Novel compound and pharmaceutical composition comprising same

Abstract

The present invention provides a compound represented by chemical formula 1 in the specification or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof as an active ingredient may be advantageously used for the prevention or treatment of BAF complex-related diseases.

Description

Novel compound and pharmaceutical composition comprising same

[0001] The present invention relates to a disease associated with the BAF complex, particularly a compound having an inhibitory effect on the BAF complex, a method for producing the same, and a use thereof.

[0002] Chromatin regulation is essential for gene expression, and ATP-dependent chromatin remodeling is the mechanism by which this gene expression occurs. The human Switch / Sucrose Non-Fermentative (SWI / SNF) chromatin remodeling complex, also known as the BAF complex (BRG / BRM-Associated Factor complex), contains two SWI2-like ATPases, BRG1 (Brahma-related gene-1) and BRM (Brahma). The transcriptional activator BRG1, also known as the ATP-dependent chromatin remodeler SMARCA4, is encoded by the SMARCA4 gene on chromosome 19. BRG1 is overexpressed in some cancers and is required for cancer cell proliferation. The possible global transcriptional activator SNF2L2 and / or the ATP-dependent chromatin remodeler BRM, also known as the SMARCA2 gene on chromosome 9, have been shown to be essential for tumor cell growth in cells characterized by BRG1 loss-of-function mutations. Inactivation of BRG and / or BRM results in downstream effects in cells, including cell cycle arrest and tumor suppression.

[0003]

[0004] Among them, SMARCA2 is a protein that plays a crucial role in controlling gene expression. It acts by pulling the ends of chromatin together, exposing DNA and enabling it to interact with transcription factors (proteins) required for gene expression. Therefore, SMARCA2 plays a crucial role in cellular biological processes such as cell differentiation, the cell cycle, and cell proliferation, and is associated with various diseases.

[0005]

[0006] Accordingly, the present invention provides an inhibitor of a BAF complex having a novel structure, and provides a method for preventing or treating a disease related to the BAF complex using a pharmaceutical composition containing the inhibitor.

[0007] The present invention provides a compound having an inhibitory effect on a BAF complex-related disease, particularly on the BAF complex, a method for producing the same, and a use thereof.

[0008] In addition, the present invention provides a pharmaceutical composition comprising the compound as an active ingredient.

[0009] To solve the above problem, the present invention provides a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0010] [Chemical Formula 1]

[0011]

[0012] In the above chemical formula 1,

[0013] A is a 4- or 5-membered heteroaliphatic ring containing 1 or 2 N, or C containing 1 or 2 N. 8-12 It is a bicyclic ring,

[0014] The above A is unsubstituted; or C 1-4 Alkyl, C 1-4 substituted with alkoxy or oxo,

[0015] B is any one divalent ring selected from the group consisting of benzene, pyridine, pyrimidine, pyrazine, and pyrrolidine,

[0016] The above B is unsubstituted; or C 1-4 Alkyl, C 1-4 substituted with alkoxy, cyano, hydroxy, amino, or halogen,

[0017] X is CH, N, O, S, or Se,

[0018] Y is CH, N, O, or S,

[0019] R1 is C 6-10 Aryl; C comprising at least one selected from the group consisting of N, O and S 3-14 Heteroaryl; or C comprising at least one selected from the group consisting of N, O and S 8-12 It is a bicyclic 1-membered ring,

[0020] The above R1 is unsubstituted; or C 1-4 Alkyl, C 1-4 Haloalkyl, (C 1-4 Alkyl)sulfonyl, (C 1-4 alkyl)carbonyl, halogen, cyano, amino, -NH-CO-O-(C 1-4 alkyl), and -CO-CO-N(C 1-4 Substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl)2,

[0021] R2 is hydrogen, or C 1-4 It is alkyl,

[0022] R3 is C 6-10 Aryl; C comprising at least one selected from the group consisting of N, O, S and B 3-14 Heteroaryl; C comprising at least one selected from the group consisting of N, O and S 3-14 Heterocycloalkyl; or C comprising at least one selected from the group consisting of N, O, S and B 8-12It is a bicyclic 1-membered ring,

[0023] The above R3 is unsubstituted; or C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, amino, amino(C 1-4 alkyl), di(C 1-4 alkyl)amino, halogen, nitro, cyano, -COO-(C 1-4 alkyl), -CONH-(C 3-6 cycloalkyl), -CO-N(C 1-4 alkyl)2, -CO-NH2, -CO-H, -CO-(C 1-4 alkyl), -SO2-NH2, -CH2-O-(C 1-4 alkyl), -(C 1-4 substituted with 1 to 4 substituents each independently selected from the group consisting of alkylene)-COOH, and piperazinyl,

[0024] However, the above B is not 1,3-phenylene and 2,6-pyridinediyl.

[0025]

[0026] Preferably, A is one selected from the group consisting of:

[0027]

[0028] In the above, R4 is hydrogen, C 1-4 Alkyl, or C 1-4 It is alkoxy. In the above, "*" means a part that is bonded to the chemical formula 1, and the bonding position is determined by the nitrogen and carbon connected to "*". For example, if A In this case, the above chemical formula 1 has the following structure.

[0029]

[0030]

[0031] Preferably, B is any one selected from the group consisting of:

[0032]

[0033] In the above,

[0034] R5 is C 1-4 Alkyl, C 1-4 Alkoxy, or halogen,

[0035] R6 is hydrogen or halogen,

[0036] R7 is C 1-4 Alkyl, C 1-4 Alkoxy, cyano, hydroxy, amino, or halogen.

[0037] In addition, “*” in the above means a part that is bonded to the chemical formula 1.

[0038]

[0039] Preferably, X is S or Se. Preferably, Y is CH. Preferably, X is S and Y is CH.

[0040]

[0041] Preferably, R1 is any one selected from the group consisting of:

[0042]

[0043] In the above,

[0044] R8 is each independently hydrogen, C 1-4 Alkyl, or deuterated C 1-4 It is alkyl,

[0045] R9 is C 1-4 It is alkyl,

[0046] R 10 Silver hydrogen, C 1-4 Alkyl, or halogen,

[0047] R 11 and R 12 are each independently hydrogen, C 1-4 Alkyl, C 1-4alkoxy, or amino, or can form a bond together,

[0048] R 13 is amino, or -NH-CO-O-(C 1-4 alkyl).

[0049]

[0050] Preferably, R2 is hydrogen.

[0051]

[0052] Preferably, R3 is any one selected from the group consisting of:

[0053]

[0054] In the above, R 14 are each independently C 1-4 It's alkyl.

[0055]

[0056] Preferably, the above chemical formula 1 is represented by the following chemical formula 2:

[0057] [Chemical Formula 2]

[0058]

[0059] In the above chemical formula 2,

[0060] Z is CH, or N,

[0061] R4 is hydrogen, C 1-4 Alkyl, or C 1-4 It is alkoxy,

[0062] R7 is C 1-4 Alkyl, C 1-4 alkoxy, cyano, hydroxy, amino, or halogen,

[0063] R8 is each independently hydrogen, C 1-4 Alkyl, or deuterated C 1-4 It is alkyl,

[0064] R9 is C 1-4 It is alkyl,

[0065] R 14 are each independently C 1-4 It is alkyl,

[0066] n is 0 or 1.

[0067]

[0068] Representative examples of compounds represented by the above chemical formula 1 are as follows:

[0069] 1) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0070] 2) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0071] 3) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(5-trideuteriomethyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0072] 4) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(1-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indole-3-carbonyl)azetidine-2-carboxamide,

[0073] 5) tert-butyl (4-((S)-2-((4-(3-((2S,6R)-2,6-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)carbamoyl)azetidine-1-carbonyl)phenyl)carbamate,

[0074] 6) (S)-1-(4-aminobenzoyl)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)azetidine-2-carboxamide,

[0075] 7) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(5-trideuteriomethyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide,

[0076] 8) (2S,3S)-N-(4-(3-((2R,6S)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-3-methyl-1-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0077] 9) (2S,3S)-N-(4-(3-((2R,6S)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-3-methyl-1-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide,

[0078] 10) (2S)-N-(4-(3-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-5-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0079] 11) (2S)-N-(4-(3-fluoro-5-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)phenyl)thiazol-2-yl)-1-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0080] 12) (S)-N-(4-(3-((2S,6R)-2-ethyl-6-methylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0081] 13) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-methoxyphenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0082] 14) (S)-N-(4-(3-(2,6-dimethylpyridin-4-yl)-5-methoxyphenyl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0083] 15) S)-N-(4-(3-(2-ethyl-6-methylpyridin-4-yl)-5-methoxyphenyl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0084] 16) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0085] 17) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-methylphenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0086] 18) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-methylphenyl)thiazol-2-yl)-1-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0087] 19) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-2-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0088] 20) (S)-N-(4-(2-((2S,6R)-2,6-dimethylmorpholino)pyridin-4-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0089] 21) (S)-N-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0090] 22) (S)-N-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)-1-(1,1-dioxido-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carbonyl)pyrrolidine-2-carboxamide,

[0091] 23) (S)-N-(4-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0092] 24) (S)-N-(4-(5-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0093] 25) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)pyrazin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0094] 26) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0095] 27) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methoxy-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide,

[0096] 28) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-4-methoxy-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide,

[0097] 29) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0098] 30) (2S)-N-(4-(1-(2,6-dimethylpyridin-4-yl)pyrrolidin-3-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0099] 31) (R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1,1-dioxido-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carbonyl)azetidine-2-carboxamide,

[0100] 32) (S)-N-(4-(4-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0101] 33) (S)-N-(4-(6-chloro-4-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0102] 34) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-4-methoxy-1-(5-methyl-1-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carbonyl)azetidine-2-carboxamide,

[0103] 35) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrazole-3-carbonyl)azetidine-2-carboxamide,

[0104] 36) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methyl-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0105] 37) (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide,

[0106] 38) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1,1-dioxido-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carbonyl)-3-methylazetidine-2-carboxamide,

[0107] 39) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methyl-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide,

[0108] 40) (S)-N-(4-(4-chloro-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0109] 41) (S)-1-((R)-4-cyano-4-methylisochroman-6-carbonyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide,

[0110] 42) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-imidazole-4-carbonyl)azetidine-2-carboxamide,

[0111] 43) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-methylpyridin-2-yl)thiazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0112] 44) (S)-1-(6-chloro-1,1-dioxido-2,3-dihydro-5H-benzo[e][1,4oxathiepine-8-carbonyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide,

[0113] 45) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(7-(ethylsulfonyl)benzo[d][1,3]dioxole-5-carbonyl)azetidine-2-carboxamide,

[0114] 46) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-celanazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0115] 47) (S)-1-(3-amino-4-(methylsulfonyl)benzoyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide,

[0116] 48) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0117] 49) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0118] 50) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(ethylsulfonyl)-5-methyl-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0119] 51) (S)-N-(4-(5-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0120] 52) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(3-methyl-4-(methylsulfonyl)-benzoyl)azetidine-2-carboxamide,

[0121] 53) (2S,3S)-1-((R)-4-cyano-4-methylisochroman-6-carbonyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methylazetidine-2-carboxamide,

[0122] 54) (S)-1-((R)-4-cyano-4-methylisochroman-6-carbonyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-selenazol-2-yl)azetidine-2-carboxamide,

[0123] 55) (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide,

[0124] 56) (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(1-(ethylsulfonyl)-5-methyl-1H-pyrrole-3-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide,

[0125] 57) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methyl-1-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide,

[0126] 58) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(ethylsulfonyl)-5-(trideuteriomethyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0127] 59) (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(1-(ethylsulfonyl)-5-(trideuteriomethyl)-1H-pyrrole-3-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide,

[0128] 60) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(ethylsulfonyl)-5-(trideuteriomethyl)-1H-pyrrole-3-carbonyl)-3-methylpyrrolidine-2-carboxamide,

[0129] 61) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-selenazol-2-yl)-1-(1-(ethylsulfonyl)-5-(trideuteriomethyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0130] 62) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0131] 63) (2S,5S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-5-methyl-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide,

[0132] 64) (2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-5-methyl-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide,

[0133] 65) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-hydroxypyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0134] 66) (S)-N-(4-(6-((2R,6S)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0135] 67) (2S)-N-(4-(6-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide,

[0136] 68) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)-2-oxoimidazolidine-4-carboxamide,

[0137] 69) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide, and

[0138] 70) (S)-N-(4-(4-amino-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide.

[0139]

[0140] Furthermore, the compounds of the present invention may exist in the form of salts, particularly pharmaceutically acceptable salts. As salts, any salt commonly used in the art, such as acid addition salts formed with pharmaceutically acceptable free acids, may be used without limitation. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound represented by Chemical Formula 1, which has a concentration that is relatively non-toxic and harmless to the patient and has an effective effect, and wherein the side effects caused by the salt do not diminish the beneficial effects of the compound represented by Chemical Formula 1.

[0141]

[0142] Pharmaceutically acceptable salts can be obtained by conventional methods using inorganic or organic acids. For example, the compound represented by the above chemical formula 1 can be dissolved in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, and an organic or inorganic acid can be added. The precipitated crystals can be filtered and dried to obtain a pharmaceutically acceptable salt. Alternatively, the salt can be prepared by removing the solvent or excess acid from a reaction mixture to which an acid has been added under reduced pressure, drying the residue, or by adding another organic solvent and filtering the precipitated salt. At this time, preferable salts include salts derived from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid.

[0143]

[0144] A pharmaceutically unacceptable salt or solvate of a compound represented by chemical formula 1 can be used as an intermediate in the production of a compound represented by chemical formula 1, a pharmaceutically acceptable salt, or a solvate thereof.

[0145]

[0146] The compound represented by the above chemical formula 1 of the present invention includes not only its pharmaceutically acceptable salts but also all possible enantiomers, stereoisomers, solvates, polymorphs, or isotopic derivatives that can be prepared therefrom.

[0147]

[0148] In addition, the compound represented by Chemical Formula 1 according to the present invention can be prepared in a crystalline or amorphous form, and when the compound represented by Chemical Formula 1 is prepared in a crystalline form, it can be optionally hydrated or solvated. The present invention may include not only stoichiometric hydrates of the compound represented by Chemical Formula 1 but also compounds containing various amounts of water. The solvates of the compound represented by Chemical Formula 1 according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

[0149]

[0150] In addition, the present invention can produce a compound represented by the chemical formula 1 through the following reaction scheme 1, for example.

[0151] [Reaction Formula 1]

[0152]

[0153] In the above reaction formula 1, A, B, X, Y, R1 to R3 are as defined above.

[0154]

[0155] The above reaction is an amidation reaction, and the catalyst and solvent for the amidation reaction can be changed according to those known in the art. The above manufacturing method can be further specified in the manufacturing examples described below.

[0156]

[0157] In addition, the present invention provides a pharmaceutical composition for preventing or treating a BAF complex-related disease, for example, a disease associated with alteration of BRG1 and / or BRM, comprising a compound represented by the above chemical formula 1, a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or isotope derivative thereof as an active ingredient.

[0158]

[0159] The term "BAF complex" refers to a BRG1- and / or HBRM-associated factor complex in human cells, and the term "BAF complex-associated disease" refers to a disease caused or influenced by the level and / or activity level of the BAF complex. Specifically, the BAF complex-associated disease includes cancer, viral infection, Coffin Siris syndrome, neurofibromatosis (e.g., NF-1, NF-2, or schwannomatosis), or multiple meningiomas. Specifically, the cancer includes non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, esophageal cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical carcinoma, appendix cancer, small intestine cancer, penile cancer, bone cancer, blood cancer, or eye cancer. In addition, the above viral infection includes an infection with a virus of the Retroviridae family, a virus of the Hepadnaviridae family, a virus of the Flaviviridae family, a virus of the Adenoviridae family, a virus of the Herpeviridae family, a virus of the Papillomaviridae family, a virus of the Parvoviridae family, a virus of the Poliomaviridae family, a virus of the Paramyxoviridae family, or a virus of the Togaviridae family.

[0160]

[0161] The term "prevention" in the present invention refers to any action that inhibits or delays the occurrence, spread, and recurrence of the disease by administering the composition of the present invention, and "treatment" refers to any action that improves or beneficially changes the symptoms of the disease by administering the composition of the present invention. In addition, the prevention or treatment is due to reducing the level and / or activity of the BAF complex in a cell or subject. In addition, the prevention or treatment is due to inhibiting BRM in a cell or subject. In addition, the prevention or treatment is due to inhibiting BRG1 in a cell or subject.

[0162]

[0163] Meanwhile, the pharmaceutical composition of the present invention can be formulated into oral or parenteral dosage forms according to standard pharmaceutical practices. These dosage forms may contain, in addition to the active ingredient, pharmaceutically acceptable additives such as carriers, adjuvants, or diluents.

[0164]

[0165] Suitable carriers include, but are not limited to, saline, polyethylene glycol, ethanol, vegetable oils, and isopropyl myristate, and diluents include, but are not limited to, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine. In addition, the compounds of the present invention can be dissolved in oils, propylene glycol, or other solvents commonly used in the preparation of injectable solutions. In addition, the compounds of the present invention can be formulated as ointments or creams for topical action.

[0166]

[0167] The compounds of the present invention can be formulated as injectables by dissolving, suspending, or emulsifying the compounds in water-soluble solvents such as normal saline, about 5% dextrose, or in water-insoluble solvents such as synthetic fatty acid glycerides, higher fatty acid esters, or propylene glycol. The formulations of the present invention can include conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifiers, stabilizers, and preservatives.

[0168]

[0169] Pharmaceutical dosage forms of the compounds of the present invention may be used alone or in combination with other pharmaceutically active compounds, as well as in appropriate combinations.

[0170]

[0171] The preferred dosage of the compound of the present invention varies depending on the patient's condition and body weight, the extent of the disease, the form of the drug, the route and duration of administration, and can be appropriately selected by those skilled in the art. However, for a desirable effect, it is recommended to administer the compound of the present invention at about 0.0001 to 100 mg / kg (body weight) per day, preferably about 0.001 to 100 mg / kg (body weight). Administration can be administered once a day or in divided doses via oral or parenteral routes. Depending on the administration method, the composition can contain about 0.001 to 99 wt%, preferably about 0.01 to 60 wt%, of the compound of the present invention.

[0172]

[0173] The pharmaceutical composition of the present invention can be administered to mammals, including rats, mice, livestock, and humans, via various routes. Any route of administration is conceivable, including oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine, or intracerebroventricular injection.

[0174] The compound represented by chemical formula 1 of the present invention, or a pharmaceutically acceptable salt, enantiomer, stereoisomer, solvate, polymorph, or isotope derivative thereof, can be usefully used for the prevention or treatment of diseases related to the BAF complex.

[0175] Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended only to illustrate the present invention and the scope of the present invention is not limited to these examples.

[0176]

[0177] Example 1: Preparation of (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0178]

[0179] (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (50 mg, 0.12 mmol), 1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (44 mg, 0.23 mmol), and HATU (133 mg, 0.35 mmol) were added to DMF (1 mL), and DIPEA (0.116 mL, 0.70 mmol) was added while stirring, and the mixture was stirred at room temperature for 12 h. After the reaction was completed, distilled water (1 mL) was added and extracted with ethyl acetate (3 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (40 mg, yield: 61%).

[0180] 1H NMR (500 MHz, CDCl3) δ 11.22 (s, 1H), 7.63 (s, 1H), 7.27-7.26 (m, 2H), 7.18 (s, 1H), 7.00-6.98 (d, 1H), 6.71 (s, 1H), 6.53-6.51 (d, 1H), 5.33 (m, 1H), 4.44-4.39 (m, 2H), 3.81-3.80 (m, 2H), 3.52-3.49 (m, 2H), 3.23 (m, 4H), 2.67-2.60 (m, 1H), 2.49-2.45 (m, 2H), 1.26 (s, 6H)

[0181]

[0182] Example 2: Preparation of (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0183]

[0184] (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (30 mg, 0.07 mmol), 5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (29 mg, 0.14 mmol), and HATU (80 mg, 0.21 mmol) were added to DMF (1 mL), and DIPEA (0.07 mL, 0.42 mmol) was added while stirring, and the mixture was stirred at room temperature for 12 h. After the reaction was completed, distilled water (1 mL) was added and extracted with ethyl acetate (3 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (6 mg, yield: 14%).

[0185] 1H NMR (500 MHz, DMSO-d6) δ 12.45 (s, 1H), 7.77 (s, 1H), 7.46 (s, 1H), 7.29 (s, 1H), 7.10-7.09 (m, 1H), 6.77-6.75 (m, 1H), 6.41 (s, 1H), 5.02 (m, 1H), 4.48-4.47 (m, 1H), 4.37-4.36 (m, 1H), 3.71-3.69 (m, 4H), 3.57 (s, 3H), 2.60 (m, 1H), 2.42 (s, 3H), 2.32-2.30 (m, 2H), 1.18-1.17 (d, 6H)

[0186]

[0187] Example 3: Preparation of (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(5-trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0188]

[0189] (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (50 mg, 0.12 mmol), 5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (48 mg, 0.23 mmol), and HATU (133 mg, 0.35 mmol) were added to DMF (1 mL), and DIPEA (0.12 mL, 0.70 mmol) was added while stirring, and the mixture was stirred at room temperature for 12 h. After the reaction was completed, distilled water (1 mL) was added and extracted with ethyl acetate (3 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (10 mg, yield: 15%).

[0190] 1H NMR (500 MHz, DMSO-d6) δ 12.45 (s, 1H), 7.78 (s, 1H), 7.46 (s, 1H), 7.29 (s, 1H), 7.10-7.09 (m, 1H), 6.78-6.75 (m, 1H), 6.42 (s, 1H), 5.02 (m, 1H), 4.48-4.47 (m, 1H), 4.37-4.36 (m, 1H), 3.71-3.67 (m, 4H), 3.57 (s, 3H), 2.60 (m, 1H), 2.35-2.30 (m, 3H), 1.18-1.17 (d, 6H)

[0191]

[0192] Example 4: Preparation of (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(1-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indole-3-carbonyl)azetidine-2-carboxamide

[0193]

[0194] (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (34 mg, 0.08 mmol), 1-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (30 mg, 0.1233 mmol), and HATU (94 mg, 0.25 mmol) were added to DMF (1 mL), and DIPEA (0.08 mL, 0.49 mmol) was added while stirring, and the mixture was stirred at room temperature for 12 h. After the reaction was completed, distilled water (1 mL) was added and extracted with ethyl acetate (3 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (10 mg, yield: 20%).

[0195] 1H NMR (500 MHz, CDCl3) δ 11.13 (s, 1H), 7.28 (s, 1H), 7.22 (s, 1H), 7.13 (s, 1H), 7.00-6.98 (m, 1H), 6.53-6.50 (m, 1H), 5.29 (m, 1H), 4.38-4.33 (m, 2H), 3.82-3.78 (m, 2H), 3.53-3.49 (m, 2H), 3.14 (s, 3H), 2.95-2.90 (m, 2H), 2.82-2.70 (m, 2H), 2.68-2.66 (m, 1H), 2.61-2.57 (m, 1H), 2.49-2.45 (m, 2H), 1.86-1.84 (m, 2H), 1.74-1.71 (m, 1H), 1.61-1.60 (m, 1H)

[0196]

[0197] Example 5: Preparation of tert-butyl (4-((S)-2-((4-(3-((2S,6R)-2,6-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)carbamoyl)azetidine-1-carbonyl)phenyl)carbamate

[0198]

[0199] (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (50 mg, 0.12 mmol), 4-((tert-butoxycarbonyl)amino)benzoic acid (56 mg, 0.23 mmol), and HATU (133 mg, 0.35 mmol) were added to DMF (1 mL), and DIPEA (0.12 mL, 0.70 mmol) was added while stirring, and the mixture was stirred at room temperature for 12 h. After the reaction was completed, distilled water (1 mL) was added and extracted with ethyl acetate (3 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (20 mg, yield: 28%).

[0200] 1H NMR (500 MHz, DMSO-d6) δ 12.46 (s, 1H), 9.69 (s, 1H), 7.78 (s, 1H), 7.65-7.64 (d, 2H), 7.57-7.55 (d, 2H), 7.30 (m, 1H), 7.10-7.09 (m, 1H), 6.77-6.75 (m, 1H), 5.06 (m, 1H), 4.49-4.48 (m, 1H), 4.30-4.29 (m, 1H), 3.71-3.67 (m, 4H), 2.61 (m, 1H), 2.37 (m, 1H), 2.35-2.30 (m, 2H), 1.49 (s, 9H), 1.17 (s, 6H)

[0201]

[0202] Example 6: Preparation of (S)-1-(4-aminobenzoyl)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)azetidine-2-carboxamide

[0203]

[0204] Tert-Butyl (4-((S)-2-((4-(3-((2S,6R)-2,6-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)carbamoyl)azetidine-1-carbonyl)phenyl)carbamate (10 mg, 0.016 mmol) was dissolved in methylene chloride (1 mL), and 4 M hydrogen chloride 1,4-dioxane solution (0.5 mL) was slowly added, followed by stirring at room temperature for 3 h. After completion of the reaction, saturated aqueous sodium bicarbonate solution (2 mL) was added, and the mixture was extracted with ethyl acetate (6 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (4 mg, yield: 48%).

[0205] 1H NMR (500 MHz, CDCl3) δ 11.05 (s, 1H), 7.58-7.56 (d, 1H), 7.22 (s, 1H), 7.13 (s, 1H), 6.98-6.96 (d, 1H), 6.68-6.66 (m, 1H), 6.52-6.51 (d, 1H), 6.52-6.50 (m, 1H), 5.32 (m, 1H), 4.47-4.42 (m, 1H), 4.31-4.26 (m, 1H), 4.06 (m, 2H), 3.83-3.3.77 (m, 2H), 3.49 (m, 2H), 2.98-2.91 (m, 1H), 2.60-2.52 (m, 1H), 2.49-2.44 (m, 2H)

[0206]

[0207] Example 7: Preparation of (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(5-trideuteriomethyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide

[0208]

[0209] (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)pyrrolidine-2-carboxamide hydrochloride (50 mg, 0.11 mmol), 5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (35 mg, 0.17 mmol), and HATU (129 mg, 0.34 mmol) were added to DMF (1 mL), and DIPEA (0.11 mL, 0.68 mmol) was added while stirring, and the mixture was stirred at room temperature for 12 h. After the reaction was completed, distilled water (1 mL) was added and extracted with ethyl acetate (3 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (19 mg, yield: 28%).

[0210] 1H NMR (500 MHz, DMSO-d6) δ 12.39 (s, 1H), 7.74 (s, 1H), 7.51 (s, 1H), 7.29 (s, 1H), 7.10-7.08 (m, 1H), 6.77-6.75 (m, 1H), 6.45 (s, 1H), 4.69-4.67 (m, 1H), 3.88-3.85 (m, 1H), 3.82-3.80 (m, 1H), 3.71-3.67 (m, 4H), 3.56 (s, 3H), 2.35-2.30 (m, 2H), 2.27-2.24 (m, 1H), 2.06-2.02 (m, 1H), 1.98-1.88 (m, 2H), 1.18-1.17 (d, 6H)

[0211]

[0212] Example 8: Preparation of (2S,3S)-N-(4-(3-((2R,6S)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-3-methyl-1-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0213]

[0214] (2S,3S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-3-methylazetidine-2-carboxamide hydrochloride (43 mg, 0.10 mmol), 5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (30 mg, 0.15 mmol), and HATU (111 mg, 0.29 mmol) were added to DMF (1 mL), stirred, and DIPEA (0.10 mL, 0.59 mmol) was added, followed by stirring at room temperature for 12 h. After completion of the reaction, distilled water (1 mL) was added and extracted with ethyl acetate (3 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (20 mg, yield: 35%).

[0215] 1H NMR (500 MHz, DMSO-d6) δ 12.47 (s, 1H), 7.78 (s, 1H), 7.46 (s, 1H), 7.26 (s, 1H), 7.11-7.09 (m, 1H), 6.78-6.75 (m, 1H), 6.42 (s, 1H), 4.61-4.59 (m, 1H), 4.58-4.56 (m, 1H), 3.97-3.95 (m, 4H), 3.57 (s, 3H), 2.71 (m, 1H), 2.35-2.30 (m, 2H), 1.33-1.32 (m, 3H), 1.18-1.17 (d, 6H)

[0216]

[0217] Example 9: Preparation of (2S,3S)-N-(4-(3-((2R,6S)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-3-methyl-1-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide

[0218]

[0219] (2S,3S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-3-methylpyrrolidine-2-carboxamide hydrochloride (50 mg, 0.11 mmol), 5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (34 mg, 0.16 mmol), and TCFH (34 mg, 0.16 mmol) were added to acetonitrile (1 mL), stirred, and N-methylimidazole (0.03 mL, 0.33 mmol) was added. The mixture was stirred at room temperature for 12 h. After completion of the reaction, distilled water (1 mL) was added and extracted with ethyl acetate (3 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (30 mg, yield: 45%).

[0220] 1H NMR (500 MHz, DMSO-d6) δ 12.42 (s, 1H), 7.73 (s, 1H), 7.52 (s, 1H), 7.30 (s, 1H), 7.11-7.09 (m, 1H), 6.77-6.75 (m, 1H), 6.44 (s, 1H), 4.25-4.23 (m, 1H), 3.89-3.87 (m, 2H), 3.71-3.67 (m, 3H), 3.56 (s, 3H), 2.37-2.28 (m, 4H), 2.18-2.13 (m, 1H), 1.69-1.57 (m, 1H), 1.18-1.17 (d, 6H), 1.16-1.14 (m, 3H)

[0221]

[0222] Example 10: Preparation of (2S)-N-(4-(3-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-5-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0223]

[0224] Step 1) Preparation of 2-bromo-1-(3-bromo-5-fluorophenyl)ethan-1-one

[0225]

[0226] 1-(3-Bromo-5-fluorophenyl)ethanone (9 g, 41.5 mmol) was dissolved in acetic acid (50 mL), and bromine (7.96 g, 49.8 mmol) and bromic acid-acetic acid solution (5.04 g, 62.2 mmol) were added. The reaction mixture was stirred at room temperature for 2 h and diluted with distilled water (10 mL) and ethyl acetate (30 mL x 3). The organic solvent layer was separated, dried over anhydrous sodium sulfate, and concentrated to obtain the target compound (9 g, yield: 66%). It was used in the next reaction without further purification.

[0227]

[0228] Step 2) Preparation of 4-(3-bromo-5-fluorophenyl)thiazol-2-amine

[0229]

[0230] 2-Bromo-1-(3-bromo-5-fluorophenyl)ethanone (10 g, 33.8 mmol) and thiourea (5.15 g, 67.6 mmol) were dissolved in ethanol and stirred at room temperature under nitrogen for 16 h. The reaction mixture was filtered, concentrated, and washed with petroleum ether (200 mL) to obtain the target compound (7 g, yield: 72%).

[0231] 1 H NMR (400 MHz, DMSO-d6) δ 9.23 - 9.07 (m, 2H), 7.87 (s, 1H), 7.72 - 7.69 (m, 1H), 7.66 - 7.57 (m, 1H), 7.49 (s, 1H).

[0232]

[0233] Step 3) Preparation of 4-(3-((2R,6S)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-5-fluorophenyl)thiazol-2-amine

[0234]

[0235] 4-(3-Bromo-5-fluorophenyl)-1,3-thiazol-2-amine (300 mg, 1.09 mmol), Pd(dppf)Cl2 (40 mg, 0.054 mmol), and potassium carbonate (455 mg, 3.29 mmol) were added to 1,4-dioxane / distilled water (10:1, 10 mL), 2-[(2R,6S)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (392 mg, 1.64 mmol) was added, and the mixture was stirred at 90°C for 2 h. After cooling the reaction mixture to room temperature, it was diluted with distilled water (30 mL) and ethyl acetate (30 mL x 3). After separating the organic solvent, the residue was dried over anhydrous sodium sulfate and concentrated. The concentrate was separated by column chromatography to obtain the target compound (200 mg, yield: 57%).

[0236] 1 H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 2H), 7.48 (d, J = 9.6 Hz, 1H), 7.21 - 7.13 (m, 4H), 6.27 (s, 1H), 7.49 (s, 1H), 4.34 (s, 1H), 3.71 (s, 1H), 1.99 (s, 2H), 1.26 - 1.21 (m, 6H).

[0237]

[0238] Step 4) Preparation of tert-butyl (S)-2-((4-(3-((2R,6S)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-5-fluorophenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0239]

[0240] 4-(3-((2R,6S)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-5-fluorophenyl)-1,3-thiazol-2-amine (200 mg, 0.65 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (159 mg, 0.78 mmol) and TCFH (368 mg, 1.31 mmol) were dissolved in DMF (5 mL), N-methylimidazole (161 mg, 1.97 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with distilled water (30 mL) and ethyl acetate (30 mL x 3), and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated mixture was purified by column chromatography to obtain the target compound (220 mg, yield: 65%).

[0241] 1 H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 7.88 (s, 1H), 7.82 (s, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.28 - 7.25 (m, 1H), 6.32 (s, 1H), 4.82 - 4.80 (m, 1H), 4.35 (s, 1H), 3.70 (s, 1H), 3.34 (s, 2H), 2.44 (s, 2H), 2.16 - 1.96 (m, 2H), 1.39 (s, 6H), 1.25 (s, 9H).

[0242]

[0243] Step 5) Preparation of (S)-N-(4-(3-((2R,6S)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-5-fluorophenyl)thiazol-2-yl)carbamoyl)azetidine-2-carboxamide

[0244]

[0245] Tert-Butyl (S)-2-((4-(3-((2R,6S)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-5-fluorophenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (220 mg, 0.45 mmol) was added 4 M hydrogen chloride solution in 1,4-dioxane (5 mL) and stirred at room temperature for 2 h under nitrogen. The reaction mixture was dried and washed with petroleum ether (20 mL) to obtain the target compound (150 mg, yield: 82%).

[0246] 1 H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 7.96 (s, 1H), 7.82 (s, 1H), 7.62 - 7.60 (m, 1H), 7.30 - 7.27 (m, 1H), 6.32 (s, 1H), 5.19 - 5.17 (m, 1H), 4.35 (s, 1H), 3.75 (s, 1H), 3.73 (s, 1H), 3.71 - 3.70 (m, 1H), 2.60 - 2.54 (m, 2H), 2.40 - 2.19 (m, 3H), 1.27 - 1.22 (m, 6H).

[0247]

[0248] Step 6) Preparation of (S)-N-(4-(3-((2R,6S)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-5-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0249]

[0250] (S)-N-(4-(3-((2R,6S)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-5-fluorophenyl)thiazol-2-yl)carbamoyl)azetidine-2-carboxamide (150 mg, 0.38 mmol), 1-methylsulfonyl-5-methylpyrrole-3-carboxylic acid (94 mg, 0.46 mmol) and HATU were dissolved in DMF (5 mL) and DIPEA was added and stirred at room temperature for 2 hours. The reaction mixture was diluted with distilled water (20 mL) and ethyl acetate (30 mL x 3), and the organic solvent layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated by column chromatography to obtain the target compound (170 mg, yield: 83%).

[0251] 1 H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 7.95 (s, 2H), 7.97 - 7.82 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.26 (d, J = 8.8 Hz, 1H), 6.41 - 6.32 (m, 2H), 5.03 (s, 1H), 4.46 (s, 1H), 4.02 (s, 3H), 3.56 (s, 3H), 2.41 (s, 2H), 1.98 (s, 3H), 1.25 - 1.15 (m, 6H).

[0252]

[0253] Step 7) Preparation of (2S)-N-(4-(3-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-5-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0254]

[0255] (S)-N-(4-(3-((2R,6S)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-5-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide (100 mg, 0.17 mmol) was dissolved in methanol (5 mL), Pd / C (37 mg, 0.34 mmol) was added, and the mixture was stirred at room temperature for 4 hours under hydrogen gas. The reaction mixture was diluted with distilled water (10 mL) and ethyl acetate (10 mL x 3), and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to obtain the title compound (20.30 mg, yield: 20%).

[0256] 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 7.81 (s, 1H), 7.66 (s, 1H), 7.53 (d, J = 9.6 Hz, 1H), 7.46 (s, 1H), 7.03 (s, 1H), 6.41 (s, 1H), 5.04 - 5.01 (m, 1H), 4.48 - 4.35 (m, 2H), 3.37 (s, 4H), 2.92 - 2.86 (m, 1H), 2.60 - 2.58 (m, 2H), 2.41 (s, 3H), 2.32 - 2.30 (m, 1H), 1.80 - 1.77 (m, 2H), 1.32 - 1.23 (m, 2H), 1.15 (d, J = 6.0 Hz, 6H).

[0257]

[0258] Example 11: Preparation of (2S)-N-(4-(3-fluoro-5-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)phenyl)thiazol-2-yl)-1-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0259]

[0260] (2S)-N-(4-(3-Fluoro-5-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)phenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (30 mg, 0.07 mmol), 5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (28 mg, 0.14 mmol), and HATU (78 mg, 0.20 mmol) were added to DMF (1 mL), stirred, and DIPEA (0.04 mL, 0.41 mmol) was added, followed by stirring at room temperature for 12 h. After completion of the reaction, distilled water (1 mL) was added and extracted with ethyl acetate (3 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (12 mg, yield: 30%).

[0261] 1 H NMR (500 MHz, CDCl3) δ 11.25 (s, 1H), 7.57 (s, 1H), 7.16 (s, 1H), 7.13 (s, 1H), 6.92-6.90 (m, 1H), 6.47-6.45 (m, 1H), 6.40 (s, 1H), 5.30-5.27 (m, 1H), 4.41-4.34 (m, 2H), 3.94-3.90 (m, 2H), 3.73-3.69 (m, 2H), 3.42-3.39 (m, 2H), 3.30-3.26 (m, 1H), 3.22 (s, 3H), 3.21-3.14 (m, 1H), 2.95 (m, 1H), 2.65-2.64 (m, 1H), 2.62-2.55 (m, 1H), 2.43-2.39 (m, 1H), 1.97-1.94 (m, 1H), 1.79-1.76 (m, 1H)

[0262]

[0263] Example 12: Preparation of (S)-N-(4-(3-((2S,6R)-2-ethyl-6-methylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0264]

[0265] (S)-N-(4-(3-((2R,6S)-2-ethyl-6-methylmorpholino)-5-fluorophenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (43 mg, 0.10 mmol), 5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (30 mg, 0.15 mmol), and HATU (113 mg, 0.30 mmol) were added to DMF (1 mL), stirred, and DIPEA (0.08 mL, 0.60 mmol) was added, followed by stirring at room temperature for 12 h. After completion of the reaction, distilled water (1 mL) was added and extracted with ethyl acetate (3 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (10 mg, yield: 11%).

[0266] 1 H NMR (500 MHz, DMSO-d6) δ 12.44 (s, 1H), 7.78 (s, 1H), 7.46 (s, 1H), 7.30 (s, 1H), 7.10-7.09 (m, 1H), 6.78-6.76 (m, 1H), 6.41 (s, 1H), 5.01 (m, 1H), 4.47 (m, 1H), 4.37-4.35 (m, 1H), 3.70-3.65 (m, 3H), 3.57 (s, 3H), 3.49-3.47 (m, 1H), 2.61-2.59 (m, 1H), 2.42 (s, 3H), 2.33-2.29 (m, 3H), 1.54-1.49 (m, 2H), 1.24 (m, 2H), 0.99-0.96 (t, 3H)

[0267]

[0268] Example 13: Preparation of (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-methoxyphenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0269]

[0270] Step 1) Preparation of tert-butyl (S)-2-((4-(3-bromo-5-methoxyphenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0271]

[0272] 4-(3-Bromo-5-methoxyphenyl)thiazol-2-amine (210.0 mg, 0.74 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (296.0 mg, 1.47 mmol), and HATU (700.0 mg, 1.84 mmol) were added to DMF (2 mL), stirred, and DIPEA (0.51 mL, 2.95 mmol) was added, followed by stirring at room temperature for 29 h. After completion of the reaction, distilled water (20 mL) was added and extracted with ethyl acetate (50 mL x 2). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (248.4 mg, yield: 72%).

[0273] LC / MS (ESI, m / z): [M+H] + = 467.8, 469.9.

[0274]

[0275] Step 2) Preparation of tert-butyl (S)-2-((4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-methoxyphenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0276]

[0277] Tert-Butyl (S)-2-((4-(3-bromo-5-methoxyphenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (92.7 mg, 0.20 mmol) was dissolved in 1,4-dioxane (1 mL), and (2S,6R)-2,6-dimethylmorpholine (0.073 mL, 0.59 mmol), Pd2(dba)3 (18.1 mg, 0.020 mmol), XPhos (18.9 mg, 0.040 mmol), and t-butoxysodium (57.1 mg, 0.59 mmol) were added and stirred at 100°C for 1 h. The reaction solution was then cooled to room temperature, distilled water (20 mL) was added, and extracted with ethyl acetate (50 mL x 2). The extracted organic layer was dried with anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (72.0 mg, yield: 72%).

[0278] LC / MS (ESI, m / z): [M+H] + = 503.0.

[0279]

[0280] Step 3) Preparation of (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-methoxyphenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride

[0281]

[0282] Tert-Butyl (S)-2-((4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-methoxyphenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (72.0 mg, 0.14 mmol) was dissolved in ethyl acetate (4 mL), and 4 M hydrogen chloride 1,4-dioxane solution (0.18 mL, 0.72 mmol) was slowly added and stirred at room temperature for 18 h. After completion of the reaction, ethyl acetate (15 mL) was added to the solution, and the solution was cooled to 0°C. The resulting solid was filtered under reduced pressure to obtain the target compound (36.7 mg, yield: 58%).

[0283] LC / MS (ESI, m / z): [M+H] + = 403.0.

[0284]

[0285] Step 4) Preparation of (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-methoxyphenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0286]

[0287] (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-methoxyphenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (15.0 mg, 0.034 mmol), 5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (13.9 mg, 0.068 mmol), and HATU (32.5 mg, 0.085 mmol) were added to DMF (0.15 mL), stirred, and DIPEA (0.030 mL, 0.17 mmol) was added. The mixture was stirred at room temperature for 22 h. After completion of the reaction, distilled water (5 mL) was added and extracted with ethyl acetate (20 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (8.7 mg, yield: 43%).

[0288] 1H NMR (500 MHz, DMSO-d6) δ 12.43 (s, 1H), 7.69 (s, 1H), 7.46 (s, 1H), 7.08 (s, 1H), 6.94 (s, 1H), 6.47 (s, 1H), 6.42 (s, 1H), 5.02-5.00 (m, 1H), 4.48-4.47 (m, 1H), 4.37-4.35 (m, 1H), 3.78 (s, 3H), 3.72-7.70 (m, 2H), 3.64-3.62 (d, 2H), 3.57 (s, 3H), 2.60-2.58 (m, 1H), 2.42 (s, 3H), 2.30-2.26 (m, 3H), 1.18-1.17 (d, 6H).

[0289] LC / MS (ESI, m / z): [M+H] + = 587.9.

[0290]

[0291] Example 14: Preparation of (S)-N-(4-(3-(2,6-dimethylpyridin-4-yl)-5-methoxyphenyl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0292]

[0293] (S)-N-(4-(3-Bromo-5-methoxyphenyl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide (50.0 mg, 0.093 mmol), (2,6-dimethylpyridin-4-yl)boronic acid (28.0 mg, 0.19 mmol), and Pd(t-Bu3P)2 (4.7 mg, 0.0093 mmol) were added to 1,4-dioxane (1.0 mL) and distilled water (0.1 mL), stirred, and DIPEA (0.08 mL, 0.46 mmol) was added. The mixture was stirred at 95°C for 5 hours. After the reaction was completed, the solution was cooled to room temperature, distilled water (5 mL) was added, and extracted with ethyl acetate (20 mL). The extracted organic layer was dried with anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (7.1 mg, yield: 14%).

[0294] 1 H NMR (500 MHz, DMSO-d6) δ 12.50 (s, 1H), 7.89-7.87 (m, 2H), 7.65 (s, 1H), 7.55 (s, 1H), 7.43 (s, 2H), 7.35 (s, 1H), 7.25 (s, 1H), 6.66 (s, 1H), 5.07-5.04 (m, 1H), 4.53-4.50 (m, 1H), 4.41-4.38 (m, 1H), 3.90 (s, 3H), 3.62 (s, 3H), 2.64-2.59 (m, 1H), 2.34-2.30 (m, 1H)

[0295]

[0296] Example 15: Preparation of (S)-N-(4-(3-(2-ethyl-6-methylpyridin-4-yl)-5-methoxyphenyl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0297]

[0298] (S)-N-(4-(3-bromophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide (50 mg, 0.093 mmol), (2-ethyl-6-methylpyridin-4-yl)boronic acid (30.6 mg, 0.19 mmol), and Pd(t-Bu3P)2 (4.7 mg, 0.0093 mmol) were added to 1,4-dioxane (1.0 mL) and distilled water (0.1 mL), stirred, and DIPEA (0.08 mL, 0.46 mmol) was added. The mixture was stirred at 95°C for 5 hours. After the reaction was completed, the solution was cooled to room temperature, distilled water (5 mL) was added, and extracted with ethyl acetate (20 mL). The extracted organic layer was dried with anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (2.5 mg, yield: 5%).

[0299] 1 H NMR (500 MHz, DMSO-d6) δ 12.50 (s, 1H), 7.89-7.86 (m, 2H), 7.65 (s, 1H), 7.55 (s, 1H), 7.44-7.42 (d, 2H), 7.34 (s, 1H), 7.26 (s, 1H), 6.66 (s, 1H), 5.08-5.01 (m, 1H), 4.53-4.51 (m, 1H), 4.43-4.39 (m, 1H), 3.90 (s, 3H), 3.62 (s, 3H), 2.81-2.76 (q, 2H), 2.62-2.58 (m, 1H), 2.36-2.31 (m, 1H), 1.29-1.26 (t, 3H)

[0300]

[0301] Example 16: Preparation of (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0302]

[0303] (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-fluorophenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (42.1 mg, 0.10 mmol), 5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (21.1 mg, 0.10 mmol), and HATU (44.9 mg, 0.12 mmol) were added to DMF (1.0 mL), stirred, and DIPEA (0.052 mL, 0.30 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, distilled water (5 mL) was added and extracted with ethyl acetate (20 mL). The extracted organic layer was dried with anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (32.5 mg, yield: 57%).

[0304] 1 H NMR (500 MHz, DMSO-d6) δ 12.55 (s, 1H), 7.67 (s, 1H), 7.53-7.46 (m, 3H), 7.22-7.18 (m, 1H), 6.41 (s, 1H), 5.03 (m, 1H), 4.48-4.47 (m, 1H), 4.37-4.36 (m, 1H), 3.79-3.77 (m, 2H), 3.57 (s, 3H), 3.30-3.29 (m, 2H), 2.66 (m, 1H), 2.42-2.37 (m, 2H), 2.30 (m, 1H), 1.17 (m, 6H)

[0305]

[0306] Example 17: Preparation of (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-methylphenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0307]

[0308] Step 1) Preparation of tert-butyl (S)-2-((4-(3-bromo-4-methylphenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0309]

[0310] 4-(3-Bromo-4-methylphenyl)thiazol-2-amine (300.0 mg, 1.11 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (336.0 mg, 1.67 mmol), and HATU (1060.0 mg, 2.79 mmol) were added to DMF (3 mL), stirred, and DIPEA (0.78 mL, 4.46 mmol) was added, followed by stirring at room temperature for 17 h. After completion of the reaction, distilled water (20 mL) was added and extracted with ethyl acetate (50 mL x 2). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (326.0 mg, yield: 65%).

[0311] LC / MS (ESI, m / z): [M+H] + = 451.9, 453.8.

[0312]

[0313] Step 2) Preparation of tert-butyl (S)-2-((4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-methylphenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0314]

[0315] Tert-Butyl (S)-2-((4-(3-bromo-4-methylphenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (295.9 mg, 0.65 mmol) was dissolved in 1,4-dioxane (3 mL), and (2S,6R)-2,6-dimethylmorpholine (0.24 mL, 1.96 mmol), Pd2(dba)3 (59.9 mg, 0.065 mmol), XPhos (62.4 mg, 0.13 mmol), and t-butoxysodium (118.6 mg, 1.96 mmol) were added and stirred at 100°C for 30 min. The reaction solution was then cooled to room temperature, distilled water (20 mL) was added, and extracted with ethyl acetate (50 mL x 2). The extracted organic layer was dried with anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (293.0 mg, yield: 92%).

[0316] LC / MS (ESI, m / z): [M+H] + = 487.1.

[0317]

[0318] Step 3) Preparation of (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-methylphenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride

[0319]

[0320] Tert-Butyl (S)-2-((4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-methylphenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (293.0 mg, 0.60 mmol) was dissolved in ethyl acetate (15 mL), and 4 M hydrogen chloride 1,4-dioxane solution (0.75 mL, 3.01 mmol) was slowly added, followed by stirring at room temperature for 25 h. After completion of the reaction, ethyl acetate (30 mL) was added to the solution, and the solution was cooled to 0°C. The resulting solid was filtered under reduced pressure to obtain the target compound (124.3 mg, yield: 49%).

[0321] LC / MS (ESI, m / z): [M+H] + = 387.1.

[0322]

[0323] Step 4) Preparation of (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-methylphenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0324]

[0325] (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-methylphenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (30.0 mg, 0.071 mmol), 5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (21.6 mg, 0.11 mmol), and HATU (53.9 mg, 0.14 mmol) were added to DMF (0.3 mL), stirred, and DIPEA (0.062 mL, 0.35 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, distilled water (5 mL) was added and extracted with ethyl acetate (20 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (12.3 mg, yield: 30%).

[0326] 1H NMR (500 MHz, DMSO-d6) δ 12.43 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 7.51-7.50 (d, 1H), 7.46 (s, 1H), 7.23-7.21 (d, 1H), 6.42 (s, 1H), 5.03-5.01 (m, 1H), 4.49-4.47 (m, 1H), 4.37-4.35 (m, 1H), 3.77-3.75 (m, 2H), 3.57 (s, 3H), 3.01-2.99 (d, 2H), 2.60-2.58 (m, 1H), 2.42 (s, 3H), 2.38-2.33 (m, 3H), 2.28 (s, 3H), 1.15-1.13 (d, 6H).

[0327] LC / MS (ESI, m / z): [M+H] + = 572.0.

[0328]

[0329] Example 18: Preparation of (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-methylphenyl)thiazol-2-yl)-1-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0330]

[0331] (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-methylphenyl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (30.0 mg, 0.071 mmol), 5-(methyl-d3)-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (21.9 mg, 0.11 mmol), and HATU (53.9 mg, 0.14 mmol) were added to DMF (0.3 mL), stirred, and DIPEA (0.062 mL, 0.35 mmol) was added. The mixture was stirred at room temperature for 16 h. After completion of the reaction, distilled water (5 mL) was added and extracted with ethyl acetate (20 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (13.0 mg, yield: 32%).

[0332] 1 H NMR (500 MHz, DMSO-d6) δ 12.43 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 7.51-7.49 (d, 1H), 7.46 (s, 1H), 7.22-7.21 (d, 1H), 6.42 (s, 1H), 5.03-5.01 (m, 1H), 4.49-4.47 (m, 1H), 4.37-4.35 (m, 1H), 3.78-3.75 (m, 2H), 3.57 (s, 3H), 3.01-2.99 (d, 2H), 2.60-2.59 (m, 1H), 2.38-2.33 (m, 3H), 3.27 (s, 3H), 1.14-1.13 (d, 6H).

[0333] LC / MS (ESI, m / z): [M+H] + = 575.0.

[0334]

[0335] Example 19: Preparation of (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-2-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0336]

[0337] Step 1) Preparation of 2-bromo-1-(3-bromo-2-fluorophenyl)ethan-1-one

[0338]

[0339] 1-(3-Bromo-2-fluoro)ethanone (2 g, 9.2 mmol) and cupric bromide (3.08 g, 13.8 mmol) were added to a mixed solvent of methylene chloride / ethyl acetate (1:1, 20 mL) and stirred at 80°C for 12 h. After cooling the reaction mixture to room temperature, the solid was filtered, and the filtrate was concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (2.3 g, yield: 76%), which was used directly in the next reaction.

[0340]

[0341] Step 2) Preparation of 4-(3-bromo-2-fluorophenyl)thiazol-2-amine

[0342]

[0343] 2-Bromo-1-(3-bromo-2-fluorophenyl)ethan-1-one (2.3 g, 7.8 mmol) and thiourea (710 mg, 9.3 mmol) were added to ethanol (20 mL), and the mixture was stirred at room temperature for 1 hour under nitrogen gas. The reaction mixture was concentrated and separated by column chromatography to obtain the target compound (1.8 g, yield: 86%).

[0344] 1 H NMR (400 MHz, DMSO-d6) δ 7.84 - 7.80 (m, 1H), 7.76 - 7.72 (m, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H).

[0345]

[0346] Step 3) Preparation of tert-butyl (S)-2-((4-(3-bromo-2-fluorophenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0347]

[0348] 4-(3-Bromo-2-fluorophenyl)thiazol-2-amine (600 mg, 2.19 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (533 mg, 2.64 mmol), TCFH (924 mg, 3.29 mmol), and N-methylimidazole (541 mg, 6.59 mmol) were dissolved in DMF (5 mL) and stirred at room temperature under nitrogen for 2 h. The reaction mixture was concentrated and separated by column chromatography to obtain the target compound (250 mg, yield: 41%).

[0349] 1 H NMR (400 MHz, CDCl3) δ 10.99 (s, 1H), 8.08 (t, J = 7.2 Hz, 1H), 7.48 (s, 1H), 7.10 (s, 1H), 4.91 (t, J = 8.0 Hz, 1H), 4.02 - 3.84 (m, 2H), 2.63 - 2.53 (m, 2H), 1.53 (s, 9H).

[0350]

[0351] Step 4) Preparation of tert-butyl (S)-2-((4-(3-((2S,6R)-2,6-dimethylmorpholino)-2-fluorophenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0352]

[0353] Tert-Butyl (S)-2-((4-(3-bromo-2-fluorophenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (500 mg, 1.09 mmol), (2R,6S)-2,6-dimethylmorpholine (188 mg, 1.64 mmol), Pd-PEPPSI-IPent (45 mg, 0.05 mmol), and cesium carbonate (1068 mg, 3.28 mmol) were added to 1,4-dioxane (10 mL), and the mixture was reacted in a microwave reactor at 120°C for 2 h. The reaction mixture was concentrated and separated by column chromatography to obtain the target compound (250 mg, yield: 41%).

[0354] 1 H NMR (400 MHz, CDCl3) δ 10.88 (s, 1H), 7.83 (s, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.17 (t, J = 7.6 Hz, 2H), 4.91-4.90 (m, 1H), 4.14-4.02 (m, 3H), 3.89-3.86 (m, 1H), 3.35-3.31 (m, 1H), 2.62-2.58 (m, 4H), 1.53 (s, 9H), 1.25 (d, J = 6.4 Hz, 6H).

[0355]

[0356] Step 5) Preparation of (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-2-fluorophenyl)thiazol-2-yl)azetidine-2-carboxamide

[0357]

[0358] Tert-Butyl (S)-2-((4-(3-((2S,6R)-2,6-dimethylmorpholino)-2-fluorophenyl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (100 mg, 0.20 mmol) was dissolved in 4 M hydrogen chloride 1,4-dioxane (5 mL) and stirred at room temperature for 2 h. The solvent was removed by vacuum concentration to obtain the target compound (80 mg), which was used in the next reaction without further purification.

[0359]

[0360] Step 6) Preparation of S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-2-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0361]

[0362] (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-2-fluorophenyl)thiazol-2-yl)azetidine-2-carboxamide (80 mg, 0.20 mmol), 1-methylsulfonyl-5-methylpyrrole-3-carboxylic acid (49 mg, 0.24 mmol), TCFH (86 mg, 0.30 mmol), and N-methylimidazole (50 mg, 0.60 mmol) were dissolved in DMF (2 mL) and stirred at room temperature for 1 h. The reaction mixture was diluted with distilled water (20 mL) and ethyl acetate (30 mL x 3), and the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to obtain the target compound (47.64 mg, yield: 36%).

[0363] 1 H NMR (400 MHz, CDCl3) δ 11.33 (s, 1H), 7.77 (t, J = 6.8 Hz, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 7.10 (t, J = 8.0 Hz, 1H), 6.89 (t, J = 7.6 Hz, 1H), 6.40 (s, 1H), 5.30-5.29 (m, 1H), 4.39-4.38 (m, 2H), 3.91 (s, 2H), 3.29-3.28 (m, 2H), 3.20 (s, 3H), 2.95 (s, 1H), 2.62 (s, 1H), 2.50-2.48 (m, 5H), 1.24 (d, J = 5.2 Hz, 6H).

[0364]

[0365] Example 20: Preparation of (S)-N-(4-(2-((2S,6R)-2,6-dimethylmorpholino)pyridin-4-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0366]

[0367] Step 1) Preparation of 2-bromo-1-(2-chloropyridin-4-yl)ethan-1-one

[0368]

[0369] 1-(2-Chloropyridin-4-yl)ethan-1-one (3 g, 19.3 mmol) was added to acetic acid (30 mL), and then bromine (3.7 g, 23.2 mmol) and bromic acid / acetic acid (1:1, 2.4 mL) were added at room temperature. The reaction mixture was stirred at 45°C for 2 h and then cooled to room temperature. The solid produced during the reaction was filtered and washed with ethanol (10 mL) to obtain the target compound (2.4 g, yield: 53%), which was used in the next reaction without further purification.

[0370] 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 4.8 Hz, 1H), 8.01 (s, 1H), 7.88-7.86 (m, 1H), 5.04 (s, 2H).

[0371]

[0372] Step 2) Preparation of 4-(2-chloropyridin-4-yl)thiazol-2-amine

[0373]

[0374] 2-Bromo-1-(2-chloropyridin-4-yl)ethan-1-one (4 g, 17.1 mmol) and thiourea (1.3 g, 17.1 mmol) were added to ethanol (40 mL) and stirred at room temperature for 2 hours. The solid produced during the reaction was filtered and washed with ethanol (10 mL) to obtain the target compound (2.4 g, yield: 66%), which was used in the next reaction without further purification.

[0375] 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.81 (s, 1H), 7.75 (s, 1H), 7.56 (s, 1H), 7.27 (s, 2H).

[0376]

[0377] Step 3) Preparation of tert-butyl (S)-2-((4-(2-chloropyridin-4-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0378]

[0379] 4-(2-Chloropyridin-4-yl)thiazol-2-amine (1 g, 4.7 mmol), N-methylimidazole (0.77 g, 9.4 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (1.04 g, 5.2 mmol), and TCFH (2.64 g, 9.4 mmol) were added to DMF (20 mL) and stirred at room temperature for 2 h. After the reaction was completed, distilled water (20 mL) was added and extracted with ethyl acetate (20 mL x 3). The extracted organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (1.3 g, yield: 70%).

[0380] 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 4.8 Hz, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.66 (m, 1H), 7.43 (s, 1H), 5.00 - 4.86 (m, 1H), 4.02 (m, 1H), 3.87 (m, 1H), 2.63 - 2.45 (m, 2H), 1.54 (s, 9H).

[0381]

[0382] Step 4) Preparation of tert-butyl (S)-2-((4-(2-((2S,6R)-2,6-dimethylmorpholino)pyridin-4-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0383]

[0384] Tert-Butyl (S)-2-((4-(2-chloropyridin-4-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (300 mg, 0.76 mmol), (2R,6S)-2,6-dimethylmorpholine (262 mg, 2.28 mmol), Pd-PEPPSI-IPENT (128 mg, 0.15 mmol), and cesium carbonate (741 mg, 2.28 mmol) were added to 1,4-dioxane (5 mL) and reacted in a microwave reactor under nitrogen at 120°C for 2 hours. The reaction mixture was filtered to remove solid residue, and the filtrate was concentrated and separated by column chromatography to obtain the target compound (0.281 g, yield: 70.07%).

[0385] 1 H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 5.6 Hz, 1H), 7.33 (s, 1H), 7.19 (s, 1H), 7.03-7.02 (m, 1H), 4.91 (t, J = 8.4 Hz, 1H), 4.16 (d, J = 7.2 Hz, 2H), 3.81-3.80 (m, 4H), 3.45-3.44 (m, 1H), 2.60-2.47 (m, 4H), 1.54 (s, 9H), 1.27-1.26 (m, 6H).

[0386]

[0387] Step 5) Preparation of (S)-N-(4-(2-((2S,6R)-2,6-dimethylmorpholino)pyridin-4-yl)thiazol-2-yl)azetidine-2-carboxamide

[0388]

[0389] Tert-Butyl (S)-2-((4-(2-((2S,6R)-2,6-dimethylmorpholino)pyridin-4-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (280 mg, 0.59 mmol) was added to a 4 M hydrogen chloride 1,4-dioxane solution (5 mL), stirred at room temperature for 1 h, and concentrated to obtain the target compound (200 mg, yield: 80%), which was used in the next reaction without further purification.

[0390]

[0391] Step 6) Preparation of (S)-N-(4-(2-((2S,6R)-2,6-dimethylmorpholino)pyridin-4-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0392]

[0393] (S)-N-(4-(2-((2S,6R)-2,6-dimethylmorpholino)pyridin-4-yl)thiazol-2-yl)azetidine-2-carboxamide (100 mg, 0.27 mmol), 1-methylsulfonylpyrrole-3-carboxylic acid (61 mg, 0.32 mmol), TCFH (151 mg, 0.54 mmol), and N-methylimidazole (66 mg, 0.81 mmol) were added to DMF and stirred at room temperature for 2 hours. After the reaction was completed, distilled water (20 mL) was added and extracted with ethyl acetate (20 mL x 3). The extracted organic layer was dried with anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (44.02 mg, yield: 33.94%).

[0394] 1 H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.15 (d, J = 5.2 Hz, 1H), 7.95 (s, 1H), 7.64 (s, 1H), 7.34 (s, 1H), 7.27 (s, 1H), 7.16 (d, J = 4.4 Hz, 1H), 6.65 (s, 1H), 5.04 (s, 1H), 4.52-4.40 (m, 2H), 4.16 (d, J = 12.4 Hz, 2H), 3.61-3.60 (m, 4H), 3.32 (s, 3H), 2.43-2.42 (m, 2H), 1.18 (d, J = 6.0 Hz, 6H).

[0395]

[0396] Example 21: Preparation of (S)-N-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0397]

[0398] Step 1) Preparation of tert-butyl (S)-2-((4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0399]

[0400] Tert-Butyl (S)-2-((4-(2-chloropyridin-4-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (200 mg, 0.50 mmol), 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (141 mg, 0.60 mmol), Pd(dppf)Cl2 (19 mg, 0.025 mmol), and potassium carbonate (209 mg, 1.50 mmol) were added to 1,4-dioxane / distilled water (10:1, 5 mL) and stirred at 90°C for 2 h. After completion of the reaction, distilled water (20 mL) was added and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dried with anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (140 mg, yield: 56%).

[0401] 1 H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 8.76 (d, J = 5.2 Hz, 1H), 8.47 (s, 1H), 8.24 (s, 1H), 7.91 (d, J = 4.8 Hz, 1H), 7.76 (s, 1H), 4.85 - 4.81 (m, 1H), 4.03 - 4.02 (m, 1H), 2.68 (s, 1H), 2.53 (s, 6H), 2.15 (s, 1H), 1.99 (s, 1H), 1.26 (s, 9H).

[0402]

[0403] Step 2) Preparation of (S)-N-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)azetidine-2-carboxamide

[0404]

[0405] Tert-Butyl (S)-2-((4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (140 mg, 0.30 mmol) was added to 4 M hydrogen chloride 1,4-dioxane (5 mL), stirred at room temperature for 1 h, concentrated, washed with petroleum ether (10 mL), and dried to obtain the target compound (100 mg, yield: 87%), which was used in the next reaction without further purification.

[0406] 1 H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 9.81 (s, 1H), 9.17 (s, 1H), 8.91 (d, J = 4.8 Hz, 1H), 8.79 (s, 1H), 8.50 (s, 2H), 8.43 (s, 1H), 8.05 (d, J = 4.8 Hz, 1H), 5.24 (s, 1H), 4.03 - 4.01 (m, 1H), 3.85 (s, 1H), 3.56 (s, 1H), 2.83 (s, 6H).

[0407]

[0408] Step 3) Preparation of (S)-N-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0409]

[0410] (S)-N-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)azetidine-2-carboxamide (100 mg, 0.27 mmol), 1-methylsulfonylpyrrole-3-carboxylic acid (62 mg, 0.32 mmol), TCFH (153 mg, 0.54 mmol), and N-methylimidazole (66 mg, 0.81 mmol) were added to DMF (5 mL) and stirred at room temperature for 2 hours. After the reaction was completed, distilled water (20 mL) was added and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dried with anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (55.56 mg, yield: 37%).

[0411] 1 H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 8.77 (d, J = 4.8 Hz, 1H), 8.50 (s, 1H), 8.13 (s, 1H), 7.93 (d, J = 4.4 Hz, 1H), 7.83 (s, 2H), 7.65 (s, 1H), 7.34 (s, 1H), 6.66 (s, 1H), 5.06 (s, 1H), 4.53 - 4.51 (m, 1H), 4.41 - 4. (m, 1H), 3.61 (s, 3H), 2.55 (s, 6H), 2.32 (s, 2H).

[0412]

[0413] Example 22: Preparation of (S)-N-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)-1-(1,1-dioxido-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carbonyl)pyrrolidine-2-carboxamide

[0414]

[0415] Step 1) Preparation of tert-butyl (S)-2-((4-(2-chloropyridin-4-yl)thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate

[0416]

[0417] 4-(2-Chloropyridin-4-yl)thiazol-2-amine (100 mg, 0.47 mmol), N-methylimidazole (116 mg, 1.42 mmol), (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (153 mg, 0.71 mmol), and TCFH (198 mg, 0.71 mmol) were added to DMF (5 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (120 mg, yield: 55%).

[0418] 1 H NMR (400 MHz, CDCl3) δ 11.01 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.80 (s, 1H), 7.65 (d, J = 4.8 Hz, 1H), 7.41 (s, 1H), 4.59-4.58 (m, 1H), 3.47-3.45(m, 2H), 3.18-3.17 (m, 1H), 2.54-2.53 (m, 1H), 1.97 (d, J = 5.6 Hz, 2H), 1.52 (s, 9H).

[0419]

[0420] Step 2) Preparation of tert-butyl (S)-2-((4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate

[0421]

[0422] Tert-Butyl (S)-2-((4-(2-chloropyridin-4-yl)thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate (120 mg, 0.29 mmol), 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (82 mg, 0.35 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), and potassium carbonate (122 mg, 0.87 mmol) were added to 1,4-dioxane / distilled water (10:1, 5 mL) and stirred at 90°C for 4 h. After completion of the reaction, distilled water (20 mL) was added and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dehydrated with anhydrous sodium sulfate and then filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (110 mg, yield: 70%).

[0423] 1 H NMR (400 MHz, CDCl3) δ 10.88 (s, 1H), 8.75 (d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 7.72 (s, 3H), 7.46 (s, 1H), 4.60-4.59 (m, 1H), 2.73-2.70 (m, 6H), 2.00-1.99 (m, 3H), 1.53 (s, 12H).

[0424]

[0425] Step 3) Preparation of (S)-N-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)pyrrolidine-2-carboxamide

[0426]

[0427] Tert-Butyl (S)-2-((4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate (100 mg, 0.21 mmol) was added to a 4 M hydrogen chloride solution in 1,4-dioxane (5 mL), stirred at room temperature for 1 h, concentrated, washed with petroleum ether (10 mL), and dried to obtain the target compound (100 mg, yield: 87%), which was used in the next reaction without further purification.

[0428]

[0429] Step 4) Preparation of (S)-N-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)-1-(1,1-dioxido-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carbonyl)pyrrolidine-2-carboxamide

[0430]

[0431] (S)-N-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)pyrrolidine-2-carboxamide (90 mg, 0.24 mmol), 2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1,1-dioxide (69 mg, 0.28 mmol), TCFH (133 mg, 0.48 mmol), and N-methylimidazole (59 mg, 0.72 mmol) were added to DMF (5 mL) and stirred at room temperature for 1 h. After completion of the reaction, distilled water (20 mL) was added and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (60.39 mg, yield: 41%).

[0432] 1H NMR (400 MHz, DMSO-d6) δ 12.69 (s, 1H), 8.80 (d, J = 4.4 Hz, 1H), 8.57 (s, 1H), 8.23 ​​(s, 1H), 8.15 (s, 1H), 7.97-7.91 (m, 4H), 7.69 (d, J = 7.6 Hz, 1H), 4.96 (s, 2H), 4.73 (d, J = 6.0 Hz, 1H), 4.22-4.21 (m, 2H), 3.69-3.68 (m, 3H), 3.56 (s, 1H), 2.61 (s, 6H), 2.35-2.34 (m, 1H), 1.97-1.90 (m, 3H).

[0433]

[0434] Example 23: Preparation of (S)-N-(4-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0435]

[0436] Step 1) Preparation of 2-bromo-1-(2-chloropyrimidin-4-yl)ethan-1-one

[0437]

[0438] 1-(2-Chloropyrimidin-4-yl)ethanone (2.5 g, 16 mmol) was added to acetic acid (20 mL), and bromine (3.07 g, 19.2 mmol) and hydrogen bromide-acetic acid solution (1.94 g, 24 mmol) were sequentially added thereto under nitrogen, followed by stirring. The reaction mixture was stirred at room temperature for 3 h, then distilled water (20 mL) was added and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure to obtain the target compound (1.3 g, yield: 33%), which was used in the next reaction without further purification.

[0439]

[0440] Step 2) Preparation of 4-(2-chloropyrimidin-4-yl)thiazol-2-amine

[0441]

[0442] 2-Bromo-1-(2-chloropyrimidin-4-yl)ethan-1-one (1.3 g, 5.5 mmol) was added to ethanol (10 mL), and then thiourea (0.50 g, 6.6 mmol) was added under nitrogen. The reaction mixture was stirred at room temperature for 16 h, then distilled water (10 mL) was added, and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (0.6 g, yield: 45%).

[0443] 1 H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 5.2 Hz, 1H), 7.75 (d, J = 5.2 Hz, 1H), 7.66 (s, 1H), 7.34 (s, 2H).

[0444]

[0445] Step 3) Preparation of tert-butyl (S)-2-((4-(2-chloropyrimidin-4-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0446]

[0447] 4-(2-Chloropyrimidin-4-yl)thiazol-2-amine (500 mg, 2.35 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (571 mg, 2.82 mmol), TCFH (1320 mg, 4.70 mmol), and N-methylimidazole (579 mg, 7.05 mmol) were added to DMF (10 mL) and stirred at room temperature for 2 h. Distilled water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (300 mg, yield: 31%).

[0448] 1 H NMR (400 MHz, CDCl3) δ 11.05 (s, 1H), 8.67 (s, 1H), 8.07 (s, 1H), 7.88 (s, 1H), 4.94 (s, 1H), 4.01 (s, 1H), 3.90-3.84 (m, 1H), 2.67 (s, 1H), 2.53 (s, 1H), 1.54 (s, 9H).

[0449]

[0450] Step 4) Preparation of tert-butyl (S)-2-((4-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0451]

[0452] Tert-Butyl (S)-2-((4-(2-chloropyrimidin-4-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (300 mg, 0.76 mmol), (2R,6S)-2,6-dimethylmorpholine (105 mg, 0.91 mmol), Pd-PEPPSI-IPent (32 mg, 0.038 mmol), and cesium carbonate (739 mg, 2.27 mmol) were added to 1,4-dioxane (10 mL) and reacted in a microwave reactor at 120 °C for 2 h. Distilled water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (200 mg, yield: 53%).

[0453] 1 H NMR (400 MHz, CDCl3) δ 10.98 (s, 1H), 8.41 (d, J = 5.2 Hz, 1H), 7.92 (s, 1H), 7.45 (s, 1H), 4.91 (s, 1H), 4.69 (s, 2H), 4.00 (s, 1H), 3.87-3.85 (m, 1H), 3.69 (s, 2H), 2.67 (s, 3H), 2.53 (s, 1H), 1.54 (s, 9H), 1.29 (d, J = 6.4 Hz, 6H).

[0454]

[0455] Step 5) Preparation of (S)-N-(4-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)thiazol-2-yl)azetidine-2-carboxamide

[0456]

[0457] Tert-Butyl (S)-2-((4-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (180 mg, 0.38 mmol) was added to a 4 M hydrogen chloride solution in 1,4-dioxane (5 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated and washed with petroleum ether to obtain the target compound (100 mg, yield: 67%).

[0458] 1 H NMR (400 MHz, DMSO-d6) δ 12.91 (s, 1H), 9.64 (s, 1H), 9.12 (s, 1H), 8.48 (d, J = 5.2 Hz, 1H), 8.22 (s, 1H), 7.11 (d, J = 5.2 Hz, 1H), 5.20-5.17 (m, 2H), 4.60 (s, 2H), 4.01 (s, 1H), 3.84 (s, 1H), 3.61-3.56 (m, 2H), 2.59-2.56 (m, 2H), 1.18 (d, J = 6.4 Hz, 6H).

[0459]

[0460] Step 6) Preparation of S)-N-(4-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0461]

[0462] (S)-N-(4-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)thiazol-2-yl)azetidine-2-carboxamide (100 mg, 0.27 mmol), 1-methylsulfonylpyrrole-3-carboxylic acid (61 mg, 0.32 mmol), TCFH (153 mg, 0.54 mmol), and N-methylimidazole (66 mg, 0.81 mmol) were added to DMF (5 mL) and stirred at room temperature for 2 h. Distilled water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (30.66 mg, yield: 20.18%).

[0463] 1 H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 8.44-8.36 (m, 1H), 8.00-7.69 (m, 1H), 7.62-7.59 (m, 1H), 7.33-7.12 (m, 2H), 6.64-6.52 (m, 1H), 5.00-4.95 (m, 1H), 4.62-4.59 (m, 2H), 4.50-4.35 (m, 1H), 4.04-3.91 (m, 1H), 3.63-3.54 (m, 4H), 3.38-3.33 (m, 3H), 2.59-2.56 (m, 1H), 2.24-2.10 (m, 1H), 1.17 (d, J = 6.4 Hz, 6H).

[0464]

[0465] Example 24: Preparation of (S)-N-(4-(5-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0466]

[0467] (S)-N-(4-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-3-yl)thiazol-2-yl)azetidine-2-carboxamide (37.4 mg, 0.09 mmol), 1-methylsulfonylpyrrole-3-carboxylic acid (18.1 mg, 0.10 mmol), HATU (41.5 mg, 0.11 mmol), and DIPEA (0.05 mL, 0.27 mmol) were added to DMF (2 mL) and stirred at room temperature for 2 h. Distilled water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (16.9 mg, yield: 34.1%).

[0468] 1 H NMR (500 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.55 (s, 1H), 8.30-8.29 (m, 1H), 7.85(s, 1H), 7.72-7.65(m, 2H), 7.35(s, 1H), 6.66(s, 1H), 5.06-5.04 (m, 1H), 4.53-4.50 (m, 1H), 4.42-4.30 (m, 1H), 3.76-3.71(m, 4H), 3.62(s, 3H), 2.62-2.57(m, 1H), 2.38-2.35(m, 2H), 1.18(m, 6H)

[0469]

[0470] Example 25: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)pyrazin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0471]

[0472] Step 1) Preparation of 2-chloro-6-(1-ethoxyvinyl)pyrazine

[0473]

[0474] 2,6-Dichloropyrazine (10 g, 67.1 mmol), tributyl(1-ethoxyvinyl)tin (29.08 g, 80.52 mmol), and Pd(PPh3)4 (3.88 g, 3.35 mmol) were added to 1,4-dioxane (50 mL) and stirred at 100°C for 4 hours under nitrogen. Distilled water (100 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL x 3). The extracted organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered solution was concentrated under reduced pressure to obtain the target compound (10 g, yield: 49%), which was used in the next reaction without further purification.

[0475]

[0476] Step 2) Preparation of 1-(6-chloropyrazin-2-yl)ethan-1-one

[0477]

[0478] 2-Chloro-6-(1-ethoxyvinyl)pyrazine (5 g, 27.1 mmol) was added to a 35% hydrochloric acid solution (20 mL) and stirred at room temperature under nitrogen for 1 h. Distilled water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dried with anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (3 g, yield: 68%).

[0479] 1 H NMR (400 MHz, DMSO-d6) δ 9.08 (d, J = 1.6 Hz, 2H), 2.63 (s, 3H).

[0480]

[0481] Step 3) Preparation of 2-bromo-1-(6-chloropyrazin-2-yl)ethan-1-one

[0482]

[0483] 1-(6-Chloropyrazin-2-yl)ethanone (3 g, 19.2 mmol) was added to acetic acid (20 mL), and then bromine (3.68 g, 23.04 mmol) and hydrogen bromide-acetic acid solution (2.33 g, 28.8 mmol) were added with stirring under nitrogen. The reaction mixture was stirred at room temperature for 2 h, then distilled water (50 mL) was added, and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure to obtain the target compound (2.5 g, yield: 47%), which was used in the next reaction without further purification.

[0484]

[0485] Step 4) Preparation of 4-(6-chloropyrazin-2-yl)thiazol-2-amine

[0486]

[0487] 2-Bromo-1-(6-chloropyrazin-2-yl)ethan-1-one (2.2 g, 9.3 mmol) was added to ethanol (10 mL), and then thiourea (0.85 g, 11.16 mmol) was added under nitrogen. The reaction mixture was stirred at room temperature for 16 h, then distilled water (50 mL) was added, and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (1.5 g, yield: 68%). It was used in the next reaction without further purification.

[0488]

[0489] Step 5) Preparation of tert-butyl (S)-2-((4-(6-chloropyrazin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0490]

[0491] 4-(6-Chloropyrazin-2-yl)thiazol-2-amine (300 mg, 1.41 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (342 mg, 1.69 mmol), TCFH (791 mg, 2.82 mmol), and N-methylimidazole (347 mg, 4.23 mmol) were added to DMF (10 mL) and stirred at room temperature for 2 hours. Distilled water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (200 mg, yield: 34%).

[0492] 1 H NMR (400 MHz, DMSO-d6) δ 12.72 - 12.63 (m, 1H), 9.09 (s, 1H), 8.74 (s, 1H), 8.09 (s, 1H), 4.81 (s, 1H), 3.93 - 3.78 (m, 2H), 1.39 (s, 2H), 1.25 (s, 9H).

[0493]

[0494] Step 6) Preparation of tert-butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)pyrazin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0495]

[0496] Tert-Butyl (S)-2-((4-(6-chloropyrazin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (140 mg, 0.35 mmol), (2R,6S)-2,6-dimethylmorpholine (48 mg, 0.42 mmol), Pd-PEPPSI-IPent (14 mg, 0.017 mmol), and cesium carbonate (344 mg, 1.05 mmol) were added to 1,4-dioxane (5 mL) and reacted in a microwave reactor at 120 °C for 2 h. Distilled water (50 mL) was added to the reaction mixture and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dried over anhydrous sodium sulfate and then filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (100 mg, yield: 57%).

[0497] 1 H NMR (400 MHz, DMSO-d6)δ 12.54 (s, 1H), 8.37 (s, 1H), 8.29 (s, 1H), 7.94 (s, 1H), 4.83 - 4.79 (m, 1H), 4.34 - 4.32 (m, 2H), 4.02 - 4.00 (m, 3H), 3.94 - 3.92 (m, 1H), 3.66 - 3.62 (m, 2H), 2.16 - 2.11 (m, 1H), 1.99 (s, 3H), 1.39 (s, 4H), 1.19 - 1.17 (m, 9H).

[0498]

[0499] Step 7) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)pyrazin-2-yl)thiazol-2-yl))azetidine-2-carboxamide

[0500]

[0501] Tert-Butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)pyrazin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (100 mg, 0.21 mmol) was added to a 4 M hydrogen chloride solution in 1,4-dioxane (5 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated and washed with petroleum ether to obtain the target compound (80 mg, yield: 91%).

[0502] 1 H NMR (400 MHz, DMSO-d6)δ 12.93 (s, 1H), 9.85 (s, 1H), 9.14 (s, 1H), 8.35 - 8.31 (m, 2H), 8.01 (s, 1H), 6.40 (s, 4H), 5.22 - 5.18 (m, 1H), 4.35 - 4.32 (m, 2H), 4.03 - 3.97 (m, 1H), 3.85 - 3.84 (m, 1H), 3.67 - 3.63 (m, 1H), 1.19 (d, J = 6.4 Hz, 6H).

[0503]

[0504] Step 8) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)pyrazin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0505]

[0506] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)pyrazin-2-yl)thiazol-2-yl))azetidine-2-carboxamide (80 mg, 0.21 mmol), 1-methylsulfonylpyrrole-3-carboxylic acid (48 mg, 0.25 mmol), TCFH (119 mg, 0.42 mmol), and N-methylimidazole (52 mg, 0.64 mmol) were added to DMF (5 mL) and stirred at room temperature for 2 h. Distilled water (20 mL) was added to the reaction mixture, and extracted with ethyl acetate (30 mL x 3). The extracted organic layer was dried over anhydrous sodium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (23.61 mg, yield: 20.04%).

[0507] 1 H NMR (400 MHz, DMSO-d6): δ 12.56 (s, 1H), 8.38 (s, 1H), 8.29 (s, 1H), 7.94 (s, 1H), 7.64 (s, 1H), 7.34 (s, 1H), 6.65 (s, 1H), 5.04 - 5.02 (m, 1H), 4.54 - 4.50 (m, 1H), 4.46 - 4.40 (m, 1H), 4.35 - 4.32 (m, 2H), 3.64 - 3.61 (m, 6H), 2.54 (s, 3H), 1.18 (d, J = 6.0 Hz, 6H).

[0508]

[0509] Example 26: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0510]

[0511] Step 1) Preparation of 2-chloro-6-(1-ethoxyvinyl)-4-fluoropyridine

[0512]

[0513] 2,6-Dichloro-4-fluoropyridine (4 g, 24.1 mmol), tributyl(1-ethoxyvinyl)tin (6.96 g, 19.2 mmol), and Pd(PPh3)4 (1.39 g, 1.2 mmol) were added to 1,4-dioxane (40 mL) and stirred at 100°C for 4 h under nitrogen. The reaction mixture was diluted with distilled water (50 mL) and extracted with ethyl acetate (30 mL x 3). The separated organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the target compound (4 g, yield: 49%), which was used in the next reaction without further purification.

[0514]

[0515] Step 2) Preparation of 1-(6-chloro-4-fluoropyridin-2-yl)ethan-1-one

[0516]

[0517] 2-Chloro-6-(1-ethoxyvinyl)-4-fluoropyridine (2 g, 9.9 mmol) was added to hydrochloric acid (10 mL) and stirred at room temperature under nitrogen for 2 h. The reaction mixture was diluted with distilled water (30 mL) and extracted with ethyl acetate (30 mL x 3). The separated organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the target compound (1 g, yield: 56%).

[0518] 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 2.61 (d, J = 0.8 Hz, 3H).

[0519]

[0520] Step 3) Preparation of 2-bromo-1-(6-chloro-4-fluoropyridin-2-yl)ethan-1-one

[0521]

[0522] 1-(6-Chloro-4-fluoropyridin-2-yl)ethan-1-one (1 g, 5.8 mmol) was added to acetic acid (10 mL), and then bromine (1.11 g, 6.96 mmol) and hydrogen bromide-acetic acid solution (0.70 g, 8.7 mmol) were added with stirring under nitrogen. The reaction mixture was stirred at room temperature for 2 h, diluted with distilled water (30 mL), and extracted with ethyl acetate (30 mL x 3). The separated organic layer was dried over anhydrous sodium sulfate. The concentrated compound was purified by column chromatography to obtain the target compound (0.8 g, yield: 52%), which was used in the next reaction without further purification.

[0523]

[0524] Step 4) Preparation of 4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-amine

[0525]

[0526] 2-Bromo-1-(6-chloro-4-fluoropyridin-2-yl)ethan-1-one (800 mg, 3.16 mmol) and thiourea (482 mg, 6.32 mmol) were added to ethanol (10 mL) and stirred at room temperature for 16 h. The reaction mixture was diluted with distilled water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the target compound (500 mg, yield: 65%).

[0527] 1 H NMR (400 MHz, DMSO-d6) δ 7.65 - 7.63 (m, 1H), 7.53 - 7.51 (m, 1H), 7.44 (s, 1H), 5.34 (s, 2H).

[0528]

[0529] Step 5) Preparation of tert-butyl (S)-2-((4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0530]

[0531] 4-(6-Chloro-4-fluoropyridin-2-yl)thiazol-2-amine (500 mg, 2.17 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (528 mg, 2.61 mmol), TCFH (1221 mg, 4.34 mmol), and N-methylimidazole (536 mg, 6.51 mmol) were added to DMF (10 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (600 mg, yield: 64%).

[0532] 1 H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 7.99 (s, 1H), 7.68 - 7.66 (m, 1H), 7.59 - 7.57 (m, 1H), 4.83 - 4.79 (m, 1H), 3.93 - 3.78 (m, 2H), 2.14 (s, 1H), 1.99 (s, 1H), 1.24 (s, 9H).

[0533]

[0534] Step 6) Preparation of tert-butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0535]

[0536] Tert-Butyl (S)-2-((4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (600 mg, 1.45 mmol), (2R,6S)-2,6-dimethylmorpholine (334 mg, 2.90 mmol), Pd-PEPPSI-IPent (61 mg, 0.072 mmol), and cesium carbonate (1417 mg, 4.35 mmol) were added to 1,4-dioxane (15 mL) and reacted in a microwave reactor at 120 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with distilled water (30 mL), and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (500 mg, yield: 67%).

[0537] 1 H NMR (400 MHz, DMSO-d6): δ 12.47 (s, 1H), 7.90 (s, 1H), 6.97 - 6.95 (m, 1H), 6.70 - 6.67 (m, 1H), 5.76 (s, 1H), 4.81 - 4.79 (m, 1H), 4.30 - 4.27 (m, 2H), 4.03 - 4.00 (m, 1H), 3.93 - 3.92 (m, 1H), 3.77 (s, 1H), 3.62 - 3.59 (m, 2H), 1.99 (s, 2H), 1.24 (s, 6H), 1.19 - 1.15 (m, 9H).

[0538]

[0539] Step 7) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide

[0540]

[0541] Tert-Butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (400 mg, 0.81 mmol) was added to a 4 M hydrogen chloride solution in 1,4-dioxane (10 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated and washed with petroleum ether to obtain the target compound (220 mg, yield: 67%), which was used in the next reaction without further purification.

[0542] 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 7.96 (s, 1H), 6.97 - 6.94 (m, 1H), 6.72 - 6.69 (m, 1H), 5.24 - 5.16 (m, 1H), 4.30 - 4.27 (m, 2H), 4.00 - 3.97 (m, 1H), 3.83 - 3.76 (m, 1H), 3.63 - 3.58 (m, 2H), 3.56 (s, 1H), 2.75 - 2.71 (m, 1H), 2.64 - 2.59 (m, 1H), 2.49 - 2.43 (m, 2H), 1.18 (d, J = 6.4 Hz, 6H).

[0543]

[0544] Step 8) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0545]

[0546] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide (200 mg, 0.51 mmol), 5-methyl-1-methylsulfonylpyrrole-3-carboxylic acid (125 mg, 0.61 mmol), TCFH (286 mg, 1.02 mmol), and N-methylimidazole (126 mg, 1.53 mmol) were added to DMF (10 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated and separated by column chromatography to obtain the target compound (45.63 mg, yield: 15%).

[0547] 1 H NMR (400 MHz, DMSO-d6) δ 12.46 (s, 1H), 7.90 (s, 1H), 7.45 (s, 1H), 6.98 (d, J = 10.0 Hz, 1H), 6.70 - 6.67 (m, 1H), 6.41 (s, 1H), 5.04 - 5.00 (m, 1H), 4.48 - 4.46 (m, 1H), 4.37 - 4.35 (m, 1H), 4.30 - 4.27 (m, 2H), 3.61 - 3.58 (m, 2H), 3.57 (s, 3H), 2.43 (s, 2H), 2.41 (s, 3H), 2.32 - 2.30 (m, 2H), 1.17 (d, J = 6.0 Hz, 6H).

[0548]

[0549] Example 27: Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methoxy-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide

[0550]

[0551] Step 1) Preparation of tert-butyl (2S,3S)-2-((4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-3-methoxypyrrolidine-1-carboxylate

[0552]

[0553] 4-(6-Chloro-4-fluoropyridin-2-yl)-1,3-thiazol-2-amine (200 mg, 0.87 mmol), (2S,3S)-1-(tert-butoxycarbonyl)-3-methoxy-pyrrolidine-2-carboxylic acid (236 mg, 0.96 mmol), TCFH (489 mg, 1.74 mmol), and N-methylimidazole (215 mg, 2.61 mmol) were added to DMF (3 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (140 mg, yield: 34%).

[0554] 1 H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 7.97 (s, 1H), 7.69 - 7.66 (m, 1H), 7.58 - 7.56 (m, 1H), 4.47 - 4.39 (m, 1H), 4.04 - 3.99 (m, 1H), 3.48 - 3.47 (m, 2H), 3.25 (s, 3H), 2.36 - 2.32 (m, 1H), 2.02 - 1.95 (m, 1H), 1.23 (s, 9H).

[0555]

[0556] Step 2) Preparation of tert-butyl (2S,3S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-3-methoxypyrrolidine-1-carboxylate

[0557]

[0558] Tert-Butyl (2S,3S)-2-((4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-3-methoxypyrrolidine-1-carboxylate (140 mg, 0.31 mmol), (2R,6S)-2,6-dimethylmorpholine (43 mg, 0.36 mmol), Pd-PEPPSI-IPent (25 mg, 0.03 mmol), and cesium carbonate (299 mg, 0.93 mmol) were added to 1,4-dioxane (3 mL) and reacted at 100°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with distilled water (20 mL), and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (100 mg, yield: 58%), which was used in the next reaction without further purification.

[0559]

[0560] Step 3) Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazole-2-)-3-methoxypyrrolidine-2-carboxamide

[0561]

[0562] Tert-Butyl (2S,3S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-3-methoxypyrrolidine-1-carboxylate (100 mg, 0.19 mmol) was added to a 4 M hydrogen chloride solution in 1,4-dioxane (3 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated and washed with petroleum ether to obtain the target compound (60 mg, yield: 70%), which was used in the next reaction without further purification.

[0563] LC / MS (ESI, m / z): [M+H] + = 436.05

[0564]

[0565] Step 4) Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methoxy-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide

[0566]

[0567] (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazole-2-)-3-methoxypyrrolidine-2-carboxamide (45 mg, 0.10 mmol), 1-methylsulfonylpyrrole-5-methyl-3-carboxylic acid (26 mg, 0.12 mmol), TCFH (58 mg, 0.20 mmol), and N-methylimidazole (25 mg, 0.30 mmol) were added to DMF (2 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (24.39 mg, yield: 37%).

[0568] 1 H NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 7.88 (s, 1H), 7.52 (s, 1H), 6.70 (d, J = 2.0 Hz, 1H), 6.67 - 6.66 (m, 1H), 6.47 (s, 1H), 4.78 (s, 1H), 4.30 - 4.27 (m, 2H), 3.98 - 3.93 (m, 2H), 3.82 - 3.78 (m, 1H), 3.62 - 3.58 (m, 2H), 3.55 (s, 3H), 3.38 (s, 3H), 2.46 - 2.43 (m, 2H), 2.40 (s, 3H), 2.20 - 2.10 (m, 2H), 1.18 (d, J = 6.0 Hz, 6H).

[0569]

[0570] Example 28: Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-4-methoxy-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide

[0571]

[0572] Step 1) Preparation of tert-butyl (2S,4R)-2-((4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-4-methoxypyrrolidine-1-carboxylate

[0573]

[0574] 4-(6-Chloro-4-fluoropyridin-2-yl)-1,3-thiazol-2-amine (200 mg, 0.87 mmol), (2S, 3S)-1-(tert-butoxycarbonyl)-4-methoxy-pyrrolidine-2-carboxylic acid (236 mg, 0.96 mmol), TCFH (489 mg, 1.74 mmol), and N-methylimidazole (215 mg, 2.61 mmol) were added to DMF (3 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (140 mg, yield: 34%).

[0575] 1 H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 1H), 7.97 (s, 1H), 7.69 - 7.66 (m, 1H), 7.58 - 7.55 (m, 1H), 4.46 - 4.39 (m, 1H), 4.04 - 3.99 (m, 1H), 3.48 - 3.47 (m, 2H), 3.25 (s, 3H), 2.36 - 2.32 (m, 1H), 2.02 - 1.95 (m, 1H), 1.23 (s, 9H).

[0576]

[0577] Step 2) Preparation of tert-butyl (2S,3S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-4-methoxypyrrolidine-1-carboxylate

[0578]

[0579] Tert-Butyl (2S,3S)-2-((4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-4-methoxypyrrolidine-1-carboxylate (140 mg, 0.31 mmol), (2R,6S)-2,6-dimethylmorpholine (43 mg, 0.36 mmol), Pd-PEPPSI-IPent (25 mg, 0.03 mmol), and cesium carbonate (299 mg, 0.93 mmol) were added to 1,4-dioxane (3 mL) and reacted at 100°C for 2 hours. The reaction mixture was cooled to room temperature, diluted with distilled water (20 mL), and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (100 mg, yield: 58%), which was used in the next reaction without further purification.

[0580] LC / MS (ESI, m / z): [M+H] + = 536.10

[0581]

[0582] Step 3) Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazole-2-)-4-methoxypyrrolidine-2-carboxamide

[0583]

[0584] Tert-Butyl (2S,3S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-4-methoxypyrrolidine-1-carboxylate (100 mg, 0.19 mmol) was added to a 4 M hydrogen chloride solution in 1,4-dioxane (3 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated and washed with petroleum ether to obtain the target compound (60 mg, yield: 70%), which was used in the next reaction without further purification.

[0585] LC / MS (ESI, m / z): [M+H] + = 436.05

[0586]

[0587] Step 4) Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-4-methoxy-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide

[0588]

[0589] (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazole-2-)-4-methoxypyrrolidine-2-carboxamide (60 mg, 0.14 mmol), 1-methylsulfonylpyrrole-5-methyl-3-carboxylic acid (34 mg, 0.17 mmol), TCFH (78 mg, 0.28 mmol), and N-methylimidazole (34 mg, 0.42 mmol) were added to DMF (2 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (31.97 mg, yield: 37%).

[0590] 1H NMR (400 MHz, DMSO-d6) δ 12.41 (s, 1H), 7.86 (s, 1H), 7.51 (d, J = 2.0 Hz, 1H), 6.98 (d, J = 9.2 Hz, 1H), 6.69 - 6.66 (m, 1H), 6.43 (s, 1H), 4.70 - 4.66 (m, 1H), 4.29 - 4.26 (m, 2H), 4.11 (s, 1H), 4.02 - 3.98 (m, 1H), 3.84 - 3.81 (m, 1H), 3.63 - 3.58 (m, 2H), 3.57 (s, 3H), 3.24 (s, 3H), 2.49 - 2.46 (m, 2H), 2.43 (s, 3H), 2.41 - 2.33 (m, 1H), 2.02 - 1.95 (m, 1H), 1.17 (d, J = 6.0 Hz, 6H).

[0591]

[0592] Example 29: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0593]

[0594] Step 1) Preparation of 2-chloro-6-(1-ethoxyvinyl)-3-fluoropyridine

[0595]

[0596] 6-Bromo-2-chloro-3-fluoropyridine (2 g, 9.5 mmol), cuprous iodide (0.36 g, 1.9 mmol), tributyl(1-ethoxyvinyl)tin (4.12 g, 11.4 mmol), and PdCl2(PPh3)2 (1.33 g, 1.9 mmol) were added to 1,4-dioxane (20 mL) and stirred at 80°C for 2 h under nitrogen. The reaction mixture was diluted with distilled water (50 mL) and extracted with ethyl acetate (30 mL x 3). The separated organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the target compound (1.5 g, yield: 75%), which was used in the next reaction without further purification.

[0597]

[0598] Step 2) Preparation of 1-(6-chloro-5-fluoropyridin-2-yl)ethan-1-one

[0599]

[0600] 2-Chloro-6-(1-ethoxyvinyl)-3-fluoropyridine (1.5 g, 7.5 mmol) was added to hydrochloric acid (20 mL) and stirred at room temperature under nitrogen for 2 h. The reaction mixture was diluted with distilled water (30 mL) and extracted with ethyl acetate (30 mL x 3). The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (0.8 g, yield: 60%).

[0601] 1 H NMR (400 MHz, DMSO-d6) δ 7.14 - 8.10 (m, 1H), 8.06 - 8.03 (m, 1H), 2.60 (s, 3H).

[0602]

[0603] Step 3) Preparation of 2-bromo-1-(6-chloro-5-fluoropyridin-2-yl)ethan-1-one

[0604]

[0605] 1-(6-Chloro-5-fluoropyridin-2-yl)ethan-1-one (1.4 g, 8.1 mmol) was added to acetic acid (15 mL), and then bromine (1.55 g, 9.72 mmol) and hydrogen bromide-acetic acid solution (0.98 g, 12.15 mol) were added with stirring under nitrogen. The reaction mixture was stirred at room temperature for 2 h, diluted with distilled water (30 mL), and extracted with ethyl acetate (30 mL x 3). The separated organic layer was dried over anhydrous sodium sulfate. The concentrated compound was purified by column chromatography to obtain the target compound (1.4 g, yield: 72%), which was used in the next reaction without further purification.

[0606]

[0607] Step 4) Preparation of 4-(6-chloro-5-fluoropyridin-2-yl)thiazol-2-amine

[0608]

[0609] 2-Bromo-1-(6-chloro-5-fluoropyridin-2-yl)ethan-1-one (1.3 g, 5.1 mmol) and thiourea (0.78 g, 10.2 mmol) were added to ethanol (15 mL) and stirred at room temperature for 16 h. The reaction mixture was diluted with distilled water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (0.9 mg, yield: 73%).

[0610] 1 H NMR (400 MHz, DMSO-d6) δ 7.65 - 7.63 (m, 1H), 7.53 - 7.51 (m, 1H), 7.44 (s, 1H), 5.34 (s, 2H).

[0611]

[0612] Step 5) Preparation of tert-butyl (S)-2-((4-(6-chloro-5-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0613]

[0614] 4-(6-Chloro-5-fluoropyridin-2-yl)thiazol-2-amine (900 mg, 3.92 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (951 mg, 4.71 mmol), TCFH (2199 mg, 7.84 mmol), and N-methylimidazole (965 mg, 11.76 mmol) were added to DMF (15 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (1.2 g, yield: 70%).

[0615] 1 H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 7.99 (s, 1H), 7.68 - 7.66 (m, 1H), 7.59 - 7.57 (m, 1H), 4.83 - 4.79 (m, 1H), 3.93 - 3.78 (m, 2H), 2.14 (s, 1H), 1.99 (s, 1H), 1.24 (s, 9H).

[0616]

[0617] Step 6) Preparation of tert-butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0618]

[0619] Tert-Butyl (S)-2-((4-(6-chloro-5-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (1.2 g, 2.9 mmol), (2R,6S)-2,6-dimethylmorpholine (0.67 g, 5.8 mmol), Pd-PEPPSI-IPent (0.12 g, 0.145 mmol), and cesium carbonate (2.83 g, 8.7 mmol) were added to 1,4-dioxane (15 mL), and the mixture was reacted at 120°C for 2 h in a microwave reactor. The reaction mixture was cooled to room temperature, diluted with distilled water (30 mL), and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (1.0 g, yield: 66%).

[0620] 1 H NMR (400 MHz, DMSO-d6): δ 12.47 (s, 1H), 7.90 (s, 1H), 6.97 - 6.95 (m, 1H), 6.70 - 6.67 (m, 1H), 5.76 (s, 1H), 4.81 - 4.79 (m, 1H), 4.30 - 4.27 (m, 2H), 4.03 - 4.00 (m, 1H), 3.93 - 3.92 (m, 1H), 3.77 (s, 1H), 3.62 - 3.59 (m, 2H), 1.99 (s, 2H), 1.24 (s, 6H), 1.19 - 1.15 (m, 9H).

[0621]

[0622] Step 7) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide

[0623]

[0624] Tert-Butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (1.2 g, 2.4 mmol) was added to a 4 M hydrogen chloride solution in 1,4-dioxane (10 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated and washed with petroleum ether to obtain the target compound (0.6 g, yield: 63%), which was used in the next reaction without further purification.

[0625] 1 H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 7.96 (s, 1H), 6.97 - 6.94 (m, 1H), 6.72 - 6.69 (m, 1H), 5.24 - 5.16 (m, 1H), 4.30 - 4.27 (m, 2H), 4.00 - 3.97 (m, 1H), 3.83 - 3.76 (m, 1H), 3.63 - 3.58 (m, 2H), 3.56 (s, 1H), 2.75 - 2.71 (m, 1H), 2.64 - 2.59 (m, 1H), 2.49 - 2.43 (m, 2H), 1.18 (d, J = 6.4 Hz, 6H).

[0626]

[0627] Step 8) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0628]

[0629] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide (500 mg, 1.27 mmol), 1-methylsulfonylpyrrole-5-methyl-3-carboxylic acid (311 mg, 1.53 mmol), TCFH (716 mg, 2.54 mmol), and N-methylimidazole (314 mg, 3.81 mmol) were added to DMF (10 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to concentrate the target compound reaction mixture, and the target compound (126.27 mg, yield: 16%) was obtained by column chromatography.

[0630] 1 H NMR (400 MHz, DMSO-d6) δ 12.45 (s, 1H), 7.72 (s, 1H), 7.59 - 7.54 (m, 1H), 7.46 (s, 1H), 7.40 - 7.38 (m, 1H), 6.41 (s, 1H), 5.05 - 5.01 (m, 1H), 4.50 - 4.44 (m, 1H), 4.39 - 4.33 (m, 1H), 3.97 - 3.93 (m, 2H), 3.73 - 3.69 (m, 2H), 3.56 (s, 3H), 2.62 - 2.56 (m, 3H), 2.41 (s, 3H), 2.32 - 2.30 (m, 2H), 1.16 (d, J = 6.0 Hz, 6H).

[0631]

[0632] Example 30: Preparation of (2S)-N-(4-(1-(2,6-dimethylpyridin-4-yl)pyrrolidin-3-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0633]

[0634] Step 1) Preparation of tert-butyl 3-(2-aminothiazol-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0635]

[0636] 4-Bromothiazol-2-amine (1 g, 5.6 mmol), tert-Butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.24 g, 6.7 mmol), P(t-Bu)3-Pd-G2 (0.57 g, 1.1 mmol), and potassium triphosphate (2.38 g, 11.2 mmol) were added to ethanol / distilled water (10:1, 12 mL) and stirred at 90 °C for 5 h. The reaction mixture was cooled to room temperature, diluted with distilled water (30 mL), and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (1.1 g, yield: 69%).

[0637] 1 H NMR (400 MHz, CDCl3) δ 6.31 - 6.28 (m, 1H), 6.22 - 6.21 (m, 1H), 5.36 - 5.25 (m, 2H), 4.38 - 4.25 (m, 4H), 1.50 (d, J = 4.4 Hz, 9H).

[0638]

[0639] Step 2) Preparation of 4-(2,5-dihydro-1H-pyrrol-3-yl)thiazol-2-amine

[0640]

[0641] Tert-Butyl 3-(2-aminothiazol-4-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (600 mg, 2.24 mmol) was added to a 4 M hydrogen chloride solution in 1,4-dioxane (10 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated and washed with petroleum ether to obtain the target compound (400 mg, crude), which was used in the next reaction without further purification.

[0642]

[0643] Step 3) Preparation of 4-(1-(2,6-dimethylpyridin-4-yl)-2,5-dihydro-1H-pyrrol-3-yl)thiazol-2-amine

[0644]

[0645] 4-(2,5-Dihydro-1H-pyrrol-3-yl)thiazol-2-amine (400 mg, 2.39 mmol), 4-chloro-2,6-dimethylpyridine (508 mg, 3.58 mmol), and DIPEA (1236 mg, 9.56 mmol) were added to DMA (10 mL) and stirred at 120°C for 2 h. The reaction mixture was cooled to room temperature, diluted with distilled water (100 mL), and extracted with ethyl acetate (50 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (500 mg, yield: 69%).

[0646] 1 H NMR (400 MHz, DMSO-d6) δ 7.10 (s, 2H), 6.65 (s, 2H), 6.61 (s, 1H), 6.22 (s, 1H), 4.52 (s, 2H), 4.40 (s, 2H), 2.48 (s, 6H).

[0647]

[0648] Step 4) Preparation of tert-butyl (S)-2-((4-(1-(2-methylpyridin-4-yl)-2,5-dihydro-1H-pyrrol-3-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0649]

[0650] 4-(1-(2,6-dimethylpyridin-4-yl)-2,5-dihydro-1H-pyrrol-3-yl)thiazol-2-amine (500 mg, 1.83 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (445 mg, 2.20 mmol), TCFH (772 mg, 2.75 mmol), and N-methylimidazole (452 ​​mg, 5.50 mmol) were added to DMF (10 mL) and stirred at 80°C for 12 h. After cooling to room temperature, the reaction mixture was diluted with distilled water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (500 mg, yield: 47%), which was used in the next reaction without further purification.

[0651]

[0652] Step 5) Preparation of tert-butyl (2S)-2-((4-(1-(2,6-dimethylpyridin-4-yl)pyrrolidin-3-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0653]

[0654] Tert-Butyl (S)-2-((4-(1-(2-methylpyridin-4-yl)-2,5-dihydro-1H-pyrrol-3-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (500 mg, 1.09 mmol) and Raney nickel (192 mg, 3.28 mmol) were added to methanol (20 mL), stirred at room temperature under 4 atm hydrogen gas for 12 h, and the solid of the reaction mixture was removed by filtration, and the filtrate was concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (300 mg, yield: 53%).

[0655] LC / MS (ESI, m / z): [M+H] + = 458.4.

[0656]

[0657] Step 6) Preparation of (2S)-N-(4-(1-(2,6-dimethylpyridin-4-yl)pyrrolidin-3-yl)thiazol-2-yl)azetidine-2-carboxamide

[0658]

[0659] Tert-Butyl (2S)-2-((4-(1-(2,6-dimethylpyridin-4-yl)pyrrolidin-3-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (200 mg, 0.43 mmol) was added to a 4 M hydrogen chloride solution in 1,4-dioxane (5 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated and washed with petroleum ether to obtain the target compound (170 mg, crude), which was used in the next reaction without further purification.

[0660] LC / MS (ESI, m / z): [M+H] + = 357.95.

[0661]

[0662] Step 7) Preparation of (2S)-N-(4-(1-(2,6-dimethylpyridin-4-yl)pyrrolidin-3-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0663]

[0664] (2S)-N-(4-(1-(2,6-dimethylpyridin-4-yl)pyrrolidin-3-yl)thiazol-2-yl)azetidine-2-carboxamide (120 mg, 0.33 mmol), 1-methylsulfonyl-5-methylpyrrole-3-carboxylic acid (81 mg, 0.40 mmol), EDCI (96 mg, 0.50 mmol), HOBt (68 mg, 0.50 mmol), and DIPEA (130 mg, 1.00 mmol) were added to DMF and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (30.96 mg, yield: 17%).

[0665] 1 H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 7.44 (s, 1H), 6.99 (s, 1H), 6.39 (s, 1H), 6.28 (s, 2H), 4.99 (s, 1H), 4.44 (s, 1H), 4.35 (s, 1H), 3.69 - 3.68 (m, 1H), 3.62 - 3.59 (m, 1H), 3.55 (s, 3H), 3.49 - 3.47 (m, 1H), 3.42 - 3.40 (m, 2H), 2.40 (s, 3H), 2.33 (s, 8H), 2.16 (s, 2H).

[0666]

[0667] Example 31: Preparation of (R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1,1-dioxido-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carbonyl)azetidine-2-carboxamide

[0668]

[0669] (R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (25 mg, 0.056 mmol), 2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1,1-dioxide (20 mg, 0.0845 mmol), and TCFH (24 mg, 0.0845 mmol) were added to acetonitrile (1 mL), stirred, and N-methylimidazole (14 mg, 0.1690 mmol) was added, followed by stirring at room temperature for 12 h. After completion of the reaction, distilled water (1 mL) was added, and extraction was performed with ethyl acetate (3 mL). The extracted organic layer was dried with anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (10 mg, yield: 29%).

[0670] 1 H NMR (500 MHz, DMSO-d6) δ 12.58 (s, 1H), 8.25 (s, 1H), 8.01 (m, 1H), 7.93 (s, 1H), 7.71-7.70 (m, 1H), 7.01-7.00 (d, 1H), 6.70-6.67 (d, 1H), 5.11 (m, 1H), 4.97 (m, 2H), 4.48 (m, 1H), 4.33-4.28 (m, 3H), 4.23 (m, 2H), 2.64 (m, 1H), 2.45 (m, 2H), 2.37 (m, 1H), 1.19-1.18 (d, 6H)

[0671]

[0672] Example 32: Preparation of (S)-N-(4-(4-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0673]

[0674] Step 1) Preparation of 2-chloro-6-(1-ethoxyvinyl)isonicotinonitrile

[0675]

[0676] 2,6-Dichloropyridine-4-carbonitrile (10 g, 57.8 mmol), tributyl(1-ethoxyvinyl)tin (16.7 g, 46.2 mmol), and Pd(PPh3)4 (3.34 g, 2.8 mmol) were added to DMF (100 mL) and stirred at 80°C for 12 h. The reaction mixture was cooled to room temperature, diluted with distilled water (200 mL), and extracted with ethyl acetate (100 mL x 3). The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and subjected to column chromatography to obtain the target compound (8 g, yield: 56%).

[0677] 1 H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 1.2 Hz, 1H), 5.59 (d, J = 2.4 Hz, 1H), 4.52 (d, J = 2.4 Hz, 1H), 3.97 (t, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H).

[0678]

[0679] Step 2) Preparation of 2-acetyl-6-chloroisonicotinonitrile

[0680]

[0681] 2-Chloro-6-(1-ethoxyvinyl)isonicotinonitrile (8 g, 38.3 mmol) was added to a 4 M hydrogen chloride 1,4-dioxane solution (80 mL) and stirred at room temperature under nitrogen for 2 h. The reaction mixture was concentrated and the target compound (4.5 g, yield: 58%) was obtained through column separation.

[0682] 1 H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 1.2 Hz, 1H), 7.74 (d, J = 1.2 Hz, 1H), 2.72 (s, 3H).

[0683]

[0684] Step 3) Preparation of 2-(2-bromoacetyl)-6-chloroisonicotinonitrile

[0685]

[0686] 2-Acetyl-6-chloroisonicotinonitrile (250 mg, 1.38 mmol) and cupric bromide (247 mg, 1.10 mmol) were added to methylene chloride / ethyl acetate (1:1, 10 mL) and stirred at 80°C for 12 h. The solid remaining during the reaction was removed by filtration, and the filtrate was concentrated to obtain the target compound (250 mg, yield: 70%), which was used in the next reaction without further purification.

[0687] LC / MS (ESI, m / z): [M+H] + = 259.1

[0688]

[0689] Step 4) Preparation of 4-(4-cyano-6-chloropyridin-2-yl)thiazol-2-amine

[0690]

[0691] 2-(2-Bromoacetyl)-6-chloroisonicotinonitrile (250 mg, 0.82 mmol) and thiourea (68 mg, 0.90 mmol) were added to ethanol (5 mL) and stirred at room temperature for 2 hours. The formed precipitate was filtered to obtain the target compound (110 mg, yield: 51%), which was used in the next reaction without further purification.

[0692] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (t, J = 6.4 Hz, 1H), 8.19 (s, 1H), 8.08 (s, 1H), 7.66 (d, J = 5.2 Hz, 2H).

[0693]

[0694] Step 5) Preparation of tert-butyl (S)-2-((4-(4-cyano-6-chloropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0695]

[0696] 4-(4-Cyano-6-chloropyridin-2-yl)thiazol-2-amine (110 mg, 0.46 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (103 mg, 0.51 mmol), TCFH (195 mg, 0.69 mmol), and N-methylimidazole (57 mg, 0.69 mmol) were added to DMF (3 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (150 mg, yield: 69%).

[0697] LC / MS (ESI, m / z): [M+H] + = 419.9

[0698]

[0699] Step 6) Preparation of tert-butyl (S)-2-((4-(4-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0700]

[0701] Tert-Butyl (S)-2-((4-(4-cyano-6-chloropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (150 mg, 0.35 mmol), (2R,6S)-2,6-dimethylmorpholine (49 mg, 0.42 mmol), Pd-PEPPSI-IPent (28 mg, 0.03 mmol), and cesium carbonate (348 mg, 1.06 mmol) were added to 1,4-dioxane (5 mL) and reacted at 100°C for 2 h. The reaction mixture was cooled to room temperature, diluted with distilled water (30 mL), and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the target compound (110 mg, yield: 55%).

[0702] 1 H NMR (400 MHz, CDCl3) δ 11.16 - 11.15 (m, 1H), 7.69 (s, 1H), 7.51 (s, 1H), 6.74 (s, 1H), 4.92 (t, J = 8.0 Hz, 1H), 4.19 - 4.17 (m, 2H), 4.01 (q, J = 8.0 Hz, 1H), 3.93 - 3.89 (m, 1H), 3.74 - 3.71 (m, 2H), 2.66 - 2.63 (m, 3H), 2.55 - 2.54 (m, 1H), 1.54 (s, 9H), 1.31 (d, J = 6.0 Hz, 6H).

[0703]

[0704] Step 7) Preparation of (S)-N-(4-(4-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide

[0705]

[0706] Tert-Butyl (S)-2-((4-(4-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (100 mg, 0.20 mmol) was added to a 4 M HCl 1,4-dioxane solution (5 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated and washed with petroleum ether to obtain the target compound (100 mg, crude), which was used in the next reaction without further purification.

[0707] LC / MS (ESI, m / z): [M+H] + = 399.0.

[0708]

[0709] Step 8) Preparation of (S)-N-(4-(4-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0710]

[0711] (S)-N-(4-(4-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide (100 mg, 0.25 mmol), 1-methylsulfonylpyrrole-5-methyl-3-carboxylic acid (61 mg, 0.30 mmol), TCFH (105 mg, 0.37 mmol), and N-methylimidazole (61 mg, 0.75 mmol) were added to DMF (3 mL), and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the target compound (54 mg, yield: 34%).

[0712] 1H NMR (400 MHz, CDCl3) δ 11.87 (s, 1H), 7.68 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.54 (s, 1H), 6.73 (s, 1H), 6.45 (s, 1H), 5.31 - 5.27 (m, 1H), 4.47 - 4.36 (m, 2H), 4.18 - 4.15 (m, 2H), 3.73 - 3.70 (m, 2H), 3.21 (s, 3H), 2.91 - 2.90 (s, 1H), 2.64 - 2.61 (m, 3H), 2.47 (s, 3H), 1.30 (d, J = 6.0 Hz, 6H).

[0713]

[0714] Example 33: Preparation of (S)-N-(4-(6-chloro-4-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0715]

[0716] (S)-N-(4-(6-chloro-4-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (30 mg, 0.068 mmol), 1-methylsulfonylpyrrole-3-carboxylic acid (19 mg, 0.101 mmol), and TCFH (28 mg, 0.101 mmol) were added to acetonitrile (1 mL), stirred, and N-methylimidazole (17 mg, 0.203 mmol) was added, followed by stirring at 25°C for 12 h. After completion of the reaction, distilled water (1 mL) was added, and extraction was performed with ethyl acetate (3 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (30 mg, yield: 45%).

[0717] 1H NMR (500 MHz, DMSO-d6) δ 12.51 (s, 1H), 7.78 (s, 1H), 7.65 (s, 1H), 7.37-7.34 (m, 2H), 6.90 (s, 1H), 6.66 (s, 1H), 5.03 (m, 1H), 4.53-4.52 (m, 1H), 4.40-4.39 (m, 1H), 3.83-3.81 (d, 2H), 3.65 (m, 2H), 3.62 (s, 3H), 2.62 (m, 1H), 2.31 (m, 1H), 1.18-1.16 (d, 6H)

[0718]

[0719] Preparation of intermediate 1:1-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid

[0720]

[0721] Step 1) Preparation of methyl 1-(methylsulfonyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylate

[0722]

[0723] At 0℃, methyl 1H-pyrrolo[3,2-b]pyridine-6-carboxylate (4 g, 22.7 mmol) and sodium hydroxide (1.09 g, 45.4 mmol) were added to THF (40 mL), and methanesulfonyl chloride (7.8 g, 68.1 mmol) was slowly added at 0℃, and the mixture was stirred at 0℃ for 2 h. The reaction mixture was diluted with distilled water (20 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the target compound (5 g, yield: 77%).

[0724] 1 H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 8.84 (s, 1H), 7.89 (s, 1H), 7.05 (s, 1H), 4.01 (s, 3H), 3.24 (s, 3H).

[0725]

[0726] Step 2) Preparation of methyl 1-(methylsulfonyl)-2,3-dihydro1H-pyrrolo[3,2-b]pyridine-6-carboxylate

[0727]

[0728] Methyl 1-(methylsulfonyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (2.5 g, 9.8 mmol) and Raney nickel (1 g) were added to methanol and stirred at room temperature under hydrogen gas for 12 h. The solid was filtered off, and the filtrate was concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (2 g, yield: 71%).

[0729] 1 H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 1.6 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 4.10 (t, J = 8.8 Hz, 2H), 3.94 (s, 3H), 3.36 (t, J = 8.8 Hz, 2H), 2.96 (s, 3H).

[0730]

[0731] Step 3) Preparation of 1-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid

[0732]

[0733] Methyl 1-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (2 g, 7.8 mmol) and lithium hydroxide monohydrate (0.37 g, 15.6 mmol) were added to THF / distilled water (4:1, 30 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated, diluted with distilled water (5 mL), and extracted with a methylene chloride / methanol solution (10:1, 100 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (1.7 g, yield: 80%).

[0734] 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 1.6 Hz, 1H), 4.06 (t, J = 8.8 Hz, 2H), 3.29 (t, J = 8.8 Hz, 2H), 3.12 (s, 3H).

[0735]

[0736] Example 34: Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-4-methoxy-1-(5-methyl-1-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carbonyl)azetidine-2-carboxamide

[0737]

[0738] (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide (100 mg, 0.25 mmol), 1-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid (74 mg, 0.30 mmol), TCFH (107 mg, 0.38 mmol) and N-methylimidazole (62 mg, 0.76 mmol) were added to DMF (3 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the desired product. The compound (75.23 mg, yield: 47%) was obtained.

[0739] 1H NMR (400 MHz, CDCl3) δ 11.12 (s, 1H), 8.52 (s, 1H), 7.89 (s, 1H), 7.71 (s, 1H), 7.14 (d, J = 9.2 Hz, 1H), 6.24 - 6.21 (m, 1H), 5.35 - 5.31 (m, 1H), 4.51 - 4.56 (m, 1H), 4.31 - 4.25 (m, 1H), 4.13 - 4.09 (m, 4H), 3.75 - 3.70 (m, 2H), 3.39 - 3.35 (m, 2H), 3.00 (s, 3H), 2.96 - 2.95 (m, 1H), 2.61 - 2.60 (m, 1H), 2.60 - 2.54 (m, 2H), 1.29 (d, J = 6.4 Hz, 6H).

[0740] LC / MS (ESI, m / z): [M+H] + = 616.40.

[0741]

[0742] Intermediate 2: Preparation of 1-(methylsulfonyl)-1H-pyrazole-3-carboxylic acid

[0743]

[0744] Step 1) Preparation of tert-butyl 1H-pyrazole-3-carboxylate

[0745]

[0746] 1H-Pyrazole-3-carboxylic acid (500 mg, 4.46 mmol) and 1,1-di-tert-butoxy N,N-dimethylmethanamine (3.6 g, 17.84 mmol) were added to toluene (5 mL) and stirred at 80°C for 2 h. The reaction mixture was cooled to room temperature and mixed with distilled water (50 mL) and ethyl acetate (50 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (500 mg, yield: 63%).

[0747] 1H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 7.79 (s, 1H), 6.66 (s, 1H), 1.52 (s, 9H).

[0748]

[0749] Step 2) Preparation of tert-butyl 1-(methylsulfonyl)-1H-pyrazole-3-carboxylate

[0750]

[0751] Tert-Butyl 1H-pyrazole-3-carboxylate (500 mg, 4.46 mmol) and triethylamine (1.35 g, 13.4 mmol) were added to THF (3 mL) at 0°C, and methanesulfonyl chloride (1.53 mg, 13.4 mmol) was slowly added at 0°C, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (20 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (490 mg, yield: 60%).

[0752] 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 2.8 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H), 3.66 (s, 3H), 1.55 (s, 9H).

[0753]

[0754] Step 3) Preparation of 1-(methylsulfonyl)-1H-pyrazole-3-carboxylic acid

[0755]

[0756] Tert-Butyl 1-(methylsulfonyl)-1H-pyrazole-3-carboxylate (490 mg, 1.98 mmol) was added to a TFA / methylene chloride solution (1:10, 5 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated to obtain the target compound (400 mg, yield: 95%).

[0757] 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 2.8 Hz, 1H), 6.95 (d, J = 2.8 Hz, 1H), 3.66 (s, 3H).

[0758]

[0759] Example 35: Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrazole-3-carbonyl)azetidine-2-carboxamide

[0760]

[0761] (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide (100 mg, 0.25 mmol), 1-(methylsulfonyl)-1H-pyrazole-3-carboxylic acid (58 mg, 0.31 mmol), TCFH (107.5 mg, 0.38 mmol), and N-methylimidazole (62.9 mg, 0.77 mmol) were added to DMF (3 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (29.41 mg, yield: 18%).

[0762] 1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.41 - 8.28 (m, 1H), 7.90 - 7.87 (m, 1H), 7.02 - 6.86 (m, 2H), 6.68 (d, J = 12.8 Hz, 1H), 5.61 - 5.09 (m, 1H), 4.65 - 4.50 (m, 1H), 4.28 (d, J = 12.8 Hz, 2H), 4.15 - 4.00 (m, 1H), 3.68 (s, 1H), 3.62 - 3.59 (m, 2H), 3.39 (s, 3H), 2.80 - 2.60 (m, 1H), 2.46 - 2.42 (m, 1H), 2.33 - 2.25 (m, 1H), 1.18 - 1.16 (m, 6H).

[0763]

[0764] Example 36: Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methyl-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0765]

[0766] (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methylazetidine-2-carboxamide hydrochloride (25 mg, 0.057 mmol), 1-methylsulfonylpyrrole-5-methyl-3-carboxylic acid (17 mg, 0.085 mmol), TCFH (24 mg, 0.085 mmol), and N-methylimidazole (14 mg, 0.17 mmol) were added to DMF (2 mL), and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (1 mL) and extracted with ethyl acetate (3 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (30 mg, yield: 45%).

[0767] 1 H NMR (500 MHz, DMSO-d6) δ 12.49 (s, 1H), 7.90 (s, 1H), 7.46 (s, 1H), 6.99-6.98 (m, 1H), 6.70-6.68 (m, 1H), 6.42 (s, 1H), 4.62-4.57 (m, 2H), 4.30-4.28 (d, 2H), 3.96 (m, 1H), 3.61 (m, 2H), 3.57 (s, 3H), 2.72 (m, 1H), 2.47 (m, 2H), 2.29 (s, 3H), 1.33-1.32 (m, 3H), 1.18-1.17 (d, 6H)

[0768]

[0769] Example 37: Preparation of (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide

[0770]

[0771] (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide (50 mg, 0.106 mmol), 5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (32 mg, 0.160 mmol), and TCFH (45 mg, 0.1595 mmol) were added to acetonitrile (1 mL), stirred, and N-methylimidazole (26 mg, 0.319 mmol) was added, followed by stirring at 25°C for 12 h. After completion of the reaction, distilled water (1 mL) was added, and extraction was performed with ethyl acetate (3 mL). The extracted organic layer was dried with anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (43 mg, yield: 67%).

[0772] 1H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 7.89 (s, 1H), 7.47 (s, 1H), 7.01-6.99 (m, 1H), 6.70-6.67 (m, 1H), 6.43 (s, 1H), 4.90 (s, 1H), 4.30-4.28 (m, 2H), 4.03-4.01 (m, 1H), 3.92-9.90 (m, 1H), 3.63-3.60 (m, 2H), 3.56 (s, 3H), 2.64 (m, 1H), 2.47-2.44 (m, 2H), 2.40 (s, 3H), 2.37 (m, 1H), 1.79 (m, 1H), 1.73-1.71 (m, 1H), 1.19-1.17 (d, 6H),

[0773]

[0774] Example 38: Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1,1-dioxido-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carbonyl)-3-methylazetidine-2-carboxamide

[0775]

[0776] (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methylazetidine-2-carboxamide (25 mg, 0.0566 mmol), 2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1,1-dioxide (21 mg, 0.0849 mmol), and TCFH (24 mg, 0.0849 mmol) were added to acetonitrile (1 mL), stirred, and N-methylimidazole (14 mg, 0.1698 mmol) was added, followed by stirring at 25°C for 12 h. After completion of the reaction, distilled water (1 mL) was added, and extraction was performed with ethyl acetate (3 mL). The extracted organic layer was dried with anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column chromatography to obtain the target compound (4 mg, yield: 12%).

[0777] 1 H NMR (500 MHz, DMSO-d6) δ 12.60 (s, 1H), 8.26 (s, 1H), 8.03-8.01 (m, 1H), 7.93 (s, 1H), 7.71-7.70 (m, 1H), 7.02-7.00 (d, 1H), 6.70-6.68 (d, 1H), 4.97-4.96 (m, 3H), 4.31-4.28 (m, 2H), 4.22 (m, 3H), 3.93 (m, 1H), 3.69 (m, 2H), 3.61 (m, 2H), 2.79 (m, 1H), 2.46 (m, 2H), 1.33 (m, 3H), 1.19-1.18 (d, 6H)

[0778]

[0779] Example 39: Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methyl-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide

[0780]

[0781] Step 1) Preparation of tert-butyl (2S,3S)-2-((4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-3-methylpyrrolidine-1-carboxylate

[0782]

[0783] 4-(6-Chloro-4-fluoropyridin-2-yl)thiazol-2-amine (40 mg, 0.17 mmol), (2S,3S)-1-(tert-butoxycarbonyl)-3-methylpyrrolidine-2-carboxylic acid (44 mg, 0.19 mmol), TCFH (73 mg, 0.26 mmol), and N-methylimidazole (43 mg, 0.52 mmol) were added to DMF (2 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (45 mg, yield: 52%).

[0784] 1 H NMR (400 MHz, CDCl3) δ 11.28 (s, 1H), 7.82 (s, 1H), 7.68 (s, 1H), 7.03 - 7.01 (m, 1H), 3.55 - 3.49 (m, 1H), 2.14 - 2.09 (m, 2H), 2.01 (s, 1H), 1.64 - 1.61 (m, 2H), 1.52 - 1.41 (m, 9H), 1.26 - 1.21 (m, 3H).

[0785]

[0786] Step 2) Preparation of tert-butyl (2S,3S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-3-methylpyrrolidine-1-carboxylate

[0787]

[0788] Tert-Butyl (2S,3S)-2-((4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-3-methylpyrrolidine-1-carboxylate (45 mg, 0.10 mmol), (2R,6S)-2,6-dimethylmorpholine (11 mg, 0.09 mmol), Pd-PEPPSI-IPent (8 mg, 0.01 mmol), and cesium carbonate (100 mg, 0.30 mmol) were added to 1.4-dioxane (3 mL) and reacted at 100°C for 4 h. The reaction mixture was cooled to room temperature, diluted with distilled water (30 mL), and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (30 mg, yield: 51%).

[0789] 1 H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 6.95 (d, J = 9.2 Hz, 1H), 6.27 (d, J = 10.0 Hz, 1H), 4.24 -4.23 (m, 2H), 3.73 - 3.72 (m, 2H), 3.64 - 3.63 (m, 1H), 2.63 - 2.57 (m, 2H), 2.12 - 2.11 (m, 1H), 1.65 - 1.63 (m, 4H), 1.50 (s, 6H), 1.38 (s, 3H), 1.32 (d, J = 6.4 Hz, 6H), 1.26 (s, 3H).

[0790]

[0791] Step 3) Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methylpyrrolidine-2-carboxamide

[0792]

[0793] Tert-Butyl (2S,3S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-3-methylpyrrolidine-1-carboxylate (30 mg, 0.06 mmol) was added to a 4 M HCl 1,4-dioxane solution (2 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated and washed with petroleum ether to obtain the target compound (30 mg, crude), which was used in the next reaction without further purification.

[0794] LC / MS (ESI, m / z): [M+H] + = 420.0.

[0795]

[0796] Step 4) Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methyl-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide

[0797]

[0798] (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methylpyrrolidine-2-carboxamide (30 mg, 0.07 mmol), 1-methylsulfonylpyrrole-5-methyl-3-carboxylic acid (17 mg, 0.09 mmol), TCFH (30 mg, 0.11 mmol), and N-methylimidazole (18 mg, 0.21 mmol) were added to DMF (2 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (15.46 mg, yield: 39%).

[0799] 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 7.86 (s, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.00 - 6.97 (m, 1H), 6.69 - 6.65 (m, 1H), 6.43 (s, 1H), 4.29 - 4.22 (m, 3H), 3.87 (d, J = 7.2 Hz, 2H), 3.60 - 3.58 (m, 2H), 3.55 (s, 3H), 2.46 - 2.43 (m, 2H), 2.40 (s, 3H), 2.29 - 2.23 (m, 1H), 2.17 - 2.13 (m, 1H), 1.67 - 1.63 (m, 1H), 1.18 - 1.14 (m, 9H).

[0800]

[0801] Example 40: Preparation of (S)-N-(4-(4-chloro-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0802]

[0803] Step 1) Preparation of 2,4-dichloro-6-(1-ethoxyvinyl)pyridine

[0804]

[0805] 2,4,6-Trichloropyridine (5 g, 24.4 mmol), tributyl(1-ethoxyvinyl)tin (7.92 g, 21.9 mmol), and Pd(PPh3)4 (1.58 g, 1.3 mmol) were added to DMF (50 mL) and stirred at 80°C for 12 h. The reaction mixture was cooled to room temperature, diluted with distilled water (300 mL), and extracted with ethyl acetate (100 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (5 g, yield: 71%).

[0806] 1H NMR (400 MHz, CDCl3) δ 7.33 (s, 1H), 7.28 (s, 1H), 5.55 (d, J = 2.4 Hz, 1H), 4.47 (d, J = 2.4 Hz, 1H), 3.99 - 3.93 (m, 2H), 1.46 (t, J = 7.2 Hz, 3H).

[0807]

[0808] Step 2) Preparation of 2-bromo-1-(4,6-dichloropyridin-2-yl)ethan-1-one

[0809]

[0810] 2,4-Dichloro-6-(1-ethoxyvinyl)pyridine (5 g, 22.9 mmol) and NBS (4.08 g, 22.9 mmol) were added to THF / distilled water (10:1, 50 mL) and stirred at room temperature for 2 hours. The mixture was diluted with distilled water (200 mL) and extracted with ethyl acetate (150 mL x 3). The separated organic layer was dried over anhydrous sodium sulfate. The concentrated compound was purified by column chromatography to obtain the target compound (5 g, yield: 69%).

[0811] 1 H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 1.6 Hz, 1H), 7.31 (s, 1H), 4.76 (s, 2H).

[0812]

[0813] Step 3) Preparation of 4-(4,6-dichloropyridin-2-yl)thiazol-2-amine

[0814]

[0815] 2-Bromo-1-(4,6-dichloropyridin-2-yl)ethan-1-one (5 g, 15.9 mmol) and thiourea (1.21 g, 15.9 mmol) were added to ethanol (50 mL) and stirred at room temperature for 2 hours. The reaction mixture was filtered to obtain the target compound (4 g, crude), which was used in the next reaction without further purification.

[0816] 1 H NMR (400 MHz, DMSO-d6) δ 8.05 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.62 (s, 1H), 5.47 (s, 2H).

[0817]

[0818] Step 4) Preparation of tert-butyl (S)-2-((4-(4,6-dichloropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0819]

[0820] 4-(4,6-Dichloropyridin-2-yl)thiazol-2-amine (500 mg, 2.03 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (493 mg, 2.43 mmol), TCFH (855 mg, 3.05 mmol), and N-methylimidazole (500 mg, 6.09 mmol) were added to DMF (5 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (400 mg, yield: 41%).

[0821] 1 H NMR (400 MHz, CDCl3) δ 11.04 (s,1H), 7.98 (s, 1H), 7.85 (s, 1H), 7.26 (s, 1H), 4.94 - 4.90 (m, 1H), 4.02 - 3.98 (m, 1H), 3.90 - 3.85 (m, 1H), 2.63 (s, 1H), 2.53 (s, 1H), 1.54 (s, 9H).

[0822]

[0823] Step 5) Preparation of tert-butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-chloropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0824]

[0825] Tert-Butyl (S)-2-((4-(4,6-dichloropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (300 mg, 0.69 mmol), (2R,6S)-2,6-dimethylmorpholine (64 mg, 0.55 mmol), Pd-PEPPSI-IPent (55 mg, 0.07 mmol), and cesium carbonate (341 mg, 1.05 mmol) were added to 1.4-dioxane (10 mL) and stirred at 100°C for 2 h. The reaction mixture was cooled to room temperature, diluted with distilled water (100 mL), and extracted with ethyl acetate (50 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (40 mg, yield: 10%).

[0826] 1 H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.38 (s, 1H), 6.56 (d, J = 1.6 Hz, 1H), 4.90 (t, J = 8.0 Hz, 1H), 4.16 - 4.09 (m, 3H), 4.00 (d, J = 8.0 Hz, 1H), 3.88 (d, J = 5.6 Hz, 1H), 3.74 - 3.71 (m, 2H), 2.61 - 2.56 (m, 4H), 1.53 (s, 9H), 1.29 (d, J = 6.4 Hz, 6H).

[0827]

[0828] Step 6) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-chloropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide

[0829]

[0830] Tert-Butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-chloropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (40 mg, 0.06 mmol) was added to a 4 M hydrogen chloride solution in 1,4-dioxane (2 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated to obtain the target compound (30 mg, crude), which was used in the next reaction without further purification.

[0831] LC / MS (ESI, m / z): [M+H] + = 408.0.

[0832]

[0833] Step 7) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-chloropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0834]

[0835] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-chloropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide (30 mg, 0.07 mmol), 5-methyl-1-methylsulfonylpyrrole-3-carboxylic acid (18 mg, 0.09 mmol), TCFH (31 mg, 0.11 mmol), and N-methylimidazole (18 mg, 0.22 mmol) were added to DMF (2 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated and separated by column chromatography to obtain the target compound (17.37 mg, yield: 39%).

[0836] 1H NMR (400 MHz, CDCl3) δ 11.64 (s, 1H), 7.69 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 1.2 Hz, 1H), 6.55 (d, J = 1.6 Hz, 1H), 6.43 (s, 1H), 5.31 - 5.27 (m, 1H), 4.47 - 4.35 (m, 2H), 4.15 - 4.12 (m, 2H), 3.75 - 3.70 (m, 2H), 3.21 (s, 3H), 2.93 - 2.91 (s, 1H), 2.66 - 2.61(m, 1H), 2.57 - 2.55 (m, 2H), 2.47 (s, 3H), 1.29 (d, J = 6.4 Hz, 6H).

[0837]

[0838] Intermediate 3: Preparation of (R)-4-cyano-4-methylisochroman-6-carboxylic acid

[0839]

[0840] Step 1) Preparation of methyl 6-bromo-4-oxoisochroman-3-carboxylate

[0841]

[0842] Methyl 5-bromo-2-(bromomethyl)benzoate (50 g, 162.4 mmol) and methyl 2-hydroxyacetate (29.26 g, 324.8 mmol) were dissolved in DMF (500 mL), and sodium hydride (7.80 g, 324.8 mmol) was slowly added at 0°C. The reaction mixture was stirred at room temperature for 1 hour, saturated aqueous ammonium chloride solution (500 mL) was added to terminate the reaction, and extracted with ethyl acetate (300 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to obtain the target compound (40 g, crude), which was used in the next reaction without further purification.

[0843]

[0844] Step 2) Preparation of 6-bromoisochroman-4-one

[0845]

[0846] Methyl 6-bromo-4-oxoisochroman-3-carboxylate (40 g, 140.3 mmol) was added to an EtOH / 12 M hydrochloric acid aqueous solution (1:2, 300 mL) and stirred at 120°C for 1 h under nitrogen gas. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (100 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated, ethanol was added, and the mixture was stirred at 0°C for 30 min. The formed solid was washed with ethanol (50 mL x 2) and filtered to obtain the target compound (12 g, yield: 36%).

[0847] 1 H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 2.0 Hz, 1H), 7.67 (s, 1H), 7.13 (d, J = 8.4 Hz, 1H), 8.84 (s, 2H), 4.36 (s, 2H).

[0848]

[0849] Step 3) 6-Bromo-4-methylisochroman-4-ol

[0850]

[0851] 6-Bromoisochroman-4-one (10 g, 44 mmol) and cerium(III) chloride (5.42 g, 22 mmol) were added to THF (200 mL), and methylmagnesium bromide was slowly added at -50°C. The reaction mixture was stirred at room temperature for 1 h, diluted with distilled water (200 mL), and the resulting solids were filtered off. The filtrate was concentrated and extracted with ethyl acetate (100 mL x 2). The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target compound (10 g, yield: 84%).

[0852] 1H NMR (400 MHz, DMSO-d6): δ 7.62 (s, 1H), 7.38 (t, J = 8.4 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 5.35 (s, 1H), 4.66 - 4.60 (m, 2H), 3.66 - 3.63 (m, 1H), 3.55 - 3.52 (m, 1H), 1.38 (s, 3H).

[0853]

[0854] Step 4) Preparation of 6-bromo-4-methylisochroman-4-carbonitrile

[0855]

[0856] 6-Bromo-4-methylisochroman-4-ol (10 g, 41.1 mmol) was added to methylene chloride (200 mL), and TMSCN (8.16 g, 82.2 mmol) and indium bromide (2.91 g, 8.22 mmol) were slowly added at 0°C. The reaction mixture was stirred at room temperature for 1 h, diluted with distilled water (200 mL), and extracted with methylene chloride (200 mLx 2). The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target compound (5 g, yield: 43%).

[0857] 1 H NMR (400 MHz, DMSO-d6): δ 7.63 (d, J = 1.6 Hz, 1H), 7.36 - 7.34 (m, 1H), 6.94 (d, J = 8.4 Hz, 1H), 4.64 - 4.52 (m, 2H), 4.02 - 3.97 (d, J = 11.6 Hz, 1H), 3.62 - 3.59 (m, 1H), 1.47 (s, 3H).

[0858]

[0859] Step 5) Preparation of (S)-4-cyano-4-methylisochroman-6-carboxylic acid and (R)-4-cyano-4-methylisochroman-6-carboxylic acid

[0860]

[0861] 6-Bromo-4-methylisochroman-4-carbonitrile (5 g, 19.8 mmol) was added to DMSO / H2O (20:1, 105 mL), followed by the addition of Pd(OAc)2 (0.44 g, 1.98 mmol), dcpp-2HBF4 (2.08 g, 3.96 mmol), and potassium carbonate (5.47 g, 39.6 mmol). The reaction mixture was purified with carbon monoxide three times and stirred at 100°C for 4 h under a carbon monoxide pressure of 15 psi. The reaction mixture was cooled to room temperature, distilled water (100 mL) was added to terminate the reaction, and the pH of the reaction mixture was adjusted to 3 using 2 N hydrochloric acid aqueous solution, followed by extraction with ethyl acetate (100 mLx 3). The separated organic layer was dried over anhydrous sodium sulfate and concentrated, and the concentrate was separated by SFC to obtain each target compound ((S)-form: 1.23 g, yield: 41%, (R)-form: 1.20 g, yield: 40%).

[0862] SFC separation

[0863] column: DAICEL AD-H 4.6mmI.D.*250mmL 5μm;

[0864] mobile phase: CO2 / MeOH [0.1% NH3(7 M Solution in MeOH)] = 75 / 25)

[0865] (S)-form: 1 H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 4.90 - 4.80 (m, 2H), 4.18 (d, J = 11.6 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 1.66 (s, 3H), SFC: rt = 1.900 min,

[0866] (R)-form: 1H NMR (400 MHz, DMSO-d6): δ 8.04 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 4.89 - 4.79 (m, 2H), 4.18 (d, J = 11.2 Hz, 1H), 3.87 (d, J = 11.2 Hz, 1H), 1.66 (s, 3H), SFC: rt = 2.236 min.

[0867]

[0868] Example 41: Preparation of (S)-1-((R)-4-cyano-4-methylisochroman-6-carbonyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide

[0869]

[0870] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (20 mg, 0.05 mmol), (R)-4-cyano-4-methylisochroman-6-carboxylic acid (15 mg, 0.07 mmol), and TCFH (19 mg, 0.07 mmol) were added to acetonitrile (1 mL), stirred, and N-methylimidazole (11 mg, 0.14 mmol) was added. The mixture was stirred at room temperature for 12 h. After completion of the reaction, the mixture was diluted with distilled water (1 mL) and extracted with ethyl acetate (3 mL). The extracted organic layer was dried over anhydrous magnesium sulfate and filtered under reduced pressure. The filtered solution was concentrated under reduced pressure and separated by column to obtain the target compound (16 mg, yield: 60%).

[0871] 1H NMR (500 MHz, DMSO-d6) δ 12.51 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 7.68-7.66 (m, 1H), 7.30-7.28 (m, 1H), 7.01-6.99 (d, 1H), 6.70-6.68 (d, 1H), 5.10 (m, 1H), 4.92-4.82 (m, 2H), 4.51 (m, 1H), 4.31-4.28 (m, 3H), 4.23-4.21 (m, 1H), 3.89-3.87 (m, 1H), 3.62 (m, 2H), 2.61 (m, 1H), 2.45 (m, 2H), 2.34 (m, 1H), 1.69 (s, 3H), 1.19-1.18 (d, 6H)

[0872]

[0873] Example 42: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-imidazole-4-carbonyl)azetidine-2-carboxamide

[0874]

[0875] Step 1) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1H-imidazole-4-carbonyl)azetidine-2-carboxamide

[0876]

[0877] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide (100 mg, 0.26 mmol), 1H-imidazole-4-carboxylic acid (37 mg, 0.033 mmol), EDCI (73 mg, 0.38 mmol), HOBt (51 mg, 0.38 mmol), and DIPEA (132 mg, 1.02 mmol) were added to DMF (2 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (80 mg, yield: 61%).

[0878] 1 H NMR (400 MHz, DMSO-d6) δ 12.56 - 12.46 (m, 2H), 7.91 - 7.57 (m, 3H), 6.98 (d, J = 8.4 Hz, 1H), 6.69 - 6.65 (m, 1H), 5.61 - 5.08 (m, 1H), 4.59 - 4.53 (m, 1H), 4.30 - 4.26 (m, 2H), 3.96 - 3.74 (m, 1H), 3.66 - 3.57 (m, 2H), 2.67 (s, 1H), 2.48 - 2.42 (m, 2H), 2.33 - 2.18 (m, 1H), 1.19 - 1.16 (m, 6H).

[0879]

[0880] Step 2) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-imidazole-4-carbonyl)azetidine-2-carboxamide

[0881]

[0882] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1H-imidazole-4-carbonyl)azetidine-2-carboxamide (70 mg, 0.14 mmol) was dissolved in pyridine (2 mL), and methanesulfonyl chloride (825 mg, 7.21 mmol) was slowly added. After stirring at room temperature for 30 minutes, the mixture was diluted with distilled water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (21.88 mg, yield: 24%).

[0883] 1 H NMR (400 MHz, DMSO-d6) δ 12.48 - 12.38 (m, 1H), 8.27 - 8.14 (m, 1H), 8.11 (s, 1H), 7.90 - 7.85 (m, 1H), 6.99 - 6.96 (m, 1H), 6.69 - 6.65 (m, 1H), 5.64 - 5.07 (m, 1H), 4.62 - 4.52 (m, 1H), 4.30 - 4.26 (m, 2H), 4.15 - 3.94 (m, 1H), 3.78 - 3.73 (m, 3H), 3.61 (s, 2H), 2.83 - 2.58 (m, 1H), 2.47 - 2.15 (m, 3H), 1.17 (d, J = 6.0 Hz, 6H).

[0884]

[0885] Example 43: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-methylpyridin-2-yl)thiazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0886]

[0887] Step 1) Preparation of 2-chloro-6-(1-ethoxyvinyl)-4-methylpyridine

[0888]

[0889] 2,6-Dichloro-4-methylpyridine (5 g, 30.9 mmol), tributyl(1-ethoxyvinyl)tin (8.93 g, 24.7 mmol), and Pd(PPh3)4 (1.79 g, 1.5 mmol) were added to DMF (50 mL) and stirred at 80°C for 12 h. The reaction mixture was cooled to room temperature, diluted with distilled water (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (2.3 g, yield: 32%).

[0890] 1 H NMR (400 MHz, CDCl3) δ 7.41 (s, 1H), 7.05 - 7.04 (m, 1H), 5.45 (d, J = 2.0 Hz, 1H), 4.38 (d, J = 2.0 Hz, 1H), 3.95 (q, J = 7.2 Hz, 2H), 2.34 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H).

[0891]

[0892] Step 2) Preparation of 2-bromo-1-(6-chloro-4-methylpyridin-2-yl)ethan-1-one

[0893]

[0894] 2-Chloro-6-(1-ethoxyvinyl)-4-methylpyridine (2.3 g, 11.7 mmol) and NBS (2.3 g, 12.9 mmol) were added to THF / distilled water (10:1, 20 mL) and stirred at room temperature for 2 h. The mixture was diluted with distilled water (200 mL) and extracted with ethyl acetate (150 mL x 3). The separated organic layer was dried over anhydrous sodium sulfate. The concentrated compound was purified by column chromatography to obtain the target compound (2.3 g, yield: 63%).

[0895] 1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.38 (s, 1H), 4.81 (s, 2H), 2.77 (s, 3H)

[0896]

[0897] Step 3) Preparation of 4-(6-chloro-4-methylpyridin-2-yl)thiazol-2-amine

[0898]

[0899] 2-Bromo-1-(6-chloro-4-methylpyridin-2-yl)ethan-1-one (1 g, 3.4 mmol) and thiourea (0.28 g, 3.7 mmol) were added to ethanol (10 mL) and stirred at room temperature for 12 h. The reaction mixture was filtered to obtain the target compound (4 g, crude), which was used in the next reaction without further purification.

[0900] 1 H NMR (400 MHz, DMSO-d6) δ 7.83 (s, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 2.38 (s, 3H).

[0901]

[0902] Step 4) Preparation of tert-butyl (S)-2-((4-(6-chloro-4-methylpyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0903]

[0904] 4-(6-Chloro-4-methylpyridin-2-yl)thiazol-2-amine (300 mg, 1.33 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (323 mg, 1.60 mmol), TCFH (559 mg, 1.99 mmol), and N-methylimidazole (327 mg, 3.99 mmol) were added to DMF (5 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the target compound (300 mg, yield: 50%).

[0905] 1 H NMR (400 MHz, CDCl3) δ 11.00 (s, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.08 (s, 1H), 4.91 (t, J = 8.0 Hz, 1H), 4.01 (q, J = 8.4 Hz, 1H), 3.91 - 3.85 (m, 1H), 2.57 - 2.56 (s, 2H), 2.40 (s, 3H), 1.53 (s, 9H).

[0906]

[0907] Step 5) Preparation of tert-butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-methylpyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0908]

[0909] Tert-Butyl (S)-2-((4-(6-chloro-4-methylpyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (300 mg, 0.73 mmol), (2R,6S)-2,6-dimethylmorpholine (101 mg, 0.88 mmol), Pd-PEPPSI-IPent (58 mg, 0.07 mmol), and cesium carbonate (716 mg, 2.20 mmol) were added to 1.4-dioxane (8 mL) and stirred at 100 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with distilled water (100 mL), and extracted with ethyl acetate (50 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (200 mg, yield: 67%).

[0910] 1 H NMR (400 MHz, CDCl3) δ 10.78 (s, 1H), 7.79 (s, 1H), 7.29 (s, 1H), 6.48 (s, 1H), 4.90 (t, J = 8.0 Hz, 1H), 4.19 - 4.15 (m, 2H), 4.01 - 3.97 (m, 1H), 3.89 - 3.82 (m, 3H), 2.64 - 2.58 (m, 4H), 2.36 (s, 3H), 1.52 (s, 9H), 1.30 (d, J = 6.4 Hz, 6H).

[0911]

[0912] Step 6) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-methylpyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide

[0913]

[0914] Tert-Butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-methylpyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (150 mg, 0.3 mmol) was added to a 4 M hydrogen chloride solution in 1,4-dioxane (3 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated to obtain the target compound (120 mg, crude), which was used in the next reaction without further purification.

[0915]

[0916] Step 7) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-chloropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0917]

[0918] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-methylpyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide (120 mg, 0.31 mmol), 5-methyl-1-methylsulfonylpyrrole-3-carboxylic acid (76 mg, 0.37 mmol), TCFH (130 mg, 0.46 mmol), and N-methylimidazole (76 mg, 0.93 mmol) were added to DMF (3 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (37.52 mg, yield: 21%).

[0919] 1H NMR (400 MHz, CDCl3) δ 11.35 (s, 1H), 7.75 (s, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.32 (s, 1H), 6.42 (d, J = 7.2 Hz, 2H), 5.31 - 5.27 (m, 1H), 4.41 - 4.36 (m, 2H), 4.16 - 4.13 (m, 2H), 3.78 - 3.77 (m, 2H), 3.20 (s, 3H), 2.96 - 2.95 (m, 1H), 2.64 - 2.63 (m, 1H), 2.58 - 2.53 (m, 2H), 2.46 (s, 3H), 2.32 (s, 3H), 1.29 (d, J = 6.4 Hz, 6H).

[0920]

[0921] Example 44: Preparation of (S)-1-(6-chloro-1,1-dioxido-2,3-dihydro-5H-benzo[e][1,4oxathiepine-8-carbonyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide

[0922]

[0923] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (20 mg, 0.0450 mmol), 6-chloro-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carboxylic acid 1,1-dioxide (19 mg, 0.0675 mmol), and TCFH (19 mg, 0.0675 mmol) were added to acetonitrile (1 mL), and N-methylimidazole (11 mg, 0.1350 mmol) was added, and the mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with distilled water (1 mL) and extracted with ethyl acetate (3 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (9 mg, yield: 31%).

[0924] 1 H NMR (500 MHz, DMSO-d6) δ 12.58 (s, 1H), 8.39 (s, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 7.02-7.00 (m, 1H), 6.70-6.67 (m, 1H), 5.20 (s, 2H), 5.10-5.06 (m, 1H), 4.50-4.46 (m, 1H), 4.34-4.32 (m, 1H), 4.30-4.28 (m, 2H), 4.24-4.22 (m, 2H), 3.80-3.78 (m, 2H), 2.63-3.60 (m, 2H), 2.66-2.61 (m, 1H), 2.67-2.45 (m, 2H), 2.40-2.33 (m, 1H), 1.19-1.17 (d, 6H)

[0925]

[0926] Intermediate 4: Preparation of 7-(ethylsulfonyl)benzo[d][1,3]dioxole-5-carboxylic acid

[0927]

[0928] Step 1) Preparation of 6-bromo-4-fluorobenzo[d][1,3]dioxole

[0929]

[0930] 5-Bromo-3-fluorobenzene-1,2-diol (4 g, 19.3 mmol) was added to DMF (40 mL), and potassium carbonate (13.34 g, 96.5 mmol) and methylene bromide (16.78 g, 96.5 mmol) were added, and the mixture was stirred at 80°C for 16 h. The reaction mixture was cooled to room temperature, diluted with distilled water (200 mL), and extracted with ethyl acetate (100 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the target compound (1.6 g, yield: 35%).

[0931] 1H NMR (400 MHz, DMSO-d6): δ 7.17 - 7.14 (m, 1H), 7.11 - 7.10 (m, 1H), 6.17 (s, 2H).

[0932]

[0933] Step 2) Preparation of 6-bromo-4-(ethylthio)benzo[d][1,3]dioxole

[0934]

[0935] 6-Bromo-4-fluorobenzo[d][1,3]dioxole (1.6 g, 7.3 mmol) and sodium ethanethiolate (1.84 g, 21.9 mmol) were added to DMF (20 mL) and stirred at room temperature for 16 h. The reaction mixture was diluted with distilled water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to obtain the target compound (1.6 g, crude), which was used in the next reaction without further purification.

[0936] 1 H NMR (400 MHz, DMSO-d6): δ 7.05 (d, J = 1.6 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.10 (s, 2H), 2.96 (s, 2H), 1.23-1.19 (m, 3H).

[0937]

[0938] Step 3) Preparation of 6-bromo-4-(ethylsulfonyl)benzo[d][1,3]dioxole

[0939]

[0940] 6-Bromo-4-(ethylthio)benzo[d][1,3]dioxole (1.6 g, 6.1 mmol) was added to acetonitrile / distilled water (1:1, 30 mL), and oxone (11.25 g, 18.3 mmol) was added, and the mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with distilled water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (1.4 g, yield: 74%).

[0941] 1 H NMR (400 MHz, DMSO-d6): δ 7.55 (d, J = 1.6 Hz, 1H), 7.23 (d, J = 1.6 Hz, 1H), 6.30 (s, 2H), 3.88-3.33 (m, 2H), 1.18-1.14 (m, 3H).

[0942]

[0943] Step 4) Preparation of 7-(ethylsulfonyl)benzo[d][1,3]dioxole-5-carboxylic acid

[0944]

[0945] 6-Bromo-4-(ethylsulfonyl)benzo[d][1,3]dioxole (900 mg, 3.07 mmol), palladium(II) acetate (69 mg, 0.31 mmol), DCCP-2HBF4 (161 mg, 0.31 mmol), and potassium carbonate (1273 mg, 9.21 mmol) were added to DMF (20 mL) and stirred at 100°C for 16 h while replacing carbon monoxide gas. After cooling the reaction mixture to room temperature, it was diluted with distilled water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (450 mg, yield: 54%).

[0946] LC / MS (ESI, m / z): [MH] + = 256.95

[0947]

[0948] Example 45: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(7-(ethylsulfonyl)benzo[d][1,3]dioxole-5-carbonyl)azetidine-2-carboxamide

[0949]

[0950] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide (90 mg, 0.23 mmol), 7-(ethylsulfonyl)benzo[d][1,3]dioxole-5-carboxylic acid (60 mg, 0.23 mmol), and TCFH (130 mg, 0.46 mmol) were added to DMF (2 mL), N-methylimidazole (57 mg, 0.69 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (20 mL) and extracted with ethyl acetate (10 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and subjected to column separation to obtain the target compound (20.40 mg, yield: 13%).

[0951] 1 H NMR (400 MHz, CDCl3): δ 12.04 (s, 1H), 7.69 - 7.68 (m, 2H), 7.60 (s, 1H), 7.06 (d, J = 8.8 Hz, 1H), 6.29 (s, 1H), 6.25 (s, 2H), 5.31 - 5.27 (m, 1H), 4.62 (s, 1H), 4.33 - 4.29 (m, 1H), 4.20 - 4.16 (m, 2H), 3.74 - 3.73 (m, 2H), 3.31 - 3.25 (m, 2H), 2.85 (s, 1H), 2.65 - 2.59 (m, 3H), 1.33 (d, J = 7.6 Hz, 3H), 1.30 (d, J = 6.0 Hz, 6H).

[0952]

[0953] Example 46: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-celanazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0954]

[0955] Step 1) Preparation of 4-(6-chloro-4-fluoropyridin-2-yl)-1,3-selenazol-2-amine

[0956]

[0957] 2-Bromo-1-(6-chloro-4-methylpyridin-2-yl)ethan-1-one (1.42 g, 5.6 mmol) and selenourea (0.64 g, 5.6 mmol) were added to methanol / distilled water (1:1, 20 mL), potassium fluoride (491 mg, 8.4 mmol) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with distilled water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (0.38 g, yield: 24%).

[0958] LC / MS (ESI, m / z): [M+H] + = 277.9

[0959]

[0960] Step 2) Preparation of tert-butyl (S)-2-((4-(6-chloro-4-fluoropyridin-2-yl)-1,3-selenazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0961]

[0962] 4-(6-Chloro-4-fluoropyridin-2-yl)-1,3-selenazol-2-amine (190 mg, 0.69 mmol), (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (152 mg, 0.76 mmol), TCFH (232 mg, 0.83 mmol), and N-methylimidazole (165 mg, 2.07 mmol) were added to DMF (5 mL) and stirred at room temperature for 5 h. The reaction mixture was diluted with distilled water (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (251 mg, yield: 79%).

[0963] LC / MS (ESI, m / z): [M+H] + = 460.9

[0964]

[0965] Step 3) Preparation of tert-butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-selenazol-2-yl)carbamoyl)azetidine-1-carboxylate

[0966]

[0967] Tert-Butyl (S)-2-((4-(6-chloro-4-fluoropyridin-2-yl)-1,3-selenazol-2-yl)carbamoyl)azetidine-1-carboxylate (251 mg, 0.55 mmol), (2R,6S)-2,6-dimethylmorpholine (126 mg, 1.09 mmol), Pd-PEPPSI-IPent (50 mg, 0.06 mmol), and cesium carbonate (537 mg, 2.20 mmol) were added to 1,4-dioxane (8 mL) and stirred at 100 °C for 4 h. The reaction mixture was cooled to room temperature, diluted with distilled water (50 mL), and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was separated by column chromatography to obtain the target compound (204 mg, yield: 70%).

[0968] LC / MS (ESI, m / z): [M+H] + = 540.1

[0969]

[0970] Step 4) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-selenazol-yl)azetidine-2-carboxamide

[0971]

[0972] Tert-Butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-selenazol-2-yl)carbamoyl)azetidine-1-carboxylate (204 mg, 0.38 mmol) was added to a 4 M hydrogen chloride solution in 1,4-dioxane (3 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated to obtain the target compound (152 mg, crude), which was used in the next reaction without further purification.

[0973] LC / MS (ESI, m / z): [M+H] + = 440.0

[0974]

[0975] Step 5) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-celanazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0976]

[0977] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-selenazol-yl)azetidine-2-carboxamide (40 mg, 0.09 mmol), 5-methyl-1-methylsulfonylpyrrole-3-carboxylic acid (19 mg, 0.09 mmol), TCFH (31 mg, 0.11 mmol), and N-methylimidazole (21 mg, 0.27 mmol) were added to DMF (1 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (1 mL) and extracted with ethyl acetate (3 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (23.7 mg, yield: 42%).

[0978] 1 H NMR (500 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.46 (s, 1H), 7.47 (s, 1H), 7.03 (d, J = 9.2 Hz, 1H), 6.69-6.66 (m, 1H), 6.42 (s, 1H), 5.07-5.04(m, 1H), 4.49-4.46(m, 1H), 4.38-4.37(m, 1H), 4.29-2.27(m, 2H), 3.64-3.60(m, 2H), 3.59(s, 3H), 2.63-2.58(m, 1H), 2.50-2.49(m, 2H), 2.47(s, 3H), 2.41-2.31(m, 1H), 1.18 (d, J = 6.2 Hz, 6H).

[0979]

[0980] Example 47: Preparation of (S)-1-(3-amino-4-(methylsulfonyl)benzoyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide

[0981]

[0982] Step 1) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(4-(methylsulfonyl)-3-nitrobenzoyl)azetidine-2-carboxamide

[0983]

[0984] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl) thiazol-2-yl) azetidine-2-carboxamide (100 mg, 0.26 mmol), 4-(methylsulfonyl)-3-nitrobenzoic acid (75 mg, 0.31 mmol), and TCFH (107 mg, 0.38 mmol) were added to DMF (2 mL), and N-methylimidazole (63 mg, 0.77 mmol) was added, and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with distilled water (40 mL) and extracted with ethyl acetate (40 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the target compound (110 mg, yield: 66%).

[0985] 1 H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.33 (s, 1H), 8.24 (d, J = 2.0 Hz, 2H), 7.92 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.70 - 6.66 (m, 1H), 5.18 - 5.04 (m, 1H), 4.49 (d, J = 6.0 Hz, 1H), 4.36 - 4.12 (m, 4H), 3.60 (d, J = 6.0 Hz, 2H), 3.54 (s, 3H), 3.35 (d, J = 3.6 Hz, 1H), 2.70 - 2.59 (m, 1H), 2.40 - 2.30 (m, 1H), 1.18 (s, 6H).

[0986]

[0987] Step 2) Preparation of (S)-1-(3-amino-4-(methylsulfonyl)benzoyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide

[0988]

[0989] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(4-(methylsulfonyl)-3-nitrobenzoyl)azetidine-2-carboxamide (110 mg, 0.18 mmol) and iron(III) chloride (86 mg, 0.54 mmol) were added to DMF / distilled water (2:1, 6 mL), and zinc (116 mg, 1.8 mmol) was added. The mixture was stirred at 100°C for 3 h. The reaction mixture was diluted with distilled water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrated mixture was purified by column chromatography to obtain the title compound (21.69 mg, yield: 20%).

[0990] 1 H NMR (400 MHz, CDCl3) δ 11.35 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.69 (s, 1H), 7.20 (s, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.26 - 6.22 (m, 1H), 5.38 - 5.03 (m, 3H), 4.46 (d, J = 6.0 Hz, 1H), 4.28 - 4.22 (m, 1H), 4.15 - 4.11 (m, 2H), 3.79 - 3.67 (m, 2H), 3.08 (s, 3H), 2.94 (s, 1H), 2.62 - 2.55 (m, 3H), 1.29 (d, J = 6.0 Hz, 6H).

[0991]

[0992] Example 48: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[0993]

[0994] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (30 mg, 0.07 mmol), 1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (20 mg, 0.11 mmol), and TCFH (30 mg, 0.11 mmol) were dissolved in acetonitrile (1 mL), N-methylimidazole (17 mg, 0.21 mmol) was added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The extracted organic layer was dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain the target compound (10 mg, yield: 25%).

[0995] 1 H NMR (500 MHz, DMSO-d6) δ 12.48 (s, 1H), 7.91 (s, 1H), 7.65 (s, 1H), 7.34 (s, 1H), 7.00 - 6.98 (m, 1H), 6.70 - 6.68 (m, 1H), 6.66 (s, 1H), 5.06 - 5.05 (m, 1H), 4.52 - 4.51 (m, 1H), 4.41 - 4.40 (m, 1H), 4.30 - 4.28 (m, 2H), 3.69 - 3.59 (m, 5H), 2.62 - 2.60 (m, 1H), 2.47 - 2.45 (m, 2H), 2.33 (m, 1H), 1.19 - 1.17 (m, 6H).

[0996]

[0997] Example 49: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamidecarbonyl)azetidine-2-carboxamide

[0998]

[0999] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (30 mg, 0.07 mmol), 5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (22 mg, 0.11 mmol), and TCFH (30 mg, 0.11 mmol) were dissolved in acetonitrile (1 mL), N-methylimidazole (17 mg, 0.21 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain the target compound (20 mg, yield: 49%).

[1000] 1 H NMR (500 MHz, DMSO-d6) δ 12.45 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 6.99 - 6.98 (m, 1H), 6.69 - 6.67 (m, 1H), 6.42 (s, 1H), 5.03 - 5.02 (m, 1H), 4.47 (m, 1H), 4.37 (m, 1H), 4.30 - 4.28 (m, 2H), 3.61 (m, 2H), 3.57 (s, 3H), 2.60 - 2.59 (m, 1H), 2.44 (m, 2H), 2.31 - 2.30 (m, 1H), 1.19 - 1.17 (d, 6H).

[1001]

[1002] Example 50: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(ethylsulfonyl)-5-methyl-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1003]

[1004] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (20 mg, 0.05 mmol), 1-(ethylsulfonyl)-5-methyl-1H-pyrrole-3-carboxylic acid (15 mg, 0.07 mmol), and TCFH (19 mg, 0.07 mmol) were dissolved in acetonitrile (1 mL), N-methylimidazole (11 mg, 0.16 mmol) was added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain the target compound (4 mg, yield: 15%).

[1005] 1 H NMR (500 MHz, DMSO-d6) δ 12.46 (s, 1H), 7.91 (s, 1H), 7.45 (s, 1H), 7.00 - 6.98 (m, 1H), 6.70 - 6.68 (m, 1H), 6.44 (s, 1H), 5.03 (m, 1H), 4.47 (m, 1H), 4.37 - 4.36 (m, 1H), 4.30 - 4.28 (m, 2H), 3.71 - 3.69 (m, 2H), 3.61 - 3.60 (m, 2H), 2.59 (m, 1H), 2.47 - 2.45 (m, 2H), 2.40 (s, 3H), 2.31 - 2.30 (m, 1H), 1.19 - 1.17 (d, 6H), 1.15 - 1.13 (m, 3H).

[1006]

[1007] Example 51: Preparation of (S)-N-(4-(5-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1008]

[1009]

[1010] Step 1) Preparation of 2-chloro-6-(1-ethoxyvinyl)nicotinonitrile

[1011]

[1012] 2,6-Dichloropyridine-3-carbonitrile (500 mg, 2.89 mmol), tributyl(1-ethoxyvinyl)tin (1044 mg, 2.89 mmol), and Pd(PPh3)4 (167 mg, 0.14 mmol) were added to DMF (8 mL), and cuprous iodide (55 mg, 0.29 mmol) was added while stirring at room temperature under nitrogen. The reaction mixture was stirred at 80°C for 2 hours, cooled to room temperature, and diluted with ethyl acetate and distilled water. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (300 mg, yield: 45%).

[1013] 1 H NMR (400 MHz, CDCl3) δ 8.50-8.48 (m, 1H), 7.77 (d, J = 8.0 Hz, 1H), 5.49 (s, 1H), 4.73 (s, 1H), 4.01 - 3.95 (m, 2H), 1.37 (t, J = 7.2 Hz, 3H).

[1014]

[1015] Step 2) Preparation of 2-((2S,6R)-2,6-dimethylmorpholino)-6-(1-ethoxyvinyl)nicotinonitrile

[1016]

[1017] 2-Chloro-6-(1-ethoxyvinyl)nicotinonitrile (300 mg, 1.44 mmol), (2R,6S)-2,6-dimethylmorpholine (182 mg, 1.58 mmol), and Pd-PEPPSI-IPent (114 mg, 0.14 mmol) were added to 1,4-dioxane (10 mL), and cesium carbonate (1405 mg, 4.31 mmol) was added while stirring at room temperature under nitrogen. The reaction mixture was reacted in a microwave reactor at 120°C for 2 h and then cooled to room temperature. The solid in the reaction mixture was removed by filtration, and the filtrate was concentrated and purified by column chromatography to obtain the target compound (300 mg, yield: 72%).

[1018] 1 H NMR (400 MHz, CDCl3) δ 7.91 - 7.77 (m, 1H), 7.43 - 7.17 (m, 1H), 4.32 - 4.21 (m, 2H), 3.94 - 3.69 (m, 1H), 3.79 - 3.76 (m, 2H), 3.51 - 3.30 (m, 1H), 2.84 - 2.72 (m, 2H), 2.63 (s, 2H), 1.28 - 1.17 (m, 9H).

[1019]

[1020] Step 3) Preparation of 6-(2-bromoacetyl)-2-((2S,6R)-2,6-dimethylmorpholino)nicotinonitrile

[1021]

[1022] 2-((2S,6R)-2,6-dimethylmorpholino)-6-(1-ethoxyvinyl)nicotinonitrile (300 mg, 1.04 mmol) and NBS (204 mg, 1.14 mmol) were added to tetrahydrofuran / distilled water (10:1 volume ratio, 5.5 mL) and stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography to obtain the target compound (300 mg, yield: 76%).

[1023] 1 H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 4.64 (s, 2H), 4.32 - 4.29 (m, 2H), 3.83 - 3.76 (m, 2H), 2.86 - 2.79 (m, 2H), 1.28 (d, J = 6.4 Hz, 6H).

[1024]

[1025] Step 4) Preparation of 6-(2-aminothiazol-4-yl)-2-((2S,6R)-2,6-dimethylmorpholino)nicotinonitrile

[1026]

[1027] 6-(2-Bromoacetyl)-2-((2S,6R)-2,6-dimethylmorpholino)nicotinonitrile (300 mg, 0.78 mmol) and thiourea (71 mg, 0.94 mmol) were added to ethanol (5 mL) and stirred at room temperature for 12 h. The reaction mixture was filtered to obtain the target compound (260 mg, yield: 95%), which was used in the next reaction without further purification.

[1028] 1H NMR (400 MHz, DMSO-d6) δ 8.36 - 8.04 (m, 1H), 7.42 - 7.28 (m, 1H), 7.22 - 7.10 (m, 2H), 4.26 - 4.17 (m, 2H), 3.69 - 3.66 (m, 2H), 2.73 - 2.66 (m, 2H), 1.19 - 1.13 (m, 6H).

[1029]

[1030] Step 5) Preparation of tert-butyl (S)-2-((4-(5-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[1031]

[1032] 6-(2-Aminothiazol-4-yl)-2-((2S,6R)-2,6-dimethylmorpholino)nicotinonitrile (300 mg, 0.95 mmol), (2S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (231 mg, 1.14 mmol), and TCFH (801 mg, 2.85 mmol) were dissolved in DMF (3 mL), and N-methylimidazole (234 mg, 2.85 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours, diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography to obtain the target compound (300 mg, yield: 50%).

[1033] 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 4.92 (t, J = 8.0 Hz, 1H), 4.34 - 4.30 (m, 2H), 4.01 - 3.98 (m, 1H), 3.87 - 3.78 (m, 3H), 2.82 - 2.76 (m, 2H), 2.63 - 2.53 (m, 2H), 1.53 (s, 9H), 1.28 (d, J = 6.0 Hz, 6H).

[1034]

[1035] Step 6) Preparation of (S)-N-(4-(5-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide

[1036]

[1037] Tert-butyl (S)-2-((4-(5-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (120 mg, 0.24 mmol) was added to a 4 M hydrochloric acid 1,4-dioxane solution (10 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated to obtain the target compound (90 mg, quant.), which was used in the next reaction without further purification.

[1038] LC / MS (ESI, m / z): [M+H] + = 399.1

[1039]

[1040] Step 7) Preparation of (S)-N-(4-(5-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1041]

[1042] (S)-N-(4-(5-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide (90 mg, 0.23 mmol), 1-methylsulfonyl-5-methylpyrrole-3-carboxylic acid (51 mg, 0.25 mmol), and TCFH (95 mg, 0.34 mmol) were dissolved in DMF (3 mL), and N-methylimidazole (56 mg, 0.68 mmol) was added. The reaction mixture was stirred at room temperature for 2 h, diluted with ethyl acetate and distilled water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to obtain the title compound (43.43 mg, yield: 21%).

[1043] 1 H NMR (400 MHz, CDCl3) δ 11.47 (s, 1H), 7.84 - 7.79 (m, 2H), 7.58 - 7.54 (m, 2H), 6.41 (s, 1H), 5.33 - 5.29 (m, 1H), 4.41 - 4.36 (m, 2H), 4.30 - 4.26 (m, 2H), 3.84 - 3.78 (m, 2H), 3.21 (s, 3H), 3.00 - 2.88 (m, 1H), 2.75 - 2.60 (m, 2H), 2.63 - 2.60 (m, 1H), 2.47 (d, J = 0.8 Hz, 3H), 1.27 (d, J = 6.4 Hz, 6H).

[1044]

[1045] Example 52: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(3-methyl-4-(methylsulfonyl)-benzoyl)azetidine-2-carboxamide

[1046]

[1047] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide hydrochloride (20 mg, 0.05 mmol), 3-methyl-4-(methylsulfonyl)benzoic acid (14 mg, 0.07 mmol), and TCFH (19 mg, 0.07 mmol) were dissolved in acetonitrile (1 mL), N-methylimidazole (11 mg, 0.14 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain the target compound (26 mg, yield: 98%).

[1048] 1 H NMR (500 MHz, CDCl3-d) δ 11.05 (s, 1H), 8.12 - 8.11 (m, 1H), 7.71 (s, 1H), 7.65 - 7.63 (m, 1H), 7.12 - 7.10 (m, 1H), 6.23 - 6.21 (m, 1H), 5.37 - 5.33 (m, 1H), 4.48 - 4.44 (m, 1H), 4.27 - 4.22 (m, 1H), 4.11 - 4.09 (m, 2H), 3.75 - 3.70 (m, 2H), 3.11 (s, 3H), 2.99 - 2.93 (m, 1H), 2.76 (s, 3H), 2.67 - 2.61 (m, 1H), 2.59 - 2.54 (m, 2H), 1.29 - 1.28 (d, 6H).

[1049]

[1050] Example 53: Preparation of (2S,3S)-1-((R)-4-cyano-4-methylisochroman-6-carbonyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methylazetidine-2-carboxamide

[1051]

[1052]

[1053] Step 1) Tert-butyl (2S,3S)-2-((4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-3-methylazetidine-1-carboxylate

[1054]

[1055] 4-(6-Chloro-4-fluoropyridin-2-yl)thiazol-2-amine (400 mg, 1.74 mmol), (2S,3S)-1-(tert-butoxycarbonyl)-3-methylazetidine-2-carboxylic acid (562 mg, 2.61 mmol), and TCFH (733 mg, 2.61 mmol) were dissolved in acetonitrile (7 mL), N-methylimidazole (429 mg, 5.23 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain the target compound (743 mg, quant.).

[1056] LC / MS (ESI, m / z): [M+H] + = 427.1

[1057]

[1058] Step 2) Preparation of tert-butyl (2S,3S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-3-methylazetidine-1-carboxylate

[1059]

[1060] Tert-Butyl (2S,3S)-2-((4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-3-methylazetidine-1-carboxylate (743 mg, 1.74 mmol), (2R,6S)-2,6-dimethylmorpholine (300 mg, 2.61 mmol), Pd2(dba)3 (159 mg, 0.17 mmol), XPhos (166 mg, 0.35 mmol), and sodium tert-butoxide (502 mg, 5.23 mmol) were dissolved in 1,4-dioxane (7 mL) and stirred at 90 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and separated by column to obtain the target compound (880 mg, quant.).

[1061] LC / MS (ESI, m / z): [M+H] + = 506.2

[1062]

[1063] Step 3) Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methylazetidine-2-carboxamide hydrochloride

[1064]

[1065] Tert-Butyl (2S,3S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-3-methylazetidine-1-carboxylate (880 mg, 1.74 mmol) was dissolved in methyl chloride (10 mL), 4 N hydrochloric acid 1,4-dioxane solution (3 mL) was slowly added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, methyl chloride (10 mL) was added to the reaction mixture and cooled to 0°C. The resulting solid was filtered to obtain the target compound (130 mg, yield: 17%).

[1066] 1H NMR (500 MHz, DMSO-d6) δ 12.90 (s, 1H), 9.63 (s, 1H), 9.05 (s, 1H), 7.98 (s, 1H), 6.98 - 6.96 (m, 1H), 6.72 - 6.70 (m, 1H), 4.79 - 4.77 (m, 1H), 4.30 - 4.28 (m, 2H), 3.96 (m, 1H), 3.61 (s, 3H), 2.98 - 2.94 (m, 1H), 2.47 - 2.45 (m, 2H), 1.36 - 1.35 (m, 3H), 1.19 - 1.18 (d, 6H).

[1067]

[1068] Step 4) Preparation of (2S,3S)-1-((R)-4-cyano-4-methylisochroman-6-carbonyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methylazetidine-2-carboxamide

[1069]

[1070] (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methylazetidine-2-carboxamide hydrochloride (50 mg, 0.11 mmol), (R)-4-cyano-4-methylisochroman-6-carboxylic acid (37 mg, 0.17 mmol), and TCFH (48 mg, 0.17 mmol) were dissolved in acetonitrile (1 mL), N-methylimidazole (28 mg, 0.34 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain the target compound (30 mg, yield: 44%).

[1071] 1H NMR (500 MHz, CDCl3-d) δ 11.09 (s, 1H), 7.94 (s, 1H), 7.70 (s, 1H), 7.58 - 7.56 (m, 1H), 7.15 - 7.11 (m, 2H), 6.23 - 6.20 (m, 1H), 4.88 - 4.86 (m, 3H), 4.55 - 4.52 (m, 1H), 4.13 - 4.09 (m, 4H), 3.85 - 3.82 (m, 1H), 3.75 - 3.70 (m, 2H), 3.33 - 3.28 (m, 1H), 2.58 - 2.54 (m, 2H), 1.77 (s, 3H), 1.39 - 1.38 (m, 3H), 1.30 (m, 6H).

[1072]

[1073] Example 54: (S)-1-((R)-4-cyano-4-methylisochroman-6-carbonyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-selenazol-2-yl)azetidine-2-carboxamide

[1074]

[1075] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-selenazol-yl)azetidine-2-carboxamide (34.7 mg, 0.08 mmol) was dissolved in DMF (1 mL), 5-methyl-1-methylsulfonylpyrrole-3-carboxylic acid (17.2 mg, 0.08 mmol), TCFH (26.6 mg, 0.10 mmol), and N-methylimidazole (18.9 mg, 0.24 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated and dried over anhydrous sodium sulfate. The separated organic layer was concentrated and purified by column chromatography to obtain the target compound (23.7 mg, yield: 47%).

[1076] 1H NMR (500 MHz, DMSO-d6) δ12.68 (s, 1H), 8.48 (s, 1H), 7.86 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 9.5 Hz, 1H), 6.67 (d, J = 9.5 Hz, 1H), 5.14 - 5.11 (m, 1H), 4.92 - 4.82 (m, 2H), 4.54 - 4.49 (m, 1H), 4.33 - 4.19 (m, 4H), 3.88 - 3.87 (m, 1H), 3.64 - 3.61 (m, 2H), 2.64 - 2.59 (m, 1H), 2.47 - 2.45 (m, 2H), 2.36 - 2.31 (m, 1H), 1.69 (s, 3H), 1.18 (d, J = 6.1 Hz, 6H).

[1077]

[1078] Example 55: Preparation of (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide

[1079]

[1080] (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride (50 mg, 0.11 mmol), 5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (33 mg, 0.16 mmol), and TCFH (45 mg, 0.16 mmol) were dissolved in acetonitrile (1 mL), N-methylimidazole (26 mg, 0.32 mmol) was added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and then separated by column to obtain the target compound (29 mg, yield: 44%).

[1081] 1 H NMR (500 MHz, DMSO-d6) δ 12.62 (s, 1H), 7.89 (s, 1H), 7.47 (s, 1H), 7.01 - 6.98 (m, 1H), 6.70 - 6.67 (m, 1H), 6.43 (s, 1H), 4.90 (m, 1H), 4.30 - 4.28 (m, 2H), 4.03 - 4.01 (m, 1H), 3.92 - 3.90 (m, 1H), 3.64 - 3.61 (m, 2H), 3.56 (s, 3H), 2.47 - 2.44 (m, 2H), 1.78 (m, 1H), 1.73 - 1.70 (m, 1H), 1.19 - 1.17 (d, 6H), 0.83 - 0.81 (m, 1H), 0.26 (m, 1H).

[1082]

[1083] Example 56: Preparation of (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(1-(ethylsulfonyl)-5-methyl-1H-pyrrole-3-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide

[1084]

[1085] (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride (50 mg, 0.11 mmol), 1-(ethylsulfonyl)-5-methyl-1H-pyrrole-3-carboxylic acid (35 mg, 0.16 mmol), and TCFH (45 mg, 0.16 mmol) were dissolved in acetonitrile (1 mL), N-methylimidazole (26 mg, 0.32 mmol) was added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and then separated by column to obtain the target compound (26 mg, yield: 40%).

[1086] 1 H NMR (500 MHz, DMSO-d6) δ 12.62 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.01 - 6.98 (m, 1H), 6.69 - 6.67 (m, 1H), 6.45 (s, 1H), 4.90 (m, 1H), 4.30 - 4.28 (m, 2H), 4.03 - 4.01 (m, 1H), 3.89 - 3.87 (m, 1H), 3.71 - 3.67 (m, 2H), 3.63 - 3.59 (m, 2H), 2.47 - 2.44 (m, 2H), 2.39 (s, 3H), 1.78 - 1.77 (m, 1H), 1.73 - 1.70 (m, 1H), 1.18 - 1.17 (d, 6H), 1.16 - 1.14 (m, 3H), 0.88 - 0.85 (m, 1H), 0.28 - 0.27 (m, 1H).

[1087]

[1088] Example 57: Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methyl-1-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide

[1089]

[1090] (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methylpyrrolidine-2-carboxamide hydrochloride (50 mg, 0.11 mmol), 5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (34 mg, 0.16 mmol), and TCFH (46 mg, 0.16 mmol) were dissolved in acetonitrile (1 mL), N-methylimidazole (27 mg, 0.33 mmol) was added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and then separated by column to obtain the target compound (32 mg, yield: 47%).

[1091] 1 H NMR (500 MHz, DMSO-d6) δ 12.43 (s, 1H), 7.86 (s, 1H), 7.52 (s, 1H), 7.00 - 6.98 (m, 1H), 6.69 - 6.67 (m, 1H), 6.44 (s, 1H), 4.30 - 4.27 (m, 2H), 4.24 - 4.23 (m, 1H), 3.90 - 3.87 (m, 2H), 3.63 - 3.58 (m, 2H), 3.56 (s, 3H), 2.49 - 2.44 (m, 2H), 2.33 - 2.27 (m, 1H), 2.19 - 2.13 (m, 1H), 1.69 - 1.62 (m, 1H), 1.19 - 1.17 (d, 6H), 1.16 - 1.15 (m, 3H).

[1092]

[1093] Intermediate 5: Preparation of 5-(trideuteriomethyl)-1-(ethylsulfonyl)-1H-pyrrole-3-carboxylic acid

[1094]

[1095] Step 1) Preparation of tert-butyl 5-(trideuteriomethyl)-1-(ethylsulfonyl)-1H-pyrrole-3-carboxylate

[1096]

[1097] Tert-Butyl 5-(trideuteriomethyl)-1H-pyrrole-3-carboxylate (493.0 mg, 2.68 mmol) was dissolved in tetrahydrofuran (17 mL), and 1 M sodium bis(trimethylsilyl)amide tetrahydrofuran solution (5.4 mL, 5.4 mmol) was slowly added at 0°C. The reaction mixture was stirred at room temperature overnight and diluted with ethyl acetate and distilled water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to obtain the target compound (437.4 mg, yield: 59.7%), which was used in the next reaction without further purification.

[1098]

[1099] Step 2) Preparation of 5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid

[1100]

[1101] Tert-Butyl 5-(trideuteriomethyl)-1-(ethylsulfonyl)-1H-pyrrole-3-carboxylate (437.4 mg, 1.60 mmol) was added to a 4 M hydrochloric acid solution in 1,4-dioxane (4.0 mL) and stirred overnight at room temperature. After concentration under reduced pressure, the residue was washed with ethyl acetate and filtered to obtain the target compound (311.6 mg, yield: 88%).

[1102] 1H NMR (500 MHz, DMSO-d6) δ 12.48 (br, 1H), 7.54 (s, 1H), 6.41 (s, 1H), 3.69 (q, J = 7.3 Hz, 2H), 1.13 (t, J = 7.3 Hz, 3H)

[1103]

[1104] Example 58: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(ethylsulfonyl)-5-(trideuteriomethyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1105]

[1106] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide (35.6 mg, 0.09 mmol), 5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (20.0 mg, 0.09 mmol), and TCFH (30.6 mg, 0.11 mmol) were dissolved in acetonitrile (1 mL), N-methylimidazole (0.02 mL, 0.27 mmol) was added, and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated and separated by column chromatography to obtain the target compound (31.1 mg, yield: 58%).

[1107] 1H NMR (500 MHz, DMSO-d6) δ 12.45 (s, 1H), 7.90 (s, 1H), 7.45 (s, 1H), 7.00 (m, 1H), 6.70 - 6.67 (m, 1H), 6.44 (s, 1H), 5.05 - 5.02 (m, 1H), 4.48 - 4.47 (m, 1H), 4.38 - 4.36 (m, 1H), 4.30 - 4.27 (m, 1H), 3.71 - 3.67 (m, 2H), 3.65 - 3.60 (m, 2H), 2.65 - 2.64 (m, 1H), 2.51 - 2.47 (m, 2H), 2.37 - 2.36 (m, 1H), 1.19 - 1.12 (m, 9H).

[1108]

[1109] Example 59: Preparation of (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(1-(ethylsulfonyl)-5-(trideuteriomethyl)-1H-pyrrole-3-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide

[1110]

[1111] (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide hydrochloride (30 mg, 0.07 mmol), 1-(ethylsulfonyl)-5-(methyl-d3)-1H-pyrrole-3-carboxylic acid (22 mg, 0.10 mmol), and TCFH (28 mg, 0.10 mmol) were dissolved in acetonitrile (1 mL), N-methylimidazole (16 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and then separated by column to obtain the target compound (23 mg, yield: 56%).

[1112] 1 H NMR (500 MHz, DMSO-d6) δ 12.62 (s, 1H), 7.89 (s, 1H), 7.46 (s, 1H), 7.01 - 6.98 (m, 1H), 6.69 - 6.67 (m, 1H), 6.45 (s, 1H), 4.90 (s, 1H), 4.30 - 4.27 (m, 2H), 4.03 - 4.01 (m, 1H), 3.88 - 3.86 (m, 1H), 3.71 - 3.67 (m, 2H), 3.63 - 3.59 (m, 4H), 2.47 - 2.44 (m, 2H), 1.78 - 1.77 (m, 1H), 1.73 - 1.70 (m, 1H), 1.18 - 1.16 (m, 9H).

[1113]

[1114] Example 60: Preparation of (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(ethylsulfonyl)-5-(trideuteriomethyl)-1H-pyrrole-3-carbonyl)-3-methylpyrrolidine-2-carboxamide

[1115]

[1116] (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methylpyrrolidine-2-carboxamide hydrochloride (30 mg, 0.07 mmol), 5-(methyl-d3)-1-(ethylsulfonyl)-1H-pyrrole-3-carboxylic acid (22 mg, 0.0987 mmol), and TCFH (28 mg, 0.10 mmol) were dissolved in acetonitrile (1 mL), N-methylimidazole (16 mg, 0.20 mmol) was added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and then separated by column to obtain the target compound (16 mg, yield: 39%).

[1117] 1H NMR (500 MHz, DMSO-d6) δ 12.43 (s, 1H), 7.86 (s, 1H), 7.51 (s, 1H), 7.00 - 6.98 (m, 1H), 6.69 - 6.66 (m, 1H), 6.46 (s, 1H), 4.30 - 4.27 (m, 2H), 4.23 - 4.22 (m, 1H), 3.89 - 3.86 (m, 2H), 3.71 - 3.66 (m, 2H), 3.63 - 3.59 (m, 2H), 2.47 - 2.44 (m, 2H), 2.31 - 2.27 (m, 1H), 2.17 - 2.14 (m, 1H), 1.69 - 1.62 (m, 1H), 1.18 - 1.17 (d, 6H), 1.15 - 1.14 (m, 6H).

[1118]

[1119] Example 61: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-selenazol-2-yl)-1-(1-(ethylsulfonyl)-5-(trideuteriomethyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1120]

[1121] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-selenazol-2-yl)azetidine-2-carboxamide hydrochloride (80 mg, 0.17 mmol), 1-(ethylsulfonyl)-5-(methyl-d3)-1H-pyrrole-3-carboxylic acid (56 mg, 0.25 mmol), and TCFH (71 mg, 0.25 mmol) were dissolved in acetonitrile (1 mL), N-methylimidazole (42 mg, 0.51 mmol) was added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and then separated by column to obtain the target compound (55 mg, yield: 51%).

[1122] 1 H NMR (500 MHz, CDCl3-d) δ 11.43 (s, 1H), 8.38 (s, 1H), 7.54 (s, 1H), 7.24 - 7.22 (m, 1H), 6.42 (s, 1H), 6.25 - 6.21 (m, 1H), 5.32 - 5.29 (m, 1H), 4.41 - 4.37 (m, 2H), 4.12 - 4.07 (m, 2H), 3.75 - 3.71 (m, 2H), 3.34 - 3.29 (m, 2H), 2.97 - 2.96 (m, 1H), 2.65 - 2.55 (m, 3H), 1.33 - 1.30 (m, 3H), 1.29 - 1.28 (d, 6H).

[1123]

[1124] Example 62: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1125]

[1126] Step 1) Preparation of 2-bromo-1-(6-bromo-3-fluoropyridin-2-yl)ethan-1-one

[1127]

[1128] 1-(6-Bromo-3-fluoropyridin-2-yl)ethan-1-one (426.7 mg, 1.96 mmol) was dissolved in methyl chloride (7.0 mL), and NBS (383.2 mg, 2.15 mmol) and para-toluenesulfonic acid hydrate (558.5 mg, 2.94 mmol) were added, and the mixture was stirred at 40°C overnight. The reaction mixture was cooled to room temperature and diluted with methyl chloride and distilled water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to obtain the target compound (734.1 mg, quant.), which was used in the next reaction without further purification.

[1129]

[1130] Step 2) Preparation of 4-(6-bromo-3-fluoropyridin-2-yl)thiazol-2-amine

[1131]

[1132] 2-Bromo-1-(6-bromo-3-fluoropyridin-2-yl)ethan-1-one (734.1 mg, 2.47 mmol) was dissolved in ethanol (12.4 mL), thiourea (282.3 mg, 3.71 mmol) was added, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain the target compound (435.9 mg, yield: 65%).

[1133] LC / MS (ESI, m / z): [M] + , [M+2] + = 273.9, 275.9

[1134]

[1135] Step 3) Preparation of tert-butyl (S)-2-((4-(6-bromo-3-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine)-1-carboxylate

[1136]

[1137] 4-(6-Bromo-3-fluoropyridin-2-yl)thiazol-2-amine (435.9 mg, 1.59 mmol) was dissolved in DMF (8.2 mL), and (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (320.0 mg, 1.59 mmol), TCFH (535.3 mg, 1.91 mmol), and N-methylimidazole (380.2 μl, 4.77 mmol) were added. The mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain the target compound (353.8 mg, yield: 49%).

[1138] LC / MS (ESI, m / z): [M] + , [M+2] + = 475.0, 459.0

[1139]

[1140] Step 4) Preparation of tert-butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[1141]

[1142] Tert-Butyl (S)-2-((4-(6-bromo-3-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine)-1-carboxylate (353.8 mg, 0.77 mmol), (2R,6S)-2,6-dimethylmorpholine (191 μl, 1.55 mmol), Pd2(dba)3 (44.5 mg, 0.08 mmol), XPhos (73.8 mg, 0.16 mmol), and sodium tert-butoxide (223.1 mg, 2.32 mmol) were dissolved in 1,4-dioxane (7 mL) and stirred at 80 °C for 5 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (117.5 mg, yield: 31%).

[1143] LC / MS (ESI, m / z): [M+H] + = 492.2

[1144]

[1145] Step 5) Preparation of (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxamide hydrochloride

[1146]

[1147] Tert-Butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (117.5 mg, 0.24 mmol) was added to a 4 N hydrochloric acid 1,4-dioxane solution (1 mL) and stirred at room temperature overnight. The reaction was monitored by TLC, and after completion of the reaction, the reaction mixture was concentrated to obtain the target compound (101.2 mg, quant.), which was used in the next reaction without further purification.

[1148]

[1149] Step 6) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1150]

[1151] (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxamide hydrochloride (35.6 mg, 0.08 mmol) was dissolved in DMF (2.6 mL) solution, 1-(methylsulfonyl)-5-methyl-1H-pyrrole-3-carboxylic acid (16.9 mg, 0.08 mmol), TCFH (27.9 mg, 0.10 mmol), and N-methylimidazole (0.02 mL, 0.25 mmol) were added, and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (34.6 mg, yield: 72%).

[1152] 1 H NMR (500 MHz, DMSO-d6) δ 12.51 (s, 1H), 7.77 (s, 1H), 7.61 - 7.57 (m, 1H), 7.46 (s, 1H), 6.90 - 6.87 (m, 1H), 6.41 (s, 1H), 5.06 - 5.03 (m, 1H), 4.49 - 4.45 (m, 1H), 4.39 - 4.35 (m, 1H), 4.15 (d, J = 11.3 Hz, 2H), 3.67 - 3.60 (m, 2H), 3.56 (s, 3H), 2.65 - 2.56 (m, 1H), 2.50 (s, 3H), 2.50 - 2.30 (m, 2H), 2.23 (m, 1H), 1.18 (d, J = 6.2 Hz, 6H).

[1153]

[1154] Example 63: Preparation of (2S,5S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-5-methyl-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide

[1155]

[1156]

[1157] Step 1) Preparation of tert-butyl (2S,5S)-2-((4-(6-bromo-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-5-methylpyrrolidine-1-carboxylate

[1158]

[1159] 4-(6-Bromo-3-fluoropyridin-2-yl)thiazol-2-amine (328.2 mg, 1.43 mmol) was dissolved in DMF (4.4 mL), and (2S,5S)-1-(tert-butoxycarbonyl)-5-methylpyrrolidine-carboxylic acid (328.0 mg, 1.43 mmol), TCFH (481.1 mg, 1.72 mmol), and N-methylimidazole (0.34 mL, 4.29 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain the target compound (472.6 mg, yield: 75%).

[1160] LC / MS (ESI, m / z): [M+H] + = 441.1

[1161]

[1162] Step 2) Preparation of tert-butyl(2S,5S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-5-methylpyrrolidine-1-carboxylate

[1163]

[1164] Tert-Butyl (2S,5S)-2-((4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-5-methylpyrrolidine-1-carboxylate (469.8 mg, 1.07 mmol) was dissolved in 1,4-dioxane, (2S,6R)-2,6-dimethylmorpholine (0.27 mL, 2.13 mmol), Pd(dba)2 (61.5 mg, 0.11 mol), Xphos (101.5 mg, 0.21 mmol), and sodium tert-butoxide (307.2 mg, 3.20 mmol) were added, and the mixture was stirred at 90 °C for 4 h. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was diluted with ethyl acetate and distilled water, and only the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to obtain the target compound (240.7 mg, yield: 44%).

[1165] LC / MS (ESI, m / z): [M+H] + = 520.2

[1166]

[1167] Step 3) Preparation of (2S,5S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-5-methylpyrrolidine-2-carboxamide hydrochloride

[1168]

[1169] Tert-Butyl (2S,5S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-5-methylpyrrolidine-1-carboxylate (240.7 mg, 0.46 mmol) was added to 4N hydrochloric acid 1,4-dioxane (1.5 mL, 5.79 mmol) and stirred at room temperature for 3 h. The reaction mixture was concentrated to obtain the target compound (216.3 mg, quant.), which was used in the next reaction without further purification.

[1170] LC / MS (ESI, m / z): [M+H] += 420.2

[1171]

[1172] Step 4) Preparation of (2S,5S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-5-methyl-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide

[1173]

[1174] To a solution of (2S,5S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-5-methylpyrrolidine-2-carboxamide hydrochloride (37.6 mg, 0.08 mmol) in acetonitrile (2.0 mL) were added 1-(methylsulfonyl)-5-methyl-1H-pyrrole-3-carboxylic acid (16.7 mg, 0.08 mmol), TCFH (27.5 mg, 0.10 mmol), and N-methylimidazole (0.02 mL, 0.27 mmol), and the mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated and purified by column chromatography to obtain the title compound (26.3 mg, yield: 53%).

[1175] 1 H NMR (500 MHz, DMSO-d6): δ 12.45 (s, 1H), 7.88 (s, 1H), 7.46 (s, 1H), 6.99 - 6.97 (m, 1H), 6.69 - 6.67 (m, 1H), 6.43 (s, 1H), 4.71 (m, 1H), 4.47 (m, 1H), 4.30 - 4.28 (m, 2H), 3.65 - 3.55 (m, 4H), 3.36 (s, 3H), 2.50 - 2.40 (m, 4H), 2.28 (m, 1H), 2.05 (m, 1H), 1.74 (m, 1H), 1.29 (m, 3H), 1.18 (d, J = 6.2 Hz, 6H).

[1176]

[1177] Example 64: Preparation of (2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-5-methyl-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide

[1178]

[1179]

[1180] Step 1) Preparation of tert-butyl(2S,5R)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-5-methylpyrrolidine-1-carboxylate

[1181]

[1182] Tert-Butyl (2S,5R)-2-((4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-5-methylpyrrolidine-1-carboxylate (294 mg, 0.67 mmol) was dissolved in 1,4-dioxane (2.2 mL), (2S,6R)-2,6-dimethylmorpholine (0.12 mL, 1.000 mmol), tris(dibenzylideneacetone)dipalladium (61 mg, 0.067 mmol), Xphos (64 mg, 0.13 mmol), and sodium tert-butoxide (192 mg, 2.000 mmol) were added, and the mixture was stirred at 90°C for 2 h. The reaction mixture was cooled to room temperature and filtered through diatomaceous earth. The filtrate was diluted with ethyl acetate and distilled water, and only the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to obtain the target compound (123 mg, yield: 35%).

[1183] LC / MS (ESI, m / z): [M+H] + = 520.4

[1184]

[1185] Step 2) Preparation of (2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-5-methylpyrrolidine-2-carboxamide hydrochloride

[1186]

[1187] To a solution of tert-butyl (2S,5R)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)-5-methylpyrrolidine-1-carboxylate (123 mg, 0.24 mmol) in methyl chloride (0.8 mL) was added 4 N hydrochloric acid 1,4-dioxane (0.3 mL, 1.18 mmol), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to obtain the target compound, which was used in the next reaction without further purification.

[1188] LC / MS (ESI, m / z): [M+H] + = 420.4

[1189]

[1190] Step 3) Preparation of (2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-5-methyl-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide

[1191]

[1192] To a solution of (2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-5-methylpyrrolidine-2-carboxamide hydrochloride (20 mg, 0.04 mmol) in acetonitrile (1.0 mL) were added 1-(methylsulfonyl)-5-methyl-1H-pyrrole-3-carboxylic acid (13 mg, 0.07 mmol), TCFH (18 mg, 0.07 mmol), and N-methylimidazole (0.01 mL, 0.13 mmol), and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by column chromatography to obtain the title compound (6.2 mg, yield: 23%).

[1193] 1 H NMR (500 MHz, DMSO-d6): δ 12.35 (br, 1H), 7.85 (s, 1H), 7.52 (s, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 12.3 Hz, 1H), 6.45 (s, 1H), 4.74 (d, J = 8.7 Hz, 1H), 4.62 - 4.59 (m, 1H), 4.28 (d, J = 12.0 Hz, 2H), 3.60 - 3.55 (m, 5H), 3.34 - 3.28 (m, 2H), 2.41 (s, 3H), 1.92 - 1.66 (m, 2H), 1.35 - 1.13 (m, 11H).

[1194]

[1195] Intermediate 6: Preparation of (S)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxylic acid

[1196]

[1197] 1-(Methylsulfonyl)-5-methylpyrrole-2-carboxylic acid (100 mg, 0.49 mmol), (S)-azetidine-2-carboxylic acid (49 mg, 0.49 mmol), and TCFH (276 mg, 0.98 mmol) were dissolved in DMF (3 mL), N-methylimidazole (121 mg, 1.47 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography to obtain the target compound (50 mg, yield: 33%).

[1198] LC / MS (ESI, m / z): [M+H] + = 287.1

[1199]

[1200] Example 65: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-hydroxypyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1201]

[1202]

[1203] Step 1) Preparation of tert-butyl N-(4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamate

[1204]

[1205] 4-(6-Chloro-4-fluoropyridin-2-yl)tisol-2-amine (1 g, 4.4 mmol), di-tert-butyl dicarbonate (1.44 g, 6.6 mmol), and 4-dimethylaminopyridine (0.81 g, 6.6 mmol) were dissolved in tetrahydrofuran (20 mL), triethylamine (0.67 g, 6.6 mmol) was added, and the mixture was stirred at 70°C for 12 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and distilled water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to obtain the target compound (0.9 g, yield: 56%).

[1206] 1 H NMR (400MHz, CDCl3): δ 8.63 (s, 1H), 7.79 (s, 1H), 7.60 (dd, J = 9.2, 2.0 Hz, 1H), 6.99 (dd, J = 7.6, 2.0 Hz, 1H), 1.52 (s, 9H).

[1207]

[1208] Step 2) Preparation of tert-butyl (4-(4-(benzyloxy)-6-chloropyridin-2-yl)thiazol-2-yl)carbamate

[1209]

[1210] Benzyl alcohol (180 mg, 1.66 mmol) and sodium hydride (72 mg, 3.03 mmol) were mixed in DMF (5 mL) at 0°C, and a solution of tert-butyl N-(4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamate (500 mg, 1.51 mmol) in N,N-dimethylacetamide (5 mL) was slowly added thereto at 0°C. The reaction mixture was stirred at 80°C for 1 h, cooled to room temperature, and diluted with ethyl acetate and distilled water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to obtain the target compound (500 mg, yield: 71%).

[1211] 1 H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.42 - 7.40 (m, 3H), 7.38 - 7.36 (m, 2H), 6.83 (d, J = 2.0 Hz, 1H), 5.15 (s, 2H), 1.52 (s, 9H).

[1212]

[1213] Step 3) Preparation of tert-butyl (4-(4-(benzyloxy)-6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)carbamate

[1214]

[1215] Tert-Butyl N-(4-(4-(benzyloxy)-6-chloropyridin-2-yl)thiazol-2-yl)carbamate (500 mg, 1.19 mmol), (2R,6S)-2,6-dimethylmorpholine (151 mg, 1.31 mmol), and Pd-PEPPSI-IPent (100 mg, 0.119 mmol) were mixed in 1,4-dioxane (15 mL), cesium carbonate (1169 mg, 3.58 mmol) was added, and the mixture was stirred at 100°C for 12 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and distilled water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to obtain the title compound (200 mg, yield: 22%).

[1216] 1 H NMR (400 MHz, CDCl3) δ 7.44 - 7.36 (m, 5H), 7.05 (s, 1H), 6.15 (d, J = 1.6 Hz, 1H), 5.16 (s, 2H), 4.17 - 4.10 (m, 2H), 3.79 (s, 2H), 2.58 (t, J = 11.6 Hz, 2H), 1.55 (s, 9H), 1.29 (d, J = 6.4 Hz, 6H).

[1217]

[1218] Step 4) Preparation of 4-(4-(benzyloxy)-6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-amine

[1219]

[1220] Tert-Butyl (4-(4-(benzyloxy)-6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)carbamate (200 mg, 0.40 mmol) was added to 4 M hydrochloric acid 1,4-dioxane (10 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated and washed with petroleum ether to obtain the target compound (180 mg, yield: 95%), which was used in the next reaction without further purification.

[1221] 1 H NMR (400 MHz, DMSO-d6) δ 7.54 (s, 1H), 7.47 - 7.36 (m, 5H), 7.05 (d, J = 1.6 Hz, 1H), 6.47 (d, J = 1.6 Hz, 1H), 5.22 (s, 2H), 4.37 (d, J = 12.0 Hz, 2H), 3.61 - 3.59 (m, 2H), 2.44 - 2.37 (m, 2H), 1.18 (d, J = 6.4 Hz, 6H).

[1222]

[1223] Step 5) Preparation of (S)-N-(4-(4-(benzyloxy)-6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-((1-methylsulfonyl)-5-methyl-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1224]

[1225] 4-(4-(Benzyloxy)-6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-amine (180 mg, 0.45 mmol), (S)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxylic acid (142 mg, 0.50 mmol), and TCFH (191 mg, 0.68 mmol) were dissolved in DMF (3 mL), N-methylimidazole (111 mg, 1.36 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (250 mg, yield: 74%).

[1226] 1 H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 2H), 7.80 (s, 1H), 7.50 - 7.38 (m, 5H), 6.98 (s, 1H), 6.40 (s, 1H), 5.19 (s, 2H), 5.03 (s, 1H), 4.46 - 4.35 (m, 2H), 4.26 (d, J = 12.0 Hz, 2H), 3.60 (d, J = 6.4 Hz, 2H), 2.89 (s, 3H), 2.73 (s, 3H), 2.41 - 2.33 (m, 4H), 1.18 - 1.16 (m, 6H).

[1227]

[1228] Step 6) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-hydroxypyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1229]

[1230] (S)-N-(4-(4-(Benzyloxy)-6-((2R,6S)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-((1-methylsulfonyl)-5-methyl-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide (100 mg, 0.15 mmol) and palladium / carbon (96 mg, 0.90 mmol) were mixed in methanol / ethyl acetate (4:1 volume ratio, 10 mL) and stirred at room temperature for 12 h under hydrogen gas. The palladium / carbon catalyst was removed by filtration, and the filtrate was concentrated and purified by column chromatography to obtain the target compound (32.96 mg, yield: 35%).

[1231] 1 H NMR (400MHz, DMSO-d6) δ 12.40 (s, 1H), 10.25 (s, 1H), 7.74 (s, 1H), 7.46 (s, 1H), 6.83 (s, 1H), 6.42 (s, 1H), 6.09 (s, 1H), 5.04 (s, 1H), 4.46 - 4.37 (m, 2H), 4.14 (d, J = 12.0 Hz, 2H), 3.74 - 3.59 (m, 2H), 3.57 (s, 3H), 2.42 - 2.38 (m, 4H), 2.34 (d, J = 11.6) Hz, 3H), 1.17 (d, J = 6.0 Hz, 6H).

[1232]

[1233] Example 66: Preparation of (S)-N-(4-(6-((2R,6S)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1234]

[1235]

[1236] Step 1) Preparation of (S)-N-(4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide

[1237]

[1238] Tert-Butyl (S)-2-((4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (2.2 g, 5.3 mmol) was added to a 4 M hydrochloric acid 1,4-dioxane solution (20 mL) and stirred at room temperature for 2 h under nitrogen. The reaction mixture was concentrated to obtain the target compound (1.5 g, yield: 87%), which was used in the next reaction without further purification.

[1239] LC / MS (ESI, m / z): [M+H] + = 312.95

[1240]

[1241] Step 2) Preparation of (S)-N-(4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1242]

[1243] (S)-N-(4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide (1.5 g, 4.8 mmol), 1-(methylsulfonyl)-5-methyl-1H-pyrrole-3-carboxylic acid (1.17 g, 5.76 mmol), and TCFH (2.69 g, 9.6 mmol) were dissolved in DMF (20 mL), and N-methylimidazole (1.18 g, 14.4 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and diluted with ethyl acetate and distilled water. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (1.6 g, yield: 64%).

[1244] LC / MS (ESI, m / z): [M+H] + = 497.95

[1245]

[1246] Step 3) Preparation of (S)-N-(4-(6-((2R,6S)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1247]

[1248] (S)-N-(4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide (500 mg, 1.00 mmol), (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride (73 mg, 0.10 mmol) were mixed in a solution of 1,4-dioxane / distilled water (10:1 volume ratio, 11 mL), and then N,N-diisopropylethylamine (416 mg, 3.0 mmol) and 2-((2R,6S)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (263 mg, 1.10 mmol) was added. The reaction mixture was stirred at 90°C for 16 hours under nitrogen. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography to obtain the target compound (300 mg, yield: 49%) as a white solid.

[1249] 1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 7.99 (s, 1H), 7.53 (d, J = 9.6 Hz, 1H), 7.46 (s, 1H), 7.43 - 7.39 (m, 1H), 6.87 (s, 1H), 6.42 (s, 1H), 5.05 (s, 1H), 4.47 (s, 1H), 4.40 (s, 2H), 3.73 - 3.71 (m, 1H), 3.57 (s, 3H), 2.72 - 2.66 (m, 2H), 2.41 (s, 3H), 2.34 - 2.32 (m, 1H), 2.23 - 2.18 (m, 1H), 1.27 (t, J = 6.4 Hz, 6H).

[1250]

[1251] Example 67: Preparation of (2S)-N-(4-(6-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1252]

[1253] (S)-N-(4-(6-((2R,6S)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide (200 mg, 0.34 mmol) and palladium / carbon (74 mg, 0.69 mmol) were added to methanol (6 mL), and the mixture was stirred at room temperature for 4 h under hydrogen gas. The palladium / carbon was removed by filtration, and the filtrate was concentrated and purified by column chromatography to obtain the target compound (31.95 mg, yield: 15%).

[1254] 1H NMR (400 MHz, DMSO-d6): δ 12.52 (s, 1H), 7.93 (s, 1H), 7.51 (d, J = 9.6 Hz, 1H), 7.46 (s, 1H), 7.19 - 7.16 (m, 1H), 6.42 (s, 1H), 5.04 (s, 1H), 4.49 - 4.70 (m, 1H), 4.38 - 4.36 (m, 1H), 3.57 (s, 3H), 3.08 - 3.02 (m, 1H), 2.60 (s, 1H), 2.41 (s, 3H), 2.33 (s, 1H), 1.88 - 1.84 (m, 2H), 1.45 - 1.39 (m, 2H), 1.26 - 1.22 (m, 2H), 1.15 (d, J = 6.4 Hz, 6H).

[1255]

[1256] Intermediate 7: Preparation of 4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-amine hydrochloride

[1257]

[1258]

[1259] Step 1) Preparation of tert-butyl (4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamate

[1260]

[1261] 4-(6-Chloro-4-fluoropyridin-2-yl)thiazol-2-amine (20 g, 88 mmol), di-tert-butyl dicarbonate (28.8 g, 132 mmol), and 4-dimethylaminopyridine (16.2 g, 132 mmol) were dissolved in tetrahydrofuran (200 mL), and triethylamine (13.4 g, 132 mmol) was added. The reaction mixture was stirred at 70°C for 24 h and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (17 g, yield: 56%).

[1262] LC / MS (ESI, m / z): [M+H] + = 329.80

[1263]

[1264] Step 2) Preparation of tert-butyl (4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamate

[1265]

[1266] Tert-Butyl (4-(6-chloro-4-fluoropyridin-2-yl)thiazol-2-yl)carbamate (5 g, 15.2 mmol), Pd-PEPPSI-IPent (2.41 g, 3.04 mmol), and cesium carbonate (14.86 g, 45.6 mmol) were mixed in 1,4-dioxane (200 mL), and (2R,6S)-2,6-dimethylmorpholine (1.75 g, 15.2 mmol) was added. The reaction mixture was stirred at 80°C for 24 h and then cooled to room temperature. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (3.5 g, yield: 53%).

[1267] LC / MS (ESI, m / z): [M+H]+ = 409.15

[1268]

[1269] Step 3) Preparation of 4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-amine

[1270]

[1271] Tert-Butyl (4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamate (2.8 g, 6.9 mmol) was dissolved in 4 M hydrochloric acid in dioxane solution (50 mL) and stirred at room temperature for 2 h under nitrogen. The reaction mixture was concentrated and washed with petroleum ether to obtain the target compound (1.8 g, yield: 80%), which was used in the next reaction without further purification.

[1272] 1 H NMR (400 MHz, CD3OD) δ 7.47 (s, 1H), 7.02 - 6.98 (m, 1H), 6.65 - 6.61 (m, 1H), 4.29 (d, J = 11.6 Hz, 2H), 3.69 - 3.66 (m, 2H), 2.57 - 2.51 (m, 2H), 1.27 (d, J = 6.4 Hz, 6H).

[1273]

[1274] Example 68: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)-2-oxoimidazolidine-4-carboxamide

[1275]

[1276] Step 1) Preparation of 3-benzyl 1,4-di-tert-butyl (S)-2-oxoimidazolidine-1,3,4-tricarboxylate

[1277]

[1278] 1-Benzyl 5-(tert-butyl) (S)-2-oxoimidazolidine-1,5-dicarboxylate (468.1 mg, 1.46 mmol) and di-tert-butyl dicarbonate (637.7 mg, 2.92 mmol) were mixed in tetrahydrofuran (9.1 mL) and stirred at 60°C for 90 minutes. 4-Dimethylaminopyridine (17.8 mg, 0.15 mmol) was added and stirred at 60°C for 3 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and distilled water. The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated to obtain the target compound (622.0 mg, quant.), which was used in the next reaction without further purification.

[1279] 1 H NMR (500 MHz, DMSO-d6) δ 7.40 - 7.36 (m, 5H), 5.26 - 5.20 (m, 2H), 4.63 - 4.60 (m, 1H), 4.01 - 3.97 (m, 1H), 3.58 - 3.55 (m, 1H), 1.46 (s, 9H), 1.36 (s, 9H).

[1280]

[1281] Step 2) Preparation of di-tert-butyl (S)-2-oxoimidazolidine-1,4-dicarboxylate

[1282]

[1283] 3-Benzyl 1,4-di-tert-butyl (S)-2-oxoimidazolidine-1,3,4-tricarboxylate (622.0 mg, 1.48 mmol) was dissolved in methanol (14.7 mL), 10% palladium / carbon (40.0 mg, quant.) was added, and the mixture was stirred at room temperature under hydrogen gas for 3 hours. The solid was removed through diatomaceous earth filtration, the filtrate was concentrated, and the target compound (287.5 mg, yield: 68%) was obtained through crystallization using ethyl acetate and n-hexane.

[1284] 1H NMR (500 MHz, DMSO-d6) δ 7.84 (s, 1H), 4.12 - 4.09 (m, 1H), 3.96 - 3.92 (m, 1H), 3.67 - 3.64 (m, 1H), 1.43 (m, 18H).

[1285]

[1286] Step 3) Preparation of di-tert-butyl (S)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)-2-oxoimidazolidine-1,4-dicarboxylate

[1287]

[1288] Di-tert-butyl (S)-2-oxoimidazolidine-1,4-dicarboxylate (282.5 mg, 0.99 mmol), 5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (237.6 mg, 1.04 mmol), and TCFH (332.2 mg, 1.18 mmol) were dissolved in DMF (4.1 mL), N-methylimidazole (0.24 mL, 2.96 mmol) was added, and the mixture was stirred at 40°C overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography to obtain the target compound (392.3 mg, yield: 84.3%).

[1289] LC / MS (ESI, m / z): [M+Na] + = 494.2

[1290]

[1291] Step 4) Preparation of (S)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)-2-oxoimidazolidine-4-carboxylic acid

[1292]

[1293] Di-tert-butyl (S)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)-2-oxoimidazolidine-1,4-dicarboxylate (392.3 mg, 0.83 mmol) was slowly added to a 4 M hydrochloric acid solution in 1,4-dioxane (2.6 mL) and stirred at room temperature overnight. The reaction mixture was concentrated and washed with ethyl acetate to obtain the target compound (126.8 mg, yield: 48%), which was used in the next reaction without further purification.

[1294] 1 H NMR (500 MHz, DMSO-d6) δ7.80 (m, 2H), 6.44 (s, 1H), 4.77 - 4.76 (m, 1H), 3.70 - 3.66 (m, 1H), 3.55 (m, 4H), 2.41 (s, 3H).

[1295]

[1296] Step 5) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)-2-oxoimidazolidine-4-carboxamide

[1297]

[1298] 4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-amine hydrochloride (27.3 mg, 0.08 mmol), (S)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)-2-oxoimidazolidine-4-carboxylic acid (26.2 mg, 0.08 mmol), and TCFH (26.6 mg, 0.10 mmol) were dissolved in DMF (2.0 mL), N-methylimidazole (0.02 mL, 0.24 mmol) was added, and the mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (11.4 mg, yield: 24%).

[1299] 1 H NMR (500 MHz, DMSO-d6) δ12.65 (s, 1H), 7.91 (s, 1H), 7.85 (s, 2H), 6.99 - 6.96 (m, 1H), 6.70 - 6.67 (m, 1H), 6.46 (s, 1H), 5.08 - 5.06 (m, 1H), 4.29 (d, J = 12.5 Hz, 2H), 3.74 - 3.70 (m, 1H), 3.63 - 3.60 (m, 2H), 3.59 (s, 3H), 2.50 - 2.45 (m, 2H), 2.40 (s, 3H), 1.18 (d, J = 6.2 Hz, 6H).

[1300]

[1301] Example 69: Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide

[1302]

[1303]

[1304] Step 1) Preparation of tert-butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate

[1305]

[1306] 4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-amine hydrochloride (100 mg, 0.29 mmol), (tert-butoxycarbonyl)-L-proline (125 mg, 0.58 mmol), and TCFH (163 mg, 0.58 mmol) were dissolved in acetonitrile (1 mL), N-methylimidazole (71 mg, 0.87 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (146 mg, quant.).

[1307] LC / MS (ESI, m / z): [M+H] + = 506.1

[1308]

[1309] Step 2) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)pyrrolidine-2-carboxamide hydrochloride

[1310]

[1311] Tert-Butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)carbamoyl)pyrrolidine-1-carboxylate (146 mg, 0.29 mmol) was dissolved in methyl chloride (4 mL), and a 4 M hydrochloric acid 1,4-dioxane solution (1 mL) was slowly added, followed by stirring at room temperature for 3 hours. After completion of the reaction, methyl chloride (5 mL) was added to the reaction mixture, and it was cooled to 0°C. The resulting solid was filtered to obtain the target compound (64 mg, yield: 50%).

[1312] 1H NMR (500 MHz, DMSO-d6) δ 12.89 (s, 1H), 8.40 - 9.38 (m, 1H), 8.87 - 8.86 (m, 1H), 7.97 (s, 1H), 6.98 - 6.96 (d, 1H), 6.73 - 6.70 (d, 1H), 4.48 - 4.45 (m, 1H), 4.30 - 4.28 (m, 2H), 3.63 - 3.60 (m, 2H), 3.30 - 3.29 (m, 2H), 2.48 - 2.45 (m, 2H), 2.42 - 2.39 (m, 1H), 2.06 - 2.01 (m, 1H), 1.97 - 1.94 (m, 2H), 1.19 - 1.18 (d, 6H).

[1313]

[1314] Step 3) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide

[1315]

[1316] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)pyrrolidine-2-carboxamide hydrochloride (50 mg, 0.11 mmol), 5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carboxylic acid (34 mg, 0.17 mmol), and TCFH (48 mg, 0.17 mmol) were dissolved in acetonitrile (1 mL), N-methylimidazole (42 mg, 0.51 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and then separated by column chromatography to obtain the target compound (30 mg, yield: 45%).

[1317] 1H NMR (500 MHz, DMSO-d6) δ 12.41 (s, 1H), 7.87 (s, 1H), 7.51 (s, 1H), 7.00 - 6.97 (d, 1H), 6.70 - 6.67 (d, 1H), 6.45 (s, 1H), 4.69 - 4.66 (m, 1H), 4.30 - 4.28 (m, 2H), 3.90 - 3.85 (m, 1H), 3.83 - 3.78 (m, 1H), 3.63 - 3.59 (m, 2H), 3.56 (s, 3H), 2.49 - 2.44 (m, 2H), 2.41 (s, 3H), 2.27 - 2.22 (m, 1H), 2.09 - 1.89 (m, 3H), 1.18 - 1.17 (d, 6H).

[1318]

[1319] Example 70: Preparation of (S)-N-(4-(4-amino-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1320]

[1321] Step 1) Preparation of 2-chloro-6-(1-ethoxyvinyl)-4-nitropyridine

[1322]

[1323] 2,6-Dichloro-4-nitropyridine (2 g, 10.4 mmol), tributyl(1-ethoxyvinyl)tin (3 g, 8.3 mmol), and Pd(PPh3)4 (0.60 g, 0.52 mmol) were added to 1,4-dioxane (20 mL) and stirred at 100°C for 4 hours under nitrogen. After cooling to room temperature, the reaction mixture was concentrated and purified by column chromatography to obtain the target compound (1.6 g, yield: 60%).

[1324] 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, J = 1.6 Hz, 1H), 8.10 (d, J = 1.6 Hz, 1H), 5.48 (d, J = 2.4 Hz, 1H), 4.70 (d, J = 2.4 Hz, 1H), 4.04 - 3.99 (m, 2H), 1.40 (t, J = 6.8 Hz, 4H).

[1325]

[1326] Step 2) Preparation of 2-bromo-1-(6-chloro-4-nitropyridin-2-yl)ethan-1-one

[1327]

[1328] 2-Chloro-6-(1-ethoxyvinyl)-4-nitropyridine (1.4 g, 6.1 mmol) was dissolved in tetrahydrofuran / distilled water (10:1 volume ratio, 15.4 mL), and NBS (1.09 g, 6.1 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and concentrated. The concentrate was purified by column chromatography to obtain the target compound (1.1 g, yield: 60%), which was used in the next reaction without further purification.

[1329]

[1330] Step 3) Preparation of 4-(6-chloro-4-nitropyridin-2-yl)thiazol-2-amine

[1331]

[1332] 2-Bromo-1-(6-chloro-4-nitropyridin-2-yl)ethan-1-one (1.1 g, 3.9 mmol) was dissolved in ethanol (10 mL), and thiourea (330 mg, 4.3 mmol) was added. The reaction mixture was stirred at room temperature for 16 h and concentrated. The concentrate was crystallized from petroleum ether and methyl chloride to obtain the target compound (1.4 g, yield: 97%), which was used in the next reaction without further purification.

[1333] LC / MS (ESI, m / z): [M+H] + = 257.0

[1334]

[1335] Step 4) Preparation of tert-butyl (S)-2-((4-(6-chloro-4-nitropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[1336]

[1337] 4-(6-Chloro-4-nitropyridin-2-yl)thiazol-2-amine (1.4 g, 5.5 mmol) was dissolved in DMF (20 mL), and (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid (1.33 g, 6.6 mmol), TCFH (3.09 g, 11.0 mmol), and N-methylimidazole (1.35 g, 16.5 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (1 g, yield: 36%).

[1338] LC / MS (ESI, m / z): [M+H] + = 440.1

[1339]

[1340] Step 5) Preparation of tert-butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-nitropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate

[1341]

[1342] Tert-Butyl (S)-2-((4-(6-chloro-4-nitropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (350 mg, 0.794 mmol) was dissolved in 1,4-dioxane (8 mL), (2R,6S)-2,6-dimethylmorpholine (183 mg, 1.59 mmol), Pd-PEPPSI-IPent (31 mg, 0.04 mmol), and cesium carbonate (776 mg, 2.38 mmol) were added, and the mixture was reacted in a microwave reactor at 120°C for 2 h. The solvent was removed by concentration, and the residue was purified by column chromatography to obtain the target compound (185 mg, yield: 42%).

[1343] 1 H NMR (400 MHz, CDCl3) δ 11.07 (s, 1H), 7.99 (s, 1H), 7.75 (s, 1H), 7.25 (d, J = 1.2 Hz, 1H), 4.92 (t, J = 8.0 Hz, 1H), 4.24 (d, J = 12.4 Hz, 2H), 4.01 (q, J = 8.4 Hz, 1H), 3.89 - 3.86 (m, 1H), 3.79 - 3.71 (m, 2H), 2.71 - 2.54 (m, 4H), 1.55 (s, 9H), 1.32 (d, J = 6.4 Hz, 6H).

[1344]

[1345] Step 6) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-nitropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide

[1346]

[1347] Tert-Butyl (S)-2-((4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-nitropyridin-2-yl)thiazol-2-yl)carbamoyl)azetidine-1-carboxylate (180 mg, 0.35 mmol) was added to a 4 M hydrogen chloride solution in 1,4-dioxane (4 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated to obtain the target compound (180 mg, yield: 99%), which was used in the next reaction without further purification.

[1348] LC / MS (ESI, m / z): [M+H] + = 419.3

[1349]

[1350] Step 7) Preparation of (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-nitropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1351]

[1352] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-nitropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide (230 mg, 0.55 mmol) was dissolved in DMF (4 mL), 1-methylsulfonyl-5-methylpyrrole-3-carboxylic acid (134 mg, 0.66 mmol), TCFH (308 mg, 1.10 mmol), and N-methylimidazole (135 mg, 1.65 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and distilled water, and the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the target compound (200 mg, yield: 54%).

[1353] 1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 8.03 (s, 1H), 7.80 (s, 1H), 7.47 (s, 2H), 6.42 (s, 1H), 5.02 (m, 1H), 4.43 - 4.40 (m, 2H), 3.64 - 3.56 (m, 5H), 2.69 (m, 1H), 2.54 - 2.50 (m, 3H), 2.41 (s, 3H), 1.20 (d, J = 6.4 Hz, 6H).

[1354]

[1355] Step 8) Preparation of (S)-N-(4-(4-amino-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide

[1356]

[1357] (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-nitropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide (95 mg, 0.16 mmol) was dissolved in methanol / methyl chloride (1:1 volume ratio, 6 mL), and Raney nickel (92 mg, 1.57 mmol) was added. The reaction mixture was stirred at room temperature under hydrogen gas for 4 h, and the solid was removed by filtration. The filtrate was concentrated and purified by column chromatography to obtain the target compound (23.30 mg, yield: 25%).

[1358] 1H NMR (400 MHz, DMSO-d6) δ 12.34 (s, 1H), 7.64 (s, 1H), 7.46 (s, 1H), 6.66 (s, 1H), 6.41 (s, 1H), 5.83 (s, 1H), 5.78 (s, 2H), 5.06 - 5.03 (m, 1H), 4.51 - 4.33 (m, 2H), 4.06 (d, J = 12.0 Hz, 2H), 3.65 - 3.56 (m, 5H), 2.41 - 2.28 (m, 7H), 1.16 (d, J = 6.4 Hz, 6H).

[1359]

[1360] Experimental Example: SMARCA2 ATPase Assay Test Method and Results

[1361] Recombinant full-length SMARCA2 (Full-length SMARCA2, EpiCypher, 15-1015) was used for the SMARCA2 ATPase activity assay. SMARCA2 was diluted to a concentration of 25 nM in the assay solution (20 mM HEPES (pH 7.5), 20 mM KCl, 1 mM MgCl2, 1 mM DTT (Sigma, 646563), 0.01% BSA (Sigma, A6003), 0.005% Tween 20) and prepared. The test compounds were first diluted in DMSO solution to a concentration 100x of the final experimental concentration, and then diluted twice in the assay solution to a concentration 5x. Plasmid DNA (Life Science Market, PVT2323) used as a substrate was prepared as a 0.25 nM stock solution using DEPC water and stored. During the experiment, it was diluted 1 / 5 in the assay solution to prepare a concentration of 0.05 nM. ATP (10 mM stock solution used) was diluted in the assay solution to prepare a concentration of 450 μM. All experiments were performed at room temperature.

[1362]

[1363] First, 10 μL of the assay solution was prepared, and 10 μL of the test compound diluted to a 5x concentration was added. 10 μL of 25 nM SMARCA2 was added, mixed, and reacted for 5 minutes. 0.05 nM Substrate and 450 μM ATP were first mixed in a 1:1 ratio, and 20 μL of the mixture was added to the reaction mixture after reacting for 5 minutes, mixed, and reacted for 2 hours.

[1364]

[1365] After the ATPase experiment, the results were confirmed using ADP-Glo ​​(Promega, V9102). The ADP-Glo ​​assay was conducted in two steps. First, 50 μL of ADP-Glo ​​reagent was added to the reaction mixture after 2 hours of reaction, mixed, and reacted for 40 minutes. At this step, the ATPase reaction by SMARCA2 was completed, and the remaining residual ATP was removed. Next, 100 μL of Kinase Detection reagent was added at a time and reacted for 40 minutes. At this step, the ATP removal reaction was completed, and a reaction that converts the remaining ADP to ATP occurred. The converted ATP emits light due to the luciferase reaction, and this luminescence signal was measured using a luminescence reader such as Envision (Perkin Elmer) to confirm the SMARCA2 inhibitory activity of the test compound.

[1366]

[1367] The above results are shown in Table 1 below. In Table 1 below, A to D each mean the following.

[1368] A: SMARCA2 IC 50 Value less than 0.1 μM

[1369] B: SMARCA2 IC 50 Value is 0.1 μM or more and less than 0.3 μM

[1370] C: SMARCA2 IC 50Value is 0.3 μM or more and less than 1.0 μM

[1371] D: SMARCA2 IC 50 Value is 1.0 μM or more

[1372]

[1373] Compound SMARCA2 IC 50 (μM) Compound SMARCA2 IC 50 (μM) Compound SMARCA2 IC 50 (μM) Example 1B Example 26A Example 51B Example 2A Example 27A Example 52D Example 3A Example 28B Example 53B Example 4D Example 29A Example 54A Example 5D Example 30D Example 55A Example 6C Example 31D Example 56A Example 7A Example 32B Example 57A Example 8A Example 33D Example 58A Example 9A Example 34D Example 59B Example 10A Example 35C Example 60B Example 11B Example 36A Example 61A Example 12A Example 37A Example 62D Embodiment 13D Embodiment 38B Embodiment 63D Embodiment 14C Embodiment 39A Embodiment 64A Embodiment 15C Embodiment 40A Embodiment 65A Embodiment 16B Embodiment 41A Embodiment 66A Embodiment 17C Embodiment 42B Embodiment 67B Embodiment 18C Embodiment 43B Embodiment 68D Embodiment 19C Embodiment 44D Embodiment 69A Embodiment 20D Embodiment 45D Embodiment 70B Embodiment 21A Embodiment 46A Embodiment 22B Embodiment 47D Embodiment 23C Embodiment 48A Embodiment 24C Embodiment 49A Embodiment 25D Embodiment 50A

[1374]

[1375] This study was supported by the National New Drug Development Project of the National Drug Development Fund (RS-2023-00259457) funded by the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare.

Claims

1. A compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, A is a 4- or 5-membered heteroaliphatic ring containing 1 or 2 N, or C containing 1 or 2 N. 8-12 It is a bicyclic ring, The above A is unsubstituted; or C 1-4 Alkyl, C 1-4 substituted with alkoxy or oxo, B is any one divalent ring selected from the group consisting of benzene, pyridine, pyrimidine, pyrazine, and pyrrolidine, The above B is unsubstituted; or C 1-4 Alkyl, C 1-4 substituted with alkoxy, cyano, hydroxy, amino, or halogen, X is CH, N, O, S, or Se, Y is CH, N, O, or S, R1 is C 6-10 Aryl; C comprising at least one selected from the group consisting of N, O and S 3-14 Heteroaryl; or C comprising at least one selected from the group consisting of N, O and S 8-12 It is a bicyclic 1-membered ring, The above R1 is unsubstituted; or C 1-4 Alkyl, C 1-4 Haloalkyl, (C 1-4 Alkyl)sulfonyl, (C 1-4 alkyl)carbonyl, halogen, cyano, amino, -NH-CO-O-(C 1-4 alkyl), and -CO-CO-N(C 1-4 Substituted with 1 to 3 substituents each independently selected from the group consisting of alkyl)2, R2 is hydrogen, or C 1-4 It is alkyl, R3 is C 6-10 Aryl; C comprising at least one selected from the group consisting of N, O, S and B 3-14 Heteroaryl; C comprising at least one selected from the group consisting of N, O and S 3-14 Heterocycloalkyl; or C comprising at least one selected from the group consisting of N, O, S and B 8-12 It is a bicyclic 1-membered ring, The above R3 is unsubstituted; or C 1-4 Alkyl, C 2-4 Alkenyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, amino, amino(C 1-4 alkyl), di(C 1-4 alkyl)amino, halogen, nitro, cyano, -COO-(C 1-4 alkyl), -CONH-(C 3-6 cycloalkyl), -CO-N(C 1-4 alkyl)2, -CO-NH2, -CO-H, -CO-(C 1-4 alkyl), -SO2-NH2, -CH2-O-(C 1-4 alkyl), -(C 1-4 substituted with 1 to 4 substituents each independently selected from the group consisting of alkylene)-COOH, and piperazinyl, However, the above B is not 1,3-phenylene and 2,6-pyridinediyl.

2. In paragraph 1, A is one selected from the group consisting of: In the above, R4 is hydrogen, C 1-4 Alkyl, or C 1-4 Alkoxy, A compound, or a pharmaceutically acceptable salt thereof.

3. In paragraph 1, B is one selected from the group consisting of: In the above, R5 is C 1-4 Alkyl, C 1-4 Alkoxy, or halogen, R6 is hydrogen or halogen, R7 is C 1-4 Alkyl, C 1-4 alkoxy, cyano, hydroxy, amino, or halogen, A compound, or a pharmaceutically acceptable salt thereof.

4. In paragraph 1, X is S, or Se, A compound, or a pharmaceutically acceptable salt thereof.

5. In paragraph 1, Y is CH, A compound, or a pharmaceutically acceptable salt thereof.

6. In paragraph 1, R1 is one selected from the group consisting of: In the above, R8 is each independently hydrogen, C 1-4 Alkyl, or deuterated C 1-4 It is alkyl, R9 is C 1-4 It is alkyl, R 10 Silver hydrogen, C 1-4 Alkyl, or halogen, R 11 and R 12 are each independently hydrogen, C 1-4 Alkyl, C 1-4 alkoxy, or amino, or can form a bond together, R 13 is amino, or -NH-CO-O-(C 1-4 alkyl), A compound, or a pharmaceutically acceptable salt thereof.

7. In paragraph 1, R2 is hydrogen, A compound, or a pharmaceutically acceptable salt thereof.

8. In paragraph 1, R3 is one selected from the group consisting of: In the above, R 14 are each independently C 1-4 alkyl, A compound, or a pharmaceutically acceptable salt thereof.

9. In paragraph 1, The above chemical formula 1 is represented by the following chemical formula 2, A compound, or a pharmaceutically acceptable salt thereof: [Chemical Formula 2] In the above chemical formula 2, Z is CH, or N, R4 is hydrogen, C 1-4 Alkyl, or C 1-4 It is alkoxy, R7 is C 1-4 Alkyl, C 1-4 alkoxy, cyano, hydroxy, amino, or halogen, R8 is each independently hydrogen, C 1-4 Alkyl, or deuterated C 1-4 It is alkyl, R9 is C 1-4 It is alkyl, R 14 are each independently C 1-4 It is alkyl, n is 0 or 1.

10. In paragraph 1, The compound represented by the above chemical formula 1 is 1) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 2) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 3) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(5-trideuteriomethyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 4) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(1-(methylsulfonyl)-4,5,6,7-tetrahydro-1H-indole-3-carbonyl)azetidine-2-carboxamide, 5) tert-butyl (4-((S)-2-((4-(3-((2S,6R)-2,6-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)carbamoyl)azetidine-1-carbonyl)phenyl)carbamate, 6) (S)-1-(4-aminobenzoyl)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)azetidine-2-carboxamide, 7) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(5-trideuteriomethyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide, 8) (2S,3S)-N-(4-(3-((2R,6S)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-3-methyl-1-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 9) (2S,3S)-N-(4-(3-((2R,6S)-2,6-dimethylmorpholino)-5-fluorophenyl)thiazol-2-yl)-3-methyl-1-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide, 10) (2S)-N-(4-(3-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-5-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 11) (2S)-N-(4-(3-fluoro-5-(hexahydrofuro[3,4-c]pyridin-5(3H)-yl)phenyl)thiazol-2-yl)-1-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 12) (S)-N-(4-(3-((2S,6R)-2-ethyl-6-methylmorpholino)-5-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 13) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-5-methoxyphenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 14) (S)-N-(4-(3-(2,6-dimethylpyridin-4-yl)-5-methoxyphenyl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 15) S)-N-(4-(3-(2-ethyl-6-methylpyridin-4-yl)-5-methoxyphenyl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 16) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 17) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-methylphenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 18) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-4-methylphenyl)thiazol-2-yl)-1-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 19) (S)-N-(4-(3-((2S,6R)-2,6-dimethylmorpholino)-2-fluorophenyl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 20) (S)-N-(4-(2-((2S,6R)-2,6-dimethylmorpholino)pyridin-4-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 21) (S)-N-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 22) (S)-N-(4-(2',6'-dimethyl-[2,4'-bipyridin]-4-yl)thiazol-2-yl)-1-(1,1-dioxido-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carbonyl)pyrrolidine-2-carboxamide, 23) (S)-N-(4-(2-((2S,6R)-2,6-dimethylmorpholino)pyrimidin-4-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 24) (S)-N-(4-(5-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 25) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)pyrazin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 26) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 27) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methoxy-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide, 28) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-4-methoxy-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide, 29) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-5-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 30) (2S)-N-(4-(1-(2,6-dimethylpyridin-4-yl)pyrrolidin-3-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 31) (R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1,1-dioxido-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carbonyl)azetidine-2-carboxamide, 32) (S)-N-(4-(4-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 33) (S)-N-(4-(6-chloro-4-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 34) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-4-methoxy-1-(5-methyl-1-(methylsulfonyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carbonyl)azetidine-2-carboxamide, 35) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrazole-3-carbonyl)azetidine-2-carboxamide, 36) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methyl-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 37) (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide, 38) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1,1-dioxido-2,3-dihydro-5H-benzo[e][1,4]oxathiepine-8-carbonyl)-3-methylazetidine-2-carboxamide, 39) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methyl-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide, 40) (S)-N-(4-(4-chloro-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 41) (S)-1-((R)-4-cyano-4-methylisochroman-6-carbonyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide, 42) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-imidazole-4-carbonyl)azetidine-2-carboxamide, 43) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-methylpyridin-2-yl)thiazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 44) (S)-1-(6-chloro-1,1-dioxido-2,3-dihydro-5H-benzo[e][1,4oxathiepine-8-carbonyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide, 45) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(7-(ethylsulfonyl)benzo[d][1,3]dioxole-5-carbonyl)azetidine-2-carboxamide, 46) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-celanazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 47) (S)-1-(3-amino-4-(methylsulfonyl)benzoyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)azetidine-2-carboxamide, 48) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 49) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 50) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(ethylsulfonyl)-5-methyl-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 51) (S)-N-(4-(5-cyano-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 52) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(3-methyl-4-(methylsulfonyl)-benzoyl)azetidine-2-carboxamide, 53) (2S,3S)-1-((R)-4-cyano-4-methylisochroman-6-carbonyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methylazetidine-2-carboxamide, 54) (S)-1-((R)-4-cyano-4-methylisochroman-6-carbonyl)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-selenazol-2-yl)azetidine-2-carboxamide, 55) (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide, 56) (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(1-(ethylsulfonyl)-5-methyl-1H-pyrrole-3-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide, 57) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-methyl-1-(5-(trideuteriomethyl)-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide, 58) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(ethylsulfonyl)-5-(trideuteriomethyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 59) (1S,2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(1-(ethylsulfonyl)-5-(trideuteriomethyl)-1H-pyrrole-3-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxamide, 60) (2S,3S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(1-(ethylsulfonyl)-5-(trideuteriomethyl)-1H-pyrrole-3-carbonyl)-3-methylpyrrolidine-2-carboxamide, 61) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)-1,3-selenazol-2-yl)-1-(1-(ethylsulfonyl)-5-(trideuteriomethyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 62) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-3-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 63) (2S,5S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-5-methyl-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide, 64) (2S,5R)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-5-methyl-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide, 65) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-hydroxypyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 66) (S)-N-(4-(6-((2R,6S)-2,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 67) (2S)-N-(4-(6-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide, 68) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-3-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)-2-oxoimidazolidine-4-carboxamide, 69) (S)-N-(4-(6-((2S,6R)-2,6-dimethylmorpholino)-4-fluoropyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)pyrrolidine-2-carboxamide, and 70) (S)-N-(4-(4-amino-6-((2S,6R)-2,6-dimethylmorpholino)pyridin-2-yl)thiazol-2-yl)-1-(5-methyl-1-(methylsulfonyl)-1H-pyrrole-3-carbonyl)azetidine-2-carboxamide Any one compound selected from the group consisting of, A compound or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition for preventing or treating a disease related to a BAF complex, comprising a compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

12. In paragraph 11, The above BAF complex-related diseases include cancer, viral infection, Coffin Siris syndrome, neurofibromatosis, or multiple meningiomas. Pharmaceutical composition.

13. In paragraph 12, The above cancer is non-small cell lung cancer, colorectal cancer, bladder cancer, cancer of unknown primary, glioma, breast cancer, melanoma, non-melanoma skin cancer, endometrial cancer, esophagogastric cancer, esophageal cancer, pancreatic cancer, hepatobiliary cancer, soft tissue sarcoma, ovarian cancer, head and neck cancer, renal cell carcinoma, bone cancer, non-Hodgkin's lymphoma, small cell lung cancer, prostate cancer, embryonal tumor, germ cell tumor, cervical cancer, thyroid cancer, salivary gland cancer, gastrointestinal neuroendocrine tumor, uterine sarcoma, gastrointestinal stromal tumor, CNS cancer, thymic tumor, adrenocortical carcinoma, appendix cancer, small intestine cancer, penile cancer, bone cancer, blood cancer, or eye cancer. Pharmaceutical composition.

14. In paragraph 12, The above viral infection is an infection with a virus of the Retroviridae family, a virus of the Hepadnaviridae family, a virus of the Flaviviridae family, a virus of the Adenoviridae family, a virus of the Herpeviridae family, a virus of the Papillomaviridae family, a virus of the Parvoviridae family, a virus of the Poliomaviridae family, a virus of the Paramyxoviridae family, or a virus of the Togaviridae family. Pharmaceutical composition.

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