) m/z 595 [M+H]+
Example 387 2-amino-N-((1S,2S)-2-((4′-(4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-(1,1,2,2-tetrafluoroethyl)-1H-pyrazol-4-yl)-nicotinamideUsing (1-(1,1,2,2-tetrafluoroethyl)-1H-pyrazol-4-yl)boronic acid, the title compound was obtained as described for the example 363.
1H NMR (600 MHz, CD3OD) δ ppm 1.64 (br dd, J=14.09, 7.04 Hz, 1H) 1.75-1.88 (m, 3H) 2.04 (br dd, J=12.33, 7.63 Hz, 1H) 2.15-2.23 (m, 1H) 2.87 (s, 3H) 2.90-3.06 (m, 4H) 3.33 (br s, 4H) 3.86 (s, 2H) 3.98-4.04 (m, 1H) 4.39-4.44 (m, 1H) 4.62-4.69 (m, 2H) 6.75-6.98 (m, 1H) 7.39-7.45 (m, 4H) 7.55 (br d, J=8.22 Hz, 2H) 7.57 (br d, J=8.22 Hz, 2H) 8.20 (s, 1H) 8.33 (d, J=1.76 Hz, 1H) 8.58 (d, J=1.76 Hz, 1H) 8.60 (s, 1H);
MS (ESI+) m/z 666.3 [M+H]+
Example 388 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideScheme for the preparation of the Compound of Example 388:
To a mixture of intermediate 3 (420 mg, 1.94 mmol) and triethylamine (0.40 ml, 2.90 mmol) in 10 ml of DMF was added HATU (884 mg, 2.32 mmol) followed by tert-butyl (3S,4 S)-3-amino-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidine-1-carboxylate (647 mg, 1.94 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified through silicagel column chromatography to give 800 mg of off-white solid.
1H NMR (600 MHz, CDCl3) δ ppm 1.14-1.22 (t, 3H) 1.41 (br s, 9H) 2.27 (s, 3H) 2.55-2.64 (q, 2H) 3.37-3.66 (m, 4H) 3.78 (dd, J=12.03, 5.58 Hz, 1H) 4.10 (br s, 1H) 4.50-4.79 (m, 2H) 6.74 (br s, 2H) 7.04-7.15 (m, 3H) 7.98 (d, J=1.76 Hz, 1H) 8.43 (br s, 1H);
MS (ESI, m/z): 534.3 [M+H]+
Example 388 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideTo a mixture of intermediate 29 (40 mg, 0.07 mmol) and 1-methylpyrazole-4-boronic acid pinacol ester (23 mg, 0.11 mmol) in 0.4 ml of 1,4-dioxane/water (3/1) was added K2CO3 (31 mg, 0.22 mmol) followed by Pd(PPh3)4 (4 mg, 0.003 mmol). The reaction mixture was heated at 100° C. for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO4 and concentrated under vacuum. The crude residue was dissolved with 0.5 ml of CH2Cl2/TFA (10/1) and the mixture was stirred for 2 hrs. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 23 mg of the title compound.
1H NMR (600 MHz, CD3OD) ppm 1.13 (t, J=7.34 Hz, 3H) 2.23 (s, 2H) 2.57 (q, J=7.24 Hz, 2H) 2.91 (dd, J=12.03, 4.40 Hz, 1H) 2.97-3.04 (m, 1H) 3.16-3.22 (m, 1H) 3.36-3.43 (m, 1H) 3.91 (s, 3H) 4.05-4.10 (m, 1H) 4.48 (br s, 1H) 4.57 (d, J=11.74 Hz, 1H) 4.65 (d, J=11.74 Hz, 1H) 7.06 (s, 2H) 7.12 (s, 1H) 7.76 (s, 1H) 7.89 (s, 1H) 8.02 (d, J=2.35 Hz, 1H) 8.26 (d, J=2.35 Hz, 1H),
MS (ESI, m/z): 435.5 [M+H]+
Example 389 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(hydroxymethyl)phenyl)nicotinamideUsing 4-hydroxymethylphenylboronic acid, the title compound was obtained as described for the example 388.
MS (ESI, m/z): 461.6 [M+H]+
Example 390 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamideUsing (4-((4-methylpiperazin-1-yl)methyl)phenyl)boronic acid, the title compound was obtained as described for the example 388.
MS (ESI, m/z): 543.4 [M+H]+
Example 391 2-amino-5-(4-carbamoylphenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamideUsing (4-carbamoylphenyl)boronic acid, the title compound was obtained as described for the example 388.
1H NMR (400 MHz, CD3OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.19-2.19 (m, 1H) 2.60 (q, J=7.70 Hz, 2H) 3.33-3.35 (m, 1H) 3.43-3.64 (m, 2H) 3.77 (br dd, J=12.72, 7.24 Hz, 1H) 4.36 (br s, 1H) 4.55-4.73 (m, 3H) 7.10 (s, 2H) 7.17 (s, 1H) 7.78 (d, J=8.22 Hz, 2H) 7.99 (d, J=8.61 Hz, 2H) 8.44 (d, J=2.35 Hz, 1H) 8.62 (d, J=1.96 Hz, 1H);
MS (ESI, m/z): 474.5 [M+H]+
Example 392 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(m-tolyl)nicotinamideUsing m-tolylboronic acid, the title compound was obtained as described for the example 388.
1H NMR (400 MHz, CD3OD) δ ppm 1.16 (t, J=7.43 Hz, 3H) 2.25 (s, 3H) 2.41 (s, 3H) 2.60 (q, J=7.56 Hz, 2H) 3.43-3.65 (m, 3H) 3.77 (dd, J=12.52, 7.04 Hz, 1H) 4.35 (br d, J=4.30 Hz, 1H) 4.62-4.74 (m, 3H) 7.09 (s, 2H) 7.16 (s, 1H) 7.25 (br d, J=7.43 Hz, 1H) 7.36 (t, J=7.63 Hz, 1H) 7.42-7.51 (m, 2H) 8.31 (d, J=1.96 Hz, 1H) 8.65 (d, J=1.96 Hz, 1H);
MS (ESI, m/z): 445.3 [M+H]+
Example 393 4-(6-amino-5-(((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-pyrrolidin-3-yl)carbamoyl)pyridin-3-yl)benzoic acidUsing 4-carboxyphenylboronic acid, the title compound was obtained as described for the example 388.
1H NMR (400 MHz, CD3OD) δ ppm 1.16 (t, J=7.43 Hz, 3H) 2.23 (s, 3H) 2.59 (q, J=7.56 Hz, 2H) 3.34-3.51 (m, 2H) 3.52-3.67 (m, 1H) 3.76 (br d, J=7.43 Hz, 1H) 4.13 (br s, 1H) 4.57-4.69 (m, 3H) 7.02-7.10 (m, 2H) 7.14 (s, 1H) 7.79 (br d, J=8.22 Hz, 2H) 8.13 (br d, J=8.22 Hz, 2H) 8.37-8.45 (m, 1H) 8.73 (d, J=1.56 Hz, 1H); MS (ESI, m/z): 475.4 [M+H]+
Example 394 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-phenylnicotinamideUsing phenylboronic acid, the title compound was obtained as described for the example 388.
1H NMR (400 MHz, CD3OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.61 (q, J=7.43 Hz, 2H) 3.42-3.51 (m, 1H) 3.51-3.65 (m, 2H) 3.77 (dd, J=12.91, 7.04 Hz, 1H) 4.35 (br d, J=4.30 Hz, 1H) 4.57-4.76 (m, 3H) 7.06-7.13 (m, 2H) 7.17 (s, 1H) 7.35-7.58 (m, 3H) 7.68 (d, J=7.04 Hz, 2H) 8.33 (d, J=2.35 Hz, 1H) 8.74 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 431.5 [M+H]+
Example 395 6-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,4′-bipyridine]-5-carboxamideUsing pyridine-4-boronic acid, the title compound was obtained as described for the example 388.
1H NMR (400 MHz, CD3OD) δ ppm 1.17 (t, J=7.63 Hz, 3H) 2.26 (s, 3H) 2.62 (q, J=7.56 Hz, 2H) 3.47 (br d, J=12.52 Hz, 1H) 3.52-3.67 (m, 2H) 3.77 (br dd, J=12.72, 6.85 Hz, 1H) 4.34 (br d, J=3.91 Hz, 1H) 4.61-4.78 (m, 3H) 7.07-7.13 (m, 2H) 7.13-7.19 (m, 1H) 7.99 (dd, J=8.02, 5.67 Hz, 1H) 8.56 (d, J=1.96 Hz, 1H) 8.68-8.82 (m, 3H) 9.14 (s, 1H);
MS (ESI, m/z): 432.3 [M+H]+
Example 396 6-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,3′-bipyridine]-5-carboxamideUsing pyridine-3-boronic acid, the title compound was obtained as described for the example 388.
1H NMR (400 MHz, CD3OD) δ ppm 1.17 (t, J=7.63 Hz, 3H) 2.26 (s, 3H) 2.62 (q, J=7.56 Hz, 2H) 3.47 (br d, J=12.52 Hz, 1H) 3.52-3.67 (m, 2H) 3.77 (br dd, J=12.72, 6.85 Hz, 1H) 4.34 (br d, J=3.91 Hz, 1H) 4.60-4.78 (m, 3H) 7.07-7.13 (m, 2H) 7.17 (d, J=7.06 Hz, 1H) 7.18 (s, 1H) 7.99 (dd, J=8.02, 5.67 Hz, 1H) 8.56 (d, J=1.96 Hz, 1H) 8.67-8.83 (m, 3H) 9.14 (s, 1H);
MS (ESI, m/z): 432.3 [M+H]+
Example 397 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-vinylnicotinamideUsing potassium vinyltrifluoroborate, the title compound was obtained as described for the example 388.
1H NMR (400 MHz, CD3OD) δ ppm 1.17 (t, J=7.43 Hz, 3H) 2.26 (s, 3H) 2.61 (q, J=7.56 Hz, 2H) 3.44-3.65 (m, 3H) 3.76 (br dd, J=12.91, 7.04 Hz, 1H) 4.33 (br d, J=3.91 Hz, 1H) 4.59-4.74 (m, 3H) 5.42 (d, J=10.96 Hz, 1H) 5.94 (d, J=17.61 Hz, 1H) 6.66 (dd, J=17.80, 11.15 Hz, 1H) 7.10 (s, 2H) 7.16 (s, 1H) 8.02-8.08 (m, 1H) 8.66 (d, J=1.96 Hz, 1H);
MS (ESI, m/z): 381.3 [M+H]+
Example 398 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-fluorophenyl)nicotinamideUsing 4-fluorophenylboronic acid, the title compound was obtained as described for the example 388.
1H NMR (600 MHz, CD3OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.60 (q, J=7.63 Hz, 2H) 3.44-3.59 (m, 2H) 3.76 (dd, J=12.62, 7.34 Hz, 2H) 4.25-4.38 (m, 1H) 4.61-4.71 (m, 3H) 7.03-7.12 (m, 2H) 7.14-7.24 (m, 3H) 7.60-7.69 (m, 2H) 8.32 (d, J=2.35 Hz, 1H) 8.48 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 499.3 [M+H]+
Example 399 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-formylphenyl)nicotinamideUsing 4-formylphenylboronic acid, the title compound was obtained as described for the example 388.
1H NMR (600 MHz, CDCl3) δ ppm 1.30 (t, J=7.63 Hz, 3H) 2.26 (br s, 3H) 2.58 (q, J=7.63 Hz, 2H), 3.43-3.49 (m, 1H) 3.50-3.65 (m, 2H) 3.77 (dd, J=12.62, 6.75 Hz, 1H), 4.17 (br s, 1H) 4.64 (br s, 2H) 4.77 (br s, 1H) 6.59 (br s, 2H) 7.05-7.20 (m, 3H) 7.55-7.73 (m, 2H) 7.86 (br d, J=5.28 Hz, 2H) 8.04 (br s, 1H) 8.46 (br s, 1H) 9.86 (br s, 1H);
MS (ESI, m/z): 459.5 [M+H]+
Example 400 2-amino-5-(4-cyanophenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamideUsing 4-cyanophenylboronic acid, the title compound was obtained as described for the example 388.
1H NMR (600 MHz, CD3OD) δ ppm 1.16 (t, J=7.34 Hz, 3H) 2.25 (s, 3H) 2.60 (q, J=7.63 Hz, 2H) 3.43-3.49 (m, 1H) 3.50-3.65 (m, 2H) 3.77 (dd, J=12.62, 6.75 Hz, 1H) 4.35 (br d, J=4.11 Hz, 1H) 4.62-4.74 (m, 3H) 7.04-7.14 (m, 2H) 7.16 (s, 1H) 7.78-7.84 (m, 2H) 7.84-7.88 (m, 2H) 8.39-8.52 (m, 1H) 8.59 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 456.3 [M+H]+
Example 401 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(methylsulfonamido)phenyl)nicotinamideUsing 4-methylsulfonylphenylboronic acid, the title compound was obtained as described for the example 388.
1H NMR (600 MHz, CD3OD) δ ppm 1.16 (t, J=7.34 Hz, 3H) 2.25 (s, 3H) 2.60 (q, J=7.63 Hz, 2H) 2.98 (s, 3H) 3.43-3.49 (m, 1H) 3.50-3.65 (m, 2H) 3.76 (dd, J=12.62, 7.34 Hz, 1H) 4.33-4.38 (m, 1H) 4.62-4.71 (m, 3H) 7.05-7.13 (m, 2H) 7.16 (s, 1H) 7.36 (d, J=8.80 Hz, 2H) 7.65 (d, J=8.22 Hz, 2H) 8.32 (d, J=1.76 Hz, 1H) 8.59 (d, J=1.76 Hz, 1H);
MS (ESI, m/z):524.6 [M+H]+
Example 402 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)nicotinamideUsing 4-phenoxyphenylboronic acid, the title compound was obtained as described for the example 388.
1H NMR (600 MHz, CD3OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.56-2.65 (m, 2H) 3.46 (br d, J=12.33 Hz, 1H) 3.52-3.61 (m, 2H) 3.76 (s, 1H) 4.32-4.40 (m, 1H) 4.62-4.73 (m, 3H) 7.02 (d, J=7.63 Hz, 2H) 7.04-7.12 (m, 4H) 7.13-7.19 (m, 2H) 7.38 (t, J=7.92 Hz, 2H) 7.66 (d, J=8.80 Hz, 2H) 8.29-8.34 (m, 1H) 8.68 (d, J=1.76 Hz, 1H); MS (ESI, m/z):523.7 [M+H]+
Example 403 5-([1,1′-biphenyl]-4-yl)-2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamideUsing 4-biphenylboronic acid, the title compound was obtained as described for the example 388.
1H NMR (600 MHz, CD3OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.60 (q, J=7.63 Hz, 2H) 3.47 (br d, J=12.91 Hz, 1H) 3.51-3.62 (m, 2H) 3.77 (dd, J=12.33, 7.04 Hz, 1H) 4.31-4.40 (m, 1H) 4.63-4.73 (m, 3H) 7.05-7.14 (m, 2H) 7.17 (s, 1H) 7.34 (s, 1H) 7.36 (br d, J=7.63 Hz, 1H) 7.45 (t, J=7.63 Hz, 2H) 7.64 (d, J=7.63 Hz, 2H) 7.70-7.79 (m, 3H) 8.40 (d, J=1.76 Hz, 1H) 8.64 (d, J=2.35 Hz, 1H);
MS (ESI, m/z):507.4 [M+H]+
Example 404 2-amino-5-(4-(benzyloxy)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamideUsing 4-benzyloxyphenylboronic acid, the title compound was obtained as described for the example 388.
1H NMR (600 MHz, CD3OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.24 (s, 3H) 2.60 (q, J=7.63 Hz, 2H) 3.46 (br d, J=12.91 Hz, 1H) 3.49-3.60 (m, 2H) 3.76 (dd, J=12.91, 7.04 Hz, 1H) 4.28-4.36 (m, 1H) 4.60-4.73 (m, 3H) 5.13 (s, 2H) 7.03-7.13 (m, 4H) 7.16 (s, 1H) 7.23-7.32 (m, 1H) 7.36 (t, J=7.63 Hz, 2H) 7.43 (d, J=7.04 Hz, 2H) 7.59 (d, J=8.80 Hz, 2H) 8.23-8.29 (m, 1H) 8.60 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 537.8 [M+H]+
Example 405 2-amino-5-(4-(dimethylamino)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamideUsing 4-dimethylaminophenylboronic acid, the title compound was obtained as described for the example 388.
1H NMR (600 MHz, CD3OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.60 (q, J=7.24 Hz, 2H) 3.07 (s, 6H) 3.47 (br d, J=12.91 Hz, 1H) 3.57 (ddd, J=18.78, 12.91, 3.52 Hz, 2H) 3.76 (br dd, J=12.91, 7.04 Hz, 1H) 4.32-4.37 (m, 1H) 4.61-4.72 (m, 3H) 7.02-7.12 (m, 4H) 7.16 (s, 1H) 7.62 (d, J=8.80 Hz, 2H) 8.26 (d, J=1.76 Hz, 1H) 8.69 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 474.4 [M+H]+
Example 406 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(quinolin-3-yl)nicotinamideUsing quinoline-3-boronic acid, the title compound was obtained as described for the example 388.
1H NMR (600 MHz, CD3OD) δ ppm 1.17 (t, J=7.34 Hz, 3H) 2.25 (s, 3H) 2.61 (q, J=7.24 Hz, 2H) 3.48 (br d, J=12.91 Hz, 1H) 3.57-3.69 (m, 2H) 3.78 (br dd, J=12.91, 7.04 Hz, 1H) 4.34-4.42 (m, 1H) 4.61-4.75 (m, 3H) 7.05-7.15 (m, 2H) 7.18 (s, 1H) 7.78-7.93 (m, 1H) 7.93-8.09 (m, 1H) 8.18 (br dd, J=8.22, 3.52 Hz, 2H) 8.63 (d, J=1.76 Hz, 1H) 8.86 (d, J=2.35 Hz, 1H) 8.99-9.07 (m, 1H) 9.37 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 482.6 [M+H]+
Example 407 2-amino-5-(benzofuran-2-yl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamideUsing benzo[b]furan-2-boronic acid, the title compound was obtained as described for the example 388.
1H NMR (600 MHz, CD3OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.61 (q, J=7.63 Hz, 2H) 3.48 (br d, J=12.33 Hz, 1H) 3.53 (br dd, J=12.91, 2.93 Hz, 1H) 3.60 (br dd, J=12.91, 4.70 Hz, 1H) 3.78 (br dd, J=12.62, 7.34 Hz, 1H) 4.37 (br s, 1H) 4.63-4.72 (m, 3H) 7.04-7.14 (m, 2H) 7.15-7.20 (m, 2H) 7.20-7.26 (m, 1H) 7.29 (br t, J=7.63 Hz, 1H) 7.51 (d, J=8.22 Hz, 1H) 7.58 (br d, J=7.63 Hz, 1H) 8.57 (d, J=1.76 Hz, 1H) 8.60 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 471.5 [M+H]+
Example 408 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(naphthalen-1-yl)nicotinamideUsing 2-naphthyleneboronic acid, the title compound was obtained as described for the example 388.
1H NMR (600 MHz, CD3OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.24 (s, 3H) 2.60 (q, J=7.43 Hz, 2H) 3.48 (br d, J=12.91 Hz, 1H) 3.53-3.69 (m, 2H) 3.78 (dd, J=12.91, 7.04 Hz, 1H) 4.31-4.46 (m, 1H) 4.55-4.72 (m, 3H) 7.05-7.14 (m, 2H) 7.17 (s, 1H) 7.47-7.58 (m, 2H) 7.79 (dd, J=8.22, 1.76 Hz, 1H) 7.85-8.02 (m, 3H) 8.16 (s, 1H) 8.47 (d, J=1.76 Hz, 1H) 8.78 (d, J=1.76 Hz, 1H); MS (ESI, m/z): 481.4 [M+H]+
Example 409 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(trifluoromethyl)phenyl)nicotinamideUsing 4-trifluoromethylbenzeneboronic acid, the title compound was obtained as described for the example 388
1H NMR (600 MHz, CD3OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.61 (q, J=7.24 Hz, 2H) 3.45 (br d, J=12.32 Hz, 1H) 3.49-3.62 (m, 2H) 3.75 (dd, J=12.62, 6.75 Hz, 1H) 4.26-4.38 (m, 1H) 4.61-4.72 (m, 3H) 7.03-7.13 (m, 2H) 7.16 (s, 1H) 7.33 (td, J=10.12, 6.75 Hz, 2H) 7.53-7.69 (m, 2H) 8.29 (s, 1H) 8.48 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 499.6 [M+H]+
Example 410 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(2,4,5-trifluorophenyl)nicotinamideUsing 2,4,5-trifluorophenylboronic acid, the title compound was obtained as described for the example 388.
1H NMR (600 MHz, CD3OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.61 (q, J=7.24 Hz, 2H) 3.45 (br d, J=12.32 Hz, 1H) 3.49-3.62 (m, 2H) 3.75 (dd, J=12.62, 6.75 Hz, 1H) 4.26-4.38 (m, 1H) 4.61-4.72 (m, 3H) 7.03-7.13 (m, 2H) 7.16 (s, 1H) 7.33 (td, J=10.12, 6.75 Hz, 1H) 7.53-7.63 (m, 1H) 8.29 (s, 1H) 8.48 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 485.3 [M+H]+
Example 411 2-amino-5-(4-(cyanomethyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamideUsing 4-cyanomethylphenylboronic acid, the title compound was obtained as described for the example 388.
1H NMR (600 MHz, CD3OD) δ ppm 1.16 (td, J=7.63, 2.35 Hz, 3H) 2.24 (d, J=4.11 Hz, 3H) 2.59 (qd, J=7.53, 3.23 Hz, 2H) 3.45-3.56 (m, 1H) 3.67-3.74 (m, 1H) 3.77-3.88 (m, 1H) 3.93 (s, 2H) 3.98 (br dd, J=11.44, 6.16 Hz, 1H) 4.11-4.28 (m, 1H) 4.58-4.70 (m, 3H) 7.07 (s, 2H) 7.14 (s, 1H) 7.86 (d, J=2.93 Hz, 1H) 8.02 (s, 1H) 8.19 (d, J=11.15 Hz, 1H) 8.24 (d, J=1.76 Hz, 1H) 8.59 (dd, J=7.04, 2.35 Hz, 1H);
MS (ESI, m/z): 470.8 [M+H]+
Example 412 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamideUsing 1-(4-N-Boc-piperidine)pyrazole-4-boronic acid, the title compound was obtained as described for the example 388 and following deprotection with TFA.
MS (ESI, m/z): 504.3 [M+H]+
Example 413 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamideUsing 1-(4-N-methylpiperidine)pyrazole-4-boronic acid, the title compound was obtained as described for the example 388.
MS (ESI, m/z): 518.3 [M+H]+
Example 414 2-amino-N-((3S,4S)-4-(benzyloxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing tert-butyl (3S,4 S)-3-amino-4-(benzyloxy)pyrrolidine-1-carboxylate, the title compound was obtained as described for the example 388.
MS (ESI, m/z): 393.2 [M+H]+
Example 415 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamideUsing tert-butyl (3S,4 S)-3-amino-4-((4-methylbenzyl)oxy)pyrrolidine-1-carboxylate, the title compound was obtained as described for the example 388.
MS (ESI, m/z): 407.2 [M+H]+
Example 416 2-amino-N-((3S,4S)-4-((3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing tert-butyl (3S,4 S)-3-amino-4-((3-ethylbenzyl)oxy)pyrrolidine-1-carboxylate, the title compound was obtained as described for the example 388.
MS (ESI, m/z): 421.2 [M+H]+
Example 417 2-amino-N-((3S,4S)-4-((3-ethyl-4-fluorobenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing tert-butyl (3S,4S)-3-amino-4-((3-ethyl-4-fluorobenzyl)oxy)pyrrolidine-1-carboxylate, the title compound was obtained as described for the example 388.
MS (ESI, m/z): 439.2 [M+H]+
Example 418 2-amino-N-((3S,4S)-4-((4-chloro-3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing tert-butyl (3S,4S)-3-amino-4-((4-chloro-3-ethylbenzyl)oxy)pyrrolidine-1-carboxylate, the title compound was obtained as described for the example 388.
MS (ESI, m/z): 455.2 [M+H]+
Example 419 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamideScheme for the preparation of the Compound of Example 419:
To a mixture of intermediate 29 (400 mg, 0.7 mmol) and 4-carboxyphenylboronic acid (230 mg, 1.10 mmol) in 4 ml of 1,4-dioxane/water (3/1) was added K2CO3 (310 mg, 2.2 mmol) followed by Pd(PPh3)4 (40 mg, 0.03 mmol). The reaction mixture was heated at 100° C. for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO4 and concentrated under vacuum. The crude product was purified through silicagel column chromatography to give 350 mg of off-white solid 1H NMR (400 MHz, CD3OD) δ ppm 1.16 (t, J=7.43 Hz, 3H) 1.46 (br d, J=1.96 Hz, 9H) 2.23 (s, 3H) 2.59 (q, J=7.56 Hz, 2H) 3.40-3.51 (m, 2H) 3.52-3.65 (m, 1H) 3.76 (br d, J=7.43 Hz, 1H) 4.13 (br s, 1H) 4.57-4.74 (m, 3H) 7.06 (s, 2H) 7.14 (s, 1H) 7.79 (br d, J=8.22 Hz, 2H) 8.13 (br d, J=8.22 Hz, 2H) 8.37-8.45 (m, 1H) 8.73 (d, J=1.56 Hz, 1H);
MS (ESI, m/z): 575.3 [M+H]+
Example 419 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamideTo a mixture of intermediate 30 (12 mg, 0.02 mmol) and triethylamine (0.04 ml, 0.03 mmol) in 0.2 ml of DMF was added HATU (10 mg, 0.03 mmol) followed by 4-amino-1-methylpiperidine (0.03 ml, 0.02 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude residue was dissolved with 0.5 ml of CH2Cl2/TFA (10/1) and the mixture was stirred for 2 hrs. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 10 mg of the title compound.
1H NMR (400 MHz, CD3OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 1.86-1.98 (m, 2H) 2.23 (br s, 3H) 2.25 (s, 3H) 2.61 (q, J=7.70 Hz, 2H) 2.89 (s, 3H) 3.10-3.26 (m, 2H) 3.47 (br d, J=12.52 Hz, 1H) 3.52-3.66 (m, 3H) 3.77 (dd, J=12.72, 6.85 Hz, 1H) 4.11-4.23 (m, 1H) 4.32-4.43 (m, 1H) 4.53-4.77 (m, 3H) 7.05-7.14 (m, 2H) 7.17 (s, 1H) 7.81 (d, J=8.22 Hz, 2H) 7.88-7.99 (m, 2H) 8.42 (d, J=1.96 Hz, 1H) 8.74 (d, J=1.96 Hz, 1H);
MS (ESI, m/z): 571.4 [M+H]+
Example 420 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylcyclohexyl)carbamoyl)phenyl)nicotinamideUsing 4-methylcyclohexylamine, the title compound was obtained as described for the example 419.
1H NMR (600 MHz, CD3OD) δ ppm 0.93 (d, J=6.46 Hz, 1H) 1.00 (d, J=6.46 Hz, 2H) 1.09 (br d, J=14.09 Hz, 1H) 1.16 (t, J=7.63 Hz, 3H) 1.38-1.48 (m, 2H) 1.59-1.73 (m, 3H) 1.75-1.84 (m, 2H) 1.96 (br d, J=11.15 Hz, 1H) 2.25 (s, 3H) 2.60 (q, J=7.63 Hz, 2H) 3.32-3.36 (m, 1H) 3.47 (br d, J=12.91 Hz, 1H) 3.51-3.61 (m, 2H) 3.76 (dd, J=12.91, 7.04 Hz, 2H) 3.99 (br s, 1H) 4.35 (br s, 1H) 4.62-4.72 (m, 3H) 7.03-7.14 (m, 2H) 7.16 (s, 1H) 7.76 (dd, J=8.51, 4.40 Hz, 2H) 7.91 (dd, J=8.22, 2.35 Hz, 2H) 8.42 (d, J=2.35 Hz, 1H) 8.58-8.62 (m, 1H);
MS (ESI, m/z): 570.5 [M+H]+
Example 421 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(4-methylpiperidine-1-carbonyl)phenyl)nicotinamideUsing 4-methylpiperidine, the title compound was obtained as described for the example 419.
1H NMR (600 MHz, CD3OD) δ ppm 0.98 (d, J=6.46 Hz, 3H) 1.09-1.22 (m, 3H) 1.16 (t, J=7.63, 3H) 1.62 (br d, J=11.74 Hz, 1H) 1.66-1.74 (m, 2H) 1.79 (br d, J=12.91 Hz, 1H) 2.23 (s, 3H) 2.53-2.63 (q, J=7.63 Hz, 2H) 2.85 (br t, J=12.33 Hz, 1H) 3.11 (br t, J=12.33 Hz, 1H) 3.39-3.49 (m, 2H) 3.55-3.61 (m, 1H) 3.68 (br d, J=12.91 Hz, 1H) 3.75 (td, J=11.74, 7.04 Hz, 1H) 4.12 (br s, 1H) 4.58-4.64 (m, 3H) 7.02-7.11 (m, 2H) 7.13 (s, 1H) 7.51 (d, J=8.22 Hz, 2H) 7.76 (d, J=8.22 Hz, 2H) 8.36 (d, J=1.76 Hz, 1H) 8.70 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 556.5 [M+H]+
Example 422 2-amino-5-(4-(dimethylcarbamoyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamideUsing dimethylamine, the title compound was obtained as described for the example 419.
1H NMR (600 MHz, CD3OD) δ ppm 1.15 (t, J=7.63 Hz, 3H) 2.22 (s, 3H) 2.58 (q, J=7.63 Hz, 2H) 3.01 (s, 3H) 3.11 (s, 3H) 3.38-3.50 (m, 2H) 3.52-3.66 (m, 1H) 3.67-3.81 (m, 1H) 4.12 (br s, 1H) 4.57-4.68 (m, 3H) 7.05 (s, 2H) 7.13 (s, 1H) 7.54 (d, J=8.80 Hz, 2H) 7.75 (d, J=8.22 Hz, 2H) 8.36 (d, J=1.76 Hz, 1H) 8.68 (d, J=2.35 Hz, 1H); MS (ESI, m/z): 502.4 [M+H]+
Example 423 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamideScheme for the preparation of the Compound of Example 423:
Using intermediate 29 and 4-formylphenylboronic acid, the title compound was obtained as described for the synthesis of intermediate 30.
1H NMR (600 MHz, CDCl3) δ ppm 1.30 (t, J=7.63 Hz, 3H), 1.42 (s, 9H), 2.26 (br s, 3H) 2.58 (q, J=7.63 Hz, 2H) 3.37-3.84 (m, 4H) 4.17 (br s, 1H) 4.64 (br s, 2H) 4.77 (br s, 1H) 6.59 (br s, 2H) 7.05-7.20 (m, 3H) 7.55-7.73 (m, 2H) 7.86 (br d, J=5.28 Hz, 2H) 8.04 (br s, 1H) 8.46 (br s, 1H) 9.86 (br s, 1H); MS (ESI, m/z): 559.4 [M+H]+
Example 423 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamideTo a mixture of intermediate 31 (40 mg, 0.07 mmol) in 0.4 ml of dichloroethane was added 4-methylpiperidine (0.017 ml, 0.14 mmol) followed by NaBH(OAc)3 (30 mg, 0.21 mmol). The mixture was stirred at room temperature for 4 hr and then water was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude residue was dissolved with 0.5 ml of CH2Cl2/TFA (10/1) and the mixture was stirred for 2 hrs. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 10 mg of the title compound.
1H NMR (600 MHz, CD3OD) δ ppm 0.99 (d, J=6.46 Hz, 3H) 1.16 (t, J=7.34 Hz, 3H) 1.34-1.46 (m, 2H) 1.91 (br d, J=14.09 Hz, 2H) 2.25 (s, 3H) 2.61 (q, J=7.63 Hz, 2H) 2.93-3.07 (m, 2H) 3.43-3.49 (m, 3H) 3.57 (ddd, J=16.43, 12.91, 3.52 Hz, 2H) 3.76 (dd, J=12.62, 6.75 Hz, 2H) 4.27-4.39 (m, 3H) 4.59-4.76 (m, 3H) 7.05-7.14 (m, 2H) 7.17 (s, 1H) 7.60 (d, J=8.22 Hz, 2H) 7.80 (d, J=8.22 Hz, 2H) 8.39 (d, J=1.76 Hz, 1H) 8.67 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 542.3 [M+H]+
Example 424 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(morpholinomethyl)phenyl)nicotinamideUsing morpholine, the title compound was obtained as described for the example 423.
1H NMR (600 MHz, CD3OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 2.25 (s, 3H) 2.61 (q, J=7.63 Hz, 2H) 3.09-3.27 (m, 2H) 3.31-3.40 (m, 2H) 3.46 (d, J=12.33 Hz, 1H) 3.52-3.67 (m, 2H) 3.76 (br dd, J=12.91, 7.04 Hz, 1H) 3.77 (br s, 2H) 4.03 (br s, 2H) 4.35 (br d, J=4.11 Hz, 1H) 4.41 (s, 2H) 4.63-4.71 (m, 2H) 4.72 (br d, J=6.46 Hz, 1H)7.06-7.12 (m, 2H) 7.17 (s, 1H) 7.63 (d, J=8.22 Hz, 2H) 7.82 (d, J=8.22 Hz, 2H) 8.40 (d, J=2.35 Hz, 1H) 8.66-8.70 (m, 1H); MS (ESI, m/z): 530.3 [M+H]+
Example 425 2-amino-5-(4-((3,3-difluoropiperidin-1-yl)methyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamideUsing 3,3-difluoropiperidine, the title compound was obtained as described for the example 423.
1H NMR (600 MHz, CD3OD) δ ppm 1.16 (t, J=7.63 Hz, 3H) 1.97-2.09 (m, 2H) 2.15 (br s, 2H) 2.25 (s, 3H) 2.61 (q, J=7.63 Hz, 2H) 3.22-3.28 (m, 2H) 3.38-3.49 (m, 4H) 3.50-3.66 (m, 2H) 3.76 (dd, J=12.33, 7.04 Hz, 1H) 4.35 (br d, J=4.70 Hz, 1H) 4.40 (s, 2H) 4.62-4.73 (m, 3H) 7.07-7.12 (m, 2H) 7.17 (s, 1H) 7.61 (d, J=8.22 Hz, 2H) 7.81 (d, J=8.22 Hz, 2H) 8.40 (d, J=2.35 Hz, 1H) 8.61 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 564.3 [M+H]+
Example 426 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideScheme for the preparation of the Compound of Example 426:
To compound 388 (40 mg, 0.09 mmol) in 0.4 ml of 1,2-dichloroethane was added formaldehyde (0.015 ml, 0.18 mmol) followed by NaBH(OAc)3 (38 mg, 0.28 mmol). The mixture was stirred at room temperature for 1 hr and then water was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 30 mg of the title compound.
1H NMR (600 MHz, CD3OD) δ ppm 1.12-1.17 (m, 3H) 2.23 (s, 3H) 2.55-2.65 (m, 2H) 3.01 (s, 3H) 3.43-3.54 (m, 1H) 3.60-3.71 (m, 1H) 3.73-3.84 (m, 1H) 3.92 (s, 3H) 4.08-4.23 (m, 1H) 4.31-4.45 (m, 1H) 4.62-4.70 (m, 2H) 4.72 (br d, J=5.87 Hz, 1H) 7.04-7.11 (m, 2H) 7.15 (s, 1H) 7.88 (s, 1H) 8.05 (s, 1H) 8.26 (d, J=2.35 Hz, 1H) 8.66 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 449.3 [M+H]+
Example 427 2-amino-N-((3S,4S)-1-benzyl-4-((3-ethyl-4-methylbenzyl)oxy)-pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing benzaldehyde, the title compound was obtained as described for the example 426.
MS (ESI, m/z): 525.7 [M+H]+
Example 428 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-(3-phenylpropyl)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 3-phenylpropanal, the title compound was obtained as described for the example 426.
1H NMR (600 MHz, CD3OD) δ ppm 1.14 (t, J=7.63 Hz, 3H) 1.97-2.13 (m, 2H) 2.22 (s, 3H) 2.58 (q, J=7.63 Hz, 2H) 2.70 (t, J=7.63 Hz, 2H) 3.27 (t, J=7.63 Hz, 2H) 3.43-3.54 (m, 1H) 3.60-3.71 (m, 1H) 3.73-3.84 (m, 1H) 3.92 (s, 3H) 4.08-4.23 (m, 1H) 4.36 (br s, 1H) 4.6-4.72 (m, 3H) 7.01-7.10 (m, 2H) 7.12-7.15 (m, 1H) 7.15-7.30 (m, 5H) 7.87 (s, 1H) 8.04 (s, 1H) 8.25 (d, J=1.76 Hz, 1H) 8.64 (br s, 1H); MS (ESI, m/z): 553.3 [M+H]+
Example 429 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-phenethylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing phenylacetaldehyde, the title compound was obtained as described for the example 426.
MS (ESI, m/z): 539.3[M+H]+
Example 430 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-isobutylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing isobutyraldehyde, the title compound was obtained as described for the example 426.
1H NMR (600 MHz, CD3OD) δ ppm 1.04 (br d, J=3.52 Hz, 6H) 1.14 (t, J=7.63 Hz, 3H) 2.10 (dt, J=13.65, 6.97 Hz, 1H) 2.22 (s, 3H) 2.58 (q, J=7.63 Hz, 2H) 3.14 (br d, J=6.46 Hz, 2H) 3.32-3.42 (m, 1H) 3.52 (br s, 1H) 3.70-3.83 (m, 1H) 3.93 (s, 3H) 3.99-4.17 (m, 1H) 4.41 (br d, J=16.43 Hz, 1H) 4.59-4.75 (m, 3H) 7.02-7.12 (m, 2H) 7.15 (br s, 1H) 7.87 (br s, 1H) 8.05 (br d, J=11.15 Hz, 1H) 8.28 (d, J=1.76 Hz, 1H) 8.59 (br s, 1H);
MS (ESI, m/z): 491.3 [M+H]+
Example 431 2-amino-N-((3S,4S)-1-butyl-4-((3-ethyl-4-methylbenzyl)-oxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing butyraldehyde, the title compound was obtained as described for the example 426.
MS (ESI, m/z): 491.4 [M+H]+
Example 432 2-amino-N-((3S,4S)-1-ethyl-4-((3-ethyl-4-methylbenzyl)oxy)-pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing acetaldehyde, the title compound was obtained as described for the example 426.
MS (ESI, m/z): 463.3 [M+H]+
Example 433 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3-yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamideFrom compound 359, the title compound was obtained as described for the example 426.
MS (ESI, m/z): 532.3 [M+H]+
Example 434 and Example 435Scheme for the preparation of the Compounds of Example 434 and 435:
To a mixture of intermediate 2 (350 mg, 1.60 mmol) and triethylamine (0.34 ml, 2.41 mmol) in 4 ml of DMF was added HATU (732 mg, 1.92 mmol) followed by tert-butyl (3S,4S)-3-amino-4-((4-bromobenzyl)oxy)pyrrolidine-1-carboxylate (657 mg, 1.76 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified through silicagel column chromatography to give 700 mg of off-white solid.
1H NMR (600 MHz, CDCl3) δ ppm 1.43 (br s, 9H) 3.42 (br d, J=10.56 Hz, 1H) 3.51-3.65 (m, 2H) 3.80 (dd, J=12.03, 5.58 Hz, 1H) 3.89 (s, 3H) 4.03-4.20 (m, 1H) 4.54-4.77 (m, 3H) 6.29 (br s, 2H) 7.25 (br d, J=8.22 Hz, 2H) 7.46 (br d, J=8.22 Hz, 2H) 7.53 (br s, 1H) 7.57-7.67 (m, 2H) 8.29 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 571.2 [M+H]+
Example 434 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-nicotinamideTo a mixture of intermediate 32 (40 mg, 0.07 mmol) and 4-((4-methylpiperazin-1-yl)-methylphenylboronic acid pinacol ester (27 mg, 0.08 mmol) in 0.4 ml of 1,4-dioxane/water (3/1) was added K2CO3 (29 mg, 0.21 mmol) followed by Pd(PPh3)4 (4 mg, 0.003 mmol) Pd(PPh3)4. The reaction mixture was heated at 100° C. for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO4 and concentrated under vacuum. The crude residue was dissolved with 0.5 ml of CH2Cl2/TFA (10/1) and the mixture was stirred for 2 hrs. After concentration under vacuum, the crude residue was purified by preparative HPLC to afford 30 mg of the title compound.
1H NMR (600 MHz, CD3OD) δ ppm 2.88 (s, 3H) 2.91-3.13 (m, 4H) 3.31-3.46 (m, 4H) 3.52-3.65 (m, 3H) 3.80 (dd, J=12.91, 7.04 Hz, 1H) 3.87-3.96 (m, 5H) 4.39-4.45 (m, 1H) 4.71-4.83 (m, 3H) 7.46 (br d, J=8.22 Hz, 2H) 7.49 (br d, J=8.22 Hz, 2H) 7.62 (dd, J=8.22, 2.35 Hz, 4H) 7.87 (s, 1H) 8.04 (s, 1H) 8.25 (d, J=1.76 Hz, 1H) 8.65 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 581.4 [M+H]+
Example 435 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-nicotinamideTo a mixture of compound 434 (52 mg, 0.09 mmol) in 0.4 ml of 1,2-dichloroethane was added formaldehyde (0.015 ml, 0.18 mmol) followed by NaBH(OAc)3 (38 mg, 0.28 mmol). The mixture was stirred at room temperature for 1 hr and then water was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 35 mg of the title compound.
1H NMR (600 MHz, CD3OD) δ ppm 2.94 (s, 3H) 3.04 (s, 3H) 3.36-3.47 (m, 6H) 3.48-3.58 (m, 6H) 3.91 (s, 3H) 4.27 (s, 2H) 4.44 (br s, 1H) 4.72-4.83 (m, 3H) 7.49 (d, J=8.22 Hz, 2H) 7.53 (d, J=8.22 Hz, 2H) 7.61 (d, J=8.22 Hz, 2H) 7.66 (d, J=8.22 Hz, 2H) 7.86 (s, 1H) 8.03 (s, 1H) 8.22 (d, J=1.76 Hz, 1H) 8.67 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 595.3 [M+H]+
Example 436 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)-pyrrolidin-3-yl)nicotinamideUsing (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 434.
MS (ESI, m/z): 649.3 [M+H]+
Example 437 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-methoxy)pyrrolidin-3-yl)nicotinamideFrom compound 436, the title compound was obtained as described for the example 435.
MS (ESI, m/z): 663.3 [M+H]+
Example 438 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-nicotinamideUsing (4-acetylphenyl)boronic acid, the title compound was obtained as described for the example 434.
MS (ESI+) m/z 595.3 [M+H]+
Example 439 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-nicotinamideFrom compound 438, the title compound was obtained as described for the example 435.
1H NMR (400 MHz, CD3OD) δ ppm 1.65 (d, J=7.04 Hz, 3H) 2.90 (s, 3H) 3.05 (s, 3H) 3.08-3.17 (m, 2H) 3.46 (br s, 4H) 3.93 (s, 3H) 4.16 (br d, J=6.65 Hz, 2H) 4.49 (s, 1H) 4.75-4.87 (m, 3H) 7.51 (dd, J=8.22, 4.70 Hz, 4H) 7.57-7.70 (m, 4H) 7.88 (s, 1H) 8.05 (s, 1H) 8.26 (d, J=1.96 Hz, 1H) 8.68 (d, J=1.96 Hz, 1H); MS (ESI+) m/z 609.4 [M+H]+
Example 440 2-amino-N-((3S,4S)-4-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 434.
1H NMR (400 MHz, CD3OD) δ ppm 1.77 (s, 6H) 3.50-3.68 (m, 6H) 3.80 (s, 1H) 3.83-3.89 (m, 2H) 3.92 (s, 3H) 4.42 (br d, J=4.30 Hz, 1H) 4.73-4.88 (m, 3H) 7.52 (d, J=8.22 Hz, 2H) 7.65 (d, J=8.22 Hz, 2H) 7.67-7.84 (m, 3H) 7.86-7.92 (m, 1H) 8.06 (s, 1H) 8.26 (d, J=2.35 Hz, 1H) 8.70 (d, J=2.35 Hz, 1H);
MS (ESI, m/z): 639.4 [M+H]+
Example 441 2-amino-N-((3S,4S)-4-((4′-((2-(4-(2-hydroxyethyl)piperazin-1-yl)-propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideFrom compound 440, the title compound was obtained as described for the example 435.
MS (ESI, m/z): 653.4 [M+H]+
Example 442 2-amino-N-((3S,4S)-4-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 434.
MS (ESI, m/z): 625.4 [M+H]+
Example 443 2-amino-N-((3S,4S)-4-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideFrom compound 442, the title compound was obtained as described for the example 435.
MS (ESI, m/z): 639.4 [M+H]+
Example 444 2-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-boronic acid pinacol ester, the title compound was obtained as described for the example 434.
MS (ESI, m/z): 679.3 [M+H]+
Example 445 2-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing 1-(4-bromo-2-(trifluoromethyl)benzyl)piperazine, the title compound was obtained as described for the example 435.
MS (ESI, m/z): 693.3 [M+H]+
Example 446 2-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)-nicotinamideUsing (4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 434.
MS (ESI, m/z): 611.3 [M+H]+
Example 447 2-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideFrom compound 446, the title compound was obtained as described for the example 435.
MS (ESI, m/z): 625.4 [M+H]+
Example 448 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-nicotinamideScheme for the preparation of the Compound of Example 448:
Using intermediate 2 and (3S,4R)-4-((4-bromobenzyl)oxy)tetrahydrofuran-3-amine, the title compound was obtained as described for the intermediate 4.
1H NMR (600 MHz, CD3OD) δ ppm 3.81 (td, J=10.27, 2.35 Hz, 2H) 3.91 (s, 3H) 4.05 (dd, J=9.98, 5.28 Hz, 1H) 4.11 (dd, J=9.39, 5.87 Hz, 1H) 4.13-4.16 (m, 1H) 4.55 (dd, J=3.81, 2.05 Hz, 1H) 4.60 (s, 2H) 4.63 (d, J=12.33 Hz, 1H) 4.74 (d, J=12.33 Hz, 1H) 7.30 (m, J=8.22 Hz, 2H) 7.45-7.49 (m, 2H) 7.78 (s, 1H) 7.90 (s, 1H) 8.07 (d, J=2.35 Hz, 1H) 8.26 (d, J=1.76 Hz, 1H);
MS (ESI, m/z): 472.1 [M+H]+
Example 448 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-nicotinamideUsing intermediate 33, the title compound was obtained as described for the example 172.
1H NMR (600 MHz, CD3OD) δ ppm 2.87 (s, 3H) 3.80-3.89 (m, 4H) 3.92 (s, 3H) 4.04-4.15 (m, 2H) 4.19-4.25 (m, 1H) 4.57-4.63 (m, 1H) 4.71 (d, J=11.74 Hz, 1H) 4.82 (d, J=11.74 Hz, 1H) 7.40-7.51 (m, 4H) 7.57-7.63 (m, 4H) 7.88 (s, 1H) 8.02 (s, 1H) 8.23 (s, 1H) 8.62 (s, 1H);
MS (ESI, m/z): 582.3 [M+H]+
Example 449 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)-tetrahydrofuran-3-yl)nicotinamideUsing (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester pinacol ester, the title compound was obtained as described for the example 448.
1H NMR (400 MHz, CD3OD) δ ppm 2.91 (s, 3H) 3.80-3.91 (m, 3H) 3.94 (s, 2H) 4.12 (td, J=9.59, 5.48 Hz, 2H) 4.23 (br s, 1H) 4.62 (br s, 1H) 4.74 (d, J=12.13 Hz, 1H) 7.52 (d, J=8.61 Hz, 2H) 7.65 (d, J=8.22 Hz, 2H) 7.88 (d, J=13.30 Hz, 4H) 8.03 (s, 1H) 8.25 (d, J=1.96 Hz, 1H) 8.63 (d, J=1.96 Hz, 1H); MS (ESI, m/z): 650.3 [M+H]+
Example 450 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamideUsing (4-formyl-3-(trifluoromethyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 448.
1H NMR (400 MHz, CD3OD) δ ppm 1.62 (s, 6H) 2.89 (s, 3H) 3.04 (br s, 2H) 3.34-3.47 (m, 4H) 3.82-3.91 (m, 2H) 3.93 (s, 3H) 4.12 (td, J=10.56, 5.48 Hz, 2H) 4.22 (br s, 1H) 4.61 (br s, 1H) 4.66-4.77 (m, 1H) 4.81-4.88 (m, 1H) 7.47 (d, J=7.83 Hz, 2H) 7.58-7.70 (m, 6H) 7.89 (s, 1H) 8.03 (s, 1H) 8.24 (d, J=1.96 Hz, 1H) 8.65 (d, J=1.96 Hz, 1H);
MS (ESI, m/z): 610.2 [M+H]+
Example 451 2-amino-N-((3S,4R)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 448.
MS (ESI, m/z): 612.3 [M+H]+
Example 452 2-amino-N-((3S,4R)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)-methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-boronic acid pinacol ester, the title compound was obtained as described for the example 448.
1H NMR (400 MHz, CD3OD) δ ppm 2.62 (br s, 4H) 3.25-3.29 (m, 2H) 3.34-3.40 (m, 2H) 3.82-3.84 (m, 2H) 3.85-3.91 (m, 2H) 3.94 (s, 2H) 4.06-4.17 (m, 2H) 4.23 (br s, 1H) 4.62 (br s, 1H) 4.74 (m, 1H) 7.52 (m, J=8.22 Hz, 2H) 7.65 (m, J=8.22 Hz, 2H) 7.86 (s, 2H) 7.89 (s, 2H) 8.03 (s, 1H) 8.25 (d, J=1.96 Hz, 1H) 8.63 (d, J=1.96 Hz, 1H);
MS (ESI, m/z): 680.3 [M+H]+
Example 453 2-amino-N-((3S,4R)-4-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)-propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamideUsing (4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2-yl)phenyl)boronic acid pinacol ester, the title compound was obtained as described for the example 448.
MS (ESI, m/z): 640.2 [M+H]+
Example 454 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl-nicotinamideUsing trans-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)-tetrahydrofuran-3-amine, the title compound was obtained as described for the example 448.
1H NMR (400 MHz, CD3OD) δ ppm 2.88 (s, 3H) 3.76-3.89 (m, 4H) 4.09 (ddd, J=16.92, 9.88, 5.28 Hz, 2H) 4.20 (br d, J=4.70 Hz, 1H) 4.57 (br s, 1H) 4.70 (br d, J=11.74 Hz, 1H) 6.98 (dd, J=7.43, 6.26 Hz, 1H) 7.46 (d, J=8.22 Hz, 4H) 7.56-7.67 (m, 4H) 7.99-8.06 (m, 1H) 8.40 (dd, J=7.43, 1.56 Hz, 1H);
MS (ESI, m/z): 582.3 [M+H]+
Example 455 2-amino-N-(trans-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamideUsing 2-aminonicotinic acid and trans-4-((4-bromobenzyl)oxy)tetrahydrofuran-3-amine, the title compound was obtained as described for the example 448.
1H NMR (400 MHz, CD3OD) δ ppm 2.88 (s, 3H) 3.76-3.89 (m, 4H) 4.09 (ddd, J=16.92, 9.88, 5.28 Hz, 2H) 4.20 (br d, J=4.70 Hz, 1H) 4.57 (br s, 1H) 4.70 (br d, J=11.74 Hz, 1H) 6.98 (dd, J=7.43, 6.26 Hz, 1H) 7.46 (d, J=8.22 Hz, 4H) 7.56-7.67 (m, 4H) 7.99-8.06 (m, 1H) 8.40 (dd, J=7.43, 1.56 Hz, 1H);
MS (ESI, m/z): 502.3 [M+H]+
Example 456 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)nicotinamideScheme for the preparation of the Compound of Example 456:
To a suspension of methyl 2-amino-6-chloronicotinate (100 mg, 0.54 mmol) in 3 ml of MeOH was added 2N NaOH (1 ml, 2 mmol) and the mixture was heated at 65° C. for 1 hr, cooled to room temperature, neutralized (1 ml of 2N HCl), and the resulting precipitate was filtered, washed with MeOH, and dried to give 80 mg of off-white solid.
1H NMR (400 MHz, DMSO-d6) δ ppm 6.61 (d, J=7.83 Hz, 1H) 7.53 (br s, 2H) 8.01 (d, J=8.22 Hz, 1H); MS (ESI, m/z): 173.2 [M+H]+
Intermediate 35To a mixture of intermediate 34 (50 mg, 0.29 mmol) and triethylamine (0.061 ml, 0.43 mmol) in 2 ml of DMF was added HATU (132 mg, 0.35 mmol) followed by (1S,2S)-2-(benzyloxy)cyclopentan-1-amine (55 mg, 0.29 mmol). The mixture was stirred at room temperature for 1 hr and then saturated sodium bicarbonate solution was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and concentrated in vacuo. The crude residue was purified by preparative HPLC to afford 80 mg of the title compound.
1H NMR (400 MHz, CDCl3) δ ppm 1.39-1.52 (m, 1H) 1.68-1.81 (m, 2H) 1.83-1.89 (m, 1H) 1.89-2.02 (m, 1H) 2.27 (td, J=13.69, 7.83 Hz, 1H) 3.80-3.87 (m, 1H) 4.27-4.37 (m, 1H) 4.58-4.67 (m, 2H) 5.79 (br d, J=6.26 Hz, 1H) 6.51 (br s, 2H) 6.56 (d, J=7.83 Hz, 1H) 7.25-7.37 (m, 5H) 7.39 (d, J=7.83 Hz, 1H);
MS (ESI, m/z): 345.3 [M+H]+
Example 456 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-((4-((4-methylpiperazin-1-yl)methyl)phenyl)amino)nicotinamideTo a mixture of intermediate 35 (186 mg, 1 mmol) and 4-((4-methylpiperazine-1-yl)methyl)aniline (240 mg, 1.2 mmol) in 5 ml of 1,4-dioxane was added 480 mg of K2CO3 followed by Pd2(dba)3 (30 mg, 0.3 mmol). The reaction mixture was heated at 100° C. for 3 hrs, cooled to room temperature, and extracted with EtOAc, dried over anhydrous MgSO4 and concentrated under vacuum. The crude product was purified by silicagel column chromatography to give 170 mg of off-white solid.
1H NMR (400 MHz, CD3OD) δ ppm 1.57 (br dd, J=13.30, 7.04 Hz, 1H) 1.66-1.87 (m, 3H) 1.97 (dt, J=13.01, 6.60 Hz, 1H) 2.13 (br dd, J=13.11, 6.85 Hz, 1H) 2.95 (s, 3H) 3.44-3.62 (m, 4H) 3.87-3.97 (m, 1H) 4.17 (s, 2H) 4.31-4.39 (m, 1H) 4.60 (s, 2H) 6.25 (d, J=9.00 Hz, 1H) 7.21-7.35 (m, 4H) 7.43 (d, J=8.22 Hz, 2H) 7.58 (d, J=8.61 Hz, 2H) 8.08 (d, J=9.00 Hz, 1H); MS (ESI, m/z): 515.3 [M+H]+
Example 457 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(phenylamino)-nicotinamideUsing aniline, the title compound was obtained as described for the example 456.
MS (ESI, m/z): 403.2 [M+H]+
Example 458 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)nicotinamideUsing 4-(4-methylpiperazin-1-yl)aniline, the title compound was obtained as described for the example 456.
MS (ESI, m/z): 501.3 [M+H]+
Biochemical AssayFor the SAR (structure-activity relationship) and compound screening, LanthaScreen™ TR-FRET (Time-Resolved fluorescence energy transfer) assay was employed using the phospho-tyrosine specific Terbium (Tb)-labelded antibody with a fluorescein labeled poly-GT (glutamate-tyrosine) as a substrate. Upon excitation at 340 nm by UV, the energy from Tb donor of the antibody is transferred to the fluorescein of the phosphorylated poly GT substrate, and fluorescein emits light at 520 nm. The ratio between the intensity of primary emission at 495 nm and that of secondary emission at 520 nm was used to quantify the level of kinase activity. The recombinant proteins of human c-MER and AXL catalytic domains, Fluorescein-labeled poly-GT substrate, Tb-labeled anti-phosphorylated tyrosine antibodies, the kinase assay buffer, and 0.5M EDTA solution were purchased (Life technologies, USA). The TR-FRET assays were carried out in the white low volume 384-well plate (Corning, USA). To measure the compound mediated inhibition of kinase activity, the recombinant kinases were pre-incubated with test compounds for 20 minutes prior to the addition of 200 nM fluorescein labeled poly-GT substrates and 10 uM ATP, and then the reaction was carried out for 1 hour at room temperature. 10 mM EDTA was added to terminate the enzyme reaction, and the level of phosphorylation of poly-GT substrate was determined following 30 min incubation with 2 nM Tb-labeled antibody. The fluorescence intensity was measured with Envision™ plate reader (PerkinElmer, USA).
In Cell MER Kinase Assay Using BaF3 Cellular System
CD8-MerTK is a chimeric fusion protein consisting of the extracellular and transmembrane domains of the human CD8a (amino acids 1 to 209) at its N-terminus and the kinase domain and intracellular parts of MerTK (amino acids 521-994) at its C-terminus. To establish an in cell kinase assay for MerTK kinase, the IL-3 dependent Ba/F3 cells of murine lymphoid origin was transfected with CD8-MerTK. The resulting Ba/F3-CDM line was then validated that Ba/F3-CDM cell proliferation is completely dependent on the activity of MerTK kinase activity when growing in the absence of IL-3. For a routine cellular assay, Ba/F3-CDM cells were seeded at 2,000 cells per well in 384-well cell culture plate containing DMEM/10% FBS culture media and incubated for 24 hours before addition of compounds pre-diluted in culture media. Following compound treatment, cells were further incubated for 48 hours and the proliferation was measured. To discriminate a Ba/F3 growth inhibition by a specific inhibition of MerTK kinase following compound treatment vs growth inhibition due to a non-specific unintended cytotoxicity of compounds, we routinely carried out control sets of Ba/F3 cells in parallel that grown in IL3-supplemented growth media. In the presence of IL-3, the proliferation of Ba/F3 is no longer dependent on the MerTK activity. Cell growth and proliferation was measured with Celltiter-Glo™ system (Promega, USA) according to the manufacturer's instruction. The half-maximal growth inhibitory concentration (GI50) value was calculated with Prism6.0 software (GraphPad, USA).
As can be seen in Table 1 above, the heterocyclic compounds of the present invention showed the activity of Mer, which compounds are useful for the prevention and/or the treatment of cancer.
Claims
1. A heterocyclic compound represented by the following Formula I, a stereoisomer thereof, an enantiomer thereof, or a pharmaceutically acceptable salt thereof:
- wherein:
- X is CR7, or N;
- Y is CHR8, NR8, or O;
- Z is CH2, CH2O, C(═O), C(═O)O, C(═O)NH, NR8 NHC(═O), O or O(C═O);
- R1 is H, halogen, C1-3 alkyl, NHR8 or OR8;
- R2 is H, halogen, C1-4 alkyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl or -L-aryl, which C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl or -L-aryl may optionally be substituted with one or more R9;
- R3 is H, halogen, CN, C1-3 alkyl, cycloalkenyl, C2-6 alkenyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl which aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl may optionally be substituted with one or more R9;
- R4 and R5 each independently is H, C1-6 alkyl, C1-6 alkoxy, C3-10 cycloalkyl, C(═O) R6, C1-2 alkylaryl, aryl; or
- R4 and R5 may be combined with each other to form a 3-7 membered cyclic ring or heterocyclic ring containing 1 or 2 of NR8, O or S, and the cyclic or heterocyclic ring may optionally be substituted with 1 or 2 halogen(s), C1-4 alkyl or C1-4 alkoxy;
- R5′ is H or R5 and R5′ may be combined with each other to form carbonyl;
- R6 is H, C1-4 alkyl, C1-6 alkoxy, —NR15R16, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl, C1-2 alkylbiaryl, -L-aryl or -L-biaryl, which C1-4 alkyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl, C1-2 alkylbiaryl, -L-aryl or -L-biaryl, may optionally be substituted with one or more R9;
- R7 is H, halogen or C1-3 alkyl;
- R8 is H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkylaryl or C(═O)R10 which C1-6 alkyl or C1-3 alkylaryl may optionally be substituted with one or more R9;
- when Z is NR8, R8 and R6 may be combined with each other to form a 3-7 membered heterocyclic ring comprising 1 to 2 N or 0 to 2 O heteroatoms;
- R9 is halogen, hydroxyl, —CN, —NO2, —COOH, —(C═O)H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —NR15R16, -L-NR15R16, -L-COOR17, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl which C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl may substituted with halogen, hydroxyl, —CN, —NR15R16, C1-6 alkyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, aryl, heterocyclyl, -L-heterocyclyl, or —(CH2)l—C(═O)—NR15R16;
- R10 is C1-3 alkyl or C1-3 alkylaryl;
- R15 and R16 each independently is H, C1-6 alkyl, C3-10 cycloalkyl or SO2R17;
- R17 is H, C1-3alkyl or C1-3 alkylaryl;
- L is C1-3 alkyl, C1-3 alkylO, C2-6 alkynyl, C3-10 cycloalkyl, —(CH2)1—C(═O)—(CH2)m—, C(═O)O, —(CH2)l—C(═O)NH—(CH2)m—, —(CH2)l—NHC(═O)—(CH2)m—, —(CH2)l—NH—(CH2)m, NR8—NH—C(═O)—CR15R16—NH—C(═O)—, NHC(═O), O, O(C═O) S, S(═O), or SO2; and
- l and m each independently is an integer of 0 to 2.
2. The heterocyclic compound, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof of claim 1, wherein the heterocyclic compound represented formula I is represented by the following Formula Ia:
- wherein:
- X is CH, or N;
- Y is NR8, or O;
- W is CH2, (CH2)2, NR11, or O;
- Z is CH2, CH2O, C(═O), C(═O)O, C(═O)NH, NR8, NHC(═O), O or O(C═O);
- R3 is H, halogen, CN, C1-3 alkyl, cycloalkenyl, C2-6 alkenyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl which aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl may optionally be substituted with one or more R9,
- R6 is H, C1-4 alkyl, C1-6 alkoxy, —NR15R16, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl, C1-2 alkylbiaryl, -L-aryl or -L-biaryl, which C1-4 alkyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, C1-2 alkylheterocyclyl, C1-2 alkylbiaryl, -L-aryl or -L-biaryl, may optionally be substituted with one or more R9;
- R8 is H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkylaryl or C(═O)R10 which C1-6 alkyl or C1-3 alkylaryl may optionally be substituted with one or more R9;
- when Z is NR8, R8 and R6 may be combined with each other to form a 3-7 membered heterocyclic ring comprising 1 to 2 N or 0 to 2 O heteroatoms;
- R9 is halogen, hydroxyl, —CN, —NO2, —COOH, —(C═O)H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —NR15R16, -L-NR15R16, -L-COOR17, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl which C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl may substituted with halogen, hydroxyl, —CN, —NR15R16, C1-6 alkyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, aryl, heterocyclyl, -L-heterocyclyl, or —(CH2)l—C(═O)—NR15R16;
- R10 is C1-3 alkyl or C1-3 alkylaryl;
- R11 is H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkylaryl or C(═O)R10 which C1-6 alkyl or C1-3 alkylaryl may optionally be substituted with one or more R9;
- R15 and R16 each independently is H, C1-6 alkyl, C3-10 cycloalkyl or SO2R17;
- R17 is H, C1-3 alkyl or C1-3 alkylaryl;
- R18 to R21 are the same as or different from each other, and are each independently H or halogen; or
- R18 and R19; or R20 and R21 may be combined with each other to form a 3-7 membered cyclic ring or heterocyclic ring containing 1 or 2 of NR8, O or S, and the cyclic or heterocyclic ring may optionally be substituted with 1 or 2 halogen(s), C1-4 alkyl or C1-4 alkoxy;
- L is C1-3 alkyl, C1-3 alkylO, C2-6 alkynyl, C3-10 cycloalkyl, —(CH2)l—C(═O)—(CH2)m—, C(═O)O, —(CH2)1—C(═O)NH—(CH2)m—, —(CH2)l—NHC(═O)—(CH2)m—, —(CH2)1—NH—(CH2)m—, NR8, —NH—C(═O)—CR15R16—NH—C(═O)—NHC(═O), O, O(C═O) S, S, S(═O), or SO2; and
- l and m each independently is an integer of 0 to 2.
3. The heterocyclic compound, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof of claim 1, wherein the heterocyclic compound represented formula I is represented by the following Formula Ib:
- wherein:
- X is CH, or N;
- W is CH2, NR11, or O;
- V1 and V2 each independently is CR13R13′ NR13 or O;
- at least one of V1 and V2 is CR13R13′;
- X1 to X5 are the same as or different from each other, and are each independently CR14 or N;
- at least one of X1 to X5 is CR14;
- R3 is H, halogen, CN, C1-3 alkyl, cycloalkenyl, C2-6 alkenyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl which aryl, biaryl, heteroaryl, heterobiaryl, heterocyclyl, C1-2 alkylaryl, C1-2 alkylheteroaryl, or C1-2 alkylheterocyclyl may optionally be substituted with one or more R9;
- R9 is halogen, hydroxyl, —CN, —NO2, —COOH, —(C═O)H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —NR15R16, -L-NR15R16, -L-COOR17, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl which C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C1-6 alkoxy, cycloalkenyl, aryl, heterocyclyl, heteroaryl, -L-alkyl, -L-C3-10 cycloalkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl may substituted with halogen, hydroxyl, —CN, —NR15R16, C1-6 alkyl, C3-10 cycloalkyl, C1-4 hydroxyalkyl, C2-6 alkenyl, aryl, heterocyclyl, -L-heterocyclyl, or —(CH2)l—C(═O)—NR15R16;
- R10 is C1-3 alkyl or C1-3 alkylaryl;
- R11 is H, C1-6 alkyl, C1-4 fluoroalkyl, C1-4 hydroxyalkyl, C1-3 alkylaryl or C(═O)R10 which C1-6 alkyl or C1-3 alkylaryl may optionally be substituted with one or more R9;
- R13 and R13′ each independently is H, C1-3 alkyl, C2-3 hydroxyalkyl;
- each R14 is independently selected from H, halogen, hydroxyl, —CN, —NO2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, —NR15R16, -L-alkyl, -L-heterocyclyl, -L-heteroaryl, or -L-aryl which C1-6 alkyl, aryl, heteroaryl, heterocyclyl may optionally be substituted with one or more R9; or adjacent groups among a plurality of R14s are bonded to each other to form a 3-7 membered cyclic ring or heterocyclic ring containing 1 or 2 of NR11 O or S, and the cyclic or heterocyclic ring may optionally be substituted with 1 or 2 halogen(s), C1-4 alkyl or C1-4 alkoxy;
- R15 and R16 each independently is H, C1-6 alkyl, C3-10 cycloalkyl or SO2R17;
- R17 is H, C1-3 alkyl or C1-3 alkylaryl;
- L is C1-3 alkyl, C1-3 alkylO, C2-6 alkynyl, C3-10 cycloalkyl, —(CH2)l—C(═O)—(CH2)m—, C(═O)O, —(CH2)l—C(═O)NH—(CH2)m—, —(CH2)l—NHC(═O)—(CH2)m—, —(CH2)l—NH—(CH2)m—, NR8—NH—C(═O)—CR15R16—NH—C(═O)—, NHC(═O), O, O(C═O) S, S, S(═O), or SO2; and
- 1 and m each independently is an integer of 0 to 2.
4. The heterocyclic compound, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof of claim 1, wherein the heterocyclic compound represented formula I is represented by any one of the following compounds: Example 1 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 2 2-amino-N-((1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 3 2-amino-N-(trans-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 4 2-amino-N-((1R,2S)-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 5 2-amino-N-(cis-2-(benzyloxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 6 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((2- methylbenzyl)oxy)cyclopentyl)nicotinamide Example 7 2-amino-N-((1S,2S)-2-((3-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 8 2-amino-N-((1S,2S)-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 9 2-amino-N-(trans-2-((4-ethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 10 2-amino-N-((1S,2S)-2-((4-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 11 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 12 2-amino-N-((1R,2R)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 13 2-amino-N-(trans-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 14 2-amino-N-((1S,2S)-2-((2,3-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 15 2-amino-N-((1S,2S)-2-((2,6-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 16 2-amino-N-((1S,2S)-2-((2,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 17 2-amino-N-((1S,2S)-2-((3,5-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 18 2-amino-N-((1S,2S)-2-((2,4-dimethylbenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 19 2-amino-N-((1S,2S)-2-((4-ethyl-3-methylbenzyl)oxy)cyclopentyl)-5-(1- methyl-1H-pyrazol-4-yl)nicotinamide Example 20 2-amino-N-((1S,2S)-2-((3,4-diethylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 21 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(1- methyl-1H-pyrazol-4-yl)nicotinamide Example 22 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3- propylbenzyl)oxy)cyclopentyl)nicotinamide Example 23 2-amino-N-((1S,2S)-2-((3-cyclopentylbenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 24 2-amino-N-((1S,2S)-2-((3-isopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 25 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(prop-1-en-2- yl)benzyl)oxy)cyclopentyl)nicotinamide Example 26 2-amino-N-((1S,2S)-2-((3-cyclopropylbenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 27 2-amino-N-((1S,2S)-2-((3-cyclobutylbenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 28 2-amino-N-((1S,2S)-2-((3-ethynylbenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 29 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4- (trifluoromethyl)benzyl)oxy)cyclopentyl)nicotinamide Example 30 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3- nitrobenzyl)oxy)cyclopentyl)nicotinamide Example 31 2-amino-N-((1S,2S)-2-((3-cyanobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 32 2-amino-N-((1S,2S)-2-((3-hydroxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 33 2-amino-N-((1S,2S)-2-((3-methyloxybenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 34 2-amino-N-((1R,2R)-2-((3-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 35 2-amino-N-((1S,2S)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 36 2-amino-N-((1R,2R)-2-((4-methoxybenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 37 2-amino-N-(trans-2-((3,5-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 38 2-amino-N-((1S,2S)-2-((2,3-dimethoxybenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 39 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3- phenoxybenzyl)oxy)cyclopentyl)nicotinamide Example 40 2-amino-N-((1S,2S)-2-(benzo[d][1,3]dioxol-5-ylmethoxy)cyclopentyl)-5-(1- methyl-1H-pyrazol-4-yl)nicotinamide Example 41 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4- (methylthio)benzyl)oxy)cyclopentyl)nicotinamide Example 42 methyl 3-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4- yl)nicotinamido)cyclopentyl)oxy)methyl)benzoate Example 43 2-amino-N-((1S,2S)-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 44 2-amino-N-(trans-2-((3-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 45 2-amino-N-(trans-2-((4-chlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 46 2-amino-N-(trans-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamid Example 47 2-amino-N-(trans-2-((2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 48 2-amino-N-((1S,2S)-2-((3-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 49 2-amino-N-(trans-2-((4-bromo-2-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 50 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-2-((2,4,5- trifluorobenzyl)oxy)cyclopentyl)nicotinamide Example 51 2-amino-N-((1S,2S)-2-((3-bromobenzyl)oxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 52 2-amino-N-(trans-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 53 2-amino-N-((1R,2R)-2-((3-bromo-4-fluorobenzyl)oxy)cyclopentyl)-5-(1- methyl-1H-pyrazol-4-yl)nicotinamide Example 54 2-amino-N-((1S,2S)-2-(1-(4-bromophenyl)ethoxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 55 methyl (3-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4- yl)nicotinamido)cyclopentyl)oxy)methyl)benzoyl)glycinate Example 56 2-amino-N-((1S,2S)-2-((3-((2-hydroxyethyl)carbamoyl)benzyl)- oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 57 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-4- carboxamido)benzyl)oxy)cyclopentyl)nicotinamide Example 58 2-amino-N-((1S,2S)-2-((3-((S)-2-aminopropanamido)benzyl)oxy)- cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 59 N-((1S,2S)-2-((3-((S)-2-acetamidopropanamido)benzyl)oxy)-cyclopentyl)-2- amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 60 2-amino-N-((1S,2S)-2-((3-(3-aminopropanamido)benzyl)oxy)-cyclopentyl)- 5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 61 N-((1S,2S)-2-((3-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5- (1-methyl-1H-pyrazol-4-yl)nicotinamide Example 62 N-((1S,2S)-2-((4-(2H-1,2,3-triazol-2-yl)benzyl)oxy)cyclopentyl)-2-amino-5- (1-methyl-1H-pyrazol-4-yl)nicotinamide Example 63 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(naphthalen-2- ylmethoxy)cyclopentyl)nicotinamide Example 64 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(quinolin-8- ylmethoxy)cyclopentyl)nicotinamide Example 65 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((2′,3′,4′,5′-tetrahydro- [1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 66 N-(trans-2-([1,1′-biphenyl]-2-ylmethoxy)cyclopentyl)-2-amino-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 67 N-((1S,2S)-2-([1,1′-biphenyl]-3-ylmethoxy)cyclopentyl)-2-amino-5-(1- methyl-1H-pyrazol-4-yl)nicotinamide Example 68 N-((1S,2S)-2-([1,1′-biphenyl]-4-ylmethoxy)cyclopentyl)-2-amino-5-(1- methyl-1H-pyrazol-4-yl)nicotinamide Example 69 2-amino-N-((1S,2S)-2-hydroxycyclopentyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 70 2-amino-N-(cis-2-hydroxycyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 71 N-((1S,2S)-2-(benzyloxy)cyclopentyl)-2-(ethylamino)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 72 N-((1S,2S)-2-(benzyloxy)cyclopentyl)-2-((3,4-dimethylbenzyl)amino)-5-(1- methyl-1H-pyrazol-4-yl)nicotinamide Example 73 2-amino-N-((6R,7S)-6-(benzyloxy)-1,4-dioxaspiro[4.4]nonan-7-yl)-5-(1- methyl-1H-pyrazol-4-yl)nicotinamide Example 74 2-amino-N-(trans-2-(benzyloxy)cyclohexyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 75 2-amino-N-((1S,2S)-2-(benzyloxy)cyclohexyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 76 2-amino-N-(trans-2-(benzyl(methyl)amino)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 77 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2- (phenoxymethyl)cyclopentyl)nicotinamide Example 78 2-amino-N-((1S,2S)-2-((3,4-dimethylphenoxy)methyl)cyclopentyl)-5-(1- methyl-1H-pyrazol-4-yl)nicotinamide Example 79 2-amino-N-(trans-2,2-difluoro-5-(phenoxymethyl)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 80 2-amino-N-((1S,2S)-2-(((2,3-dihydro-1H-inden-5- yl)oxy)methyl)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 81 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4,5- trimethylphenoxy)methyl)cyclopentyl)nicotinamide Example 82 2-amino-N-((1S,2S)-2-((3-(dimethylamino)phenoxy)methyl)-cyclopentyl)-5- (1-methyl-1H-pyrazol-4-yl)nicotinamide Example 83 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3-(piperidine-1- carbonyl)phenoxy)methyl)cyclopentyl)nicotinamide Example 84 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4- phenoxyphenoxy)methyl)cyclopentyl)nicotinamide Example 85 2-amino-N-((1S,2S)-2-((benzyloxy)methyl)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 86 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-(((4′-((4-methyl- piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)oxy)methyl)cyclopentyl)- nicotinamide Example 87 (1S,2S)-2-(benzyloxy)cyclopentyl 2-amino-5-(1-methyl-1H-pyrazol-4- yl)nicotinate Example 88 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2- phenethylcyclopentyl)nicotinamide Example 89 2-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 90 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4- morpholinotetrahydrofuran-3-yl)nicotinamide Example 91 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-(pyrrolidin-1- yl)tetrahydrofuran-3-yl)nicotinamide Example 92 2-amino-N-(cis-4-hydroxytetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 93 2-amino-N-(4-(benzyloxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol- 4-yl)nicotinamide Example 94 2-amino-N-(trans-4-(benzyloxy)-1-isopropylpyrrolidin-3-yl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 95 (R)-2-amino-N-(2-(benzyloxy)propyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 96 (S)-2-amino-N-(2-(benzyloxy)propyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 97 (S)-2-amino-N-(1-(benzyloxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 98 (R)-2-amino-N-(1-(benzyloxy)propan-2-yl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 99 2-amino-N-(1-(benzyloxy)-2-methylpropan-2-yl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 100 (R)-2-amino-N-(1-((3,4-dimethylbenzyl)oxy)propan-2-yl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 101 (S)-2-amino-N-(2-((3,4-dimethylbenzyl)oxy)propyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 102 (R)-2-amino-N-(1-((4-chlorobenzyl)oxy)propan-2-yl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 103 (S)-2-amino-N-(2-((4-chlorobenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 104 (R)-2-amino-N-(1-((3,4-dichlorobenzyl)oxy)propan-2-yl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 105 (S)-2-amino-N-(2-((3,4-dichlorobenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol- 4-yl)nicotinamide Example 106 (R)-2-amino-N-(1-((3-methoxybenzyl)oxy)propan-2-yl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 107 (S)-2-amino-N-(2-((3-methoxybenzyl)oxy)propyl)-5-(1-methyl-1H-pyrazol- 4-yl)nicotinamide Example 108 (R)-2-amino-N-(1-(benzyloxy)butan-2-yl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 109 (S)-2-amino-N-(1-(benzyloxy)-3-methylbutan-2-yl)-5-(1-methyl-1H-pyrazol- 4-yl)nicotinamide Example 110 (R)-2-amino-N-(1-(benzyloxy)-3-methylbutan-2-yl)-5-(1-methyl-1H-pyrazol- 4-yl)nicotinamide Example 111 (S)-2-amino-N-(1-(benzyloxy)-4-methylpentan-2-yl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 112 (R)-2-amino-N-(1-(benzyloxy)-4-methylpentan-2-yl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 113 (R)-2-amino-N-(2-(benzyloxy)-1-cyclohexylethyl)-5-(1-methyl-1H-pyrazol- 4-yl)nicotinamide Example 114 (R)-2-amino-N-(1-cyclohexyl-2-hydroxyethyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 115 (S)-2-amino-N-(2-(benzyloxy)-1-phenylethyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 116 (R)-2-amino-N-(2-(benzyloxy)-1-phenylethyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 117 (S)-2-amino-N-(1-(benzyloxy)-3-phenylpropan-2-yl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 118 (R)-2-amino-N-(1-(benzyloxy)-3-phenylpropan-2-yl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 119 (R)-2-amino-N-(1-(cyclobutylmethoxy)propan-2-yl)-5-(1-methyl-1H-pyrazol- 4-yl)nicotinamide Example 120 methyl N-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-O-benzyl-L- serinate Example 121 methyl N-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-O-benzyl-L- threoninate Example 122 2-amino-N-((2S,3R)-3-(benzyloxy)-1-(methylamino)-1-oxobutan-2-yl)-5-(1- methyl-1H-pyrazol-4-yl)nicotinamide Example 123 2-amino-N-((2S,3R)-3-(benzyloxy)-1-oxo-1-(propylamino)butan-2-yl)-5-(1- methyl-1H-pyrazol-4-yl)nicotinamide Example 124 2-amino-N-((2S,3R)-3-(benzyloxy)-1-(cyclopentylamino)-1-oxobutan-2-yl)- 5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 125 2-amino-N-((2S,3R)-3-(benzyloxy)-1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-5- (1-methyl-1H-pyrazol-4-yl)nicotinamide Example 126 benzyl (2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-alaninate Example 127 benzyl (2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-valinate Example 128 benzyl (2-amino-5-(1-methyl-1H-pyrazol-4-yl)nicotinoyl)-L-serinate Example 129 3-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-methyl-1H-pyrazol-4- yl)pyrazine-2-carboxamide Example 130 3-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6-(1-methyl- 1H-pyrazol-4-yl)pyrazine-2-carboxamide Example 131 (S)-3-amino-6-(1-methyl-1H-pyrazol-4-yl)-N-(1,2,3,4-tetrahydronaphthalen- 1-yl)pyrazine-2-carboxamide Example 132 3-amino-N-(trans-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H- pyrazol-4-yl)pyrazine-2-carboxamide Example 133 3-amino-N-(cis-4-(benzyloxy)tetrahydrofuran-3-yl)-6-(1-methyl-1H-pyrazol- 4-yl)pyrazine-2-carboxamide Example 134 2-amino-N-((1S,2S)-2-((3′-amino-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)- 5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 135 2-amino-N-((1S,2S)-2-((4′-amino-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)- 5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 136 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(methylamino)- [1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 137 2-amino-N-((1S,2S)-2-((4′-(dimethylamino)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 138 2-amino-N-((1S,2S)-2-((4′-((dimethylamino)methyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 139 2-amino-N-((1S,2S)-2-((3′-amino-2′-methyl-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 140 2-amino-N-((1S,2S)-2-((3′-hydroxy-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 141 2-amino-N-((1S,2S)-2-((3′-(hydroxymethyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 142 2-amino-N-((1S,2S)-2-((4′-(hydroxymethyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 143 2-amino-N-((1S,2S)-2-((3′-(aminomethyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 144 2-amino-N-((1S,2S)-2-((4′-(aminomethyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 145 2-amino-N-((1S,2S)-2-((4′-(2-aminoethyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 146 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(4-methylpiperazin- 1-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 147 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(piperazin-1- yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 148 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-(4- methylpiperazin-1-yl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 149 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-(piperazin-1-yl)- [1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 150 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-(4-methylpiperazin- 1-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 151 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-((4- methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)nicotinamide Example 152 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(morpholine-4- carbonyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 153 2-amino-N-((1S,2S)-2-((4′-ethyl-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)- 5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 154 2-amino-N-((1S,2S)-2-((4′-(cyanomethyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 155 2-amino-N-((1S,2S)-2-((4′-carbamoyl-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 156 2-amino-N-((1S,2S)-2-((3-fluoro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 157 2-amino-N-((1S,2S)-2-((3-fluoro-4′-((cis-3,4,5-trimethylpiperazin-1- yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 158 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4- methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)nicotinamide Example 159 2-amino-N-((1S,2S)-2-((2-chloro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 160 2-amino-N-((1S,2S)-2-((3-fluoro-4′-((cis-4-(2-hydroxyethyl)-3,5- dimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5- (1-methyl-1H-pyrazol-4-yl)nicotinamide Example 161 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(2-(4- methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)nicotinamide Example 162 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-(piperidin-4-yl)- 1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 163 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(1-(1- methylpiperidin-4-yl)-1H-pyrazol-4-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 164 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2R)-2-((4′-((4- methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)nicotinamide Example 165 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1R,2S)-2-((4′-((4- methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)nicotinamide Example 166 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4- methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclohexyl)nicotinamide Example 167 2-amino-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 168 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 169 2-amino-N-((1S,2S)-2-((3′-hydroxy-[1,1′-biphenyl]-3- yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 170 2-amino-N-((1S,2S)-2-((3′-amino-[1,1′-biphenyl]-3-yl)methoxy)cyclopentyl)- 5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 171 2-amino-N-((1S,2S)-2-((3′-(hydroxymethyl)-[1,1′-biphenyl]-3- yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 172 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4- methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)nicotinamide Example 173 2-amino-N-((1S,2S)-2-((4′-(((2-hydroxyethyl)amino)methyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 174 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′- (morpholinomethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 175 2-amino-N-((1S,2S)-2-((4′-((3,3-difluoropiperidin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 176 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methyl- piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)- nicotinamide Example 177 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(piperazin-1- ylmethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 178 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-phenyl- piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)- nicotinamide Example 179 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-(pyrrolidin-1- yl)piperidin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)- nicotinamide Example 180 2-amino-N-((1S,2S)-2-((4′-((4-hydroxypiperidin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 181 2-amino-N-((1S,2S)-2-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 182 2-amino-N-((1S,2S)-2-((4′-((4-(2-hydroxy-2-methylpropyl)piperazin-1- yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 183 2-amino-N-((1S,2S)-2-((4′-((4-ethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 184 2-amino-N-((1S,2S)-2-((4′-((4-cyclopropylpiperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 185 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(((R)-3-methyl- piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)- nicotinamide Example 186 2-amino-N-((1S,2S)-2-((4′-(((R)-3,4-dimethylpiperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 187 2-amino-N-((1S,2S)-2-((4′-(((R)-2,4-dimethylpiperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 188 2-amino-N-((1S,2S)-2-((4′-((3-ethyl-4-methylpiperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 189 2-amino-N-((1S,2S)-2-((4′-((cis-3,5-dimethylpiperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 190 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((cis-3,4,5- trimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)nicotinamide Example 191 2-amino-N-((1S,2S)-2-((4′-((trans-2,5-dimethylpiperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 192 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(((2R,5S)-2,4,5- trimethylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)- nicotinamide Example 193 2-amino-N-((1S,2S)-2-((4′-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 194 3-amino-6-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4- methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)- pyrazine-2-carboxamide Example 195 2-amino-N-((1S,2S)-2-((3′-fluoro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 196 2-amino-N-((1S,2S)-2-((3′,5′-difluoro-4′-((4-methylpiperazin-1-yl)methyl)- [1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 197 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4- methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)- methoxy)cyclopentyl)nicotinamide Example 198 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3′-methyl-4′-((4- methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)- methoxy)cyclopentyl)nicotinamide Example 199 2-amino-N-((1S,2S)-2-((3′-hydroxy-4′-((4-methylpiperazin-1-yl)methyl)- [1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 200 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((4-methyl- piperazin-1-yl)methyl)-3′-nitro-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)- nicotinamide Example 201 2-amino-N-((1S,2S)-2-((3′-methoxy-4′-((4-methylpiperazin-1-yl)methyl)- [1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 202 2-amino-N-((1S,2S)-2-((2′-chloro-4′-((4-methylpiperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 203 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(6-((4-methyl- piperazin-1-yl)methyl)pyridin-3-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 204 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(5-((4-methyl- piperazin-1-yl)methyl)pyridin-2-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 205 2-amino-N-((1S,2S)-2-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3′- (trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 206 2-amino-N-((1S,2S)-2-((2′-chloro-4′-((4-(2-hydroxyethyl)piperazin-1-yl)- methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol- 4-yl)nicotinamide Example 207 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-3′-(trifluoro- methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 208 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(1-(4-methyl- piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 209 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(1-((3S,5R)-3,4,5- trimethylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)- nicotinamide Example 210 2-amino-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 211 2-amino-N-((1S,2S)-2-((4′-(1-((3S,5R)-4-(2-hydroxyethyl)-3,5-dimethyl- piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 212 2-amino-N-((1S,2S)-2-((3′,5′-difluoro-4′-(1-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol- 4-yl)nicotinamide Example 213 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((R)-1-(piperazin-1- yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 214 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((R)-1-(4-methyl- piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 215 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((S)-1-(4-methyl- piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 216 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(1-(4-methyl- piperazin-1-yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)- nicotinamide Example 217 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-(2-(4-methyl- piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)- nicotinamide Example 218 2-amino-N-((1S,2S)-2-((4′-((R)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)- [1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 219 2-amino-N-((1S,2S)-2-((4′-((S)-1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)- [1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 220 2-amino-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)- cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 221 2-amino-N-((1S,2S)-2-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2- yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 222 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-((S)-1-(4-methylpiperazin-1-yl)ethyl)- [1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 223 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-((R)-1-(4-methylpiperazin-1-yl)ethyl)- [1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 224 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)cyclopropyl)- [1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 225 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-(2-(4-methylpiperazin-1-yl)propan-2-yl)- [1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 226 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-((S)-1-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5- carboxamide Example 227 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-4((R)-1-(4-(2-hydroxyethyl)piperazin-1- yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5- carboxamide Example 228 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1- yl)cyclopropyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]- 5-carboxamide Example 229 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)- propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5- carboxamide Example 230 6-amino-5′-fluoro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 231 2-amino-5-chloro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 232 2-amino-5-fluoro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 233 2-amino-5-cyano-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 234 2-amino-6-chloro-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 235 2-amino-N-((1S,2S)-2-((4′-(1-(4-methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)nicotinamide Example 236 6-amino-5′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)- ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5- carboxamide Example 237 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)- ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5- carboxamide Example 238 6-amino-2′-fluoro-N-((1S,2S)-2-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)- ethyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5- carboxamide Example 239 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((1-methyl- piperidin-4-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)- nicotinamide Example 240 2-amino-N-((1S,2S)-2-((4′-((1-(2-hydroxyethyl)piperidin-4-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 241 methyl 2-(4-((4′-((((1S,2S)-2-(2-amino-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamido)cyclopentyl)oxy)methyl)-[1,1′-biphenyl]-4-yl)methyl)piperidin- 1-yl)acetate Example 242 2-amino-N-((1S,2S)-2-((4′-((1-(2-amino-2-oxoethyl)piperidin-4-yl)methyl)- [1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 243 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(3-(4-methyl- piperazin-1-yl)propyl)benzyl)oxy)cyclopentyl)nicotinamide Example 244 2-amino-N-((1S,2S)-2-((4-(3-(dimethylamino)propyl)benzyl)oxy)- cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 245 2-amino-N-((1S,2S)-2-((4′-(2-(dimethylamino)ethoxy)-[1,1′-biphenyl]-4-yl)- methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 246 2-amino-N-((1S,2S)-2-((4′-(3-(dimethylamino)propoxy)-[1,1′-biphenyl]-4- yl)methoxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 247 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4′-((1-methyl- piperidin-4-yl)oxy)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 248 2-amino-N-((1S,2S)-2-((4-(3-(dimethylamino)prop-1-yn-1-yl)benzyl)- oxy)cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 249 2-amino-N-((1S,2S)-2-((4-(4-hydroxybut-1-yn-1-yl)benzyl)oxy)cyclopentyl)- 5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 250 2-amino-N-((1S,2S)-2-((4-(5-hydroxypent-1-yn-1-yl)benzyl)oxy)- cyclopentyl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 251 2-amino-N-((1S,2S)-2-((4-(6-hydroxyhex-1-yn-1-yl)benzyl)oxy)cyclopentyl)- 5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 252 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((4-(4-(4-methyl- piperazin-1-yl)but-1-yn-1-yl)benzyl)oxy)cyclopentyl)nicotinamide Example 253 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-((4-methylpiperazin-1- yl)methyl)phenyl)nicotinamide Example 254 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H- pyrazol-4-yl)nicotinamide Example 255 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-methylpiperidin-4- yl)-1H-pyrazol-4-yl)nicotinamide Example 256 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-ethylpiperidin-4-yl)- 1H-pyrazol-4-yl)nicotinamide Example 257 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-isopropylpiperidin-4- yl)-1H-pyrazol-4-yl)nicotinamide Example 258 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(1-(1-(pyrrolidin-3-yl- methyl)piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 259 2-amino-N-((1R,2R)-2-(benzyloxy)cyclopentyl)-5-(1-(piperidin-4-yl)-1H- pyrazol-4-yl)nicotinamide Example 260 2-amino-N-((1S,2S)-2-((3,4-dichlorobenzyl)oxy)cyclopentyl)-5-(1-(piperidin- 4-yl)-1H-pyrazol-4-yl)nicotinamide Example 261 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(hydroxymethyl)-1- methyl-1H-pyrazol-4-yl)nicotinamide Example 262 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-(((2-hydroxyethyl)- amino)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide Example 263 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((3-hydroxypiperidin-1- yl)methyl)-1-methyl-1H-pyrazol-4-yl)nicotinamide Example 264 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-cyanophenyl)- nicotinamide Example 265 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-cyanophenyl)- nicotinamide Example 266 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-(cyanomethyl)- phenyl)nicotinamide Example 267 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(4-phenoxyphenyl)- nicotinamide Example 268 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-5-(3-((1-methylpiperidin-4- yl)carbamoyl)phenyl)nicotinamide Example 269 6-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6′-(hydroxymethyl)-[3,3′- bipyridine]-5-carboxamide Example 270 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4-methyl- piperazin-1-yl)methyl)phenyl)nicotinamide Example 271 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-(4-methyl- piperazine-1-carbonyl)phenyl)nicotinamide Example 272 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-(4- (pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 273 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(3-((4-methyl- piperazin-1-yl)methyl)phenyl)nicotinamide Example 274 2-amino-5-(3-fluoro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-N-((1S,2S)- 2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamide Example 275 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-((4- (pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamide Example 276 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-methyl- piperazine-1-carbonyl)phenyl)nicotinamide Example 277 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4- (pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 278 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-((1- methylpiperidin-4-yl)amino)-2-oxoethyl)phenyl)nicotinamide Example 279 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4- methylpiperazin-1-yl)acetyl)phenyl)nicotinamide Example 280 2-amino-5-(3-fluoro-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)-N- ((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)nicotinamide Example 281 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(4-(4- methylpiperazin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 282 2-amino-N-((1S,2S)-2-((3-methylbenzyl)oxy)cyclopentyl)-5-(4-(piperazin-1- ylmethyl)phenyl)nicotinamide Example 283 2-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4- methylpiperazine-1-carbonyl)phenyl)nicotinamide Example 284 2-amino-N-((1S,2S)-2-((4-methylbenzyl)oxy)cyclopentyl)-5-(4-(4- (pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 285 2-amino-5-(1,5-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethyl- benzyl)oxy)cyclopentyl)nicotinamide Example 286 2-amino-5-(1,3-dimethyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4-dimethyl- benzyl)oxy)cyclopentyl)nicotinamide Example 287 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(2- hydroxypropan-2-yl)-4-methylthiazol-5-yl)nicotinamide Example 288 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-(3- hydroxytetrahydrofuran-3-yl)-4-methylthiazol-5-yl)nicotinamide Example 289 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4- methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 290 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4- methylpiperazin-1-yl)-2-oxoethyl)phenyl)nicotinamide Example 291 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4- (morpholinomethyl)phenyl)nicotinamide Example 292 2-amino-5-(4-((dimethylamino)methyl)phenyl)-N-((1S,2S)-2-((3,4- dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 293 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4-(2- hydroxyethyl)piperazin-1-yl)methyl)phenyl)nicotinamide Example 294 6-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-2′-methoxy- [3,3′-bipyridine]-5-carboxamide Example 295 2-amino-5-(4-(dimethylamino)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)- oxy)cyclopentyl)nicotinamide Example 296 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-hydroxy- phenyl)nicotinamide Example 297 2-amino-5-(3-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)- cyclopentyl)nicotinamide Example 298 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(methyl- sulfonamido)phenyl)nicotinamide Example 299 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(hydroxy- methyl)phenyl)nicotinamide Example 300 2-amino-5-(3-(aminomethyl)phenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)- oxy)cyclopentyl)nicotinamide Example 301 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(3- hydroxypropyl)phenyl)nicotinamide Example 302 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((1r,4S)- 4-hydroxycyclohexyl)amino)methyl)phenyl)nicotinamide Example 303 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(((1- methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamide Example 304 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-((((S)- piperidin-3-yl)amino)methyl)phenyl)nicotinamide Example 305 3-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)- carbamoyl)pyridin-3-yl)-5-hydroxybenzoic acid Example 306 4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)carbamoyl)- pyridin-3-yl)-2-methylbenzoic acid Example 307 2-amino-5-(4-aminophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)- cyclopentyl)nicotinamide Example 308 3-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)- carbamoyl)pyridin-3-yl)benzoic acid Example 309 3-amino-5-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)- carbamoyl)pyridin-3-yl)benzoic acid Example 310 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-methyl-5- (4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 311 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4- (4-methylpiperazine-1-carbonyl)phenyl)nicotinamide Example 312 2-amino-5-(3-amino-5-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)-N- ((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 313 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(hydroxy- methyl)phenyl)nicotinamide Example 314 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-formyl- phenyl)nicotinamide Example 315 4-(6-amino-5-(((1S,2S)-2-((3,4- dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acid Example 316 3-(4-(6-amino-5-(((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)- carbamoyl)pyridin-3-yl)phenyl)propanoic acid Example 317 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(2-hydroxy- phenyl)nicotinamide Example 318 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((1- methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide Example 319 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4- (dimethylcarbamoyl)phenyl)nicotinamide Example 320 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((1- methylpiperidin-4-yl)amino)methyl)phenyl)nicotinamide Example 321 6-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-6′- (hydroxymethyl)-[3,3′-bipyridine]-5-carboxamide Example 322 2-amino-4-(6-amino-5-(((1S,2S)-2-((3,4- dimethylbenzyl)oxy)cyclopentyl)carbamoyl)pyridin-3-yl)benzoic acid Example 323 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4- (hydroxymethyl)-3-methoxyphenyl)nicotinamide Example 324 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4- (hydroxymethyl)phenyl)nicotinamide Example 325 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-fluoro-4- ((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)nicotinamide Example 326 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(1- hydroxyethyl)phenyl)nicotinamide Example 327 2-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N- ((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 328 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((4- hydroxypiperidin-1-yl)methyl)phenyl)nicotinamide Example 329 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((((1- methylpiperidin-4-yl)methyl)amino)methyl)phenyl)nicotinamide Example 330 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-methyl-4- (4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)nicotinamide Example 331 2-amino-5-(3-amino-4-(4-(pyrrolidin-1-yl)piperidine-1-carbonyl)phenyl)-N- ((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 332 2-amino-5-(3-amino-4-((4-(pyrrolidin-1-yl)piperidin-1-yl)methyl)phenyl)-N- ((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 333 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4- (hydroxymethyl)-3-methylphenyl)nicotinamide Example 334 2-amino-5-(3-chlorophenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)- cyclopentyl)nicotinamide Example 335 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(m-tolyl)- nicotinamide Example 336 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3,5- dimethylphenyl)nicotinamide Example 337 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3- morpholinopyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 338 2-amino-5-(4-((4-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4- dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 339 2-amino-5-(4-((3-aminopiperidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4- dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 340 2-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)phenyl)-N-((1S,2S)-2-((3,4- dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 341 2-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3-fluorophenyl)-N-((1S,2S)- 2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 342 2-amino-5-(4-((3-aminopyrrolidin-1-yl)methyl)-3-fluorophenyl)-N-((1S,2S)- 2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 343 2-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N- ((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 344 2-amino-5-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-4-methoxyphenyl)- N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 345 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3- hydroxyazetidin-1-yl)methyl)phenyl)nicotinamide Example 346 2-amino-5-(4-(((R)-3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N- ((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 347 2-amino-5-(4-(((S)-3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N- ((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 348 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((R)-3- hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 349 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-(((S)-3- hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 350 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-((3- hydroxypiperidin-1-yl)methyl)phenyl)nicotinamide Example 351 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4- hydroxyphenyl)nicotinamide Example 352 2-amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(4-hydroxy- 3-methoxyphenyl)nicotinamide Example 353 2-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)- cyclopentyl)nicotinamide Example 354 amino-N-((1S,2S)-2-((3,4-dimethylbenzyl)oxy)cyclopentyl)-5-(3-(pyrrolidin- 1-yl)phenyl)nicotinamide Example 355 2-amino-5-(5-amino-1-methyl-1H-pyrazol-4-yl)-N-((1S,2S)-2-((3,4- dimethylbenzyl)oxy)cyclopentyl)nicotinamide Example 356 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4- (hydroxymethyl)phenyl)nicotinamide Example 357 2-amino-5-(4-((3-(dimethylamino)pyrrolidin-1-yl)methyl)phenyl)-N- ((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)nicotinamide Example 358 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-((3- hydroxypyrrolidin-1-yl)methyl)phenyl)nicotinamide Example 359 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2- (piperazin-1-yl)propan-2-yl)phenyl)nicotinamide Example 360 2-amino-N-((1S,2S)-2-((3-ethyl-4-methylbenzyl)oxy)cyclopentyl)-5-(4-(2-(4- (2-hydroxyethyl)piperazin-1-yl)propan-2-yl)phenyl)nicotinamide Example 361 3-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-(1-(piperidin-4-yl)-1H- pyrazol-4-yl)pyrazine-2-carboxamide Example 362 (S)-3-amino-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-N-(1,2,3,4- tetrahydronaphthalen-1-yl)pyrazine-2-carboxamide Example 363 2-amino-5-(4-fluorophenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1- yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 364 2-amino-5-(3,4-difluorophenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1- yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 365 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)-5-(4-(trifluoromethyl)phenyl)nicotinamide Example 366 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)- nicotinamide Example 367 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)nicotinamide Example 368 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)- nicotinamide Example 369 2-amino-5-(4-(hydroxymethyl)phenyl)-N-((1S,2S)-2-((4′-((4-methyl- piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)- nicotinamide Example 370 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)-5-(m-tolyl)nicotinamide Example 371 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)-5-phenylnicotinamide Example 372 2-amino-5-(4-hydroxyphenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1- yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 373 2-amino-5-(4-chloro-3-fluorophenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin- 1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 374 2-amino-5-methyl-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 375 6-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 376 2-amino-5-(4-methoxyphenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1- yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 377 6-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)-[3,4′-bipyridine]-5-carboxamide Example 378 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)-5-(4-((4-methylpiperidin-1-yl)methyl)phenyl)- nicotinamide Example 379 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)-5-(4-(morpholinomethyl)phenyl)nicotinamide Example 380 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4- yl)nicotinamide Example 381 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)-5-(4-morpholinophenyl)nicotinamide Example 382 2-amino-5-(cyclohex-1-en-1-yl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1- yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 383 2-amino-5-(3,4-dimethoxyphenyl)-N-((1S,2S)-2-((4′-((4-methylpiperazin-1- yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)nicotinamide Example 384 6-amino-2′,6′-difluoro-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)- [1,1′-biphenyl]-4-yl)methoxy)cyclopentyl)-[3,4′-bipyridine]-5-carboxamide Example 385 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)-5-(4-methylthiophen-3-yl)nicotinamide Example 386 6-amino-6′-fluoro-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)cyclopentyl)-[3,3′-bipyridine]-5-carboxamide Example 387 2-amino-N-((1S,2S)-2-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]- 4-yl)methoxy)cyclopentyl)-5-(1-(1,1,2,2-tetrafluoroethyl)-1H-pyrazol-4-yl)- nicotinamide Example 388 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1- methyl-1H-pyrazol-4-yl)nicotinamide Example 389 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4- (hydroxymethyl)phenyl)nicotinamide Example 390 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4- ((4-methylpiperazin-1-yl)methyl)phenyl)nicotinamide Example 391 2-amino-5-(4-carbamoylphenyl)-N-((3S,4S)-4-((3-ethyl-4- methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 392 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(m- tolyl)nicotinamide Example 393 4-(6-amino-5-(((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3- yl)carbamoyl)pyridin-3-yl)benzoic acid Example 394 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5- phenylnicotinamide Example 395 6-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,4′- bipyridine]-5-carboxamide Example 396 6-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-[3,3′- bipyridine]-5-carboxamide Example 397 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5- vinylnicotinamide Example 398 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4- fluorophenyl)nicotinamide Example 399 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4- formylphenyl)nicotinamide Example 400 2-amino-5-(4-cyanophenyl)-N-((3S,4S)-4-((3-ethyl-4- methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 401 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4- (methylsulfonamido)phenyl)nicotinamide Example 402 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4- phenoxyphenyl)nicotinamide Example 403 5-([1,1′-biphenyl]-4-yl)-2-amino-N-((3S,4S)-4-((3-ethyl-4- methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 404 2-amino-5-(4-(benzyloxy)phenyl)-N-((3S,4S)-4-((3-ethyl-4- methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 405 2-amino-5-(4-(dimethylamino)phenyl)-N-((3S,4S)-4-((3-ethyl-4- methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 406 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5- (quinolin-3-yl)nicotinamide Example 407 2-amino-5-(benzofuran-2-yl)-N-((3S,4S)-4-((3-ethyl-4- methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 408 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5- (naphthalen-1-yl)nicotinamide Example 409 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4- (trifluoromethyl)phenyl)nicotinamide Example 410 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5- (2,4,5-trifluorophenyl)nicotinamide Example 411 2-amino-5-(4-(cyanomethyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4- methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 412 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1- (piperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 413 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-(1- methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 414 2-amino-N-((3S,4S)-4-(benzyloxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol- 4-yl)nicotinamide Example 415 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4- methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 416 2-amino-N-((3S,4S)-4-((3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 417 2-amino-N-((3S,4S)-4-((3-ethyl-4-fluorobenzyl)oxy)pyrrolidin-3-yl)-5-(1- methyl-1H-pyrazol-4-yl)nicotinamide Example 418 2-amino-N-((3S,4S)-4-((4-chloro-3-ethylbenzyl)oxy)pyrrolidin-3-yl)-5-(1- methyl-1H-pyrazol-4-yl)nicotinamide Example 419 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4- ((1-methylpiperidin-4-yl)carbamoyl)phenyl)nicotinamide Example 420 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4- ((4-methylcyclohexyl)carbamoyl)phenyl)nicotinamide Example 421 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4-(4- methylpiperidine-1-carbonyl)phenyl)nicotinamide Example 422 2-amino-5-(4-(dimethylcarbamoyl)phenyl)-N-((3S,4S)-4-((3-ethyl-4- methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 423 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4- ((4-methylpiperidin-1-yl)methyl)phenyl)nicotinamide Example 424 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)-5-(4- (morpholinomethyl)phenyl)nicotinamide Example 425 2-amino-5-(4-((3,3-difluoropiperidin-1-yl)methyl)phenyl)-N-((3S,4S)-4-((3- ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)nicotinamide Example 426 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3- yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 427 2-amino-N-((3S,4S)-1-benzyl-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3- yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 428 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-(3- phenylpropyl)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 429 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-phenethylpyrrolidin- 3-yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 430 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-isobutylpyrrolidin-3- yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 431 2-amino-N-((3S,4S)-1-butyl-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3- yl)-5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 432 2-amino-N-((3S,4S)-1-ethyl-4-((3-ethyl-4-methylbenzyl)oxy)pyrrolidin-3-yl)- 5-(1-methyl-1H-pyrazol-4-yl)nicotinamide Example 433 2-amino-N-((3S,4S)-4-((3-ethyl-4-methylbenzyl)oxy)-1-methylpyrrolidin-3- yl)-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)nicotinamide Example 434 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4′-((4-methyl- piperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)- nicotinamide Example 435 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4′-((4- methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3- yl)nicotinamide Example 436 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4′-((4- methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4- yl)methoxy)pyrrolidin-3-yl)nicotinamid Example 437 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4′-((4- methylpiperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4- yl)methoxy)pyrrolidin-3-yl)nicotinamide Example 438 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-4-((4′-(1-(4-methyl- piperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)- nicotinamide Example 439 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4S)-1-methyl-4-((4′-(1-(4- methylpiperazin-1-yl)ethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)- nicotinamide Example 440 2-amino-N-((3S,4S)-4-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2- yl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 441 2-amino-N-((3S,4S)-4-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2- yl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 442 2-amino-N-((3S,4S)-4-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′- biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 443 2-amino-N-((3S,4S)-4-((4′-(1-(4-(2-hydroxyethyl)piperazin-1-yl)ethyl)-[1,1′- biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 444 2-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3′- (trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl- 1H-pyrazol-4-yl)nicotinamide Example 445 2-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3′- (trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5- (1-methyl-1H-pyrazol-4-yl)nicotinamide Example 446 2-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)pyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 447 2-amino-N-((3S,4S)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)-1-methylpyrrolidin-3-yl)-5-(1-methyl-1H-pyrazol-4- yl)nicotinamide Example 448 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-((4- methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran- 3-yl)nicotinamide Example 449 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-((4-methyl- piperazin-1-yl)methyl)-3′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)- tetrahydrofuran-3-yl)nicotinamide Example 450 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-((3S,4R)-4-((4′-(2-(4-methyl- piperazin-1-yl)propan-2-yl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3- yl)nicotinamide Example 451 2-amino-N-((3S,4R)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-[1,1′- biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H-pyrazol-4-yl)- nicotinamide Example 452 2-amino-N-((3S,4R)-4-((4′-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)-3′- (trifluoromethyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1- methyl-1H-pyrazol-4-yl)nicotinamide Example 453 2-amino-N-((3S,4R)-4-((4′-(2-(4-(2-hydroxyethyl)piperazin-1-yl)propan-2- yl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)-5-(1-methyl-1H- pyrazol-4-yl)nicotinamide Example 454 2-amino-5-(1-methyl-1H-pyrazol-4-yl)-N-(trans-4-((4′-((4-methylpiperazin-1- yl)methyl)-[1,1′-biphenyl]-4-yl)methoxy)tetrahydrofuran-3-yl)nicotinamide Example 455 2-amino-N-(trans-4-((4′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4- yl)methoxy)tetrahydrofuran-3-yl)nicotinamide Example 456 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-((4-((4-methylpiperazin-1- yl)methyl)phenyl)amino)nicotinamide Example 457 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6- (phenylamino)nicotinamide; and Example 458 2-amino-N-((1S,2S)-2-(benzyloxy)cyclopentyl)-6-((4-(4-methylpiperazin-1- yl)phenyl)amino)nicotinamide.
5. A pharmaceutical composition comprising the heterocyclic compound, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof according to claim 1 together with a pharmaceutically acceptable carrier.
6. The pharmaceutical composition of claim 5, wherein the composition comprises, as an active ingredient, the heterocyclic compound, the stereoisomer thereof, the enantiomer thereof, or the pharmaceutically acceptable salt thereof in an amount effective for prevention or treatment of a disease that is influenced by inhibition of Mer kinase.
7. The pharmaceutical composition of claim 6, wherein the disease which is influenced by inhibition of Mer kinase is cancer or an immune-related disease.
8. The pharmaceutical composition of claim 7, wherein the cancer is selected from the group consisting of: glioma, gliosarcoma, anaplastic astrocytoma, medulloblastoma, lung cancer, small cell lung carcinoma, cervical carcinoma, colon cancer, rectal cancer, chordoma, throat cancer, Kaposi's sarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, colorectal cancer, endometrium cancer, ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, hepatic carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, testicular tumor, Wilms' tumor, Ewing's tumor, bladder carcinoma, angiosarcoma, endotheliosarcoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland sarcoma, papillary sarcoma, papillary adenosarcoma, cystadenosarcoma, bronchogenic carcinoma, medullary carcinoma, mastocytoma, mesotheliorma, synovioma, melanoma, leiomyosarcoma, rhabdomyosarcoma, neuroblastoma, retinoblastoma, oligodentroglioma, acoustic neuroma, hemangioblastoma, meningioma, pinealoma, ependymoma, craniopharyngioma, epithelial carcinoma, embryonal carcinoma, squamous cell carcinoma, base cell carcinoma, fibrosarcoma, myxoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, leukemia and metastatic lesions secondary to these primary tumors.
9. The pharmaceutical composition of claim 7, wherein the immune-related disease is selected from the group consisting of infection and sepsis.
10. A method of treating or preventing an immune-related disease or cancer, the method comprising administering to a mammal in need thereof compositions comprising, as active ingredients, the heterocyclic compounds, isomers thereof or pharmaceutically acceptable salts thereof according to claim 1.
11. The method of claim 10, wherein the mammal is a human.
Type: Application
Filed: Aug 31, 2016
Publication Date: Dec 14, 2017
Inventors: Myeong-Seop KIM (Gyeonggi-do), Sumin KIM (Seoul), Jin Kwan KIM (Gyeonggi-do), Hadong KIM (Seoul), Ki Moon RYU (Gyeonggi-do), Seong Jin PARK (Seoul), Taesun PARK (Gyeonggi-do), Joon-Ho SHEEN (Seoul), Taeyoung YOON (Seoul), Mi Yeon JANG (Gyeonggi-do)
Application Number: 15/253,773
