Improved methods, kits, compositions, and administration regimens for the use of heterocyclic inhibitors of ERK1 and ERK2

Abstract

The present application provides improved compositions, methods, kits, and administration regimens for the use of heterocyclic compounds, and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof. These compositions, methods, kits, and administration regimens are useful for modulating ERK1 / 2. By administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, or compositions thereof, these compounds and methods are effective in treating diseases associated with dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of Erk1 / 2, wherein X, Y, Z, J, M, and R are each independently selected from the group consisting of: 1 ~R 8 is defined herein. These compounds and methods can be used to treat a variety of diseases, including diseases characterized by abnormal cell proliferation. In one embodiment, the disease is cancer. [Formula 1] JPEG2022553351000336.jpg35170

Description

[Technical Field]

[0001] Citation by reference This application claims priority to U.S. Provisional Patent Application No. 62 / 926,869, which is incorporated herein by reference in its entirety.

[0002] Technical Field The present disclosure relates to improved methods, kits, compositions, and administration regimens for the use of heterocyclic inhibitors of ERK1 and ERK2 in the treatment of diseases such as cancer that are associated with dysregulation of the RAS / RAF / MEK / ERK pathway or that are treatable by inhibition of Erk1 / 2. [Background technology]

[0003] ERK1 and ERK2 (collectively "ERK1 / 2") are related protein-serine / threonine kinases involved in, among other things, the Ras-Raf-MEK-ERK signaling pathway, sometimes referred to as the mitogen-activated protein kinase (MAPK) pathway. This pathway is thought to play a central role in regulating many fundamental cellular processes, including one or more of cell proliferation, survival, adhesion, cycling, migration, differentiation, metabolism, and transcription. Activation of the MAPK pathway has been reported in many types of tumors, including lung, colon, pancreatic, rectal, and ovarian cancers. Therefore, agents that can reduce activation are attracting attention as potential therapeutic approaches.

[0004] ERK1 / 2 are thought to be activated by MEK through phosphorylation of both threonine and tyrosine residues, namely Tyr204 / 187 and Thr202 / 185. Once activated, ERK1 / 2 catalyzes the phosphorylation of serine / threonine residues to activate both cytosolic and nuclear proteins associated with cell growth, proliferation, survival, angiogenesis, and differentiation, all hallmarks of the cancer phenotype. Therefore, targeting ERK1 and ERK2 may be beneficial for developing and using ERK1 / 2 inhibitors as a method to inhibit tumor growth.

[0005] Furthermore, ERK inhibitors may be useful in combination with other kinase inhibitors, such as MAPK inhibitors. Recently, it has been reported that dual inhibition of MEK and ERK by small molecule inhibitors is synergistic and acts to overcome acquired resistance to MEK inhibitors. See Hatzivassiliou et al., ERK Inhibition Overcomes Acquired Resistance to MEK Inhibition, Mol. Cancer Ther. 2012, 11, 1143-1154.

[0006] Small molecule ERK inhibitors have been reported in the literature, including U.S. Patent No. 6,743,941, U.S. Patent No. 8,546,404, and Ren et al., "Discovery of Highly Potent, Selective and Efficacious Small Molecule Inhibitors of ERK1 / 2," J. Med. Chem., 2015, 58(4), 1976-1991. A few ERK inhibitors (e.g., BVD-523 and GDC-0994) are in early stages of clinical development. However, no ERK inhibitors have been reported to have entered late-stage clinical trials. Therefore, there remains a need for the development of effective and improved ERK1 / 2 inhibitors for the treatment of cancer. Summary of the Invention

[0007] The present disclosure relates to compositions, methods of treatment, administration regimens, and kits that employ the disclosed compounds.

[0008] In one embodiment, the disclosure provides a method of treating a disease characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of Erkl / 2, comprising administering to a subject in need thereof, on a regular or irregular schedule, a therapeutically effective amount of a compound of formula (I) or a composition for use in treating a disease characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of Erkl / 2, or use of the composition in the manufacture of a medicament for said treatment, wherein the composition comprises a therapeutically effective amount of a compound of formula (I):

[0009] [ka] and pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, wherein: R 1 is C 6-12 aryl or 5-10 membered heteroaryl, which is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4- to 6-membered heterocyclyl), or -C 1-6 Alkyl-NH-C 0-6 substituted with 1 to 3 substituents selected from alkyl-(5- to 6-membered heteroaryl), C 1-6 The alkyl, cycloalkyl, heterocyclyl, and / or heteroaryl may be unsubstituted or may include halogen, C 1-6 Alkyl, NH2, HydroxyC 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl; J is -C(R 2 )(R 8 )(CH)—, R 2 and R8 are each independently H, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4-6 membered heterocyclyl), -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, -C(O)-N(C1-6 alkyl)2, or -C 1-6 Alkyl-NH-C 0-6 alkyl-(5-6 membered heteroaryl), C 1-6 The alkyl, heterocyclyl, or heteroaryl may be unsubstituted or may contain halogen, C 1-6 Alkyl, cycloalkyl, NH2, hydroxy C 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl; Alternatively, R 2 , R 8 , and R 2 and R 8 The C atoms together join to form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclyl ring, where the cycloalkyl or heterocyclyl is unsubstituted or substituted with hydroxyl, halogen, or C 1-6 substituted with 1 to 3 substituents selected from alkyl; n is 0 to 6, R 3 is H or C 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; M is a single bond or NH; X and Y are independently CH, CR 7 , or N, Z is CH or N; R 5 H, halogen, C 1-6 Alkyl, or OC 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; R 6 is H or C 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; R 7 is C 1-6 alkyl, C 1-6The alkyl is unsubstituted or substituted with 1 to 5 halogens, and R 4 is C 1-6 Alkyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, -C 1-6 Alkyl-phenyl, -C 1-6 Alkyl-(5-6 membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclyl), 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocyclyl is unsubstituted or is substituted with halogen, CN, —C(O)—NH, —C(O)—NH—C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC 1-6 Alkyl-NH-(C 1-6 alkyl), -OC 1-6 Alkyl-N(C 1-6 alkyl), 4- to 6-membered heterocyclyl, -C(O)-(4- to 6-membered heterocyclyl), -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6 Alkyl, C 2-6 Alkynyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6 and heterocyclyl or heteroaryl are unsubstituted or substituted with 1 to 3 substituents selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 It is substituted with 1 to 3 substituents selected from alkyl, or 4- to 6-membered heterocyclyl. In one embodiment, the therapeutically effective amount is from about 80 mg to about 350 mg.

[0010] In certain embodiments, the therapeutically effective amount is about 120 mg to about 250 mg, about 120 mg, about 180 mg, or about 250 mg, or about 250 mg.

[0011] In certain embodiments, the compound of formula (I) is administered to a subject in need thereof about once per week on a regular schedule or about once per week on an irregular schedule.

[0012] In one embodiment, R 1 is C6-C 12 aryl or 5- or 6-membered heteroaryl, which is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen.

[0013] In one embodiment, R in the compound of Formula (I) 1 is C6-C12 aryl, pyridyl, thienyl, or thiazolyl, which is unsubstituted or 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen. 1 is phenyl.

[0014] In certain embodiments, n is 0 or 1.

[0015] In one embodiment, R 2 is C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4-6 membered heterocyclyl), -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, -C(O)-N(C 1-6alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, or -C 1-6 Alkyl-NH-C 0-6 alkyl-(5-6 membered heteroaryl), C 1-6 The alkyl, heterocyclyl, or heteroaryl may be unsubstituted or may contain halogen, C 1-6 Alkyl, NH2, HydroxyC 1-6 Alkyl or amino C 1-6 alkyl; R 8 is H.

[0016] In one embodiment, R 2 is CH3, CH2OH, CH2NH2, -CH2NH(CH3), -CH2NHCH2CH2OH, -CH2NH- (tetrahydro-2H-pyran), or -CH2NH-CH2- (1H-pyrrole), and R 8 is H.

[0017] In one embodiment, R 3 is H or CH3.

[0018] In certain embodiments, M is a single bond.

[0019] In one embodiment, X and Y are each independently CH, CR 7 , or N.

[0020] In certain embodiments, Z is N.

[0021] In one embodiment, R 5 is H, halogen, or C 1-6 It is alkyl.

[0022] In one embodiment, R 6 is H.

[0023] In one embodiment, R 4 teeth,

[0024] [ka] is.

[0025] In one embodiment, the present disclosure provides a method of treating a disease characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of Erk1 / 2, the method comprising administering a therapeutically effective amount of a compound of formula (II):

[0026] [ka] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, to a subject in need thereof, wherein: R 1 is phenyl or 5-10 membered heteroaryl, which is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4- to 6-membered heterocyclyl), or -C 1-6 Alkyl-NH-C 0-6substituted with 1 to 3 substituents selected from alkyl-(5- to 6-membered heteroaryl), C 1-6 The alkyl, cycloalkyl, heterocyclyl, and / or heteroaryl may be unsubstituted or may include halogen, C 1-6 Alkyl, NH2, HydroxyC 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl; n is 0 to 6, R 2 is C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4-6 membered heterocyclyl), -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, -C(O)-N(C 1-6 alkyl)2, or -C 1-6 Alkyl-NH-C 0-6 alkyl-(5-6 membered heteroaryl), C 1-6 The alkyl, cycloalkyl, heterocyclyl, or heteroaryl may be unsubstituted or may contain halogen, C 1-6 Alkyl, NH2, HydroxyC 1-6Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl; R 8 is H or C 1-6 is alkyl, Alternatively, R 2 , R 8 , and R 2 and R 8 The C atoms together join to form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclyl ring, where the cycloalkyl or heterocyclyl is unsubstituted or substituted with hydroxyl, halogen, or C 1-6 substituted with 1 to 3 substituents selected from alkyl; R 3 is H or C 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; M is a single bond or NH; X and Y are independently CH, CR 7 , or N, Z is CH or N; R 5 H, halogen, C 1-6 Alkyl, or OC 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; R 6 is H or C 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; R 7 is C 1-6 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 5 halogens, and R 4 is C 1-6 Alkyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, -C 1-6 Alkyl-phenyl, -C 1-6Alkyl-(5-6 membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclyl), 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocyclyl is unsubstituted or is substituted with halogen, CN, —C(O)—NH, —C(O)—NH—C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC 1-6 Alkyl-NH-(C 1-6 alkyl), -OC 1-6 Alkyl-N(C 1-6 alkyl), 4- to 6-membered heterocyclyl, -C(O)-(4- to 6-membered heterocyclyl), -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6 Alkyl, C 2-6 Alkynyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6 and heterocyclyl or heteroaryl are unsubstituted or substituted with 1 to 3 substituents selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 It is substituted with 1 to 3 substituents selected from alkyl, or 4- to 6-membered heterocyclyl.

[0027] In one embodiment, the present disclosure provides a method of treating a disease characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of Erk1 / 2, the method comprising administering a therapeutically effective amount of a compound of formula (III):

[0028] [ka] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, to a subject in need thereof, wherein: R 1is phenyl or 5-10 membered heteroaryl, wherein the phenyl or heteroaryl is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4-6 membered heterocyclyl), -C 1-6 Alkyl-NH-C 0-6 Alkyl-(5-6 membered heteroaryl), -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, or -C(O)-N(C 1-6 alkyl)2, and C 1-6 The alkyl, cycloalkyl, heterocyclyl, and / or heteroaryl may be unsubstituted or may include halogen, C 1-6 Alkyl, Hydroxy C 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl; n is 0 to 6, R 3 is H or C 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; M is a single bond or NH; X and Y are independently CH, CR 7 , or N, Z is CH or N; R 5 H, halogen, C 1-6 Alkyl, or OC 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; R 6 is H or C 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; R 7 is C 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; R 4 is C 1-6 Alkyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, -C 1-6 Alkyl-phenyl, -C 1-6 Alkyl-(5-6 membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclyl), 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocyclyl is unsubstituted or is substituted with halogen, CN, —C(O)—NH, —C(O)—NH—C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC 1-6 Alkyl-NH-(C 1-6 alkyl), -OC 1-6 Alkyl-N-(C 1-6 alkyl), 4- to 6-membered heterocyclyl, -C(O)-(4- to 6-membered heterocyclyl), -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6Alkyl, C 2-6 Alkynyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6 and heterocyclyl or heteroaryl are unsubstituted or substituted with 1 to 3 substituents selected from halogen, C 1-6 Alkyl, C-(O)-C 1-6 It is substituted with 1 to 3 substituents selected from alkyl, or 4- to 6-membered heterocyclyl.

[0029] The present disclosure provides: (S)-1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, 1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, 1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, 1-(2-((2,3-dihydrobenzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydro-benzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, 1-(2-(chroman-6-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxy-ethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide, (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (R)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-(2-hydroxy-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-(((1H-pyrrol-2-yl)methyl)amino)-1-(3-chlorophenyl)-ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-(tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-((2-hydroxyethyl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, and N-(3-chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof. The present disclosure further addresses a compound selected from: (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate, (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate, (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate, and (S)-N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate is selected from.

[0030] The present disclosure further relates to compositions and kits comprising compounds of Formula (I-III), or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, compositions comprising these compounds, and methods of use and administration regimens thereof in treating diseases characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of Erk1 / 2. In certain embodiments, the methods of use and administration regimens comprise administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, on a regular or irregular schedule.

[0031] In some embodiments, a therapeutically effective amount of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, is administered to a subject in need thereof on a regular or irregular schedule, wherein the therapeutically effective amount is about 80 mg to about 350 mg, about 120 mg to about 250 mg, or about 120 mg, about 180 mg, or about 250 mg. In some embodiments, the therapeutically effective amount of a compound of Formula (I), Formula (II), or Formula (III) comprises a formulation containing at least one compound of Formula (I), Formula (II), or Formula (III).

[0032] In certain embodiments, the method of treatment or dosing regimen comprises administering a compound of Formula (I), Formula (II), or Formula (III), or a formulation comprising a compound of Formula (I), Formula (II), or (III), to a subject in need thereof about once a week on a regular or irregular schedule.

[0033] In certain embodiments, the disclosure provides a formulation comprising a compound of Formula (I-III), for example, the compound is (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate or (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate. In certain embodiments, kits are provided that include one or more dosage forms of the disclosed compounds or formulations for treating a disease characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of Erk1 / 2, and optionally instructions for administering the dosage forms to a subject, wherein the instructions include the treatment methods or administration regimens described above. [Brief explanation of the drawings]

[0034] [Figure 1A] FIG. 1 shows a series of graphs depicting tumor volume over time in xenografts in athymic nude mice treated with compositions of the present disclosure in a once daily (QD) dosing regimen (top left panel). [Figure 1B] FIG. 1 shows a series of graphs depicting tumor volume over time in xenografts in athymic nude mice treated with compositions of the present disclosure in a twice-daily (BID) dosing regimen in the upper right panel. [Figure 1C] FIG. 10 depicts a series of graphs showing tumor volume over time in xenografts in athymic nude mice treated with compositions of the present disclosure in a three times daily (Q3D) dosing regimen (bottom left panel). [Figure 1D] FIG. 10 depicts a series of graphs showing tumor volume over time in xenografts in athymic nude mice treated with compositions of the present disclosure in a once-weekly (QW) dosing regimen, bottom right panel. [Figure 2] FIG. 1 is a diagram of the study design for the clinical trial described in Example 39 below. [Figure 3]

[0023] Figure 1 shows a Swimmer Plot demonstrating clinical disease control and response in subjects receiving the indicated amounts of test article once daily. "SD" indicates stable disease. [Figure 4]

[0023] Figure 1 shows swimmer plots demonstrating clinical disease control and response in subjects receiving the indicated amounts of test article once weekly. "SD" indicates stable disease. [Figure 5A] FIG. 1 shows replicate scans of two subjects who received the test article as indicated, demonstrating tumor regression. [Figure 5B] FIG. 1 shows replicate scans of two subjects who received the test article as indicated, demonstrating tumor regression. [Figure 5C] FIG. 1 shows replicate scans of two subjects who received the test article as indicated, demonstrating tumor regression. [Figure 6A] FIG. 1 shows plasma concentrations over time measured on day 1 following once-daily administration of 10 mg / kg, 20 mg / kg, 40 mg / kg, 60 mg / kg, and 80 mg / kg of the test substance. [Figure 6B] FIG. 1 shows plasma concentrations over time measured on day 15 following once-daily administration of 10 mg / kg, 20 mg / kg, 40 mg / kg, 60 mg / kg, and 80 mg / kg of the test substance. [Figure 6C] FIG. 1 shows Cmax and AUC on day 1 after administration of the test substance at doses of 10 mg / kg, 20 mg / kg, 40 mg / kg, 60 mg / kg, and 80 mg / kg. [Figure 6D] FIG. 1 shows Cmax and AUC on day 15 after administration of the test substance at doses of 10 mg / kg, 20 mg / kg, 40 mg / kg, 60 mg / kg, and 80 mg / kg. [Figure 7A] FIG. 1 shows plasma concentrations over time measured on day 1 following weekly administration of 80 mg / kg, 120 mg / kg, 180 mg / kg, 250 mg / kg, and 350 mg / kg of the test substance. [Figure 7B]FIG. 1 shows plasma concentrations over time measured on day 15 after weekly administration of 80 mg / kg, 120 mg / kg, 180 mg / kg, 250 mg / kg, and 350 mg / kg of the test substance. [Figure 7C] FIG. 1 shows Cmax and AUC on day 1 after administration of the test substance at doses of 80 mg / kg, 120 mg / kg, and 180 mg / kg. [Figure 7D] FIG. 1 shows Cmax and AUC on day 15 after administration of the test substance at 80 mg / kg, 120 mg / kg, and 180 mg / kg. DETAILED DESCRIPTION OF THE INVENTION

[0035] The present disclosure provides a compound of formula (I):

[0036] [ka] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, wherein: R 1 is phenyl or 5-10 membered heteroaryl, which is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4- to 6-membered heterocyclyl), or -C 1-6 Alkyl-NH-C 0-6 substituted with 1 to 3 substituents selected from alkyl-(5- to 6-membered heteroaryl), C 1-6 The alkyl, cycloalkyl, heterocyclyl, and / or heteroaryl may be unsubstituted or may include halogen, C 1-6 Alkyl, NH2, HydroxyC 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl; J is -C(R 2 )(R 8 )(CH2) n -, and R 2 and R 8 are independently H, C 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6Alkyl-(4-6 membered heterocyclyl), -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, -C(O)-N-(C 1-6 alkyl)2, or -C 1-6 Alkyl-NH-C 0-6 alkyl-(5-6 membered heteroaryl), C 1-6 The alkyl, cycloalkyl, heterocyclyl, or heteroaryl may be unsubstituted or may contain halogen, C 1-6 Alkyl, NH2, HydroxyC 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl; or R 2 , R 8 , and R 2 and R 8 The C atoms together join to form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclyl ring, the cycloalkyl or heterocyclyl ring being unsubstituted or substituted with hydroxyl, halogen, or C 1-6 substituted with 1 to 3 substituents selected from alkyl; n is 0 to 6, R 3 is H or C 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; M is a single bond or NH; X and Y are independently CH, CR 7 , or N, Z is CH or N; R 5 H, halogen, C 1-6 Alkyl, or OC 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; R 6 is H or C 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; R7 is C 1-6 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 5 halogens, and R 4 is C 1-6 Alkyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, -C 1-6 Alkyl-phenyl, -C 1-6 Alkyl-(5-6 membered heteroaryl), C 1-6 alkyl-(4- to 6-membered heterocyclyl), 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocyclyl is unsubstituted or substituted with halogen, CN, —C(O)—NH, —C(O)—NH—C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC 1-6 Alkyl-NH-(C 1-6 alkyl), -OC 1-6 Alkyl-N(C 1-6 alkyl), 4- to 6-membered heterocyclyl, -C(O)-(4- to 6-membered heterocyclyl), -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6 Alkyl, C 2-6 Alkynyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6 and heterocyclyl or heteroaryl are unsubstituted or substituted with 1 to 3 substituents selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 It is substituted with 1 to 3 substituents selected from alkyl, or 4- to 6-membered heterocyclyl.

[0037] The present disclosure also provides a compound of formula (II):

[0038] [ka] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, wherein: R 1 is phenyl or 5-10 membered heteroaryl, which is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4- to 6-membered heterocyclyl), or -C 1-6 Alkyl-NH-C 0-6 substituted with 1 to 3 substituents selected from alkyl-(5- to 6-membered heteroaryl), C 1-6 The alkyl, cycloalkyl, heterocyclyl, and / or heteroaryl may be unsubstituted or may include halogen, C 1-6 Alkyl, NH2, HydroxyC 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl; n is 0 to 6, R 2 is C 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4-6 membered heterocyclyl), -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, -C(O)-N(C 1-6 alkyl)2, or -C 1-6 Alkyl-NH-C 0-6 alkyl-(5-6 membered heteroaryl), C 1-6 The alkyl, cycloalkyl, heterocyclyl, or heteroaryl may be unsubstituted or may contain halogen, C 1-6 Alkyl, NH2, HydroxyC 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl; R 8 is H or C 1-6 is alkyl, Alternatively, R 2 , R 8 , and R 2 and R 8 The C atoms together join to form a 3- to 10-membered cycloalkyl or 4- to 10-membered heterocyclyl ring, where the cycloalkyl or heterocyclyl is unsubstituted or substituted with hydroxyl, halogen, or C 1-6substituted with 1 to 3 substituents selected from alkyl; R 3 is H or C 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; M is a single bond or NH; X and Y are independently CH, CR 7 , or N, Z is CH or N; R 5 H, halogen, C 1-6 Alkyl, or OC 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; R 6 is H or C 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; R 7 is C 1-6 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 5 halogens, and R 4 is C 1-6 Alkyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, -C 1-6 Alkyl-phenyl, -C 1-6 Alkyl-(5-6 membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclyl), 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocyclyl is unsubstituted or is substituted with halogen, CN, —C(O)—NH, —C(O)—NH—C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC 1-6 Alkyl-NH-(C 1-6 alkyl), -OC1-6 Alkyl-N(C 1-6 alkyl), 4- to 6-membered heterocyclyl, -C(O)-(4- to 6-membered heterocyclyl), -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6 Alkyl, C 2-6 Alkynyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6 and heterocyclyl or heteroaryl are unsubstituted or substituted with 1 to 3 substituents selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 It is substituted with 1 to 3 substituents selected from alkyl, or 4- to 6-membered heterocyclyl.

[0039] In one embodiment, a compound of formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein: R 1 is phenyl, pyridyl, thienyl, or thiazolyl, which is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen; n is 0 to 1, R 2 is C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4-6 membered heterocyclyl), -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, -C(O)-N(C 1-6 alkyl)2, or -C 1-6 Alkyl-NH-C 0-6 alkyl-(5-6 membered heteroaryl), C 1-6 The alkyl, cycloalkyl, heterocyclyl, or heteroaryl may be unsubstituted or may contain halogen, C 1-6 Alkyl, NH2, HydroxyC 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl; R 8 is H or C 1-6 is alkyl, Alternatively, R 2 , R 8 , and R 2 and R 8 The C atoms together join to form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl ring, where the cycloalkyl or heterocyclyl is unsubstituted or substituted with hydroxyl, halogen, or C 1-6 substituted with 1 to 3 substituents selected from alkyl; R 3 is H or C 1-6 alkyl, C 1-6 the alkyl is unsubstituted or substituted with 1 to 3 halogens; M is a single bond or NH; X and Y are independently CH, CR 7 , or N, Z is CH or N; R 5 H, halogen, C 1-6 Alkyl, or OC 1-6 alkyl, C 1-6 the alkyl is unsubstituted or substituted with 1 to 3 halogens; R 6 is H or C 1-6 alkyl, C 1-6 the alkyl is unsubstituted or substituted with 1 to 3 halogens; R 7 is C 1-6 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 3 halogens, and R 4 is C 1-6 Alkyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, -C 1-6 Alkyl-phenyl, -C 1-6 Alkyl-(5-6 membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclyl), 4- or 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocyclyl is unsubstituted or is substituted with halogen, CN, —C(O)—NH, —C(O)—NH—C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC 1-6 Alkyl-NH-(C 1-6 alkyl), -OC 1-6 Alkyl-N(C 1-6 alkyl), 4- to 6-membered heterocyclyl, -C(O)-(4- to 6-membered heterocyclyl), -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6 Alkyl, C 2-6 Alkynyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6and heterocyclyl or heteroaryl are unsubstituted or substituted with 1 to 3 substituents selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 It is substituted with 1 to 3 substituents selected from alkyl, or 4- to 6-membered heterocyclyl.

[0040] In one embodiment, R 1 is unsubstituted or substituted C 6-12 aryl or unsubstituted or substituted 5-10 membered heteroaryl. In one embodiment, R 1 is phenyl or 5-6 membered heteroaryl containing 1-2 ring heteroatoms selected from O, N, or S, and the phenyl or heteroaryl is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4- to 6-membered heterocyclyl), or -C 1-6 Alkyl-NH-C 0-6 substituted with 1 to 3 substituents selected from alkyl-(5- to 6-membered heteroaryl), C 1-6The alkyl, cycloalkyl, heterocyclyl, and / or heteroaryl may be unsubstituted or may include halogen, C 1-6 Alkyl, NH2, HydroxyC 1-6 Alkyl or amino C 1-6 In one embodiment, R 1 is phenyl, pyridyl, thienyl, or thiazolyl, which is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen. 1 is phenyl, pyridyl, thienyl, or thiazolyl, which is unsubstituted or contains F, Cl, C 1-3 Alkyl, CN, hydroxy C 1-3 Alkyl or amino C 1-3 substituted with 1 to 3 substituents selected from alkyl, C 1-3 The alkyl is unsubstituted or substituted with 1 to 3 substituents selected from F. In one embodiment, R 1 is phenyl, pyridyl, thienyl, or thiazolyl, which is unsubstituted or substituted with 1 to 3 substituents selected from F, Cl, CH, —C(CH), CF, —CHOH, —CHCHOH, CHNH, CN, or —C(CH)OH. In one embodiment, R 1 is phenyl, which is unsubstituted or substituted with 1 to 3 substituents selected from F, Cl, CH, —C(CH), CF, —CHOH, —CHCHOH, CHNH, CN, or —C(CH)OH.

[0041] In one embodiment, n is 0 to 6. In one embodiment, n is 0 to 2. In one embodiment, n is 0 to 1. In one embodiment, n is 0.

[0042] In one embodiment, R 2 is C 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4-6 membered heterocyclyl), -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, -C(O)-N(C 1-6 alkyl)2, or -C 1-6 Alkyl-NH-C 0-6 alkyl-(5-6 membered heteroaryl), C 1-6 The alkyl, cycloalkyl, heterocyclyl, or heteroaryl may be unsubstituted or may contain halogen, C 1-6 Alkyl, NH2, HydroxyC 1-6 Alkyl or amino C 1-6 alkyl; R 8 is H or C 1-6 In one embodiment, R 2 is C 1-3 Alkyl, hydroxy C 1-3 Alkyl, Amino C 1-3 Alkyl, -C 1-3 Alkyl-OC 1-3Alkyl, -C 1-3 Alkyl-NH-C 1-3 Alkyl, -C 1-3 Alkyl-N-(C 1-3 alkyl)2, -C 1-3 Alkyl-NH-C 1-3 Alkyl-OH, -C 1-3 Alkyl-NH-C 1-3 Alkyl-C 3-6 Cycloalkyl, -C 1-3 Alkyl-NH-C 1-3 Alkyl-NH-C 1-3 Alkyl, -C 1-3 Alkyl-NH-C(O)-C 1-3 Alkyl, -C 1-3 Alkyl-OC(O)-C 1-3 Alkyl, -C 1-3 Alkyl-NH-C 0-3 Alkyl-(4-6 membered heterocyclyl), -C(O)-NH2, -C(O)-NH-C 1-3 Alkyl, -C(O)-N(C 1-3 alkyl)2, or -C 1-3 Alkyl-NH-C 0-3 alkyl-(5-6 membered heteroaryl), C 1-3 The alkyl, cycloalkyl, heterocyclyl, or heteroaryl may be unsubstituted or may contain halogen, C 1-3 Alkyl, NH2, HydroxyC 1-3 Alkyl or amino C 1-3 alkyl; R 8 is H or C 1-3 In one embodiment, R 2 is C 1-3 Alkyl, hydroxy C 1-3 Alkyl, Amino C 1-3 Alkyl, -C 1-3 Alkyl-NH-C 1-3 Alkyl, -C 1-3 Alkyl-NH-C 1-3 Alkyl-OH, -C 1-3 Alkyl-NH-C 0-3 Alkyl-(4- to 6-membered heterocyclyl), or -C 1-3 Alkyl-NH-C0-3 alkyl-(5-6 membered heteroaryl), and R 8 is H. In one embodiment, R 2 is CH3, -CH2OH, -CH2NH2, -CH2OCH3, -CH2N(CH3)2, -CH2NH(CH3), -CH2NHCH2CH2OH, -CH2NHC(O)CH3, -CH2OC(O)CH(NH2)CH2CH(CH3)2, -C(O)NH2, -CH2NH- (tetrahydro-2H-pyran), or -CH2NHCH2- (pyrrole); R 8 is H. In one embodiment, R 2 is CH3, -CH2OH, -CH2NH2, -CH2NH(CH3), -CH2NHCH2CH2OH, -CH2NH- (tetrahydro-2H-pyran), or -CH2NHCH2- (pyrrole), and R 8 is H. In one embodiment, R 2 is -CH2OH or -CH2NH2, and R 8 is H.

[0043] In another embodiment, R 2 , R 8 , and R 2 and R 8 The C atoms together join to form a 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl ring, where the cycloalkyl or heterocyclyl is unsubstituted or substituted with hydroxyl, halogen, or C 1-6 In one embodiment, R 2 , R 8 , and R 2 and R 8 The C atoms together join to form a 3-6 membered cycloalkyl, which is unsubstituted or substituted with 1-3 substituents selected from hydroxyl. 2 , R 8 , and R 2 and R 8 The C atoms with both bond together to form a cyclobutyl, which is unsubstituted or substituted with a hydroxyl.

[0044] In one embodiment, R 3 is H or C 1-6 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 5 halogens. In one embodiment, R 3 is H or C 1-3 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 3 halogens. 3 is H or CH3.

[0045] In one embodiment, M is a single bond or NH. In one embodiment, M is a single bond.

[0046] In one embodiment, X and Y are each independently CH, CR 7 In one embodiment, X is CH, C-CH, or N. In one embodiment, X is CH. In one embodiment, Y is CH, C-CH, or N. In one embodiment, Y is N.

[0047] In one embodiment, R 7 is C 1-6 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 5 halogens. In one embodiment, R 7 is C 1-6 In one embodiment, R 7 is CH3.

[0048] In one embodiment, Z is CH or N. In one embodiment, Z is N.

[0049] In one embodiment, R 5 H, halogen, C 1-6 Alkyl, or OC 1-6 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 5 halogens. In one embodiment, R 5 are H, Cl, F, and C 1-3Alkyl, or -OC 1-3 alkyl, C 1-3 The alkyl is unsubstituted or substituted with 1 to 3 halogens. 5 is H, Cl, F, CH3, or -OCH3.

[0050] In one embodiment, R 6 is H or C 1-6 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 5 halogens. In one embodiment, R 6 is H or CH. In one embodiment, R 6 is H.

[0051] In one embodiment, R 4 is C 1-6 Alkyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, -C 1-6 Alkyl-phenyl, -C 1-6 Alkyl-(5-6 membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclyl), 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocyclyl is unsubstituted or is substituted with halogen, CN, —C(O)—NH, —C(O)—NH—C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC 1-6 Alkyl-NH-(C 1-6 alkyl), -OC 1-6 Alkyl-N(C 1-6 alkyl), 4- to 6-membered heterocyclyl, -C(O)-(4- to 6-membered heterocyclyl), -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6 Alkyl, C 2-6 Alkynyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6and heterocyclyl or heteroaryl are unsubstituted or substituted with 1 to 3 substituents selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 It is substituted with 1 to 3 substituents selected from alkyl, or 4- to 6-membered heterocyclyl.

[0052] In one embodiment, R 4 teeth,

[0053] [ka]

[0054] [ka] and wherein each L is independently halogen, CN, C 2-6 Alkynyl, C 1-6 Alkoxy, -C(O)NHC 1-6 Alkyl, -C(O)NH(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NHC 1-6 Alkyl, or -OC 1-6 Alkyl-N(C 1-6 alkyl)2, where x is 0, 1, 2, or 3.

[0055] In one embodiment, R 4 is C 1-6 alkyl, which is unsubstituted or substituted with hydroxyl or C 1-6 In one embodiment, R is substituted with 1 to 3 substituents selected from alkoxy. 4 teeth,

[0056] [ka] is.

[0057] In one embodiment, R 4 is C 3-10 Cycloalkyl or C4-10 Cycloalkenyl, which is unsubstituted or substituted with hydroxyl, halogen, or hydroxy C 1-6 In one embodiment, R 4 is C 3-6 Cycloalkyl or C 4-6 Cycloalkenyl, which is unsubstituted or substituted with hydroxyl, F, Cl, or hydroxy C 1-3 In one embodiment, R 4 teeth,

[0058] [ka] is.

[0059] In one embodiment, R 4 is a 4-10 membered monocyclic or bicyclic heterocyclyl containing 1-2 ring heteroatoms or hetero groups selected from O, N, S, S(=O), S(=O)2, or C(=O), which is unsubstituted or 1-6 In one embodiment, R 4 is a 4-6 membered monocyclic heterocyclyl containing 1-2 ring heteroatoms or hetero groups selected from O, N, or S(=O)2, which is unsubstituted or 1-3 In one embodiment, R 4 teeth,

[0060] [ka] is.

[0061] In one embodiment, R 4 is phenyl, which is unsubstituted or substituted with halogen, CN, C 2-6 Alkynyl, -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, -C(O)-N-(C1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC 1-6 Alkyl-NH-(C 1-6 alkyl), -OC 1-6 Alkyl-N(C 1-6 alkyl), 4- to 6-membered heterocyclyl, -C(O)-(4- to 6-membered heterocyclyl), -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6 Alkyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6 and heterocyclyl or heteroaryl are unsubstituted or substituted with 1 to 3 substituents selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 In one embodiment, R is substituted with 1 to 3 substituents selected from alkyl, or 4- to 6-membered heterocyclyl. 4 teeth,

[0062] [ka] and wherein each L is independently halogen, CN, C 2-6 Alkynyl, C 1-6 Alkoxy, -C(O)NHC 1-6 Alkyl, or C(O)NH(C 1-6 alkyl)2, and n is 0, 1, 2, or 3. In one embodiment, each L is independently selected from F, Cl, CN, C 1-3 alkoxy, —C(O)N(CH 3 ) 2 , where x is 0, 1, 2, or 3.

[0063] In one embodiment, R 4 is a 5-10 membered monocyclic or bicyclic heteroaryl containing 1-2 ring heteroatoms or heterogroups selected from N, O, C(=O), or S, which is unsubstituted or substituted with halogen, C 1-6 Alkyl, or C 4-6cycloalkenyl. In one embodiment, R 4 is a 5- or 6-membered monocyclic heteroaryl containing 1-2 heteroatoms selected from N or O, which is unsubstituted or substituted with 1-3 substituents selected from halogen or CH. In one embodiment, R 4 teeth,

[0064] [ka] is.

[0065] In one embodiment, R 4 Ha-C 1-6 alkyl-(5-6 membered heteroaryl), which is unsubstituted or substituted with halogen or C 1-6 In one embodiment, R 4 teeth,

[0066] [ka] is.

[0067] In one embodiment, R 4 Ha-C 1-6 alkyl-phenyl, which is unsubstituted or substituted with halogen or C 1-6 In one embodiment, R 4 is -CH-phenyl, which is unsubstituted or substituted with CH. In one embodiment, R 4 teeth,

[0068] [ka] is.

[0069] In one embodiment, R 4 Ha-C 1-6alkyl-(4-6 membered heterocyclyl), which is unsubstituted or substituted with halogen or C 1-6 In one embodiment, R 4 teeth,

[0070] [ka] is.

[0071] In one embodiment, R 4 teeth,

[0072] [ka] is.

[0073] In one embodiment, R 4 teeth,

[0074] [ka] is.

[0075] In one embodiment, R 4 teeth,

[0076] [ka] is.

[0077] In one embodiment, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein: R 1 is phenyl, pyridyl, thienyl, or thiazolyl, which is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl, C 1-6alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen; n is 0, R 2 is C 1-6 Alkyl, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4-6 membered heterocyclyl), -C(O)-NH2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C(O)-NH-C 1-6 Alkyl, -C(O)-N(C 1-6 alkyl)2, or -C 1-6 Alkyl-NH-C 0-6 alkyl-(5-6 membered heteroaryl), C 1-6 The alkyl, cycloalkyl, heterocyclyl, or heteroaryl may be unsubstituted or may contain halogen, C 1-6 Alkyl, NH2, HydroxyC 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl; R 8 is H, R 3 is H, M is a single bond, X is CH, Y is CH or N; Z is N, R 5 is H, halogen, or C 1-6 is alkyl, R 6 is H, and R 4 teeth,

[0078] [ka] which is unsubstituted or is substituted with halogen or C 1-6 It may be substituted with 1 to 3 substituents selected from alkoxy.

[0079] In one embodiment, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein: R 1 is phenyl or thienyl, which is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen; n is 0, R 2 is C 1-6 Alkyl, Hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4-6 membered heterocyclyl), -C(O)-NH2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C(O)-NH-C 1-6 Alkyl, -C(O)-N(C 1-6 alkyl)2, or -C 1-6 Alkyl-NH-C 0-6 alkyl-(5-6 membered heteroaryl), C 1-6 The alkyl, cycloalkyl, heterocyclyl, or heteroaryl may be unsubstituted or may contain halogen, C 1-6Alkyl, NH2, HydroxyC 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl; R 8 is H, R 3 is H, M is a single bond, X is CH, Y is CH or N; Z is N, R 5 is H, halogen, or C 1-6 is alkyl, R 6 is H, R 4 teeth,

[0080] [ka] which is unsubstituted or is substituted with halogen or C 1-6 It may be substituted with 1 to 3 substituents selected from alkoxy.

[0081] In one embodiment, there is provided a compound of formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein: R 1 is phenyl, which is unsubstituted or substituted with 1 to 3 substituents selected from F or Cl; n is 0, R 2 is CH2OH, CH2NH2, -CH2NH(CH3), -CH2NHCH2CH2OH, -C(O)NH2, -CH2NH-(tetrahydro-2H-pyran), or -CH2NH-CH2-(1H-pyrrole); R 8 is H, R 3 is H, M is a single bond, X is CH, Y is N, Z is N, R 5 is CH3, R 6 is H, and R 4 teeth,

[0082] [ka] is.

[0083] The present disclosure also provides a compound of formula (III):

[0084] [ka] or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, wherein: R 1 is phenyl or 5-10 membered heteroaryl, wherein the phenyl or heteroaryl is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4-6 membered heterocyclyl), -C1-6 Alkyl-NH-C 0-6 Alkyl-(5-6 membered heteroaryl), -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, or -C(O)-N(C 1-6 alkyl)2, and C 1-6 The alkyl, cycloalkyl, heterocyclyl, and / or heteroaryl may be unsubstituted or may include halogen, C 1-6 Alkyl, Hydroxy C 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl; n is 0 to 6, R 3 is H or C 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; M is a single bond or NH; X and Y are independently CH, CR 7 , or N, Z is CH or N; R 5 H, halogen, C 1-6 Alkyl, or OC 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; R 6 is H or C 1-6 alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 5 halogens; R 7 is C 1-6 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 5 halogens, and R 4 is C 1-6 Alkyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, -C 1-6 Alkyl-phenyl, -C 1-6Alkyl-(5-6 membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclyl), 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocyclyl is unsubstituted or is substituted with halogen, CN, —C(O)—NH, —C(O)—NH—C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC 1-6 Alkyl-NH-(C 1-6 alkyl), -OC 1-6 Alkyl-N-(C 1-6 alkyl), 4- to 6-membered heterocyclyl, -C(O)-(4- to 6-membered heterocyclyl), -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6 Alkyl, C 2-6 Alkynyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6 and heterocyclyl or heteroaryl are unsubstituted or substituted with 1 to 3 substituents selected from halogen, C 1-6 Alkyl, C-(O)-C 1-6 It is substituted with 1 to 3 substituents selected from alkyl, or 4- to 6-membered heterocyclyl.

[0085] In one embodiment, there is provided a compound of formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein: R 1 is phenyl, pyridyl, thienyl, or thiazolyl, which is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen; n is 1 to 2, R 3 is H or C 1-6 alkyl, C 1-6 the alkyl is unsubstituted or substituted with 1 to 3 halogens; M is a single bond or NH; X and Y are independently CH, CR 7 , or N, Z is CH or N; R 5 H, halogen, C 1-6 Alkyl, or OC 1-6 alkyl, C 1-6 the alkyl is unsubstituted or substituted with 1 to 3 halogens; R 6 is H or C 1-6 alkyl, C 1-6 the alkyl is unsubstituted or substituted with 1 to 3 halogens; R 7 is C 1-6 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 3 halogens, and R 4 is C 1-6 Alkyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, -C 1-6 Alkyl-phenyl, -C 1-6 Alkyl-(5-6 membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclyl), 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocyclyl is unsubstituted or is substituted with halogen, CN, —C(O)—NH, —C(O)—NH—C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC 1-6 Alkyl-NH-(C 1-6 alkyl), -OC 1-6 Alkyl-N(C 1-6alkyl), 4- to 6-membered heterocyclyl, -C(O)-(4- to 6-membered heterocyclyl), -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6 Alkyl, C 2-6 Alkynyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6 and heterocyclyl or heteroaryl are unsubstituted or substituted with 1 to 3 substituents selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 It is substituted with 1 to 3 substituents selected from alkyl, or 4- to 6-membered heterocyclyl.

[0086] In one embodiment, R 1 is unsubstituted or substituted C 6-12 aryl or unsubstituted or substituted 5-10 membered heteroaryl. In one embodiment, R 1 is phenyl or 5-6 membered heteroaryl containing 1-2 ring heteroatoms selected from O, N, or S, and the phenyl or heteroaryl is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 1-6Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4-6 membered heterocyclyl), -C 1-6 Alkyl-NH-C 0-6 Alkyl-(5-6 membered heteroaryl), C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, or -C(O)-N(C 1-6 alkyl)2, and C 1-6 The alkyl, cycloalkyl, heterocyclyl, and / or heteroaryl may be unsubstituted or may include halogen, C 1-6 Alkyl, NH2, HydroxyC 1-6 Alkyl or amino C 1-6 In one embodiment, R 1 is phenyl, pyridyl, thienyl, or thiazolyl, which is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen. 1 is phenyl, pyridyl, thienyl, or thiazolyl, which is unsubstituted or contains F, Cl, C 1-3 Alkyl, CN, hydroxy C 1-3 Alkyl or amino C 1-3 substituted with 1 to 3 substituents selected from alkyl, C 1-3 The alkyl is unsubstituted or substituted with 1 to 3 substituents selected from F. In one embodiment, R 1 is phenyl, pyridyl, thienyl, or thiazolyl, which is unsubstituted or substituted with 1 to 3 substituents selected from F, Cl, CH, —C(CH), CF, —CHOH, —CHCHOH, CHNH, CN, or —C(CH)OH. In one embodiment, R 1is phenyl, which is unsubstituted or substituted with 1 to 3 substituents selected from F, Cl, CH, —C(CH), CF, —CHOH, —CHCHOH, CHNH, CN, or —C(CH)OH.

[0087] In one embodiment, n is 0 to 6. In one embodiment, n is 1 to 2. In one embodiment, n is 1.

[0088] In one embodiment, R 3 is H or C 1-6 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 5 halogens. In one embodiment, R 3 is H or C 1-3 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 3 halogens. 3 is H or CH3.

[0089] In one embodiment, M is a single bond or NH. In one embodiment, M is a single bond.

[0090] In one embodiment, X and Y are each independently CH, CR 7 In one embodiment, X is CH, C-CH, or N. In one embodiment, X is CH. In one embodiment, Y is CH, C-CH, or N. In one embodiment, Y is N.

[0091] In one embodiment, R 7 is C 1-6 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 5 halogens. In one embodiment, R 7 is C 1-6 In one embodiment, R 7 is CH3.

[0092] In one embodiment, Z is CH or N. In one embodiment, Z is N.

[0093] In one embodiment, R 5 H, halogen, C 1-6 Alkyl, or OC 1-6 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 5 halogens. In one embodiment, R 5 are H, Cl, F, and C 1-3 Alkyl, or -OC 1-3 alkyl, C 1-3 The alkyl is unsubstituted or substituted with 1 to 3 halogens. 5 is H, Cl, F, CH3, or -OCH3.

[0094] In one embodiment, R 6 is H or C 1-6 alkyl, C 1-6 The alkyl is unsubstituted or substituted with 1 to 5 halogens. In one embodiment, R 6 is H or CH. In one embodiment, R 6 is H.

[0095] In one embodiment, R 4 is C 1-6 Alkyl, C 3-10 Cycloalkyl, C 4-10 Cycloalkenyl, -C 1-6 Alkyl-phenyl, -C 1-6 Alkyl-(5-6 membered heteroaryl), -C 1-6 alkyl-(4- to 6-membered heterocyclyl), 4- to 10-membered heterocyclyl, phenyl, or 5- to 10-membered heteroaryl, wherein the alkyl, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or heterocyclyl is unsubstituted or is substituted with halogen, CN, —C(O)—NH, —C(O)—NH—C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC1-6 Alkyl-NH-(C 1-6 alkyl), -OC 1-6 Alkyl-N(C 1-6 alkyl), 4- to 6-membered heterocyclyl, -C(O)-(4- to 6-membered heterocyclyl), -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6 Alkyl, C 2-6 Alkynyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6 and heterocyclyl or heteroaryl are unsubstituted or substituted with 1 to 3 substituents selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 It is substituted with 1 to 3 substituents selected from alkyl, or 4- to 6-membered heterocyclyl.

[0096] In one embodiment, R 4 teeth,

[0097] [ka]

[0098] [ka] and wherein each L is independently halogen, CN, C 2-6 Alkynyl, C 1-6 Alkoxy, -C(O)NHC 1-6 Alkyl, -C(O)NH(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NHC 1-6 Alkyl, or -OC 1-6 Alkyl-N(C 1-6 alkyl)2, where x is 0, 1, 2, or 3.

[0099] In one embodiment, R 4 is C 1-6 alkyl, which is unsubstituted or substituted with hydroxyl or C1-6 In one embodiment, R is substituted with 1 to 3 substituents selected from alkoxy. 4 teeth,

[0100] [ka] is.

[0101] In one embodiment, R 4 is C 3-10 Cycloalkyl or C 4-10 Cycloalkenyl, which is unsubstituted or substituted with hydroxyl, halogen, or hydroxy C 1-6 In one embodiment, R 4 is C 3-6 Cycloalkyl or C 4-6 Cycloalkenyl, which is unsubstituted or substituted with hydroxyl, F, Cl, or hydroxy C 1-3 In one embodiment, R 4 teeth,

[0102] [ka] is.

[0103] In one embodiment, R 4 is a 4-10 membered heterocyclyl containing 1-2 ring heteroatoms or hetero groups selected from O, N, S, S(=O), S(=O)2, or C(=O), which is unsubstituted or 1-6 In one embodiment, R 4 is a 4-6 membered monocyclic heterocyclyl containing 1-2 ring heteroatoms or hetero groups selected from O, N, or S(O)2, which is unsubstituted or 1-3 In one embodiment, R 4 teeth,

[0104] [ka] is.

[0105] In one embodiment, R 4 is phenyl, which is unsubstituted or substituted with halogen, C 2-6 Alkynyl, CN, -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC 1-6 Alkyl-NH-(C 1-6 alkyl), -OC 1-6 Alkyl-N(C 1-6 alkyl), 4- to 6-membered heterocyclyl, -C(O)-(4- to 6-membered heterocyclyl), -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6 Alkyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6 and heterocyclyl or heteroaryl are unsubstituted or substituted with 1 to 3 substituents selected from halogen, C 1-6 Alkyl, -C(O)-C 1-6 In one embodiment, R is substituted with 1 to 3 substituents selected from alkyl, or 4- to 6-membered heterocyclyl. 4 teeth,

[0106] [ka] and wherein each L is independently halogen, CN, C 2-6 Alkynyl, C 1-6 Alkoxy, -C(O)NHC 1-6 Alkyl, or C(O)NH(C 1-6 alkyl)2, and n is 0, 1, 2, or 3. In one embodiment, each L is independently selected from F, Cl, CN, C 1-3alkoxy, —C(O)N(CH 3 ) 2 , where x is 0, 1, 2, or 3.

[0107] In one embodiment, R 4 is a 5-10 membered monocyclic or bicyclic heteroaryl containing 1-2 ring heteroatoms or heterogroups selected from O, N, S, S(=O), S(=O)2, or C(=O), which is unsubstituted or substituted with halogen, C 1-6 Alkyl, or C 4-6 cycloalkenyl. In one embodiment, R 4 is a 5- or 6-membered monocyclic heteroaryl containing 1-2 heteroatoms selected from N or O, which is unsubstituted or substituted with 1-3 substituents selected from halogen or CH. In one embodiment, R 4 teeth,

[0108] [ka] is.

[0109] In one embodiment, R 4 Ha-C 1-6 alkyl-(5-6 membered heteroaryl), which is unsubstituted or substituted with halogen or C 1-6 In one embodiment, R 4 teeth,

[0110] [ka] is.

[0111] In one embodiment, R 4 Ha-C 1-6 alkyl-phenyl, which is unsubstituted or substituted with halogen or C 1-6 In one embodiment, R 4is -CH2-phenyl, which is unsubstituted or substituted with CH3. In one embodiment, R 4 teeth,

[0112] [ka] is.

[0113] In one embodiment, R 4 -C 1-6 alkyl-(4-6 membered heterocyclyl), which is unsubstituted or substituted with halogen or C 1-6 In one embodiment, R 4 teeth,

[0114] [ka] is.

[0115] In one embodiment, R 4 teeth,

[0116] [ka] is.

[0117] In one embodiment, R 4 teeth,

[0118] [ka] is.

[0119] In one embodiment, R 4 teeth,

[0120] [ka] is.

[0121] In one embodiment, there is provided a compound of formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein: R 1 is phenyl or thienyl, which is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl, C 1-6 alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen; n is 1, R 3 is H, M is a single bond, X is CH, Y is N, Z is N, R 5 is H, halogen, or C 1-6 is alkyl, R 6 is H, and R 4 teeth,

[0122] [ka] which is unsubstituted or is substituted with halogen or C 1-6 It may be substituted with 1 to 3 substituents selected from alkoxy.

[0123] In one embodiment, there is provided a compound of formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein: R 1 is phenyl, which is unsubstituted or substituted with halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl or amino C 1-6 substituted with 1 to 3 substituents selected from alkyl, C 1-6alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen; n is 1, R 3 is H, M is a single bond, X is CH, Y is N, Z is N, R 5 is CH3, R 6 is H, and R 4 teeth,

[0124] [ka] which is unsubstituted or is substituted with halogen or C 1-6 It may be substituted with 1 to 3 substituents selected from alkoxy.

[0125] In one embodiment, there is provided a compound of formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein: R 1 is phenyl, which is unsubstituted or substituted with 1 to 3 substituents selected from halogen, CHOH, or CHNH; n is 1, R 3 is H, M is a single bond, X is CH, Y is N, Z is N, R 5 is CH3, R 6 is H, and R 4 teeth,

[0126] [ka] which is unsubstituted or is substituted with halogen or C1-6 It may be substituted with 1 to 3 substituents selected from alkoxy.

[0127] In one embodiment, a compound of formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein: R 1 is phenyl, which is substituted with 1 to 3 substituents selected from F, Cl, CHOH, or CHNH, and at least one ortho moiety is substituted; n is 1, R 3 is H, M is a single bond, X is CH, Y is N, Z is N, R 5 is CH3, R 6 is H, and R 4 teeth,

[0128] [ka] is.

[0129] In one embodiment, there is provided a compound of formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, or stereoisomer thereof, wherein: R 1 is phenyl, which is substituted with 1 to 3 substituents selected from F, Cl, CHOH, or CHNH, and at least one ortho moiety is substituted with CHOH or CHNH; n is 1, R 3 is H, M is a single bond, X is CH, Y is N, Z is N, R 5 is CH3, R 6is H, and R 4 teeth,

[0130] [ka] is.

[0131] In one embodiment, the compound of the present disclosure is (S)-1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, 1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, 1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, 1-(2-((2,3-dihydrobenzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydro-benzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, 1-(2-(chroman-6-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxy-ethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (R)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-(2-hydroxy-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-(((1H-pyrrol-2-yl)methyl)amino)-1-(3-chlorophenyl)-ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-(tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-((2-hydroxyethyl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, and N-(3-chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof.

[0132] In certain embodiments, the compound is (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate.

[0133] In certain embodiments, the compound is (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate.

[0134] The compound (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate is sometimes referred to herein as “(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (S)-2-hydroxy-2-phenylacetate.”

[0135] The compound (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate is sometimes referred to herein as “(S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide besylate.”

[0136] In one embodiment, the compounds of formula (I) as defined in each of the preceding embodiments are substantially pure stereoisomers.

[0137] The compounds of formulas (I-III) are limited to chemically feasible and stable compounds. Therefore, combinations of substituents or variables in the above compounds are permissible only if they result in chemically feasible and stable compounds. A stable or chemically feasible compound is one whose chemical structure does not change significantly when maintained at a temperature of 40°C or less for at least one week in the absence of moisture or other chemically reactive conditions.

[0138] The compounds of formulas (I-III), and each of their species, alone or in combination, are provided as their respective salts, prodrugs, solvates, hydrates, racemates, enantiomers, diastereomers, metabolites, and mixtures thereof, wherever possible, unless otherwise indicated or contradicted by context.

[0139] Representative "pharmaceutically acceptable salts" include, but are not limited to, water soluble and water insoluble salts. In one embodiment, the salt is derived from a base. The salt may be derived from a base selected from alkali metal salt bases, such as sodium, lithium, or potassium salt bases, or organic bases, such as ammonium, mono-, di-, and trimethylammonium, mono-, di-, and triethylammonium, mono-, di-, and tripropylammonium, ethyl-dimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzylammonium, dibenzylammonium, piperidium, morpholinium, pyrrolidium, piperadium, 1-methylpiperidium, 4-ethyl-morpholinium, 1-isopropyl-pyrrolidium, 1,4-dimethylpiperadium, 1-n-butylpiperidium, 2-methyl-piperidium, 1-ethyl-2-methylpiperidium, mono-, di-, and triethanolammonium, ethyldiethanolammonium, n-butylmonoethanolammonium, tris(hydroxymethyl)-methyl-ammonium, phenylmonoethanolammonium bases, among others. In another embodiment, the salt is derived from an acid. The salts may be derived from, for example, an acid selected from acetic acid, propionic acid, lactic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malonic acid, mandelic acid, malic acid, phthalic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, methanesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, and camphorsulfonic acid, among others. Optionally, the compositions of the present disclosure may contain both pharmaceutically acceptable salts and free base forms of the compounds of the present disclosure. In one embodiment, besylate and mandelate salts are pharmaceutically acceptable salts of the compounds of the present disclosure.In further embodiments, pharmaceutically acceptable salts of compounds of the present disclosure are (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate and (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate.

[0140] In one embodiment, the compounds of Formula (I-III), compositions comprising compounds of Formula (I-III), uses, methods of treatment, dosing regimens, kits may include the besylate salt, mandelate salt, or free base form of the compounds of the present disclosure. In one embodiment, the compound of Formula (I-III), compositions, uses, methods of treatment, dosing regimens, and kits comprising the compound of Formula (I-III) may include (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate (Example 302), (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate (Example 349), or the free base form (Example 275).

[0141] Prodrugs of compounds of formula (I-III), such as Examples 302, 349, or 275, can be used to modify the pharmacokinetic properties using various methods known to those skilled in the art. See, for example, Jarkko Rautio et al., Nature Reviews Drug Discovery, 7:255-270 (2008), which is incorporated herein by reference. 2For drugs containing an amine moiety, such as when is CH2NH2, various prodrug approaches are reviewed in ALSimplicio, Molecules, 13:519-547 (2008), which is incorporated herein by reference. More specifically, (alkoxycarbonyloxy)alkylcarbamates, (acyloxy)alkylcarbamates, and (oxodioxolenyl)alkylcarbamates have been reported as effective prodrug strategies for amines in Zhong Li, Bioorg. Med. Chem. Lett., 7:2909-2912 (1997); J. Alexander, J. Med. Chem., 34:78-81 (1991); J. Alexander, J. Med. Chem., 31:318-322 (1988); and J. Alexander, J. Med. Chem., 39:480-486 (1996), all of which are incorporated herein by reference. In one embodiment, the prodrug is an amide of formula (I-III), e.g., Example 302, 349, or 275. In one embodiment, R 2 When is CH2NH2, the amide is

[0142] [ka] and C 1-6 The alkyl may be optionally substituted. In another embodiment, the prodrug is an ester of Formula (I-III), e.g., Examples 302, 349, or 275. In one embodiment, R 2 is CHOH, the ester is

[0143] [ka] and C 1-6 The alkyl may be optionally substituted.

[0144] In further embodiments, the compounds of the present disclosure may be solvates. As used herein, a "solvate" does not significantly alter the physiological activity or toxicity of the compound and therefore can function pharmacologically equivalently to the unsolvated compounds of the present disclosure. The term "solvate," as used herein, refers to a combination, physiological association, and / or solvation of a compound of the present disclosure with a solvent molecule. This physiological association requires varying degrees of ionic and covalent bonding, including hydrogen bonding. In some instances, a solvate may be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, the term "solvate" encompasses both solution-phase and isolatable forms. A hydrate is a special form of a solvate that contains water in a defined ratio for crystallization.

[0145] The compounds described herein may contain asymmetric centers and therefore may exist as enantiomers. When compounds of the present disclosure possess two or more asymmetric centers, they may exist as diastereomers. When a bond to a chiral center is depicted as a straight line in the formulae of the present disclosure, it is understood that both the (R) and (S) configurations, and thus enantiomers and mixtures thereof, are encompassed. The present disclosure encompasses all such possible stereoisomers unless a particular stereochemistry is specifically indicated. It is well known in the art how to prepare substantially pure stereoisomers, such as by resolution of racemic forms or synthesis from optically active starting materials. In one embodiment, a compound of Formula (I-III), e.g., Example 302, 349, or 275, is a substantially pure stereoisomer. A "substantially pure stereoisomer" refers to a stereoisomeric form that is at least 95% pure relative to other stereoisomers of otherwise identical structure.

[0146] The following definitions are used in connection with the compounds described herein. In general, the number of carbon atoms present in a given group is indicated by the symbol "C x-y" where x and y are the lower and upper limits, respectively. Carbon numbers, as used in the definitions herein, refer to the carbon backbone and carbon branches, but do not include carbon atoms of substituents such as alkoxy substituents. Unless otherwise specified, the naming of substituents not explicitly defined herein is determined by naming the terminal portion of the functionality, followed by the adjacent functionality, from left to right toward the point of attachment. As used herein, "optionally substituted" means that at least one hydrogen atom on a specified atom, such as a carbon or nitrogen atom, is optionally replaced with another substituent, provided that the normal valence of the specified atom is not exceeded, and that the substitution results in a stable compound. When more than one substituent is present on an atom or group, the selected substituents are independent of each other (i.e., the same or different).

[0147] "Alkyl" refers to a hydrocarbon chain which may be a straight or branched alkyl radical. In one embodiment, "C 1-7 "Alkyl" means an alkyl containing 1 to 7 (inclusive) carbon atoms. In another embodiment, "C 1-6 "Alkyl" means an alkyl containing 1 to 6 (inclusive) carbon atoms. 1-4 "Alkyl" means an alkyl containing 1 to 4 (inclusive) carbon atoms. Examples of alkyl groups that are hydrocarbon chains include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl, and all isomers of these examples are contemplated.

[0148] "Substituted alkyl" refers to a group as defined above that contains one or more F, one or more Cl, one or more OH, one amino group, one (C 1-6 alkyl)amino groups (i.e., C 1-6 alkyl-NH-), one (di-C 1-6 (alkyl)amino group (i.e., (alkyl)2N-), one or two C 1-6 Alkoxy group, one -NH-C(O)-C 1-6alkyl group, one -C(O)-NH2 group, one -C(O)-NH-(C 1-6 alkyl) group, one -C(O)-N-(C 1-6 "Substituted" refers to an alkyl group substituted with groups including, but not limited to, two alkyl groups, one cyano group, or one cyano group, or any combination of these substituents. "Substituted" means that one or more of the alkyl group's hydrogen atoms is replaced with a substituent group listed above.

[0149] "Hydroxyalkyl" refers to -(alkyl)OH, where alkyl is optionally substituted and is defined above. The OH portion of the hydroxyalkyl may be attached to any carbon atom, for example, any one of the internal or terminal carbon atoms of the hydrocarbon alkyl chain. Examples of hydroxyalkyl include, but are not limited to, -CHOH, -CHCHOH, -CH(OH)CH, -CHCHCHOH, -CHCH(OH)CH, -CH(OH)CHCH, -C(OH)(CH), -(2-hydroxy)-cyclopentyl, (3-hydroxy)-cyclobutyl, and the like.

[0150] "C 3-10 "Cycloalkyl" refers to a saturated cyclic alkyl group, which may be a monocyclic, bicyclic, polycyclic, or fused / bridged ring system, having from 3 to 10 carbon atoms. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. Typical bridged cycloalkyls include, but are not limited to, adamantyl, noradamantyl, bicyclo[1.1.0]butanyl, norbornyl (bicyclo[2.2.1]heptanyl), and the like. C 3-10 Cycloalkyl may be unsubstituted or may be substituted with hydroxyl, halogen, or C 1-6 It may be substituted with one or more groups including, but not limited to, alkyl.

[0151] "C 4-10"Cycloalkenyl" refers to an unsaturated or partially saturated non-aromatic cyclic alkyl group, which may be a monocyclic, bicyclic, polycyclic, or fused / bridged ring system, having from 4 to 10 carbon atoms. Exemplary cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexa-1,4-diene, and the like.

[0152] "C 2-6 "Alkenyl" refers to a linear monovalent hydrocarbon radical or a branched divalent hydrocarbon radical of two to six carbon atoms containing at least one double bond. Exemplary cycloalkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.

[0153] "C 2-6 "Alkynyl" refers to a linear monovalent hydrocarbon radical or a branched divalent hydrocarbon radical of two to six carbon atoms containing at least one triple bond. Exemplary cycloalkyl groups include, but are not limited to, ethynyl and propynyl.

[0154] "Alkoxy" refers to (alkyl)O, where alkyl is optionally substituted and is defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy. The alkyl radical of an alkoxy group can be unsubstituted or substituted as defined above.

[0155] "Aryl" refers to a monocyclic, bicyclic, or polycyclic aromatic hydrocarbon group containing carbon atoms. In one embodiment, an aryl contains 6 to 12 carbon atoms. In one embodiment, an aryl is phenyl. In one embodiment, an aryl is an aromatic or partially aromatic bicyclic group. In another embodiment, an aryl is naphthyl (such as α-naphthyl or β-naphthyl), 1,2,3,4-tetrahydronaphthyl, or indanyl. An aryl group may be unsubstituted or substituted with halogen, C 1-6Alkyl, C 2-6 Alkynyl, CN, HydroxyC 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4- to 6-membered heterocyclyl), or -C 1-6 Alkyl-NH-C 0-6 may be substituted with one or more groups including, but not limited to, alkyl-(5-6 membered heteroaryl), C 1-6 The alkyl, cycloalkyl, heterocyclyl, and / or heteroaryl may be unsubstituted or may include halogen, C 1-6 Alkyl, hydroxy C 1-6 Alkyl or amino C 1-6 In one embodiment, the aryl group is unsubstituted or substituted with 1 to 3 substituents selected from halogen, CN, —C(O)—NH, —C(O)—NH—C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC 1-6 Alkyl-NH-(C 1-6 alkyl), -OC 1-6 Alkyl-N(C 1-6alkyl), 4- to 6-membered heterocyclyl, -C(O)-(4- to 6-membered heterocyclyl), -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6 Alkyl, C 2-6 Alkynyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6 The heterocyclyl or heteroaryl may be unsubstituted or substituted with one or more groups including, but not limited to, halogen, C 1-6 Alkyl, C(O)-C 1-6 It is substituted with 1 to 3 substituents selected from alkyl, or 4- to 6-membered heterocyclyl.

[0156] "Substituted phenyl" means a phenyl group containing halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, HydroxyC 1-6 Alkyl, Amino C 1-6 Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4- to 6-membered heterocyclyl), or -C 1-6 Alkyl-NH-C 0-6refers to a phenyl group substituted with one or more groups including, but not limited to, alkyl-(5-6 membered heteroaryl), C 1-6 The alkyl, cycloalkyl, heterocyclyl, and / or heteroaryl may be unsubstituted or may include halogen, C 1-6 Alkyl, Hydroxy C 1-6 Alkyl or amino C 1-6 In one embodiment, the phenyl group is unsubstituted or substituted with 1 to 3 substituents selected from halogen, CN, C 2-6 Alkynyl, -C(O)-NH2, -C(O)-NH-C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC 1-6 Alkyl-NH-(C 1-6 alkyl), -OC 1-6 Alkyl-N(C 1-6 alkyl), 4- to 6-membered heterocyclyl, -C(O)-(4- to 6-membered heterocyclyl), -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6 Alkyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6 The heterocyclyl or heteroaryl may be unsubstituted or substituted with one or more groups including, but not limited to, halogen, C 1-6 Alkyl, C(O)-C 1-6 It is substituted with 1 to 3 substituents selected from alkyl, or 4- to 6-membered heterocyclyl.

[0157] "Halogen" refers to F, Cl, Br, or I.

[0158] "Heteroaryl" refers to a monocyclic, bicyclic, or polycyclic aromatic or partially aromatic ring system having one to three heteroatoms or heterogroups selected from O, N, S, S(=O), S(=O)2, or C(=O). "Partially aromatic" refers to a multicyclic fused ring system in which at least one ring, but not all, is aromatic, such as a benzodioxole group. In one embodiment, a heteroaryl is a 5- to 10-membered ring system. In another embodiment, a heteroaryl is a 5- to 6-membered ring system. Exemplary heteroaryl ring groups include furanyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, thiazinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, imidazothiazolyl, oxadiazolyl, indolizidinyl, indolinyl, indazolyl, chromanyl, oxoindolinyl, indolyl, oxoindolyl, quinolinyl, 3,4-dihydroisoquinolin-2(1H)-yl, quinazolinyl, benzofuranyl, benzoxazolyl, benzo[d]isoxazolyl, benzo[d]thiazolyl, benzo[d][1,3]dioxolyl, 1H-benzo[d][1,2,3]triazolyl, 2H-indazolyl, and the like. aryl, 1H-indazolyl, quinoxalin-2-yl, 1H-benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl, dihydrobenzo[b][1,4]dioxinyl, (5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl), 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, 5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl), 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazinyl, pyrazolo[1,5a]pyridinyl and the like.

[0159] "Substituted heteroaryl" refers to any group, as defined above, including halogen, C 1-6 Alkyl, CN, hydroxy C 1-6 Alkyl, Amino C 1-6Alkyl, -C 1-6 Alkyl-OC 1-6 Alkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-N-(C 1-6 alkyl)2, -C 1-6 Alkyl-NH-C 1-6 Alkyl-OH, -C 1-6 Alkyl-NH-C 1-6 Alkyl-C 3-10 Cycloalkyl, -C 1-6 Alkyl-NH-C 1-6 Alkyl-NH-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C(O)-C 1-6 Alkyl, -C 1-6 Alkyl-OC(O)-C 1-6 Alkyl, -C 1-6 Alkyl-NH-C 0-6 Alkyl-(4- to 6-membered heterocyclyl), or -C 1-6 Alkyl-NH-C 0-6 refers to a heteroaryl group substituted with one or more groups including, but not limited to, alkyl-(5-6 membered heteroaryl), C 1-6 The alkyl, cycloalkyl, heterocyclyl, and / or heteroaryl may be unsubstituted or may include halogen, C 1-6 Alkyl, Hydroxy C 1-6 Alkyl or amino C 1-6 In one embodiment, the heteroaryl group is unsubstituted or substituted with 1 to 3 substituents selected from halogen, C 1-6 Alkyl, NH2, HydroxyC 1-6 Alkyl or amino C 1-6 In one embodiment, the heteroaryl group is unsubstituted or substituted with one or more groups, including, but not limited to, halogen, CN, -C(O)-NH, -C(O)-NH-C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC 1-6Alkyl-NH-(C 1-6 alkyl), -OC 1-6 Alkyl-N(C 1-6 alkyl), 4- to 6-membered heterocyclyl, -C(O)-(4- to 6-membered heterocyclyl), -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6 Alkyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6 The heterocyclyl or heteroaryl may be unsubstituted or substituted with one or more groups including, but not limited to, halogen, C 1-6 Alkyl, C(O)-C 1-6 It is substituted with 1 to 3 substituents selected from alkyl, or 4- to 6-membered heterocyclyl.

[0160] "Heterocycle" or "heterocyclyl" refers to a monocyclic, bicyclic, or polycyclic saturated ring system having 1 to 3 heteroatoms or heterogroups selected from O, N, S, S(=O), S(=O)2, or C(=O). Monocyclic heterocycles can be 4-10 membered, while bicyclic heterocycles contain two fused or bridged 4-6 membered rings having 5 to 10 ring atoms. Exemplary heterocyclyl groups include, but are not limited to, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl (thiolanyl), piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydro-2H-pyranyl, morpholinyl, thiomorpholinyl, dioxanyl, 2,5-diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, and the like.

[0161] "Substituted heterocycle" or "substituted heterocyclyl" means any of halogen, CN, -C(O)-NH, -C(O)-NH-C 1-6 Alkyl, -C(O)-N-(C 1-6 Alkyl)2, -OC 1-6 Alkyl-NH2, -OC 1-6 Alkyl-NH-(C 1-6alkyl), -OC 1-6 Alkyl-N-(C 1-6 alkyl)2, 4- to 6-membered heterocyclyl, -C(O)-heterocyclyl, -O-phenyl, -OC 1-6 Alkyl-(4-6 membered heterocyclyl), C 1-6 Alkyl, Hydroxyl, C 1-6 Alkoxyl or hydroxyl C 1-6 refers to a heterocycle or heterocyclyl group substituted with one or more groups including, but not limited to, alkyl; heterocyclyl or heteroaryl may be unsubstituted or substituted with halogen, C 1-6 Alkyl, C-(O)-C 1-6 In one embodiment, the heterocyclyl group is unsubstituted or substituted with 1 to 3 substituents selected from halogen, C 1-6 Alkyl, NH2, HydroxyC 1-6 Alkyl or amino C 1-6 In one embodiment, the heterocyclyl group is unsubstituted or substituted with one or more groups, including, but not limited to, hydroxyl, halogen, or C 1-6 It may be substituted with one or more groups including, but not limited to, alkyl.

[0162] The words "comprise", "comprises", and "comprising" are to be interpreted inclusively rather than exclusively. The words "consist", "consisting", and variations thereof are to be interpreted inclusively rather than exclusively.

[0163] As used herein, the term "about" means a 10% variation from a given reference value, unless otherwise specified.

[0164] The terms "patient" or "subject" are used interchangeably herein and refer to a mammal, e.g., a human or veterinary patient or subject, e.g., a mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, baboon, or gorilla.

[0165] The terms "treating" or "treatment" are intended to encompass administering a compound or composition of the present disclosure to a subject for the purpose of ameliorating one or more symptoms of a disease or disorder, including palliative care. A "therapeutically effective amount" refers to the minimum amount of an active compound that achieves treatment. For example, a therapeutically effective amount of a compound of the present disclosure when used to treat a disease is an amount that substantially stops, slows, or reverses the progression of the disease or any associated symptoms. For example, a therapeutically effective amount of a compound of the present disclosure when used to treat cancer is an amount that can slow the progression of the cancer, reduce the number of cancer cells in a fluid (e.g., blood, peripheral blood, or lymph), reduce tumor size, prevent metastasis, prevent tumor growth, and / or ameliorate one or more symptoms of the cancer. Efficacy in treating cancer can be measured, for example, by assessing tumor size and number, assessing the time to disease progression, and / or determining the response rate. As used herein, "disease" can include a disease or a disorder.

[0166] The present disclosure also provides compositions comprising a compound of Formula (I)-(III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275. Such compositions may contain a pharmaceutically acceptable carrier, optionally with other pharmaceutically inactive or active ingredients. In another embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, is present in a single composition. In a further embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, is combined with one or more other therapeutic agents, as described below. Compositions of the present disclosure for use in or intended for the treatment of a subject are also contemplated and may be referred to as "formulations" or "pharmaceutical compositions."

[0167] The compositions of the present disclosure comprise one or more of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, in an amount effective to treat a disease characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of Erk1 / 2. The dose at which a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, achieves a therapeutic effect depends on factors such as the patient's age, weight, and sex, and the route of delivery. Treatment and administration of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, e.g., Examples 302, 349, or 275, may be administered in unit dosage form, and it is contemplated that one of skill in the art will adjust the unit dosage form accordingly to reflect the desired relative activity level. The determination of the specific dosage to be utilized (and the number of times such dosage should be administered per time unit) is within the discretion of a skilled physician and may be varied by titration of the dosage to a particular situation to achieve the desired therapeutic effect. In one embodiment, the therapeutically effective amount is about 0.01 mg / kg to 10 mg / kg. In another embodiment, the therapeutically effective amount is about 5 g / kg, about 500 mg / kg, about 400 mg / kg, about 300 mg / kg, about 200 mg / kg, about 100 mg / kg, about 50 mg / kg, about 25 mg / kg, about 10 mg / kg, about 1 mg / kg, about 0.5 mg / kg, about 0.25 mg / kg, about 0.1 mg / kg, about 100 μg / kg, about 75 μg / kg, about 50 μg / kg, about 25 μg / kg, about 10 μg / kg, or about 1 μg / kg or less. The therapeutically effective amount of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, will be determined by the treating physician and may depend on the disease being treated, the compound being administered, the route of delivery, the patient's age, weight, severity of symptoms, and response pattern.

[0168] In one embodiment, a therapeutically effective amount of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, can be from about 80 mg to about 350 mg. In one embodiment, a therapeutically effective amount of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, can be from about 120 mg to about 250 mg. In one embodiment, a therapeutically effective amount of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, may be about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, or about 350 mg. In one embodiment, a therapeutically effective amount of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, may be about 80 mg, about 120 mg, about 180 mg, about 250 mg, or about 350 mg. In one embodiment, a therapeutically effective amount of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, may be about 120 mg, about 180 mg, or about 250 mg. In one embodiment, a therapeutically effective amount of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, may be about 250 mg.

[0169] The therapeutically effective amount described herein refers to the total amount administered over a given period of time. That is, if more than one compound of formula (I-III), or a pharmaceutically acceptable salt, prodrug, or solvate thereof, such as Examples 302, 349, or 275, is administered, the therapeutically effective amount corresponds to the total amount administered over a given period of time.

[0170] In one embodiment, the therapeutically effective amount in one or more administrations may be greater than the therapeutically effective amount in one or more subsequent administrations. In another embodiment, the therapeutically effective amount in one or more administrations may be less than the therapeutically effective amount in one or more subsequent administrations. In one embodiment, the therapeutically effective amount may comprise 250 mg in one or more administrations and 180 mg, 120 mg, or a combination thereof in one or more subsequent administrations. In one embodiment, the therapeutically effective amount may comprise 250 mg in one or more administrations and 120 mg in one or more subsequent administrations. In one embodiment, the therapeutically effective amount may comprise 120 mg in one or more administrations and 180 mg, 250 mg, or a combination thereof in one or more subsequent administrations. In one embodiment, the therapeutically effective amount may comprise 180 mg in one or more administrations and 250 mg in one or more subsequent administrations.

[0171] Pharmaceutical compositions containing a compound of Formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, may be formulated neat or with one or more pharmaceutically acceptable carriers for administration. The amount of pharmaceutical carrier is determined by the solubility and chemical properties of the compound of Formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, the selected route of administration, and standard pharmaceutical practice. Pharmaceutical carriers may be solid or liquid, or may incorporate both solid and liquid carriers. A variety of suitable liquid carriers are known and can be readily selected by one of ordinary skill in the art. Such carriers include, for example, DMSO, saline, buffered saline, hydroxypropyl cyclodextrin, and mixtures thereof. Similarly, a variety of solid carriers and excipients are known to those skilled in the art. The compounds of formula (I-III), or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, such as Examples 302, 349, or 275, can be administered by any suitable route, taking into consideration the particular conditions under which the route is selected. The compounds of formula (I-III), or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, such as Examples 302, 349, or 275, can be administered, for example, orally, by injection, inhalation (including oral, nasal, and intratracheal), intraocularly, intradermally, intravascularly, subcutaneously, intramuscularly, sublingually, intracerebrally, epidurally, rectally, or vaginally, among others.

[0172] A compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, may be administered alone or with one or more physiologically compatible pharmaceutical carriers. The carrier may be in dry or liquid form and must be pharmaceutically acceptable. Liquid pharmaceutical compositions are generally sterile solutions or suspensions. When used for parenteral administration, the liquid carrier is preferably a sterile liquid. Liquid carriers are generally used in preparing solutions, suspensions, emulsions, syrups, and elixirs. In one embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, is dissolved in a liquid carrier. In another embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, is suspended in a liquid carrier. One skilled in the art in formulation can select an appropriate liquid carrier depending on the route of administration.

[0173] The compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, e.g., Examples 302, 349, or 275, may alternatively be formulated in a solid carrier. In one embodiment, the composition may be compressed into a unit dosage form, i.e., a tablet or caplet. In another embodiment, the composition may be added to a unit dosage form, i.e., a capsule. In a further embodiment, the composition may be formulated for administration as a powder. The solid carrier may perform a variety of functions, i.e., may perform the functions of two or more of the excipients described below. For example, the solid carrier may further act as a flavoring agent, lubricant, solubilizer, suspending agent, filler, glidant, compression aid, binder, disintegrant, or encapsulating material.

[0174] The composition may be subdivided to contain appropriate quantities of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275. For example, the unit dose may be a packaged composition, such as a packeted powder, vial, ampoule, pre-filled syringe, or sachet containing a liquid.

[0175] Examples of excipients that may be combined with one or more compounds of Formula (I-III), or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, such as Examples 302, 349, or 275, include, but are not limited to, adjuvants, antioxidants, binders, buffers, coatings, colorants, compression aids, diluents, disintegrants, emulsifiers, emollients, encapsulating materials, fillers, flavorings, glidants, bulking agents, lubricants, metal chelators, osmotic pressure adjusting agents, pH adjusting agents, preservatives, solubilizers, sorbents, stabilizers, sweeteners, surfactants, suspending agents, syrups, thickeners, and viscosity modifiers. See, for example, "Handbook of Pharmaceutical Excipients," 5 th Edition, Eds.: Rowe, Sheskey, and Owen, APhA Publications (Washington, DC), December 14, 2005.

[0176] In one embodiment, the compositions of the present disclosure may be utilized as inhalants. For this route of administration, the compositions may be prepared as unit-dose fluids using a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, and a vehicle for delivery by nebulizer spray pump or dry powder for insufflation.

[0177] In another embodiment, the composition may be utilized as an aerosol, i.e., oral or nasal aerosol. For this route of administration, the composition is formulated for use in a pressurized aerosol container with a gaseous or liquefied propellant, such as dichlorodifluoromethane, carbon dioxide, nitrogen, propane, etc. Additionally, delivery of a metered dose in one or more doses is also provided.

[0178] In another embodiment, the composition may be administered by a continuous delivery device. "Continuous delivery," as used herein, refers to the delivery of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, which delivery is delayed or otherwise controlled. Suitable continuous delivery formulations or devices are known to those skilled in the art. For use with such continuous delivery devices, the compound of Formula (I-III) can be formulated as described herein.

[0179] In one embodiment, the composition of the present disclosure is in the form of a tablet comprising at least one compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, and a pharmaceutically acceptable carrier.

[0180] In one embodiment, the composition of the present disclosure is in the form of a tablet comprising a compound of Formula (I), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, e.g., Examples 302, 349, or 275, and pharmaceutically acceptable excipients. In one embodiment, the tablet comprises granules comprising a compound of Formula (I), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, e.g., Examples 302, 349, or 275, hydroxypropyl cellulose, crospovidone, and microcrystalline cellulose. In one embodiment, the granules are prepared by dry granulation. In one embodiment, the granules are milled and combined with an extragranular excipient, e.g., magnesium stearate, and compressed into a tablet. In one embodiment, the tablet is coated with OPADRY® II White. In one embodiment, the composition is in the form of a tablet comprising a mandelate salt of a compound of Formula (I), and pharmaceutically acceptable excipients. In one embodiment, the composition is in the form of a tablet comprising the besylate salt of the compound of formula (I) and pharmaceutically acceptable excipients.

[0181] In one embodiment, the composition is in the form of a tablet comprising a compound of Formula (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, e.g., Examples 302, 349, or 275, and pharmaceutically acceptable excipients. In one embodiment, the tablet comprises granules comprising a compound of Formula (II), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, e.g., Examples 302, 349, or 275, hydroxypropyl cellulose, crospovidone, and microcrystalline cellulose. In one embodiment, the granules are prepared by dry granulation. In one embodiment, the granules are milled and combined with an extragranular excipient, e.g., magnesium stearate, and compressed into a tablet. In one embodiment, the tablet is coated with OPADRY® II White. In one embodiment, the composition is in the form of a tablet comprising a mandelate salt of a compound of Formula (II), and pharmaceutically acceptable excipients. In one embodiment, the composition is in the form of a tablet comprising the besylate salt of the compound of formula (II) and pharmaceutically acceptable excipients.

[0182] In one embodiment, the composition is in the form of a tablet comprising a compound of Formula (III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, and pharmaceutically acceptable excipients. In one embodiment, the tablet comprises granules comprising a compound of Formula (III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, hydroxypropyl cellulose, crospovidone, and microcrystalline cellulose. In one embodiment, the granules are prepared by dry granulation. In one embodiment, the granules are milled and combined with an extragranular excipient, such as magnesium stearate, and compressed into a tablet. In one embodiment, the tablet is coated with OPADRY® II White. In one embodiment, the composition is in the form of a tablet comprising a mandelate salt of a compound of Formula (III), and pharmaceutically acceptable excipients. In one embodiment, the composition is in the form of a tablet comprising a besylate salt of a compound of Formula (III), and pharmaceutically acceptable excipients.

[0183] In one embodiment, the composition of the present disclosure comprises: (S)-1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, 1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, 1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, 1-(2-((2,3-dihydro-benzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydro-benzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, 1-(2-(chroman-6-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (R)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-(2-hydroxy-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-(((1H-pyrrol-2-yl)methyl)amino)-1-(3-chlorophenyl)-ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-(tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-((2-hydroxyethyl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, and N-(3-chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, and a pharmaceutically acceptable carrier. For example, the composition of the present disclosure comprises (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate or (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate, and a pharmaceutically acceptable carrier. In another embodiment, a composition of the disclosure comprises (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate or (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate and a pharmaceutically acceptable carrier, further comprising pharmaceutically acceptable ingredients and additional therapeutic agents.

[0184] In one embodiment, the composition of the present disclosure is in the form of a tablet comprising (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In one embodiment, the tablet comprises granules comprising (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide or a pharmaceutically acceptable salt thereof, hydroxypropyl cellulose, crospovidone, and microcrystalline cellulose. In one embodiment, the granules are prepared by dry granulation. In one embodiment, the granules are prepared by dry granulation. In one embodiment, the granules are milled, combined with an extragranular excipient, such as magnesium stearate, and compressed into tablets. In one embodiment, the tablets are coated with OPADRY® II White.

[0185] In one embodiment, the composition is in the form of a tablet comprising (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate and pharmaceutically acceptable excipients. In one embodiment, the tablet comprises granules comprising (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate, hydroxypropyl cellulose, crospovidone, and microcrystalline cellulose. In one embodiment, the granules are produced by dry granulation. In one embodiment, the granules are produced by dry granulation. In one embodiment, the granules are milled, combined with an extragranular excipient, such as magnesium stearate, and compressed into tablets. In one embodiment, the tablets are coated with OPADRY® II White.

[0186] In one embodiment, the composition is in the form of a tablet comprising (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide besylate and pharmaceutically acceptable excipients. In one embodiment, the tablet comprises granules comprising (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide besylate, hydroxypropyl cellulose, crospovidone, and microcrystalline cellulose. In one embodiment, the granules are produced by dry granulation. In one embodiment, the granules are produced by dry granulation. In one embodiment, the granules are milled, combined with an extragranular excipient, such as magnesium stearate, and compressed into tablets. In one embodiment, the tablets are coated with OPADRY® II White.

[0187] In addition to the components described above for use in the compositions of the present disclosure, the compositions and kits described herein may include one or more drugs or therapeutic agents in addition to a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, e.g., Examples 302, 349, or 275. In one embodiment, the compositions and kits described herein may include one or more additional drugs or therapeutic agents used in the treatment of cancer, e.g., cancers characterized by solid tumors, "liquid" or "non-solid" tumor cancers (e.g., lymphomas). In one embodiment, the additional drug is a chemotherapeutic agent. Examples of chemotherapeutic agents include the compounds of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, e.g., Examples 302, 349, or 275. thEdition, Thomson Reuters, 2010. Therapeutically effective amounts of additional drugs or therapeutic agents are well known to those skilled in the art, and it is within the purview of the attending physician, who is skilled in the art, to determine, for example, the amount of other drug to be delivered.

[0188] A compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, and / or an additional drug or therapeutic agent may be formulated and administered in a single composition. However, the present disclosure is not limited to such an embodiment. In other embodiments, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, may be administered in one or more compositions separate from other compounds of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, and / or other therapeutic agents (including chemotherapeutic agents), if desired.

[0189] Further provided herein is a kit or package comprising a compound of Formula (I-III) as described herein, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition of a compound of Formula (I-III) or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof. The kit may be organized and / or include instructions indicating which composition or combination of compositions to take at desired time intervals.

[0190] In some embodiments, the kit includes a package or container with a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof formulated for a desired delivery route. In some embodiments, the kit includes instructions for use and, optionally, a package insert for the active ingredient. In other embodiments, the kit may further include instructions for monitoring circulating levels of a compound of Formula (I-III), such as Examples 302, 349, or 275, and, optionally, materials for conducting such an assay, such as reagents, well plates, containers, markers, labels, etc. Such kits are readily packaged in a manner suitable for treating the desired indication. For example, the kit may include instructions for use of a spray pump or other delivery device. Other appropriate components for including such kits will be readily apparent to those skilled in the art, taking into account the desired indication and delivery route.

[0191] The compounds of formula (I-III) described herein, or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, such as Examples 302, 349, or 275, or compositions thereof, can be formulated and administered as a single dose, or for continuous or cyclic intermittent administration. For continuous administration, the disclosed dosing regimens, methods of treatment, packages, or kits include individual dosage units (e.g., solutions, lotions, tablets, pills, or other units described above or utilized for drug delivery) of the compounds of formula (I-III) or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, such as Examples 302, 349, or 275, and may optionally include instructions for daily, weekly, biweekly, or monthly administration, or for administration for a predetermined period or as prescribed. When a compound of formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, is delivered periodically in an intermittent manner according to the present treatment method or dosing regimen, the package or kit containing the compound of formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, may include a placebo to be administered to the subject during the periods when the compound of formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, is not administered. When varying concentrations of the composition, components of the composition, or relative ratios of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, e.g., Examples 302, 349, or 275, over time are desired, a package or kit may include a series of dosage units that provide the desired variability when administered according to the treatment methods or dosing regimens of the present disclosure.

[0192] Many packages or kits for periodic medication dispensing, including periodic oral use, are known in the art. In one embodiment, the package has indicators for each period. In another embodiment, the package is a labeled blister pack, a dial dispenser package, or a bottle.

[0193] The packaging means of the kit may be designed as, for example, an inhaler, syringe, pipette, eyedropper, or other device for administering the pharmaceutical agent, from which a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, may be applied or delivered to an affected area of ​​a subject's body (such as the lungs), injected into the subject, or even applied to and mixed with other kit components prior to or simultaneously with administration to the subject, all in accordance with the treatment methods or administration regimens of the present disclosure.

[0194] The compound of formula (I-III) or its pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer, e.g., Examples 302, 349, or 275, or a composition thereof, included in the kit of the present disclosure may be provided in a dried or lyophilized form. When the compound or composition of the present disclosure is provided in a dried or lyophilized form, reconstitution is generally achieved by the addition of a suitable solvent, such as water or saline. It is contemplated that the solvent may be provided in the kit of the present disclosure or in a separate package.

[0195] Kits of the present disclosure may include a means for containing the vials or other containers in close confinement for sale, such as a syringe or blow-molded plastic container into which the desired vials or other containers are retained. Regardless of the number or type of packages or containers as discussed above, the kit may further include or be packaged with a separate device to aid in the injection / administration or placement of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, into the body of a subject. Such a device may be an inhaler, syringe, pipette, forceps, measuring spoon, eyedropper, or any suitable delivery means.

[0196] In one embodiment, the kit of the present disclosure may optionally include instructions for administering a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, to a subject suffering from a disease characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of Erkl / 2. In another embodiment, the kit of the present disclosure may include instructions for administering a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, to a subject suffering from a disease characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of Erkl / 2.

[0197] In further embodiments, a kit is provided that includes a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, in a second dosage unit, and one or more of the above-mentioned carriers or excipients in a third dosage unit. The kit may optionally include instructions for administering the agent and a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, to a subject with a disease or disorder characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or a disease or disorder treatable by inhibition of Erk 1 / 2.

[0198] The compounds described herein, e.g., Examples 302, 349, or 275, are useful for modulating diseases associated with the RAS / RAF / MEK / ERK pathway or treatable by inhibition of Erk 1 / 2. In one embodiment, the disease is associated with abnormal cell proliferation. The term "abnormal cell proliferation" refers to the uncontrolled growth of cells normally present in a mammalian body. In one embodiment, diseases characterized by abnormal cell proliferation include cancer of the prostate, head, neck, eye, mouth, throat, esophagus, bronchi, larynx, pharynx, breast, bone, lung, colon, rectum, stomach, bladder, uterus, cervix, breast, ovaries, vagina, testes, skin, thyroid, blood, lymph nodes, kidney, liver, intestine, pancreas, brain, central nervous system, adrenal gland, skin, salivary gland, small intestine, bile duct, leukemia, lymphoma, non-small cell lung cancer (NSCLC), colon cancer, endometrial cancer, oropharyngeal cancer, or gastric cancer. In one embodiment, the disease characterized by abnormal cell proliferation is melanoma, skin cancer, lung cancer, colon cancer, breast cancer, or prostate cancer. In another embodiment, the abnormal cell proliferation is associated with a solid tumor or a blood cancer.In one embodiment, the disease is colon Ca BRAF 506, colon Ca BRAG Gly12Asp(GGT>GAT)V, WT KRAS, colon Ca KRAS G12 any, endometrial KRAS G12 any, pancreatic Ca KRAS G12 any, melanoma NRAS Q61 any, colon Ca BRAG V600E:NRAS TW, KRAS WT, colon Ca KRAS Gly12Asp(GGT>GAT), gastric cancer RAS / RAF wt, melanoma NF1, colon Ca NRAS G13 any, colon Ca BRAF V600E, gallbladder Ca NF1 loss, pancreatic BRAF FRY-BRAF, ovarian-LGSC KRAS G12 any, melanoma BRAF, prostate Ca BRAF K601E, pharynx ACC BRAF D594N, melanoma NRAS Q61 any, colon Ca KRAS G13 any, prostate Ca BRAF, NSCLC BRAF G466V, salivary gland Ca HRAS, melanoma BRAF-nm004333 rearrangement, skin SCC BRAF-SGCE translocation, thyroid cancer (MTC) HRAS Q61R, melanoma BRAF, thyroid Ca NRAS Q61, melanoma GNA11 Q209L, melanoma, eye GNA11 Q209L, prostate Ca MAP3K1, small intestine Ca BRAF K601E, melanoma BRAF N581F, prostate Ca BRAF K601E, thyroid Ca BRAF V600E, melanoma NRAS Q61 any, NSCLC BRAF fusion, ovarian Ca KRAS, NSCLC BRAF(K601E), ovarian Ca BRAF, PIK3CA, colon Ca NRAS G12 any, KRAS G12 any, melanoma NRAS Q61 any, bile duct KRAS G12 any, and / or ovarian Ca RAS / RAF wt.

[0199] The term "modulation," or variations thereof, as used herein, refers to the ability of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, to modulate one or more components of a biological pathway. In one embodiment, "modulation" refers to inhibition of ERK1 / 2 activity. In another embodiment, modulation includes inhibition of the RAS / RAF / MEK / ERK pathway.

[0200] The activity of compounds of Formula (I-III), or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, such as Examples 302, 349, or 275, has been established multiple times in in vitro and in vivo assays. For example, compounds of the present disclosure have been demonstrated to cause inhibition of ERK1 and ERK2 enzyme activity in biochemical assays using homogeneous time-resolved fluorescence (HTRF) technology, with representative data shown in Table 3. Furthermore, compounds of the present disclosure have been found to be active in cell-based mechanistic assays. That is, compounds of the present disclosure have been demonstrated to inhibit phosphorylation of RSK1 (S380) (a downstream protein target of ERK1 / 2) by enzyme-linked immunosorbent assay (ELISA). Representative data are shown in Table 3. The functional utility of compounds of Formula (I-III), or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, such as Examples 302, 349, or 275, is demonstrated by their activity in in vitro tumor cell proliferation assays in a panel of tumor cell lines with mutations in the RAS / BRAF / MEK / ERK pathway. Representative data is shown in Table 3. Compounds of Formula (I-III), or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, exhibit ERK1 / 2 inhibitory activity and can be used to inhibit abnormal cell proliferation in which the RAS / RAF / MEK / ERK pathway plays a role. Thus, compounds of Formula (I-III), or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, such as Examples 302, 349, or 275, are effective in treating diseases such as cancer associated with the aberrant cell proliferation effects of RAS / RAF / MEK / ERK dysregulation. Those skilled in the art will recognize that a correlation has been established between activity in in vitro tumor cell proliferation assays and anti-tumor activity in a clinical setting.For example, the therapeutic utility of various pharmaceutical agents, such as taxol (Silvestrini, Stem Cells, 1993, 11(6):528-535), taxotere (Bissery, Anti Cancer Drugs, 1995, 6(3):330), and topoisomerase inhibitors (Edelman, Cancer Chemother. Pharmacol., 1996, 37(5):385-39), has been demonstrated using in vitro tumor growth assays.

[0201] In one embodiment, there is provided a method of modulating the RAS / RAF / MEK / ERK pathway or inhibiting Erk 1 / 2, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Example 302, 349, or 275, or a composition thereof.

[0202] In another embodiment, there is provided a method for treating a disease or disorder characterized by abnormal cell proliferation resulting from dysregulation of the RAS / RAF / MEK / ERK pathway, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof.

[0203] In a further embodiment, there is provided a method of treating a disease or disorder treatable by inhibition of ERK1 / 2, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof.

[0204] A therapeutically effective amount of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, may be administered on a regular schedule, such as daily, weekly, biweekly, every two weeks, monthly, bimonthly, or yearly, or on an irregular schedule, with administration varying within 12 or 24 hours, days, weeks, or months. In one embodiment, a regular schedule may refer to approximately similar intervals. In one embodiment, an irregular schedule may refer to varying intervals. In one embodiment, the therapeutically effective amount to be administered may vary. In one embodiment, the therapeutically effective amount in one or more administrations, e.g., the first administration, is greater than the therapeutically effective amount in one or more subsequent administrations. In another embodiment, the therapeutically effective amount in one or more administrations, e.g., the first administration, is less than the therapeutically effective amount in one or more subsequent administrations. Equivalent doses may be administered over various time periods, including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every 2 weeks, about every 3 weeks, about every month, and about every 2 months. The number and frequency of administrations that constitute a complete course of treatment are generally determined according to the judgment of a medical professional. A therapeutically effective amount as used herein refers to the total amount administered in a given period of time. That is, when more than one compound of Formula (I-III) or a pharmaceutically acceptable salt, prodrug, or solvate thereof, such as Examples 302, 349, or 275, is administered, the therapeutically effective amount corresponds to the total amount administered in a given period of time.

[0205] In one embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, can be administered to a subject on a regular or irregular dosing schedule. A regular schedule can consist of approximately equal intervals, while an irregular schedule can consist of intervals of different lengths. In a further embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, can be administered to a subject on a regular or irregular schedule, such as about once a week, about once every two weeks, about once every three weeks, about once a month, or about once every two months. In one embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, can be administered to a subject about once per week on a regular or irregular schedule. In one embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, can be administered to a subject about once per week on a regular schedule. The number and frequency of administrations that represent a complete course of treatment can be determined according to the judgment of a healthcare professional.

[0206] In one embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, can be administered to a subject in need thereof in an amount of about 80 mg once a week, about 120 mg once a week, about 180 mg once a week, about 250 mg once a week, or about 350 mg once a week, using a regular or irregular schedule. In one embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, can be administered to a subject in need thereof in an amount of about 120 mg once a week, about 180 mg once a week, or about 250 mg once a week, using a regular or irregular schedule. In one embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, can be administered to a subject in need thereof in an amount of about 250 mg once a week using a regular or irregular schedule. In one embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, can be administered to a subject in need thereof in an amount of about 250 mg once a week using an irregular schedule.

[0207] Therapeutically effective amounts of a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, e.g., Examples 302, 349, or 275, or compositions thereof, and dosing regimens disclosed herein, improve the safety profile, PK profile, rash profile (e.g., reduced rash), and / or increase the on-target residence time, resulting in broader activity in KRAS and BRAF models, including PDX models resistant to BRAF inhibitors and MEK inhibitors (e.g., as shown in Figures 1-7).

[0208] In one embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, e.g., Examples 302, 349, or 275, or a composition thereof, can be formulated to achieve desired pharmacokinetic (PK) parameters, and the methods and dosing regimens disclosed herein can achieve these parameters, as shown, for example, in Example 39 and Figures 6-7. In one embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, e.g., Examples 302, 349, or 275, or a composition thereof, exhibits the following PK parameters after administration of the compound or composition: * ng / mL~about 6120h * ng / mL, about 1100~5100h * ng / mL, about 2480~3720h * ng / mL, or approximately 3100 h * AUC in ng / mL tau , about 68 ng / mL to about 2330 ng / mL, about 85 to about 1940 ng / mL, about 584 to about 876 ng / mL, or about 730 ng / mL C max , about 11 ng / mL to about 48 ng / mL, about 14 to about 40 ng / mL, about 20 to about 30 ng / mL, or about 25 ng / mL C min It can be formulated in an amount of 120 mg QW to achieve one or more of the following:

[0209] In one embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, exhibits the following PK parameter after administration of the compound or composition: * ng / mL~approx. 7080h * ng / mL, about 1490~5900h * ng / mL, about 2400~3600h * ng / mL, or approximately 3000h * AUC in ng / mL tau, about 80 ng / mL to about 1520 ng / mL, about 100 to about 430 ng / mL, about 184 to about 276 ng / mL, or about 230 ng / mL C max , about 0.8 ng / mL to about 23 ng / mL, about 1.1 to about 19 ng / mL, about 4.8 to about 7.2 ng / mL, or about 5.6 ng / mL C min It can be formulated in an amount of 180 mg QW to achieve one or more of the following:

[0210] In one embodiment, a compound of Formula (I-III), or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Examples 302, 349, or 275, or a composition thereof, exhibits the following PK parameter after administration of the compound or composition: * ng / mL~approx. 18,120h * ng / mL, about 2300~15,100h * ng / mL, about 4400~6600h * ng / mL, or approximately 5500 h * AUC in ng / mL tau , about 128 ng / mL to about 960 ng / mL, about 160 to about 800 ng / mL, about 400 to about 600 ng / mL, or about 500 ng / mL C max , about 0.4 ng / mL to about 60 ng / mL, about 0.5 to about 50 ng / mL, about 6.9 to about 10.3 ng / mL, or about 8.6 ng / mL C min It can be formulated in an amount of 250 mg QW to achieve one or more of the following:

[0211] The compound of formula (I-III), or its pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer, for example, Example 302, 349, or 275, has been demonstrated to inhibit in vivo tumor growth when administered to human tumor xenograft models, such as the A375 human melanoma xenograft model with B-RAF V600E mutation, the HT-29 human colon cancer xenograft model with B-RAF V600E mutation, the HCT116 human colon cancer xenograft model with KRAS mutation, the A549 human lung carcinoma xenograft model with KRAS mutation, and the BxPC3 human pancreatic carcinoma xenograft model.The compound has also been demonstrated to inhibit the phospho-RSK level of tumors in the A375 xenograft model upon administration of the compound, thereby demonstrating the effective in vivo inhibition of target protein RK1 / 2 by the compound of the present disclosure. Those skilled in the art will recognize that the correlation between activity in human tumor xenograft models and anti-tumor activity in the clinical setting has been established.

[0212] Compounds of formula (I-III), or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, such as Examples 302, 349, or 275, have particularly promising utility and can be identified by the assays described herein. For example, compounds of formula (I-III), or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, such as Examples 302, 349, or 275, exhibit IC<0.05 in the ERK1 / 2 biochemical assay. 50 IC values ​​below 100 nM in phospho-RSK1 and cell proliferation assays 50 These compounds have been shown to have a potency of 500 nM and produce tumor growth inhibition of 40% or greater in one or more human tumor xenograft models, and would be identified as particularly useful compounds of the present disclosure.

[0213] As can be seen in Examples 36-39 below, compounds of Formula (I-III), or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, e.g., Examples 302, 349, or 275, when administered at extended intervals, such as weekly, biweekly, or every two weeks, can provide clinical efficacy equivalent to or greater than once-daily administration. See Figure 1 and Table 4. These data demonstrate that administration of the compound of Example 302 at extended intervals (i.e., weekly, biweekly, or every two weeks) provides activity equivalent to once-daily administration.

[0214] The efficacy of compounds of Formula (I-III), or pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers thereof, such as Examples 302, 349, or 275, when administered once daily, once weekly, every other week, or every two weeks, was further observed in the clinical trial summarized in Example 39. When (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate (Example 349) was administered once daily at 10 mg to 80 mg to cancer patients, a best response of stable disease was observed in 5 of 17 evaluable patients. When the compound of Example 349 was administered once weekly at doses ranging from 80 mg to 350 mg, a best partial response was observed in four patients, one of whom achieved complete remission of target lesions. A best stable disease response was observed in an additional 14 patients out of 30 evaluable patients, for an overall response rate. These data suggest that the compound of Example 349 can provide clinical efficacy equivalent to or greater than that achieved by once-daily administration when administered more frequently than once daily (i.e., once weekly, every other week, or every two weeks).

[0215] In one embodiment, a method for treating a disease characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of ERK1 / 2 comprises administering to a subject in need thereof a composition comprising a therapeutically effective amount of at least one compound of Formula (I-III) as defined in each of the preceding embodiments, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Example 302, 349, or 275. In one embodiment, the present disclosure provides a composition comprising a therapeutically effective amount of at least one compound of Formula (I-III) as defined in each of the preceding embodiments, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, such as Example 302, 349, or 275, for use in treating a disease characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of ERK1 / 2, or the use of this composition in the manufacture of a medicament for such treatment. Additionally, in one embodiment, the disease treatable by the method or dosing regimen is cancer of the prostate, head, neck, eye, mouth, throat, esophagus, bronchi, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, bladder, uterus, cervix, breast, ovaries, vagina, testes, skin, thyroid, blood, lymph nodes, kidney, liver, intestine, pancreas, brain, central nervous system, adrenal gland, skin, leukemia, or lymphoma.

[0216] In one embodiment, a method for treating a disease characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of ERK1 / 2 comprises: (S)-1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, 1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, 1-(2-(benzofuran-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide, N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((3,4,5-trimethoxyphenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, 1-(2-((2,3-dihydro-benzofuran-5-yl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydro-benzo[b][1,4]dioxin-6-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((R)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, 1-(2-(chroman-6-ylamino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxy-ethyl)-1-(2-((4-fluoro-3-morpholinophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxy-ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((4-morpholinophenyl)amino)pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (R)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-fluoro-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-pyrrole-3-carboxamide, N-(2-hydroxy-1-(thiophen-2-yl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(2-(((1H-pyrrol-2-yl)-methyl)amino)-1-(3-chlorophenyl)-ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-(tetrahydrofuran-3-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-(methylamino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, (S)—N-(1-(3-chlorophenyl)-2-((2-hydroxyethyl)amino)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide, and N-(3-chloro-5-fluoro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, or stereoisomer thereof, e.g., Examples 302, 349, or 275, to a subject in need thereof. For example, a method for treating a disease characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of ERK1 / 2 comprises administering to a subject in need thereof a composition of the present disclosure comprising (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate or (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate and a pharmaceutically acceptable carrier.

[0217] In one embodiment, the compositions disclosed herein can be used to treat a disease characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of ERK1 / 2. In one embodiment, the disclosure provides for the use of the composition in the manufacture of a medicament for treating a disease characterized by dysregulation of the RAS / RAF / MEK / ERK pathway or treatable by inhibition of ERK1 / 2.

[0218] Compound Preparation Process Methods useful for preparing compounds of Formula (I-III), such as Examples 302, 349, or 275, are set forth in the Examples and generalized in the following Schemes. One of skill in the art will recognize that these Schemes are applicable to other compounds of Formula (I-III), and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers.

[0219] In the following reactions described for preparing the compounds described herein, it may be necessary to protect reactive functional groups desired in the final product, such as hydroxyl, amino, imino, thio, or carboxyl groups, to prevent their unwanted participation in the reaction. Conventional protecting groups can be used in accordance with standard practice; see, for example, Green et al., Protective Groups in Organic Chemistry, John Wiley & Sons, 1991.

[0220] The following schemes outline the synthesis of compounds of formula (I-III), such as Examples 302, 349, or 275. The examples that follow are illustrated as representative examples prepared in each scheme and are not intended to limit the scope of the disclosure.

[0221] Abbreviations used have the definitions indicated: MHz is megahertz (frequency), m is multiplet, t is triplet, d is quartet, s is singlet, br is broad, CDCl3 is deuterochloroform, calcd is yield, min is minute, h is hour, g is gram, mmol is millimole, mL is milliliter, N is normal (concentration), M is molar (concentration), μM is micromolar, ee is enantiomeric excess, °C is degrees Celsius, HPLC is high performance liquid chromatography, LC-MS is liquid chromatography mass spectrometry, mp is melting point, NMR is nuclear magnetic resonance imaging, TLC is thin layer chromatography, THF is tetrahydrofuran, MeOH is methanol, DCM is dichloromethane, DMF is N,N-dimethylformamide, DMSO is dimethylsulfoxide d) is ethyl alcohol, EtOH is ethyl alcohol, EtOAc is ethyl acetate, MeOH is methanol, RT is room temperature, HCl is hydrogen chloride or hydrochloric acid, TFA is trifluoroacetic acid, EtMgBr is ethylmagnesium bromide, n-BuLi is n-butyllithium, NaHCO3 is sodium bicarbonate, Na2CO3 is sodium carbonate, Na2SO4 is sodium sulfate, NMP is N-methyl-2-pyrrolidone, EDC or EDC.HCl is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, TEA is triethylamine, DIPEA is diisopropyl-ethylamine, HOBt is N-hydroxy-benzotriazole or N-hydroxy-benzotriazole hydrate, and T3P is propylphosphonic anhydride.

[0222] Scheme

[0223] [ka]

[0224] Scheme 1 depicts one synthetic method for preparing compounds of formula (I), where M is NH, Z=N, X=N, J=-CH(R 2 )- or -CH(R 2 )CH2-, R 2 =H, C 1-4 Alkyl, CH2OH, CH2OC 1-6Alkyl, or CH2N(C 1-6 In one embodiment, 4-nitropyrazole [A] is reacted with 2,4-dichloropyrimidine [B] to give pyrazolyl-pyrimidine [C]. This reaction is carried out in the presence of a base such as potassium carbonate in a suitable solvent such as acetone or dioxane. The reaction may also be carried out in an elevated solvent temperature up to reflux. Intermediate [C] is then reacted with an amine R 4 The amine intermediate [E] is then reacted with amine [F] to yield the compound of the present disclosure, i.e., urea (IA). The coupling reaction can be carried out in the presence of a palladium catalyst, such as Pd(dba) [tris(dibenzylideneacetone)-dipalladium(0)], BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), or potassium carbonate, in a suitable solvent, such as dioxane. The reaction can be carried out in a sealed glass tube at elevated temperatures, e.g., 90°C, in dioxane. Reduction of the nitro moiety in [D] then yields the amino-pyrazolyl intermediate [E]. This reduction process can be carried out in a solvent, such as THF:methanol (2:1), by reaction with zinc powder and ammonium chloride at temperatures between 0°C and 25°C. The amine intermediate [E] is then reacted with amine [F] to yield the compound of the present disclosure, i.e., urea (IA). The coupling reaction can be carried out using CDI (1,1'-carbonyldiimidazole) in a solvent, such as THF. The reaction can be carried out in THF under microwave irradiation at elevated temperatures, such as 85° C. to 120° C. This coupling reaction can also be carried out using 4-nitro-phenyl chloroformate, pyridine, and DIPEA (diisopropylethylamine) instead of CDI.

[0225] [ka]

[0226] Scheme 2 depicts an alternative synthetic method for preparing compounds of formula (I), in this example, where M is NH, Z=N, X=N, J=-CH(R 2 )- or -CH(R 2 )CH2-, R2 =H, C 1-4 Alkyl, CH2OH, CH2OC 1-6 Alkyl, or CH2N(C 1-6 In this example, intermediate [C] is prepared as described in Scheme 1 and then undergoes a reduction process to give amino-pyrazole [G]. This reduction process can be carried out by reaction with zinc powder and ammonium chloride in a solvent such as THF:methanol (2:1) at a temperature such as 0°C to 25°C. Amine intermediate [G] is then reacted with amine [F] to give urea intermediate [H]. This reaction can be carried out using 4-nitro-phenylchloroformate, pyridine, and DIPEA (diisopropylamine) in a suitable solvent such as DCM (dichloromethane) at a temperature such as 0°C to 25°C. Intermediate [H] is then converted to amine R 4 -NH2 to give compound (IA) of the present disclosure. This coupling reaction may be carried out in the presence of a palladium catalyst such as Pd2(dba)3, BINAP, and potassium carbonate in a suitable solvent such as dioxane. The reaction may be carried out in a sealed glass tube at elevated temperature, e.g., 90°C, in dioxane. As an alternative to the last step, intermediate [H] may be converted to amine R in ethanol or isopropanol, optionally in the presence of DIPEA, with warming in a sealed glass tube. 4 -NH2.

[0227] [ka]

[0228] Scheme 3 depicts one synthetic method for preparing compounds of formula (I), in this example, where M is a single bond, Z=N, J=-CH(R 2 )- or -CH(R 2 )CH2-, R 2 =H, C 1-4 Alkyl, CH2OH, CH2OC 1-6 Alkyl, or CH2N(C 1-6 alkyl)2, Y=CR 7In this example, 2,4-dichloropyrimidine or 2-chloro-4-bromopyrimidine [B] is reacted with a heterocyclic ester [J] to give intermediate [K]. This reaction can be carried out in the presence of a base, e.g., potassium carbonate, in a suitable solvent, such as acetonitrile. The reaction can also be carried out at elevated temperatures, up to reflux. Intermediate [K] can then be converted to an amine R 4 -NH2 to give intermediate [L]. This coupling reaction may be carried out in the presence of a palladium catalyst such as Pd2(dba)3, BINAP, potassium carbonate, or the like, in a suitable solvent such as dioxane. The reaction may be carried out in a sealed glass tube at elevated temperatures, e.g., 90-100°C, in dioxane. As an alternative method to give intermediate [L], intermediate [K] may be reacted with amine R in ethanol or isopropanol, optionally in the presence of DIPEA, with warming in a sealed glass tube. 4 The ester moiety in intermediate [L] is reacted with —NH2. For example, the ester moiety in intermediate [L] is hydrolyzed by treatment with aqueous sodium hydroxide or aqueous lithium hydroxide in a solvent such as methanol or THF at a temperature such as 0°C to 50°C to give the corresponding carboxylic acid [M]. Intermediate [M] is then coupled with an amine [F] to give a compound of the present disclosure, i.e., amide (IB). This amide coupling reaction can be carried out using the amide coupling reagent EDC [1-ethyl-3-(3-dimethylaminopropyl)carbodiimide], optionally in the presence of HOBt (1-hydroxybenzotriazole) and triethylamine, in a suitable solvent such as NMP (N-methyl-2-pyrrolidone). The reaction can be carried out at a temperature such as 0°C to 25°C. This coupling reaction can alternatively be carried out using N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethaneammonium hexafluorophosphate N-oxide (HATU) and N,N-diisopropylethylamine (DIPEA) in N,N-dimethylformamide (DMF).

[0229] The use of a variety of other amide coupling reagents known to those skilled in the art, such as T3P (propylphosphonic anhydride), is also contemplated.

[0230] [ka]

[0231] Scheme 3a represents a variation of Scheme 3, in which an amide coupling reaction with an amine [F] is first carried out, followed by reaction with a pyrimidine [B], and then with an amine R 4 Reaction with -NH2 provides the compound of the present disclosure, namely, the amide (IB).

[0232] [ka]

[0233] Scheme 4 depicts a synthetic method for preparing compounds of formula (I), wherein M is a single bond and R 2 =CH2NH2, Z=N, and X=CR 7 In this example, 2,4-dichloropyrimidine or 2-chloro-4-bromopyrimidine [B] is coupled with heterocyclic ester [N] to give intermediate [O] by a method similar to that described for the preparation of [K] in Scheme 3. Compound [O] is then converted to amine R by a method similar to that described for the preparation of [L] in Scheme 3. 4—NH to yield intermediate [P]. The ester moiety in [P] is hydrolyzed to yield the corresponding carboxylic acid [Q] by methods similar to those described for the preparation of [M] in Scheme 3. Intermediate [Q] is then reacted with an amine [R] to yield the amide [S] using an amide coupling method, such as that described for the preparation of (IB) in Scheme 3. Alternatively, the ester intermediate [P] can be directly converted to (S) by reaction with an amine [R] in the presence of trimethylaluminum in a suitable solvent, such as toluene. The reaction is carried out at temperatures such as 0° C. to 100° C., optionally with microwave irradiation. Reduction of the nitrile moiety in [S] is achieved by hydrogenation using Raney nickel in ammonia-methanol to yield the corresponding amine (IC), a compound of the present disclosure. This reaction is carried out, for example, at about room temperature for 16 hours at 25 psi of hydrogen.

[0234] [ka]

[0235] Scheme 5 depicts another method for synthesizing compounds of formula (I), in this example, where M is a single bond, Z=N, and J=—CH(R 2 )- or -CH(R 2 )CH2-, R 2 =H, C 1-4 Alkyl, CH2OH, CH2OC 1-6 Alkyl, or CH2N(C 1-6 alkyl)2, Y=N, X=CR 7 In this example, an aldehyde building block [T] is reacted with 2,4-dichloropyrimidine (or 2-chloro-4-bromopyrimidine) to prepare an aldehyde intermediate [U], which is then converted to the corresponding carboxylic acid intermediate [V] by methods known in the art. Intermediate [V] is then coupled with an amine [F] by an amide coupling method, such as that described in Scheme 3, to generate an amide intermediate [W]. [W] is then coupled to an amine R by methods such as those described for the formation of [L] in Scheme 3. 4-NH2 to give the compound (ID) of the present disclosure.

[0236] [ka]

[0237] Scheme 6 depicts another method for synthesizing compounds of formula (I), where M is a single bond, Z=N, J=-CH(R 2 )- or -CH(R 2 )CH2-, R 2 =H, C 1-4 Alkyl, CH2OH, CH2OC 1-6 Alkyl, or CH2N(C 1-6 alkyl)2, X=CR 7 In this example, intermediate [X] is prepared by a method similar to that used to prepare intermediate [P] in Scheme 4. The ester intermediate [X] is then reacted with an amine [F] in the presence of trimethylaluminum in a suitable solvent such as toluene. The reaction is carried out at temperatures such as 0°C to 100°C, optionally using microwave irradiation, to provide compounds (IE) of the present disclosure. This method involves the addition of R 4 There is particular utility when is optionally substituted alkyl.

[0238] [ka]

[0239] Scheme 7 depicts a method for preparing compounds of formula (I), in this example, where M is a single bond, Z=CH, J=-CH(R 2 )- or -CH(R 2 )CH2-, R 2 =H, C 1-4 Alkyl, CH2OH, CH2OC 1-6 Alkyl, or CH2N(C 1-6 alkyl)2, and X=CR 7 In this example, 2-amino-4-bromopyridine [Y] is converted to an iodo compound R in the presence of a palladium(0) catalyst. 4-I to give the pyridine intermediate [Z]. Intermediate [Z] is then reacted with a heterocyclic ester [AA] to give intermediate [AB]. This reaction is carried out in a sealed glass tube in the presence of copper(I) iodide, L-proline, and potassium phosphate in a solvent such as DMF at a temperature such as 25°C to 150°C. The ester moiety in intermediate [AB] is hydrolyzed by methods such as those described for the formation of [M] in Scheme 3, and the carboxylic acid intermediate [AC] is then reacted with [F] using an amide coupling method such as that described in Scheme 3 to give compound (IF) of the present disclosure. Alternatively, intermediate [AB] can be directly converted to (IF) using trimethylaluminum in a suitable solvent such as toluene using the method described in Scheme 6.

[0240] [ka]

[0241] Scheme 8 depicts a further method for preparing compounds of formula (I), in this example where M is a single bond, Z=CH, J=-CH(R 2 )- or -CH(R 2 )CH2-, R 2 =H, C 1-4 Alkyl, CH2OH, CH2OC 1-6 Alkyl, or CH2N(C 1-6 In this example, 2-chloropyridine [AD] is oxidized and nitrated to give the amine R 4 -NH2 to give the 4-nitro-pyridine N-oxide intermediate [AG]. The N-oxide and nitro moieties in [AG] are reduced, and the 4-amino group in the resulting [AH] is converted to a bromide moiety. The 4-bromo-pyridine intermediate [AI] is then reacted with an appropriate heterocycle, such as a pyrrole derivative [AJ], to give the compound (IG) of the present disclosure.

[0242] [ka]

[0243] Scheme 9 depicts a method for preparing compounds of formula (I), in which M is a single bond, Z=CH, and X=CR. 7 , J = -CH(R 2 )-, R 2 =CH2NH2. In this method, aspects of the general method depicted in Schemes 4 and 7 are utilized and combined to provide compounds (IH) of the present disclosure.

[0244] [ka]

[0245] Scheme 10 depicts a method for preparing compounds of formula (I), in this example, where M is a single bond, Z=CH, J=-CH(R 2 )- or -CH(R 2 )CH2-, R 2 =H, C 1-4 Alkyl, CH2OH, CH2OC 1-6 Alkyl, or CH2N(C 1-6 alkyl)2, and R 5 =Cl, X=CR 7 , where Y=N. In this method, 4-chloro-pyridine [AL] is converted in three steps to 3,4-dichloro-pyridine [AO], which is then converted in subsequent steps to compound (IJ) of the present disclosure using methods similar to those described in the above scheme.

[0246] [ka]

[0247] Scheme 11 depicts a method for preparing compounds of formula (I), in this example, where M is a single bond and Z=CH, R 2 =CH2NH2, X=CR 7, where Y=N. In this example, 2,4-dichloro-pyridine or 2-chloro-4-bromopyridine [AT] is reacted with a heterocyclic ester [AQ] in the presence of a base such as potassium carbonate in a suitable solvent such as DMF. The reaction may be carried out at room temperature to elevated temperatures, for example 100°C or reflux, for example. The 2-chloro-pyridine intermediate [AU] is then reacted with an amine R 4 The intermediate [AV] is reacted with —NH2 to give intermediate [AV]. This coupling reaction may be carried out in the presence of a palladium catalyst, such as Pd2(dba)3, BINAP, or potassium carbonate, in a suitable solvent, such as dioxane. This reaction may be carried out in a sealed glass tube at elevated temperatures, for example, 90°C in dioxane, or at 100°C using microwave irradiation. The ester moiety of intermediate [AV] is then hydrolyzed to give the corresponding carboxylic acid [AW] by treatment with aqueous sodium hydroxide in a solvent, such as methanol or THF, at temperatures, for example, between 0°C and 50°C. The carboxylic acid [AW] is then coupled with an amine [R] to give the amide [AX] using an amide coupling method, such as that described for the preparation of (IB) in Scheme 3. The nitrile moiety in [AX] is reduced by hydrogenation using Raney nickel in ammonia methanol to give the corresponding amine (IK), a compound of the present disclosure. This reaction is carried out, for example, at about room temperature for about 6-16 hours under 15 psi to 25 psi of hydrogen.

[0248] [ka]

[0249] Scheme 12 depicts a method for preparing a compound of formula (I), where M is a single bond, Z=CH, X=N, and Y=N. In this example, 2,4-dichloro-pyridine (or 2-chloro-4-bromopyridine) [AT] is reacted with sodium azide to give 4-azido-pyridine [AY], which is then condensed with methyl propiolate to give the triazole intermediate [AZ]. The ester moiety in intermediate [AZ] is hydrolyzed by a method such as that described in Scheme 11 to give the corresponding carboxylic acid, which is then reacted with an amine such as [F] using an amide coupling method such as that described in Scheme 10, or with an amine such as [R] using an amide coupling method such as that described in Scheme 11, to give a compound (IL) of the present disclosure.

[0250] [ka]

[0251] Scheme 13 depicts a method for preparing compounds of formula (I), in this example, where M is a single bond and Z=CH, R 5 =H, X=CR 7 In this example, 2-fluoro-4-iodo-pyridine [BA] is reacted with amine R 4The intermediate [BB] is then reacted with a heterocyclic ester [N] to give intermediate [BC]. The reaction can be carried out in a suitable solvent, such as DMF or NMP, at elevated temperatures, e.g., 90°C to 100°C, in a sealed glass tube. Intermediate [BB] is then reacted with a heterocyclic ester [N] to give intermediate [BC]. This reaction is carried out in a sealed glass tube in the presence of L-proline, copper(I) iodide, and a base, e.g., potassium carbonate, in a suitable solvent, e.g., DMF or NMP, at temperatures from 25°C to elevated temperatures, e.g., 100°C to 150°C. The ester moiety in intermediate [BC] is hydrolyzed by a method such as that described in Scheme 11 to give the corresponding carboxylic acid, which is then reacted with an amine, e.g., [F], using an amide coupling method, e.g., that described in Scheme 10, or with an amine, e.g., [R], using an amide coupling method, e.g., that described in Scheme 11, to give compound (IM) of the present disclosure.

[0252] Methods useful for the preparation of synthetic building blocks used in the synthesis of compounds of formula (I) are set forth in the following schemes. Those skilled in the art will recognize that these schemes are applicable to other compounds of formula (I), and their pharmaceutically acceptable salts, prodrugs, solvates, hydrates, or stereoisomers.

[0253] [ka]

[0254] [ka]

[0255] [ka]

[0256] [ka]

[0257] Examples of methods useful for preparing compounds such as (IN) and (IO) that can act as prodrugs of compounds of formula (I) are set forth below in Schemes 18 and 19. Those skilled in the art will recognize that these schemes can be adapted to produce additional compounds that can act as prodrugs of other compounds of formula (I).

[0258] [ka]

[0259] [ka]

[0260] [ka]

[0261] Scheme 20 depicts a further method for preparing compounds of formula (I), in this example where M is a single bond and R 2 =CH2NH2, Z=N, X=CR 7This method provides an alternative to the method described in Scheme 4. In this method, the amino-alcohol (in this example, a single enantiomer) [BD] is converted to an N-Boc-protected analog [BE] by standard methods, and the hydroxyl moiety is then converted to the corresponding methanesulfonate ester by reaction with methanesulfonyl chloride and trimethylamine in a solvent such as dichloromethane. This methanesulfonate compound [BF] is then reacted with sodium azide to produce the corresponding azide derivative [BG]. The azide reaction is carried out in a suitable solvent, such as DMF or NMP, and may be carried out at an elevated temperature, for example, about 50°C. The N-Boc group is then removed by standard methods, for example, treatment with 4M HCl in dioxane. The resulting amino azide compound [BH] is then coupled with intermediate [Q] to produce amide [BI] using an amide coupling method such as that described for the preparation of (IB) in Scheme 3. For example, reaction with zinc dust and ammonium chloride in a solvent such as methanol provided the azide moiety as a ring atom, in this example a compound of the present disclosure (IP), as a single enantiomer. Alternatively, the azide moiety can be reduced with triphenylphosphine in aqueous THF. [Example]

[0262] All reactions were carried out under a dry nitrogen and / or argon atmosphere unless otherwise specified. Unless otherwise specified, all raw starting materials, solvents, and reagents were purchased from commercial suppliers (e.g., Avocado Research Chemicals, Apollo Scientific Limited, Bepharma Ltd., Combi-Blocks Inc., Sigma Aldrich Chemicals Pvt. Ltd., Ultra Labs, Toronto Research Chemicals Inc., Chemical House, RFCL Limited, Spectro Chem Pvt. Ltd., Leonid Chemicals, Loba Chemie, Changzhou Yangyuan, NeoSynth., Rankem, etc.) and used directly without further purification, or the reagents can be synthesized by procedures known in the art. Generally, the progress of each reaction is monitored by TLC analysis.

[0263] Biotage Isolera® One and CombiFlash® (Teledyne Isco) Automated Flash Purification Systems were often used for the purification of crude products using the eluent combinations mentioned in each procedure. Flash chromatography was performed using silica gel (60-100, 100-200, and 230-400 mesh) from ChemLabs, with nitrogen and / or compressed air used to enable pressurized flow of eluent. Preparative thin-layer chromatography (preparative TLC) was performed using silica gel (GF 1500 μM 20 × 20 cm and GF 2000 μM 20 × 20 cm Prep-scored plates from Analtech, Inc., Delaware, USA). Analytical thin-layer chromatography (TLC) was performed using pre-coated silica gel sheets (Merck 60 F 254) for detection. Visual detection was performed using ultraviolet light, p-anisaldehyde stain, ninhydrin stain, dinitrophenylhydrazine stain, potassium permanganate stain, or iodine. Low-temperature reactions were performed using cold baths, e.g., H2O / ice at 0°C, and acetone / dry ice at -78°C. Microwave reactions were performed in a CEM Discover SP 909155 microwave oven. Melting points were determined using a LabIndia MR-VIS visual melting range apparatus. 1 H NMR spectra were recorded at 400 MHz using a Varian V400 spectrometer, Bruker 400 (unless otherwise specified) at ambient temperature, using tetramethylsilane as an internal standard. Chemical shift values ​​are quoted in δ (parts per million). Mass spectra of all intermediates and final compounds were recorded using an Acquity® UPLC-SQD (Waters) & Agilent 1290 Infinity® UHPLC equipped with a 6150 SQD machine. HPLC spectra were recorded using an Agilent 1290 Infinity® UHPLC and Alliance (Waters) system. LCMS spectra were recorded using an Agilent 1200® LCMS with diode array detector (DAD) detection LC-MS instrument, an Agilent 1290® UHPLC-SQD with a BEH C18 column and a Zorbax® HD C18 column (50 mm x 2.1 mm x 1.7 μm) and (50 mm x 2.1 mm x 1.8 μm), using a mobile phase of 0.01% formic acid and acetonitrile or 0.01% trifluoroacetic acid and acetonitrile, a flow rate of 0.3 mL / min, a column temperature of 70 or 50 °C, and a run time of 3 to 5 min. The purity of each final compound was determined using a Waters® PDA with SQD and Agilent® DAD with a 6150 SQD instrument under the following conditions:

[0264] Condition 1: Column: BEH C18 (Waters), Mobile phase: 0.01% acetic acid and acetonitrile & 0.01% acetic acid and methanol, Gradient: (B / %T): 0 / 0, 1.2 / 100, 2.5 / 100, 2.8 / 0, 3.0 / 0, Flow rate: 0.3 mL / min, Temperature: 70 °C, Run time: 3.0 min.

[0265] Condition 2: Column: Zorbax® HD C18, Mobile phase: 0.01% acetic acid and acetonitrile & 0.01% acetic acid and methanol, Gradient: (B / %T): 0 / 0, 2.5 / 100, 4.5 / 100, 4.8 / 0, 5.0 / 0, Flow rate: 0.3 mL / min, Temperature: 50°C, Run time: 5.0 min.

[0266] For use in preparing certain compounds of the present disclosure, the following intermediates were produced as follows.

[0267] Preparation 1: 2-amino-2-(3-chlorophenyl)acetonitrile

[0268] [ka]

[0269] A solution of 3-chlorobenzaldehyde (5 g, 35.0 mmol) in methanol (100 mL) was purged with ammonia gas at room temperature for 2 hours. The mixture was cooled to 0 °C, and trimethylsilyl cyanide (5.293 g, 53.0 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by gradient column chromatography using ethyl acetate in hexane as the eluent to give 2-amino-2-(3-chlorophenyl)acetonitrile as a yellow solid (4.8 g, 81% yield). H NMR (400 MHz, DMSO-d): δ 7.57 (s, 1H), 7.47-7.40 (m, 3H), 5.06 (s, 1H), 2.92 (s, 2H).

[0270] Preparation 2: 2-amino-3-phenylpropanenitrile

[0271] [ka]

[0272] To a stirred solution of 2-phenylacetaldehyde (10.0 g, 83.33 mmol) in MeOH (50 mL) was added NH3 and Ti(OiPr)4 (30.7 g, 108.33 mmol) in MeOH (80.0 mL), and the resulting solution was stirred at room temperature for 2 h. Trimethylsilyl cyanide (TMSCN) (14.88 g, 149.9 mmol) was then added to the reaction mixture, and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was quenched with water, and the resulting white precipitate was filtered off. The filtrate was concentrated under reduced pressure, combined with ethyl acetate, and washed with brine (2 × 15 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Combiflash eluting with MeOH in DCM to give 2-amino-3-phenylpropanenitrile (5.4 g, 45%). 1HNMR (400MHz, DMSO-d6): δ 7.37-7.21 (m, 5H), 3.93 (t, J = 7.2Hz, 1H), 3.33-3.23 (m, 2H), 2.36 (br s, 2H). LC-MS calcd exact mass 146.08,found m / z 147.04[M+H] + .

[0273] Representative Examples of Scheme 1:

[0274] Example 1: (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(2-chlorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea (Compound #2)

[0275] [ka]

[0276] Step 1: 2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine

[0277] [ka]

[0278] A reaction mixture of 4-nitro-1H-pyrazole (1.0 g, 8.8 mmol), 2,4-dichloro-5-methylpyrimidine (1.18 g, 7.96 mmol), potassium carbonate (3.6 g, 26.4 mmol), and acetone (30 mL) was warmed to 65 °C over 6 h. The reaction mixture was evaporated, and the residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, evaporated, and the residue was purified by column chromatography on silica gel using ethyl acetate in hexane as the eluent to give 2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine (0.73 g, 56%). H NMR (400 MHz, CDCl): 9.32 (s, 1H), 8.62 (s, 1H), 8.31 (s, 1H), 2.69 (s, 3H). LC-MS calcd exact mass 239.02,found m / z 240.1[M+H] + .

[0279] Step 2: N-(2-chlorophenyl)-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidin-2-amine

[0280] [ka]

[0281] A reaction mixture of 2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine (0.4 g, 1.67 mmol), 2-chloroaniline (0.19 mL, 1.84 mmol), potassium carbonate (0.34 g, 2.5 mmol), and dioxane (15 mL) in a glass tube was purged with nitrogen gas for 20 minutes. Tris(dibenzylideneacetone)dipalladium(0) (0.076 g, 0.083 mmol) and BINAP (0.103 g, 0.167 mmol) were added to the reaction mixture, which was purged with nitrogen gas for an additional 15 minutes. The tube was then sealed and heated at 90 °C for 4 hours. The reaction mixture was filtered through Celite, the filtrate was evaporated, and the residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, evaporated, and the residue was purified by column chromatography on silica gel using 20% ​​ethyl acetate in hexane as eluent to give N-(2-chlorophenyl)-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidin-2-amine (0.33 g, 60%). H NMR (400 MHz, DMSO-d): 9.23 (s, 1H), 9.17 (s, 1H), 8.61 (s, 1H), 8.54 (s, 1H), 7.78 (d, J = 8 Hz, 1H), 7.51 (d, J = 8 Hz, 1H), 7.35 (t, J = 8 Hz, 1H), 7.18 (t, 1H, J = 8 Hz), 2.38 (s, 3H). LC-MS calculated exact mass 330.06, found m / z 331.1 [M+H]. + .

[0282] Step 3: 4-(4-amino-1H-pyrazol-1-yl)-N-(2-chlorophenyl)-5-methylpyrimidin-2-amine

[0283] [ka]

[0284] A solution of the compound N-(2-chlorophenyl)-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidin-2-amine (0.33 g, 1.0 mmol) in THF:methanol (2:1) (10 mL) was cooled to 0 °C and zinc powder (0.39 g, 6.0 mmol) and ammonium chloride (0.43 g, 8.0 mmol) were added. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite, the filtrate was evaporated, and the residue was suspended in water and extracted with DCM. The organic layer was dried over sodium sulfate and evaporated to give 4-(4-amino-1H-pyrazol-1-yl)-N-(2-chlorophenyl)-5-methylpyrimidin-2-amine (0.24 g, 80%). This product was used in the next step without further purification. 1HNMR(400MHz,DMSO-d6):8.63(s,1H),8.26(s,1H),7.83(t,J=8Hz,1H),7.72(s,1H),7.48(d ,J=7.6Hz,1H),7.42(s,1H),7.38-7.32(m,1H),7.13-7.11(m,1H),4.39(s,2H),2.40(s,3H). LC-MS calcd exact mass 300.09,found m / z 301.1[M+H] + .

[0285] Step 4: (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(2-chlorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea

[0286] [ka]

[0287] A reaction mixture of 4-(4-amino-1H-pyrazol-1-yl)-N-(2-chlorophenyl)-5-methylpyrimidin-2-amine (0.15 g, 0.5 mmol), 1,1'-carbonyldiimidazole (0.32 g, 2.0 mmol), and THF (5 mL) in a CEM microwave vial was stirred at 85° C. for 20 minutes under CEM microwave. (S)-2-Amino-2-(3-chlorophenyl)ethanol (0.25 g, 1.5 mmol) was added to the reaction mixture, which was stirred at 120° C. for 20 minutes under CEM microwave. The reaction mixture was evaporated, and the residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, evaporated, and the residue was purified by preparative thin-layer chromatography using methanol as eluent in DCM to give (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-(2-chlorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)urea (0.02 g, 8%). 1HNMR(400MHz,DMSO-d6):δ 8.79(s,1H),8.63(s,1H),8.46(s,1H),8.31(s,1H),7.79(s,1H),7.78(s,1H),7.47(d,J=7.6Hz,1H),7.35-7.26(m,4 H),7.13(t,J=7.8Hz,1H),6.79(d,J=8Hz,1H),4.99-4.91(m,1H),4.74-4.72(m,1H),3.65-3.55(m,2H),2.41(s,3H). LC-MS m / z calcd exact mass 497.11,found m / z 498.3[M+H] + ;HPLC purity 99.17%.

[0288] Representative Examples of Scheme 2:

[0289] Example 2: (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-4-(5-methoxy-1H-indazol-3-yl)-1H-pyrrole-2-carboxamide (Compound #20)

[0290] [ka]

[0291] Step 1: 2-chloro-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine

[0292] [ka]

[0293] 4-Nitro-1H-pyrazole (4.0 g, 35.3 mmol), 2,4-dichloro-pyrimidine (5.23 g, 35.3 mmol), potassium carbonate (14.6 g, 106 mmol), and acetone (200 mL) were heated at 65 °C for 4 hours. The reaction mixture was evaporated, and the residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, evaporated, and the residue was purified by column chromatography on silica gel using ethyl acetate in hexane as the eluent to give 2-chloro-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine (1.7 g, 21%). 1H NMR (400 MHz, CDCl3): 9.30 (s, 1H), 8.78 (d, J = 5.6 Hz, 1H), 8.32 (s, 1H), 7.74 (d, J = 5.2 Hz, 1H).

[0294] Step 2: 1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-amine

[0295] [ka]

[0296] A solution of 2-chloro-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine (0.4 g, 1.77 mmol) in THF:methanol (2:1) (20 mL) was cooled to 0 °C and zinc powder (0.7 g, 10.6 mmol) and ammonium chloride (0.75 g, 14.16 mmol) were added. The mixture was stirred at room temperature for 30 min. The reaction mixture was filtered through Celite, the filtrate was evaporated, and the residue was suspended in water and extracted with DCM. The organic layer was dried over sodium sulfate and evaporated to give 1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-amine (0.33 g, 97%). This product was used in the next step without further purification. 1HNMR (400MHz, DMSO-d6): 8.60 (d, J = 5.6 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 8 Hz, 1H), 7.58 (s, 1H), 5.21 (br s, 2H). LC-MS calcd exact mass 195.03,found m / z 196.1[M+H] + .

[0297] Step 3: (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-yl)urea

[0298] [ka]

[0299] A mixture of 1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-amine (0.1 g, 0.51 mmol), pyridine (0.041 mL, 0.51 mmol) in DCM (6 mL) was cooled to 0 °C, and then 4-nitrophenyl carbonochloridate (0.102 g, 0.51 mmol) was added. The mixture was stirred at room temperature for 1.5 h. The reaction mixture was cooled to 0 °C, and DIPEA (0.28 mL, 1.53 mmol) and (S)-2-amino-2-(3-chlorophenyl)ethanol (0.088 g, 0.51 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over sodium sulfate, evaporated, and the residue was purified by column chromatography on silica gel using 60% ethyl acetate in hexane as eluent to give (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-yl)urea (0.045 g, 23%). 1HNMR(400MHz,DMSO-d6):8.74(s,1H),8.68(d,J=5.6Hz,1H),8.45(s,1H),7.92(s,1H),7.80(d,J=5.6Hz,1H,),7.3 6-7.32(m,2H),7.28(d,J=7.6Hz,2H),6.96(d,J=8Hz,1H),5.00-4.98(m,1H),4.76-4.72(m,1H),3.65-3.58(m,2H). LC-MS calcd exact mass 392.06,found m / z 393.1[M+H] + .

[0300] Step 4: (S)-1-(1-(2-(2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)-2-hydroxyethyl)urea

[0301] [ka]

[0302] A mixture of (S)-1-(1-(3-chlorophenyl)-2-hydroxyethyl)-3-(1-(2-chloropyrimidin-4-yl)-1H-pyrazol-4-yl)urea (0.02 g, 0.05 mmol), 2-chloro-4-fluoroaniline (0.009 g, 0.6 mmol), potassium carbonate (0.01 g, 0.075 mmol), and dioxane (2 mL) in a glass tube was stirred with nitrogen gas for 20 minutes. Tris(dibenzylideneacetone)dipalladium(0) (0.002 g, 0.0025 mmol) and BINAP (0.003 g, 0.005 mmol) were added to the reaction mixture, which was stirred with nitrogen gas for an additional 15 minutes. The tube was sealed and heated at 90 °C for 4 hours. The reaction mixture was filtered through Celite, the filtrate was evaporated, and the residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, evaporated, and the residue was purified by column chromatography on silica gel using 60% ethyl acetate in hexane as eluent to give (S)-1-(1-(2-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(1-(3-chlorophenyl)-2-hydroxyethyl)urea (0.003 g, 12%). H NMR (400 MHz, CDCl3, plus a few drops of MeOD): 8.50 (s, 1H), 8.33 (d, J = 5.2 Hz, 1H), 8.27-8.25 (m, 1H), 7.51 (s, 1H), 7.28-7.19 (m, 1H), 7.23-7.12 (m, 3H), 7.12-7.10 (m, 1H), 7.04-6.99 (m, 1H), 6.23 (d, J = 6.8 Hz, 1H), 4.87-4.84 (m, 1H), 3.81-3.77 (m, 1H), 3.64-3.61 (m, 1H). LC-MS calculated exact mass 501.09, found m / z 502.3 [M+H]. + . HPLC purity 98.17%.

[0303] Example 3: (S)-1-(1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea (Compound #55)

[0304] [ka]

[0305] Step 1: 2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine

[0306] [ka]

[0307] To a stirred solution of 4-nitro-1H-pyrazole (4.0 g, 35.36 mmol) in acetone (100 mL) was added potassium carbonate (14.66 g, 106.1 mmol). The mixture was stirred at room temperature for 15 minutes, followed by the addition of 2,4-dichloro-5-methylpyrimidine (5.76 g, 35.36 mmol), and the mixture was then stirred at 70 °C for 8 hours. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 × 100 mL), followed by washing with brine (30 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by gradient column chromatography eluting with 8% ethyl acetate in n-hexane to give 2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine as a colorless solid (4.2 g, 50% yield). 1HNMR (400MHz CDCl3): δ 9.31 (s, 1H), 8.61 (s, 1H), 8.31 (s, 1H), 2.68 (s, 3H). LC-MS calcd exact mass 239.02,found m / z 240.2[M+H] + .

[0308] Step 2: 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-amine

[0309] [ka]

[0310] To a stirred solution of 2-chloro-5-methyl-4-(4-nitro-1H-pyrazol-1-yl)pyrimidine (4.2 g, 17.2 mmol) in THF:methanol (50:25 mL) was added ammonium chloride (6.85 g, 172.0 mmol) and zinc (5.28 g, 87.4 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was then filtered through Celite using methanol (50 mL), and the filtrate was evaporated under reduced pressure. It was then combined with water (100 mL) and extracted with ethyl acetate (3 × 100 mL), followed by brine (50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-amine as an off-white solid (3.0 g, 82% yield). 1HNMR (400MHz CDCl3): δ 8.36 (s, 1H), 8.11 (s, 1H), 7.49 (d, J = 8Hz, 1H), 3.19 (s, 2H), 2.62 (s, 3H). LC-MS calcd exact mass 209.04,found m / z 210.2[M+H] + .

[0311] Step 3: (S)-1-(1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea

[0312] [ka]

[0313] To a stirred solution of 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-amine (0.2 g, 0.95 mmol) in DCM (15 mL) was added 4-nitrophenyl carbonochloridate (0.23 g, 0.11 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hours. DIPEA (0.5 mL, 2.86 mmol), (S)-2-amino-2-phenylethanol (0.13 g, 0.95 mmol) in DCM (3 mL), and pyridine (0.08 mL, 0.95 mmol) were then added to the mixture, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by the addition of water (25 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure, washed with ether, and then dried under high vacuum to give (S)-1-(1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)-urea as an off-white solid (0.1 g, 28%). 1HNMR(400MHz DMSO-d6):δ 8.68(s,1H),8.61(s,1H),8.52(s,1H),7.89(s,1H),7.3(d,J=4.4Hz,4H),7.24-7.19(m,1H),6 .83(d,J=7.6Hz,1H),4.93(t,J=5.2Hz,1H),4.75-4.71(m,1H),3.65-3.55(m,2H),2.48(s,3H). LC-MS calcd exact mass 372.11,found m / z 373.1[M+H] + .

[0314] Step 4: (S)-1-(1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea

[0315] [ka]

[0316] To a stirred solution of (S)-1-(1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea (0.1 g, 0.26 mmol) in dioxane (5 mL) was added potassium carbonate (0.055 g, 0.40 mmol), benzo[d][1,3]dioxol-5-amine (0.044 g, 0.32 mmol), and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.016 g, 0.026 mmol). The mixture was then degassed with nitrogen gas for 20 min. Tris(dibenzylideneacetone)-dipalladium(0) (0.012 g, 0.013 mmol) was then added, and the mixture was stirred at 100 °C for 4 h in a sealed glass tube. The reaction mixture was filtered through a Celite bed, and the filtrate was quenched with water (15 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography eluting with 3.5% methanol in DCM to give (S)-1-(1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-1H-pyrazol-4-yl)-3-(2-hydroxy-1-phenylethyl)urea as an off-white solid (4 mg, 4%). 1HNMR(400MHz,DMSO-d6):δ 9.44(s,1H),8.81(s,1H),8.56(s,1H),8.34(d,J=12.4Hz,1H),7.77(s,1H),7.37(d,J=1.6Hz,1H),7.31-7.29(m,4H),7.23-7.19(m,1H) 7.12-7.09(m,1H),6.9(d,J=7.6Hz,1H),6.8(d,J=8Hz,1H),5.97(s,2H),4.95(s,1H),4.74-4.69(m,1H),3.63-3.55(m,2H),2.45(s,3H). LC-MS calcd exact mass 473.18,found m / z 474.5[M+H] + HPLC purity 98.33%, chiral HPLC purity 99.01%, mp 208.3℃.

[0317] Representative Examples of General Scheme 3

[0318] Example 4: (S)-1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide (Compound #29)

[0319] [ka]

[0320] Step 1: Methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate

[0321] [ka]

[0322] To a solution of methyl 1H-pyrrole-3-carboxylate (3.0 g, 24 mmol) in acetonitrile (100 mL) was added 2,4-dichloro-5-methylpyrimidine (5.9 g, 36 mmol) and potassium carbonate (6.6 g, 48 mmol). The reaction was stirred at reflux for 12 hours. The reaction mixture was diluted with ethyl acetate (500 mL) and then washed with water and brine. The ethyl acetate layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in hexane as the eluent to give methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate as an off-white solid (3.2 g, 53%). 1 HNMR (400MHz, CDCl3): δ 8.51(s,1H),8.0(s,1H),7.41(d,J=2.4Hz,1H,),6.79(t,J=1.2Hz,1H,),3.85(s,3H),2.51(s,3H). LC-MS calcd exact mass 251.05,found m / z 252.2[M+H] + .

[0323] Step 2: Methyl 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate

[0324] [ka]

[0325] To a solution of methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate (0.3 g, 0.1195 mmol) in dioxane (10 mL) was added 2-chloro-4-fluoroaniline (0.17 g, 0.1195 mmol) and potassium carbonate (0.24 g, 1.17 mmol). The resulting reaction mixture was purged with nitrogen gas for 15 minutes, followed by the addition of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.074 g, 0.119 mmol) and palladium(dibenzylideneacetone)dipalladium(0) (0.054 g, 0.059 mmol). The reaction mixture was stirred at 100 °C for 12 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and filtered through Celite. The Celite bed was washed with ethyl acetate (2 × 50 mL), and the filtrate was washed several times with ice water and then with brine. The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in hexane as the eluent to give methyl 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate as an off-white solid (0.25 g, 58%). 1 HNMR(400MHz,CDCl3):δ 8.40-8.36(m,2H),7.95(s,1H),7.51(s,1H),7.40-7.34(m,1H),7.19-7.1 6(m,1H),7.07-6.99(m,1H),6.77-6.76(m,1H),3.86(s,3H),2.40(s,3H). LC-MS calcd exact mass 360.08,found m / z 361.3[M+H] +.

[0326] Step 3: 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid

[0327] [ka]

[0328] To a solution of methyl 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate (0.25 g, 0.833 mmol) in methanol (20.0 mL) was added 2N sodium hydroxide solution (10 mL). The reaction mixture was stirred at 50 °C for 2 h. Methanol was removed under reduced pressure, and the pH was adjusted to 6.5-7 by adding dilute hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3 × 50 mL), and the combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid as an off-white solid (0.17 g, 71%). 1 HNMR(400MHz,DMSO-d6):δ 12.14(s,1H),9.06(s,1H),8.39(s,1H),7.86(s,1H),7.67-7.64(m,1H),7.50-7.48( m,1H),7.36(t,J=2.8Hz,1H),7.24-7.19(m,1H),6.57(t,J=2.0Hz,2H),2.27(s,3H). LC-MS calcd exact mass 346.06,found m / z 347.3[M+H] + .

[0329] Step 4: (S)-1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide

[0330] [ka]

[0331] To a solution of 1-(2-(2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid (0.05 g, 0.144 mmol) in NMP (2.0 mL) was added (S)-2-amino-2-(3-chlorophenyl)ethanol (0.029 g, 0.173 mmol), EDC (0.055 g, 0.288 mmol), and HOBt (0.005 g, 0.043 mmol). Triethylamine (0.04 g, 0.432 mmol) was added dropwise to the resulting reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into ice water (10 mL) and then extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was dissolved in a small amount of DCM and then diluted with ether. The solvent was decanted. The resulting solid was washed with ether and n-pentane to give (S)-1-(2-((2-chloro-4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide as an off-white solid (0.022 g, 31%). 1HNMR(400MHz,DMSO-d6):δ 8.99(s,1H),8.37(s,1H),8.25(d,J=8.4Hz,1H),7.95(s,1H),7.69-7.65(m,1H) ,7.49-7.41(m,1H),7.37-7.18(m,6H),6.75(s,1H),5.04-4.99(m,1H),4.92(br s, 1H), 3.65-3.64 (m, 2H), 2.28 (s, 3H). LC-MS calcd exact mass 499.10,found m / z 500.3[M+H] + ; HPLC purity: 99.03%, Chiral HPLC: 99.66%.

[0332] Example 5: (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxamide (Compound #39)

[0333] [ka]

[0334] Step 1: Methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate

[0335] [ka]

[0336] To a solution of methyl-1H-pyrazole-4-carboxylate (1.00 g, 6.134 mmol) in acetonitrile (20 mL) was added potassium carbonate (2.543 g, 18.40 mmol), and the mixture was stirred at room temperature for 5 minutes. 2,4-Dichloro-5-methylpyrimidine (0.773 g, 6.134 mmol) was added to the mixture, and the mixture was stirred at 80 °C overnight. The mixture was cooled, water (15 mL) was added, and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate and then evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in n-hexane as the eluent to give methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate as a colorless solid (0.65 g, 42%). 1HNMR (400MHz, CDCl3): δ 9.08(s,1H),8.54(s,1H),8.15(s,1H),3.89(s,3H),2.67(s,3H).

[0337] Step 2: Methyl 1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate

[0338] [ka]

[0339] To a solution of methyl-1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate (0.3 g, 1.18 mmol) in isopropanol (7 mL) was added DIPEA (0.43 mL, 2.47 mmol) and cyclopropylamine (0.09 mL, 1.3 mmol). The reaction mixture was stirred overnight at 85 °C in a sealed glass tube. The reaction mixture was cooled, quenched with water (10 mL), and extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in n-hexane as the eluent to give methyl 1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate as a colorless solid (0.17 g, 52%). 1HNMR(400MHz,CDCl3):δ 8.97(s,1H),8.27(s,1H),8.09(s,1H),5.26(s,1H),3.87(s,3H),2.80-2.76(m,1H),2.47(s,3H),0.87-0.83(m,2H),0.56(t,J=7.2Hz,2H). LC-MS calcd exact mass 273.12,found m / z 274.6[M+H] + .

[0340] Step 3: 1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylic acid

[0341] [ka]

[0342] To a stirred solution of methyl 1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylate (0.2 g, 0.72 mmol) in THF (7 mL) and water (1 mL) was added lithium hydroxide monohydrate (0.306 g, 7.29 mmol). The reaction mixture was stirred at 50 °C for 4 h. The mixture was cooled, concentrated under reduced pressure, and neutralized (pH ~ 7) by the addition of 1 N HCl. The resulting solid was filtered to give 1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylic acid as a colorless solid (0.122 g, 65%). 1HNMR(400MHz,DMSO-d6):δ 12.0(br s,1H),8.82(s,1H),8.31(s,1H),8.09(s,1H),7.48(s,1H),2.74-2.71(m,1H),2.30(s,3H),0.69-0.65(m,2H),0.48-0.44(m,2H). LC-MS calcd exact mass 259.11,found m / z 260.2[M+H] + .

[0343] Step 4: (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxamide

[0344] [ka]

[0345] To a stirred solution of 1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxylic acid (0.035 g, 0.134 mmol) in NMP (0.8 mL) was added EDC (0.051 g, 0.26 mmol), HOBt (0.005 g, 0.04 mmol), and triethylamine (0.05 mL, 0.4 mmol), and the mixture was stirred at room temperature for 10 minutes. To this mixture was added (S)-2-amino-2-(3-chlorophenyl)ethanol (0.027 g, 0.16 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (2 × 20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by column chromatography using methanol in DCM as the eluent to give (S)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(cyclopropylamino)-5-methylpyrimidin-4-yl)-1H-pyrazole-4-carboxamide as a colorless solid (0.011 g, 20%). 1HNMR(400MHz,DMSO-d6):δ 9.00(s,1H),8.61(d,J=8Hz,1H),8.32(s,1H),8.22(s,1H),7.44(d,J=11.2Hz,2H),7.36-7.27(m,3H),5.07-5.01(m,1 H),4.98-4.95(m,1H),3.66-3.65(m,2H),2.76-2.73(m,1H),2.34(s,3H),0.68(d,J=5.2Hz,2H),0.48(d,J=2.4Hz,2H). LC-MS calcd exact mass 412.14,found m / z 413.2[M+H] + HPLC purity 99.32%, chiral HPLC purity 99.76%.

[0346] Representative Examples of General Scheme 4

[0347] Example 6: N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-(2,2-difluoro-benzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide (Compound #136)

[0348] [ka]

[0349] Step 1: Methyl 1H-pyrrole-3-carboxylate

[0350] [ka]

[0351] To a stirred solution of 1H-pyrrole-3-carboxylic acid (4.3 g, 38.7 mmol) in methanol (40 mL) cooled to 0-5 °C was added 6 N HCl (9 mL). The mixture was stirred at room temperature for 5 minutes and then stirred at reflux overnight. The reaction mixture was cooled and concentrated under reduced pressure, then cooled to 0 °C and the pH adjusted to 7 by the addition of saturated sodium bicarbonate. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure to give methyl 1H-pyrrole-3-carboxylate as a brown solid (4 g, 83%). 1 HNMR (400MHz, CDCl3): δ 8.56 (br s, 1H), 7.43 (s, 1H), 6.75 (s, 1H), 6.65 (s, 1H), 3.92 (s, 3H). LC-MS calcd exact mass 125.05,found m / z 126.2[M+H] + .

[0352] Step 2: Methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate

[0353] [ka]

[0354] To a solution of methyl-1H-pyrrole-3-carboxylate (1.4 g, 11.2 mmol) in acetonitrile (50 mL) was added potassium carbonate (3.09 g, 22.4 mmol). The mixture was stirred at room temperature for 15 minutes, and then 2,4-dichloro-5-methylpyrimidine (2.738 g, 16.8 mmol) was added. The resulting mixture was heated at reflux overnight. The reaction mixture was cooled, then evaporated under reduced pressure, combined with water, and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in n-hexane as the eluent to give methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate as a white solid (1.2 g, 43%). 1 HNMR (400MHz, CDCl3): δ 8.50 (s, 1H), 7.99 (s, 1H), 7.40-7.39 (m, 1H), 6.78-6.77 (m, 1H), 3.85 (s, 3H), 2.51 (s, 3H). LC-MS calcd exact mass 251.05,found m / z 252.3[M+H] + .

[0355] Step 3: Methyl 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate

[0356] [ka]

[0357] To a solution of methyl-1-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate (3.1 g, 12.31 mmol) in dioxane (20 mL) was added potassium carbonate (2.549 g, 18.47 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (0.766 g, 1.231 mmol), and 2,2-difluoro-benzo[d][1,3]dioxol-5-amine (2.23 g, 12.92 mmol). The reaction mixture was degassed with argon for 15 minutes, followed by the addition of tris(dibenzylideneacetone)-dipalladium(0) (0.563 g, 0.615 mmol). The resulting mixture was stirred in a sealed glass tube at 100 °C for 9 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate, and the combined organic phases were washed with water and brine. The combined organic phases were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in n-hexane as the eluent to give methyl 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate as an off-white solid (2.3 g, 48%). 1 HNMR(400MHz,CDCl3):δ 8.34(s,1H),7.95(s,1H),7.69(d,J=1.6Hz,1H),7.34(t,J=2.8Hz,1H),7.23(s,C Integrated with DCl3 peak, 1H), 7.06-6.99(m,2H), 6.78-6.77(m,1H), 3.86(s,3H), 2.40(s,3H). LC-MS calcd exact mass 388.10,found m / z 389.3[M+H] + .

[0358] Step 4: 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid

[0359] [ka]

[0360] To a solution of methyl 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylate (1.0 g, 2.5 mmol) in THF (40 mL) and water (20 mL) was added lithium hydroxide monohydrate (0.648 g, 15.4 mmol). The resulting mixture was warmed to reflux at 70° C. for 12 hours. The reaction mixture was cooled and then concentrated under reduced pressure, and the pH was adjusted to 6 by the addition of 1 N HCl. The solid was filtered and washed with n-pentane and diethyl ether to give 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid as a white solid (0.85 g, 88%). 1 HNMR(400MHz,DMSO-d6):δ 11.98(br s,1H),9.58(s,1H),8.38(s,1H),7.94-7.82(m,2H),7.36(d,2H J=8Hz),7.0(d,1H J=8.4Hz), 6.69(s, 1H), 2.38(s, 3H). LC-MS calcd exact mass 374.08,found m / z 375.1[M+H] + .

[0361] Step 5: N-((3-chlorophenyl)(cyano)methyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide

[0362] [ka]

[0363] To a solution of 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid (0.2 g, 0.53 mmol) in DCM (15 mL) and THF (3 mL) was added triethylamine (0.2 mL, 1.6 mmol), and the mixture was stirred under a nitrogen atmosphere for 5 minutes. 2-Amino-2-(3-chlorophenyl)acetonitrile (0.1 g, 0.64 mmol), EDC (0.2 g, 1.06 mmol), and HOBt (0.021 g, 0.16 mmol) were then added to the mixture. The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in n-hexane as eluent to give N-((3-chlorophenyl)(cyano)methyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide as a white solid (0.1 g, 36%). 1HNMR(400MHz,CDCl3):δ 8.35(s,1H),7.95(s,1H),7.6(s,1H),7.56(s,1H),7.4(d,J=6.8Hz,1H),7.41-7.38(m,3 H),7.0-6.99(m,2H),6.6(s,1H),6.4(d,J=8.8Hz,2H),6.34(d,J=8.8Hz,2H),2.4(s,3H). LC-MS calcd exact mass 522.10,found m / z 523.2[M+H] + ,HPLC purity 98.03%.

[0364] Step 6: N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((2,2-difluorobenzo[I][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide

[0365] [ka]

[0366] To a solution of N-(3-chlorophenyl)(cyano)methyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide (0.1 g, 0.191 mmol) in methanol (10 mL) was added ammonia methanol (20 mL) at 0° C., followed by Raney nickel (0.05 g). The resulting reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere using a bladder. The reaction mixture was filtered over Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by gradient column chromatography using methanol in DCM as eluent to give N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyrimidin-4-yl)-1H-pyrrole-3-carboxamide as an off-white solid (0.03 g, 30%). 1HNMR(400MHz,CDCl3):δ 8.34(s,1H),7.95(s,1H),7.69(d,J=1.6Hz,1H),7.34(t,J=2.8Hz,1H),7.23(s,merged with CDCl3 peak, 1H), 7.06-6.99 (m, 2H), 6.78-6.77 (m, 1H), 3.86 (s, 3H), 2.40 (s, 3H). LC-MS calcd exact mass 526.13,found m / z 527.5[M+H] + .

[0367] Example 7: N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (Compound #225)

[0368] [ka]

[0369] Step 1: Methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate

[0370] [ka]

[0371] To a solution of methyl-1H-imidazole-4-carboxylate (10.37 g, 74.0 mmol) in acetonitrile (200 mL) was added 2,4-dichloro-5-methylpyrimidine (10 g, 61.7 mmol) and potassium carbonate (25.5 g, 185.2 mmol), and the mixture was stirred at room temperature under an inert atmosphere for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in hexane as the eluent to give methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate as a white solid (11 g, 75%). 1HNMR (400MHz, DMSO-d6): δ 8.88 (s, 1H), 8.38 (s, 2H), 3.80 (s, 3H), 2.41 (s, 3H). LC-MS exact mass calcd 252.04,found m / z 253.2[M+H] + .

[0372] Step 2: Methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate

[0373] [ka]

[0374] To a solution of 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate (5 g, 19.7 mmol) in isopropanol (30 mL) was added DIPEA (7.658 g, 59.0 mmol) and tetrahydro-2H-pyran-4-amine (2.402 g, 23.0 mmol). The resulting mixture was stirred at 100 °C for 17 h in a sealed glass tube. The reaction mixture was cooled to room temperature, and crystals formed. The crystals were filtered, washed with hexane, and dried under vacuum to give methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate as an off-white solid (5.2 g, 83%). 1HNMR(400MHz,DMSO-d6):δ 8.36(s,1H),8.30(s,1H),8.27(s,1H),7.39(d,J=7.6Hz,1H),3.90-3.83(m,3H),3.78(s ,3H),3.37(t,J=11.6Hz,2H),2.16(s,3H),1.82(d,J=12Hz,2H),1.54-1.45(m,2H),LC-MS exact mass calcd 317.15,found m / z 318.2[M+H] + .

[0375] Alternatively, methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate may be prepared as follows.

[0376] [ka]

[0377] N,N-Dimethylacetamide (DMAC) (4.6 L), 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate (1150 g, 4.55 mol), DIPEA (3.2 L), and tetrahydro-2H-pyran-4-amine hydrochloride (940 g, 6.83 mol) were sequentially charged to a reactor. The resulting mixture was heated to 100 °C and stirred until the HPLC content of 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate in the reaction mixture was 5% or less. The mixture was cooled, water was charged to the reactor, and the mixture was stirred at 15–18 °C. The mixture was then cooled and stirred at 3–10 °C. The solid was collected by filtration, and the filter cake was washed with water and dried to give methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate.

[0378] Step 3: N-((3-chlorophenyl)(cyano)methyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide

[0379] [ka]

[0380] To a solution of methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate (0.500 g, 1.57 mmol) in toluene (20 mL) was added 2-amino-2-(3-chlorophenyl)acetonitrile (0.392 g, 2.3 mmol) and trimethylaluminum (2 M solution in toluene, 1.96 mL, 2.5 eq). The resulting mixture was stirred at 100° C. for 1 h under CEM microwave. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with ice water, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified twice by gradient column chromatography using methanol in DCM as the eluent to give N-((3-chlorophenyl)(cyano)methyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide as a yellow solid (0.29 g). LC-MS exact mass calcd 451.15, found m / z 452.2 [M+H] + .

[0381] Step 4: N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

[0382] [ka]

[0383] To a solution of N-((3-chlorophenyl)(cyano)methyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (0.700 g, 1.54 mmol) in methanol (15 mL) was added nickel chloride hexahydrate (0.552 g, 2.3 mmol) under an inert atmosphere at 0° C., and the mixture was stirred to give a clear solution. Sodium borohydride (0.175 g, 4.6 mmol) was added slowly to the reaction mixture at 0° C., and the mixture was stirred at 0° C. for 10 minutes. The reaction mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by gradient column chromatography using methanol in dichloromethane as the eluent to give N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (racemic mixture) as an off-white solid (0.050 g, 7%), which was used directly for chiral HPLC separation. Data obtained on separate batches were prepared in a similar manner. 1HNMR(400MHz,DMSO-d6):δ 8.53(d,J=8Hz 1H),8.32(s,1H),8.25(s,1H),8.06(s,1H),7.40(s,1H),7.32-7.27(m,4H),4.98-4.88(m,1H),3.83-3. 81(m,3H),3.37-3.35(m,2H),2.95-2.88(m,2H),2.16(s,3H),1.79(d,J=11.2Hz,2H),1.50-1.40(m,2H). LC-MS exact mass calcd 455.18,found m / z 456.5[M+H] + .

[0384] Example 8a: Enantiomer #1, (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide, and Example 8b: Enantiomers, (R)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (Compound #225a and Compound #225b, respectively)

[0385] [ka]

[0386] Racemic N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide (50 mg) was dissolved in 1 mL of 50:50 methanol / DCM and subjected to chiral HPLC purification using a Chiralpak® IA column [250 mm × 4.6 mm × 5 μm] with a mobile phase of isopropyl alcohol and 0.01% diethylamine (100%) at a flow rate of 1 mL / min. The elution fractions for the two enantiomers were collected separately and evaporated separately to give 12 mg (48% recovery) of Enantiomer #1 ((S), compound #225a) as the first eluting enantiomer and 10 mg (40% recovery) of Enantiomer #2 ((R), compound #225b) as the second eluting enantiomer, with >98.1% ee and >98.7% ee, respectively.

[0387] Example 8a, Compound #225a (Enantiomer #1, (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide): H NMR (400 MHz, DMSO-d): δ 8.58 (d, J=6.8 Hz, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.41 (s, 1H), 7.36-7.28 (m, 4H), 4.97 (br s,1H),3.84-3.82(m,3H),3.38-3.33(m,2H),3.01-2.94(m,2H),2.16(s,3H),1.80(d,J=11.6Hz,2H),1.52-1.44(m,2H). LC-MS exact mass calcd 455.18,found m / z 456.2[M+H] + .

[0388] Example 8b, Compound #225b (Enantiomer #2, (R)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide): ¹H NMR (400 MHz, DMSO-d₆): δ 8.58(d,J=8Hz,1H),8.33(s,1H),8.27(s,1H),8.07(s,1H),7.42(s,1H),7.36-7.27(m,4H),5.02-4.91(m,1H) ),3.84-3.82(m,3H),3.35(m,2H),3.05-2.91(m,2H),2.16(s,3H),1.79(d,J=11.6Hz,2H),1.51-1.4(m,2H). LC-MS exact mass calcd 455.18,found m / z 456.2[M+H] + .

[0389] Representative Examples of General Scheme 5:

[0390] Example 9: 1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-2-methyl-1H-imidazole-4-carboxamide (Compound #153)

[0391] [ka]

[0392] Step 1: 1-(2-chloro-5-methylpyrimidin-4-yl)-2-methyl-1H-imidazole-4-carbaldehyde

[0393] [ka]

[0394] A mixture of 2,4-dichloro-5-methylpyrimidine (2.50 g, 15.33 mmol), 2-methyl-1H-imidazole-4-carbaldehyde (1.85 g, 16.87 mmol), and potassium carbonate (4.65 g, 33.74 mmol) in DMF (30 mL) was stirred at room temperature for 18 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 100 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (100-200 mesh) using 80-90% ethyl acetate in hexane as the eluent to give 1-(2-chloro-5-methylpyrimidin-4-yl)-2-methyl-1H-imidazole-4-carbaldehyde (0.5 g, 15%). 1HNMR (400MHz, DMSO-d6): δ 9.76 (s, 1H), 8.99 (s, 1H), 8.40 (s, 1H), 2.35 (s, 1H), 2.22 (s, 3H). LC-MS:exact mass calcd 236.05,found m / z 237.07[M+H] + ,Purity:99.23%.

[0395] Step 2: 1-(2-chloro-5-methylpyrimidin-4-yl)-2-methyl-1H-imidazole-4-carboxylic acid

[0396] [ka]

[0397] To a solution of 1-(2-chloro-5-methylpyrimidin-4-yl)-2-methyl-1H-imidazole-4-carbaldehyde (0.5 g, 2.11 mmol) in t-butanol (1.5 mL) and THF (7 mL) at room temperature was added 2-methyl-2-butane. To this mixture was slowly added a solution of sodium chlorite (1.87 g, 20.7 mmol) and sodium dihydrogen phosphate (1.5 g, 12.28 mmol) in water (5 mL). After TLC showed the reaction was complete, the mixture was diluted with water (25 mL) and washed with ethyl acetate (2 × 10 mL). The aqueous layer was concentrated in vacuo and extracted with 10% methanol in DCM (3 × 50 mL). The organic layer was concentrated under reduced pressure to give 1-(2-chloro-5-methylpyrimidin-4-yl)-2-methyl-1H-imidazole-4-carboxylic acid (0.70 g) as a white solid. LC-MS exact mass: 252.04, found m / z: 253.0 [M+H] + .

[0398] Step 3: 1-(2-chloro-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-2-methyl-1H-imidazole-4-carboxamide

[0399] [ka]

[0400] To a solution of 1-(2-chloro-5-methylpyrimidin-4-yl)-2-methyl-1H-imidazole-4-carboxylic acid (0.5 g, 1.98 mmol) and triethylamine (0.5 mL, 3.96 mmol) in DCM was slowly added (DL)-2-amino-2-phenylethan-1-ol (0.288 g, 2.18 mmol). To this mixture was added T3P (2.5 mL, 3.96 mmol, 50% solution in ethyl acetate), and the mixture was stirred at room temperature for 18 h. After TLC showed the reaction was complete, the mixture was quenched by the addition of water (30 mL). The mixture was extracted with DCM (3 × 30 mL), and the organic layer was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (230-400 mesh) using 5% MeOH in DCM as eluent to give 1-(2-chloro-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-2-methyl-1H-imidazole-4-carboxamide (0.580 g, 79%) as an off-white solid. 1HNMR(400MHz,DMSO-d6):δ 8.95(s,1H),8.26(d,J=8.4Hz,1H),7.98(s,1H),7.36-7.35(m,2H),7.33-7.34(m,3H ),7.22-7.21(m,1H),5.02-4.98(m,2H),3.74-3.69(m,2H),2.36(s,3H),2.21(s,3H). LC-MS Exact mass calcd 371.11,found m / z 372.0[M+H] + .

[0401] Step 4: 1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-2-methyl-1H-imidazole-4-carboxamide

[0402] [ka]

[0403] A mixture of 1-(2-chloro-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-2-methyl-1H-imidazole-4-carboxamide (0.5 g, 1.42 mmol), 4-fluoroaniline (0.173 g, 1.56 mmol), and potassium carbonate (0.39 g, 2.84 mmol) in dioxane (20 mL) was purged with argon gas for 10 minutes in a glass tube. Tris(dibenzylideneacetone)dipalladium(0) (0.130 g, 0.142 mmol) and BINAP (0.089 g, 0.142 mmol) were added to the reaction mixture, which was then purged with argon gas for an additional 10 minutes. The mixture was heated in a sealed glass tube at 90 °C for 6 hours. After completion of the reaction, the reaction mixture was cooled, diluted with water, and extracted with ethyl acetate (3 x 100 mL). The organic layer was dried over sodium sulfate, evaporated, and the residue was purified by flash column chromatography on silica gel (230-400 mesh) using 80% ethyl acetate in hexane as eluent to give 1-(2-((4-fluorophenyl)amino)-5-methylpyrimidin-4-yl)-N-(2-hydroxy-1-phenylethyl)-2-methyl-1H-imidazole-4-carboxamide (0.109 g, 17%) as a white solid. 1HNMR(400MHz,DMSO-d6):δ 9.89(s,1H),8.60(s,1H),8.21(d,J=8.4Hz,1H),7.92(s,1H),7.70-7.67(m,2H),7.37(d,J=7.2Hz,2H),7.31(t,J=7.2H) z,2H),7.24(d,J=7.2Hz,1H),7.16(t,J=8.8Hz,2H),5.02(d,J=4.8Hz,2H),3.77-3.69(m,2H),2.35(s,3H),2.03(s,3H). LC-MS calcd exact mass 446.19,found m / z 447.52[M+H] + ,Purity:96.12%.

[0404] Representative Examples of General Scheme 6:

[0405] Example 10: N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (Compound #192)

[0406] [ka]

[0407] Step 1: Methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate

[0408] [ka]

[0409] To a stirred solution of methyl 1H-imidazole-4-carboxylate (7 g, 42.9 mmol) in acetonitrile (50 mL) was added potassium carbonate (11.87 g, 85.88 mmol). The mixture was stirred at room temperature, and then 2,4-dichloro-5-methylpyrimidine (5.41 g, 42.9 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was combined with water (50 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in n-hexane as the eluent to give methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate as a white solid (4.5 g, 41%). 1HNMR (400MHz, DMSO-d6): δ 8.88 (s, 1H), 8.38 (s, 1H), 3.8 (s, 3H), 2.41 (s, 3H). LC-MS calcd exact mass 252.04,found m / z 253.2[M+H] + .

[0410] Step 2: (S)-Methyl 1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate

[0411] [ka]

[0412] To a solution of methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate (0.6 g, 2.37 mmol) in isopropanol (30 mL) was added (S)-tetrahydrofuran-3-amine (0.310 g, 3.56 mmol) and DIPEA (1.53 g, 11.8 mmol), and the mixture was stirred at 100 °C for 36 h in a sealed glass tube. The mixture was cooled, then concentrated under reduced pressure, diluted with water (50 mL), and extracted with ethyl acetate (2 × 100 mL). The organic layer was washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in hexane as eluent to give (S)-methyl 1-(5-methyl-2-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate as a white solid (0.45 g, 63% yield). 1HNMR(400MHz,CDCl3):δ 8.28(s,1H),8.16(d,J=2.4Hz,2H,),5.47(s,1H),4.56(s,1H),4.0-3.88(m,5H),3.87-3 .85(m,1H),3.75-3.71(m,1H),2.31(s,3H),2.36-2.33(m,1H),1.92-1.85(m,2H),LC-MS calcd exact mass 303.13,found m / z 304.4[M+H] + .

[0413] Step 3: N-((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(((S)-tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

[0414] [ka]

[0415] To a stirred solution of (S)-methyl-1-(5-methyl-2-(tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate (0.45 g, 1.48 mmol) in toluene (25 mL) was added (S)-2-amino-2-(3-chlorophenyl)ethanol (0.509 g, 2.96 mmol) and trimethylaluminum (2 M solution in toluene, 2.2 mL, 4.45 mmol) at 0 °C in a CEM microwave vial. The vial was sealed, and the reaction mixture was stirred at 100 °C for 2 h under CEM microwave irradiation. The mixture was cooled, quenched with water, and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using methanol in DCM as eluent to give N-(S)-1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(S)-tetrahydro-furan-3-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide as a white solid (0.23 g, 35%). 1HNMR(400MHz,DMSO-d6):δ 8.38(t,J=8.4Hz,2H)8.29(s,1H),8.11(s,1H),7.60(d,J=5.2Hz,1H),7.43(s,1H),7.31(d,J=15.6Hz,3H),5.02(d,J=5.2Hz, 2H),4.34(s,1H),3.87-3.78(m,2H),3.72-3.67(m,3H),3.55-3.28(m,1H),2.19(s,3H),2.19-2.08(m,1H),1.89-1.85(m,1H). LC-MS calcd exact mass 442.15,found m / z 443.5[M+H] + . HPLC purity 99.2%, chiral HPLC purity 99.7%; mp 117℃.

[0416] Example 11: N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (Compound #201)

[0417] [ka]

[0418] Step 1: Methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate

[0419] [ka]

[0420] To a stirred solution of methyl 1H-imidazole-4-carboxylate (2.32 g, 18.4 mmol) in acetonitrile (75 mL) was added potassium carbonate (5.08 g, 36.8 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and then 2,4-dichloro-5-methylpyrimidine (2 g, 18.4 mmol) was added. The resulting mixture was stirred at room temperature overnight. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 × 150 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in n-hexane as the eluent to give methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate as an off-white solid (53.7%). 1 HNMR (400MHz, CDCl3): δ 8.63 (s, 1H), 8.25 (d, J=5.2Hz, 2H), 3.95 (s, 3H), 2.52 (s, 3H). LC-MS calcd exact mass 252.04,found m / z 253.1[M+H] + .

[0421] Step 2: Methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate

[0422] [ka]

[0423] To a solution of 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate (0.27 g, 1.07 mmol) in isopropanol (5 mL) was added DIPEA (0.58 mL, 3.21 mmol) and tetrahydro-2H-pyran-4-amine (0.16 mL, 1.60 mmol). The resulting mixture was stirred in a sealed glass tube at 100° C. for 20 minutes. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using methanol in DCM as the eluent to give methyl 1-(5-methyl-2-(tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate as an off-white solid (0.25 g, 76%). H NMR (400 MHz, DMSO-d): δ 8.35 (s, 1H), 8.29 (s, 1H), 8.26 (s, 1H), 7.38 (d, J = 7.6 Hz, 1H), 3.85-3.82 (m, 3H), 3.77 (s, 3H), 3.37 (t, J = 10 Hz, 2H), 2.15 (s, 3H), 1.80 (d, J = 10.4 Hz, 2H), 1.50-1.46 (m, 2H). LC-MS calcd exact mass 317.15,found m / z 318.4[M+H] + .

[0424] Alternatively, methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate may be prepared as follows.

[0425] [ka]

[0426] N,N-Dimethylacetamide (DMAC) (4.6 L), 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate (1150 g, 4.55 mol), DIPEA (3.2 L), and tetrahydro-2H-pyran-4-amine hydrochloride (940 g, 6.83 mol) were sequentially charged to a reactor. The resulting mixture was heated to 100 °C and stirred until the HPLC content of 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate in the reaction mixture was 5% or less. The mixture was cooled, water was charged to the reactor, and the mixture was stirred at 15–18 °C. The mixture was then cooled and stirred at 3–10 °C. The solid was collected by filtration, and the filter cake was washed with water and dried to give methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate (1224 g, 85%).

[0427] Step 3: N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

[0428] [ka]

[0429] To a solution of methyl-1-(5-methyl-2-(tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxylate (0.1 g, 0.315 mmol) in toluene (10 mL) was added 2-amino-2-(3-chlorophenyl)ethanol (0.10 g, 0.63 mmol) and trimethylaluminum (2 M solution in toluene, 0.78 mL, 1.57 mmol). The resulting mixture was stirred at 100° C. for 1.5 hours under CEM microwave irradiation. The mixture was cooled, then quenched with water (10 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using methanol in DCM as the eluent to give N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide as an off-white solid (0.12 g, 86%). 1HNMR(400MHz,DMSO-d6):δ 8.41(d,J=7.8Hz,1H),8.34(s,1H),8.28(s,1H),8.09(s,1H),7.42(s,1H),7.38(d,J=9.6Hz,1H),7.32-7.27(m,3H),5.05-4. 98(m,2H),3.85-3.77(m,3H),3.71(t,J=4Hz,2H),3.38(t,J=8Hz,2H),2.16(s,3H),1.80(d,J=11.2Hz,2H),1.51-1.44(m,2H). LC-MS calcd exact mass 456.17,found m / z 457.5[M+H] + ;HPLC purity 99.53%.

[0430] Example 12: (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (Compound #211)

[0431] [ka]

[0432] Step 1 and Step 2: The procedure followed is similar to that described in Example 11.

[0433] Step 3: (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-(tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

[0434] [ka]

[0435] To a solution of methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate (0.07 g, 0.22 mmol) in toluene (2 mL) was added (S)-2-amino-2-(3-chlorophenyl)ethanol (0.075 g, 0.44 mmol) and trimethylaluminum (2 M solution in toluene, 0.22 mL, 0.44 mmol). The resulting mixture was stirred at 100° C. for 1.5 h under CEM microwave irradiation. The mixture was cooled, quenched with water (10 mL), and extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using methanol in DCM as the eluent, followed by washing of the isolated product with n-pentane to give (S)—N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide as an off-white solid (0.060 g, 60%). 1HNMR(400MHz,DMSO-d6):δ 8.39(d,J=8Hz,1H),8.34(s,1H),8.28(s,1H),8.09(s,1H),7.43(s,1H),7.37-7.32(m,3H),7.29(br s,1H),5.02(d,J=8Hz,2H),3.85-3.82(m,3H),3.72(t,J=8Hz,2H),3.39-3.26(m,2H),2.17(s,3H),1.81(d,J=8Hz,2H),1.48(d,J=8Hz,2H). LC-MS calcd exact mass 456.17,found m / z 457.2[M+H] + HPLC purity 99.81%, chiral HPLC purity 99.92%; mp 145℃.

[0436] Representative examples of combinations of methods used in Schemes 4 and 3

[0437] Example 13: N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (Compound #93)

[0438] [ka]

[0439] Step 1 and Step 2: The procedure followed was similar to that described in Example 11.

[0440] Step 3: 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylic acid

[0441] [ka]

[0442] To a stirred solution of methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate (1.5 g, 4.731 mmol) in tetrahydrofuran (30 mL) was added potassium trimethylsilanolate (1.82 g, 14.18 mmol) at 0 °C. The reaction mixture was stirred at 45 °C for 1.5 h. The reaction mixture was then quenched with water (25 mL) and washed with ethyl acetate (2 × 10 mL). The pH of the aqueous layer was adjusted to a maximum of 5–6 by the addition of 4 N HCl solution. The aqueous layer was then extracted with ethyl acetate (3 × 60 mL) and the combined organic layers were concentrated under reduced pressure to give 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylic acid as an off-white solid (1.2 g, 84%). 1HNMR(400MHz,DMSO-d6):δ 12.47(br s,1H),8.33(s,1H),8.23(br s,1H),8.20(s,1H),7.36(d,J=7.6Hz,1H),3.88(br s,1H),3.83(d,J=11.6Hz,2H),3.36(t,J=10.8Hz,2H),2.15(s,3H),1.80(d,J=10.4Hz,2H),1.52-1.42(m,2H). LC-MS calcd exact mass 303.13,found m / z 304.4[M+H] + .

[0443] Step 4: Methyl 2-(bromomethyl)-6-chlorobenzoate

[0444] [ka]

[0445] To a solution of methyl 2-chloro-6-methylbenzoate (1 g, 5.4 mmol) in carbon tetrachloride (50 mL) was added N-bromosuccinimide (1 g, 5.9 mmol) and benzoyl peroxide (0.131 g, 0.5 mmol). The resulting mixture was stirred at 80 °C for 10 h. The reaction mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure to give methyl 2-(bromomethyl)-6-chlorobenzoate (1.2 g). LC-MS calculated exact mass 261.94, found m / z 263.0 [M+H]. + .

[0446] Step 5: Methyl 2-(azidomethyl)-6-chlorobenzoate

[0447] [ka]

[0448] To a solution of methyl 2-(bromomethyl)-6-chlorobenzoate (1 g, 3.8 mmol) in DMF (10 mL) was added sodium azide (0.494 g, 7.6 mmol) at 0 °C. The resulting mixture was stirred at 70 °C for 12 h. The reaction mixture was diluted with ice-cold water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give methyl 2-(azidomethyl)-6-chlorobenzoate (1.2 g). LC-MS calculated exact mass 225.03, found m / z 198.1 [M+H-N2]. + .

[0449] Step 6: (2-(aminomethyl)-6-chlorophenyl)methanol

[0450] [ka]

[0451] To a solution of methyl 2-(azidomethyl)-6-chlorobenzoate (0.5 g, 2.2 mmol) in tetrahydrofuran (10 mL) was slowly added lithium aluminum hydroxide (0.337 g, 8.8 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with ice-cold water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give (2-(aminomethyl)-6-chlorophenyl)methanol (0.4 g). LC-MS calculated exact mass 171.05, found m / z 172.1 [M+H]. + .

[0452] Step 7: N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

[0453] [ka]

[0454] To a solution of 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylic acid (0.1 g, 0.3 mmol) in DCM (10 mL) was added (2-(aminomethyl)-6-chlorophenyl)methanol (0.84 g, 0.4 mmol) and DIPEA (0.17 mL, 0.9 mmol), followed by T3P (0.24 mL, 0.8 mmol). The resulting mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with cold ice water (50 mL) and extracted with DCM (2 × 100 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by Biotage Isolera using methanol in DCM as the eluent to give N-(3-chloro-2-(hydroxymethyl)benzyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide as an off-white solid (0.43 g, 29%). HNMR(400MHz,DMSO-d6):δ 8.62(t,J=6Hz,1H),8.33(s,1H),8.25(s,1H),8.10(s,1H),7.36-7.23(m,4 H),5.24(t,J=5.0Hz,1H),4.76(d,J=5.2Hz,2H),4.61(d,J=6Hz,2H),3.9(br s,1H),3.83(d,J=11.2Hz,2H),3.36(t,J=11.0Hz,2H),2.17(s,3H),1.80(d,J=11.6Hz,2H),1.52-1.43(m,2H). LC-MS calcd exact mass 456.17,found m / z 457.0[M+H] + ;HPLC purity 99.05%.

[0455] Representative Examples of General Scheme 7:

[0456] Example 14: N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxamide (Compound #77)

[0457] [ka]

[0458] Step 1: 4-Bromo-N-phenylpyridin-2-amine

[0459] [ka]

[0460] A solution of 4-bromopyridin-2-amine (1.0 g, 5.7 mmol), iodobenzene (2.35 g, 11.56 mmol), and cesium carbonate (8.82 g, 24.855 mmol) in 1,4-dioxane was degassed with argon for 30 minutes, followed by the addition of Xantphos (0.66 g, 1.156 mmol) and tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (0.528 g, 0.578 mmol). The resulting mixture was stirred at 150 °C for 12 hours in a sealed glass tube. The reaction mixture was cooled, combined with water (50 mL), and extracted with ethyl acetate (3 × 200 mL). The combined organic layers were washed with water (100 mL) and brine (50 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in n-hexane as the eluent to give 4-bromo-N-phenylpyridin-2-amine as a yellow solid (0.81 g, 56%). LC-MS calculated exact mass 247.99 and 249.99, found m / z 251.1 [M+H] + .

[0461] Step 2: Methyl 1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylate

[0462] [ka]

[0463] To a solution of 4-bromo-N-phenylpyridin-2-amine (0.5 g, 2.00 mmol) in DMF (3 mL) was added methyl 1H-imidazole-4-carboxylate (0.37 g, 3.01 mmol) and potassium phosphate (2.12 g, 10.00 mmol). The mixture was degassed with argon for 15 minutes, and then copper(I) iodide (0.076 g, 0.40 mmol) and L-proline (0.046 g, 0.40 mmol) were added. The resulting mixture was stirred at 150 °C for 12 hours in a sealed glass tube. The reaction mixture was cooled, combined with water (30 mL), and extracted with ethyl acetate (50 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in n-hexane as the eluent to give methyl 1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylate as a colorless solid (0.15 g, 25%). 1 HNMR(400MHz,DMSO-d6):δ 9.18(s,1H),8.45(d,J=11.6Hz,2H),8.25(d,J=5.6Hz,1H),7.64(d,J=8Hz,2H),7.28(t, LC-MS calcd exact mass 294.11,found m / z 295.2[M+H] + .

[0464] Step 3: 1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid

[0465] [ka]

[0466] To a solution of methyl 1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylate (0.1 g, 0.77 mmol) in THF (6 mL) and water (6 mL) was added lithium hydroxide monohydrate (0.057 g, 1.36 mmol). The resulting mixture was stirred at room temperature for 6 hours. The mixture was evaporated under reduced pressure, and the pH was adjusted to a maximum of 6 by the addition of 1N HCl. The resulting solid was removed by filtration, washed with water (5 mL), and then dried under reduced pressure to give 1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid as a colorless solid (0.08 g, 88%). 1HNMR(400MHz,DMSO-d6):δ 12(br s,1H),9.30(s,1H),8.42(s,1H),8.37(s,1H),8.24(d,J=5.6Hz,1H),7.64(d,J=8Hz, 2H),7.28(t,J=7.6Hz,2H),7.17(d,J=1.6Hz,1H),7.06(s,1H),6.94(t,J=7.2Hz,1H). LC-MS calcd exact mass 280.10,found m / z 281.1[M+H] + .

[0467] Step 4: N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxamide

[0468] [ka]

[0469] To a solution of 1-(2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid (0.04 g, 0.178 mmol) in DCM (6 mL) and DMF (0.2 mL) was added triethylamine (0.053 mL, 0.534 mmol), EDC (0.068 g, 0.356 mmol), and HOBt (0.007 g, 0.053 mmol). The reaction mixture was stirred at room temperature for 15 minutes, and then 2-amino-2-(3-chlorophenyl)ethanol (0.036 g, 0.213 mmol) was added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using methanol in DCM as the eluent to give N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(phenylamino)-pyridin-4-yl)-1H-imidazole-4-carboxamide as a colorless solid (0.015 g, 24%). 1HNMR(400MHz,DMSO-d6):δ 9.17(s,1H),8.45(s,1H),8.40(d,J=8.4Hz,1H),8.24(d,J=7.6Hz,2H),7.64(d,J=7.6Hz,2H),7.42(s,1H),7.32-7.28(m,2) H),7.27-7.25(m,3H),7.15(d,J=5.6Hz,1H),7.02(s,1H),6.92(t,J=7.2Hz,1H),5.04-4.99(m,2H),3.73(t,J=5.6Hz,2H). LC-MS calcd exact mass 433.13,found m / z 434.2[M+H] + .HPLC purity 99.52%;mp 130.0℃.

[0470] Representative Examples of General Scheme 8:

[0471] Example 15: 1-(2-(benzo[d][1,3]dioxol-5-ylamino)-5-methylpyrimidin-4-yl)-N-(1-(3,5-dichlorophenyl)-2-hydroxyethyl)-1H-pyrrole-3-carboxamide (Compound #74)

[0472] [ka]

[0473] Step 1: 2-chloro-5-methylpyridine 1-oxide

[0474] [ka]

[0475] To a solution of 2-chloro-5-methylpyridine (2.0 g, 15.7 mmol) in CHCl3 (20 mL), meta-chloroperoxybenzoic acid (3.2 g, 18.89 mmol) was added portionwise, and the mixture was then warmed to 50 °C for 16 h. The reaction mixture was cooled to -10 °C, and the solid was filtered through Celite. The filtrate was evaporated and purified by column chromatography on silica gel using 80% ethyl acetate in hexane as eluent to give 2-chloro-5-methylpyridine 1-oxide (1.9 g, 84%). ¹H NMR (400 MHz, DMSO-d6): δ 8.33 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 2.22 (s, 3H). LC-MS calcd exact mass 143.01,found m / z 144.1[M+H] + .

[0476] Step 2: 2-chloro-5-methyl-4-nitropyridine 1-oxide

[0477] [ka]

[0478] To a mixture of fuming nitric acid (4.5 mL) and sulfuric acid (6 mL) was added 2-chloro-5-methylpyridine-1-oxide (1.4 g, 9.7 mmol). The mixture was then heated at 100 °C for 2 h. The mixture was cooled to room temperature, poured onto crushed ice, and neutralized by the addition of solid sodium carbonate. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and evaporated under reduced pressure to give 2-chloro-5-methyl-4-nitropyridine-1-oxide (1.3 g, 72%). H NMR (400 MHz, CDCl): δ 8.27 (s, 1H), 8.26 (s, 1H), 2.60 (s, 3H). LC-MS calculated exact mass 188.00, found m / z 189.1 [M+H]. + .

[0479] Step 3: 5-Methyl-4-nitro-2-(phenylamino)pyridine 1-oxide.

[0480] [ka]

[0481] A mixture of 2-chloro-5-methyl-4-nitropyridine 1-oxide (0.5 g, 2.6 mmol), aniline (0.5 g, 5.3 mmol), and potassium carbonate (0.73 g, 5.3 mmol) in dioxane (10 mL) was purged with nitrogen gas for 30 minutes. Tris(dibenzylideneacetone)dipalladium(0) (0.12 g, 0.13 mmol) and BINAP (0.16 g, 0.26 mmol) were added to the mixture, which was purged with nitrogen gas for an additional 20 minutes and then heated at 100 °C for 16 hours. The mixture was filtered through Celite, and the filtrate was evaporated under reduced pressure. The residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel using 60% ethyl acetate in hexane as eluent to give 5-methyl-4-nitro-2-(phenylamino)pyridine 1-oxide (0.4 g, 56%). H NMR (400 MHz, CDCl): δ 8.48 (s, 1H), 8.17 (s, 1H), 7.73 (s, 1H), 7.45 (t, J = 8.4 Hz, 2H), 7.29-7.25 (m, 3H), 2.50 (s, 3H). LC-MS calculated exact mass 245.08, found m / z 246.1 [M+H]. + .

[0482] Step 4: 5-methyl-N-2-phenylpyridine-2,4-diamine

[0483] [ka]

[0484] Iron powder (0.53 g, 9.57 mmol) was added to a solution of 5-methyl-4-nitro-2-(phenylamino)pyridine-1-oxide (0.35 g, 1.42 mmol) in acetic acid (7 mL), and the mixture was warmed to 100 °C for 20 min. The mixture was cooled and then poured into 1 M NaOH solution and extracted with DCM. The organic layer was washed with water and brine, dried over sodium sulfate, and evaporated under reduced pressure to give 5-methyl-N-2-phenylpyridine-2,4-diamine (0.26 g, 93%). 1HNMR(400MHz,DMSO-d6):8.75(s,1H),7.52(s,1H),7.38(d,J=8Hz,2H),7.25(t,J=7.6Hz,2H),6.92(t,J=7.2Hz,1H),6.26(br s, 2H), 6.07 (s, 1H), 1.93 (s, 3H). LC-MS calcd exact mass 199.11,found m / z 200.2[M+H] + .

[0485] Step 5: 4-Bromo-5-methyl-N-phenylpyridin-2-amine

[0486] [ka]

[0487] A mixture of copper(II) bromide (0.56 g, 2.51 mmol) and tert-butyl nitrite (0.25 mL, 3.12 mmol) in acetonitrile (5 mL) was stirred at room temperature for 30 minutes, cooled to 0 °C, and then 5-methyl-N-2-phenylpyridine-2,4-diamine (0.25 g, 1.25 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with aqueous ammonium hydroxide (until the blue color disappeared), water, and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using 6% ethyl acetate in hexane as eluent to give 4-bromo-5-methyl-N-phenylpyridin-2-amine (0.07 g, 18%). 1HNMR (400MHz, CDCl3): 8.21 (s, 1H), 8.15 (s, 1H), 7.53-7.39 (m, 4H), 7.04 (d, J = 7.2Hz, 2H), 2.39 (s, 3H). LC-MS calcd exact mass 262.01 and 264.01,found m / z 265.1[M+H] + .

[0488] Step 6: N-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-(phenylamino)pyridin-4-yl)-1H-pyrrole-3-carboxamide

[0489] [ka]

[0490] A mixture of 4-bromo-5-methyl-N-phenylpyridin-2-amine (0.07 g, 0.26 mmol), N-(2-hydroxy-1-phenylethyl)-1H-pyrrole-3-carboxamide (0.07 g, 0.29 mmol), and potassium phosphate (0.16 g, 0.79 mmol) in DMF (2 mL) was purged with nitrogen gas for 15 minutes. L-Proline (0.006 g, 0.053 mmol) and copper iodide (0.01 g, 0.053 mmol) were added to the reaction mixture, which was purged with nitrogen gas for an additional 10 minutes and then stirred in a sealed glass tube at 100 °C for 16 hours. The mixture was cooled, suspended in water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel using 2% methanol in DCM as eluent to give N-(2-hydroxy-1-phenylethyl)-1-(5-methyl-2-(phenylamino)pyridin-4-yl)-1H-pyrrole-3-carboxamide (0.04 g, 40%). 1HNMR(400MHz,DMSO-d6):9.04(s,1H),8.13(s,1H),8.09(d,J=8.4Hz,1H),7.66(s,1H),7.61(d,J=8Hz,2H),7.31(t,J=7.2Hz,2H)7.29-7.22(m ,5H),7.19-7.08(m,1H),6.87(t,J=7.6Hz,1H),6.74(d,J=7.6Hz,2H),5 .06-5.01(m,1H),4.85(t,J=5.6Hz,1H),3.66-3.63(m,2H),2.14(s,3H). LC-MS calcd exact mass 412.19,found m / z 413.3[M+H] + .HPLC purity 99.39%.

[0491] Representative Examples of General Scheme 9:

[0492] Example 16: N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide (Compound #159)

[0493] [ka]

[0494] Step 1: Methyl 1-(2-chloro-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylate

[0495] [ka]

[0496] To a stirred solution of methyl 1H-pyrrole-3-carboxylate (1.24 g, 9.97 mmol) in DMF (15 mL) was added cesium carbonate (1.22 g, 3.72 mmol). The reaction mixture was stirred at room temperature for 15 minutes, and then 2,4-dichloro-5-methylpyridine (2 g, 1.24 mmol) was added. The resulting mixture was heated at 100 °C for 10 hours. The mixture was combined with water (200 mL) and extracted with ethyl acetate (800 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in n-hexane as the eluent to give methyl 1-(2-chloro-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylate as a colorless solid (1.3 g, 43%). 1 HNMR (400MHz, DMSO-d6): δ 8.44(s,1H),7.80(s,1H),7.59(s,1H),7.22(t,J=2.0Hz,1H),6.66-6.65(m,1H),3.73(s,3H),2.25(s,3H). LC-MS calcd exact mass 250.05,found m / z 251.1[M+H] + .

[0497] Step 2: Methyl 1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylate

[0498] [ka]

[0499] To a solution of methyl 1-(2-chloro-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylate (0.4 g, 1.60 mmol) in dioxane (10 mL) was added potassium carbonate (0.66 g, 4.8 mmol) and 4-fluoroaniline (0.26 g, 2.40 mmol). The mixture was degassed with argon for 15 minutes, followed by the addition of tris(dibenzylideneacetone)dipalladium(0) (0.073 g, 0.08 mmol) and 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (0.09 g, 0.16 mmol). The resulting mixture was stirred in a sealed glass tube at 100 °C for 12 hours. The mixture was cooled, quenched with water (50 mL), and extracted with ethyl acetate (200 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in n-hexane as the eluent to give methyl 1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylate as an off-white solid (0.4 g, 76%). 1H NMR (400 MHz, DMSO-d6): δ 9.06 (s, 1H), 8.12 (s, 1H), 7.69 (s, 1H), 7.64-7.60 (m, 2H), 7.14-7.07 (m, 3H), 6.69 (s, 1H), 6.64-6.63 (m, 1H), 3.73 (s, 3H), 2.10 (s, 3H). LC-MS calcd exact mass 325.12,found m / z 326.2[M+H] + .

[0500] Step 3: 1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylic acid

[0501] [ka]

[0502] To a mixture of methyl 1-(2-(4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylate (0.5 g, 1.33 mmol) in THF (10 mL) and water (10 mL) was added lithium hydroxide monohydrate (0.25 g, 6.15 mmol). The resulting mixture was warmed to reflux for 12 hours. The mixture was cooled, concentrated under reduced pressure, and the pH was adjusted to a maximum of 6 by the addition of 1N HCl. The solid was removed by filtration, washed with water, and dried under vacuum to give 1-(2-(4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylic acid as an off-white solid (0.45 g, 94%). 1 HNMR (400MHz, DMSO-d6): δ 9.16(s,1H),8.11(s,1H),7.62(t,J=7.6Hz,3H),7.11(t,J=8.4Hz,3H),6.71(s,1H),6.59(s,1H),2.12(s,3H). LC-MS calcd exact mass 311.11,found m / z 312.2[M+H] + .

[0503] Step 4: N-((3-chlorophenyl)(cyano)methyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide

[0504] [ka]

[0505] To a solution of 1-(2-(4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxylic acid (0.1 g, 0.32 mmol) in NMP (5 mL) was added triethylamine (0.09 g, 0.96 mmol), EDC (0.12 g, 0.69 mmol), and HOBt (0.013 g, 0.096 mmol). The reaction mixture was stirred at room temperature for 15 minutes, and then 2-amino-2-(3-chlorophenyl)acetonitrile (0.064 g, 0.38 mmol) was added. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using methanol in DCM as the eluent to give N-(3-chlorophenyl)(cyano)methyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide as a colorless solid (0.03 g, 20%). 1HNMR(400MHz,DMSO-d6):δ 9.21(d,J=8Hz,1H),9.07(s,1H),8.12(s,1H),7.71(s,1H),7.64-7.60(m,2H),7.54(s,1H),7.49(s,3 H),7.13(s,1H),7.10(t,J=8.8Hz,2H),6.75(s,1H),6.68(s,1H),6.40(d,J=7.6Hz,1H),2.13(s,3H). LC-MS calcd exact mass 459.13,found m / z 460.2[M+H] + .

[0506] Step 5: N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide

[0507] [ka]

[0508] To a solution of N-(3-chlorophenyl)(cyano)methyl)-1-(2-(4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide (0.03 g, 0.065 mmol) in methanol (15 mL) was added Raney nickel (up to 0.05 g) under an argon atmosphere, followed by ammonia in methanol (10 mL). The resulting mixture was stirred at room temperature under an H atmosphere using a bladder for 12 hours. The reaction mixture was filtered through Celite, washed with methanol (100 mL), and the filtrate was evaporated under reduced pressure. The residue was purified by gradient column chromatography using methanol in DCM as eluent to give N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-pyrrole-3-carboxamide as a colorless solid (0.015 g, 50%). 1HNMR(400MHz,DMSO-d6):δ 9.07(s,1H),8.15-8.12(m,2H),7.67-7.61(m,3H),7.39(s,1H),7.36-7.26(m,3H),7.09-7 .06(m,3H),6.75(s,1H),6.69(s,1H),4.90(d,J=6.8Hz,1H),2.84(d,J=7.2Hz,2H),1.88(br s,2H),2.14(s,3H). LC-MS calcd exact mass 463.16,found m / z 464.5[M+H] + , HPLC purity 99.71%, mp 118.1℃.

[0509] Representative Examples of General Scheme 10:

[0510] Example 17: 1-(5-chloro-2-(phenylamino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-imidazole-4-carboxamide (Compound #106)

[0511] [ka]

[0512] Step 1: Tert-butyl (4-chloropyridin-2-yl)carbamate

[0513] [ka]

[0514] To a stirred solution of 4-chloropyridin-2-amine (1.5 g, 1.16 mmol) in pyridine (15 mL) was added trimethylacetyl chloride (1.688 g, 1.4 mmol). The mixture was stirred at room temperature overnight. The mixture was combined with water (20 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were dried over sodium sulfate, evaporated under reduced pressure, and purified by gradient column chromatography on basic alumina using ethyl acetate in n-hexane as the eluent to give tert-N-(4-chloropyridin-2-yl)pivalamide as a white solid (1.7 g, 69%). 1 HNMR(400MHz,CDCl3):δ 8.35(s,1H),8.14(d,J=5.6Hz,1H),8.02(br s,1H),7.04-7.02(m,1H),1.32(s,9H).

[0515] Step 2: Tert-butyl (4,5-dichloropyridin-2-yl)carbamate

[0516] [ka]

[0517] To a solution of N-(4-chloropyridin-2-yl)pivalamide (1.6 g, 7.5 mmol) in acetonitrile (40 mL) was added N-chlorosuccinimide (5.02 g, 3.76 mmol). The mixture was stirred at reflux overnight. The mixture was cooled, combined with water (10 mL), and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate, evaporated under reduced pressure, and purified by gradient column chromatography using ethyl acetate in n-hexane as the eluent to give N-(4,5-dichloropyridin-2-yl)pivalamide as a white solid (1.3 g, 70%). 1 HNMR (400MHz, CDCl3): δ 8.48(s,1H),8.25(s,1H),7.98(br s,1H),1.32(s,9H).

[0518] Step 3: 4,5-Dichloropyridin-2-amine

[0519] [ka]

[0520] A mixture of N-(4,5-dichloropyridin-2-yl)pivalamide (1.25 g, 5.04 mmol) in 6 N HCl (20 mL) was stirred at 100° C. for 10 h. The mixture was cooled, combined with water (20 mL), and made basic by the addition of sodium bicarbonate solution (20 mL). The mixture was extracted with ethyl acetate (3×40 mL), and the combined organic layers were dried over sodium sulfate, evaporated under reduced pressure, and purified by gradient column chromatography using ethyl acetate in n-hexane as the eluent to give 4,5-dichloropyridin-2-amine as a white solid (0.7 g, 85%). 1 HNMR (400MHz, CDCl3): δ 8.06 (s, 1H), 6.60 (s, 1H), 4.48 (br s, 2H). LC-MS calcd exact mass 161.98,found m / z 162.8[M+H] + .

[0521] Step 4: 4,5-Dichloro-N-phenylpyridin-2-amine

[0522] [ka]

[0523] To a stirred solution of 4,5-dichloropyridin-2-amine (0.1 g, 0.61 mmol) in dioxane (5 mL) was added iodobenzene (0.25 g, 1.22 mmol), cesium carbonate (0.597 g, 1.83 mmol), and Xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) (0.035 g, 0.06 mmol). The mixture was degassed with argon for 10 min, then tris(dibenzylideneacetone)-dipalladium(0) (0.029 g, 0.03 mmol) was added and the mixture was degassed with argon for 10 min. The mixture was degassed for 1 minute. The mixture was stirred at 100°C for 3 hours. The mixture was cooled, concentrated under reduced pressure, diluted with water (10 mL), and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in hexane as the eluent to give 4,5-dichloro-N-phenylpyridin-2-amine as an off-white solid (82 mg, 56% yield). 1H NMR (400 MHz, CDCl3): δ 8.17(s,1H),7.36(t,J=7.2Hz,2H),7.28(s,2H),7.12(t,J=7.6Hz,1H),6.92(s,1H),6.51(br s,1H). LC-MS calcd exact mass 238.01,found m / z 239.1[M+H] + .

[0524] Step 5: Methyl 1-(5-chloro-2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylate

[0525] [ka]

[0526] To a stirred solution of 4,5-dichloro-N-phenylpyridin-2-amine (0.3 g, 1.25 mmol) in DMF (7 mL) was added potassium carbonate (0.867 g, 6.2 mmol). The mixture was stirred at room temperature for 15 minutes, then methyl 1H-imidazole-4-carboxylate (0.159 g, 1.25 mmol) was added, and the mixture was stirred at 100 °C for 10 hours. The mixture was cooled, combined with water (40 mL), and extracted with ethyl acetate (3 × 100 mL). The combined organic layers were dried over sodium sulfate and then evaporated under reduced pressure. The residue was purified by gradient column chromatography using ethyl acetate in n-hexane as the eluent to give methyl 1-(5-chloro-2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylate as an off-white solid (103 mg, 25% yield). 1HNMR(400MHz,DMSO-d6):δ 9.44(s,1H),8.39(s,1H),8.26(d,J=1.6Hz,1H),8.14(d,J=1.2Hz,1H),7 .62-7.59(m,2H),7.3(t,J=5.2Hz,2H),6.96(t,J=8Hz,2H),3.78(s,3H). LC-MS calcd exact mass 328.07,found m / z 329.1[M+H] + .

[0527] Step 4: 1-(5-chloro-2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid

[0528] [ka]

[0529] To a stirred solution of methyl 1-(5-chloro-2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylate (0.075 g, 0.22 mmol) in THF (14 mL) and water (4 mL) was added lithium hydroxide monohydrate (0.039 g, 0.91 mmol). The reaction mixture was stirred at 50° C. overnight. The mixture was concentrated under reduced pressure and neutralized by the addition of 1N HCl to a pH of 7. The resulting solid was removed by filtration to give 1-(5-chloro-2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid as a gray solid (35 mg, 49% yield). 1HNMR (400MHz, DMSO): δ 9.45(s,1H),8.38(s,1H),8.16(s,1H),8.11(s,1H),7.61(d,J=8Hz,2H),7.29(t,J=7.6Hz,2H),6.97-6.93(m,2H). LC-MS calcd exact mass 314.06,found m / z 315.1[M+H] + .

[0530] Step 7: 1-(5-chloro-2-(phenylamino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-imidazole-4-carboxamide

[0531] [ka]

[0532] To a stirred solution of 1-(5-chloro-2-(phenylamino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid (0.035 g, 0.11 mmol) in NMP (1.5 mL) was added EDC (0.065 g, 0.33 mmol), HOBt (0.005 g, 0.033 mmol), triethylamine (0.02 mL, 0.22 mmol), and 2-amino-2-(3-chlorophenyl)ethanol (0.022 g, 0.13 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and evaporated under reduced pressure. The crude residue was purified by preparative TLC using methanol in DCM as the eluent to give 1-(5-chloro-2-(phenylamino)pyridin-4-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1H-imidazole-4-carboxamide as an off-white solid (19 mg, 36% yield). 1HNMR(400MHz,DMSO-d6):δ 9.44(s,1H),8.41(s,1H),8.38(d,J=4.0Hz,1H),8.16(s,1H),8.02(s,1H),7.61(d,J=7.6Hz,2H),7.4 4(s,1H),7.33-7.30(m,2H),7.29-7.27(m,3H),6.93(s,2H),5.02-5.01(m,2H),3.72(t,J=5.6Hz,2H). LC-MS calcd exact mass 467.09,found m / z 468.1[M+H] + ;HPLC purity 99.88%.

[0533] Representative Examples of General Scheme 11:

[0534] Example 18: N-(2-amino-1-phenylethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide (Compound #191)

[0535] [ka]

[0536] Step 1: Methyl 1-(2-chloro-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylate

[0537] [ka]

[0538] To a solution of 2,4-dichloro-5-methylpyridine (1.285 g, 7.93 mmol) in DMF (15 mL) was added methyl 1H-imidazole-4-carboxylate (1 g, 7.93 mmol) and KCO (5.476 g, 39.68 mmol), and the mixture was stirred at 100 °C for 6 h. The mixture was cooled and diluted with water, and the resulting solid was removed by filtration and dried to give the crude product. The crude product was purified by Biotage Isolera (50% ethyl acetate in hexanes as eluent) to give methyl 1-(2-chloro-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylate (0.670 g, 34%). 1HNMR (400MHz, CDCl3): δ 8.44 (s, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.27 (s, 1H), 3.94 (s, 3H), 2.28 (s, 3H). LC-MS calcd exact mass 251.05,found m / z 252.1[M+H] + .

[0539] Step 2: Methyl 1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylate

[0540] [ka]

[0541] To a solution of methyl 1-(2-chloro-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylate (0.4 g, 1.59 mmol) in dioxane (10 mL) was added 4-fluoroaniline (0.353 g, 3.18 mmol) and K2CO3 (0.439 g, 3.18 mmol). The reaction mixture was degassed with argon, and then tris(dibenzylideneacetone)dipalladium(0) (0.072 g, 0.079 mmol) and BINAP (0.099 g, 0.15 mmol) were added. The mixture was heated at 100 °C for 1 h under a CEM microwave system. The mixture was cooled, diluted with water, and extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (4% methanol in DCM as eluent) to give methyl 1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylate (0.4 g, 77%). 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 1H), 7.74 (s, 1H), 7.61 (s, 1H), 7.29-7.25 (m, 2H), 7.06 (t, J = 8 Hz, 2H), 6.55 (s, 1H), 5.29 (s, 1H), 3.92 (s, 3H), 2.14 (s, 3H). LC-MS calculated exact mass 326.12, found m / z 327.2 [M+H]. + .

[0542] Step 3: 1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylic acid

[0543] [ka]

[0544] To a solution of methyl 1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylate (0.450 g, 1.38 mmol) in THF (12 mL) was added LiOH (0.289 g, 6.90 mmol) in water (8 mL). The mixture was stirred at reflux overnight, the mixture was cooled, concentrated under reduced pressure, and neutralized by the addition of 2 N HCl. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylic acid (0.210 g, 49%). 1HNMR(400MHz,CDCl3):δ 12.0(br s,1H),9.15(s,1H),8.15(d,J=11.2Hz,2H),8.04(s,1H),7.64-7.60(m,2H),7.09(t,J=17.2Hz,2H),6.73(s,1H),2.08(s,3H),LC-MS calcd exact mass 312.10,found m / z 313.1[M+H] + .

[0545] Step 4: N-(cyano(phenyl)methyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide

[0546] [ka]

[0547] To a solution of 1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxylic acid (0.2 g, 0.0641 mmol) in DCM (16 mL) was added 2-amino-2-phenylacetonitrile (0.151 g, 0.0769 mmol), EDC (0.345 g, 0.128 mmol), HOBt (0.040 g, 0.019 mmol), and TEA (0.194 g, 0.192 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the crude product. The crude product was purified by Biotage Isolera (6% methanol in DCM as eluent) to give N-(cyano(phenyl)methyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide (0.040 g, 15%). H NMR (400 MHz, CDCl): δ 8.36 (s, 1H), 8.12 (d, J = 14.4 Hz, 2H), 7.63-7.60 (m, 3H), 7.52 (d, J = 12 Hz, 2H), 7.45-7.34 (m, 4H), 7.09 (t, J = 8 Hz, 2H), 6.73 (s, 1H), 6.34 (d, J = 8 Hz, 1H), 2.87 (s, 1H), 2.08 (s, 3H). LC-MS calcd exact mass 426.16,found m / z 427.2[M+H] + .

[0548] Step 5: N-(2-amino-1-phenylethyl)-1-(2-((4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide

[0549] [ka]

[0550] To a solution of N-(cyano(phenyl)methyl)-1-(2-(4-fluorophenyl)amino)-5-methylpyridin-4-yl)-1H-imidazole-4-carboxamide (0.04 g, 0.0094 mmol) in methanol (5 mL) was added Raney nickel (0.060 g) and ammonium hydroxide (5 mL). The resulting reaction mixture was stirred under a hydrogen atmosphere at room temperature using a bladder for 6 hours. The reaction mixture was filtered through a Celite bed, washed with methanol, and the filtrate was evaporated under reduced pressure. The residue was purified by preparative TLC (3.5% methanol in DCM as eluent) to give the desired product (0.010 g, 25%). 1HNMR(400MHz,DMSO-d6):δ 9.14(s,1H),8.45(d,J=8.4Hz,8.15(s,1H),8.08(s,1H),7.97(s,1H),7.61(t,J=8.4Hz,2H),7.37-7.29(m,4H), 7.24-7.22(m,1H),7.11-7.06(m,2H),6.72(s,1H),4.98(d,J=5.2Hz,1H),3.06-2.93(m,2H),2.09(s,3H). calcd exact mass 430.19,found m / z 431.5[M+H] + , HPLC purity 98.54%, mp 154.7℃.

[0551] Representative Examples of General Scheme 12:

[0552] Example 19: N-(1-cyano-2-phenylethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (Compound #134)

[0553] [ka]

[0554] Step 1: 4-Azido-2-chloro-5-methylpyridine

[0555] [ka]

[0556] To a stirred solution of 2,4-dichloro-5-methylpyridine (1.0 g, 6.7 mmol) in DMF (15 mL) was added sodium azide (0.52 g, 8.1 mmol), and the resulting solution was stirred at 100 °C for 4 h. The mixture was then cooled to 0 °C, quenched with water (35 mL), and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure, and the residue (crude product, 1.2 g) was used in the next step without purification.

[0557] Step 2: Methyl 1-(2-chloro-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxylate

[0558] [ka]

[0559] To a stirred solution of 4-azido-2-chloro-5-methylpyridine (1.0 g, 5.93 mmol, crude) in DMSO (10 mL) and HO (2 mL), CuSO4.5HO (0.074 g, 0.0297 mmol), methyl propiolate (0.499 g, 5.95 mmol), sodium ascorbate (0.117 g, 0.595 mmol), sodium carbonate (0.126 g, 1.19 mmol), and DL-proline (0.126 g, 1.19 mmol) were added at room temperature. The resulting mixture was stirred at 65 °C for 18 h. The reaction mixture was then cooled to 0 °C, quenched with water (35 mL), and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography using 40% ethyl acetate in n-hexane as eluent to give the desired product as a white solid (0.87 g, 56%). LC-MS calculated exact mass 252.04, found m / z 253.06 [M+H]+ .

[0560] Step 3: Methyl 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxylate

[0561] [ka]

[0562] To a stirred solution of methyl 1-(2-chloro-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxylate (0.4 g, 1.58 mmol) in dioxane (20 mL) was added K2CO3 (0.438 g, 3.17 mmol), BINAP (0.098 g, 0.158 mmol), and 2,2-difluorobenzo[d][1,3]dioxol-5-amine (0.549 g, 3.17 mmol) at room temperature. The resulting solution was degassed with argon gas for 20 min, and then Pd2(dba)3 (0.145 g, 0.18 mmol) was added. The reaction mixture was stirred at 100 °C for 8 h in a sealed glass tube. The reaction mixture was then cooled to 0 °C, quenched with water (35 mL), and extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure, and the crude residue was purified by column chromatography using ethyl acetate in n-hexane as eluent to give the desired product as a white solid (0.43 g, 70%). LC-MS calculated exact mass 389.09, found m / z 388.19 [M−H] - .

[0563] Step 4: 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxylic acid

[0564] [ka]

[0565] To a stirred solution of methyl 1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxylate (0.24 g, 1.02 mmol) in THF:HO (5 mL:2 mL) was added LiOH (0.215 g, 5.14 mmol), and the reaction mixture was stirred at 80 °C for 4 h. The mixture was cooled to 0 °C and acidified by the addition of 2 N HCl solution (10 mL), followed by extraction with ethyl acetate (3 × 20 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the desired product as a yellowish solid (0.21 g, 91%). LC-MS calculated exact mass 375.08, found m / z 376.0 [M+H] + .

[0566] Step 5: N-(1-cyano-2-phenylethyl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide

[0567] [ka]

[0568] To a stirred solution of 1-(2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxylic acid (0.2 g, 0.533 mmol) in DCM (10 mL) was added EDC (0.2 g, 1.06 mmol), triethylamine (0.18 mL, 1.33 mmol), and HOBt (0.1 g, 0.799 mmol). 2-Amino-3-phenylpropanenitrile (0.155 g, 1.066 mmol) was then added, and the resulting mixture was stirred at room temperature for 18 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure, and the residue was purified by gradient chromatography using 60–120 mesh silica gel eluted with 25% ethyl acetate in n-hexane to give the desired product as a yellowish solid (0.15 g, 56%).

[0569] Step 6: N-(1-amino-3-phenylpropan-2-yl)-1-(2-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide

[0570] [ka]

[0571] To a stirred solution of N-(1-cyano-2-phenylethyl)-1-(2-((2,2-difluoro-benzo[d][1,3]dioxol-5-yl)amino)-5-methylpyridin-4-yl)-1H-1,2,3-triazole-4-carboxamide (0.13 g, 0.258 mmol) in methanol (10 mL) was added DCM (2 mL) to give a clear solution. NiCl (0.006 g, 0.051 mmol) and NaBH (0.049 g, 1.29 mmol) were then added to this solution, and the mixture was stirred at room temperature for 14 h. The reaction mixture was quenched with water (20 mL), filtered through Celite, and extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated under reduced pressure, and the crude product residue was purified by gradient chromatography using 60-120 mesh silica gel, eluting with 8% MeOH in DCM to give the desired product as a yellowish solid (0.03 g, 23%). 1HNMR(400MHz,DMSO-d6):δ 11.29(s,1H),9.49(s,1H),9.04(s,1H),8.59(d,J=8.8Hz,1H),8.28(s,1H),7.93(d,J=1.6Hz,1H), 7.33-7.14(m,8H),6.94(d,J=9.6Hz,1H),4.29(s,1H),3.50(s,1H),3.16-2.83(m,3H),1.97(s,3H). LC-MS calcd exact mass 507.18,found m / z 508.22[M+H] + ;HPLC purity 97.94%.

[0572] Representative Examples of General Scheme 13:

[0573] Example 20: N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(((S)-1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide (Compound #105)

[0574] [ka]

[0575] Step 1: (S)-2-((4-iodopyridin-2-yl)amino)butan-1-ol

[0576] [ka]

[0577] To a stirred solution of 2-fluoro-4-iodopyridine (2.0 g, 8.97 mmol) in NMP (10 mL) was added (S)-2-aminobutan-1-ol (1.197 g, 13.45 mmol), and the mixture was stirred at 100° C. in a sealed glass tube for 12 hours. The reaction mixture was then cooled, quenched with water (50 mL), and extracted with ethyl acetate (3×80 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by gradient column chromatography eluting with 20% ethyl acetate in n-hexane to give (S)-2-((4-iodopyridin-2-yl)amino)-butan-1-ol as an off-white solid (0.8 g, 30%). 1HNMR(400MHz,DMSO-d6):δ 7.61(d,J=5.6Hz,1H),6.91(s,1H),6.74-6.72(m,1H),6.34(d,J=8Hz,1H),4.57(t,J=6Hz,1H),3.73(d,J=5 .2Hz,1H),3.42-3.38(m,1H),3.31(s,1H),1.60(t,J=6Hz,1H),1.36(t,J=7.2Hz,1H),0.84(t,J=7.6Hz,3H). LC-MS calcd exact mass 292.01,found m / z 293.0[M+H] + .

[0578] Step 2: (S)-Methyl 1-(2-((1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylate

[0579] [ka]

[0580] To a stirred solution of (S)-2-((4-iodopyridin-2-yl)amino)butan-1-ol (0.8 g, 1.71 mmol) in DMF (5 mL) was added potassium phosphate (0.32 g, 2.57 mmol), methyl lH-imidazole-4-carboxylate (0.323 g, 2.57 mmol), and L-proline (0.039 g, 0.34 mmol). The mixture was degassed with nitrogen gas for 20 minutes, then copper(I) iodide (0.065 g, 0.34 mmol) was added, and the mixture was stirred at 150 °C for 12 hours in a sealed glass tube. The reaction mixture was then cooled, quenched with water (35 mL), and extracted with ethyl acetate (3 × 60 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure, and the residue was purified by gradient column chromatography eluting with 80% ethyl acetate in n-hexane to give (S)-methyl 1-(2-((1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylate as an off-white semi-solid (0.25 g, 32% yield). 1 HNMR(400MHz,DMSO-d6):δ 8.42(s,1H),8.38(s,1H),8.02(d,J=6Hz,1H,),7.67(m,1H),6.85(m,1 H),6.75(s,1H),6.36(d,J=8.4Hz,1H),5.72(s,1H),4.61(s,1H),4.12( m,1H),3.81(d,J=4Hz,1H),3.78(s,3H),3.46(t,J=5.6Hz,1H),3.34(t, J=5.6Hz,2H),1.60-1.44(m,1H),1.33-1.24(m,1H),0.89-0.83(m,3H). LC-MS calcd exact mass 290.14,found m / z 291.2[M+H] + .

[0581] Step 3: (S)-1-(2-((1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid

[0582] [ka]

[0583] To a stirred solution of (S)-methyl 1-(2-((1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylate (0.25 g, 0.86 mmol) in THF:water (5 mL:5 mL) was added lithium hydroxide monohydrate (0.179 g, 4.29 mmol), and the mixture was stirred at 50 °C for 12 h. The mixture was cooled, concentrated under reduced pressure, combined with water (15 mL), and washed with ethyl acetate (2 × 5 mL). The pH of the aqueous layer was adjusted to 6-6.5 by the addition of 4 N HCl, and the resulting solid was removed by filtration and dried under high vacuum to give the desired product as an off-white solid (0.15 g, 63% yield). 1HNMR(400MHz,DMSO-d6):δ 12.5(br s,1H),8.32(d,J=12Hz,2H),8.02(d,J=5.2Hz,1H),6.84-6.82(m,1H),6.74(s,1H),6.37(d,J=8.4Hz,1H),3.81(d,J=5.6H) z,1H),3.48-3.44(m,1H),1.67-1.60(m,1H),1.46-1.40(m,1H),1.37-1.31(m,1H),1.26-1.24(m,1H),0.89-0.86(m,3H). LC-MS calcd exact mass 276.12,found m / z 277.2[M+H] + .

[0584] Step 4: N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(((S)-1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide

[0585] [ka]

[0586] To a stirred solution of (S)-1-(2-((1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylic acid (0.07 g, 0.25 mmol) in NMP (3 mL) was added triethylamine (0.076 g, 0.76 mmol), followed by EDC (0.097 g, 0.51 mmol) and HOBt (0.01 g, 0.075 mmol). The mixture was stirred at room temperature for 20 min, then 2-amino-2-(3-chlorophenyl)ethanol (0.052 g, 0.30 mmol) was added, and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, filtered, evaporated under reduced pressure, and the residue was purified by gradient column chromatography eluting with 3% methanol in DCM to give N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-(((S)-1-hydroxybutan-2-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide as an off-white solid (15 mg, 14%). H NMR (400 MHz, DMSO-d): δ 8.38(t,J=7.2Hz,2H),8.18(s,1H),8.01(d,J=5.6Hz,1H),7.42(s,1H),7.32-7.26(m,3 H),6.84(d,J=5.6Hz,1H),6.74(s,1H),6.36(d,J=7.6Hz,1H),5.02-4.99(m,2H),4.61( d,J=5.6Hz,1H),3.81(s,1H),3.71(t,J=5.6Hz,1H),3.47-3.44(m,1H),3.34-3.27(m,1 H),1.67-1.65(m,1H),1.63-1.61(m,1H),1.07(t,J=7.2Hz,1H),0.87(t,J=6.8Hz,3H). LC-MS calcd exact mass 429.16,found m / z 430.2[M+H] + ;HPLC purity 99.46%.

[0587] Example 21: N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzofuran-5-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide (Compound #163)

[0588] [ka]

[0589] Step 1: N-(2,3-dihydrobenzofuran-5-yl)-4-iodopyridin-2-amine

[0590] [ka]

[0591] To a suspension of 2,3-dihydrobenzofuran-5-amine (1 g, 7.4 mmol) in 1:1 dioxane:water (200 mL) was added 2-fluoro-4-iodopyridine (1.982 g, 8.8 mmol) and aqueous HCl (2 mL, 35%). The mixture was stirred in a sealed glass tube at 100 °C for 15 h. The reaction mixture was cooled, basified by the addition of saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The combined organic layers were dried over NaSO, filtered, and evaporated to give the crude product residue, which was purified by gradient column chromatography using ethyl acetate in n-hexane as the eluent to give N-(2,3-dihydrobenzofuran-5-yl)-4-iodopyridin-2-amine as a yellow solid (600 mg, 24%). 1HNMR(400MHz,CDCl3):δ 7.76(d,J=4.8Hz,1H),7.13(s,1H),7.00-6.97(m,3H),6.77(d,J=8.4Hz,1H),6.48(s,1H),4.60(t,J=8.8Hz,2H),3.23(t,J=8.8Hz,2H). LC-MS calcd exact mass 337.99,found m / z 339.0[M+H] + .

[0592] Step 2: Methyl 1-(2-((2,3-dihydrobenzofuran-5-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylate

[0593] [ka]

[0594] To a solution of N-(2,3-dihydrobenzofuran-5-yl)-4-iodopyridin-2-amine (300 mg, 0.88 mmol) in DMF (3 mL) was added methyl lH-imidazole-4-carboxylate (167 mg, 1.3 mmol), potassium phosphate (564 mg, 2.6 mmol), and L-proline (20 mg, 0.17 mmol) under a nitrogen atmosphere. The reaction mixture was purged with nitrogen for 10 minutes, and then copper iodide (33 mg, 0.17 mmol) was added. The reaction mixture was stirred in a sealed glass tube at 140 °C for 15 hours. The reaction mixture was cooled and filtered through Celite. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, evaporated under reduced pressure, and the residue was purified by gradient column chromatography using ethyl acetate in n-hexane as eluent to give methyl 1-(2-((2,3-dihydrobenzofuran-5-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylate as a yellow semi-solid (0.10 g, 17%). LC-MS calculated exact mass 336.12, found m / z 337.2 [M+H] + .

[0595] Step 3: N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzofuran-5-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide

[0596] [ka]

[0597] To a solution of methyl 1-(2-((2,3-dihydrobenzofuran-5-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxylate (90 mg, 0.26 mmol) in toluene (3 mL) was added 2-amino-2-(3-chlorophenyl)ethanol (91 mg, 5.3 mmol) in toluene (2 M, 0.26 mL, 2 eq) and trimethylaluminum under nitrogen atmosphere. The mixture was stirred at 100° C. for 45 min under CEM microwave. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure to give a residue that was purified by gradient column chromatography using methanol in DCM as the eluent to give N-(1-(3-chlorophenyl)-2-hydroxyethyl)-1-(2-((2,3-dihydrobenzofuran-5-yl)amino)pyridin-4-yl)-1H-imidazole-4-carboxamide as an off-white solid (20 mg, 16%). 1HNMR(400MHz,DMSO-d6):δ 8.88(s,1H),8.42-8.37(m,2H),8.20-8.16(m,2H),7.51(s,1H),7.42(s,1H),7.32-7.28(m, 4H),7.21(d,J=8.4Hz,1H),7.05(d,J=4.8Hz,1H),6.88(s,1H),6.8(d,J=8.4Hz,1H),5.02(br s,2H),4.47(t,J=8.8Hz,2H),3.72(s,2H),3.15(t,J=8.4Hz,2H). LC-MS calcd exact mass 475.14,found m / z 476.1[M+H] + .

[0598] Representative Examples of General Scheme 20:

[0599] Example 22: (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (Alternative Synthesis of Compound #225a)

[0600] [ka]

[0601] Step 1: (S)-tert-butyl (1-(3-chlorophenyl)-2-hydroxyethyl)carbamate

[0602] [ka]

[0603] To a stirred solution of (S)-2-amino-2-(3-chlorophenyl)ethanol (1.0 g, 5.83 mmol) in t-butanol (15 mL) was added 2 M sodium hydroxide solution (0.29 g, 7.28 mmol) and di-tert-butyl-dicarbonate (1.92 mL, 8.16 mmol). The reaction mixture was stirred at 70 °C for 16.0 h. The reaction progress was monitored by TLC (30% ethyl acetate in n-hexane, KMnO activity). The reaction mixture was quenched with water (40 mL), extracted with ethyl acetate (3 × 40 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by gradient chromatography using 60-120 mesh silica gel, and the collected fractions were eluted with 20% ethyl acetate in n-hexane, and concentrated under reduced pressure to give (S)-tert-butyl (1-(3-chlorophenyl)-2-hydroxyethyl)carbamate as a white solid (1.0 g, 63%). 1 HNMR (400MHz, DMSO-d6): δ 7.32-7.21(m,5H),4.78(t,J=5.6Hz,1H),4.49(d,J=5.6Hz,1H),3.51-3.41(m,2H),1.34(s,9H).

[0604] Step 2: (S)-2-((tert-butoxycarbonyl)amino)-2-(3-chlorophenyl)ethyl methanesulfonate

[0605] [ka]

[0606] To a stirred solution of (S)-tert-butyl (1-(3-chlorophenyl)-2-hydroxyethyl)carbamate (1.0 g, 3.68 mmol) in dichloromethane (15 mL) was added triethylamine (0.62 mL, 4.42 mmol), and the mixture was cooled to 0 °C. Methanesulfonyl chloride (0.313 mL, 4.049 mmol) was added at 0 °C, and the mixture was then stirred at room temperature for 1.5 h. The progress of the reaction was monitored by TLC (25% ethyl acetate in n-hexane). The reaction mixture was quenched with saturated ammonium chloride (20 mL), extracted with dichloromethane (3 × 30 mL), and the combined organic layers were dried over sodium sulfate, filtered, concentrated under reduced pressure, washed with n-pentane, and dried under vacuum to give (S)-2-((tert-butoxycarbonyl)amino)-2-(3-chlorophenyl)ethyl methanesulfonate as a yellow oil (0.65 g, 51%).

[0607] Step 3: (S)-tert-butyl (2-azido-1-(3-chlorophenyl)ethyl)carbamate

[0608] [ka]

[0609] To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-2-(3-chlorophenyl)ethyl methanesulfonate (0.65 g, 1.86 mmol) in N,N-dimethylformamide (10 mL) was added sodium azide (0.242 g, 3.72 mmol), and the mixture was stirred at 50 °C for 16 h. The reaction progress was monitored by TLC (20% ethyl acetate in n-hexane). The reaction mixture was quenched with saturated ammonium chloride (15 mL), followed by water (30 mL), extracted with ethyl acetate (3 × 30 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by gradient chromatography using 60–120 mesh silica gel, eluting with 8% ethyl acetate in n-hexane. The appropriate fractions were combined and concentrated under reduced pressure to give (S)-tert-butyl (2-azido-1-(3-chlorophenyl)ethyl)carbamate as a colorless oil (0.5 g, 91%). 1 HNMR (400MHz, DMSO-d6): δ 7.67-7.58(m,1H),7.42(br s,1H),7.37-7.31(m,3H),4.73(br s,1H),3.44(t,J=8.4Hz,2H),1.35(s,9H).

[0610] Step 4: (S)-2-Azido-1-(3-chlorophenyl)ethanamine hydrochloride

[0611] [ka]

[0612] To a stirred solution of (S)-tert-butyl (2-azido-1-(3-chlorophenyl)ethyl)carbamate (0.5 g, 1.69 mmol) in dioxane (5 mL) was added 4 M HCl in dioxane (10 mL) at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, triturated with n-pentane, and dried under vacuum to give (S)-2-azido-1-(3-chlorophenyl)ethanamine hydrochloride as an off-white solid (0.43 g, HCl salt). LCMS calculated exact mass 196.05, m / z found 197.1 [M+H]. + .

[0613] Step 5: 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylic acid

[0614] [ka]

[0615] To a stirred solution of methyl 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylate (10.0 g, 31.53 mmol) in tetrahydrofuran (450 mL) was added potassium trimethylsilanolate (12.13 g, 94.60 mmol) at 0° C., and the resulting mixture was stirred at 45° C. for 1.5 hours. The reaction progress was monitored by TLC (5% methanol in dichloromethane). The reaction mixture was quenched with water (250 mL) and washed with ethyl acetate (3 × 50 mL), then 4 N HCl solution was added to adjust the pH of the aqueous layer to 4-5, extracted with 10% methanol in dichloromethane (8 × 250 mL), and the combined organic layers were concentrated under reduced pressure to give 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylic acid as an off-white solid (7.0 g, 73%). 1HNMR(400MHz,DMSO-d6):δ 12.46(br s,1H),8.34(s,1H),8.23(br s,1H),8.20(s,1H),7.36(d,J=7.6Hz,1H),3.89(br s,1H),3.83(d,J=11.6Hz,2H),3.39-3.33(m,2H),2.16(s,3H),1.80(d,J=10.4Hz,2H),1.52-1.42(m,2H). LCMS calcd exact mass 303.13,found m / z 304.1[M+H] + .

[0616] Step 6: (S)—N-(2-azido-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

[0617] [ka]

[0618] To a stirred solution of 1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxylic acid (6.0 g, 19.80 mmol) in dichloromethane (150 mL) and N,N-dimethylformamide (50 mL) was added triethylamine (13.81 mL, 98.97 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (5.99 g, 59.40 mmol), hydroxybenzotriazole (0.605 g, 3.96 mmol), and (S)-2-azido-1-(3-chlorophenyl)ethanamine hydrochloride (4.65 g, 19.80 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC (5% methanol in dichloromethane). The reaction mixture was then quenched with saturated sodium bicarbonate solution (50 mL), extracted with dichloromethane (3 × 50 mL), and washed with water (100 mL) and brine (50 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by gradient chromatography using 60-120 mesh silica gel, eluting with 4% methanol in dichloromethane. The appropriate fractions were collected and concentrated under reduced pressure to give (S)-N-(2-azido-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide as an off-white solid (5.65 g, 59%). LCMS calculated exact mass 481.17, found m / z 482.1 [M+H]. + .

[0619] Step 7: (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide

[0620] [ka]

[0621] To a stirred solution of (S)—N-(2-azido-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (7.12 g, 14.77 mmol) in methanol (75 mL) was added zinc dust (4.82 g, 73.87 mmol), and the resulting solution was stirred at room temperature for 10 minutes, followed by the addition of ammonium chloride (3.95 g, 73.87 mmol) in water (15 mL). The reaction mixture was stirred at 55° C. for 1 hour. The progress of the reaction was monitored by TLC (5% methanol in dichloromethane). The reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL), filtered through Celite, and washed with 10% methanol in dichloromethane. The organic layer was washed with water (2 × 25 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by Biotage chromatography using 60-120 mesh silica gel and eluted with 13% (methanol / isopropylamine) in dichloromethane. The appropriate fractions were collected and concentrated under reduced pressure to give (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide as an off-white solid (4.38 g, 65%). 1 HNMR(400MHz,DMSO-d6):δ 8.52(d,J=8.0Hz,1H),8.33(s,1H),8.26(s,1H),8.07(s,1H),7.40(s,1H),7.36-7.25(m,4H),4.92-4.87(m,1H),3.86(br s,1H),3.84-3.81(d,J=11.2Hz,2H),3.33(t,J=11.6Hz,2H),2.97-2.92(m,1H ),2.88-2.85(m,1H),2.17(s,3H),1.80(d,J=11.6Hz,2H),1.51-1.44(m,4H). LCMS calcd exact mass 455.18,found m / z 456.1[M+H] +.HPLC purity: 99.47%, Chiral HPLC purity: 99.68%.

[0622] The following examples illustrate the preparation of some of the compounds.

[0623] Example 23: (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide (Compound #259)

[0624] [ka]

[0625] Step 1: Methyl 1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate

[0626] [ka]

[0627] To a stirred solution of methyl 1-(2-chloro-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate (10.0 g, 39.59 mmol) in isopropanol (60 mL) was added N,N-diisopropylethylamine (28.36 mL) and 3,3-difluorocyclobutanamine hydrochloride (6.81 g, 47.50 mmol). The reaction mixture was stirred in a sealed tube at 100 °C for 20 min. The reaction progress was monitored by TLC (5% methanol in dichloromethane). The reaction mixture was cooled to 0 °C, and the resulting crystals were filtered and dried under reduced pressure to give the compound methyl 1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate as an off-white solid (23.0 g, 89%). LCMS calcd exact mass 323.12,found m / z 324.2[M+H]+ .

[0628] Step 2: 1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylic acid

[0629] [ka]

[0630] Methyl 1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylate (30.5 g, 94.3 mmol) was filtered through THF (1.0 L), potassium trimethylsilanolate (48.38 g, 377.4 mmol) was added at 0 °C, and the resulting reaction mixture was stirred at room temperature for 1.5 h using a mechanical stirrer. The reaction progress was monitored by TLC (5% methanol in dichloromethane). The reaction mixture was quenched with water (1.0 L) and washed with ethyl acetate (3 × 200 mL). The pH of the aqueous phase was adjusted to a maximum of 3–4 by adding concentrated HCl, and the mixture was extracted with 10% methanol in dichloromethane (8 × 1.5 L). The combined organic layers were concentrated under reduced pressure to give 1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylic acid as an off-white solid (27.0 g, 93%). 1 HNMR(400MHz,DMSO-d6):δ 12.50(br s,1H),8.38(s,1H),8.26(s,1H),8.22(s,1H),7.88(d,J=6.0Hz,1H),4.17 (t,J=6.4Hz,1H),2.98-2.88(m,2H),2.68-2.57(m,2H),2.18(s,3H).LCMS calcd exact mass 309.10,found m / z 310.1[M+H] + .

[0631] Step 3: (S)—N-(2-azido-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide

[0632] [ka]

[0633] To a stirred solution of 1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxylic acid (5.5 g, 17.79 mmol) in dichloromethane:N,N-dimethylformamide (150 mL:50 mL) was added N,N-diisopropylethylamine (15.49 mL, 88.98 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (6.82 g, 35.54 mmol), hydroxybenzotriazole (1.399 g, 88.99 mmol), and (S)-2-azido-1-(3-chlorophenyl)ethanamine hydrochloride (4.950 g, 19.41 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC (5% methanol in dichloromethane). The reaction mixture was quenched with water (500 mL), followed by the addition of saturated sodium bicarbonate solution (50 mL) and extraction with ethyl acetate (3 × 250 mL). The combined organics were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by gradient chromatography using 60-120 mesh silica gel, eluting with 3% methanol in dichloromethane. The collected fractions were concentrated under reduced pressure to give (S)—N-(2-azido-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methyl-pyrimidin-4-yl)-1H-imidazole-4-carboxamide as a yellow sticky oil (6.0 g, 69%). 1HNMR(400MHz,DMSO-d6):δ 8.87(d,J=9.2Hz,1H),8.38(s,1H),8.30(s,1H),8.13(s,1H),7.86(d,J=6.0Hz,1H),7.55(s,1H),7.42(d,J=7.2Hz,1H),7.36-7 .28(m,2H),5.25(d,J=5.2Hz,1H),4.17(t,J=6.4Hz,1H),3.86(t,J=12.0Hz ,1H),3.65-3.60(m,1H),2.95-2.90(m,2H),2.67-2.60(m,2H),2.20(s,3H). LCMS calcd exact mass 487.14,found m / z 488.1[M+H] + .

[0634] Step 4: (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide

[0635] [ka]

[0636] To a stirred solution of (S)—N-(2-azido-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide (6.0 g, 12.30 mmol) in methanol (100 mL) was added zinc dust (6.43 g, 98.38 mmol) and ammonium chloride (5.35 g, 98.38 mmol) in water (25 mL), and the mixture was stirred at room temperature for 4 hours. The progress of the reaction was monitored by TLC (5% methanol in dichloromethane). The reaction mixture was quenched with ammonia solution (50 mL), filtered through Celite, washed with 5% methanol in dichloromethane (25 mL), and the organic layer was separated. The aqueous layer was extracted with 5% methanol in dichloromethane (3 × 80 mL), and the combined organic layers were concentrated under reduced pressure. The residue was purified by gradient chromatography using 60-120 mesh silica gel, eluting with 8% (methanol / isopropylamine) in dichloromethane. Collected fractions were concentrated under reduced pressure to give (S)—N-(2-amino-1-(3-chlorophenyl)ethyl)-1-(2-((3,3-difluorocyclobutyl)amino)-5-methylpyrimidin-4-yl)-1H-imidazole-4-carboxamide as a white solid (4.1 g, 72%). 1 HNMR(400MHz,DMSO-d6):δ 8.54(d,J=8.0Hz,1H),8.38(s,1H),8.29(s,1H),8.10(s,1H),7.86(d,J=5.6Hz,1H),7.40(s,1H),7.35-7.25 (m,3H),4.93-4.88(m,1H),4.17(d,J=6.0Hz,1H),2.90-2.84(m,4H),2.68-2.55(m,2H),2.20(s,3H),1.54(br s,2H). LCMS calcd exact mass 461.15,found m / z 462.1[M+H] + .HPLC purity: 99.98%, Chiral HPLC: 99.97%, mp 104.3℃.

[0637] Example 24: (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1H-imidazole-4-carboxamide (Compound #275)

[0638] [ka]

[0639] Step 1: (S)-tert-butyl (1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)carbamate

[0640] [ka]

[0641] To a stirred solution of (S)-2-amino-2-(3-chloro-5-fluorophenyl)ethanol hydrochloride (10 g, 44.44 mmol) in t-butanol (100 mL) was added 2 N NaOH (2.22 g, 55.55 mmol, in 111 mL of water) and di-tert-butyl dicarbonate (13.56 g, 62.22 mmol). The resulting mixture was stirred at 70 °C for 12 h. The reaction progress was monitored by TLC. The reaction was then quenched with water (2 × 100 mL), extracted with ethyl acetate (2 × 100 mL), and the combined organic layers were washed with water (30 mL), followed by brine (30 mL), dried over sodium sulfate, filtered, and evaporated under reduced pressure to give 13 g of crude product. This crude product was combined with two additional batches of crude product prepared in a similar manner, and the combined material was purified by gradient chromatography using ethyl acetate in n-hexane as the eluent to give (S)-tert-butyl (1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)carbamate as an off-white solid (94% yield). 1HNMR(400MHz,DMSO-d6):δ 7.26-7.23(m,2H),7.20(s,1H),7.11(d,J=8Hz,1H),4.83(t,J=4Hz,1 H), 4.52-4.50(m, 1H), 3.50-3.43(m, 2H), 1.34(s, 9H). LC-MS calcd exact mass 289.74,found m / z 190.0[M+H-Boc] + .

[0642] Step 2: (S)-2-((tert-butoxycarbonyl)amino)-2-(3-chloro-5-fluorophenyl)ethyl methanesulfonate

[0643] [ka]

[0644] To a stirred solution of (S)-tert-butyl (1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)carbamate (12 g, 41.52 mmol) in dichloromethane (100 mL) at 0 °C, triethylamine (6.93 mL, 49.83 mmol) was added, and the mixture was stirred at 0 °C for 10 min. Methanesulfonyl chloride (3.73 mL, 45.674 mmol) was then added, and the mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by TLC. The reaction was quenched with water (100 mL), extracted with dichloromethane (3 × 100 mL), and the combined organic layers were washed with saturated ammonium chloride solution (100 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated under reduced pressure to give (S)-2-((tert-butoxycarbonyl)amino)-2-(3-chloro-5-fluorophenyl)ethyl methanesulfonate (15.25 g) as a pale yellow solid, which was further purified to give 1HNMR (400MHz, DMSO-d6): δ 7.68(d,J=8.4Hz,1H),7.36(s,1H),7.33(s,1H),7.29(d,J=9.6Hz,1H),4.28-4.19(m,2H),3.15(s,3H),1.36(s,9H). LC-MS calcd exact mass 367.07,found m / z 268.0[M+H-Boc] + .

[0645] Step 3: (S)-tert-butyl (2-azido-1-(3-chloro-5-fluorophenyl)ethyl)carbamate

[0646] [ka]

[0647] To a stirred solution of (S)-2-((tert-butoxycarbonyl)amino)-2-(3-chloro-5-fluorophenyl)ethyl methanesulfonate (15.25 g, 41.55 mmol) in N,N-dimethylformamide (100 mL) at room temperature was added sodium azide (5.4 g, 83.11 mmol). The reaction mixture was warmed to 60° C. for 12 hours. The progress of the reaction was monitored by TLC, after which the reaction mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (100 mL...

Claims

1. 1. Use of a compound in the manufacture of a medicament for use in a method for treating a disease treatable by inhibiting ERK1 / 2, said method comprising administering to a subject in need thereof once weekly a therapeutically effective amount of said compound, wherein said compound (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate, (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate, or (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide and The therapeutically effective amount is from about 80 mg to about 350 mg.

2. 2. The use of claim 1, wherein the therapeutically effective amount is selected from the group consisting of about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, and about 250 mg.

3. 3. The use of claim 1 or 2, wherein the disease treatable by inhibiting ERK1 / 2 is cancer of the prostate, head, neck, eye, mouth, throat, esophagus, bronchi, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, bladder, uterus, cervix, breast, ovary, vagina, testicle, skin, thyroid, blood, lymph nodes, kidney, liver, intestine, pancreas, brain, central nervous system, or adrenal gland, or leukemia or lymphoma.

4. (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide mandelate, (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide benzenesulfonate, or (S)—N-(2-amino-1-(3-chloro-5-fluoro-phenyl)ethyl)-1-(5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)-pyrimidin-4-yl)-1H-imidazole-4-carboxamide An oral pharmaceutical composition comprising: (a) Approximately 880 hours after administration of the compound ＊ ng / mL ~ about 6120h ＊ AUC in ng / mL ｔａｕ , C of about 68 ng / mL to about 2330 ng / mL ｍａｘ and / or a C of about 11 ng / mL to about 48 ng / mL ｍｉｎ or (b) Approximately 1190 hours after administration of the compound ＊ ng / mL ~ about 7080h ＊ AUC in ng / mL ｔａｕ , C of about 80 ng / mL to about 1520 ng / mL ｍａｘ and / or a C of about 0.8 ng / mL to about 23 ng / mL ｍｉｎ or (c) Approximately 1840 hours after administration of the compound ＊ ng / mL ~ about 18,120h ＊ AUC in ng / mL ｔａｕ , C of about 128 ng / mL to about 960 ng / mL ｍａｘ and / or a C of about 0.4 ng / mL to about 60 ng / mL ｍｉｎ An oral pharmaceutical composition comprising:

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