Azetidinyl benzoxazole compounds and their use as Mer and Axl inhibitors

Abstract

Formula (I): JPEG2025536322000043.jpg74140 (in the formula, L, R 1 , R 2 , R 3 and W is as defined in the specification. and their enantiomers, diastereomers, racemates, tautomers, prodrugs, hydrates, solvates and pharmaceutically acceptable salts are useful in the treatment of diseases and conditions affected by the inhibition of Mer kinase, such as cancer.

Description

[Technical Field]

[0001] Disclosed are compounds of formula (I) and methods for inhibiting Mer kinase and Axl kinase. Additionally, the disclosure relates to compositions comprising the disclosed compounds and methods of using the same. [Background technology]

[0002] Receptor tyrosine kinases (RTKs) are enzymes that can phosphorylate specific tyrosine residues in target proteins using ATP and share a highly conserved catalytic domain. This high conservation of the catalytic domain of receptor tyrosine kinases makes the development of selective tyrosine kinase inhibitors (TKIs) challenging. The TAM receptor family, consisting of Tyro3, ​​Axl, and Mer, plays important roles in cancer, hemostasis, and inflammation. In particular, Mer is a key regulator of macrophage and dendritic cell activation. Mer activation promotes the clearance of apoptotic cells by macrophages and other cell types, such as retinal pigment epithelial cells. Furthermore, Mer is aberrantly overexpressed in human cancers, including AML, ALL, lung cancer, glioma, melanoma, prostate cancer, schwannoma, mantle cell lymphoma, and rhabdomyosarcoma. Axl is more widely expressed in various cell types and tissues and is involved in diverse cellular processes, such as angiogenesis and tumorigenesis. Overexpression of Axl is crucial for tumor initiation, growth, and progression, involving tumor proliferation, invasiveness, and immune regulation. Axl has also been implicated in resistance to chemotherapy and to treatments targeting oncogenic drivers such as BRAF and EGFR. Overexpression of Axl in resistant tumors correlates with poor survival in many aggressive tumors, including triple-negative breast cancer, acute myeloid leukemia, non-small cell lung cancer, pancreatic cancer, and ovarian cancer. While much remains unknown about Tyro3, ​​its primary functions are implicated in innate immune responses, platelet aggregation, and neuronal signaling.

[0003] The search for specific inhibitors of Mer and Axl kinases has been challenging due to the similarity of the ATP-binding sites in all protein kinases. Compound 52, a 2,6,9-trisubstituted purine that competitively binds to the ATP-binding pocket, was the first molecule to successfully inhibit Mer (J Struct Biol. 2009 Feb;165(2):88-96). However, this inhibitor had limited efficacy and lacked selectivity. Several compounds have been discovered, most of which were discovered by modifying compound 52, including UNC-569, UNC-1062, and UNC-2025 (ACS Med Chem Lett. 2012 Feb 9;3(2):129-134, Eur J Med Chem. 2013 Jul;65:83-93, J Med Chem. 2014 Aug 28;57(16):7031-41). More recently, highly potent Mer kinase selective inhibitors have been disclosed in US Patent Publication No. 10,125,118 and WO2018071343.

[0004] The present invention provides reagents and methods for modulating the receptor tyrosine kinases Mer and Axl. This and other objects of the present invention are achieved by one or more of the embodiments described below. Summary of the Invention [Problem to be solved by the invention]

[0005] The present disclosure provides a compound of formula (I): [ka] (In the formula, W is N or CH; L is a bond, -CH=CHCR a R b -,-(CR a R b ) n -O-, -(CR a R b )n -C(O)-, -O-, -O-(CR a R b ) n -, -O-(CR a R b ) n selected from the group consisting of —O—, —OCHC(O)—, and —C(O)—; Each R a are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C2 hydroxyalkyl; Each R b are each independently selected from the group consisting of hydrogen and C1-C4 alkyl; R a and R b may be taken together to form a C3-C6 cycloalkyl or a 3-6 membered heterocycle; R 1 is selected from the group consisting of H, C1-C6 alkyl, and 5- to 6-membered heterocyclic groups; R 1 The C1-C6 alkyl is one or two R 4 may be substituted with; R 2 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, and C1-C4 alkyl; R 3 is hydrogen, fluoro, chloro, bromo, -CN, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -OR 3a , -NR 3b R 3c , -P(O)(OR 3d )2, -C(O)CHR 3e NR 3b R 3c , -C(O)OH, -C(O)OR 3a , -C(O)NR 3b R 3c , C3-C8 cycloalkyl, C5-C7 cycloalkenyl, 3- to 6-membered heterocyclic group, C5-C7 heterocycloalkenyl, C6 aryl, 5- to 6-membered heteroaryl, and [ka] selected from the group consisting of: R 3 C3-C8 cycloalkyl, C6 aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 may be substituted with; R 3a is C1-C4 alkyl; R 3b and R 3c are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and -COR 3f selected from the group consisting of: R 3d is selected from the group consisting of hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; R 3e is selected from the group consisting of hydrogen and C1-C4 alkyl, and R 3d The C1-C4 alkyl is one R 3g may be substituted with; R 3f is C1-C4 alkyl; R 3g is selected from the group consisting of -OH, -SH, -SCH, -NH, -C(O)OH, -C(O)NH, -NHC(NH)NH, Caryl, and 5-9 membered heteroaryl; R 3g The C6 aryl may be substituted with one -OH; R 4 -OH, -OR 4a , -C(O)NR 4b R 4c and 5- to 6-membered heterocyclic groups, R 4 The 5-6 membered heterocyclic group may be substituted with one or two C1-C4 alkyl groups; R 4a is C1-C4 alkyl, and R 4a The C1-C4 alkyl is one -Si(R 4d ) optionally substituted with 3; R 4b and R 4c are each independently selected from the group consisting of hydrogen and C1-C4 alkyl; R 4d is C1-C4 alkyl; R 5 -Fluoro, -CN, -OH, -OR 5a , =O, -CH2CO2R 5b , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 hydroxyalkoxy, and C2-C6 alkoxyalkyl; R 5a is C1-C4 alkyl; R 5b is C1-C4 alkyl; n is an integer from 1 to 3. or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

[0006] In certain embodiments, the present disclosure provides a compound wherein L is —O—(CR a R b ) n or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof, wherein:

[0007] In certain embodiments, the present disclosure provides L is a bond; R 3 is hydrogen, fluoro, chloro, bromo, -CN, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -OR 3a , -NR 3b R 3c , -C(O)OH, -C(O)OR 3a , -C(O)NR 3b R 3c , C3-C8 cycloalkyl, C5-C7 cycloalkenyl, 3-6 membered heterocyclic group, C5-C7 heterocycloalkenyl, C6 aryl, and 5-6 membered heteroaryl; R 3C3-C8 cycloalkyl, C6 aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 optionally substituted with, The present invention relates to a compound of formula (I) or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:

[0008] In certain embodiments, the present disclosure provides R 1 is C1-C6 alkyl, and R 1 C1-C6 alkyl is one or two R 4 may be substituted with; L is a bond; R 3 is hydrogen, fluoro, chloro, bromo, -CN, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -OR 3a , -NR 3b R 3c , -C(O)OH, -C(O)OR 3a , -C(O)NR 3b R 3c , C3-C8 cycloalkyl, C5-C7 cycloalkenyl, 3-6 membered heterocyclic group, C5-C7 heterocycloalkenyl, C6 aryl, and 5-6 membered heteroaryl; R 3 C3-C8 cycloalkyl, C6 aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 may be substituted with; R 4 -OH, -OR 4a , -C(O)NR 4b R 4c and 5- to 6-membered heterocyclic groups, In certain embodiments, R 1 is methyl.

[0009] In certain embodiments, the present disclosure provides R 1 is methyl; L is a bond; R 3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C6 aryl, and 5-6 membered heteroaryl; R 3 and a 5- to 6-membered heteroaryl, each of which is selected from one or two R 5 may be substituted with; R 5 -OH, -OR 5a , C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 hydroxyalkoxy, and C2-C6 alkoxyalkyl; The present invention relates to a compound of formula (I) or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:

[0010] In certain embodiments, the present disclosure provides L is -O-(CR a R b ) n - and; R 3 is selected from the group consisting of -CN, C-C cycloalkyl, 3- to 6-membered heterocyclic group, C aryl, and 5- to 6-membered heteroaryl; R 3 C3-C8 cycloalkyl, C6 aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 may be substituted with; R 5 -OH, -CH2CO2R 5b , C1-C4 alkyl, and C1-C4 hydroxyalkyl; The present invention relates to a compound of formula (I) or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:

[0011] In certain embodiments, the present disclosure provides a compound of formula (II): [ka] (In the formula, R 1 is selected from the group consisting of hydrogen, C1-C6 alkyl, and 5- to 6-membered heterocyclic groups; R 1 The C1-C6 alkyl is one or two R 4 may be substituted with; R 3 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -P(O)(OR 3d )2, -C(O)CHR 3e NR 3b R 3c , -C(O)OH, -C(O)OR 3a , -C(O)NR 3b R 3c , C3-C8 cycloalkyl, C5-C7 cycloalkenyl, 3-6 membered heterocyclic group, C5-C7 heterocycloalkenyl, C6 aryl, and 5-6 membered heteroaryl; R 3 C3-C8 cycloalkyl, C6 aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 may be substituted with; R 3a is C1-C4 alkyl; R 3b and R 3c are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and -COR 3f selected from the group consisting of: R 3d is selected from the group consisting of hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; R 3e is selected from the group consisting of hydrogen and C1-C4 alkyl, and R 3d The C1-C4 alkyl is one R 3g may be substituted with; R 3f is C1-C4 alkyl; R 3g is selected from the group consisting of -OH, -SH, -SCH, -NH, -C(O)OH, -C(O)NH, -NHC(NH)NH, Caryl, and 5-9 membered heteroaryl; R 3g The C6 aryl may be substituted with one -OH; R 4 -OH, -OR 4a , -C(O)NR 4b R 4c and 5- to 6-membered heterocyclic groups, R 4 The 3-10 membered heterocyclic group, which is: R 4a is C1-C4 alkyl, and R 4a The C1-C4 alkyl is one -Si(R 4d ) optionally substituted with 3; R 4b and R 4c are each independently selected from the group consisting of H and C1-C4 alkyl; R 4d is C1-C4 alkyl; R 5 -Fluoro, -CN, -OH, -OR 5a , =O, -CH2CO2R 5b , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 hydroxyalkoxy, and C2-C6 alkoxyalkyl; R 5a is C1-C4 alkyl; R 5b is C1-C4 alkyl; n is an integer from 1 to 3. or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof.

[0012] In certain embodiments, the present disclosure provides R 3is hydrogen, C1-C4 alkyl, -P(O)(OR 3d )2, and -C(O)CHR 3e NR 3b R 3c or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0013] In certain embodiments, the present disclosure provides R 1 is selected from the group consisting of hydrogen and C1-C6 alkyl, and R 1 C1-C6 alkyl is one or two R 4 may be substituted with; R 3 is hydrogen, C1-C4 alkyl, -P(O)(OR 3d )2, and -C(O)CHR 3e NR 3b R 3c selected from the group consisting of: R 4 -OH and -OR 4a selected from the group consisting of The present invention relates to a compound of formula (II) or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof:

[0014] In certain embodiments, the compound of formula (I) or formula (II) is [ka] In certain embodiments, compounds of the above formula or pharmaceutically acceptable salts thereof are also provided.

[0015] In certain embodiments, the compound of formula (I) or formula (II) is [ka] In certain embodiments, compounds of the above formula or pharmaceutically acceptable salts thereof are also provided.

[0016] In certain embodiments, the compound of Formula (I) or Formula (II), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, is 6-[1-(6-hydroxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl 6-[1-(6-chloro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(5,6-dimethyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(6-ethyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(cyclohex-1-en-1-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(6-bromo-1, 3-Benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(6-cyclohexyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-[1-(6-phenyl-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide;6-[1-(6-Methoxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(6-Cyclopentyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(cyclopent-1-en-1-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl 6-{1-[6-(3,6-dihydro-2H-pyran-4-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(3,6-dihydro-2H-pyran-4-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(trifluoromethyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine 2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazole-6-carboxylate;6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(oxolan-3-yl)-1,3-benzoxazole-6-yl] 6-{1-[6-(2,5-dihydrofuran-3-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(hydroxymethyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(1E)-3-hydroxy-3-methylbut-1-en-1-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-N,N-dimethyl-1,3-benzoxazole-6-carboxamide;2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-N,N-dimethyl-1,3-benzoxazole-6-carboxamide 6-{1-[6-(2-hydroxypropan-2-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(6-hydroxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-( 3-Hydroxy-3-methylbutyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(1E)-3-methoxyprop-1-en-1-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]azetidin-3 -yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(cyanomethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[3-hydroxy-2-(hydroxymethyl)propyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(oxan-4-yl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide;6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(2-fluoro- 6-[1-(1,3-Benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(2-methoxyethyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide;6-[1-(1,3-Benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide;6-{1-[6-(3-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide 6-{1-[6-(3-hydroxypropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(3-hydroxypropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(1E)-3-hydroxyprop-1-en-1-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl) 6-{1-[6-(3-methoxypropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-({1-[2-(dimethylamino)-2-oxoethyl]-1H-pyrazol-4-yl}amino)pyrazine-2-carboxamide;6-{1-[6-(2-Methoxyethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-{[1-(2,3-dihydroxypropyl)-1H-pyrazol-4-yl]amino}-6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide;6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide 6-{1-[6-(2-amino-2-oxoethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-({1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-1H-pyrazol-4-yl}amino)-6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide;6-{1-[6-( 2-Hydroxy-2-methylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[2-(dimethylamino)-2-oxoethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(2-hydroxyethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl 3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(oxetan-3-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide;6-(1-{6-[(3-hydroxycyclobutyl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(2,3-Dihydroxypropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(1-hydroxycyclobutyl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[2-(3-hydroxyoxetan-3-yl)ethyl]ethyl) ]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(morpholine-4-carbonyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide;6-(1-{6-[2-(dimethylamino)-2-oxoethyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3 -[(1-Methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(6-{[(2R)-1,4-dioxan-2-yl]methoxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl) 6-(1-{6-[2-(methylamino)-2-oxoethyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[3-hydroxy-2-(hydroxymethyl)propoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;N-tert-butyl-2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazole-6-carboxamide;2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-N-cyclopropyl-1,3-benzoxazole-6-carboxamide; 3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide;3-{[1-(2-methoxyethyl)-1H-pyrazol-4-yl]amino}-6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide;6-[1-(6-{[3-(hydroxymethyl)cyclobutyl]methoxy}-1,3-benzoxazol 6-(1-{6-[(3-hydroxyoxetan-3-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(3-hydroxyoxetan-3-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(6-{[(1S,2R)-2-(hydroxymethyl)cyclopropyl]methoxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide 6-(1-{6-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(3-phenylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl]- 6-{1-[6-(3-hydroxy-2,2-dimethylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[3-(dimethylamino)-3-oxopropyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[3-oxo-3-(pyrrolidin-1-yl)propyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide;6-(1-{6-[(2R)-2-(methoxymethyl)pyrrolidine-1-carbonyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4 -yl)amino]-6-(1-{6-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide;[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]acetic acid;6-[1-(6-{2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-oxoethyl}-1,3-benzoxazol-2- 6-{1-[6-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(2R)-2-hydroxypropoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-[1-(6-{[(3S)-oxolan-3-yl]oxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide;6-[1-(6-{2-[(3S)-3-methoxypyrrolidin-1-yl]-2-oxoethyl}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(6-{2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]-2-oxoethyl}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(1-methyl-2-oxopyrrolidin-3-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6- [2-(azetidin-1-yl)-2-oxoethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}acetic acid;6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1H -pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(2R)-2-(2-hydroxypropan-2-yl)pyrrolidine-1-carbonyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(1-methyl-2-oxopiperidin-3-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl dihydrogen phosphate;4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl diprop-2-en-1-yl phosphate;6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide;6-(1-{6-[(2-hydroxycyclopentyl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(1-methyl-1H-pyrazol-3-yl)methoxy]-1,3-benzoxazole -2-yl}azetidin-3-yl)pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-[1-(6-{2-oxo-2-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(5-methyl-1,3-thiazol-2-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide; 6-(1-{6-[2-(dimethylamino)-2-oxoethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide;6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide;6-[1-(6-hydroxy-1,3-benzoxazol 6-{1-[6-(2-hydroxy-2-methylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide;6-{1-[6-(2-hydroxy-2-methylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide;6-(1-{6-[(5-methyl-1,3,4-oxadiazol-2-yl)methoxy]-1,3-benzoxazol-2-yl}azetidine- 3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(2-cyclopropyl-2-oxoethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(4-hydroxyphenyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide ]pyrazine-2-carboxamide;6-(1-{6-[4-(2-hydroxyethoxy)phenyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(1-methyl-1H-pyrazol-4-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide;3-[(1-methyl-1 H-pyrazol-4-yl)amino]-6-(1-{6-[(1H-pyrazol-4-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide;3-[(1-tert-butyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide;4-{[2-(3-{6-carbamoyl-5-[(1-methyl -1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl glycinate;[(tert-Butoxycarbonyl)amino]acetic acid 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl;6-{1-[6-(3-Hydroxycarbonyl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl ... 6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-{[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide;6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(1-methyl-1H-pyrazol-4-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide;6-(1-{6-[(1-methyl-1H-imidazol-4-yl) 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(2-methyl-1,3-thiazol-5-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide;6-(1-{6-[4-(2-methoxyethoxy)phenyl]-1,3-benzoxazol-2-yl}azetidine -3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(2-ethoxypropan-2-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(5-methoxypyrimidin-2-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(pyridazin-3-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyridine-2-carboxamide;6-[1-(6-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methoxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}methyl)-1H-pyrazol-1-yl]ethyl acetate;6-{1-[6-(1-methyl-1H-imidazol-4-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;1-{[2-(3-{6-carbamoyl)-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl]acetate ... 6-{1-[6-(2-cyano-2-methylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-yl]pyridin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl glycinate;4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl dihydrogen phosphate;4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl dihydrogen phosphate 6-{1-[6-(1-hydroxy-2-methylpropan-2-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;2-[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]-2-methylpropanoate;1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl dihydrogen phosphate; and 1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl glycinate.

[0017] In certain embodiments, 6-{1-[6-(2-hydroxy-2-methylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide or a pharmaceutically acceptable salt thereof is provided. In certain embodiments, 6-{1-[6-(2-hydroxy-2-methylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide is provided.

[0018] In certain embodiments, 1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-ylglycinate or a pharmaceutically acceptable salt thereof is provided. In certain embodiments, 1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-ylglycinate is provided.

[0019] Certain embodiments of the present disclosure relate to pharmaceutical compositions comprising a compound of the present disclosure, or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. [Means for solving the problem]

[0020] The present invention provides novel compounds capable of selectively inhibiting Mer kinase and Axl kinase, which are useful for the prevention and / or treatment of cancer and other immune-related diseases (e.g., infections, sepsis, etc.). Herein, highly potent receptor tyrosine kinase Mer-selective inhibitors and Axl-selective inhibitors based on an aminopyridine scaffold are described. These compounds have the following formula (I):

[0021] As used herein, the term "compound of formula (I)" refers to a compound of formula (I): [ka] (In the formula, L, R 1 , R 2 , R 3 and W are as defined in the Summary of the Invention above and in the Detailed Description below. or a pharmaceutically acceptable salt thereof. Additionally, compositions comprising the compounds of the present disclosure are disclosed.

[0022] The compounds disclosed herein may contain one or more variable atoms that are described multiple times in the substituents or formulas described herein.The definition of a variable atom in each description is independent of the definition of that variable atom in another description.Furthermore, a combination of substituents is only permitted if such a combination results in a stable compound.A stable compound is a compound that can be isolated from a reaction mixture.

[0023] definition Certain terms used in this specification and claims have the definitions set out below. These definitions are explained in detail below.

[0024] As used in the specification and claims, it should be noted that the singular forms "a," "an," and "the" include the plural unless expressly stated otherwise. Thus, for example, when referring to a "compound," this includes a single compound and one or more of the same or different compounds. When referring to a "pharmaceutically acceptable carrier," this pharmaceutically acceptable carrier means a single pharmaceutically acceptable carrier and one or more pharmaceutically acceptable carriers.

[0025] As used in this specification and the appended claims, the following terms have the meanings set forth below unless otherwise specified.

[0026] As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon chain group containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, etc.

[0027] As used herein, the term "alkoxy" refers to an alkyl group, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like.

[0028] As used herein, the term "alkoxyalkyl" refers to an alkoxy group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, methoxymethyl, and the like.

[0029] As used herein, the term "alkyl" refers to a straight or branched saturated hydrocarbon chain group. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, 1,2,2-trimethylpropyl, and the like.

[0030] As used herein, the term "aryl" refers to a monocyclic hydrocarbon ring system group in which one or more hydrocarbon rings are aromatic, or a bicyclic or tricyclic fused hydrocarbon ring system group. Bicyclic aryl is naphthyl, a phenyl fused to a cycloalkyl, or a phenyl fused to a cycloalkenyl. Bicyclic aryl and tricyclic aryl are bonded to the parent molecular moiety via a carbon atom contained in the ring system. Representative examples of aryl groups include, but are not limited to, phenyl, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, tetrahydronaphthalenyl, etc.

[0031] As used herein, the term "cycloalkenyl" refers to a non-aromatic monocyclic hydrocarbon ring system or a non-aromatic bicyclic hydrocarbon ring system containing at least one double bond. A "monocyclic cycloalkenyl" has 5, 6, or 7 carbon atoms. A 5- or 6-membered ring system has one or two double bonds, and a 7-membered ring system has one, two, or three double bonds. Representative examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, etc.

[0032] As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon ring group containing ring carbon atoms. Cycloalkyls may be monocyclic cycloalkyls, bicyclic cycloalkyls, or spirocyclic cycloalkyls. Monocyclic cycloalkyls are carbocyclic ring systems containing 3 to 8 carbon atoms but no heteroatoms or double bonds. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyls are monocyclic cycloalkyls fused to a monocyclic cycloalkyl ring or bridged monocyclic ring systems in which two non-adjacent carbon atoms of the monocyclic cycloalkyl ring are connected by an alkylene bridge containing 1, 2, 3, or 4 carbon atoms. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, and the like. Examples of spirocyclic cycloalkyls include monocyclic or bicyclic cycloalkyls in which two substituents on one carbon atom of the cycloalkyl ring, taken together with that carbon atom, form a 4-, 5-, or 6-membered monocyclic cycloalkyl. Examples of spirocyclic cycloalkyls include spiro[2.5]octanyl.

[0033] In a fused ring system, two rings share one bond.

[0034] As used herein, the term "halo" or "halogen" refers to Cl, Br, I and F.

[0035] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein, in which one or more hydrogen atoms are replaced with halogen.Representative examples of haloalkyl include but are not limited to chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, fluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, trifluorobutyl, trifluoropropyl etc.

[0036] As used herein, the term "heteroaryl" refers to an aromatic ring group containing one or more heteroatoms or a ring system containing one or more heteroaryl rings. Monocyclic heteroaryls are 4-, 5-, or 6-membered rings. Five-membered rings contain two double bonds and one or more heteroatoms selected from O, S, and N. Six-membered rings contain three double bonds and one, two, three, or four nitrogen atoms. Representative examples of monocyclic heteroaryls include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, triazinyl, and the like.

[0037] As used herein, the term "heteroatom" means a nitrogen atom, an oxygen atom, or a sulfur atom.

[0038] As used herein, the term "heterocycle" or "heterocyclic group" refers to a hydrocarbon ring group in which at least one carbon atom is replaced by a heteroatom independently selected from the group consisting of O, N, and S. Examples of monocyclic ring systems include three- or four-membered rings containing heteroatoms independently selected from oxygen, nitrogen, and sulfur, and five- or six-membered rings containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. Five-membered rings have zero to two double bonds, and six-membered rings have zero to three double bonds. Representative examples of monocyclic heterocyclic ring systems include 1,3-dioxolanyl, dioxanyl, dithianyl, furanyl (furyl), imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, These include, but are not limited to, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrazinyl, tetrazolyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, thienyl, thiomorpholinyl, thiopyranyl, triazinyl, triazolyl, trithianyl, and the like.

[0039] The term "heterocycloalkenyl" refers to a monocyclic or polycyclic partially unsaturated non-aromatic heterocycloalkene group containing one or more heteroatoms and ring carbon atoms independently selected from S, N, and O. A heterocycloalkenyl may be a single ring (monocyclic). Examples of monocyclic heterocycloalkenyls include 2,5-dihydrofuranyl, 3,6-dihydro-2H-pyranyl, 2,3,4,5-tetrahydro-1H-azepinyl, 3,4,5,6-tetrahydro-2H-oxocinyl, 1,2,3,6-tetrahydropyridinyl, and 4,5-dihydro-1H-imidazolyl. Alternatively, a heterocycloalkenyl may be polycyclic (containing two or more rings). Examples of polycyclic heterocycloalkenyls include bridged, fused, or spirocyclic heterocycloalkenyls in which at least one ring is a heterocycloalkenyl ring and the remaining rings are heterocycloalkenyl, heterocycloalkyl, cycloalkenyl, or cycloalkyl rings. Alternatively, a polycyclic heterocycloalkenyl may be composed of one or more heterocycloalkyl rings and one or more cycloalkenyl rings.

[0040] As used herein, the term "hydroxyalkoxy" refers to a hydroxy group, as defined herein, attached to the parent molecular moiety through an alkoxy group, as defined herein. Representative examples of hydroxyalkoxy include, but are not limited to, hydroxymethoxy, hydroxyethoxy, hydroxypropoxy, and the like.

[0041] As used herein, the term "hydroxyalkyl" refers to a hydroxy group, as defined herein, attached to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropan-2-yl, and the like.

[0042] In some cases, the number of carbon atoms in a moiety is referred to as "C x ~C y ". In this prefix, x indicates the minimum number of carbon atoms contained in the substituent, and y indicates the maximum number of carbon atoms contained in the substituent. Thus, for example, "C1-C6 alkyl" means an alkyl substituent containing 1 to 6 carbon atoms, and "C1-C3 alkyl" means an alkyl substituent containing 1 to 3 carbon atoms. Also, for example, in this specification, "C6-C 10 "Aryl" means phenyl or bicyclic aryl having 6 to 10 carbon atoms.

[0043] In some cases, the number of ring atoms in a moiety is indicated with the prefix "x- to y-membered." In this prefix, x indicates the minimum number of ring atoms in the substituent, and y indicates the maximum number of ring atoms in the substituent. Thus, for example, a "5- or 6-membered heteroaryl" means a heteroaryl containing 5 or 6 ring atoms.

[0044] When a moiety is described as being "optionally substituted," the moiety can be either (1) unsubstituted or (2) substituted. When a moiety is described as being optionally substituted with up to a certain number of non-hydrogen groups, the moiety can be either (1) unsubstituted or (2) substituted with up to the certain number of non-hydrogen groups or the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, when a moiety is described as being heteroaryl that is optionally substituted with up to three non-hydrogen groups, a heteroaryl having fewer than three substitutable positions can be substituted with up to the same number of non-hydrogen groups as there are substitutable positions on the heteroaryl. To illustrate this, a tetrazolyl (which has only one substitutable position) can be substituted with up to one non-hydrogen group. To further illustrate, when a moiety is described as being optionally substituted with up to two non-hydrogen groups, the nitrogen of a primary amino group can be substituted with up to two non-hydrogen groups, and the nitrogen of a secondary amino group can be substituted with up to only one non-hydrogen group.

[0045] It should be noted that where the terms "comprise" or "comprising" are used in this patent application (including the claims), it is the applicants' intention, and it is clearly intended, that these terms be construed as inclusive rather than exclusive terms unless the context otherwise requires. It should also be noted that the applicants intend these terms to be so construed in interpreting this patent application, including the claims set forth below.

[0046] The term "pharmaceutical composition" refers to a composition suitable for administration in medical and veterinary applications.

[0047] The term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans or lower animals without excessive toxicity, irritation, allergic response, or the like, commensurate with a reasonable benefit / risk ratio.

[0048] The terms "prevent" and "prevention" refer to a method of preventing the onset of a disease and / or its associated symptoms or barring a subject from contracting a disease. As used herein, the terms "prevent" and "prevention" also include delaying the onset of a disease and / or its associated symptoms, as well as reducing a subject's risk of contracting or developing a disease or disorder.

[0049] As used herein, the term "subject" refers to an animal, such as, but not limited to, a mammal, such as a primate (e.g., a human), cow, sheep, goat, pig, horse, dog, cat, rabbit, rat, mouse, etc. In one embodiment, the subject is a human. The terms "human," "patient," and "subject" are used interchangeably herein.

[0050] When a moiety is described as "substituted," a hydrogen radical on a substitutable atom within the moiety has been replaced with a radical other than hydrogen. Thus, for example, a substituted heterocyclic moiety is one in which a hydrogen radical on the heterocycle has been replaced with at least one radical other than hydrogen. When there are two or more substituents on a moiety, each radical other than hydrogen can be the same or different (unless otherwise specified).

[0051] The term "therapeutically effective amount" refers to an amount of a compound or a pharmaceutically acceptable salt thereof that, when administered to a particular subject or population of subjects, alone or in combination with one or more other therapeutic agents, is sufficient to prevent the onset of, or alleviate to some extent, one or more symptoms of, the condition or disorder being treated. A "therapeutically effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, health, etc., of the subject being treated. For example, a therapeutically effective amount in a human or other mammal may be determined by experiments conducted in a laboratory or clinical setting, or may be the amount required for the particular disease and subject being treated, according to guidelines from the U.S. Food and Drug Administration or equivalent foreign authority.

[0052] As used herein, the terms "treat" and "treatment" refer to a method of alleviating or alleviating a disease and / or its associated symptoms.

[0053] compound The compounds of the present disclosure have the general formula (I), as set forth in the Summary and Detailed Description above.

[0054] In certain embodiments, compounds of the present disclosure, as well as enantiomers, diastereomers, racemates, tautomers, prodrugs, hydrates, solvates, and pharmaceutically acceptable salts thereof, have the formula (I): [ka] (In the formula, W is N or CH; L is a bond, -CH=CHCR a R b -,-(CR a R b ) n -O-, -(CR a R b ) n -C(O)-, -O-, -O-(CR a R b ) n -, -O-(CR a Rb ) n selected from the group consisting of —O—, —OCHC(O)—, and —C(O)—; Each R a are each independently selected from the group consisting of hydrogen, C1-C4 alkyl, and C1-C2 hydroxyalkyl; Each R b are each independently selected from the group consisting of hydrogen and C1-C4 alkyl; R a and R b may be taken together to form a C3-C6 cycloalkyl or a 3-6 membered heterocycle; R 1 is selected from the group consisting of H, C1-C6 alkyl, and 5- to 6-membered heterocyclic groups; R 1 The C1-C6 alkyl is one or two R 4 may be substituted with; R 2 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, and C1-C4 alkyl; R 3 is hydrogen, fluoro, chloro, bromo, -CN, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -OR 3a , -NR 3b R 3c , -P(O)(OR 3d )2, -C(O)CHR 3e NR 3b R 3c , -C(O)OH, -C(O)OR 3a , -C(O)NR 3b R 3c , C3-C8 cycloalkyl, C5-C7 cycloalkenyl, 3- to 6-membered heterocyclic group, C5-C7 heterocycloalkenyl, C6 aryl, 5- to 6-membered heteroaryl, and [ka] selected from the group consisting of: R 3 C3-C8 cycloalkyl, C6 aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R5 may be substituted with; R 3a is C1-C4 alkyl; R 3b and R 3c are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and -COR 3f selected from the group consisting of: R 3d is selected from the group consisting of hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; R 3e is selected from the group consisting of hydrogen and C1-C4 alkyl, and R 3d The C1-C4 alkyl is one R 3g may be substituted with; R 3f is C1-C4 alkyl; R 3g is selected from the group consisting of -OH, -SH, -SCH, -NH, -C(O)OH, -C(O)NH, -NHC(NH)NH, Caryl, and 5-9 membered heteroaryl; R 3g The C6 aryl may be substituted with one -OH; R 4 -OH, -OR 4a , -C(O)NR 4b R 4c and 5- to 6-membered heterocyclic groups, R 4 The 5-6 membered heterocyclic group may be substituted with one or two C1-C4 alkyl groups; R 4a is C1-C4 alkyl, and R 4a The C1-C4 alkyl is one -Si(R 4d ) optionally substituted with 3; R 4b and R 4c are each independently selected from the group consisting of hydrogen and C1-C4 alkyl; R 4d is C1-C4 alkyl; R 5 -Fluoro, -CN, -OH, -OR5a , =O, -CH2CO2R 5b , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 hydroxyalkoxy, and C2-C6 alkoxyalkyl; R 5a is C1-C4 alkyl; R 5b is C1-C4 alkyl; n is an integer from 1 to 3. It is shown as follows.

[0055] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, R 3e is selected from the group consisting of hydrogen, —CH, —CH(CH), —CH(CH)CHCH, —CHCH(CH), —CHOH, —CH(OH)CH, —CHCHSCH, —CHSH, —CHCHCHCHNH, —CHC(O)OH, —CHCHC(O)OH, —CHC(O)NH, —CHCHC(O)NH, —CHCHCHNHC(NH)NH, —CHCHH, —CHCHH(OH), —CH(indol-3-yl), and —CH(imidazol-4-yl); the remaining variable atoms are as defined in formula (I).

[0056] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is -O-(CR a R b ) n -; and the remaining variable atoms are as defined in formula (I).

[0057] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, R 3is hydrogen, C1-C4 alkyl, -P(O)(OR 3d )2, -C(O)CHR 3e NR 3b R 3c L is selected from the group consisting of -O-(CR a R b ) n -; and the remaining variable atoms are as defined in formula (I).

[0058] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, R 3 is -C(O)CHR 3e NR 3b R 3c and L is -O-(CR a R b ) n -; and the remaining variable atoms are as defined in formula (I).

[0059] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, R 3 is -C(O)CHR 3e NR 3b R 3c and;R 3e is selected from the group consisting of hydrogen, CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, CH2OH, CH(OH)CH3, CH2CH2SCH3, CH2SH, -CH2CH2CH2CH2NH2, CH2C(O)OH, CH2CH2C(O)OH, CH2C(O)NH2, CH2CH2C(O)NH2, -CH2CH2CH2NHC(NH)NH2, CH2C6H5, CH2C6H4(OH), CH2(indol-3-yl), and CH2(imidazol-4-yl); L is -O-(CR a R b ) n -; and the remaining variable atoms are as defined in formula (I).

[0060] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, R 1 is selected from the group consisting of hydrogen and C1-C6 alkyl; R 1 The C1-C6 alkyl is one or two R 4 may be substituted with R 3 is -C(O)CHR 3e NR 3b R 3c and;R 3e is selected from the group consisting of hydrogen, CH3, CH(CH3)2, CH(CH3)CH2CH3, CH2CH(CH3)2, -CH2OH, CH(OH)CH3, CH2CH2SCH3, CH2SH, CH2CH2CH2CH2NH2, CH2C(O)OH, -CH2CH2C(O)OH, CH2C(O)NH2, CH2CH2C(O)NH2, CH2CH2CH2NHC(NH)NH2, CH2C6H5, CH2C6H4(OH), CH2(indol-3-yl), and CH2(imidazol-4-yl); R 4 OH and OR 4a L is selected from the group consisting of -O-(CR a R b ) n -; and the remaining variable atoms are as defined in formula (I).

[0061] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, R 1 is methyl; R 3 is -C(O)CHR 3e NR 3b R 3c and;R 3eis selected from the group consisting of hydrogen, -CH, -CH(CH), -CH(CH)CHCH, -CHCH(CH), -CHOH, -CH(OH)CH, -CHCHSCH, -CHSH, -CHCHCHCHNH, -CHC(O)OH, -CHCHC(O)OH, -CHC(O)NH, -CHCHC(O)NH, -CHCHCHNHC(NH)NH, -CHCH, -CHCH(OH), -CH(indol-3-yl), and -CH(imidazol-4-yl); L is -O-(CR a R b ) n -; and the remaining variable atoms are as defined in formula (I).

[0062] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, R 1 is selected from the group consisting of hydrogen and C1-C6 alkyl; R 1 The C1-C6 alkyl is one or two R 4 may be substituted with R 3 is hydrogen, C1-C4 alkyl, -P(O)(OR 3d )2, -C(O)CHR 3e NR 3b R 3c R 4 -OH and -OR 4a L is selected from the group consisting of -O-(CR a R b ) n -; and the remaining variable atoms are as defined in formula (I).

[0063] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, R 1 is methyl; R 3 is hydrogen, C1-C4 alkyl, -P(O)(OR 3d )2, -C(O)CHR3e NR 3b R 3c L is selected from the group consisting of -O-(CR a R b ) n -; and the remaining variable atoms are as defined in formula (I).

[0064] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is a bond; R 3 is hydrogen, fluoro, chloro, bromo, -CN, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -OR 3a , -NR 3b R 3c , -C(O)OH, -C(O)OR 3a , -C(O)NR 3b R 3c , C3-C8 cycloalkyl, C5-C7 cycloalkenyl, 3-6 membered heterocyclic group, C5-C7 heterocycloalkenyl, C6 aryl, and 5-6 membered heteroaryl; R 3 C3-C8 cycloalkyl, C6 aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 the remaining variable atoms are as defined in formula (I).

[0065] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is a bond; R 1 is C1-C6 alkyl; R 1 The C1-C6 alkyl is one or two R 4 may be substituted with R 4 -OH, -OR 4a , -C(O)NR 4b R 4c and 5- to 6-membered heterocyclic groups; R 3is hydrogen, fluoro, chloro, bromo, -CN, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -OR 3a , -NR 3b R 3c , -C(O)OH, -C(O)OR 3a , -C(O)NR 3b R 3c , C3-C8 cycloalkyl, C5-C7 cycloalkenyl, 3-6 membered heterocyclic group, C5-C7 heterocycloalkenyl, C6 aryl, and 5-6 membered heteroaryl; R 3 C3-C8 cycloalkyl, C6 aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 may be substituted with R 5 -Fluoro, -CN, -OH, -OR 5a , =O, -CH2CO2R 5b , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 hydroxyalkoxy, and C2-C6 alkoxyalkyl; the remaining variable atoms are as defined in formula (I).

[0066] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is a bond; R 1 is methyl; R 3 is hydrogen, fluoro, chloro, bromo, -CN, C1-C4 alkyl, C1-C4 haloalkyl, -OH, -OR 3a , -NR 3b R 3c , -C(O)OH, -C(O)OR 3a , -C(O)NR 3b R 3c , C3-C8 cycloalkyl, C5-C7 cycloalkenyl, 3-6 membered heterocyclic group, C5-C7 heterocycloalkenyl, C6 aryl, and 5-6 membered heteroaryl; R 3C3-C8 cycloalkyl, C6 aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 may be substituted with R 5 -Fluoro, -CN, -OH, -OR 5a , =O, -CH2CO2R 5b , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 hydroxyalkoxy, and C2-C6 alkoxyalkyl; the remaining variable atoms are as defined in formula (I).

[0067] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is a bond; R 1 is methyl; R 3 is selected from the group consisting of hydrogen, C1-C4 alkyl, C6 aryl, and 5-6 membered heteroaryl; R 3 C6 aryl and 5-6 membered heteroaryl are each selected from one or two R 5 may be substituted with R 5 -OH, -OR 5a , C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 hydroxyalkoxy, and C2-C6 alkoxyalkyl; the remaining variable atoms are as defined in formula (I).

[0068] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is -O-(CR a R b ) n - and;R 3 is selected from the group consisting of -CN, C3-C8 cycloalkyl, 3-6 membered heterocyclic group, C6 aryl, and 5-6 membered heteroaryl; R 3C3-C8 cycloalkyl, C6 aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 may be substituted with R 5 -OH, -CH2CO2R 5b , C1-C4 alkyl, and C1-C4 hydroxyalkyl; the remaining variable atoms are as defined in formula (I).

[0069] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is -O-(CR a R b ) n - and;R 1 is methyl; R 3 is selected from the group consisting of -CN, C3-C8 cycloalkyl, 3-6 membered heterocyclic group, C6 aryl, and 5-6 membered heteroaryl; R 3 C3-C8 cycloalkyl, C6 aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 may be substituted with R 5 -OH, -CH2CO2R 5b , C1-C4 alkyl, and C1-C4 hydroxyalkyl; the remaining variable atoms are as defined in formula (I).

[0070] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is -O-(CR a R b ) n - and;R 1 is methyl; R 3 is a 5-6 membered heteroaryl; the remaining variable atoms are as defined in formula (I).

[0071] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is -O-(CR a R b ) n - and;R 3 is selected from the group consisting of hydrogen and C1-C4 alkyl; the remaining variable atoms are as defined in formula (I).

[0072] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is -O-(CR a R b ) n - and;R 3 is hydrogen; the remaining variable atoms are as defined in formula (I).

[0073] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is -O-(CR a R b ) n - and;R 1 is methyl; R 3 is hydrogen; the remaining variable atoms are as defined in formula (I).

[0074] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is -(CR a R b ) n -C(O)-; R 3 -OH, -OR 3a , -NR 3b R 3c and 3- to 6-membered heterocyclic groups; R 3 The 3- to 6-membered heterocyclic group is 5may be substituted with R 5 -OH, -OR 5a , C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and C2-C6 alkoxyalkyl; the remaining variable atoms are as defined in formula (I).

[0075] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is -(CR a R b ) n -C(O)-; R 3 is one or two R 5 is a 3- to 6-membered heterocyclic group optionally substituted with R 5 -OH, -OR 5a , C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and C2-C6 alkoxyalkyl; the remaining variable atoms are as defined in formula (I).

[0076] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is -(CR a R b ) n -C(O)-; R 1 is methyl; R 3 is one or two R 5 is a 3- to 6-membered heterocyclic group optionally substituted with R 5 -OH, -OR 5a , C1-C4 haloalkyl, C1-C4 hydroxyalkyl, and C2-C6 alkoxyalkyl; the remaining variable atoms are as defined in formula (I).

[0077] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is —C(O)—; R3 -OH, -OR 3a , -NR 3b R 3c and 3- to 6-membered heterocyclic groups; R 3 The 3- to 6-membered heterocyclic group is 5 may be substituted with R 5 is selected from the group consisting of C1-C4 hydroxyalkyl and C2-C6 alkoxyalkyl; the remaining variable atoms are as defined in formula (I).

[0078] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is —C(O)—; R 3 is one or two R 5 is a 3- to 6-membered heterocyclic group optionally substituted with R 5 is selected from the group consisting of C1-C4 hydroxyalkyl and C2-C6 alkoxyalkyl; the remaining variable atoms are as defined in formula (I).

[0079] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is —C(O)—; R 1 is methyl; R 3 is one or two R 5 is a 3- to 6-membered heterocyclic group optionally substituted with R 5 is selected from the group consisting of C1-C4 hydroxyalkyl and C2-C6 alkoxyalkyl; the remaining variable atoms are as defined in formula (I).

[0080] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is —O—; R 3is selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C8 cycloalkyl, 3-6 membered heterocyclic group, and 5-6 membered heteroaryl; R 3 C3-C8 cycloalkyl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 may be substituted with R 5 -OH, -OR 5a , ═O, and C1-C4 alkyl; the remaining variable atoms are as defined in formula (I).

[0081] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is —OCHC(O)—; R 3 -OH, -OR 3a , -NR 3b R 3c , C3-C8 cycloalkyl, and 3-6 membered heterocyclic groups; the remaining variable atoms are as defined in formula (I).

[0082] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is —OCHC(O)—; R 1 is methyl; R 3 -OH, -OR 3a , -NR 3b R 3c , C3-C8 cycloalkyl, and 3-6 membered heterocyclic groups; the remaining variable atoms are as defined in formula (I).

[0083] In certain embodiments of a compound of Formula (I), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, L is —OCHC(O)—; R 1 is methyl; R 3 is -NR 3b R3c and the remaining variable atoms are as defined in formula (I).

[0084] In certain embodiments, the compounds of the present disclosure, or enantiomers, diastereomers, racemates, tautomers, prodrugs, hydrates, solvates, or pharmaceutically acceptable salts thereof, have the formula (II): [ka] (In the formula, R 1 is selected from the group consisting of hydrogen, C1-C6 alkyl, and 5- to 6-membered heterocyclic groups; R 1 The C1-C6 alkyl is one or two R 4 may be substituted with; R 3 is hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, -P(O)(OR 3d )2, -C(O)CHR 3e NR 3b R 3c , -C(O)OH, -C(O)OR 3a , -C(O)NR 3b R 3c , C3-C8 cycloalkyl, C5-C7 cycloalkenyl, 3-6 membered heterocyclic group, C5-C7 heterocycloalkenyl, C6 aryl, and 5-6 membered heteroaryl; R 3 C3-C8 cycloalkyl, C6 aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 may be substituted with; R 3a is C1-C4 alkyl; R 3b and R 3c are each independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, and -COR 3f selected from the group consisting of: R 3d is selected from the group consisting of hydrogen, C1-C4 alkyl, and C2-C4 alkenyl; R3e is selected from the group consisting of hydrogen and C1-C4 alkyl, and R 3e The C1-C4 alkyl is one R 3g may be substituted with; R 3f is C1-C4 alkyl; R 3g is selected from the group consisting of -OH, -SH, -SCH, -NH, -C(O)OH, -C(O)NH, -NHC(NH)NH, Caryl, and 5-9 membered heteroaryl; R 3g The C6 aryl may be substituted with one -OH; R 4 -OH, -OR 4a , -C(O)NR 4b R 4c and 5- to 6-membered heterocyclic groups, R 4 The 3-10 membered heterocyclic group, which is: R 4a is C1-C4 alkyl, and R 4a is one -Si(R 4d ) C1-C4 alkyl optionally substituted with 3; R 4b and R 4c are each independently selected from the group consisting of H and C1-C4 alkyl; R 4d is C1-C4 alkyl; R 5 -Fluoro, -CN, -OH, -OR 5a , =O, -CH2CO2R 5b , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 hydroxyalkoxy, and C2-C6 alkoxyalkyl; R 5a is C1-C4 alkyl; R 5b is C1-C4 alkyl) It is shown as follows.

[0085] In certain embodiments of a compound of Formula (II), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, R 3 is hydrogen, C1-C4 alkyl, -P(O)(OR 3d )2, and -C(O)CHR 3e NR 3b R 3c the remaining variable atoms are as defined in formula (I).

[0086] In certain embodiments of a compound of Formula (II), or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, R 1 is selected from the group consisting of hydrogen and C1-C6 alkyl; R 1 The C1-C6 alkyl is one or two R 4 may be substituted with R 4 -OH and -OR 4a R 3 is hydrogen, C1-C4 alkyl, -P(O)(OR 3d )2, and -C(O)CHR 3e NR 3b R 3c the remaining variable atoms are as defined in formula (I).

[0087] In certain embodiments, a compound of the present disclosure, or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, is [ka] is.

[0088] In certain embodiments, a compound of the present disclosure, or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, is [ka] is.

[0089] Compound names were generated using the Advanced Chemical Development (ACD) / ChemSketch 2019.1.1 naming algorithm, Name 2019.

[0090] In one embodiment, the compound of formula (I) is 6-[1-(6-hydroxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(6-chloro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide 6-[1-(5,6-dimethyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(5,6-dimethyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine- 2-Carboxamide;6-[1-(6-ethyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(cyclohex-1-en-1-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(6-bromo-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide 6-[1-(6-cyclohexyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-[1-(6-phenyl-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide;6-[1-(6-Methoxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(6-Cyclopentyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(cyclopent-1-en-1-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl 6-{1-[6-(3,6-dihydro-2H-pyran-4-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(3,6-dihydro-2H-pyran-4-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(trifluoromethyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine 2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazole-6-carboxylate;6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(oxolan-3-yl)-1,3-benzoxazole-6-yl] 6-{1-[6-(2,5-dihydrofuran-3-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(hydroxymethyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(1E)-3-hydroxy-3-methylbut-1-en-1-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-N,N-dimethyl-1,3-benzoxazole-6-carboxamide;2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-N,N-dimethyl-1,3-benzoxazole-6-carboxamide 6-{1-[6-(2-hydroxypropan-2-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(6-hydroxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-( 3-Hydroxy-3-methylbutyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(1E)-3-methoxyprop-1-en-1-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]azetidin-3 -yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(cyanomethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[3-hydroxy-2-(hydroxymethyl)propyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(oxan-4-yl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide;6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(2-fluoro- 6-[1-(1,3-Benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(2-methoxyethyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide;6-[1-(1,3-Benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide;6-{1-[6-(3-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide 6-{1-[6-(3-hydroxypropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(3-hydroxypropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(1E)-3-hydroxyprop-1-en-1-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl) 6-{1-[6-(3-methoxypropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-({1-[2-(dimethylamino)-2-oxoethyl]-1H-pyrazol-4-yl}amino)pyrazine-2-carboxamide;6-{1-[6-(2-Methoxyethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-{[1-(2,3-dihydroxypropyl)-1H-pyrazol-4-yl]amino}-6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide;6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide 6-{1-[6-(2-amino-2-oxoethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-({1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-1H-pyrazol-4-yl}amino)-6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide;6-{1-[6-( 2-Hydroxy-2-methylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[2-(dimethylamino)-2-oxoethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(2-hydroxyethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl 3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(oxetan-3-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide;6-(1-{6-[(3-hydroxycyclobutyl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(2,3-Dihydroxypropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(1-hydroxycyclobutyl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[2-(3-hydroxyoxetan-3-yl)ethyl]-1,3-benzoxazol-2-yl} azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(morpholine-4-carbonyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide;6-(1-{6-[2-(dimethylamino)-2-oxoethyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(6-{[(2R)-1,4-dioxan-2-yl]methoxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide;6-(1-{6-[2-(methyl 6-(1-{6-[3-hydroxy-2-(hydroxymethyl)propoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(2,2-dimethyl-1,3-dioxan-5-yl) N-tert-butyl-2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazole-6-carboxamide;2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazole-6-carboxamide;2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)- azetidin-1-yl)-N-cyclopropyl-1,3-benzoxazole-6-carboxamide;3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide;3-{[1-(2-methoxyethyl)-1H-pyrazol-4-yl]amino}-6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide;6-[1-(6-{[3-(hydroxymethyl)cyclobutyl]methoxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(3-hydroxyoxetan-3-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-[1-(6-{[(1S,2R)-2-(hydroxymethyl) 6-(1-{6-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(3- 6-{1-[6-(3-hydroxy-2,2-dimethylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide;6-{1-[6-(3-hydroxy-2,2-dimethylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[3-(dimethylamino)-3-oxopropyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazole-4 -yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[3-oxo-3-(pyrrolidin-1-yl)propyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide;6-(1-{6-[(2R)-2-(methoxymethyl)pyrrolidine-1-carbonyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-Methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide;[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]acetic acid;6-[1-(6-{2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-oxoethyl} 6-{1-[6-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(2R)-2-hydroxypropoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl- 1H-Pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-[1-(6-{[(3S)-oxolan-3-yl]oxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide;6-[1-(6-{2-[(3S)-3-methoxypyrrolidin-1-yl]-2-oxoethyl}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine -2-carboxamide;6-[1-(6-{2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]-2-oxoethyl}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(1-methyl-2-oxopyrrolidin-3-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[2-(azetidin-1-yl)-2-oxoethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}acetic acid; 6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[(2R)-2-(2-hydroxypropan-2-yl)pyrrolidine-1-carbonyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[(1-methyl-2-oxopiperidin-3-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl dihydrogen phosphate;4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl phosphate Diprop-2-en-1-yl;6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide;6-(1-{6-[(2-hydroxycyclopentyl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(1-methyl-1H-pyrazol-3-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(1-methyl-1H-pyrazol-3-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-[1-(6-{2-oxo-2-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(5-methyl-1,3-thiazolinone 6-(1-{6-[2-(dimethylamino)-2-oxoethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide;6-(1-{6-[2-(dimethylamino)-2-oxoethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide;6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide;6-[1-(6-hydroxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide;6-{1-[6-(2-hydroxy-2-methylpropoxy)-1,3-benzoxazole-2 -yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide;6-(1-{6-[(5-methyl-1,3,4-oxadiazol-2-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(2-cyclopropyl-2-oxoethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl} -3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(4-hydroxyphenyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[4-(2-hydroxyethoxy)phenyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine- 2-Carboxamide;6-(1-{6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(1-methyl-1H-pyrazol-4-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(1H-pyrazol-4-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide;3-[(1-tert-butyl- 1H-pyrazol-4-yl)amino]-6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide;4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl glycinate;[(tert-butoxycarbonyl)amino]pyrazin-2-yl 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl acetate;6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-{[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carbamoyl acetate Boxamide;6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(1-methyl-1H-pyrazol-4-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide;6-(1-{6-[(1-methyl-1H-imidazol-4-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(1-methyl-1H-pyrazol-4-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide 6-(1-{6-[4-(2-methoxyethoxy)phenyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-{1-[6-(2-ethoxypropan-2-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}- 3-[(1-Methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;6-(1-{6-[(5-methoxypyrimidin-2-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;3-[(1-Methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(pyridazin-3-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyridine-2-carboxamide Boxamide;6-[1-(6-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methoxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;[4-({[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}methyl)-1H-pyrazol-1-yl]acetic acid ethyl ester;6-{1-[6-(1-methyl-1H-imidazol-4-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl dihydrogen phosphate;6-{1-[6-(2-cyano-2-methylpropoxy) -1,3-Benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide;1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-ylglycinate;4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine dihydrogen phosphate -2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl;4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl glycinate;6-{1-[6-(1-hydroxy-2-methylpropan-2-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H- [pyrazol-4-yl)amino]pyrazine-2-carboxamide;2-[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]-2-methylpropanoic acid ethyl ester;1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl dihydrogen phosphate;and 1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl glycinate;

[0091] Exemplary compounds of Formula (I) include, but are not limited to, the compounds set forth below in Table 1, and pharmaceutically acceptable salts thereof. In the event that a compound name described herein differs from the structure set forth in Table 1, the structure in Table 1 shall prevail. [Table 1] JPEG2025536322000014.jpg216166 JPEG2025536322000015.jpg216166 JPEG2025536322000016.jpg216166 JPEG2025536322000017.jpg217166 JPEG2025536322000018.jpg217166 JPEG2025536322000019.jpg217166 JPEG2025536322000020.jpg216166 JPEG2025536322000021.jpg216166 JPEG2025536322000022.jpg216166 JPEG2025536322000023.jpg217166 JPEG2025536322000024.jpg217166 JPEG2025536322000025.jpg218166 JPEG2025536322000026.jpg217166 JPEG2025536322000027.jpg217166 JPEG2025536322000028.jpg217166 JPEG2025536322000029.jpg164166

[0092] Also included within the scope of the invention are single stereochemical isomers, enantiomers, diastereomers, racemates, tautomers, prodrugs, hydrates, solvates, and pharmaceutically acceptable salts of the compounds exemplified above.

[0093] The compounds of formula (I) or (II) may be used in the form of a pharmaceutically acceptable salt.

[0094] The compounds of formula (I) or (II) may contain basic or acidic functional groups, or both, and may be converted, if desired, into pharmaceutically acceptable salts using an appropriate acid or base. Pharmaceutically acceptable salts may be prepared in situ during the final isolation and purification of the compounds of the invention.

[0095] Acid addition salts can be prepared by reacting the purified compound, if possible in free base form, with a suitable organic or inorganic acid and isolating the salt formed. Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid, etc., or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, etc.

[0096] Base addition salts can be prepared by reacting the purified compound in its acid form with a suitable organic or inorganic base and isolating the resulting salt. Such salts include alkali metal salts (e.g., sodium, lithium, and potassium), alkaline earth metal salts (e.g., magnesium and calcium), ammonium salts, and N + (C 1-4 Examples of suitable salts include, but are not limited to, alkyl)4 salts.

[0097] Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, gluconate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydrogen phosphate, and 2-hydroxybenzoates. Examples of suitable salts include ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0098] The novel compounds of the present invention, or their enantiomers, diastereomers, racemates, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts, exhibit the effect of effectively inhibiting Mer kinase.

[0099] The novel compounds of the present invention, or their enantiomers, diastereomers, racemates, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts, can be used in the prevention or treatment of cancer or immune-related diseases.

[0100] General synthesis method The compounds of the present disclosure can be further understood by reference to the following synthetic schemes and methods, which illustrate the means by which these compounds can be prepared. The compounds of the present disclosure can be prepared by a variety of synthetic procedures. Representative procedures are shown below in Schemes 1-5, but are not limited thereto. In Schemes 1-5, the variable atoms R 1 , R2 , R 3 , L and W are explained in the Summary of the Invention.

[0101] Intermediate 1-7 may be prepared from compound 1-1 as shown in Scheme 1. 6 R 1 Alternatively, compound 1-3 can be obtained by treating chloronitrile 1-2 with the nitrogen-protecting aminopyrazole 1-1 at elevated temperatures. Metal halides 1-4 can be prepared by treating the corresponding halides, such as chloride, bromide, or iodide, with a metal, such as zinc. Chloride 1-3 can then be coupled with a metal halide of formula 1-4 using a suitable palladium catalyst, such as tris(dibenzylideneacetone)dipalladium(0), and a tri(furan-2-yl)phosphine ligand, to give coupling product 1-5. Nitrile 1-5 can then be hydrolyzed at elevated temperatures using a suitable base, such as KCO, to give amide 1-6. Acidic deprotection of the boc group provides intermediate 1-7. [ka] (In Scheme 1, M is Zn and X is halo, for example, chloro, bromo, iodo, etc.)

[0102] As shown in Scheme 2, intermediate 2-3 may be prepared from compound 2-1. For example, ester 2-1 (where R is alkyl, benzyl, or other suitable carboxylic acid protecting group) may be treated with a metal halide of formula 1-4 using a suitable palladium catalyst, such as tris(dibenzylideneacetone)dipalladium(0), and a tri(furan-2-yl)phosphine ligand to give the coupled product 2-2. Deprotection of the boc group with acid gives intermediate 2-3. [ka]

[0103] Compounds of formula 3-8 may be prepared from compound 3-1 as shown in Scheme 3. 6 But R 1 Alternatively, compounds of formula 3-2, which are nitrogen-protecting groups such as (trimethylsilyl)ethyl, may be prepared from 4-nitro-1H-pyrazole (1-1) by alkylation, acylation, or other methods known to those skilled in the art. The nitro group of compound 3-2 may be reduced, for example, with palladium on carbon to give amine 1-1. This amine 1-1 may then undergo an addition-elimination reaction with a compound of formula 3-3 (where X is Cl, Br, or I) at elevated temperatures using, for example, a catalytic base such as N,N-diisopropylethylamine to give halide 3-4. Halide 3-4 may then be coupled with a metal halide of formula 1-4 as previously described to give coupled product 3-5. Amidation of this ester 3-5 with ammonia gives amide 1-6, and subsequent deprotection of the boc group with acid gives compound 1-7. Addition of oxazole 3-6 to compound 1-7 gives pyrazole 3-8 (where R 6 is R 1 or pyrazole 3-7 (wherein R 6 is a protecting group), the protected pyrazole 3-7 can be deprotected to give compound 3-8 (wherein R 1 is hydrogen), or by alkylation using conditions known to those skilled in the art to give pyrazoles 3-8 (where R 1 is an alkyl or heterocyclic group). [ka]

[0104] Compounds of formula 3-8 may be prepared from compounds of formula 2-3, as shown in Scheme 4. For example, azetidine 2-3 may be treated with chlorooxazole 3-6 in the presence of a base such as potassium carbonate to give compound 4-1. Amine 1-1 (wherein R 6 is R 1or a protecting group) to compound 4-1 to give ester 4-2. Ester 4-2 is then amidated with ammonia to give pyrazole 3-8 (where R 6 is R 1 or pyrazole 3-7 (wherein R 6 is a protecting group) to give the protected pyrazole 3-7, which may be converted to the pyrazole 3-8 as previously described with reference to Scheme 3. [ka]

[0105] Compounds of formula 3-8 may be prepared from compounds of formula 5-1, as shown in Scheme 5. Compound 5-1 (wherein R 6 R 1 Compound 1-7, where R 7 may be added to a halide, hydroxy, or protected hydroxy) to give compounds of formula 5-3. 7 is a halide, R 12 Compound 5-4 (or R 12Compound 5-3 can be coupled to a boronic acid ester equivalent (wherein 1 is alkyl) to give pyrazole 3-8. This reaction typically requires the use of a base and a catalyst. Examples of bases include, but are not limited to, potassium carbonate, potassium tert-butoxide, sodium carbonate, cesium carbonate, and cesium fluoride. Examples of catalysts include, but are not limited to, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), tetrakis(triphenylphosphine)palladium(0), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane, bis(triphenylphosphine)palladium(II) dichloride, and tris(dibenzylideneacetone)dipalladium(0). The above reaction can be carried out in a solvent, such as, but not limited to, water, dioxane, 1,2-dimethoxyethane, N,N-dimethylformamide, toluene, ethanol, tetrahydrofuran, or the like, or a mixture thereof. The above reaction may also be carried out at ambient temperature or at elevated temperatures, or in a microwave oven. 7 is hydroxy, compound 5-5 (wherein LG 1 Compounds of formula 3-8 may be obtained by alkylation of compounds 5-3 with (wherein T is a leaving group such as, for example, a halogen or a sulfonic acid group, and T is alkylene). This nucleophilic substitution reaction is carried out in the presence of a suitable base such as, for example, potassium tert-butoxide, in a suitable solvent such as, for example, dimethyl sulfoxide. [ka]

[0106] The synthetic schemes and specific examples described in the Examples section are for illustrative purposes only and should not be construed as limiting the scope of the disclosure, which is defined by the appended claims, which include all alternatives, modifications, and equivalents of the synthetic methods and specific examples.

[0107] Pharmaceutical Composition Additionally, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0108] As used herein, the term "pharmaceutically acceptable carrier" means any non-toxic and inert solid, semi-solid or liquid excipient, diluent, encapsulating material or formulation auxiliary.

[0109] The carriers used in the present invention may be those conventionally used in the art, and examples thereof include, but are not limited to, sugars, starch, crystalline cellulose, lactose (lactose hydrate), glucose, dimannitol, alginates, alkaline earth metal salts, clay, polyethylene glycol, anhydrous calcium hydrogen phosphate, and mixtures thereof.

[0110] The pharmaceutical compositions of the present disclosure may be in unit dosage form, in which the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient.

[0111] The dosage administered to a subject may be determined according to the effectiveness of the specific compound used, the condition of the subject, and the body weight or body surface area of ​​the subject to be treated.In addition, the dosage is determined according to the presence, nature and extent of adverse side effects associated with the administration of a specific compound to a specific subject.When determining the effective amount of a compound to be administered in the treatment or prevention of disease, a doctor can evaluate factors such as the circulating plasma volume of the compound, the toxicity of the compound and / or the progression of the disease.

[0112] In one embodiment, the pharmaceutical composition of the present disclosure comprises a compound of formula (I) or a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0113] Furthermore, according to another embodiment of the present invention, the additives include binders, disintegrants, lubricants, pH adjusters, antioxidants, and the like.

[0114] Examples of binders that may be used in the present invention include, but are not limited to, starch, microcrystalline cellulose, highly dispersed silica, mannitol, dimannitol, sucrose, lactose hydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymer (copovidone), hypromellose, hydroxypropyl cellulose, natural gums, synthetic gums, copovidone, gelatin, and mixtures thereof.

[0115] Examples of disintegrants that may be used in the present invention include, but are not limited to, starches or modified starches such as sodium starch glycolate, corn starch, potato starch, pregelatinized starch, etc.; clays such as bentonite, montmorillonite, and veegum; celluloses such as microcrystalline cellulose, hydroxypropyl cellulose, and carboxymethyl cellulose; algins such as sodium alginate and alginic acid; cross-linked celluloses such as croscarmellose sodium; gums such as guar gum and xanthan gum; cross-linked polymers such as cross-linked polyvinylpyrrolidone (crospovidone); effervescent agents such as sodium bicarbonate and citric acid; and mixtures thereof.

[0116] Examples of lubricants that may be used in the present invention include, but are not limited to, talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, colloidal silicon dioxide, and mixtures thereof.

[0117] Examples of pH adjusters that may be used in the present invention include, but are not limited to, acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium etherate, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid, and the like; and basifying agents such as precipitated calcium carbonate, aqueous ammonia, meglumine, sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate, tricalcium phosphate, and the like.

[0118] Examples of antioxidants that may be used in the present invention include, but are not limited to, dibutylhydroxytoluene, butylhydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium bisulfite, sodium metabisulfite, and the like.

[0119] In one embodiment, the pharmaceutical composition of the present disclosure comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0120] In one embodiment, the pharmaceutical composition of the present disclosure comprises a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0121] In one embodiment, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound of formula (I) or a compound of formula (II), or a stereoisomer, enantiomer or pharmaceutically acceptable salt thereof, for use in the prevention or treatment of diseases affected by inhibition of Mer kinase.

[0122] According to the present invention, the disease affected by inhibition of Mer kinase is cancer or an immune-related disease.

[0123] The cancers include glioma, gliosarcoma, anaplastic astrocytoma, medulloblastoma, lung cancer, small cell lung cancer, cervical cancer, colon cancer, rectal cancer, chordoma, laryngeal cancer, Kaposi's sarcoma, lymphangiosarcoma, lymphangioendothelioma, colorectal cancer, endometrial cancer, ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, seminoma, testicular tumor, Wilms' tumor, Ewing's tumor, bladder cancer, angiosarcoma, endothelioma, adenocarcinoma, sweat gland carcinoma, sebaceous gland sarcoma, papillary sarcoma, The tumor is selected from the group consisting of papillary adenosarcoma, cystic adenosarcoma, bronchogenic carcinoma, medullary carcinoma, mast cell tumor, mesothelioma, synovioma, melanoma, leiomyosarcoma, rhabdomyosarcoma, neuroblastoma, retinoblastoma, oligodendroglioma, acoustic neuroma, hemangioblastoma, meningioma, pinealoma, ependymoma, craniopharyngioma, epithelial carcinoma, embryonal carcinoma, squamous cell carcinoma, basal cell carcinoma, fibrosarcoma, myxoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, leukemia, and metastatic lesions secondary to these primary tumors.

[0124] The immune-related disease is selected from the group consisting of infection and sepsis.

[0125] The term "treatment" is used to refer to the prevention of disease as well as the treatment of existing conditions.

[0126] The therapeutic amount varies depending on the specific disease and can be determined by a person skilled in the art without undue effort.

[0127] Furthermore, subjects in the preventive or therapeutic methods of the present invention include mammals, particularly humans.

[0128] Doses vary depending on the particular compound used, the particular disease, the patient's condition, etc. A therapeutic amount is typically sufficient to reduce the undesirable cell population in the target tissue while maintaining patient survival. Treatment is typically continued until a significant reduction is observed, e.g., until the cell count is reduced by at least about 50%, and may be continued until the undesirable cells are substantially undetectable in the body.

[0129] Methods for preventing or treating immune-related diseases or cancer The present invention provides a method for treating or preventing an immune-related disease or cancer, the method comprising the step of administering a composition comprising, as an active ingredient, a compound of formula (I) or a compound of formula (II), or an isomer, enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof, to a mammal (including a human) in need of such treatment or prevention of an immune-related disease or cancer.

[0130] Compositions used in the present methods of preventing or treating immune-related diseases or cancer include pharmaceutical compositions described herein.

[0131] Furthermore, the present invention provides use of a composition comprising, as an active ingredient, a compound of formula (I) or a compound of formula (II), or a stereoisomer, enantiomer or pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention or treatment of cancer or an immune-related disease.

[0132] Method for preparing novel Mer kinase inhibitors The compounds of the present invention can be prepared according to one or more of the schemes illustrated below.

[0133] These methods can be used as is or with modifications that would be apparent to a trained chemist to prepare key intermediates and specific compounds of the present invention.

[0134] Further benefit of the applicants' disclosure will be appreciated by those skilled in the art from a perusal of this patent application.

[0135] The following examples are for illustrative purposes and are not intended to limit the scope of the present disclosure. [Effects of the Invention]

[0136] The compounds of the present disclosure, or their enantiomers, diastereomers, racemates, tautomers, prodrugs, hydrates, solvates or pharmaceutically acceptable salts, exhibit a modulatory effect on Mer kinase and Axl kinase. [Example]

[0137] General matters The following examples are set forth to facilitate a better understanding of the invention described herein. The synthetic and biological examples described herein are intended to illustrate, but not to limit the scope of, the compounds, pharmaceutical compositions, and methods provided herein.

[0138] Common abbreviations known to those skilled in the art are used throughout this specification: DMSO refers to dimethyl sulfoxide; HATU refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, N,N,N',N'-tetramethyl-3-oxo-1H-3λ; 5 -[1,2,3]triazolo[4,5-b]pyridine-1-carboxymidoamidium hexafluoride phosphate(1-), or N,N,N',N'-tetramethyl-1-oxo-3H-1λ 5 -[1,2,3]triazolo[4,5-b]pyridine-3-carboxymidoamidium hexafluoride phosphate (1-). TFA represents trifluoroacetic acid.

[0139] Other common abbreviations known to those skilled in the art are used throughout this specification: ATP refers to adenosine triphosphate; BSA refers to bovine serum albumin; EDTA refers to ethylenediaminetetraacetic acid; DMEM refers to Dulbecco's modified Eagle's medium; DTT refers to dithiothreitol; FBS refers to fetal bovine serum; GI 50indicates half-maximal growth inhibitory concentration. FRET indicates fluorescence energy transfer. GT indicates glutamic acid-tyrosine. HEPES indicates (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid). HTRF indicates homogeneous time-resolved fluorescence. IC 50 indicates half maximal inhibitory concentration. RPMI indicates Roswell Park Memorial Institute medium. SAR indicates structure-activity relationship. TK indicates tyrosine kinase.

[0140] Additionally, other abbreviations known to those skilled in the art are used throughout this specification: APCI refers to atmospheric pressure chemical ionization; atm refers to atmospheric pressure; ESI refers to electrospray ionization; g refers to grams; h refers to hours; HPLC refers to high performance liquid chromatography; LC / MS or LCMS refers to liquid chromatography mass spectrometry; μL refers to microliters; μm refers to micrometers; mg refers to milligrams; min refers to minutes; mL refers to milliliters; mmol refers to millimole; MS refers to mass spectrometry; NMR refers to nuclear magnetic resonance; psi refers to pounds per square inch; rt refers to room temperature; and SFC refers to supercritical fluid chromatography.

[0141] Unless otherwise noted, all reagents were of commercial grade and used as is without further purification. Commercially available anhydrous solvents were used for reactions performed under an inert atmosphere. In all other cases, reagent-grade solvents were used unless otherwise noted. Column chromatography was performed using silica gel 60 (35-70 μm). Thin-layer chromatography was performed using precoated silica gel F-254 plates (0.25 mm thick). 1 1 H NMR spectral data were recorded using an Agilent 400 MHz NMR spectrometer, or a Varian or Bruker 500 MHz or 501 MHz spectrometer. 1Chemical shifts (δ) for H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (δ=0.00) or the appropriate residual solvent peak, i.e., CHCl3 (δ=7.27), as an internal standard. Multiplicities were indicated as singlet (s), doublet (d), doublet-doublet-doublet (ddd), doublet-doublet-doublet-doublet (dddd), quartet-doublet-doublet (ddq), triplet-doublet-doublet (ddt), quartet-doublet-doublet (dq), doublet-triplet-doublet (dtd), heptet (hept), triplet (t), doublet-doublet-triplet (tdd), quartet-triplet (tq), quartet (q), doublet-quartet (qd), triplet-quartet (qt), quintet (quin), multiplet (m), and broad (br). Electrospray ionization MS spectra were obtained using a Thermo Fisher Vanquish UPLC coupled to a Thermo Fisher MSQ Plus mass spectrometer using a Waters Xselect HSS T3 C18 2.5 μm column (2.1 mm x 50 mm). A gradient of 0.1% formic acid and 10 mM ammonium acetate in water (A) and 0.1% formic acid in acetonitrile (B) was used (linear gradient from 100 to 20% A over 0 to 2.3 min). Microwave heating was performed using a Biotage® Initiator.

[0142] Flash chromatography purification was performed using a Biotage® Isolera One Flash, Teledyne ISCO CombiFlash® RF+, or Analogix IntelliFlash 280 system. Reverse-phase HPLC purification was performed using a Waters Prep LC 2487, Gilson PLC 2020, Gilson GX-281, or Shimadzu LC-8A system with a mobile phase consisting of A: 0.075% trifluoroacetic acid / water and B: CH3CN, A: 0.04% HCl / H2O and B: CH3CN, or A: 10 mM aqueous NH4HCO3 and B: CH3CN.

[0143] Supercritical fluid chromatography purification was performed using an SFC 80 system. The mobile phase consisted of supercritical CO2 delivered at a flow rate of 80 mL / min from a non-certified dewar containing dry CO2 pressurized to 350 psi. The column was set at ambient temperature, and the backpressure control unit was set to maintain 100 bar. Each sample was dissolved in methanol at a concentration of 50 mg / mL and injected as a 2 mL (100 mg) aliquot into the modifier stream. The mobile phase was maintained at isocratic conditions with 20% cosolvent / CO2.

[0144] Intermediate 1 6-(azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Intermediate 1A 6-chloro-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carbonitrile To a solution of 3,6-dichloropyrazine-2-carbonitrile (11.25 g, 64.7 mmol) in acetonitrile (100 mL) was added 1-methyl-1H-pyrazol-4-amine (8.16 g, 84 mmol) at 20 °C, and the resulting mixture was heated at 85 °C for 5 h. Three additional reactions were prepared using this procedure. After cooling, all four reaction mixtures were combined, diluted with ethyl acetate, and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate 50 / 1 to 3 / 1 to give the title compound (40 g). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 3.82 (s, 3H), 7.61 (s, 1H), 7.94 (d, J=2.19 Hz, 1H), 8.52-8.58 (m, 1H), 9.85 (s, 1H).

[0145] Intermediate 1B [1-(tert-butoxycarbonyl)azetidin-3-yl](iodide)zinc Under a nitrogen atmosphere, 1,2-dibromoethane (0.73 g, 3.89 mmol) was added to a vial containing a solution of zinc (3.46 g, 53 mmol) in tetrahydrofuran (40 mL), and the resulting suspension was stirred at 65°C for 5 minutes. After cooling, chlorotrimethylsilane (0.422 g, 3.89 mmol) was added, and the resulting mixture was stirred at 20°C for 1 hour. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (10 g, 35.3 mmol) in tetrahydrofuran (40 mL) was added, and the resulting mixture was stirred at 20°C for 1.5 hours. This solution was used directly without further purification.

[0146] Intermediate 1C tert-Butyl 3-{6-cyano-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidine-1-carboxylate A flask containing Intermediate 1A (5 g, 21.3 mmol) was flushed with nitrogen for 1 hour, and tetrahydrofuran (100 mL) was added. A separate flask was charged with tri(furan-2-yl)phosphine (0.99 g, 4.26 mmol) and tris(dibenzylideneacetone)dipalladium(0) (1.95 g, 2.13 mmol), flushed with nitrogen for 1 hour, and tetrahydrofuran (25 mL) was added. The palladium catalyst solution was transferred to the solution of Intermediate 1B (145 mL, 63.9 mmol). The combined catalyst-zinc reagent solution was added to the flask containing Intermediate 1A via cannula at 20 °C, and the resulting mixture was heated at 65 °C for 4 hours. One additional reaction was prepared using this procedure. After cooling, the two reaction mixtures were combined, filtered, and the filtrate was diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 50 / 1 to 5 / 1 ethyl acetate / methanol to give the title compound (5 g). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.40 (s, 9H), 3.81 (s, 3H), 3.91 (br s, 3H), 4.15 (br s, 2H), 7.62 (s, 1H), 7.96 (s, 1H), 8.37 (s, 1H), 9.60 (s, 1H).

[0147] Intermediate 1D tert-Butyl 3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidine-1-carboxylate To a solution of Intermediate 1C (1.667 g, 4.69 mmol) in a mixture of dioxane (20 mL) and water (5 mL) was added K2CO3 (1.945 g, 14.07 mmol), and the resulting mixture was heated at 100 °C for 12 h. Two additional reactions were prepared using this same procedure. After cooling, all three reaction mixtures were combined, diluted with water, and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the title compound (5 g). 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.40 (s, 9H), 3.81 (s, 3H), 3.89-3.97 (m, 1H), 4.04-4.24 (m, 4H), 7.59-7.63 (m, 1H), 7.94-8.01 (m, 1H), 8.04 (s, 1H), 8.27 (br s, 1H), 8.31 (s, 1H), 10.67 (s, 1H).

[0148] Intermediate 1E 6-(azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide To a solution of Intermediate 1D (1.25 g, 3.35 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (4 mL, 3.35 mmol) at 20° C., and the resulting mixture was stirred at 20° C. for 12 hours. Three additional reactions were prepared using this same procedure. All four reaction mixtures were combined and concentrated to give the title compound (4 g) as the trifluoroacetic acid salt, which was used without further purification. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 3.81 (s, 3H), 4.05-4.22 (m, 3H), 4.23-4.39 (m, 2H), 7.61 (s, 1H), 8.04 (s, 1H), 8.09 (br s, 1H), 8.26 (s, 1H), 8.71 (br s, 1H), 8.90 (br s, 1H), 10.80 (s, 1H).

[0149] Intermediate 2 6-(azetidin-3-yl)-3-chloropyrazine-2-carboxylic acid methyl ester Intermediate 2A 6-[1-(tert-butoxycarbonyl)azetidin-3-yl]-3-chloropyrazine-2-carboxylate methyl ester A flask containing methyl 6-bromo-3-chloropyrazine-2-carboxylate (2.5 g, 9.94 mmol) was flushed with nitrogen for 1 hour, and tetrahydrofuran (50 mL) was added. A separate flask was charged with tri(furan-2-yl)phosphine (0.462 g, 1.988 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.910 g, 0.994 mmol), and the mixture was flushed with nitrogen for 1 hour, and tetrahydrofuran (12.5 mL) was added. The palladium catalyst solution was transferred to the previously prepared solution of Intermediate 1B (45.2 mL, 19.88 mmol). The combined catalyst-zinc reagent solution was added to the methyl 6-bromo-3-chloropyrazine-2-carboxylate solution via cannula at 20 °C, and the resulting mixture was heated at 65 °C for 1.5 hours. Three additional reactions were prepared using this procedure. After cooling, all four reaction mixtures were combined and filtered, and the filtrate was diluted with ethyl acetate and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate from 80 / 1 to 20 / 1 to give the title compound (7.2 g). 1 H NMR (400 MHz, CDCl3) δ ppm 1.47 (d, J=0.61 Hz, 9H), 3.95-4.02 (m, 1H), 4.04 (d, J=0.73 Hz, 3H), 4.17 (dd, J=8.38, 6.05 Hz, 2H), 4.30-4.38 (m, 2H), 8.44 (s, 1H).

[0150] Intermediate 2B 6-(azetidin-3-yl)-3-chloropyrazine-2-carboxylic acid methyl ester To a solution of Intermediate 2A (2.4 g, 7.32 mmol) in dichloromethane (40 mL) was added trifluoroacetic acid (8 mL, 7.32 mmol) dropwise at 20° C., and the resulting mixture was stirred at 20° C. for 12 hours. Two additional reactions were prepared using this same procedure. All three reaction mixtures were combined and concentrated to give the title compound (5.8 g), which was used as the trifluoroacetate salt without further purification. 1H NMR (400 MHz, CD3OD) δ ppm 4.03 (s, 3H), 4.31-4.38 (m, 2H), 4.40-4.46 (m, 3H), 8.52 (s, 1H).

[0151] Intermediate 3 6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-chloropyrazine-2-carboxylate methyl ester To a solution of Intermediate 2B (13.5 g, 39.5 mmol) in N,N-dimethylformamide (135 mL) was added K2CO3 (21.84 g, 158 mmol) and 2-chlorobenzoxazole (5.52 mL, 47.4 mmol), and the resulting mixture was stirred at 20 °C for 12 h. One additional reaction was prepared using this procedure. The two reaction mixtures were combined, poured into water, and extracted with ethyl acetate. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 50 / 1 to 0 / 1 petroleum ether / ethyl acetate to give the title compound (23 g). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 3.92 (s, 3H), 4.34-4.45 (m, 3H), 4.55-4.63 (m, 2H), 7.02-7.09 (m, 1H), 7.17 (td, J=7.66, 0.99 Hz, 1H), 7.33 (d, J=7.50 Hz, 1H), 7.43 (d, J=7.94 Hz, 1H), 8.78 (s, 1H).

[0152] Intermediate 4 6-(azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide Intermediate 4A 3-Bromo-6-chloropyridine-2-carboxylic acid methyl ester To a solution of 3-bromo-6-chloropicolinic acid (10 g, 42.3 mmol) in methanol (100 mL) was added concentrated sulfuric acid (10 mL, 188 mmol), and the resulting mixture was stirred at 70° C. for 16 h. This reaction was repeated nine more times, and the combined reaction mixture was concentrated and purified by silica gel chromatography eluting with petroleum ether / ethyl acetate 20 / 1 to 5 / 1 to give the title compound (90 g). 1 H NMR (400 MHz, CDCl3) δ ppm 4.00 (s, 3H), 7.33 (d, J=8.44 Hz, 1H), 7.94 (d, J=8.44 Hz, 1H).

[0153] Intermediate 4B 6-chloro-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxylate methyl ester To a solution of Intermediate 4A (15 g, 59.9 mmol) in dioxane (150 mL) under a nitrogen atmosphere, 1-methyl-1H-pyrazol-4-amine hydrochloride (8.80 g, 65.9 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (3.47 g, 5.99 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.74 g, 2.99 mmol), and CsCO (58.5 g, 180 mmol) were added. The resulting mixture was stirred at 80 °C for 16 h. This reaction was repeated five more times, and the combined mixture was diluted with tetrahydrofuran, filtered, and the filtrate was concentrated. The residue was purified by silica gel chromatography eluting with petroleum ether / tetrahydrofuran (50 / 1 to 0 / 1) to give the title compound (50 g). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 3.83 (s, 3H), 3.87 (s, 3H), 7.32-7.39 (m, 1H), 7.41-7.48 (m, 2H), 7.83 (s, 1H), 8.81 (s, 1H).

[0154] Intermediate 4C 6-[1-(tert-butoxycarbonyl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxylate methyl ester Under a nitrogen atmosphere, 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane complex (3.83 g, 4.69 mmol), a solution of Intermediate 1B (562 mL, 281 mmol), and copper(I) iodide (1.785 g, 9.37 mmol) were added to a solution of Intermediate 4B (25 g, 94 mmol) in dimethylacetamide (250 mL). The resulting mixture was stirred at 80 °C for 12 h. This reaction was repeated once, and the combined mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography eluting with petroleum ether / ethyl acetate (50 / 1 to 0 / 1) to give the title compound (38 g). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.39 (s, 9H), 3.78-3.85 (m, 4H), 3.87 (s, 3H), 3.91-4.00 (m, 2H), 4.14 (br s, 2H), 7.26-7.33 (m, 1H), 7.34-7.41 (m, 1H), 7.44 (s, 1H), 7.80 (s, 1H), 8.71 (s, 1H).

[0155] Intermediate 4D tert-Butyl 3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridin-2-yl}azetidine-1-carboxylate To a solution of Intermediate 4C (9.5 g, 24.52 mmol) in methanol (80 mL) was added anhydrous ammonia (80 mL, 800 mmol), and the resulting mixture was stirred at 80° C. for 16 hours. After cooling to ambient temperature, this reaction was repeated three times, and the combined reaction mixture was concentrated and filtered, and the residue was dried under reduced pressure to give the title compound (35 g). 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.39 (s, 9H), 3.82 (s, 3H), 4.00 (dd, J=8.13, 6.05 Hz, 2H), 4.15 (br s, 2H), 7.28 (s, 2H), 7.42 (s, 1H), 7.67 (br d, J=2.20 Hz, 1H), 7.78 (s, 1H), 8.05 (br d, J=2.32 Hz, 1H), 9.76 (s, 1H).

[0156] Intermediate 4E 6-(azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide To a solution of Intermediate 4D (7 g, 18.80 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (14 mL, 182 mmol), and the resulting mixture was stirred for 16 hours at 20° C. This reaction was repeated five times, and the combined reaction mixture was concentrated, and ethyl acetate (30 mL) and petroleum ether (60 mL) were added, stirred for 1 hour, filtered, and dried to give the title compound as a trifluoroacetic acid salt (29.2 g). 1 H NMR (400 MHz, CD3OD) δ ppm 3.89 (s, 3H), 4.06-4.19 (m, 1H), 4.28-4.43 (m, 4H), 7.20 (d, J=8.60 Hz, 1H), 7.31 (d, J=8.60 Hz, 1H), 7.44 (s, 1H), 7.65 (s, 1H).

[0157] Example 0 6-[1-(6-hydroxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Example 0A 4-Nitro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole Under a nitrogen atmosphere, sodium hydride (10.61 g, 265 mmol) was added portionwise to a solution of 4-nitro-1H-pyrazole (15 g, 133 mmol) in tetrahydrofuran (150 mL) at 0 °C. The resulting mixture was stirred at 20 °C for 30 minutes, and then 2-(trimethylsilyl)ethoxymethyl chloride (28.2 mL, 159 mmol) was added dropwise, and the resulting mixture was stirred at 20 °C for 3 hours. Following this procedure, 19 additional reactions were prepared. All 20 reaction mixtures were combined, quenched with brine, and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography eluting with 100 / 0 to 90 / 10 petroleum ether / ethyl acetate to give the title compound (450 g). 1 H NMR (400 MHz, CD3OD) δ ppm -0.10-0.02 (m, 9H), 0.87-0.95 (m, 2H), 3.62-3.69 (m, 2H), 5.49 (s, 2H), 8.17 (s, 1H), 8.74 (s, 1H).

[0158] Example 0B 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-amine To a solution of the compound from Example OA (28 g, 115 mmol) in ethyl acetate (600 mL) was added wet palladium on carbon (3.67 g, 3.45 mmol), and the resulting mixture was stirred under hydrogen at 20° C. for 5 hours. Nine additional reactions were prepared using this same procedure. All ten reaction mixtures were combined, filtered through diatomaceous earth, and concentrated to give the title compound (230 g). 1 H NMR (400 MHz, CDCl3) δ ppm -0.02 (s, 9H), 0.87-0.93 (m, 2H), 2.96 (br s, 2H), 3.53 (br d, J=8.38 Hz, 2H), 5.30 (s, 2H), 7.17 (d, J=0.66 Hz, 1H), 7.21 (s, 1H).

[0159] Example 0C 6-Bromo-3-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)amino]pyrazine-2-carboxylate methyl ester A solution of methyl 3,6-dibromopyrazine-2-carboxylate (37 g, 125 mmol), the compound from Example 0B (32 g, 150 mmol), and N,N-diisopropylethylamine (54.6 mL, 313 mmol) in methanol (400 mL) was stirred at 80° C. for 2 hours. Four additional reactions were prepared using this same procedure. After cooling to 20° C., all five reaction mixtures were combined, diluted with water, and stirred for 2 hours. The resulting precipitate was filtered and dried under reduced pressure to give the title compound (222.7 g). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm -0.06--0.04 (m, 9H), 0.75-0.91 (m, 2H), 3.44-3.60 (m, 2H), 3.92 (s, 3H), 5.38 (s, 2H), 7.81 (s, 1H), 8.21 (s, 1H), 8.59 (s, 1H), 9.77 (s, 1H).

[0160] Example 0D 6-[1-(tert-butoxycarbonyl)azetidin-3-yl]-3-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)amino]pyrazine-2-carboxylate methyl ester A flask containing Intermediate 0C (18.5 g, 43.2 mmol) was flushed with nitrogen for 1 hour, and tetrahydrofuran (200 mL) was added. A separate flask was charged with tri(furan-2-yl)phosphine (0.551 g, 2.375 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.593 g, 0.648 mmol). This was flushed with nitrogen for 1 hour, and then tetrahydrofuran (20 mL) was added. This catalyst solution was transferred to the previously prepared solution of Intermediate 1B (294 mL, 130 mmol). This catalyst-zinc reagent solution was added via cannula to the flask containing the solution of the intermediate from Example 0C at 20°C, and the resulting mixture was heated at 65°C for 1 hour. Eleven additional reactions were prepared using this same procedure. All 12 reaction mixtures were combined, cooled to 20°C, filtered, diluted with ethyl acetate, and washed with water. The organic layer was dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography eluting with petroleum ether / ethyl acetate from 80 / 1 to 0 / 1 to give the title compound (150 g). 1 H NMR (400 MHz, CD3OD) δ ppm -0.02 (s, 9H), 0.89 (br t, J=8.05 Hz, 2H), 1.48 (s, 9H), 3.58 (t, J=8.05 Hz, 2H), 3.92-3.99 (m, 1H), 4.01 (s, 3H), 4.12 (br d, J=7.28 Hz, 2H), 4.21-4.31 (m, 2H), 5.42 (s, 2H), 7.77 (s, 1H), 8.28 (s, 1H), 8.36 (s, 1H).

[0161] Example 0E tert-Butyl 3-{6-carbamoyl-5-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidine-1-carboxylate To a solution of the compound of Example 0D (32 g, 63.4 mmol) in methanol (100 mL) was added a 7 M solution of ammonia in methanol (725 mL, 5073 mmol) at 25° C., and the resulting mixture was heated at 65° C. for 12 hours. After cooling to ambient temperature, the mixture was filtered, and the precipitate was dried under reduced pressure to give the title compound (31 g). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm -0.04 (s, 9H), 0.83 (t, J=8.01 Hz, 2H), 1.41 (s, 9H), 3.52 (t, J=8.07 Hz, 2H), 3.91-3.99 (m, 1H), 4.04-4.12 (m, 2H), 4.15 (br d, J=6.11 Hz, 2H), 5.38 (s, 2H), 7.74 (s, 1H), 7.98 (br s, 1H), 8.23 ​​(s, 1H), 8.27 (br s, 1H), 8.34 (s, 1H), 10.72-10.76 (m, 1H), 10.73 (s, 1H).

[0162] Example 0F 6-(Azetidin-3-yl)-3-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide To a solution of the compound from Example 0E (15 g, 30.6 mmol) in dichloromethane (400 mL) was added zinc(II) bromide (138 g, 613 mmol) in several portions at 0 °C, and the resulting mixture was stirred at 20 °C for 12 hours. Ten additional reactions were prepared using this same procedure. All 11 reaction mixtures were combined, and water was added. The resulting mixture was diluted with tetrahydrofuran and ethyl acetate and washed with saturated Na2CO3 solution. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 100 / 1 to 10 / 1 tetrahydrofuran / methanol, followed by 20 / 1 to 10 / 1 methanol (saturated with NH3) / tetrahydrofuran to give the title compound (30.3 g). 1H NMR (400 MHz, CD3OD) δ ppm -0.02 (s, 9H), 0.89 (t, J=8.05 Hz, 2H), 3.58 (t, J=8.05 Hz, 2H), 3.84-3.92 (m, 2H), 3.99-4.13 (m, 3H), 5.40 (s, 2H), 7.72 (s, 1H), 8.24 (d, J=4.85 Hz, 2H); LCMS (ESI+): m / z 390.1 (M+H) + .

[0163] Example 0G 6-[1-(6-hydroxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide To a mixture of the compound from Example 0F (1 g, 2.054 mmol) and K2CO3 (0.710 g, 5.13 mmol) in N,N-dimethylformamide (3 mL) was added 2-chloro-1,3-benzoxazol-6-ol (0.348 g, 2.054 mmol) at 20 °C, and the resulting mixture was stirred for 5 h. Two additional reactions were prepared using this same procedure. All three reaction mixtures were combined, and the reaction was quenched by the addition of water and ethyl acetate. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography eluting with 10 / 1 to 1 / 1 petroleum ether / tetrahydrofuran to give the title compound (1.2 g). 1H NMR (400 MHz, CD3OD) δ ppm -0.03 (s, 9H), 0.88 (t, J=8.05 Hz, 2H), 3.58 (t, J=8.05 Hz, 2H), 4.18-4.29 (m, 1H), 4.44 (t, J=7.06 Hz, 2H), 4.52-4.60 (m, 2H), 5.40 (s, 2H), 5.49 (s, 1H), 6.67 (dd, J=8.60, 2.21 Hz, 1H), 6.80 (d, J=1.98 Hz, 1H), 7.10 (d, J=8.38 Hz, 1H), 7.72 (s, 1H), 8.25 (s, 1H), 8.33 (s, 1H); LCMS (ESI+): m / z 523.3 (M+H) + .

[0164] Example 1 6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide To a mixture of Intermediate 1 (31 mg, 0.080 mmol) and K2CO3 (27.7 mg, 0.20 mmol), N,N-dimethylformamide (0.5 mL) and 2-chlorobenzo[d]oxazole (10 μL, 0.088 mmol) were added, and the resulting mixture was stirred at ambient temperature for 2 h. Water and ethyl acetate were added, and the resulting mixture was allowed to stand at ambient temperature overnight. The precipitate was filtered and dried under reduced pressure to give the title compound (17 mg). 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.40 - 8.36 (m, 1H), 8.35 (s, 1H), 8.01 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.13 (td, J = 7.6, 1.1 Hz, 1H), 7.01 (td, J = 7.8, 1.3 Hz, 1H), 4.45 (dd, J = 7.6, 1.4 Hz, 4H), 4.22 (p, J = 7.5 Hz, 1H), 3.79 (s, 3H). LCMS (ESI+): m / z 391.1 (M+H) + .

[0165] Example 2 6-[1-(6-chloro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 1, except that 2,6-dichlorobenzo[d]oxazole was used instead of 2-chlorobenzo[d]oxazole. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.38 (s, 1H), 8.34 (s, 1H), 8.00 (d, J = 0.7 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.58 - 7.54 (m, 2H), 7.26 (d, J = 8.3 Hz, 1H), 7.17 (dd, J = 8.4, 2.0 Hz, 1H), 4.45 (d, J = 7.8 Hz, 4H), 4.22 (p, J = 7.6 Hz, 1H), 3.78 (s, 3H). LCMS (ESI+): m / z 425.3 (M+H) + .

[0166] Example 3 6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Example 3A 6-Methyl-1,3-benzoxazole-2-thiol A mixture of 2-amino-5-methylphenol (5.0 g, 40.6 mmol), tetramethylthiuram disulfide (5.86 g, 24.4 mmol), and water (100 mL) was heated at 80° C. for 4 hours. The mixture was cooled to ambient temperature and adjusted to pH 3 with 1 N hydrochloric acid. The resulting precipitate was collected by filtration and rinsed with water to give the title compound (7.33 g). LCMS (ESI+): m / z 166.1 (M+H) + .

[0167] Example 3B 2-chloro-6-methyl-1,3-benzoxazole To a solution of the compound from Example 3A (7.3 g, 44.2 mmol) in dichloromethane (100 mL) was added thionyl chloride (13.4 g, 113 mmol) dropwise at 0 °C, followed by the addition of N,N-dimethylformamide (4.1 mL, 53 mmol). The mixture was warmed to ambient temperature and stirred overnight. The mixture was concentrated, and the residue was treated with ethyl acetate and saturated NaHCO3. After stirring for 30 min, the aqueous layer was extracted with ethyl acetate, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with heptane / ethyl acetate from 100 / 0 to 96 / 4 to give the title compound (4.6 g). LCMS (ESI+): m / z 168.3 (M+H) + .

[0168] Example 3C 6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide To a mixture of Intermediate 1 (347 mg, 0.895 mmol) and KCO (309 mg, 2.24 mmol), a solution of the compound from Example 3B (150 mg, 0.895 mmol) in N,N-dimethylformamide (3 mL) was added, and the resulting mixture was stirred at ambient temperature overnight. The mixture was partitioned with water and ethyl acetate, and the resulting precipitate was washed with water and ethyl acetate and dried to give the title compound (268 mg). 1 H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.36 (app s, 2H), 8.02 (s, 1H), 7.90 - 7.82 (m, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.22 (s, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.99 - 6.90 (m, 1H), 4.43 (d, J = 7.7 Hz, 4H), 4.22 (p, J = 7.6 Hz, 1H), 3.80 (s, 3H), 2.33 (s, 3H). LCMS (ESI+): m / z 405.3 (M+H) +

[0169] Example 4 6-[1-(5,6-dimethyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Examples 3B and 3C, except that 5,6-dimethylbenzo[d]oxazole-2-thiol was used in place of the compound of Example 3A. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.66 (s, 1H), 8.34 (s, 1H), 8.33 (s, 1H), 8.00 (s, 1H), 7.84 (s, 1H), 7.56 (d, J = 0.8 Hz, 1H), 7.17 (s, 1H), 7.06 (s, 1H), 4.41 (d, J = 7.6 Hz, 4H), 4.24 - 4.15 (m, 1H), 3.78 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H). LCMS (ESI+): m / z 419.3 (M+H) + .

[0170] Example 5 6-[1-(6-ethyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared as in Examples 3A-C, except that 2-amino-5-ethylphenol was used instead of 2-amino-5-methylphenol. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.34 (s, 2H), 8.00 (s, 1H), 7.88 - 7.80 (m, 1H), 7.57 (s, 1H), 7.26 - 7.21 (m, 1H), 7.17 (d, J = 7.9 Hz, 1H), 6.97 (dd, J = 7.9, 1.6 Hz, 1H), 4.42 (d, J = 7.6 Hz, 4H), 4.21 (p, J = 7.6 Hz, 1H), 3.78 (s, 3H), 2.61 (q, J = 7.6 Hz, 2H), 1.15 (t, J = 7.6 Hz, 3H). LCMS (ESI+): m / z 419.4 (M+H) + .

[0171] Example 6 6-{1-[6-(cyclohex-1-en-1-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Example 6A 6-[1-(6-bromo-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Examples 3A-C, except that 2-amino-5-bromophenol was used instead of 2-amino-5-methylphenol. 1 H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.43 - 8.37 (m, 1H), 8.35 (s, 1H), 8.02 (s, 1H), 7.87 - 7.81 (m, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.31 (dd, J = 8.3, 1.9 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 4.46 (d, J = 7.7 Hz, 4H), 4.24 (p, J = 7.7 Hz, 1H), 3.79 (s, 3H). LCMS (ESI+): m / z 469, 471 (M+H) + .

[0172] Example 6B 6-{1-[6-(cyclohex-1-en-1-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide A mixture of the compound from Example 6A (50 mg, 0.107 mmol), 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (33 mg, 0.160 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (7.8 mg, 10.65 mmol), and Na2CO3 (25 mg, 0.234 mmol) was degassed with nitrogen. Dioxane (0.6 mL) and nitrogen-sparged water (0.15 mL) were added, and the resulting mixture was heated at 90 °C for 16 hours. The mixture was cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, concentrated and purified by flash chromatography on silica gel eluting with dichloromethane / methanol 100 / 0 to 93 / 7 to give the title compound (35 mg). 1 H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.02 (d, J = 0.8 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.43 (d, J = 1.3 Hz, 1H), 7.23 - 7.18 (m, 2H), 6.11 - 6.08 (m, 1H), 4.45 (d, J = 7.7 Hz, 4H), 4.23 (p, J = 7.6 Hz, 1H), 3.80 (s, 3H), 2.36 (tt, J = LCMS (ESI+): m / z 471.2 (M+H) + .

[0173] Example 7 6-[1-(6-cyclohexyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide To a solution of the compound of Example 6 (17.7 mg, 0.038 mmol) in 1,2-dichloroethane (1 mL) under a hydrogen atmosphere (50 psi), 5% palladium on carbon (17 mg, 0.071 mmol) was added, and the resulting mixture was heated at 55° C. for 22 h. The mixture was filtered, concentrated, and purified by silica gel flash chromatography eluting with 100 / 0 to 94 / 6 dichloromethane / methanol to give the title compound (11 mg). 1 H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.37 - 8.34 (m, 2H), 8.01 (d, J = 0.8 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.1, 1.6 Hz, 1H), 4.47 - 4.39 (m, 4H), 4.22 (p, J = 7.6 Hz, 1H), 3.79 (s, 3H), 2.48 (p, J = LCMS (ESI+): m / z 473.4 (M+H) + .

[0174] Example 8 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-[1-(6-phenyl-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 6, except phenylboronic acid was used instead of 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.01 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.71 (d, J = 1.7 Hz, 1H), 7.64 (dd, J = 7.7, 1.5 Hz, 2H), 7.57 (s, 1H), 7.46 (dd, J = 8.2, 1.7 Hz, 1H), 7.41 (t, J = 7.7 Hz, 2H), 7.34 (d, J = 8.2 Hz, 1H), 7.29 (t, J = 7.4 Hz, 1H), 4.48 (d, J = 7.6 Hz, 4H), 4.24 (p, J = 7.6 Hz, 1H), 3.78 (s, 3H). LCMS (ESI+): m / z 467.3 (M+H) + .

[0175] Example 9 6-[1-(6-methoxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared as in Examples 3A-C, except that 2-amino-5-methoxyphenol was used instead of 2-amino-5-methylphenol. 1 H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.39 - 8.31 (m, 2H), 8.02 (s, 1H), 7.93 - 7.81 (m, 1H), 7.58 (s, 1H), 7.18 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.6, 2.5 Hz, 1H), 4.42 (d, J = 7.7 Hz, 4H), 4.21 (p, J = 7.6 Hz, 1H), 3.79 (s, 3H), 3.73 (s, 3H). LCMS (ESI+): m / z 421.2 (M+H) + .

[0176] Example 10 6-[1-(6-cyclopentyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Example 10A 6-{1-[6-(cyclopent-1-en-1-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 6, except cyclopent-1-en-1-ylboronic acid was used instead of 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.39 - 8.36 (m, 1H), 8.34 (s, 1H), 8.00 (d, J = 0.8 Hz, 1H), 7.88 - 7.81 (m, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.25 (dd, J = 8.2, 1.6 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 6.21 - 6.14 (m, 1H), 4.44 (d, J = 7.7 Hz, 4H), 4.22 (p, J = 7.6 Hz, 1H), 3.78 (s, 3H), 2.67 - 2.58 (m, 2H), 2.49 - 2.41 (m, 2H), 1.92 (p, J = 7.5 Hz, 2H). LCMS (ESI+): m / z 457.4 (M+H) + .

[0177] Example 10B 6-{1-[6-(cyclopent-1-en-1-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 7, except that the compound of Example 10A was used instead of the compound of Example 6. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.36 - 8.32 (m, 2H), 8.00 (d, J = 0.8 Hz, 1H), 7.87 - 7.80 (m, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.02 (dd, J = 8.3, 1.7 Hz, 1H), 4.42 (d, J = 7.7 Hz, 4H), 4.21 (p, J = 7.6 Hz, 1H), 3.78 (s, 3H), 3.02 - 2.92 (m, 1H), 1.98 (q, J = 12.2, 9.0 Hz, 2H), 1.79 - 1.67 (m, 2H), 1.67 - 1.43 (m, 4H). LCMS (ESI+): m / z 459.3 (M+H) + .

[0178] Example 11 6-{1-[6-(3,6-dihydro-2H-pyran-4-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 6, except that 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.38 - 8.36 (m, 1H), 8.35 (s, 1H), 8.01 (d, J = 0.8 Hz, 1H), 7.87 - 7.83 (m, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H), 7.25 (dd, J = 8.3, 1.7 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 6.21 - 6.15 (m, 1H), 4.45 (d, J = 7.7 Hz, 4H), 4.27 - 4.15 (m, 3H), 3.81 - 3.77 (m, 5H), 2.44 - 2.39 (m, 2H). LCMS (ESI+): m / z 473.3 (M+H) + .

[0179] Example 12 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(trifluoromethyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide Example 12A 6-(trifluoromethyl)-1,3-benzoxazole-2-thiol To a solution of potassium hydroxide (317 mg, 5.65 mmol) in ethanol (5 mL) and water (2 mL) was added carbon disulfide (0.187 mL, 3.11 mmol), and the resulting mixture was stirred for 15 minutes. 2-Amino-5-(trifluoromethyl)phenol (500 mg, 2.82 mmol) was added, and the resulting mixture was heated to reflux for 3 hours and then allowed to stand at ambient temperature overnight. The mixture was diluted with water and adjusted to pH 3-4 using 1N hydrochloric acid. The precipitate was filtered and purified by silica gel flash chromatography eluting with 25 / 75 to 40 / 60 ethyl acetate / heptane to give the title compound (205 mg). LCMS (ESI-): m / z 217.9 (MH) - .

[0180] Example 12B 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(trifluoromethyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide The title compound was prepared in a manner similar to Examples 3B and 3C, except that the compound of Example 12A was used instead of the compound of Example 3A. 1 H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.45 - 8.40 (m, 1H), 8.36 (s, 1H), 8.02 (d, J = 0.7 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J = 1.7 Hz, 1H), 7.58 (d, J = 0.7 Hz, 1H), 7.53 - 7.49 (m, 1H), 7.43 (d, J = 8.2 Hz, 1H), 4.51 (d, J = 7.7 Hz, 4H), 4.27 (p, J = 7.7 Hz, 1H), 3.80 (s, 3H). LCMS (ESI+): m / z 459.3 (M+H) + .

[0181] Example 13 2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazole-6-carboxylate methyl ester The title compound was prepared in a manner similar to Examples 3A-C, except that methyl 4-amino-3-hydroxybenzoate was used instead of 2-amino-5-methylphenol. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.73 (s, 1H), 8.48 - 8.43 (m, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.90 - 7.87 (m, 1H), 7.85 (dd, J = 8.3, 1.6 Hz, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 4.54 (d, J = 7.7 Hz, 4H), 4.28 (p, J = 7.6 Hz, 1H), 3.84 (s, 3H), 3.82 (s, 3H). LCMS (ESI+): m / z 449.3 (M+H) + .

[0182] Example 14 6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Examples 27A-C, except that 2-chlorobenzoxazole was used instead of the compound of Example 36A and tert-butyl 4-amino-1H-pyrazole-1-carboxylate was used instead of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 14.18 (br s, 1H), 12.61 (s, 1H), 10.71 (s, 1H), 8.40 (s, 2H), 8.12 - 7.62 (br, 1H), 7.88 (d, 2.4 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.32 (dd, J = 7.8, 1.2 Hz, 1H), 7.17 (td, J = 7.7, 1.1 Hz, 1H), 7.05 (td, J = 7.7, 1.2 Hz, 1H), 4.52 - 4.45 (m, 4H), 4.26 (p, J = 7.7 Hz, 1H). LCMS (ESI+): m / z 377.3 (M+H) + .

[0183] Example 15 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(oxolan-3-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide Example 15A 6-{1-[6-(2,5-dihydrofuran-3-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 6, except 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.39 - 8.36 (m, 1H), 8.35 (s, 1H), 8.00 (d, J = 0.8 Hz, 1H), 7.88 - 7.81 (m, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.18 (dd, J = 8.1, 1.6 Hz, 1H), 6.40 - 6.34 (m, 1H), 4.86 (td, J = 4.8, 2.0 Hz, 2H), 4.69 (td, LCMS (ESI+): m / z 459.4 (M+H) + .

[0184] Example 15B 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(oxolan-3-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 7, except that the compound of Example 15A was used instead of the compound of Example 6. 1 H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.40 - 8.32 (m, 2H), 8.02 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.33 (d, J = 1.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.06 (dd, J = 8.2, 1.7 Hz, 1H), 4.44 (d, J = 7.7 Hz, 4H), 4.23 (p, J = 7.7 Hz, 1H), 4.01 (t, J = 7.7 Hz, 1H), 3.93 (td, J = 8.3, 4.4 Hz, 1H), 3.80 (s, 3H), 3.80 - 3.73 (m, 1H), 3.51 (t, J = 8.0 Hz, 1H), 3.41 (dd, J = 15.9, 8.0 Hz, 1H), 2.28 (dtd, J = 12.1, 7.6, 4.4 Hz, 1H), 1.91 (dq, J = 12.2, 8.2 Hz, 1H). LCMS (ESI+): m / z 461.4 (M+H) + .

[0185] Example 16 6-{1-[6-(hydroxymethyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide To an ice-cold suspension of the compound of Example 13 (30 mg, 0.067 mmol) in tetrahydrofuran (1 mL) was added diisobutylaluminum hydride (1 M in tetrahydrofuran, 0.3 mL, 0.3 mmol) dropwise, and the resulting mixture was stirred at ambient temperature for 2 h. The mixture was quenched with methanol (1 mL) and water (0.2 mL), stirred for 30 min, and concentrated. The residue was partitioned between water and ethyl acetate, and the resulting organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 100 / 0 to 90 / 10 dichloromethane / methanol to give the title compound (13 mg). 1 H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.39 - 8.35 (m, 2H), 8.02 (d, J = 0.8 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.33 (dd, J = 1.5, 0.7 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 7.16 - 6.99 (m, 1H), 5.15 (t, J = 5.7 Hz, 1H), 4.50 (d, J = 5.5 Hz, 2H), 4.45 (d, J = 7.6 Hz, 4H), 4.23 (p, J = 7.7 Hz, 1H), 3.80 (s, 3H). LCMS (DCI+): m / z 421.3 (M+H) + .

[0186] Example 17 6-(1-{6-[(1E)-3-hydroxy-3-methylbut-1-en-1-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide A mixture of the compound from Example 6A (75 mg, 0.16 mmol), (E)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-ol (46 mg, 0.22 mmol), KCO (44 mg, 0.32 mmol), (1S,3R,5R,7S)-1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (2.3 mg, 8.0 μmol), and tris(dibenzylideneacetone)dipalladium(0) (3.7 mg, 4.0 μmol) was sparged with nitrogen and water (200 μL) and dioxane (600 μL) were added. The resulting mixture was heated at 65° C. for 16 hours, cooled, and partitioned with water and ethyl acetate. The organic extract was dried over Na2SO4, concentrated and purified by silica gel flash chromatography eluting with 100 / 0 to 90 / 10 methanol / dichloromethane to give the title compound (50 mg). 1 H NMR (501 MHz,dimethylsulfoxide-d6) δ ppm 10.69 (s, 1H), 8.39 (d, J = 2.2 Hz, 1H), 8.36 (s, 1H), 8.02 (d, J = 0.8 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.47 (d, J = 1.2 Hz, 1H), 7.22 - 7.18 (m, 2H), 6.50 (d, J = 16.0 Hz, 1H), 6.31 (d, J = 16.1 Hz, 1H), 4.65 (s, 1H), 4.46 (d, J = 7.8 Hz, 4H), 4.24 (p, J = 7.6 Hz, 1H), 3.80 (s, 3H), 1.25 (s, 6H). LCMS (ESI+): m / z 474.9 (M+H) + .

[0187] Example 18 2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-N,N-dimethyl-1,3-benzoxazole-6-carboxamide Example 18A 2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazole-6-carboxylic acid A suspension of the compound from Example 13 (150 mg, 0.334 mmol) in tetrahydrofuran (1.5 mL) / methanol (0.5 mL) was treated with 2N lithium hydroxide (1 mL), and the resulting mixture was stirred at ambient temperature for 3 hours, followed by stirring at 50° C. for 1 hour. The mixture was concentrated, diluted with water, and adjusted to pH 4 with 1N hydrochloric acid. The precipitate was collected by filtration, rinsed with water, and purified by silica gel chromatography eluting with 100 / 0 to 88 / 12 dichloromethane / methanol to provide the title compound (15 mg). 1 H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.43 (d, J = 2.3 Hz, 1H), 8.36 (s, 1H), 8.02 (s, 1H), 7.91 - 7.84 (m, 2H), 7.81 (dd, J = 8.2, 1.6 Hz, 1H), 7.58 (s, 1H), 7.32 (d, J = 8.2 Hz, 1H), 4.51 (d, J = 7.7).

[0188] Example 18B 2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-N,N-dimethyl-1,3-benzoxazole-6-carboxamide The compound of Example 18A (100 mg, 0.23 mmol), dimethylamine hydrochloride (28 mg, 0.35 mmol), and N 1 -((ethylimino)methylene)-N 3 ,N 3To a mixture of 1H-dimethylpropane-1,3-diamine hydrochloride (88 mg, 0.46 mmol) and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (42 mg, 0.28 mmol) in N,N-dimethylformamide (1.2 mL) was added N-ethyl-N-isopropylpropan-2-amine (200 μL, 1.15 mmol), and the resulting mixture was stirred at ambient temperature for 3 h. The mixture was partitioned with water and ethyl acetate, and the extract was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash chromatography eluting with 100 / 0 to 92 / 8 dichloromethane / methanol to give the title compound (34 mg). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.39 (s, 1H), 8.35 (s, 1H), 8.01 (d, J = 0.8 Hz, 1H), 7.85 (s, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.46 (d, J = 1.5 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.20 (dd, J = 8.0, 1.5 Hz, 1H), 4.47 (d, J = 7.8 Hz, 4H), 4.24 (p, J = 7.6 Hz, 1H), 3.78 (s, 3H), 2.93 (s, 6H). LCMS (ESI+): m / z 462.02 (M+H) + .

[0189] Example 19 6-{1-[6-(2-hydroxypropan-2-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide To an ice-cold suspension of the compound of Example 13 (43 mg, 0.096 mmol) in tetrahydrofuran (1 mL) was added dropwise methylmagnesium bromide (3 M in diethyl ether, 0.15 mL, 0.45 mmol), and the resulting mixture was stirred at ambient temperature for 16 h. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography eluting with 100 / 0 to 90 / 10 dichloromethane / methanol, followed by trituration with a minimal amount of ethyl acetate to give the title compound (14 mg). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.66 (s, 1H), 8.36 - 8.33 (m, 2H), 8.00 (s, 1H), 7.84 (s, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.45 (d, J = 1.7 Hz, 1H), 7.24 (dd, J = 8.2, 1.7 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 4.98 (s, 1H), 4.43 (d, J = 7.7 Hz, 4H), 4.21 (p, J = 7.6 Hz, 1H), 3.78 (s, 3H), 1.41 (s, 6H). LCMS (ESI+): m / z 448.98 (M+H) + .

[0190] Example 20 6-[1-(6-hydroxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was obtained in the same manner as in Example 1, except that 2-chlorobenzo[d]oxazol-6-ol was used instead of 2-chlorobenzo[d]oxazole. 1H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 9.25 (s, 1H), 8.38 (d, J = 4.3 Hz, 2H), 8.04 (s, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.60 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.63 (dd, J = 8.4, 2.3 Hz, 1H), 4.43 (d, J = 7.7 Hz, 4H), 4.23 (t, J = 7.7 Hz, 1H), 3.81 (s, 3H). LCMS (ESI+): m / z 407.0 (M+H) + .

[0191] Example 21 6-{1-[6-(3-hydroxy-3-methylbutyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in the same manner as in Example 7, except that the compound of Example 17 was used instead of the compound of Example 6. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.38 - 8.32 (m, 2H), 8.00 (d, J = 0.7 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.20 (d, J = 1.5 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.95 (dd, J = 8.0, 1.6 Hz, 1H), 4.42 (d, J = 7.6 Hz, 4H), 4.25 - 4.16 (m, 2H), 3.78 (s, 3H), 2.66 - 2.58 (m, 2H), 1.64 - 1.57 (m, 2H), 1.10 (s, 6H). LCMS (ESI+): m / z 477.2 (M+H) + .

[0192] Example 22 6-(1-{6-[(1E)-3-methoxyprop-1-en-1-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 17, except that (E)-2-(3-methoxyprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of (E)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-ol. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.40 - 8.36 (m, 1H), 8.35 (s, 1H), 8.01 (d, J = 0.8 Hz, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.54 (s, 1H), 7.25 - 7.17 (m, 2H), 6.59 (dt, J = 16.0, 1.5 Hz, 1H), 6.25 (dt, J = 15.9, 5.9 Hz, 1H), 4.45 (d, J = 7.7 Hz, 4H), 4.22 (p, J = 7.6 Hz, 1H), 3.99 (dd, J = 6.0, 1.4 Hz, 2H), 3.78 (s, 3H), 3.24 (s, 3H). LCMS (ESI+): m / z 461.2 (M+H) + .

[0193] Example 23 6-{1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide A solution of the compound from Example 20 (0.050 g, 0.123 mmol) and sodium hydride (5.4 mg, 0.135 mmol, 60% dispersion in mineral oil) in N,N-dimethylformamide (0.5 mL) was stirred at ambient temperature for 15 minutes. (Iodomethyl)cyclopropane (2.7 mg, 0.0148 mmol) was added, and the resulting mixture was stirred at ambient temperature for 1.5 hours. The mixture was quenched with water and diluted with ethyl acetate. The aqueous layer was washed with ethyl acetate, and the organic layer was washed with water, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography eluting with 100:0 to 100:10 dichloromethane / methanol to give the title compound (21 mg). 1 H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.69 (s, 1H), 8.38 (s, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.18 (d, J = 8.6 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 8.6, 2.4 Hz, 1H), 4.43 (d, J = 7.7 Hz, 4H), 4.23 (t, J = 7.7 Hz, 1H), 3.81 (s, 3H), 3.79 (d, J = 6.9 Hz, 2H), 1.22 (d, J = 13.6 Hz, 1H), 0.59 - 0.49 (m, 2H), 0.35 - 0.23 (m, 2H). LCMS (ESI+): m / z 461.5 (M+H) + .

[0194] Example 24 6-{1-[6-(cyanomethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 23, except 2-iodoacetonitrile was used instead of (iodomethyl)cyclopropane. 1H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.39 (d, J = 11.6 Hz, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 0.7 Hz, 1H), 7.34 - 7.23 (m, 2H), 6.92 (dd, J = 8.6, 2.5 Hz, 1H), 5.14 (s, 2H), 4.46 (dd, J = 7.7, 1.7 Hz, 4H), 4.26 (q, J = 7.8 Hz, 1H), 3.81 (s, 3H). LCMS (ESI+): m / z 446.3 (M+H) + .

[0195] Example 25 6-(1-{6-[3-hydroxy-2-(hydroxymethyl)propyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide A mixture of the compound from Example 6A (50 mg, 0.107 mmol), potassium trifluoro(oxetan-3-ylmethyl)borate (24.65 mg, 0.139 mmol), dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine (5.08 mg, 10.65 μmol), cesium carbonate (104 mg, 0.32 mmol), and diacetoxypalladium (1.196 mg, 5.33 μmol) was sparged with nitrogen for 30 minutes. Water (0.1 mL) and cyclopentyl methyl ether (1 mL) were added, and the resulting mixture was heated at 85°C for 16 hours. The mixture was cooled and partitioned between water and ethyl acetate, and the organic extract was dried over Na2SO4, concentrated and purified by silica gel chromatography eluting with 100 / 0 to 88 / 12 dichloromethane / methanol to give the title compound (5.7 mg). 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 8.01 (d, J = 0.8 Hz, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.20 (d, J = 1.5 Hz, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.95 (dd, J = 8.0, 1.6 Hz, 1H), 4.42 (dd, J = 7.7, 1.6 Hz, 4H), 4.34 (t, J = 5.1 Hz, 2H), 4.21 (p, J = LCMS (ESI+): m / z 479.02 (M+H) + .

[0196] Example 26 Ethyl {[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}acetate A solution of the compound from Example 20 (0.036 g, 0.089 mmol) and potassium carbonate (0.018 g, 0.133 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at ambient temperature for 15 minutes. Ethyl iodoacetate (0.025 g, 0.115 mmol) was added, and the resulting mixture was heated at 90 °C for 5 hours. The mixture was cooled, quenched with water, and diluted with ethyl acetate. The aqueous layer was washed with ethyl acetate, and the organic layer was washed with water, washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel chromatography eluting with 100 / 0 to 100 / 10 dichloromethane / methanol to give the title compound (26 mg). 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.57 (s, 1H), 8.35 (s, 1H), 8.00 (s, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.6, 2.5 Hz, 1H), 4.71 (s, 2H), 4.50 - 4.31 (m, 4H), 4.23 (d, J = 8.5 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.79 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). LCMS (ESI+): m / z 493.4 (M+H) + .

[0197] Example 27 6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(oxan-4-yl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide Example 27A 3-chloro-6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxylate methyl ester To a mixture of Intermediate 2B (500 mg, 1.46 mmol) and potassium carbonate (506 mg, 3.66 mmol), dimethylformamide (2 mL) was added, followed by the compound from Example 36A (276 mg, 1.61 mmol). The resulting mixture was stirred overnight at ambient temperature, diluted with water, and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 90 / 10 to 40 / 60 heptane / ethyl acetate to give the title compound (0.41 g). LCMS (ESI+): m / z 363.1 (M+H) + .

[0198] Example 27B 6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(oxan-4-yl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxylate methyl ester A mixture of the compound from Example 27A (50 mg, 0.14 mmol), 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine (23 mg, 0.14 mmol), K2CO3 (191 mg, 1.38 mmol), diacetoxypalladium (1.5 mg, 0.0069 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (8.0 mg, 0.014 mmol) was degassed with nitrogen for 30 minutes. Dioxane (0.7 mL) was added, and the vial was degassed with nitrogen for an additional 5 minutes. The resulting mixture was heated at 80 °C overnight, cooled, diluted with water, and extracted with ethyl acetate. The extract was dried over Na2SO4, concentrated, and purified by silica gel flash chromatography eluting with 100 / 0 to 95 / 5 dichloromethane / methanol to give the title compound (34 mg). LCMS (ESI+): m / z 494.3 (M+H) + .

[0199] Example 27C 6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(oxan-4-yl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide A solution of the compound from Example 27B (34 mg, 0.069 mmol) and a mixture of 7 M ammonia in methanol (1.0 mL, 7.0 mmol) was heated at 55° C. for 3 hours. After cooling, the precipitate was collected by filtration and rinsed with methanol to give the title compound (19 mg). 1H NMR (501 MHz,dimethylsulfoxide-d6) δ ppm 10.72 (s, 1H), 8.41 (d, J = 2.2 Hz, 1H), 8.38 (s, 1H), 8.11 (d, J = 0.7 Hz, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.67 (d, J = 0.7 Hz, 1H), 7.44 (dd, J = 8.5, 2.5 Hz, 1H), 7.28 (dd, J = 8.6, 4.9 Hz, 1H), 7.02 (ddd, J = 10.2, 8.6, 2.5 Hz, 1H), 4.49 - 4.43 (m, 4H), 4.36 (tt, J = LCMS (ESI+): m / z 479.4 (M+H) + .

[0200] Example 28 6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 27B, except 1-(4-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol was used instead of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine. 1H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.75 (s, 1H), 8.41 (d, J = 2.3 Hz, 1H), 8.39 (s, 1H), 8.06 (s, 1H), 7.90 - 7.86 (m, 1H), 7.62 (s, 1H), 7.44 (dd, J = 8.5, 2.5 Hz, 1H), 7.28 (dd, J = 8.6, 4.9 Hz, 1H), 7.02 (ddd, J = 10.9, 8.7, 2.6 Hz, 1H), 4.66 (s, 1H), 4.50 - 4.43 (m, 4H), 4.24 (p, J = 7.7 Hz, 1H). 3.98 (s, 2H), 1.05 (s, 6H). LCMS (ESI+): m / z 467.2 (M+H) + .

[0201] Example 29 6-[1-(1,3-Benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(2-methoxyethyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide To a solution of the compound of Example 14 (100 mg, 0.266 mmol) in N,N-dimethylformamide (1 mL) were added CsCO (104 mg, 0.319 mmol) and 1-bromo-2-methoxyethane (44.3 mg, 0.319 mmol), and the resulting mixture was stirred at 50° C. for 5 hours. The mixture was filtered, and the filtrate was purified by preparative HPLC to give the title compound (62 mg). 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 3.22 (s, 3H), 3.67 (t, J=5.48 Hz, 2H), 4.19-4.31 (m, 1H), 4.19-4.30 (m, 3H), 4.46-4.52 (m, 4H), 7.00-7.10 (m, 1H), 7.18 (t, J=7.45 Hz, 1H), 7.32 (d, J=7.89 Hz, 1H), 7.44 (d, J=7.89 Hz, 1H), 7.64 (s, 1H), 7.92 (s, 1H), 8.08 (s, 1H), 8.40 (s, 1H), 8.45 (br s, 1H), 10.75 (s, 1H).

[0202] Example 30 6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide To a solution of the compound from Example 14 (200 mg, 0.53 mmol) and 2,2-dimethyloxirane (115 mg, 1.59 mmol) in N,N-dimethylformamide (3 mL) was added cesium carbonate (346 mg, 1.06 mmol), and the resulting mixture was stirred at 120 °C for 3 h. The mixture was quenched with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over NaSO, concentrated, and purified by preparative HPLC to give the title compound (86 mg). 1 H NMR (400 MHz, CD3OD) δ ppm 1.18 (s, 6H), 4.07 (s, 2H), 4.31-4.42 (m, 1H), 4.60-4.69 (m, 2H), 4.70-4.78 (m, 2H), 7.21-7.27 (m, 1H), 7.33 (t, J=7.28 Hz, 1H), 7.37-7.42 (m, 1H), 7.48 (d, J=8.16 Hz, 1H), 7.70 (s, 1H), 8.12 (s, 1H), 8.33 (s, 1H). LCMS (ESI+): m / z 449.1 (M+H) + .

[0203] Example 31 6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide A mixture of the compound from Example 20 (15.0 g, 36.9 mmol) and sodium hydride (2.21 g, 55.4 mmol, 60% mineral oil dispersion) in N,N-dimethylformamide (130 mL) was stirred at ambient temperature for 15 minutes. A solution of 4-bromo-2-methylbutan-2-ol (8.22 g, 44.3 mmol) in N,N-dimethylformamide (20 mL) was added, and the resulting mixture was stirred at 70 °C for 16 hours. The mixture was cooled to ambient temperature, quenched with cold water, and diluted with ethyl acetate. The organic layer was washed with water, and the aqueous layer was washed with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluting with 100:0 to 100:20 dichloromethane / methanol to give the title compound (12 g). 1 H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.38 (s, 2H), 8.04 (s, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 8.6, 2.4 Hz, 1H), 4.49 - 4.39 (m, 4H), 4.36 (s, 1H), 4.23 (p, J = 7.7 Hz, 1H), 4.06 (t, J = 7.2 Hz, 2H), 3.81 (s, 3H), 1.83 (t, J = 7.2 Hz, 2H), 1.16 (s, 6H). LCMS (ESI+): m / z 493.3 (M+H) + .

[0204] Example 32 6-{1-[6-(3-hydroxypropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Example 32A 6-(1-{6-[(1E)-3-hydroxyprop-1-en-1-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 17, except that (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-1-ol was used instead of (E)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-ol. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.40 - 8.36 (m, 1H), 8.35 (s, 1H), 8.01 (d, J = 0.8 Hz, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.54 (s, 1H), 7.25 - 7.17 (m, 2H), 6.59 (dt, J = 16.0, 1.5 Hz, 1H), 6.25 (dt, J = 15.9, 5.9 Hz, 1H), 4.45 (d, J = 7.7 Hz, 4H), 4.22 (p, J = 7.6 Hz, 1H), 3.99 (dd, J = 6.0, 1.4 Hz, 2H), 3.78 (s, 3H), 3.24 (s, 3H). LCMS (ESI+): m / z 447.3 (M+H) + .

[0205] Example 32B 6-{1-[6-(3-hydroxypropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 7, except that the compound of Example 32A was used instead of the compound of Example 6. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.66 (s, 1H), 8.37 - 8.32 (m, 2H), 8.00 (d, J = 0.8 Hz, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.56 (d, J = 0.8 Hz, 1H), 7.22 (d, J = 1.5 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 6.96 (dd, J = 8.0, 1.6 Hz, 1H), 4.47 - 4.38 (m, 5H), 4.21 (p, J = 7.6 Hz, 1H), 3.78 (s, 3H), 3.40 - 3.35 (m, 2H), 2.65 - 2.57 (m, 2H), 1.73 - 1.62 (m, 2H). LCMS (ESI+): m / z 449.3 (M+H) + .

[0206] Example 33 6-{1-[6-(3-methoxypropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Example 33A 6-(1-{6-[(1E)-3-methoxyprop-1-en-1-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 17, except that (E)-2-(3-methoxyprop-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of (E)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-ol. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.40 - 8.36 (m, 1H), 8.35 (s, 1H), 8.01 (d, J = 0.8 Hz, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.54 (s, 1H), 7.25 - 7.17 (m, 2H), 6.59 (dt, J = 16.0, 1.5 Hz, 1H), 6.25 (dt, J = 15.9, 5.9 Hz, 1H), 4.45 (d, J = 7.7 Hz, 4H), 4.22 (p, J = 7.6 Hz, 1H), 3.99 (dd, J = 6.0, 1.4 Hz, 2H), 3.78 (s, 3H), 3.24 (s, 3H). LCMS (ESI+): m / z 461.2 (M+H) + .

[0207] Example 33B 6-{1-[6-(3-methoxypropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 7, except that the compound of Example 33A was used instead of the compound of Example 6. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 8.41 - 8.39 (d, J = 2.4 Hz, 1H), 8.39 (s, 1H), 8.05 (s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.61 (s, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.00 (dd, J = 8.0, 1.6 Hz, 1H), 4.46 (dd, J = 7.7, 1.6 Hz, 4H), 4.25 (p, J = 7.6 Hz, 1H), 3.82 (s, 3H), 3.34 - 3.28 (m, 2H), 3.23 (s, 3H), 2.66 (dd, J = 8.8, 6.6 Hz, 2H), 1.84 - 1.75 (m, 2H). LCMS (ESI+): m / z 463.3 (M+H) + .

[0208] Example 34 6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-({1-[2-(dimethylamino)-2-oxoethyl]-1H-pyrazol-4-yl}amino)pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 29, except 2-bromo-N,N-dimethylacetamide was used instead of 1-bromo-2-methoxyethane. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 2.85 (s, 3H), 3.02 (s, 3H), 4.23-4.32 (m, 1H), 4.47-4.53 (m, 4H), 5.08 (s, 2H), 7.04-7.09 (m, 1H), 7.19 (t, J=7.64 Hz, 1H), 7.33 (d, J=7.70 Hz, 1H), 7.45 (d, J=7.83 Hz, 1H), 7.62 (s, 1H), 7.91 (s, 1H), 8.05 (s, 1H), 8.39 (s, 1H), 8.44 (br s, 1H), 10.76-10.81 (m, 1H), 10.76-10.81 (m, 1H), 10.78 (s, 1H). LCMS (ESI+): m / z 462.3 (M+H) + .

[0209] Example 35 6-{1-[6-(2-methoxyethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 31, except 2-bromoethyl methyl ether was used instead of 4-bromo-2-methylbutan-2-ol. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.38 (d, J = 2.8 Hz, 2H), 8.06 - 8.00 (m, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 6.78 (dd, J = 8.6, 2.5 Hz, 1H), 4.48 - 4.39 (m, 4H), 4.24 (q, J = 7.6 Hz, 1H), 4.11 - 4.03 (m, 2H), 3.82 (s, 3H), 3.68 - 3.61 (m, 2H), 3.31 (s, 3H). LCMS (ESI+): m / z 465.3 (M+H) + .

[0210] Example 36 3-{[1-(2,3-dihydroxypropyl)-1H-pyrazol-4-yl]amino}-6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide Example 36A 2-chloro-6-fluoro-1,3-benzoxazole The title compound was prepared in a manner similar to Examples 3A and 3B, except that 2-amino-5-fluorophenol was used instead of 2-amino-5-methylphenol. LCMS (ESI+): m / z 172.2 (M+H) + .

[0211] Example 36B 3-chloro-6-(1-(6-fluorobenzo[d]oxazol-2-yl)azetidin-3-yl)pyrazine-2-carboxylate methyl ester The title compound was prepared in a manner similar to that of Example 1, except that the compound of Example 36A was used instead of 2-chlorobenzo[d]oxazole and Intermediate 2B was used instead of Intermediate 1. LCMS (ESI+): m / z 363.1 (M+H) + .

[0212] Example 36C 6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 27B, except tert-butyl 4-amino-1H-pyrazole-1-carboxylate was used instead of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 12.57 (s, 1H), 10.67 (s, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 8.00 - 7.70 (br m, 2H), 7.84 (d, J = 2.2 Hz, 1H), 7.41 (dd, J = 8.5, 2.5 Hz, 1H), 7.25 (dd, J = 8.6, 5.0 Hz, 1H), 6.99 (ddd, J = 10.2, 8.6, 2.6 Hz, 1H), 4.43 (dd, J = 7.7, 1.2 Hz, 4H), 4.21 (p, J = 7.6 Hz, 1H). LCMS (ESI+): m / z 395.2 (M+H) + .

[0213] Example 36D 3-({1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-1H-pyrazol-4-yl}amino)-6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 29, except that the compound of Example 36C was used instead of the compound of Example 14 and 4-(bromomethyl)-2,2-dimethyl-1,3-dioxolane was used instead of 1-bromo-2-methoxyethane. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.40 - 8.37 (m, 1H), 8.35 (s, 1H), 8.07 (d, J = 0.7 Hz, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.62 (d, J = 0.8 Hz, 1H), 7.41 (dd, J = 8.5, 2.5 Hz, 1H), 7.25 (dd, J = 8.6, 4.9 Hz, 1H), 6.99 (ddd, J = 10.1, 8.6, 2.6 Hz, 1H), 4.48 - 4.40 (m, 4H), 4.38 - 4.31 (m, 1H), 4.27 - 4.12 (m, 3H), 3.97 (dd, J = 8.4, 6.3 Hz, 1H), 3.67 (dd, J = 8.5, 5.9 Hz, 1H), 1.28 (s, 3H), 1.22 (s, 3H). LCMS (ESI+): m / z 509.2 (M+H) + .

[0214] Example 36E 3-{[1-(2,3-dihydroxypropyl)-1H-pyrazol-4-yl]amino}-6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide A mixture of the compound from Example 36D (27 mg, 0.053 mmol), 4-methylbenzenesulfonic acid hydrate (14 mg, 0.074 mmol), tetrahydrofuran (0.53 mL), and water (0.53 mL) was stirred at 20° C. for 1 hour, then at 50° C. for 4 hours. The resulting mixture was cooled, diluted with water and saturated NaHCO3, and allowed to stand for 15 minutes. The precipitate was collected by filtration and rinsed with water and ethyl acetate to give the title compound (15 mg). 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.41 - 8.37 (m, 1H), 8.35 (s, 1H), 8.03 (d, J = 0.8 Hz, 1H), 7.88 - 7.81 (m, 1H), 7.59 (d, J = 0.8 Hz, 1H), 7.41 (dd, J = 8.5, 2.5 Hz, 1H), 7.25 (dd, J = 8.6, 4.9 Hz, 1H), 6.99 (ddd, J = 10.2, 8.6, 2.5 Hz, 1H), 4.91 (d, J = 5.3 Hz, 1H), 4.67 (t, J = 5.6 Hz, 1H), 4.44 (dd, J = 7.7, 1.7 Hz, 4H), 4.21 (p, J = 7.8 Hz, 1H), 4.15 (dd, J = 13.9, 4.1 Hz, 1H), 3.92 (dd, J = 13.8, 7.6 Hz, 1H), 3.80 - 3.71 (m, 1H), 3.28 - 3.21 (m, 2H). LCMS (ESI+): m / z 469.3 (M+H) + .

[0215] Example 37 6-{1-[6-(2-amino-2-oxoethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 31, except 2-bromoacetamide was used instead of 4-bromo-2-methylbutan-2-ol. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.34 (s, 2H), 8.00 (d, J = 0.8 Hz, 1H), 7.92 - 7.79 (m, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.42 (d, J = 47.9 Hz, 2H), 7.18 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 8.6, 2.4 Hz, 1H), 4.41 (dd, J = 7.7, 1.5 Hz, 4H), 4.37 (s, 2H), 4.29 - 4.13 (m, 1H), 3.78 (s, 3H). LCMS (ESI+): m / z 464.3 (M+H) + .

[0216] Example 38 6-{1-[6-(2-hydroxy-2-methylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 31, except 1-bromo-2-methylpropan-2-ol was used instead of 4-bromo-2-methylbutan-2-ol. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.34 (d, J = 1.7 Hz, 2H), 8.01 (d, J = 0.7 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.82 - 6.68 (m, 1H), 4.57 (s, 1H), 4.41 (d, J = 7.8 Hz, 4H), 4.20 (p, J = 7.5 Hz, 1H), 3.78 (s, 3H), 3.66 (s, 2H), 1.17 (s, 6H). LCMS (ESI+): m / z 479.4 (M+H)+ .

[0217] Example 39 6-(1-{6-[2-(dimethylamino)-2-oxoethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 31, except 2-bromo-N,N-dimethylacetamide was used instead of 4-bromo-2-methylbutan-2-ol. 1 H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.38 (s, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 7.11 (s, 1H), 6.78 (dd, J = 8.6, 2.5 Hz, 1H), 4.77 (s, 2H), 4.51 - 4.37 (m, 4H), 4.24 (p, J = 7.6 Hz, 1H), 3.82 (s, 3H), 3.00 (s, 3H), 2.84 (s, 3H). LCMS (ESI+): m / z 492.4 (M+H) + .

[0218] Example 40 6-{1-[6-(2-hydroxyethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 31, except 2-bromoethanol was used instead of 4-bromo-2-methylbutan-2-ol. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.38 (s, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.88 (s, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.86 - 6.71 (m, 1H), 4.84 (t, J = 5.5 Hz, 1H), 4.44 (dd, J = 7.6, 1.3 Hz, 4H), 4.24 (p, J = 7.6 Hz, 1H), 4.02 - 3.86 (m, 2H), 3.82 (s, 3H), 3.71 (q, J = 5.2 Hz, 2H). LCMS (ESI+): m / z 451.2 (M+H) + .

[0219] Example 41 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(oxetan-3-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 31, except 3-(bromomethyl)oxetane was used instead of 4-bromo-2-methylbutan-2-ol. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 8.39 (s, 2H), 8.05 (d, J = 0.8 Hz, 1H), 7.95 - 7.79 (m, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.27 - 7.06 (m, 2H), 6.81 (dd, J = 8.6, 2.4 Hz, 1H), 4.71 (dd, J = 7.9, 6.0 Hz, 2H), 4.52 - 4.36 (m, 6H), 4.25 (q, J = 7.7 Hz, 1H), 4.19 (d, J = 6.7 Hz, 2H), 3.38 (s, 1H). LCMS (ESI+): m / z 477.4 (M+H) + .

[0220] Example 42 6-(1-{6-[(3-hydroxycyclobutyl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide A solution of the compound from Example 20 (0.05 g, 0.123 mmol) and cesium carbonate (0.08 g, 0.246 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at ambient temperature for 15 minutes. (3-Hydroxycyclobutyl)methyl 4-methylbenzenesulfonate (0.038 g, 0.148 mmol) was added, and the resulting mixture was heated at 90 °C for 16 hours. The mixture was cooled, quenched with water, and diluted with ethyl acetate. The aqueous layer was washed with ethyl acetate, and the organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography eluting with 100:0 to 100:10 dichloromethane / methanol to give the title compound (23 mg). 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 8.39 (d, J = 3.5 Hz, 2H), 8.05 (s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.81 - 6.62 (m, 1H), 5.04 (d, J = 6.4 Hz, 1H), 4.50 - 4.39 (m, 4H), 4.24 (p, J = 7.6 Hz, 1H), 4.07 - 3.92 (m, 1H), 3.90 (d, J = 6.4 Hz, 2H), 3.82 (s, 3H), 2.31 (dddd, J = 11.0, 9.4, 5.0, 2.6 Hz, 2H), 2.10 (dtd, J = 13.5, 6.6, 2.6 Hz, 1H), 1.69 - 1.58 (m, 2H). LCMS (ESI+): m / z 491.5 (M+H) + .

[0221] Example 43 6-{1-[6-(2,3-dihydroxypropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide A solution of the compound from Example 20 (0.05 g, 0.123 mmol) and sodium hydride (7.4 mg, 0.135 mmol, 60% mineral oil dispersion) in N,N-dimethylformamide (0.5 mL) was stirred at ambient temperature for 15 minutes. 4-(Bromomethyl)-2,2-dimethyl-1,3-dioxolane (0.029 g, 0.148 mmol) was added, and the resulting mixture was stirred at 70 °C for 16 hours. The mixture was quenched with water and diluted with ethyl acetate. The aqueous layer was washed with ethyl acetate, and the organic layer was washed with water and brine, dried over Na2SO4, and concentrated. Tetrahydrofuran (0.5 mL) and 4-methylbenzenesulfonic acid (21.2 mg, 0.123 mmol) were added to the residue, and the resulting mixture was heated to 50 °C for 4 hours. The mixture was cooled, concentrated and purified by silica gel chromatography eluting with 100:0 to 100:10 dichloromethane / methanol to give the title compound (21 mg). 1H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.38 (d, J = 3.7 Hz, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.88 (s, 1H), 7.60 (d, J = 0.7 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.6, 2.4 Hz, 1H), 4.92 (d, J = 5.0 Hz, 1H), 4.64 (t, J = 5.7 Hz, 1H), 4.50 - 4.37 (m, 4H), 4.23 (p, J = 7.7 Hz, 1H), 3.97 (dd, J = 9.9, 4.2 Hz, 1H), 3.85 (dd, J = 9.8, 6.0 Hz, 1H), 3.81 (s, 3H), 3.77 (dt, J = 10.9, 5.4 Hz, 1H), 3.44 (td, J = 5.6, 1.2 Hz, 2H). LCMS (ESI+): m / z 481.4 (M+H) + .

[0222] Example 44 6-(1-{6-[(1-hydroxycyclobutyl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 31, except 1-(bromomethyl)cyclobutan-1-ol was used instead of 4-bromo-2-methylbutan-2-ol. 1H NMR (501 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.38 (s, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.88 (s, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 8.5, 2.4 Hz, 1H), 5.20 (s, 1H), 4.44 (dd, J = 7.7, 1.4 Hz, 4H), 4.23 (p, J = 7.6 Hz, 1H), 3.88 (s, 2H), 3.82 LCMS (ESI+): m / z 491.2 (M+H) + .

[0223] Example 45 6-(1-{6-[2-(3-hydroxyoxetan-3-yl)ethyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Example 45A 6-(1-{6-[(3-hydroxyoxetan-3-yl)ethynyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide A mixture of the compound from Example 6A (50 mg, 0.107 mmol), 3-ethynyloxetan-3-ol (20.90 mg, 0.213 mmol), copper(I) iodide (2.0 mg, 11 μmol), and tetrakis(triphenylphosphine)palladium(0) (6.2 mg, 5.3 μmol) was sparged with nitrogen. N,N-Dimethylformamide (0.5 mL) and triethylamine (0.04 mL, 0.287 mmol) were added, and the resulting mixture was bubbled with nitrogen for 5 minutes. The mixture was heated at 90 °C for 16 hours and then partitioned with water and ethyl acetate. The organic extract was dried over Na2SO4, concentrated, and purified by silica gel flash chromatography, eluting with 100 / 0 to 94 / 6 dichloromethane / methanol, to give the title compound (22 mg). LCMS (ESI+): m / z 487.4 (M+H) + .

[0224] Example 45B 6-(1-{6-[2-(3-hydroxyoxetan-3-yl)ethyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 7, except that the compound of Example 45A was used instead of the compound of Example 6. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.38 - 8.32 (m, 2H), 8.01 (d, J = 0.8 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 0.9 Hz, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.17 (d, J = 7.9 Hz, 1H), 7.01 (dd, J = 8.0, 1.6 Hz, 1H), 5.61 (s, 1H), 4.43 (d, J = 7.7 Hz, 4H), 4.36 (d, J = 6.2 Hz, 2H), 4.27 (d, J LCMS (ESI+): m / z 491.3 (M+H) + .

[0225] Example 46 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(morpholine-4-carbonyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 18B, except morpholine was used instead of dimethylamine hydrochloride. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.39 (s, 1H), 8.35 (s, 1H), 8.01 (s, 1H), 7.86 (s, 1H), 7.57 (s, 1H), 7.50 - 7.44 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.21 (dd, J = 8.1, 1.5 Hz, 1H), 4.47 (d, J = 7.7 Hz, 4H), 4.24 (p, J = 7.7 Hz, 1H), 3.78 (s, 3H), 3.61 - 3.37 (m, 8H). LCMS (ESI+): m / z 504.3 (M+H)+ .

[0226] Example 47 6-(1-{6-[2-(dimethylamino)-2-oxoethyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 18B, except that the compound of Example 65C was used instead of the compound of Example 18A. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.37 - 8.32 (m, 2H), 8.01 (s, 1H), 7.84 (s, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.23 (d, J = 1.6 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 6.98 (dd, J = 7.9, 1.6 Hz, 1H), 4.50 - 4.37 (m, 4H), 4.22 (p, J = 7.6 Hz, 1H), 3.78 (s, 3H), 3.68 (s, 2H), 2.97 (s, 3H), 2.79 (s, 3H). LCMS (ESI+): m / z 476.3 (M+H) + .

[0227] Example 48 6-[1-(6-{[(2R)-1,4-dioxan-2-yl]methoxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 31, except using [(2R)-1,4-dioxan-2-yl]methyl 4-methylbenzene-1-sulfonate instead of 4-bromo-2-methylbutan-2-ol. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.34 (s, 2H), 8.00 (d, J = 0.8 Hz, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.74 (dd, J = 8.6, 2.4 Hz, 1H), 4.45 - 4.34 (m, 4H), 4.20 (p, J = 7.6 Hz, 1H), 3.94 - 3.86 (m, 2H), 3.85 - 3.78 LCMS (ESI+): m / z 507.3 (M+H) + .

[0228] Example 49 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 31, except 2-bromo-1-(pyrrolidin-1-yl)ethan-1-one was used instead of 4-bromo-2-methylbutan-2-ol. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.34 (s, 2H), 8.00 (d, J = 0.8 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.16 (d, J = 8.6 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.74 (dd, J = 8.6, 2.4 Hz, 1H), 4.65 (s, 2H), 4.47 - 4.35 (m, 4H), 4.20 (p, J = 7.6 Hz, 1H), 3.78 (s, 3H), 3.43 (t, J = 6.7 Hz, 2H), 1.94 - 1.82 (m, 2H), 1.80 - 1.62 (m, 2H). LCMS (ESI+): m / z 518.4 (M+H) + .

[0229] Example 50 6-(1-{6-[2-(methylamino)-2-oxoethyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 18B, except that the compound of Example 65C was used instead of the compound of Example 18A and methylamine was used instead of dimethylamine hydrochloride. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.35 (br s, 2H), 8.01 (s, 1H), 7.88-7.82 (m, 2H), 7.57 (d, J = 0.7 Hz, 1H), 7.27 (d, J = 1.6 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 7.01 (dd, J = 8.0, 1.6 Hz, 1H), 4.43 (d, J = 7.6 Hz, 4H), 4.26 - 4.16 (m, 1H), 3.78 (s, 3H), 3.38 (s, 2H), 2.53 (d, J = 4.6 Hz, 3H). LCMS (ESI+): m / z 362.5 (M+H) + .

[0230] Example 51 6-(1-{6-[3-hydroxy-2-(hydroxymethyl)propoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Example 51A 6-(1-{6-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 31, except 5-(bromomethyl)-2,2-dimethyl-1,3-dioxane was used instead of 4-bromo-2-methylbutan-2-ol. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.35 (s, 2H), 8.00 (d, J = 0.8 Hz, 1H), 7.85 (s, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 8.6, 2.4 Hz, 1H), 4.41 (d, J = 7.8 Hz, 4H), 4.21 (q, J = 7.6 Hz, 1H), 4.03 - 3.88 (m, 4H), 3.78 (s, 3H), 3.71 (dd, J = 11.8, 6.0 Hz, 2H), 2.01 (s, 1H), 1.31 (d, J = 11.1 Hz, 6H). LCMS (ESI+): m / z 535.2 (M+H) + .

[0231] Example 51B 6-(1-{6-[3-hydroxy-2-(hydroxymethyl)propoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide To a solution of the compound from Example 51A (0.020 g, 0.037 mmol) in tetrahydrofuran (374 μL) was added p-toluenesulfonic acid (8.38 mg, 0.049 mmol), and the resulting mixture was stirred at 50° C. for 2 h. The mixture was concentrated, quenched with water, and acidified with dilute acetic acid. The mixture was washed with ethyl acetate, and the organic layer was dried over NaSO, concentrated, and purified by flash chromatography eluting with 100 / 0 to 100 / 10 dichloromethane / methanol to give the title compound (13 mg). 1H NMR (400 MHz,dimethylsulfoxide-d6) δ ppm 10.67 (s, 1H), 8.35 (s, 2H), 8.00 (d, J = 0.8 Hz, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.73 (dd, J = 8.6, 2.4 Hz, 1H), 4.48 (t, J = 5.2 Hz, 2H), 4.41 (d, J = 7.7 Hz, 4H), 4.20 (p, J = 7.7 Hz, 1H), 3.92 (d, J = 5.8 Hz, 2H), 3.78 (s, 3H), 3.48 (q, J = 5.1 Hz, 4H), 1.95 - 1.88 (m, 1H). LCMS (ESI+): m / z 495.4 (M+H) + .

[0232] Example 52 N-tert-butyl-2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazole-6-carboxamide The title compound was prepared in a manner similar to Example 18B, except 2-methylpropan-2-amine was used instead of dimethylamine hydrochloride. 1H NMR (500 MHz,dimethylsulfoxide-d6) δ ppm 10.74 (s, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.40 (s, 1H), 8.06 (d, J = 0.8 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.88 (dd, J = 1.6, 0.5 Hz, 1H), 7.72 (dd, J = 8.2, 1.7 Hz, 1H), 7.65 (s, 1H), 7.62 (d, J = 0.8 Hz, 1H), 7.31 (dd, J = 8.2, 0.5 Hz, 1H), 4.57 - 4.50 (m, 4H), 4.33 - 4.25 (m, 1H), 3.84 (s, 3H), 1.40 (s, 9H). LCMS (ESI+): m / z 490.4 (M+H) + .

[0233] Example 53 2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-N-cyclopropyl-1,3-benzoxazole-6-carboxamide The title compound was prepared in a manner similar to Example 18B, except cyclopropanamine was used instead of dimethylamine hydrochloride. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.40 (s, 1H), 8.35 (s, 1H), 8.29 (d, J = 4.1 Hz, 1H), 8.01 (d, J = 0.7 Hz, 1H), 7.85 (s, 1H), 7.81 (d, J = 1.7 Hz, 1H), 7.68 (dd, J = 8.2, 1.7 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 4.53 - 4.43 (m, 4H), 4.24 (p, J = 7.6 Hz, 1H), 3.78 (s, 3H), 2.84 - 2.75 (m, 1H), 0.70 - 0.62 (m, 2H), 0.56 - 0.50 (m, 2H). LCMS (ESI+): m / z 474.3 (M+H) + .

[0234] Example 54 3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide Example 54A 3-chloro-6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxylate methyl ester The title compound was prepared in a manner similar to that of Example 1, except that the compound of Example 3B was used instead of 2-chlorobenzo[d]oxazole and Intermediate 2 was used instead of Intermediate 1. LCMS (ESI+): m / z 359.1 (M+H) + .

[0235] Example 54B 6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Examples 27B and 27C, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate was used instead of 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine. LCMS (ESI+): m / z 391.2 (M+H) + .

[0236] Example 54C 3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide The title compound was prepared in a manner analogous to Example 29, except that the compound of Example 54B was used instead of the compound of Example 14 and 2-bromoethanol was used instead of 1-bromo-2-methoxyethane. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 10.75 (s, 1H), 8.43–8.40 (m, 2H), 8.10 (d, J = 0.8 Hz, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.65 (d, J = 0.8 Hz, 1H), 7.26 (dt, J = 1.5, 0.7 Hz, 1H), 7.20 (d, J = 7.9 Hz, 1H), 6.99 (ddd, J = 7.9, 1.6, 0.8 Hz, 1H), 4.89 (t, J = 5.3 Hz, 1H), 4.51–4.43 (m, 4H), 4.31–4.20 (m, 1H), 4.13 (t, J = 5.6 Hz, 2H), 3.74 (q, J = 5.5 Hz, 2H), 2.37 (s, 3H). LCMS (ESI+): m / z 435.2 (M+H) + .

[0237] Example 55 3-{[1-(2-methoxyethyl)-1H-pyrazol-4-yl]amino}-6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 29, except that the compound of Example 54B was used instead of the compound of Example 14. 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 10.75 (s, 1H), 8.43 - 8.40 (m, 2H), 8.09 (d, J = 0.8 Hz, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 0.8 Hz, 1H), 7.26 - 7.25 (m, 1H), 7.20 (d, J = 7.9 Hz, 1H), 6.99 (ddd, J = 7.9, 1.6, 0.8 Hz, 1H), 4.51 - 4.44 (m, 4H), 4.29 - 4.21 (m, 3H), 3.68 (dd, J = 5.6, 5.0 Hz, 2H), 3.24 (s, 3H), 2.37 (s, 3H). LCMS (ESI+): m / z 449.3 (M+H) + .

[0238] Example 56 6-[1-(6-{[3-(hydroxymethyl)cyclobutyl]methoxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 31, except (3-(hydroxymethyl)cyclobutyl)methyl 4-methylbenzenesulfonate was used instead of 4-bromo-2-methylbutan-2-ol. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.38 (s, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 0.7 Hz, 1H), 7.18 (dd, J = 8.6, 2.4 Hz, 1H), 7.10 (dd, J = 9.5, 2.4 Hz, 1H), 6.76 (ddd, J = 8.6, 7.9, 2.4 Hz, 1H), 4.52 - 4.34 (m, 5H), 4.23 (p, J = 7.6 Hz, 1H), 3.96 (d, J = 7.0 Hz, 1H), 3.86 (d, J = 6.7 Hz, 1H), 3.42 (dd, J = 6.7, 5.3 Hz, 1H), 3.35 (s, 1H), 2.60 (dq, J = 22.9, 8.2, 7.8 Hz, 1H), 2.44 - 2.24 (m, 1H), 2.13 - 2.01 (m, 1H), 1.90 - 1.79 (m, 2H), 1.55 (dt, J = 11.6, 8.9 Hz, 1H). LCMS (ESI+): m / z 505.5 (M+H) + .

[0239] Example 57 6-(1-{6-[(3-hydroxyoxetan-3-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 31, except using (3-hydroxyoxetan-3-yl)methyl 4-methylbenzenesulfonate instead of 4-bromo-2-methylbutan-2-ol. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 8.38 (s, 2H), 8.05 (dd, J = 5.0, 0.8 Hz, 1H), 7.92 - 7.82 (m, 1H), 7.62 (dd, J = 11.9, 0.8 Hz, 1H), 7.22 (dd, J = 8.5, 2.4 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 6.84 (ddd, J = 8.6, 2.5, 1.6 Hz, 1H), 6.00 (d, J = 0.7 Hz, 1H), 4.52 - 4.42 (m, 10H), 4.24 (p, J = 7.6 Hz, 1H), 3.82 (d, J = 1.8 Hz, 3H). LCMS (ESI+): m / z 193.3 (M+H) + .

[0240] Example 58 6-[1-(6-{[(1S,2R)-2-(hydroxymethyl)cyclopropyl]methoxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 31, except ((1R,2S)-2-(hydroxymethyl)cyclopropyl)methyl 4-methylbenzenesulfonate was used instead of 4-bromo-2-methylbutan-2-ol. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.38 (s, 2H), 8.04 (s, 1H), 7.88 (s, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.78 (dd, J = 8.5, 2.4 Hz, 1H), 4.44 (d, J = 7.7 Hz, 4H), 4.23 (p, J = 7.6 Hz, 1H), 4.11 (dd, J = 10.6, 6.6 Hz, 1H), 4.00 (dd, J = 10.6, 7.4 Hz, 1H), 3.82 (s, 3H), 3.78 (d, J = 7.7 Hz, 2H), 1.54 - 1.33 (m, 2H), 0.95 (td, J = 8.4, 4.8 Hz, 1H), 0.49 (q, J = 5.4 Hz, 1H). LCMS (ESI+): m / z 491.4 (M+H) + .

[0241] Example 59 6-(1-{6-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 18B, except R-pyrrolidin-2-ylmethanol was used instead of dimethylamine hydrochloride. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.40 (s, 1H), 8.35 (s, 1H), 8.01 (d, J = 0.8 Hz, 1H), 7.87 - 7.82 (m, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.55 - 7.53 (m, 1H), 7.35 - 7.26 (m, 2H), 4.78 - 4.68 (m, 1H), 4.52 - 4.44 (m, 4H), 4.24 (p, J = 7.6 Hz, 1H), 4.17 - 4.06 (m, 1H), 3.79 (s, 3H), 3.64 - 3.40 (m, 3H), 1.98 - 1.77 (m, 4H), 1.73 - 1.57 (m, 1H). LCMS (ESI+): m / z 518.2 (M+H) + .

[0242] Example 60 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(3-phenylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide The title compound was obtained in the same manner as in Example 31, except that 1-bromo-3-phenylpropane was used instead of 4-bromo-2-methylbutan-2-ol. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.38 (s, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.33 - 7.13 (m, 6H), 7.11 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.6, 2.4 Hz, 1H), 4.49 - 4.36 (m, 4H), 4.23 (p, J = 7.6 Hz, 1H), 3.95 (t, J = 6.3 Hz, 2H), 3.82 (s, 3H), 2.74 (dd, J = 8.7, 6.7 Hz, 2H), 2.11 - 1.87 (m, 2H). LCMS (ESI+): m / z 525.2 (M+H) + .

[0243] Example 61 6-{1-[6-(3-hydroxy-2,2-dimethylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was obtained in the same manner as in Example 31, except that 3-bromo-2,2-dimethyl-1-propanol was used instead of 4-bromo-2-methylbutan-2-ol. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.38 (s, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 2.3 Hz, 1H), 6.76 (dd, J = 8.5, 2.4 Hz, 1H), 4.58 (t, J = 5.3 Hz, 1H), 4.44 (d, J = 7.7 Hz, 4H), 4.23 (p, J = 7.5 Hz, 1H), 3.82 (s, 3H), 3.68 (s, 2H), 3.28 (d, J = 5.3 Hz, 2H), 0.92 (s, 6H). LCMS (ESI+): m / z 493.2 (M+H) + .

[0244] Example 62 6-(1-{6-[3-(dimethylamino)-3-oxopropyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Example 62A tert-Butyl (2E)-3-[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]prop-2-enoate A mixture of the compound from Example 6A (500 mg, 1.065 mmol) and bis(triphenylphosphine)palladium(II) dichloride (37.4 mg, 0.053 mmol) was sparged with nitrogen, and N,N-dimethylformamide (2.66 mL), triethylamine (0.418 mL, 3.0 mmol), and tert-butyl acrylate (0.31 mL, 2.13 mmol) were added. The resulting mixture was sparged for 5 minutes and heated at 90 °C for 18 hours. The mixture was cooled and partitioned between water and ethyl acetate. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography eluting with 100 / 0 to 95 / 5 dichloromethane / methanol to give the title compound (340 mg). LCMS (ESI+): m / z 517.23 (M+H) + .

[0245] Example 62B tert-Butyl 3-[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]propanoate The title compound was prepared in a manner similar to that of Example 7, except that the compound of Example 62A was used instead of the compound of Example 6. LCMS (ESI+): m / z 519.06 (M+H) + .

[0246] Example 62C 3-[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]propanoic acid A mixture of the compound from Example 62B (184 mg, 0.366 mmol), dichloromethane (3.5 mL), and trifluoroacetic acid (0.27 mL) was stirred at ambient temperature for 18 hours. Additional trifluoroacetic acid (1 mL) was added, and the resulting mixture was stirred for an additional 2.5 hours. The mixture was concentrated, treated with cyclopentyl methyl ether (10 mL), and concentrated. Additional cyclopentyl methyl ether (10 mL) was added. The resulting slurry was allowed to stand overnight and filtered to provide the title compound (185 mg) as the trifluoroacetic acid salt. LCMS (ESI+): m / z 463.04 (M+H) + .

[0247] Example 62D 6-(1-{6-[3-(dimethylamino)-3-oxopropyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 18B, except that the compound of Example 62C was used instead of the compound of Example 18A. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.36 - 8.32 (m, 2H), 8.01 (d, J = 0.7 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.28 (d, J = 1.5 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0, 1.6 Hz, 1H), 4.42 (d, J = 7.6 Hz, 4H), 4.21 (p, J = 7.6 Hz, 1H), 3.78 (s, 3H), 2.89 (s, LCMS (ESI+): m / z 490.18 (M+H) + .

[0248] Example 63 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[3-oxo-3-(pyrrolidin-1-yl)propyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 18B, except that the compound of Example 62C was used instead of the compound of Example 18A and pyrrolidine was used instead of dimethylamine hydrochloride. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.67 (s, 1H), 8.37 - 8.32 (m, 2H), 8.00 (s, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.28 (d, J = 1.5 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0, 1.6 Hz, 1H), 4.42 (d, J = 7.6 Hz, 4H), 4.21 (p, J = 7.6 Hz, 1H), 3.78 (s, 3H), 3.34 - 3.21 (m, 4H), 2.82 (t, J = 7.7 Hz, 2H), 2.52 - 2.47 (m, 2H), 1.84 - 1.65 (m, 4H). LCMS (ESI+): m / z 516.21 (M+H) + .

[0249] Example 64 6-(1-{6-[(2R)-2-(methoxymethyl)pyrrolidine-1-carbonyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 18B, except (R)-2-(methoxymethyl)pyrrolidine was used instead of dimethylamine hydrochloride. 1H NMR (400 MHz,dimethylsulfoxide-d6) δ ppm 10.69 (s, 1H), 8.40 (d, J = 2.2 Hz, 1H), 8.35 (s, 1H), 8.01 (d, J = 0.8 Hz, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.53 (t, J = 1.1 Hz, 1H), 7.32 - 7.25 (m, 2H), 4.48 (d, J = 7.8 Hz, 4H), 4.29 - 4.15 (m, 2H), 3.79 (s, 3H), 3.63 - 3.18 (m, 7H), 2.01 - 1.91 (m, 1H), 1.89 - 1.61 (m, 3H). LCMS (ESI+): m / z 532.47 (M+H) + .

[0250] Example 65 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide Example 65A 6-(1-{6-[(E)-2-ethoxyethenyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 17, except that (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was used instead of (E)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)but-3-en-2-ol. LCMS (ESI+): m / z 461.4 (M+H) + .

[0251] Example 65B 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(2-oxoethyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide A solution of the compound from Example 65A (59 mg, 0.128 mmol) in dichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.5 mL, 6.49 mmol), stirred at ambient temperature for 30 minutes, and diluted with dichloromethane (5 mL) and saturated NaHCO (15 mL). The aqueous phase was extracted with dichloromethane, and the organic layer was dried over NaSO, filtered, and concentrated to give the title compound (52 mg). LCMS (ESI-): m / z 430.9 (MH) - .

[0252] Example 65C [2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]acetic acid To a suspension of the compound from Example 65B (300 mg, 0.694 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added 2-methylbut-2-ene (0.735 mL, 6.94 mmol), followed by sodium chlorite (502 mg, 5.55 mmol) and sodium dihydrogen phosphate dihydrate (974 mg, 6.24 mmol). The resulting mixture was stirred at 20°C for 3 hours and then diluted with 1N sodium hydroxide (10 mL) and dichloromethane (15 mL). The organic layer was extracted with water, and the combined aqueous layer was adjusted to pH 2 with 1N hydrochloric acid. The resulting precipitate was collected by filtration, and the filtrate was extracted with dichloromethane. The precipitate and the organic extract were combined and concentrated. The residue was purified by silica gel chromatography eluting with 100 / 0 to 88 / 12 methanol / dichloromethane to give the title compound (148 mg). 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 12.23 (s, 1H), 10.67 (s, 1H), 8.37 - 8.33 (m, 2H), 8.01 (d, J = 0.7 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.29 (d, J = 1.6 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.02 (dd, J = 8.0, 1.6 Hz, 1H), 4.44 (d, J = 7.7 Hz, 4H), 4.27 - 4.17 (m, 1H), 3.78 (s, 3H), 3.57 (s, 2H). LCMS (ESI+): m / z 449.30 (M+H) + .

[0253] Example 65D 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 18B, except that the compound of Example 65C was used instead of the compound of Example 18A and pyrrolidine was used instead of dimethylamine hydrochloride. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.35 (d, J = 3.4 Hz, 2H), 8.01 (d, J = 0.8 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.25 (d, J = 1.6 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.00 (dd, J = 8.0, 1.6 Hz, 1H), 4.43 (d, J = 7.7 Hz, 4H), 4.22 (p, J = 7.7 Hz, 1H), 3.79 (s, 3H), 3.62 LCMS (ESI+): m / z 502.38 (M+H) + .

[0254] Example 66 6-[1-(6-{2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-oxoethyl}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide To a mixture of the compound from Example 65C (60 mg, 0.134 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (102 mg, 0.268 mmol), N,N-dimethylformamide (0.5 mL), N-ethyl-N-isopropylpropan-2-amine (0.12 mL, 0.694 mmol), and (S)-pyrrolidin-2-ylmethanol (0.02 mL, 0.20 mmol) were added, and the resulting mixture was stirred at ambient temperature for 18 hours. The mixture was partitioned with water and ethyl acetate. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography eluting with 100 / 0 to 92 / 8 dichloromethane / methanol to give the title compound (340 mg). 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 10.73 (s, 1H), 8.44 - 8.41 (m, 1H), 8.40 (s, 1H), 8.06 (s, 1H), 7.92 - 7.89 (m, 1H), 7.62 (s, 1H), 7.29 (dd, J = 5.3, 1.5 Hz, 1H), 7.24 (dd, J = 8.0, 3.5 Hz, 1H), 7.04 (dt, J = 8.1, 2.1 Hz, 1H), 5.00 (t, J = 5.7 Hz, 0.3H), 4.76 (t, J = 5.6 Hz, 0.7H), 4.48 (dd, J = 7.7, 2.4 Hz, 4H), 4.27 (p, J = 7.6 Hz, 1H), 4.04 (d, J = 6.4 Hz, 0.3H), 3.96 (dt, J = 8.5, 4.5 Hz, 0.7H), 3.83 (s, 3H), 3.67 (s, 2H), 3.56-3.42 (m, 2H), 3.40 - 3.23 (m, 2H), 1.98 - 1.75 (m, 4H). LCMS (ESI+): m / z 532.18 (M+H) + .

[0255] Example 67 6-{1-[6-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Example 67A Methyl [2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]acetate A mixture of the compound from Example 65C (200 mg, 0.446 mmol), methanol (5 mL), and thionyl chloride (2 drops) was stirred for 18 hours. Additional thionyl chloride (2 drops) was added, and the resulting mixture was stirred for an additional 2.5 hours. The mixture was concentrated and partitioned with half-saturated NaHCO3 and ethyl acetate. The organic layer was dried over Na2SO4, filtered, and concentrated to give the title compound (180 mg), which was used without further purification. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.36 (s, 1H), 8.35 (s, 1H), 8.01 (d, J = 0.8 Hz, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.30 (d, J = 1.6 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.02 (dd, J = 8.0, 1.6 Hz, 1H), 4.46 - 4.41 (m, 4H), 4.22 (p, J = 7.6 Hz, 1H), 3.78 (s, 3H), 3.68 (s, 2H), 3.57 (s, 3H). LCMS (ESI+): m / z 463.11 (M+H) + .

[0256] Example 67B 6-{1-[6-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 19, except that the compound of Example 67A was used instead of the compound of Example 13. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.37-8.34 (m, 2H), 8.01 (s, 1H), 7.86 - 7.83 (m, 1H), 7.57 (d, J = 0.7 Hz, 1H), 7.22 (d, J = 1.5 Hz, 1H), 7.15 (d, J = 7.9 Hz, 1H), 6.96 (dd, J = 7.9, 1.6 Hz, 1H), 4.43 (dd, J = 7.7, 1.7 Hz, 4H), 4.24 (s, 1H), 4.21 (p, J = 7.6 Hz, 1H), 3.79 (s, 3H), 2.65 (s, 2H), 1.02 (s, 6H). LCMS (ESI+): m / z 463.06 (M+H) + .

[0257] Example 68 6-(1-{6-[(2R)-2-hydroxypropoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide A solution of the compound from Example 20 (0.05 g, 0.123 mmol) and cesium carbonate (0.06 g, 0.185 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at ambient temperature for 15 minutes. (R)-Propylene oxide (15 mg, 0.27 mmol) was added, and the resulting mixture was heated at 70 °C for 10 hours. The mixture was cooled, quenched with water, and diluted with ethyl acetate. The aqueous layer was washed with ethyl acetate, and the organic layer was washed with water, washed with brine, dried over NaSO, and concentrated. The residue was purified by silica gel chromatography eluting with 100:0 to 100:10 dichloromethane / methanol to give the title compound (31 mg). 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 8.39 (d, J = 9.3 Hz, 2H), 8.04 (s, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.61 (s, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 8.6, 2.4 Hz, 1H), 4.47 (m, 5H), 4.27 - 4.23 (m, 1H), 3.98 - 3.89 (m, 1H), 3.82 (s, 3H), 3.77 (dt, J = 9.6, 4.5 Hz, 1H), 1.15 (d, J = 6.3 Hz, 3H). LCMS (ESI+): m / z 465.2 (M+H) + .

[0258] Example 69 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-[1-(6-{[(3S)-oxolan-3-yl]oxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 31, except using (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate instead of 4-bromo-2-methylbutan-2-ol. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.38 (s, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.97 - 7.82 (m, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.75 (dd, J = 8.5, 2.4 Hz, 1H), 4.99 (d, J = 1.8 Hz, 1H), 4.44 (dd, J = 7.6, 1.8 Hz, 4H), 4.25 (d, J = 7.6 Hz, 1H), 3.90 - 3.83 (m, 2H), 3.82 (s, 3H), 3.80 - 3.70 (m, 2H), 2.26 - 2.13 (m, 1H), 1.96 (dt, J = 12.6, 5.6 Hz, 1H). LCMS (ESI+): m / z 477.4 (M+H) + .

[0259] Example 70 6-[1-(6-{2-[(3S)-3-Methoxypyrrolidin-1-yl]-2-oxoethyl}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 66, except (S)-3-methoxypyrrolidine hydrochloride was used instead of (S)-pyrrolidin-2-ylmethanol. 1H NMR (400 MHz, dimethyl sulfoxide-d6, T = 90 ℃) δ ppm 10.51 (s, 1H), 8.34 (s, 1H), 8.02 (br s, 1H), 7.93 (d, J = 0.8 Hz, 1H), 7.50 (br s, 1H), 7.54 (d, J = 0.8 Hz, 1H), 7.24 (d, J = 1.6 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.01 (dd, J = 8.1, 1.6 Hz, 1H), 4.50 (t, J = 8.3 Hz, 2H), 4.42 (dd, J = 7.9, 6.4 Hz, 2H), 4.21 (tt, J = 8.6, 6.4 Hz, 1H), 4.01 - 3.88 (m, 1H), 3.79 (s, 3H), 3.62 (s, 2H), 3.59 - 3.25 (m, 4H), 3.21 (s, 3H), 2.00 - 1.81 (m, 2H). LCMS (ESI+): m / z 490.4 (M+H) + .

[0260] Example 71 6-[1-(6-{2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]-2-oxoethyl}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 66, except (R)-2-(methoxymethyl)pyrrolidine was used instead of (S)-pyrrolidin-2-ylmethanol. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.68 (s, 1H), 8.36 (d, J = 2.7 Hz, 1H), 8.35 (s, 1H), 8.01 (d, J = 0.7 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.23 (d, J = 1.5 Hz, 1H), 7.19 (dd, J = 7.9, 2.3 Hz, 1H), 6.99 (dt, J = 8.1, 2.1 Hz, 1H), 4.44 (d, J = 7.8 Hz, 4H), 4.22 (p, J = 7.6 Hz, 1H), 4.05 - 3.98 (m, 1H), 3.79 (s, 3H), 3.62 (d, J = 4.9 Hz, 1H), 3.45 - 3.40 (m, 1H), 3.38 (dd, J = 9.0, 3.4 Hz, 1H), 3.29-3.17 (m, 7H), 1.93 - 1.71 (m, 4H). LCMS (ESI+): m / z 546.4 (M+H) + .

[0261] Example 72 6-(1-{6-[(1-methyl-2-oxopyrrolidin-3-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide A solution of the compound from Example 20 (0.25 g, 0.615 mmol) in N,N-dimethylformamide (2.6 mL) was treated with cesium carbonate (0.401 g, 1.23 mmol) and potassium iodide (112 mg, 0.677 mmol) under a nitrogen atmosphere, and the resulting mixture was stirred at ambient temperature for 20 minutes. 3-Bromo-1-methylpyrrolidin-2-one (120 mg, 0.677 mmol) was added, and the resulting mixture was stirred at ambient temperature overnight. The mixture was washed with ethyl acetate, and the organic layer was dried over Na2SO4, concentrated, and purified by silica gel chromatography eluting with 0:100 to 30:100 methanol / dichloromethane to give the title compound (0.17 g).1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 8.39 (d, J = 15.7 Hz, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.22 - 7.17 (m, 1H), 6.85 (dd, J = 8.6, 2.4 Hz, 1H), 4.91 (dd, J = 7.8, 6.8 Hz, 1H), 4.50 - 4.38 (m, 4H), 4.29 - 4.19 (m, 1H), 3.82 (s, 3H), 3.44 - 3.36 (m, 1H), 3.32 - 3.30 (m, 1H), 2.79 (d, J = 0.5 Hz, 3H), 2.57 - 2.52 (m, 1H), 1.91 (ddt, J = 13.3, 8.8, 6.8 Hz, 1H). LCMS (ESI+): m / z 504.2 (M+H) + .

[0262] Example 73 6-(1-{6-[2-(azetidin-1-yl)-2-oxoethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Example 73A {[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}acetic acid To a solution of the compound of Example 26 (0.553 g, 1.123 mmol) in ethanol (1 mL) was added a solution of lithium hydroxide (0.134 g, 5.61 mmol) in tetrahydrofuran (1 mL), and the resulting mixture was heated at 50° C. for 2 hours. The mixture was concentrated, washed with ethyl acetate, and filtered to give the title compound, which was used in the next step without further purification.

[0263] Example 73B 6-(1-{6-[2-(azetidin-1-yl)-2-oxoethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide To a mixture of the compound from Example 73A (0.045 g, 0.097 mmol), azetidine hydrochloride (0.01 g, 0.107 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.037 g, 0.194 mmol), and 1-hydroxybenzotriazole (0.018 mg, 0.116 mmol) was added N,N-dimethylformamide (0.5 mL), followed by N,N-diisopropylethylamine (0.084 mL, 0.484 mmol), and the resulting mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate, washed with water, washed with brine, dried over Na2SO4, and concentrated. Purification by silica gel chromatography, eluting with 0:100 to 20:100 methanol / ethyl acetate, gave the title compound (0.021 g). 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 8.39 (d, J = 10.4 Hz, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.95 - 7.82 (m, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 6.77 (dd, J = 8.6, 2.5 Hz, 1H), 4.55 (s, 2H), 4.51 - 4.37 (m, 4H), 4.24 (td, J = 7.5, 2.6 Hz, 3H), 3.90 (t, J = 7.8 Hz, 2H), 3.82 (s, 3H), 2.30 - 2.16 (m, 2H). LCMS (ESI+): m / z 504.3 (M+H) + .

[0264] Example 74 6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Example 74A 6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 0G, except that the compound of Example 3B was used instead of 2-chlorobenzo[d]oxazol-6-ol. LCMS (ESI+): m / z 521.2 (M+H) + .

[0265] Example 74B 6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide To a solution of the compound from Example 74A (0.61 g, 1.172 mmol) in tetrahydrofuran (5 mL) was added dropwise a solution of 1N tetrabutylammonium fluoride in tetrahydrofuran (7.03 mL, 7.03 mmol). The resulting mixture was heated to reflux overnight, diluted with water, and extracted with ethyl acetate. The extract was washed with water, dried over MgSO4, and concentrated to give the title compound (421 mg). 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 12.61 (s, 1H), 10.71 (s, 1H), 8.39 (s, 1H), 8.38 (d, J = 2.2 Hz, 1H), 8.04 (s, 1H), 7.89 - 7.86 (m, 1H), 7.71 (s, 1H), 7.24 (dt, J = 1.5, 0.7 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 6.98 (ddd, J = 7.9, 1.6, 0.7 Hz, 1H), 4.50 - 4.42 (m, 4H), 4.28 - 4.20 (m, 1H), 2.35 (s, 3H). LCMS (ESI+): m / z 391.1 (M+H) + .

[0266] Example 75 6-(1-{6-[(2R)-2-(2-hydroxypropan-2-yl)pyrrolidine-1-carbonyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 18B, except that (R)-2-(pyrrolidin-2-yl)propan-2-ol hydrochloride was used instead of dimethylamine hydrochloride. 1H NMR (600 MHz,dimethylsulfoxide-d6) δ ppm 10.72 (s, 1H), 8.44 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.65 (s, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 4.89 (s, 1H), 4.51 (dd, J = 7.6, 5.8 Hz, 4H), 4.34 - 4.24 (m, 2H), 3.82 (s, 3H), 3.53 (td, J = 10.3, 6.8 Hz, 1H), 3.45 - 3.37 (m, 1H), 1.90 (q, J = 7.5 Hz, 2H), 1.81 (s, 1H), 1.56 (q, J = 9.7 Hz, 1H), 1.13 (s, 3H), 1.10 (s, 3H). LCMS (ESI+): m / z 546.4 (M+H) + .

[0267] Example 76 6-(1-{6-[(1-methyl-2-oxopiperidin-3-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 72, except 3-bromo-1-methylpiperidin-2-one was used instead of 3-bromo-1-methylpyrrolidin-2-one. 1H NMR (400 MHz,dimethylsulfoxide-d6) δ ppm 10.67 (s, 1H), 8.35 (s, 2H), 8.01 (d, J = 0.8 Hz, 1H), 7.84 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.21 - 7.11 (m, 2H), 6.80 (dd, J = 8.6, 2.4 Hz, 1H), 4.69 (dd, J = 7.0, 4.8 Hz, 1H), 4.41 (dd, J = 7.5, 1.5 Hz, 4H), 4.20 (p, J = 7.6 Hz, 1H), 3.78 (s, 3H), 3.27 (s, LCMS (ESI+): m / z 518.2 (M+H) + .

[0268] Example 77 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl dihydrogen phosphate Example 77A 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl diprop-2-en-1-yl phosphate Under a nitrogen atmosphere, a mixture of the compound from Example 31 (1.00 g, 2.03 mmol) in N,N-dimethylformamide (20 mL) and 0.45 M tetrazole in acetonitrile (13.54 mL, 6.09 mmol) was treated with diallyl N,N-diisopropylphosphoramidite (1.25 g, 5.08 mmol), and the resulting mixture was stirred at ambient temperature for 2 h. The mixture was cooled to 0 °C, and hydrogen peroxide (30% w / w) (2.09 mL, 20.3 mmol) was added. The resulting mixture was stirred for 16 h. The mixture was diluted with ethyl acetate, washed with sodium thiosulfate, water, and brine, and dried over Na2SO4. Concentration and purification by preparative HPLC (100:0 to 100:70 acetonitrile / water) afforded the title compound (1.10 g). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 8.38 (d, J = 3.9 Hz, 2H), 8.04 (s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.60 (s, 1H), 7.28 - 7.08 (m, 2H), 6.78 (dd, J = 8.6, 2.4 Hz, 1H), 5.92 (ddt, J = 17.2,10.5, 5.3 Hz, 2H), 5.32 (dq, J = 17.2, 1.8 Hz, 2H), 5.20 (dq, J = 10.4, 1.5 Hz, 2H), 4.56 - 4.38 LCMS (ESI+): m / z 653.5 (M+H) + .

[0269] Example 77B 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl dihydrogen phosphate A solution of the compound from Example 77A (1.1 g, 1.685 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.195 g, 0.169 mmol) in tetrahydrofuran (8.43 mL) was treated with pyrrolidine (0.599 g, 8.43 mmol) under a nitrogen atmosphere, and the resulting mixture was stirred at ambient temperature for 2 h. Concentration and purification by preparative HPLC (acetonitrile / water, 100:0 to 100:70) afforded the title compound (0.70 g). 1 H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 10.73 (s, 1H), 8.41 (d, J = 15.2 Hz, 2H), 8.06 (s, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.62 (d, J = 0.7 Hz, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 8.6, 2.4 Hz, 1H), 4.50 - 4.45 (m, 4H), 4.28 (s, 1H), 4.13 (s, 2H), 3.83 (s, 3H), 2.12 (t, J = 7.0 Hz, 2H), 1.46 (s, 6H). LCMS (ESI+): m / z 573.1 (M+H) + .

[0270] Example 78 6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide The title compound was prepared in a manner similar to that of Example 1, except that 2-chloro-6-methylbenzo[d]oxazole was used instead of 2-chlorobenzo[d]oxazole and intermediate 4 was used instead of intermediate 1. 1H NMR (400 MHz,dimethylsulfoxide-d6) δ ppm 9.77 (s, 1H), 8.13 (d, J = 3.1 Hz, 1H), 7.75 (s, 1H), 7.56 (d, J = 3.1 Hz, 1H), 7.39 (d, J = 0.8 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 7.20 (d, J = 1.7 Hz, 1H), 7.14 (d, J = 7.9 Hz, 1H), 6.94 (ddd, J = 8.0, 1.6, 0.8 Hz, 1H), 4.43 (t, J = 8.2 Hz, 2H), 4.36 (dd, J = 7.9, 6.4 Hz, 2H), 4.09 (tt, J = 8.7, 6.4 Hz, 1H), 3.78 (s, 3H), 2.31 (s, 3H). LCMS (ESI+): m / z 404.2 (M+H) + .

[0271] Example 79 6-(1-{6-[(2-hydroxycyclopentyl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 68, except 6-oxobicyclo[3.1.0]hexane was used instead of (R)-propylene oxide. 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 8.39 (d, J = 9.7 Hz, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 8.6, 2.4 Hz, 1H), 4.96 (s, 1H), 4.48 - 4.37 (m, 5H), 4.29 - 4.19 (m, 1H), 4.05 (s, 1H), 3.82 (s, 3H), 2.08 (ddt, J = 13.2, 9.0, 6.4 Hz, 1H), 1.93 - 1.82 (m, 1H), 1.77 - 1.65 (m, 2H), 1.62 (dddd, J = 21.5, 10.6, 5.6, 3.2 Hz, 1H), 1.52 (dddd, J = 13.2, 8.4, 5.2, 3.5 Hz, 1H). LCMS (ESI+): m / z 491.2 (M+H) + .

[0272] Example 80 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(1-methyl-1H-pyrazol-3-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide A mixture of the compound from Example 20 (100 mg, 0.246 mmol) and potassium carbonate (102 mg, 0.738 mmol) in N,N-dimethylformamide (2 mL) was stirred at ambient temperature for 15 minutes. 3-(Bromomethyl)-1-methyl-1H-pyrazole hydrobromide (63 mg, 0.246 mmol) was added, and the resulting mixture was stirred at ambient temperature overnight. Water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography eluting with 100 / 0 to 100 / 10 dichloromethane / methanol to give the title compound (90 mg). 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 10.72 (s, 1H), 8.39 (d, J = 14.9 Hz, 2H), 8.05 (d, J = 0.8 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.23 - 7.18 (m, 2H), 6.83 (dd, J = 8.6, 2.5 Hz, 1H), 6.30 (d, J = 2.2 Hz, 1H), 4.97 (s, 2H), 4.48 - 4.41 (m, 4H), 4.24 (tt, J = 8.6, 7.0 Hz, 1H), 3.82 (d, J = 3.9 Hz, 6H). LC / MS (ESI+): m / z 501(M+H) + .

[0273] Example 81 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-[1-(6-{2-oxo-2-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 66, except (R)-2-(trifluoromethyl)pyrrolidine was used instead of (S)-pyrrolidin-2-ylmethanol. 1H NMR (400 MHz, dimethyl sulfoxide-d6, 90 ℃) δ ppm 10.51 (s, 1H), 8.34 (s, 1H), 8.02 (br s, 1H), 7.92 (s, 1H), 7.54 (s, 1H), 7.50 (br s, 1H), 7.23 (d, J = 1.6 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.01 (dd, J = 8.0, 1.6 Hz, 1H), 4.50 (t, J = 8.3 Hz, 2H), 4.43 (dd, J = 7.9, 6.4 Hz, 2H), 4.22 (tt, J = 8.6, 6.4 Hz, 1H), 3.79 (s, 3H), 3.81-3.57 (m, 3H), 3.51 - 3.40 (m, 1H), 3.15-3.09 (m, 1H), 2.13 - 1.88 (m, 4H). LC / MS (ESI+): m / z 570.3 (M+H) + .

[0274] Example 82 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(5-methyl-1,3-thiazol-2-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide 3-(Bromomethyl)-1-methyl-1H-pyrazole The title compound was prepared in a manner similar to that of Example 80 except 2-(chloromethyl)-5-methylthiazole was used instead of hydrobromic acid. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 10.72 (s, 1H), 8.39 (d, J = 15.8 Hz, 2H), 8.05 (d, J = 0.8 Hz, 1H), 7.90 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.50 (q, J = 1.2 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 6.88 (dd, J = 8.5, 2.5 Hz, 1H), 5.33 (s, 2H), 4.52 - 4.40 (m, 4H), 4.29 - 4.19 (m, 1H), 3.82 (s, 3H), 2.44 (d, J = 1.2 Hz, 3H). LCMS (ESI+): m / z 518 (M+H) + .

[0275] Example 83 6-(1-{6-[2-(dimethylamino)-2-oxoethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide The title compound was prepared in a manner similar to Example 23, except 2-chloro-N,N-dimethylacetamide was used instead of (iodomethyl)cyclopropane. 1H NMR (400 MHz,dimethylsulfoxide-d6) δ ppm 9.79 (s, 1H), 8.16 (d, J = 3.1 Hz, 1H), 7.78 (s, 1H), 7.59 (d, J = 3.0 Hz, 1H), 7.42 (d, J = 3.0 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 2.5 Hz, 1H), 6.78 (dd, J = 8.6, 2.5 Hz, 1H), 4.77 (s, 2H), 4.46 (t, J = 8.2 Hz, 2H), 4.38 (t, J = 7.1 Hz, 2H), 4.19 - 4.07 (m, 1H), 3.82 (s, 3H), 3.00 (s, 3H), 2.84 (s, 3H). LCMS (ESI+): m / z 491.3 (M+H) + .

[0276] Example 84 6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide Example 84A 6-[1-(6-hydroxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide To a solution of Intermediate 4E (500 mg, 1.0 mmol) and potassium carbonate (552 mg, 4.0 mmol) in N,N-dimethylformamide (0.5 mL) was added 2-chlorobenzo[d]oxazol-6-ol (169 mg, 1.0 mmol), and the resulting mixture was stirred for 2 h. The mixture was diluted with water, washed with ethyl acetate, and dried over Na2SO4. Concentration and purification on silica gel using 100 / 0 to 100 / 5 ethyl acetate / methanol afforded the title compound (200 mg). 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 9.79 (s, 1H), 9.26 (s, 1H), 8.16 (d, J = 3.2 Hz, 1H), 7.84 - 7.74 (m, 1H), 7.60 (d, J = 3.2 Hz, 1H), 7.42 (d, J = 0.8 Hz, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.09 (dd, J = 8.4, 0.4 Hz, 1H), 6.83 (dd, J = 2.3, 0.4 Hz, 1H), 6.61 (dd, J = 8.4, 2.3 Hz, 1H), 4.42 (dd, J = 8.6, 7.7 Hz, 2H), 4.35 (dd, J = 7.8, 6.5 Hz, 2H), 4.17 - 4.04 (m, 1H), 3.82 (s, 3H). LCMS (ESI+): m / z 406.2 (M+H) + .

[0277] Example 84B 6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide The title compound was prepared in a manner similar to that of Example 31, except that the compound of Example 84A was used instead of the compound of Example 20. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 9.82 (s, 1H), 8.18 (d, J = 3.1 Hz, 1H), 7.81 (d, J = 0.8 Hz, 1H), 7.63 (d, J = 3.1 Hz, 1H), 7.44 (d, J = 0.8 Hz, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.5, 2.4 Hz, 1H), 4.46 (dd, J = 8.6, 7.8 Hz, 2H), 4.43 - 4.35 (m, 3H), 4.19 - 4.11 (m, 1H), 4.08 (t, J = 7.2 Hz, 2H), 1.84 (t, J = 7.2 Hz, 2H), 1.18 (s, 6H). LCMS (ESI+): m / z 492.3 (M+H) + .

[0278] Example 85 6-{1-[6-(2-hydroxy-2-methylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide The title compound was prepared in a manner similar to that of Example 31, except that 1-bromo-2-methylpropan-2-ol was used instead of 4-bromo-2-methylbutan-2-ol and the compound of Example 84A was used instead of the compound of Example 20. 1H NMR (600 MHz,dimethylsulfoxide-d6) δ ppm 9.80 (s, 1H), 8.17 (d, J = 3.2 Hz, 1H), 7.79 (d, J = 0.8 Hz, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7.42 (d, J = 0.9 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.78 (dd, J = 8.5, 2.4 Hz, 1H), 4.61 (s, 1H), 4.45 (dd, J = 8.6, 7.7 Hz, 2H), 4.38 (dd, J = 7.8, 6.4 Hz, 2H), 4.12 (tt, J = 8.6, 6.5 Hz, 1H), 3.82 (s, 3H), 3.69 (s, 2H), 1.20 (s, 6H). LCMS (ESI+): m / z 478.2 (M+H) + .

[0279] Example 86 6-(1-{6-[(5-methyl-1,3,4-oxadiazol-2-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 80, except that 2-(bromomethyl)-5-methyl-1,3,4-oxadiazole was used instead of 3-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide and cesium carbonate was used instead of potassium carbonate. 1H NMR (400 MHz,dimethylsulfoxide-d6) δ ppm 10.71 (s, 1H), 8.39 (d, J = 8.8 Hz, 2H), 8.04 (s, 1H), 7.88 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.28 (d, J = 2.5 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 6.90 (dd, J = 8.6, 2.5 Hz, 1H), 5.34 (s, 2H), 4.52 - 4.39 (m, 4H), 4.25 (q, J = 7.7 Hz, 1H), 3.82 (s, 3H), 2.53 (s, 3H). LCMS (ESI+): m / z 503 (M+H) + .

[0280] Example 87 6-{1-[6-(2-cyclopropyl-2-oxoethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to Example 31, except 2-bromo-1-cyclopropylethanone was used instead of 4-bromo-2-methylbutan-2-ol. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.38 (s, 2H), 8.04 (s, 1H), 7.88 (s, 1H), 7.60 (s, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.6, 2.5 Hz, 1H), 4.92 (s, 2H), 4.53 - 4.37 (m, 4H), 4.24 (p, J = 7.6 Hz, 1H), 3.82 (s, 3H), 2.22 (tt, J = 7.7, 4.6 Hz, 1H), 1.04 - 0.84 (m, 4H). LCMS (ESI+): m / z 489.0 (M+H) + .

[0281] Example 88 6-{1-[6-(4-hydroxyphenyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide A mixture of the compound from Example 6A (410 mg, 0.76 mmol), 4-hydroxyphenylboronic acid (159 mg, 1.15 mmol), and aqueous potassium phosphate (375 mg, 2.02 mmol, 1 mL of aqueous solution) was combined with dioxane (3 mL) in a microwave tube (20 mL). After sparging with nitrogen for 20 minutes, tris(dibenzylideneacetone)dipalladium(0) (20.9 mg, 0.023 mmol) and (1S,3R,5R,7S)-1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphaadamantane (14.1 mg, 0.048 mmol) were added. The microwave vial was heated at 65 °C for 18 hours and cooled to ambient temperature. The mixture was filtered, washed with methanol, and dried under reduced pressure to give the title compound (358 mg). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 9.48 (s, 1H), 8.41 (s, 1H), 8.39 (s, 1H), 8.04 (s, 1H), 7.92 - 7.86 (m, 1H), 7.63 (d, J = 1.7 Hz, 1H), 7.61 (s, 1H), 7.52 - 7.43 (m, 2H), 7.39 (dd, J = 8.2, 1.8 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 6.87 - 6.79 (m, 2H), 4.50 (d, J = 7.7 Hz, 4H), 4.27 (p, J = 7.6 Hz, 1H), 3.82 (s, 3H). LCMS (APCI+) m / z 483.8 (M+H) + .

[0282] Example 89 6-(1-{6-[4-(2-hydroxyethoxy)phenyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared as in Example 88, except that 4-(2-hydroxyethoxy)phenylboronic acid was used instead of 4-hydroxyphenylboronic acid. The crude reaction mixture was concentrated and purified using RP-HPLC (Sunfire column) with a 30-minute gradient elution of 5 / 95 to 70 / 30 acetonitrile / 0.1% aqueous trifluoroacetic acid to give the title compound as the trifluoroacetate salt. The resulting trifluoroacetate salt of the title compound was dissolved in methanol and loaded onto a Silicycle carbonate column (2 g). The free base was eluted from the column with methanol. Concentration under reduced pressure gave the title compound. 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 10.73 (s, 1H), 8.45–8.41 (m, 1H), 8.39 (s, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.68 (dd, J = 1.8, 0.6 Hz, 1H), 7.63–7.56 (m, 3H), 7.43 (dd, J = 8.2, 1.7 Hz, 1H), 7.34 (dd, J = 8.2, 0.5 Hz, 1H), 7.04–6.98 (m, 2H), 4.89 (t, J = 5.5 Hz, 1H), 4.54 - 4.47 (m, 4H), 4.31 - 4.23 (m, 1H), 4.02 (dd, J = 5.4, 4.6 Hz, 2H), 3.82 (s, 3H), 3.74 (q, J = 5.2 Hz, 2H). LCMS (APCI+) m / z 527.4 (M+H) + .

[0283] Example 90 6-(1-{6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared as in Example 88, except that 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol was used instead of 4-hydroxyphenylboronic acid. Purification was carried out as in Example 89. 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 10.72 (s, 1H), 8.43 (d, J = 2.2 Hz, 1H), 8.39 (s, 1H), 8.10 (d, J = 0.8 Hz, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.86 (d, J = 0.8 Hz, 1H), 7.69 - 7.64 (m, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.39 (dd, J = 8.1, 1.6 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.94 (s, LCMS (APCI+) m / z 501.5 (M+H) + .

[0284] Example 91 6-(1-{6-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 88, except that 1-(2-methoxyethyl)-1H-pyrazol-4-ylboronic acid was used instead of 4-hydroxyphenylboronic acid. Purification was carried out in a manner similar to that of Example 89. 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 10.72 (s, 1H), 8.45 - 8.42 (m, 1H), 8.39 (s, 1H), 8.11 (d, J = 0.8 Hz, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.93 - 7.89 (m, 1H), 7.87 (d, J = 0.8 Hz, 1H), 7.65 (dd, J = 1.7, 0.6 Hz, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.39 (dd, J = 8.1, 1.7 Hz, 1H), 7.27 (dd, J = 8.1, 0.5 Hz, 1H), 4.52 - 4.45 (m, 4H), 4.30 - 4.22 (m, 3H), 3.82 (s, 3H), 3.71 (dd, J = 5.7, 5.0 Hz, 2H), 3.25 (s, 3H). LCMS (APCI+) m / z 515.1 (M+H) + .

[0285] Example 92 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(1-methyl-1H-pyrazol-4-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide The title compound was prepared as in Example 88, except that 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 4-hydroxyphenylboronic acid. Purification was carried out as in Example 89. 1H NMR (500 MHz,dimethylsulfoxide-d6) δ ppm 10.72 (s, 1H), 8.43 (d, J = 2.3 Hz, 1H), 8.39 (s, 1H), 8.08 (d, J = 0.8 Hz, 1H), 8.05 (d, J = 0.7 Hz, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.38 (dd, J = 8.1, 1.6 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 4.53 - 4.44 (m, 4H), 4.31 - 4.21 (m, 1H), 3.86 (s, 3H), 3.82 (s, 3H). LCMS (APCI+) m / z 471.1 (M+H) + .

[0286] Example 93 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(1H-pyrazol-4-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide Example 93A tert-Butyl 4-{[(methanesulfonyl)oxy]methyl}-1H-pyrazole-1-carboxylate A mixture of tert-butyl 4-(hydroxymethyl)-1H-pyrazole-1-carboxylate (120 mg, 0.605 mmol), N,N-dimethylpyridin-4-amine (7.4 mg, 0.061 mmol), and triethylamine (169 μL, 1.21 mmol) in dichloromethane (3 mL) was cooled to 0 °C, and methanesulfonyl chloride (47 μL, 0.605 mmol) was added. After warming to ambient temperature overnight, the mixture was diluted with dichloromethane, washed with saturated NaHCO3, washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 100 / 0 to 100 / 10 dichloromethane / methanol to give the title compound (100 mg).1 H NMR (400 MHz, dimethyl sulfoxide) δ ppm 8.57–8.02 (m, 1H), 7.83 (d, J = 0.7 Hz, 1H), 4.67 (s, 2H), 3.31 (s, 3H), 1.54 (s, 9H).

[0287] Example 93B tert-Butyl 4-({[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}methyl)-1H-pyrazole-1-carboxylate A mixture of the compound from Example 20 (60 mg, 0.148 mmol), cesium carbonate (120 mg, 0.369 mmol), and the compound from Example 93A (44.9 mg, 0.162 mmol) in tetrahydrofuran (2 mL) was stirred at 70 °C for 3 h. Water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography eluting with 100 / 0 to 100 / 10 dichloromethane / methanol to give the title compound (40 mg). LCMS (ESI+): m / z 587 (M+H) + .

[0288] Example 93C 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(1H-pyrazol-4-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide To a solution of the compound from Example 93B (40 mg, 0.068 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (105 μL, 1.36 mmol), and the resulting mixture was stirred at ambient temperature for 1 hour. The mixture was concentrated, and the residue was redissolved in methanol and loaded onto a SilicaPrep carbonate column. Concentration afforded the title compound (17 mg). 1H NMR (400 MHz, dimethyl sulfoxide) δ ppm 12.78 (s, 1H), 10.67 (s, 1H), 8.35 (d, J = 6.9 Hz, 2H), 8.01 (d, J = 0.8 Hz, 1H), 7.93 - 7.62 (m, 2H), 7.57 (d, J = 0.8 Hz, 2H), 7.29 - 6.95 (m, 2H), 6.77 (dd, J = 8.6, 2.4 Hz, 1H), 4.93 (s, 2H), 4.40 (dd, J = 7.6, 2.0 Hz, 4H), 4.30 - 4.11 (m, 1H), 3.78 (s, 3H). LCMS (ESI+): m / z 487(M+H) + .

[0289] Example 94 3-[(1-tert-butyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide Example 94A 3-chloro-6-[1-(6-hydroxy-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxylate methyl ester The title compound was prepared in a manner similar to that of Intermediate 3, except that 2-chlorobenzo[d]oxazol-6-ol was used instead of 2-chlorobenzoxazole. 1 H NMR (400 MHz, dimethylsulfoxide-d6) δ ppm 9.26 (s, 1H), 8.77 (s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 2.3 Hz, 1H), 6.62 (dd, J = 8.4, 2.3 Hz, 1H), 4.52 (dd, J = 8.3, 7.2 Hz, 2H), 4.45 - 4.36 (m, 1H), 4.36 - 4.23 (m, 2H), 3.93 (s, 3H). LCMS (ESI+): m / z 361.3 (M+H) + .

[0290] Example 94B 3-[(1-tert-butyl-1H-pyrazol-4-yl)amino]-6-[1-(6-hydroxy-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxylate methyl ester To a solution of the compound from Example 94A (0.16 g, 0.444 mmol) in methanol (4.43 mL) were added 1-(tert-butyl)-1H-pyrazol-4-amine (0.105 g, 0.754 mmol) and N,N-diisopropylethylamine (0.093 mL, 0.532 mmol), and the resulting mixture was heated at 70° C. for 4 hours. The mixture was cooled to ambient temperature, quenched with water, and extracted with ethyl acetate. The organic extract was washed with brine, dried over NaSO, concentrated, and purified by silica gel chromatography to give the title compound (0.11 g, 90% pure). This material was used in the next step without further purification. LCMS (ESI+): m / z 464.1 (M+H) + .

[0291] Example 94C 3-[(1-tert-butyl-1H-pyrazol-4-yl)amino]-6-[1-(6-hydroxy-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide To a solution of the compound from Example 94B (0.10 g, 0.215 mmol) in methanol (2.15 mL) was added a 7 M solution of ammonia in methanol (0.614 mL, 4.30 mmol), and the resulting mixture was heated at 65° C. for 12 hours. After cooling to ambient temperature, the mixture was filtered, and the residue was dried under reduced pressure to give the title compound (0.085 g). 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 9.25 (s, 1H), 8.39 (d, J = 13.9 Hz, 2H), 8.11 (d, J = 0.7 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.68 (d, J = 0.7 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 2.4 Hz, 1H), 6.61 (dd, J = 8.4, 2.3 Hz, 1H), 4.47 - 4.34 (m, 4H), 4.21 (q, J = 7.8 Hz, 1H), 1.51 (s, 9H). LCMS (ESI+): m / z 449.4 (M+H) + .

[0292] Example 94D 3-[(1-tert-butyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 31, except that the compound of Example 94C was used instead of the compound of Example 20. 1 H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 10.72 (s, 1H), 8.41 (d, J = 9.0 Hz, 2H), 8.11 (d, J = 0.8 Hz, 1H), 7.94 - 7.85 (m, 1H), 7.69 (d, J = 0.8 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.6, 2.4 Hz, 1H), 4.45 (d, J = 7.7 Hz, 4H), 4.23 (p, J = 7.6 Hz, 1H), 4.06 (t, J = 7.2 Hz, 2H), 1.83 (t, J = 7.2 Hz, 2H), 1.51 (s, 9H), 1.16 (s, 6H). LCMS (ESI+):536.2 (M+H)+ .

[0293] Example 95 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl glycinate Example 95A [(tert-Butoxycarbonyl)amino]acetic acid 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl To a mixture of the compound from Example 31 (6.81 g, 13.83 mmol), Boc-glycine (7.27 g, 41.5 mmol), and 4-pyrrolopyridine (2.05 g, 13.83 mmol) in dichloromethane (45 mL) was slowly added a solution of N,N'-diisopropylcarbodiimide (5.23 g, 41.5 mmol) in dichloromethane (25 mL) over 1 hour under reflux, and the resulting mixture was refluxed for an additional 3 hours. (The resulting mixture contained the desired coupling product and the imide, which could be converted to the desired coupling product by a second acylation via careful treatment with hydrazine.) The reaction mixture was cooled to ambient temperature, and hydrazine hydrate (50% solution, 12.13 mL, 124 mmol) was added. The resulting mixture was stirred for 2 hours, allowing complete conversion of the imide to the desired product. The mixture was cooled to 0°C, filtered, and the filtrate was washed with cold 1N hydrochloric acid, saturated NaHCO3, and brine. The organic layer was dried, concentrated, and purified by silica gel chromatography (100:0 to 100:10 ethyl acetate / methanol) to give the title compound (7.5 g). 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 8.38 (d, J = 4.4 Hz, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.23 - 7.14 (m, 3H), 6.78 (dd, J = 8.5, 2.4 Hz, 1H), 4.48 - 4.39 (m, 4H), 4.29 - 4.19 (m, 1H), 4.05 (t, J = 7.0 Hz, 2H), 3.82 (s, 3H), 3.58 (d, J = 6.2 Hz, 2H), 2.22 (t, J = 7.0 Hz, 2H), 1.47 (s, 6H), 1.37 (s, 9H). LCMS (ESI+): m / z 650.4 (M+H) + .

[0294] Example 95B 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl glycinate A solution of the compound from Example 95A (7.32 g, 11.27 mmol) in 1 mL of trifluoroacetic acid / dichloromethane (1:2) was stirred at ambient temperature for 2 hours. The mixture was concentrated, redissolved in dichloromethane, washed with saturated aqueous NaHCO3, washed with brine, and dried over Na2SO4. Concentration and purification by silica gel chromatography (100:0 to 100:30 ethyl acetate / methanol) gave the title compound (5.21 g). 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.38 (s, 2H), 8.04 (d, J = 0.7 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.19 (d, J = 8.6 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.6, 2.4 Hz, 1H), 4.44 (dd, J = 7.7, 1.8 Hz, 4H), 4.29 - 4.18 (m, 1H), 4.05 (t, J = 6.9 Hz, 2H), 3.82 (s, 3H), 3.18 (s, 2H), 2.23 (t, J = 6.9 Hz, 2H), 1.48 (s, 6H); only observable peaks. LCMS (ESI+): m / z 550.4 (M+H) + .

[0295] Example 96 6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-{[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide Example 96A 6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Under a nitrogen atmosphere, a solution of the compound from Example 0 (500 mg, 0.957 mmol) in N,N-dimethylformamide (3.8 mL) was treated with 60% sodium hydride (57.4 mg, 1.435 mmol), and the resulting mixture was stirred at ambient temperature for 20 minutes. 4-Bromo-2-methylbutan-2-ol (90%, 213 mg, 1.148 mmol) was added, and the resulting mixture was heated at 70 °C overnight. The mixture was cooled to ambient temperature, quenched with water, washed with ethyl acetate, and dried over Na SO . Concentration and purification by silica gel chromatography (0:100 to 10:100 methanol / dichloromethane) afforded the title compound (539 mg). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.77 (s, 1H), 8.40 (d, J = 3.3 Hz, 2H), 8.23 ​​(d, J = 0.7 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.74 (d, J = 0.7 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 8.6, 2.4 Hz, 1H), 5.38 (s, 2H), 4.49 - 4.41 (m, 4H), 4.36 (s, 1H), 4.24 (p, J = 7.6 Hz, LCMS (ESI+): m / z 609.2 (M+H) + .

[0296] Example 96B 6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Under a nitrogen atmosphere, a solution of the compound from Example 96A (573 mg, 0.941 mmol) in tetrahydrofuran (7.76 mL) was treated with tetrabutylammonium fluoride (9.41 mL, 9.41 mmol, 1 M tetrahydrofuran solution), and the resulting mixture was stirred at 85 °C for 16 h. The mixture was cooled, diluted with ethyl acetate, washed with water, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (0:100 to 10:100 methanol / dichloromethane) to give the title compound (343 mg). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 12.60 (s, 1H), 10.71 (s, 1H), 8.39 (d, J = 6.8 Hz, 2H), 8.04 (s, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.70 (s, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 6.76 (dd, J = 8.5, 2.4 Hz, 1H), 4.44 (dd, J = 7.7, 1.2 Hz, 4H), 4.35 (s, 1H), 4.23 (p, J = 7.6 Hz, 1H), 4.06 (t, J = 7.2 Hz, 2H), 1.83 (t, J = 7.2 Hz, 2H), 1.16 (s, 6H). LCMS (ESI+): m / z 479.3 (M+H) + .

[0297] Example 96C 6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-{[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide To a solution of the compound from Example 96B (31 mg, 0.065 mmol) and cesium carbonate (42.2 mg, 0.13 mmol) in N,N-dimethylformamide (0.65 mL) was added 2,2-dimethyloxirane (0.012 mL, 0.13 mmol), and the resulting mixture was heated at 70 °C for 16 h. The mixture was cooled, diluted with ethyl acetate, washed with water, and washed with brine. The organic layer was dried over NaSO, concentrated, and purified by silica gel chromatography (0:100 to 20:100 methanol / dichloromethane) to give the title compound (0.015 g). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.75 (s, 1H), 8.39 (d, J = 2.9 Hz, 2H), 8.07 (s, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.62 (s, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.77 (dd, J = 8.6, 2.4 Hz, 1H), 4.45 (d, J = 7.7 Hz, 4H), 4.24 (q, J = 7.5 Hz, 1H), 4.07 (d, J = 7.1 Hz, 2H), 3.98 (s, 2H), 1.83 (t, J = 7.2 Hz, 2H), 1.16 (s, 6H), 1.06 (s, 6H). LCMS (ESI+): m / z 551.9 (M+H) + .

[0298] Example 97 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(1-methyl-1H-pyrazol-4-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 80, except that 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide was used instead of 3-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide and cesium carbonate was used instead of potassium carbonate. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 8.39 (d, J = 12.1 Hz, 2H), 8.05 (d, J = 0.8 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.78 (s, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.48 (d, J = 0.8 Hz, 1H), 7.25 - 7.06 (m, 2H), 6.80 (dd, J = 8.5, 2.5 Hz, 1H), 4.93 (s, 2H), 4.57 - 4.37 (m, 4H), 4.32 - 4.13 (m, 1H), 3.82 (d, J = 2.8 Hz, 6H). LCMS (ESI+): m / z 501 (M+H) +

[0299] Example 98 6-(1-{6-[(1-methyl-1H-imidazol-4-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 80, except that 4-(bromomethyl)-1-methyl-1H-imidazole hydrobromide was used instead of 3-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide and sodium hydride was used instead of potassium carbonate. 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 8.39 (d, J = 11.2 Hz, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.59 - 7.44 (m, 1H), 7.32 - 7.07 (m, 3H), 6.82 (dd, J = 8.6, 2.4 Hz, 1H), 4.88 (s, 2H), 4.57 - 4.37 (m, 4H), 4.24 (tt, J = 8.7, 7.0 Hz, 1H), 3.82 (s, 3H), 3.63 (s, 3H). LCMS (ESI+): m / z 501(M+H) + .

[0300] Example 99 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(2-methyl-1,3-thiazol-5-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 88, except that 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole was used instead of 4-hydroxyphenylboronic acid. Purification was carried out in a manner similar to that of Example 89. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.72 (s, 1H), 8.46 - 8.41 (m, 1H), 8.38 (s, 1H), 8.04 (s, 1H), 7.96 (s, 1H), 7.93 - 7.85 (m, 1H), 7.74 (d, J = 1.7 Hz, 1H), 7.61 (s, 1H), 7.39 (dd, J = 8.1, 1.8 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 4.51 (d, J = 7.8 Hz, 4H), 4.27 (p, J = 7.6 Hz, 1H), 3.82 (s, 3H), 2.66 (s, 3H). LCMS (ESI+) m / z 487.8 (M+H) + .

[0301] Example 100 6-(1-{6-[4-(2-methoxyethoxy)phenyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared as in Example 88, except that [4-(2-methoxyethoxy)phenyl]boronic acid was used instead of 4-hydroxyphenylboronic acid. Purification was carried out as in Example 89. 1H NMR (500 MHz,dimethylsulfoxide-d6) δ ppm 10.73 (s, 1H), 8.43 (d, J = 2.3 Hz, 1H), 8.39 (s, 1H), 8.05 (d, J = 0.7 Hz, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 1.7, 0.5 Hz, 1H), 7.63 - 7.56 (m, 3H), 7.43 (dd, J = 8.2, 1.7 Hz, 1H), 7.34 (dd, J = 8.1, 0.6 Hz, 1H), 7.05 - 6.98 (m, 2H), 4.55 - 4.46 (m, 4H), 4.32 - 4.22 (m, 1H), 4.15 - 4.10 (m, 2H), 3.82 (s, 3H), 3.70 - 3.65 (m, 2H), 3.32 (s, 3H). LCMS (ESI+) m / z 541.2 (M+H) + .

[0302] Example 101 6-{1-[6-(2-ethoxypropan-2-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide To a solution of the compound of Example 19 (100 mg, 0.223 mmol) in ethanol (5 mL) was added 4-methylbenzenesulfonic acid hydrate (4.24 mg, 0.022 mmol), and the resulting mixture was stirred at 25° C. for 12 hours. The mixture was adjusted to pH 8 and concentrated. The residue was purified by preparative HPLC to give the title compound (46.5 mg). 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.06 (t, J=6.91 Hz, 3H), 1.47 (s, 6H), 3.13 (q, J=6.85 Hz, 2H), 3.82 (s, 3H), 4.17-4.32 (m, 1H), 4.39-4.53 (m, 4H), 7.10-7.31 (m, 2H), 7.41 (s, 1H), 7.60 (s, 1H), 7.90 (br s, 1H), 8.04 (s, 1H), 8.31-8.52 (m, 2H), 10.72 (s, 1H).

[0303] Example 102 6-(1-{6-[(5-methoxypyrimidin-2-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide A mixture of the compound from Example 20 (60 mg, 0.148 mmol), 2-chloro-5-methoxypyrimidine (25.6 mg, 0.177 mmol), and cesium carbonate (144 mg, 0.443 mmol) in dimethyl sulfoxide (2 mL) was heated in a microwave oven at 120 °C for 1 h. Water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography eluting with 100 / 0 to 100 / 10 dichloromethane / methanol to give the title compound (50 mg). 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 10.72 (s, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.38 (d, J = 2.6 Hz, 3H), 8.05 (d, J = 0.8 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 6.97 (dd, J = 8.4, 2.3 Hz, 1H), 4.53 - 4.42 (m, 4H), 4.26 (ddd, J = 15.4, 8.4, 7.0 Hz, 1H), 3.84 (d, J = 16.8 Hz, 6H). LCMS (ESI+): m / z 515(M+H) + .

[0304] Example 103 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(pyridazin-3-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyridine-2-carboxamide The title compound was prepared in a manner similar to Example 102, except 3-chloropyridazine was used instead of 2-chloro-5-methoxypyrimidine and the compound of Example 84A was used instead of the compound of Example 20. 1H NMR (500 MHz, dimethyl sulfoxide) δ ppm 10.74 (s, 1H), 9.01 (dd, J = 4.5, 1.3 Hz, 1H), 8.46 (d, J = 2.1 Hz, 1H), 8.40 (s, 1H), 8.06 (d, J = 0.7 Hz, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.77 (dd, J = 9.0, 4.5 Hz, 1H), 7.62 (d, J = 0.8 Hz, 1H), 7.53 - 7.28 (m, 3H), 7.06 (dd, J = 8.5, 2.3 Hz, 1H), 4.59 - 4.43 (m, 4H), 4.37 - 4.21 (m, 1H), 3.84 (s, 3H). LCMS (ESI+): m / z 485(M+H) + .

[0305] Example 104 6-[1-(6-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methoxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Example 104A Ethyl [4-(hydroxymethyl)-1H-pyrazol-1-yl]acetate A solution of (1H-pyrazol-4-yl)methanol (1 g, 10.19 mmol), potassium carbonate (2.82 g, 20.39 mmol), and ethyl 2-bromoacetate (2.04 g, 12.23 mmol) in acetone (20 mL) was heated overnight at 60° C. The mixture was filtered, and the filtrate was concentrated and purified on silica gel eluting with 100 / 0 to 100 / 10 dichloromethane / methanol to give the title compound (1 g). 1H NMR (500 MHz, dimethyl sulfoxide) δ ppm 7.62 (d, J = 0.8 Hz, 1H), 7.39 (d, J = 0.7 Hz, 1H), 5.01 (s, 2H), 4.87 (t, J = 5.5 Hz, 1H), 4.37 (d, J = 5.4 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H).

[0306] Example 104B Ethyl [4-(chloromethyl)-1H-pyrazol-1-yl]acetate A solution of the compound from Example 104A (188 mg, 1.02 mmol) in dichloromethane (3 mL) was cooled to 0° C. and sulfite dichloride (372 μL, 5.1 mmol) was added. The resulting mixture was warmed to ambient temperature for 4 hours and concentrated to provide the title compound as the hydrochloride salt (233 mg).

[0307] Example 104C Ethyl [4-({[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}methyl)-1H-pyrazol-1-yl]acetate 3-(Bromomethyl)-1-methyl-1H-pyrazole The title compound was prepared in a manner analogous to Example 80, except using the compound of Example 104B instead of hydrobromide and cesium carbonate instead of potassium carbonate. 1H NMR (500 MHz,dimethylsulfoxide-d6) δ ppm 10.71 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.04 (d, J = 0.8 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 0.7 Hz, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.55 (d, J = 0.7 Hz, 1H), 7.20 (dd, J = 5.5, 3.0 Hz, 2H), 6.82 (dd, J = 8.6, 2.4 Hz, 1H), 5.05 (s, 2H), 4.96 (s, 2H), 4.49 - 4.40 (m, 4H), 4.29 - 4.19 (m, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). LCMS (ESI+): m / z 573(M+H) + .

[0308] Example 104D 6-[1-(6-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methoxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide To a solution of the compound from Example 104C (104 mg, 0.182 mmol) in tetrahydrofuran (3 mL) was added diisobutylaluminum hydride solution (1453 μL, 1.453 mmol, 1 M toluene solution), and the resulting mixture was stirred at ambient temperature for 4 hours. Saturated ammonium chloride solution was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and purified by silica gel chromatography eluting with 100 / 0 to 100 / 10 dichloromethane / methanol to give the title compound (20 mg). 1H NMR (500 MHz,dimethylsulfoxide-d6) δ ppm 10.71 (s, 1H), 8.40 (d, J = 2.4 Hz, 1H), 8.38 (s, 1H), 8.04 (d, J = 0.8 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 0.8 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.51 (d, J = 0.8 Hz, 1H), 7.23 - 7.17 (m, 2H), 6.81 (dd, J = 8.6, 2.4 Hz, 1H), 4.93 (s, 2H), 4.89 (t, J = 5.2 Hz, 1H), 4.48 - 4.40 (m, 4H), 4.24 (p, J = 7.6 Hz, 1H), 4.12 (t, J = 5.7 Hz, 2H), 3.82 (s, 3H), 3.72 (q, J = 5.5 Hz, 2H). LCMS (ESI+): m / z 531(M+H) + .

[0309] Example 105 6-{1-[6-(1-methyl-1H-imidazol-4-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared as in Example 88, except that (1-methyl-1H-imidazol-4-yl)boronic acid was used instead of 4-hydroxyphenylboronic acid. Purification was carried out as in Example 89. 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 10.72 (s, 1H), 8.45 - 8.41 (m, 1H), 8.39 (s, 1H), 8.08 (d, J = 0.8 Hz, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.92 - 7.89 (m, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.64 (dd, J = 1.7, 0.5 Hz, 1H), 7.61 (d, J = 0.8 Hz, 1H), 7.38 (dd, J = 8.1, 1.6 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 4.52 - 4.45 (m, 4H), 4.30 - 4.22 (m, 1H), 3.86 (s, 4H), 3.82 (s, 3H). LCMS (ESI+) m / z 471.2 (M+H) + .

[0310] Example 106 1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl dihydrogen phosphate The title compound was prepared in a manner similar to that of Example 77, except that the compound of Example 85 was used instead of the compound of Example 31. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 9.81 (s, 1H), 8.18 (d, J = 3.0 Hz, 1H), 7.80 (d, J = 0.8 Hz, 1H), 7.62 (d, J = 2.8 Hz, 1H), 7.43 (d, J = 0.9 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.79 (dd, J = 8.5, 2.4 Hz, 1H), 4.47 (t, J = 8.2 Hz, 2H), 4.40 (dd, J = 7.8, 6.5 Hz, 2H), 4.13 (tt, J = 8.7, 6.5 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 2H), 1.20 (s, 6H). LCMS (ESI+): m / z 558.3 (M+H) + .

[0311] Example 107 6-{1-[6-(2-cyano-2-methylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide The title compound was prepared in a manner similar to that of Example 31, except 2-cyano-2-methylpropyl 4-methylbenzenesulfonate was used instead of 4-bromo-2-methylbutan-2-ol. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 8.39 (d, J = 4.2 Hz, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.27 - 7.15 (m, 2H), 6.84 (dd, J = 8.5, 2.4 Hz, 1H), 4.45 (dd, J = 7.7, 1.2 Hz, 4H), 4.25 (q, J = 7.8 Hz, 1H), 3.99 (s, 2H), 3.82 (s, 3H), 1.41 (s, 6H). LCMS (ESI+): m / z 487.9 (M) + .

[0312] Example 108 1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl glycinate The title compound was prepared in a manner similar to that of Example 95, except that the compound of Example 85 was used instead of the compound of Example 31. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 9.81 (s, 1H), 8.17 (d, J = 3.1 Hz, 1H), 7.79 (s, 1H), 7.62 (d, J = 3.1 Hz, 1H), 7.43 (d, J = 0.9 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.80 (dd, J = 8.6, 2.4 Hz, 1H), 4.46 (t, J = 8.2 Hz, 2H), 4.39 LCMS (ESI+): m / z 535.3 (M+H) + .

[0313] Example 109 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl dihydrogen phosphate The title compound was prepared in a manner similar to that of Example 77, except that the compound of Example 84 was used instead of the compound of Example 31. 1H NMR (500 MHz, dimethyl sulfoxide-d6) δ ppm 9.81 (s, 1H), 8.24 - 8.11 (m, 1H), 7.79 (d, J = 0.9 Hz, 1H), 7.67 - 7.55 (m, 1H), 7.42 (d, J = 0.9 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.15 (d, J = 2.5 Hz, 1H), 6.79 (dd, J = 8.6, 2.4 Hz, 1H), 4.47 (t, J = 8.3 Hz, 2H), 4.40 (dd, J = 7.9, 6.4 Hz, 2H), 4.17 - 4.12 (m, 1H), 4.10 (t, J = 7.0 Hz, 2H), 3.82 (s, 3H), 2.11 (t, J = 7.0 Hz, 2H), 1.45 (s, 6H). LCMS (ESI+): m / z 572.3 (M+H) + .

[0314] Example 110 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl glycinate The title compound was prepared in a manner similar to that of Example 95, except that the compound of Example 84 was used instead of the compound of Example 31. 1H NMR (400 MHz,dimethylsulfoxide-d6) δ ppm 9.80 (s, 1H), 8.15 (d, J = 3.1 Hz, 1H), 7.78 (s, 1H), 7.60 (d, J = 3.1 Hz, 1H), 7.42 (d, J = 0.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.19 (d, J = 8.5 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 8.5, 2.4 Hz, 1H), 4.54 - 4.30 (m, 4H), 4.12 (ddd, J LCMS (ESI+): m / z 549.4 (M+H) + .

[0315] Example 111 6-{1-[6-(1-hydroxy-2-methylpropan-2-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide Example 111A Ethyl 2-(3-methoxy-4-nitrophenyl)-2-methylpropanoate To a solution of sodium tert-butoxide (5.78 g, 60.2 mmol) in N,N-dimethylformamide (250 mL) was added ethyl 2-(3-methoxy-4-nitrophenyl)acetate (12 g, 50.2 mmol) in several portions at 0 °C. Methyl iodide (4.7 mL, 75 mmol) was added dropwise at 0 °C, and the resulting mixture was stirred at 20 °C for 1 h. After cooling the resulting mixture to 0 °C, sodium tert-butoxide (5.78 g, 60.2 mmol) and methyl iodide (4.70 mL, 75 mmol) were added, and the resulting mixture was stirred at 20 °C for 12 h. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4, and concentrated to give the title compound (10 g), which was used directly in the next step without further purification. 1 H NMR (400 MHz, CDCl3) δ ppm 1.19 (t, J=7.17 Hz, 3H), 1.59 (s, 6H), 3.95 (s, 3H), 4.10-4.16 (m, 2H), 6.96-7.05 (m, 2H), 7.82 (d, J=8.38 Hz, 1H).

[0316] Example 111B Ethyl 2-(3-hydroxy-4-nitrophenyl)-2-methylpropanoate To a solution of the compound from Example 111A (10 g, 37.4 mmol) in N,N-dimethylformamide (100 mL) was added lithium chloride (4.76 g, 112 mmol) at 20° C., and the resulting mixture was stirred at 140° C. for 16 hours. The mixture was cooled to ambient temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography eluting with petroleum ether / ethyl acetate from 60 / 1 to 10 / 1 to give the title compound (6 g).

[0317] Example 111C Ethyl 2-(4-amino-3-hydroxyphenyl)-2-methylpropanoate To a solution of palladium on carbon (2.52 g, 23.69 mmol) in tetrahydrofuran (150 mL) was added the compound from Example 111B (6 g, 23.69 mmol) at 20° C., and a hydrogen balloon was attached and the mixture was stirred at 20° C. for 12 hours. The resulting suspension was filtered through a silica gel pad, and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated to give the title compound (5 g). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.10 (t, J=7.09 Hz, 3 H), 1.39 (s, 6 H), 3.94 - 4.07 (m, 2 H), 4.42 (br s, 2 H), 6.47 - 6.54 (m, 2 H), 6.61 (s, 1 H), 8.94 (br s, 1 H).

[0318] Example 111D Ethyl 2-methyl-2-(2-sulfanyl-1,3-benzoxazol-6-yl)propanoate To a solution of the compound of Example 111C (5 g, 22.39 mmol) in ethanol (100 mL), potassium o-ethyl carbonodithioate (10.77 g, 67.2 mmol) and potassium hydroxide (1.885 g, 33.6 mmol) were added at 20° C., and the resulting mixture was stirred at 80° C. for 12 hours. The mixture was concentrated, poured into water, and adjusted to pH 5 with acetic acid. After standing for 12 hours, the precipitate was collected by filtration and dried under reduced pressure to give the title compound (5 g). 1 H NMR (400 MHz, CDCl3) δ ppm 1.18 (t, J=7.15 Hz, 3H), 1.55-1.65 (m, 6H), 4.13 (q, J=7.11 Hz, 2H), 7.11 (d, J=8.34 Hz, 1H), 7.23-7.26 (m, 1H), 7.36 (d, J=1.43 Hz, 1H), 10.95 (br s, 1H).

[0319] Example 111E Ethyl 2-(2-chloro-1,3-benzoxazol-6-yl)-2-methylpropanoate To a solution of the compound from Example 111D (5 g, 18.84 mmol) in thionyl chloride (20 mL, 274 mmol) was added N,N-dimethylformamide (1.46 mL, 18.84 mmol), and the resulting mixture was stirred at 20 °C for 20 minutes. The mixture was slowly poured into saturated Na2CO3 and extracted with ethyl acetate. The organic extract was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography eluting with petroleum ether / ethyl acetate 50 / 1 to 5 / 1 to give the title compound (4 g).

[0320] Example 111F Ethyl 2-[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]-2-methylpropanoate To a solution of Intermediate 1 (4.8 g, 12.39 mmol) in N,N-dimethylformamide (80 mL) were added potassium carbonate (6.85 g, 49.6 mmol) and the compound from Example 111E (3.98 g, 14.87 mmol), and the resulting mixture was stirred at 20 °C for 12 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography eluting with 10 / 1 to 1 / 1 petroleum ether / tetrahydrofuran to give the title compound (4 g). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.10 (t, J=7.09 Hz, 3H), 1.51 (s, 6H), 3.82 (s, 3H), 4.05 (q, J=7.15 Hz, 2H), 4.18-4.32 (m, 1H), 4.39-4.52 (m, 4H), 7.10 (dd, J=8.23, 1.55 Hz, 1H), 7.25 (d, J=8.23 Hz, 1H), 7.38 (d, J=1.31 Hz, 1H), 7.61 (s, 1H), 7.91 (br s, 1H), 8.04 (s, 1H), 8.30-8.48 (m, 2H), 10.73 (s, 1H).

[0321] Example 111G 6-{1-[6-(1-hydroxy-2-methylpropan-2-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide To an ice-cooled suspension of the compound from Example 111F (4 g, 7.93 mmol) in tetrahydrofuran (80 mL) was added lithium triethylborohydride (31.7 mL, 31.7 mmol), and the resulting mixture was stirred at 20 °C for 4 h. The mixture was quenched with saturated ammonium chloride, the organic phase was separated, and the aqueous layer was extracted with ethyl acetate. The organic extract was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography eluting with 10 / 1 to 1 / 1 petroleum ether / tetrahydrofuran to give the title compound (2 g). 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 1.24 (s, 6H), 1.76 (s, 1H), 3.41 (d, J=5.50 Hz, 2H), 3.82 (s, 3H), 4.19-4.30 (m, 1H), 4.41-4.51 (m, 4H), 4.63 (t, J=5.38 Hz, 1H), 7.13-7.25 (m, 2H), 7.42 (s, 1H), 7.60 (s, 1H), 7.89 (br s, 1H), 8.04 (s, 1H), 8.38 (s, 2H), 10.71 (s, 1H).

[0322] Example 112 1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl dihydrogen phosphate The title compound was prepared in a manner similar to that of Example 77, except that the compound of Example 38 was used instead of the compound of Example 31. 1H NMR (600 MHz, dimethyl sulfoxide-d6) δ ppm 10.71 (s, 1H), 8.39 (d, J = 10.7 Hz, 2H), 8.04 (d, J = 0.8 Hz, 1H), 7.89 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 0.7 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 6.82 (dd, J = 8.6, 2.4 Hz, 1H), 4.47 (d, J = 7.7 Hz, 4H), 4.28 - 4.25 (m, 1H), 3.96 (s, 2H), 3.82 (s, 3H), 1.50 (s, 6H). LCMS (ESI+): m / z 559.4 (M+H) + .

[0323] Example 113 1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl glycinate The title compound was prepared in a manner similar to that of Example 95, except that the compound of Example 38 was used instead of the compound of Example 31. 1 H NMR (400 MHz, dimethyl sulfoxide-d6) δ ppm 10.70 (s, 1H), 8.38 (d, J = 2.2 Hz, 2H), 8.04 (s, 1H), 7.88 (s, 1H), 7.60 (d, J = 0.8 Hz, 1H), 7.23 - 7.08 (m, 2H), 6.80 (dd, J = 8.5, 2.4 Hz, 1H), 4.44 (d, J = 7.7 Hz, 4H), 4.24 (q, J = 7.6 Hz, 1H), 4.11 (s, 2H), 3.82 (s, 3H), 3.15 (s, 2H), 1.51 (s, 6H). LCMS (ESI+): m / z 536.4 (M+H) + .

[0324] Measurement of biological activity Biochemical HTRF kinase activity assay To perform SAR (structure-activity relationship) and compound screening, Cisbio's HTRF (registered trademark) KinEASE TM Homogeneous time-resolved fluorescence (HTRF) kinase activity assays were performed for MER kinase, AXL kinase, and TYRO3 kinase using a HTRF-TK kit (Cisbio, USA). This kit contains biotin-labeled TK substrate, streptavidin-XL665, and Eu 3+ The assay contained a cryptate-labeled TK antibody and HTRF® detection buffer. This kinase assay involves two main steps: kinase reaction and detection of phosphorylated substrate. The reaction was performed in a white 384-well low-volume plate (Corning, USA) with 25 nL of each compound in dimethyl sulfoxide solution per well. To measure the inhibition of kinase activity by each compound, 2.5 μL of recombinant kinase was preincubated with each test compound for 30 minutes in kinase reaction buffer (20 mM HEPES pH 7.4, 2 mM MnCl2, 10 mM MgCl2, 100 μM Na3VO4, 0.0075% Triton X 100, 0.005% BSA, and 1 mM DTT), followed by the addition of 2.5 μL of 1 μM biotin-labeled TK substrate and 10 μM ATP. After 1 hour of incubation at room temperature, 0.375 nM Eu was added. 3+ The reaction was stopped by adding 5 μL of HTRF® detection buffer containing cryptate-labeled TK antibody and 0.062 μM streptavidin-XL665 (SA-XL665), and the phosphorylated peptide product was detected. After incubation at room temperature for 1 hour, the fluorescence intensity was measured using an Envision® plate reader (PerkinElmer, USA). When excited with 340 nm ultraviolet light, Eu 3+ Eu of cryptate-labeled TK antibody 3+The energy from the donor is transferred to the FRET acceptor XL665, which emits light at 665 nm. The kinase activity level was quantified by the HTRF ratio (665 nm fluorescence intensity / 620 nm fluorescence intensity × 10,000) calculated from the emission intensities at 665 nm and 620 nm. Recombinant human MER protein (528-end) was purchased from Carna Biosciences, Inc. (Japan). Recombinant human AXL protein (473-end) and recombinant human TYRO3 protein (455-end) were purchased from SignalChem (Canada). [Table 2] JPEG2025536322000036.jpg227158

[0325] MC-38 efficacy assay MC-38 cells were maintained in Dulbecco's modified Eagle's medium (DMEM) (Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine serum. Female C57BL / 6 mice were obtained from Charles River (Wilmington, MA). Mice weighed 18–20 g upon arrival. Food and water were available ad libitum. Mice were allowed to acclimate to the animal facility for at least 1 week before the start of experiments. Mice were tested on a 12-hour light / 12-hour dark schedule (lights on at 6:00 AM).

[0326] Tumor growth inhibition (TGI) represents the difference between the mean tumor volume of the drug-treated group and the mean tumor volume of the control group, and is expressed as a percentage of the mean tumor volume of the control group. TGI values ​​were determined at the final time point before the first mouse to reach the tumor burden limit was removed from the group. Statistical significance of the mean tumor volume between the groups treated with each compound and the vehicle-treated group was assessed by Student's t-test.

[0327] Stocks of each MerTK inhibitor were stored in powder form in a storage desiccator and, at the time of administration, resuspended in a solution consisting of 10% EtOH, 30% PEG 400, and 60% Phozol 50. Each MerTK inhibitor was administered once daily for 21 days.

[0328] On day 0, 1 x 10 5 Mice were inoculated subcutaneously into the right flank with 0.1 mL of live MC-38 cells in a 1:1 mixture of S-MEM and Matrigel (BD, Franklin Lakes, NJ). Unless otherwise noted, tumors were approximately 150–200 mm. 3 Treatment was initiated within 24 hours of tumor size matching. Mice weighed approximately 20 g at the start of treatment. Tumor volume was measured 2-3 times a week. The length (L) and width (W) of the tumor were measured with electronic calipers and calculated using the formula V = L × W. 2 The tumor volume was calculated by dividing the tumor volume by 2. 3 Mice were euthanized when the stool reached 0.05 mg / kg or when skin ulcers developed.

[0329] MC-38 cells were cultured in vitro for up to three passages. On day 0, female C57BL6 mice were inoculated subcutaneously into the right flank at 100,000 cells per mouse. All tumors were size-matched on day 7. The average tumor volume at tumor stage was approximately 150 mm. 3 It was. [Table 3]

[0330] Further advantages of Applicants' invention will be readily apparent to those skilled in the art upon perusal of this patent application. The foregoing detailed description and accompanying examples are intended for illustrative purposes only and are not intended to limit the scope of the present disclosure, which is defined by the appended claims and their equivalents. Various modifications and improvements to the embodiments described herein will be apparent to those skilled in the art. Such modifications and improvements include, but are not limited to, combinations of modifications and improvements in chemical structure, substituents, derivatives, intermediates, synthesis, formulation, or method, or in the use of the present disclosure, and these modifications and improvements may be made without departing from the spirit and scope of the present invention.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, W is N or CH; L is a bond, -CH=CHCR a R b -,-(CR a R b ) n -O-, -(CR a R b ) n -C(O)-, -O-, -O-(CR a R b ) n -, -O-(CR a R b ) n -O-, -OCH 2 selected from the group consisting of —C(O)—, and —C(O)—; Each R a are each independently hydrogen, C 1 ~C 4 Alkyl, and C 1 ~C 2 hydroxyalkyl; Each R b are each independently hydrogen and C 1 ~C 4 selected from the group consisting of alkyl; R a and R b Together, C 3 ~C 6 may form a cycloalkyl or a 3- to 6-membered heterocycle; R 1 is H, C 1 ~C 6 alkyl, and 5- to 6-membered heterocyclic groups; R 1 C 1 ~C 6 Alkyl is one or two R 4 optionally substituted with; R 2 is hydrogen, fluoro, chloro, bromo, and C 1 ~C 4 selected from the group consisting of alkyl; R 3 is hydrogen, fluoro, chloro, bromo, -CN, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, -OH, -OR 3a , -NR 3b R 3c , -P(O)(OR 3d ) 2 , -C(O)CHR 3e NR 3b R 3c , -C(O)OH, -C(O)OR 3a , -C(O)NR 3b R 3c , C 3 ~C 8 Cycloalkyl, C 5 ~C 7 Cycloalkenyl, 3- to 6-membered heterocyclic group, C 5 ~C 7 Heterocycloalkenyl, C 6 aryl, 5- to 6-membered heteroaryl, and 【Chemistry 2】 selected from the group consisting of: R 3 C 3 ~C 8 Cycloalkyl, C 6 Aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 optionally substituted with; R 3a is C 1 ~C 4 is alkyl; R 3b and R 3c are each independently hydrogen, C 1 ~C 4 Alkyl, C 3 ~C 6 Cycloalkyl, and -CO 2 R 3f selected from the group consisting of: R 3d is hydrogen, C 1 ~C 4 Alkyl, and C 2 ~C 4 alkenyl; R 3e is hydrogen and C 1 ~C 4 alkyl; R 3e C 1 ~C 4 Alkyl is one R 3g optionally substituted with; R 3f is C 1 ~C 4 is alkyl; R 3g -OH, -SH, -SCH 3 , -NH 2 , -C(O)OH, -C(O)NH 2 , -NHC(NH)NH 2 , C 6 aryl, and 5- to 9-membered heteroaryl; R 3g C 6 The aryl may be optionally substituted with one -OH; R 4 -OH, -OR 4a , -C(O)NR 4b R 4c and 5- to 6-membered heterocyclic groups; R 4 The 5- to 6-membered heterocyclic group is 1 ~C 4 optionally substituted with alkyl; R 4a is C 1 ~C 4 alkyl, and R 4a C 1 ~C 4 Alkyl is one -Si(R 4d ) 3 optionally substituted with; R 4b and R 4c are each independently hydrogen and C 1 ~C 4 selected from the group consisting of alkyl; R 4d is C 1 ~C 4 is alkyl; R 5 -Fluoro, -CN, -OH, -OR 5a , =O, -CH 2 CO 2 R 5b , C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Hydroxyalkyl, C 1 ~C 4 Hydroxyalkoxy, and C 2 ~C 6 alkoxyalkyl; R 5a is C 1 ~C 4 is alkyl; R 5b is C 1 ~C 4 is alkyl; n is an integer from 1 to 3. or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof.

2. L is -O-(CR a R b ) n 2. The compound of claim 1, wherein R is O-, or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

3. The compound has the following formula (II): 【Transformation 3】 (In the formula, R 1 is hydrogen, C 1 ~C 6 alkyl, and 5- to 6-membered heterocyclic groups; R 1 C 1 ~C 6 Alkyl is one or two R 4 optionally substituted with; R 3 is hydrogen, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, -P(O)(OR 3d ) 2 , -C(O)CHR 3e NR 3b R 3c , -C(O)OH, -C(O)OR 3a , -C(O)NR 3b R 3c , C 3 ~C 8 Cycloalkyl, C 5 ~C 7 Cycloalkenyl, 3- to 6-membered heterocyclic group, C 5 ~C 7 Heterocycloalkenyl, C 6 selected from the group consisting of aryl, and 5-6 membered heteroaryl; R 3 C 3 ~C 8 Cycloalkyl, C 6 Aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 optionally substituted with; R 3a is C 1 ~C 4 is alkyl; R 3b and R 3c are each independently hydrogen, C 1 ~C 4 Alkyl, C 3 ~C 6 Cycloalkyl, and -CO 2 R 3f selected from the group consisting of: R 3d is hydrogen, C 1 ~C 4 Alkyl, and C 2 ~C 4 alkenyl; R 3e is hydrogen and C 1 ~C 4 alkyl; R 3d C 1 ~C 4 Alkyl is one R 3g optionally substituted with; R 3f is C 1 ~C 4 is alkyl; R 3g -OH, -SH, -SCH 3 , -NH 2 , -C(O)OH, -C(O)NH 2 , -NHC(NH)NH 2 , C 6 aryl, and 5- to 9-membered heteroaryl; R 3g C 6 The aryl may be optionally substituted with one -OH; R 4 -OH, -OR 4a , -C(O)NR 4b R 4c and 5- to 6-membered heterocyclic groups; R 4 The 3- to 10-membered heterocyclic group is 1 ~C 4 optionally substituted with alkyl; R 4a is C 1 ~C 4 alkyl, and R 4a C 1 ~C 4 Alkyl is one -Si(R 4d ) 3 optionally substituted with; R 4b and R 4c are each independently H and C 1 ~C 4 selected from the group consisting of alkyl; R 4d is C 1 ~C 4 is alkyl; R 5 -Fluoro, -CN, -OH, -OR 5a , =O, -CH 2 CO 2 R 5b , C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Hydroxyalkyl, C 1 ~C 4 Hydroxyalkoxy, and C 2 ~C 6 alkoxyalkyl; R 5a is C 1 ~C 4 is alkyl; R 5b is C 1 ~C 4 is alkyl; n is an integer from 1 to 3.

2. The compound of claim 1, wherein: or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof.

4. R 3 But hydrogen, C 1 ~C 4 Alkyl, -P(O)(OR 3d ) 2 , and -C(O)CHR 3e NR 3b R 3c 4. The compound of claim 3, or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, selected from the group consisting of:

5. R 1 But hydrogen and C 1 ~C 6 alkyl; R 1 C 1 ~C 6 Alkyl is one or two R 4 may be substituted with R 4 -OH and -OR 4a 5. The compound of claim 4, or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof, selected from the group consisting of:

6. The compound is 【Chemistry 4】 6. The compound of claim 5, wherein:

7. The compound is 【Transformation 5】 6. The compound of claim 5, wherein:

8. L is a bond; R 3 is hydrogen, fluoro, chloro, bromo, -CN, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, -OH, -OR 3a , -NR 3b R 3c , -C(O)OH, -C(O)OR 3a , -C(O)NR 3b R 3c , C 3 ~C 8 Cycloalkyl, C 5 ~C 7 Cycloalkenyl, 3- to 6-membered heterocyclic group, C 5 ~C 7 Heterocycloalkenyl, C 6 selected from the group consisting of aryl, and 5-6 membered heteroaryl; R 3 C 3 ~C 8 Cycloalkyl, C 6 Aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 optionally substituted with, 10. The compound of claim 1, or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

9. R 1 But C 1 ~C 6 alkyl, and R 1 C 1 ~C 6 Alkyl is one or two R 4 may be substituted with R 4 -OH, -OR 4a , -C(O)NR 4b R 4c and a 5- to 6-membered heterocyclic group, or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

10. R 1 10. The compound of claim 9, or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein is methyl.

11. R 3 But hydrogen, C 1 ~C 4 Alkyl, C 6 selected from the group consisting of aryl, and 5-6 membered heteroaryl; R 3 C 6 Aryl, and 5- to 6-membered heteroaryl are substituted with one or two R 5 optionally substituted with; R 5 -OH, -OR 5a , C 1 ~C 4 Alkyl, C 1 ~C 4 Hydroxyalkyl, C 1 ~C 4 Hydroxyalkoxy, and C 2 ~C 6 alkoxyalkyl, 11. The compound of claim 10, or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

12. L is -O-(CR a R b ) n - and; R 3 But -CN, C 3 ~C 8 Cycloalkyl, 3- to 6-membered heterocyclic group, C 6 selected from the group consisting of aryl, and 5-6 membered heteroaryl; R 3 C 3 ~C 8 Cycloalkyl, C 6 Aryl, 3- to 6-membered heterocyclic group, and 5- to 6-membered heteroaryl are each independently selected from one or two R 5 optionally substituted with; R 5 -OH, -CH 2 CO 2 R 5b , C 1 ~C 4 Alkyl, and C 1 ~C 4 hydroxyalkyl, 10. The compound of claim 1, or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

13. 6-[1-(6-hydroxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(6-chloro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(5,6-dimethyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(6-ethyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(cyclohex-1-en-1-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(6-bromo-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(6-cyclohexyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-[1-(6-phenyl-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide; 6-[1-(6-methoxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(6-cyclopentyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(cyclopent-1-en-1-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(3,6-dihydro-2H-pyran-4-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(trifluoromethyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide; Methyl 2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazole-6-carboxylate; 6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(oxolan-3-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide; 6-{1-[6-(2,5-dihydrofuran-3-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(hydroxymethyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[(1E)-3-hydroxy-3-methylbut-1-en-1-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-N,N-dimethyl-1,3-benzoxazole-6-carboxamide; 2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazole-6-carboxylic acid; 6-{1-[6-(2-hydroxypropan-2-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(6-hydroxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(3-hydroxy-3-methylbutyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[(1E)-3-methoxyprop-1-en-1-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(cyanomethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[3-hydroxy-2-(hydroxymethyl)propyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; {[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}acetic acid ethyl ester; 6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(oxan-4-yl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide; 6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide; 6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(2-methoxyethyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide; 6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-{[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide; 6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(3-hydroxypropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[(1E)-3-hydroxyprop-1-en-1-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(3-methoxypropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(1,3-benzoxazol-2-yl)azetidin-3-yl]-3-({1-[2-(dimethylamino)-2-oxoethyl]-1H-pyrazol-4-yl}amino)pyrazine-2-carboxamide; 6-{1-[6-(2-methoxyethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-{[1-(2,3-dihydroxypropyl)-1H-pyrazol-4-yl]amino}-6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide; 6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-({1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-1H-pyrazol-4-yl}amino)-6-[1-(6-fluoro-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide; 6-{1-[6-(2-amino-2-oxoethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(2-hydroxy-2-methylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[2-(dimethylamino)-2-oxoethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(2-hydroxyethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(oxetan-3-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide; 6-(1-{6-[(3-hydroxycyclobutyl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(2,3-dihydroxypropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[(1-hydroxycyclobutyl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[2-(3-hydroxyoxetan-3-yl)ethyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(morpholine-4-carbonyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide; 6-(1-{6-[2-(dimethylamino)-2-oxoethyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(6-{[(2R)-1,4-dioxan-2-yl]methoxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide; 6-(1-{6-[2-(methylamino)-2-oxoethyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[3-hydroxy-2-(hydroxymethyl)propoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[(2,2-dimethyl-1,3-dioxan-5-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; N-tert-butyl-2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazole-6-carboxamide; 2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-N-cyclopropyl-1,3-benzoxazole-6-carboxamide; 3-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}-6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide; 3-{[1-(2-methoxyethyl)-1H-pyrazol-4-yl]amino}-6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide; 6-[1-(6-{[3-(hydroxymethyl)cyclobutyl]methoxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[(3-hydroxyoxetan-3-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(6-{[(1S,2R)-2-(hydroxymethyl)cyclopropyl]methoxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[(2R)-2-(hydroxymethyl)pyrrolidine-1-carbonyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(3-phenylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide; 6-{1-[6-(3-hydroxy-2,2-dimethylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[3-(dimethylamino)-3-oxopropyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[3-oxo-3-(pyrrolidin-1-yl)propyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide; 6-(1-{6-[(2R)-2-(methoxymethyl)pyrrolidine-1-carbonyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide; [2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]acetic acid; 6-[1-(6-{2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-oxoethyl}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(2-hydroxy-2-methylpropyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[(2R)-2-hydroxypropoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-[1-(6-{[(3S)-oxolan-3-yl]oxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide; 6-[1-(6-{2-[(3S)-3-methoxypyrrolidin-1-yl]-2-oxoethyl}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-[1-(6-{2-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]-2-oxoethyl}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[(1-methyl-2-oxopyrrolidin-3-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[2-(azetidin-1-yl)-2-oxoethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; {[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}acetic acid; 6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[(2R)-2-(2-hydroxypropan-2-yl)pyrrolidine-1-carbonyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[(1-methyl-2-oxopiperidin-3-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl dihydrogen phosphate; 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl diprop-2-en-1-yl phosphate; 6-[1-(6-methyl-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide; 6-(1-{6-[(2-hydroxycyclopentyl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(1-methyl-1H-pyrazol-3-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-[1-(6-{2-oxo-2-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]ethyl}-1,3-benzoxazol-2-yl)azetidin-3-yl]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(5-methyl-1,3-thiazol-2-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide; 6-(1-{6-[2-(dimethylamino)-2-oxoethoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide; 6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide; 6-[1-(6-hydroxy-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide; 6-{1-[6-(2-hydroxy-2-methylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyridine-2-carboxamide; 6-(1-{6-[(5-methyl-1,3,4-oxadiazol-2-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(2-cyclopropyl-2-oxoethoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(4-hydroxyphenyl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[4-(2-hydroxyethoxy)phenyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(1-methyl-1H-pyrazol-4-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(1H-pyrazol-4-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide; 3-[(1-tert-butyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide; 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl glycinate; [(tert-Butoxycarbonyl)amino]acetic acid 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl; 6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-{[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]amino}pyrazine-2-carboxamide; 6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(3-hydroxy-3-methylbutoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(1-methyl-1H-pyrazol-4-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyrazine-2-carboxamide; 6-(1-{6-[(1-methyl-1H-imidazol-4-yl)methoxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-{1-[6-(2-methyl-1,3-thiazol-5-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}pyrazine-2-carboxamide; 6-(1-{6-[4-(2-methoxyethoxy)phenyl]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-{1-[6-(2-ethoxypropan-2-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 6-(1-{6-[(5-methoxypyrimidin-2-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 3-[(1-methyl-1H-pyrazol-4-yl)amino]-6-(1-{6-[(pyridazin-3-yl)oxy]-1,3-benzoxazol-2-yl}azetidin-3-yl)pyridine-2-carboxamide; 6-[1-(6-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]methoxy}-1,3-benzoxazol-2-yl)azetidin-3-yl]-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; [4-({[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}methyl)-1H-pyrazol-1-yl]acetic acid ethyl; 6-{1-[6-(1-methyl-1H-imidazol-4-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl dihydrogen phosphate; 6-{1-[6-(2-cyano-2-methylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; 1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl glycinate; 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl dihydrogen phosphate; 4-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyridin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylbutan-2-yl glycinate; 6-{1-[6-(1-hydroxy-2-methylpropan-2-yl)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide; Ethyl 2-[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]-2-methylpropanoate; 1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl dihydrogen phosphate; and 1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl glycinate 10. The compound of claim 1, selected from the group consisting of: or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

14. 14. The compound of claim 13, wherein the compound is 6-{1-[6-(2-hydroxy-2-methylpropoxy)-1,3-benzoxazol-2-yl]azetidin-3-yl}-3-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide, or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

15. 14. The compound of claim 13, wherein the compound is 1-{[2-(3-{6-carbamoyl-5-[(1-methyl-1H-pyrazol-4-yl)amino]pyrazin-2-yl}azetidin-1-yl)-1,3-benzoxazol-6-yl]oxy}-2-methylpropan-2-yl glycinate, or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof.

16. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1, or an enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

17. 17. The pharmaceutical composition of claim 16, for use in the prevention or treatment of diseases affected by inhibition of Mer kinase.

18. 18. The pharmaceutical composition of claim 17, wherein the disease affected by inhibition of Mer kinase is cancer or an immune-related disease.

19. The cancer is selected from the group consisting of glioma, gliosarcoma, anaplastic astrocytoma, medulloblastoma, lung cancer, small cell lung cancer, cervical cancer, colon cancer, rectal cancer, chordoma, laryngeal cancer, Kaposi's sarcoma, lymphangiosarcoma, lymphangioendothelioma, colorectal cancer, endometrial cancer, ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, liver cancer, bile duct carcinoma, choriocarcinoma, seminoma, testicular tumor, Wilms' tumor, Ewing's tumor, bladder cancer, angiosarcoma, endothelioma, adenocarcinoma, sweat gland carcinoma, sebaceous gland sarcoma, papillary sarcoma, papillary adenosarcoma, 19. The pharmaceutical composition of claim 18, wherein the tumor is selected from the group consisting of cystic sarcoma, bronchogenic carcinoma, medullary carcinoma, mast cell tumor, mesothelioma, synovioma, melanoma, leiomyosarcoma, rhabdomyosarcoma, neuroblastoma, retinoblastoma, oligodendroglioma, acoustic neuroma, hemangioblastoma, meningioma, pinealoma, ependymoma, craniopharyngioma, epithelial carcinoma, embryonal carcinoma, squamous cell carcinoma, basal cell carcinoma, fibrosarcoma, myxoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, leukemia, and metastatic lesions secondary to these primary tumors.

20. 19. The pharmaceutical composition of claim 18, wherein the immune-related disease is selected from the group consisting of infectious diseases and sepsis.

21. A method for treating or preventing an immune-related disease or cancer, the method comprising the step of administering a composition comprising, as an active ingredient, a compound according to any one of claims 1 to 15, or an isomer, enantiomer, diastereomer, racemate, tautomer, prodrug, hydrate, solvate, or pharmaceutically acceptable salt thereof, to a mammal, including a human, in need of such treatment or prevention of an immune-related disease or cancer.

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