Novel compound as polymerase theta inhibitor, and pharmaceutical composition comprising thereof

Abstract

The present disclosure relates to novel compounds as polymerase theta inhibitor.

Description

NOVEL COMPOUND AS POLYMERASE THETA INHIBITOR, AND PHARMACEUTICAL COMPOSITION COMPRISING THEREOF

[0001] The present disclosure relates to a novel compound as Polymerase Theta (Polθ) inhibitor, a pharmaceutical composition including the same, and a pharmaceutical use thereof, which inhibits an activity of a Polymerase theta and thus may be used valuably in preventing or treating diseases related thereto.

[0002] DNA damage occurs continually under conditions exposed by various exogenous or endogenous factors. The damaged DNA remains usually in one of two forms: DNA single-strand breaks (SSBs) or DNA double-strand breaks (DSBs). DSBs are largely known as toxic DNA lesions that disrupt genetic stability of cells. To maintain genetic stability, cells generally utilize the DNA damage response (DDR) pathways: homologous recombination (HR),　non-homologous end joining (NHEJ) or polymerase theta-mediated end joining (TMEJ, also referred to as microhomology-mediated end joining (MMEJ)). Among them, HR is widely accepted as the most accurate DDR pathway, and some of HR-related genes (e.g.BRCA1andBRCA2) are considered the gatekeepers of genomic integrity. Not surprisingly, mutations or alterations of HR-related genes such asBRCA1,　BRCA2,　RAD51C,or　PALB2can cause HR-deficiency (HRD), which is eventually related to higher risks for development of several types of cancers. As Poly(ADP-ribose)-polymerase (PARP) is known as an crucial protein involved in both the NHEJ pathway and the base excision repair of cancer cells, PARP inhibitors have potential for inhibiting viability of HRD cancer cells. Although several FDA-approved PARP inhibitors have emerged as the effective therapeutic options for patients with HRD cancers, there still need for developing other therapeutic agents targeting DDR pathways to offer a wider spectrum of therapies for patients with cancers.

[0003] Polθ has recently been emerged as a promising therapeutic target for cancer. DNA polymerase theta (Polθ, encoded by POLQ) functions a central role in TMEJ, which is one of the DDR pathways characterized by a back-up pathway in cells with HR or NHEJ defects. Furthermore, Polθ overexpression has frequently been observed in various types of cancers and is related to poor prognosis of cancers. Thus, a therapeutic agent modulating Polθ activity can give a new option for patients with cancers.

[0004] An objective of the present disclosure is to provide a novel compound showing Polymerase Theta (Polθ) inhibitory activity, a tautomer, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof.

[0005] An objective of the present disclosure is to provide a method for preparing the compound of the present disclosure, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof.

[0006] An objective of the present disclosure is to provide a pharmaceutical composition for treating or preventing Polθ-related diseases, comprising the compound of the present disclosure, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof as an active ingredient.

[0007] An objective of the present disclosure is to provide a method for preventing or treating Polθ-related diseases, comprising administering a therapeutically effective amount of the compound of the present disclosure, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof into a subject.

[0008] An objective of the present disclosure is to provide a use of the compound of the present disclosure, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof in preparation of a medicament for preventing or treating Polθ-related diseases.

[0009] An objective of the present disclosure is to provide a use of the compound of the present disclosure, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof for preventing or treating Polθ-related diseases.

[0010] An objective of the present disclosure is to provide a method for inhibiting Polθ activity, comprising administering a therapeutically effective amount of the compound of the present disclosure, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof into a subject.

[0011] The present disclosure provides a compound represented by a following formula (I), a tautomer, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:

[0012] [Formula (I)]

[0013]

[0014] wherein

[0015] A and B are independently -H, hydroxyl, or joined to form a 3-membered ring;

[0016] m is 0,1, or 2;

[0017] Each Y is independently selected from the group consisting of halo, C1-3 alkyl, C1-3 haloalkyl, cyano, and C1-3 alkoxy;

[0018] X is selected from the group consisting of -C(O)NR1R2, -C(S)NR1R2, -R4, -R4-R5, or -L1-R7;

[0019] R1is selected from the group consisting of -H, C1-3alkyl, C1-3 alkenyl, C1-3 alkynyl, methyl-d3, 3 to 10-membered cycloalkyl unsubstituted or substituted with cyano, -C1-3 alkyl-3 to 10-membered cycloalkyl unsubstituted or substituted with cyano, allyl unsubstituted or substituted with pyridine, propargyl unsubstituted or substituted with pyridine, aminopyridine, pyridazine, aminopyridazine, pyrimidine, or aminopyrimidine, -C1-3 alkyl-indole, -C1-3 alkyl-triazole, and -C1-3 alkyl-triazole-phenyl;

[0020] R2is selected from the group consisting of -H, C1-3alkyl, amino, C1-3 aminoalkyl, propargyl, phenyl, -L2-phenyl, pyridine, -C1-3 alkyl-pyridine, pyrimidine, -C1-3 alkyl-pyrimidine, benzyl, C1-3 alkylbenzyl, 3 to 10-membered cycloalkyl, triazole, -C1-3 alkyl-triazole, imidazole, -C1-3 alkyl-imidazole, tetrahydropyran, benzofuran, dihydrobenzofuran, benzothiophene, indole, -C1-3 alkyl-indole, benzoxazole, dihydrobenzoxazole, benzisoxazole, benzothiazole, thiazolopyridine, pyrrolopyridine, benzimidazole, benzimidazolone, dihydrobenzimidazole, dihydrobenzimidazolone, indazole, piperidine, -methyleneamino-C1-3 alkylamino, pyrazole, -C1-3 alkyl-pyrazole, and quinoline, wherein R2is unsubstituted or substituted with one or more substituents selected from R3;

[0021] or R1and R2are joined to form isoindolinyl or azabicycloheptanyl, unsubstituted or substituted with COOH;

[0022] each R3is independently selected from the group consisting of C1-3alkyl, phenyl, halogen, C1-3 haloalkyl, hydroxyl, C1-3 alkoxy, C1-3 alkoxycarbonyl, and C1-3 alkylamino;

[0023] R4is selected from the group consisting of triazole, dihydrotriazolone, imidazole, oxadiazine, oxadiazinone, oxadiazole, oxadiazolone, pyrimidine, pyrimidinone, benzimidazole, benzoxazole, benzothiazole, and triazolodiazepine, unsubstituted or substituted with one or more substituents selected from halo, C1-3 alkyl, C1-3 alkenyl, and C1-3 alkynyl, C1-3 haloalkyl, acetyl, and sulfonyl;

[0024] R5is selected from the group consisting of 3 to 10-membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 6 to 20-membered aryl, and 6 to 20-membered heteroaryl, wherein R5is unsubstituted or substituted with one or more substituents selected from R6;

[0025] each R6is independently selected from the group consisting of halo, hydroxy, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;

[0026] R7is selected from the group consisting of phenyl, azabicycloheptane, imidazole, isoindoline, and pyrrolopyridine, unsubstituted or substituted with C1-3 alkyl, COOH, or phenyl;

[0027] L1 is selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, -CO-, -C1-3 alkoxy-CO-, -C1-3 alkyl-NH-CO-, and -C1-3 alkyl-N(C1-3 alkyl)-CO-; and

[0028] L2 is selected from the group consisting of C1-3 alkyl, -C1-3 alkyl-CONH-, -C1-3 alkyl-CO-N(C1-3 alkyl)-, -C1-3 alkyl-pyrimidine-, -C1-3 alkyl-dihydropyrimidine-, -C1-3 alkyl-pyrimidinone-, 3 to 10-membered cycloalkyl, -3 to 10-membered cycloalkyl-CONH-, -3 to 10-membered cycloalkyl-CO-N(C1-3 alkyl)-, 3 to 10-membered heterocycloalkyl, -3 to 10-membered heterocycloalkyl-CONH-, and -3 to 10-membered heterocycloalkyl-CO-N(C1-3 alkyl)-.

[0029]

[0030] In one embodiment, X may be -R4or -R4-R5.

[0031] In one embodiment, R1and R2are joined to form isoindolinyl or azabicyclo[2.2.1]heptanyl, unsubstituted or substituted with COOH.

[0032] In one embodiment, R2may be selected from the group consisting of -H, C1-3alkyl, amino, C1-3 aminoalkyl, 3 to 10-membered cycloalkyl, phenyl, -L2-phenyl, pyridine, pyrimidine, triazole, tetrahydropyran, benzofuran, indole, -C1-3 alkyl-indole, benzoxazole, benzothiazole, pyrrolopyridine, dihydrobenzimidazolone, and -methyleneamino-C1-3 alkylamino, wherein R2may be unsubstituted or substituted with one or more substituents selected from R3.

[0033] In one embodiment, R4may be selected from the group consisting of triazole, dihydrotriazolone, imidazole, oxadiazine, oxadiazinone, oxadiazole, oxadiazolone, pyrimidine, pyrimidinone, benzimidazole, benzoxazole, benzothiazole, and triazolodiazepine, wherein the triazole may be unsubstituted or substituted with C1-3 alkyl, C1-3 alkenyl, or C1-3 alkynyl, wherein the imidazole may be unsubstituted or substituted with one or more substituents selected from halo, C1-3 alkyl, C1-3 alkenyl, and C1-3 alkynyl, wherein the pyrimidine may be unsubstituted or substituted with halo, wherein pyrimidinone may be unsubstituted or substituted with C1-3 alkyl, or C1-3 haloalkyl, wherein the benzimidazole may be unsubstituted or substituted with one or more substituents selected from halo, C1-3 alkyl, C1-3 alkenyl, and C1-3 alkynyl, and wherein the triazolodiazepine may be unsubstituted or substituted with acetyl, or sulfonyl.

[0034] In one embodiment, R5may be selected from the group consisting of 3 to 10-membered monocyclic cycloalkyl, 3 to 10-membered monocyclic heterocycloalkyl comprising one or more heteroatoms selected from N, O and S, 6 to 20-membered monocyclic aryl, and 6 to 20-membered monocyclic or bicyclic heteroaryl comprising one or more heteroatoms selected from N, O and S, wherein R5may be unsubstituted or substituted with one or more substituents selected from R6.

[0035] In one embodiment, R5may be selected from the group consisting of cyclohexyl, phenyl, piperidine, piperazine, imidazole, pyridine, pyrazole, triazole, benzofuran, dihydrobenzofuran, benzoxazole, benzoxazolone, benzoisoxazole, benzothiazole, benzothiophene, indazole, indole, pyrrolopyridine, and quinoline, wherein R5may be unsubstituted or substituted with one or more substituents selected from R6.

[0036] In one embodiment, R7may be selected from the group consisting of phenyl, azabicycloheptane (for example, azabicyclo[2.2.1]heptane), imidazole, isoindoline, and pyrrolopyridine, wherein the azabicycloheptane (for example, azabicyclo[2.2.1]heptane) may be unsubstituted or substituted with COOH, wherein the imidazole may be unsubstituted or substituted with phenyl, and wherein the phenyl may be unsubstituted or substituted with C1-3 alkyl.

[0037] In one embodiment, L1 may be selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, -C1-3 alkoxy-CO-, -C1-3 alkyl-NH-CO-, and -C1-3 alkyl-N(C1-3 alkyl)-CO-.

[0038] In one embodiment, L2 may be selected from the group consisting of -C1-3 alkyl-CONH-, -C1-3 alkyl-CO-N(C1-3 alkyl)-, -C1-3 alkyl-pyrimidinone-, 3 to 6-membered cycloalkyl, -3 to 6-membered cycloalkyl-CONH-, -3 to 6-membered cycloalkyl-CO-N(C1-3 alkyl)-, oxetane, -oxetane -CONH-, and -oxetane-CO-N(C1-3 alkyl)-.

[0039] In one embodiment, the formula (I) may be a following formula (Ia):

[0040] [Formula (Ia)]

[0041]

[0042] wherein n is 0 or 1.

[0043]

[0044] In one embodiment, representative examples of the compound represented by the formula (I) are described in Table 1:

[0045] ExampleNameStructure1)(1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 2)(1R,3S,4S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 3)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 4)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 5)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-ethyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 6)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-isopropyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 7)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-propyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 8)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-cyclopropyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 9)(1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 10)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 11)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 12)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2,5-difluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 13)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 14)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-2-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 15)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(p-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 16)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 17)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(o-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 18)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3,4-difluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 19)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 20)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-bromophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 21)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-methoxy-4-methylphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 22)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 23)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-hydroxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 24)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-methoxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 25)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-hydroxy-4-methylphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 26)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-phenyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 27)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-4-methylphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 28)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3,4-dichlorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 29)methyl 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamido)-4-chloro-5-fluorobenzoate 30)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluoro-3-methoxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 31)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2,4-dichlorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 32)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chlorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 33)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3,5-difluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 34)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-chloro-3-methoxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 35)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-bromo-2-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 36)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-hydroxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 37)(1R,3S,4S)-N-([1,1'-biphenyl]-4-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 38)(1R,3S,4S)-N-([1,1'-biphenyl]-2-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 39)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-chlorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 40)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 41)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 42)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(6-(dimethylamino)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 43)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluoropyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 44)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(6-fluoropyridin-3-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 45)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(5-methylpyridin-3-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 46)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(6-methylpyridin-3-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 47)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(6-methylpyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 48)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(5-methylpyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 49)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(4-methylpyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 50)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 51)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 52)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 53)(1R,3S,4S)-N-(4-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 54)(1R,3S,4S)-N-(4-fluorophenyl)-N-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 55)(1R,3S,4S)-2-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 56)(1R,3S,4S)-N-(4-fluorophenyl)-2-(6-methoxy-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 57)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 58)(1R,3S,4S)-N-(benzofuran-6-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 59)(1R,3S,4S)-N-(benzo[d]thiazol-5-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 60)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 61)(1R,3S,4S)-N-(benzo[d]oxazol-2-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 62)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-methyl-1H-indol-5-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 63)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-methyl-1H-indol-4-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 64)(1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-6-azatricyclo[3.2.1.02,4]octane-7-carboxamide 65)(1S,3R,4R)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 66)(1S,3R,4R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 67)(1S,3R,4R)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(3-methyl-5-(trifluoromethyl)phenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 68)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(methyl-d3)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 69)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(methyl-d3)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 70)(1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(methyl-d3)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 71)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carbothioamide 72)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-cyclohexyl-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 73)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-cyclopentyl-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 74)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 75)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2,5-difluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 76)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 77)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-2-fluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 78)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(o-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 79)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(p-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 80)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-2,4-difluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 81)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3,4-difluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 82)(1R,3S,4S)-N-((1H-indol-3-yl)methyl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 83)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 84)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(1-cyanocyclopropyl)-N-(4-fluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 85)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-((1-cyanocyclopropyl)methyl)-N-(4-fluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 86)((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)(isoindolin-2-yl)methanone 87)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-(dimethylamino)ethyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide 88)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(prop-2-yn-1-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 89)(1R,3S,4S)-N-(3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 90)(1R,3S,4S)-N-((1H-1,2,3-triazol-4-yl)methyl)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 91)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 92)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(pyridin-2-yl)prop-2-yn-1-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 93)(1R,3S,4S)-N-allyl-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 94)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-((E)-3-(pyridin-2-yl)allyl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 95)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(prop-2-yn-1-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 96)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 97)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 98)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-isopropyl-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 99)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(2-(methyl(m-tolyl)amino)-2-oxoethyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 100)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-(methyl(m-tolyl)amino)-2-oxoethyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 101)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-((R)-1-(methyl(m-tolyl)amino)-1-oxopropan-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 102)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(2-methyl-1-(methyl(m-tolyl)amino)-1-oxopropan-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 103)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-(methyl(m-tolyl)carbamoyl)cyclopropyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 104)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-(methyl(m-tolyl)carbamoyl)cyclobutyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 105)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-(methyl(m-tolyl)carbamoyl)cyclopentyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 106)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-(methyl(m-tolyl)carbamoyl)cyclohexyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 107)(1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(3-(methyl(m-tolyl)carbamoyl)oxetan-3-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 108)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(4H-1,2,4-triazol-4-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 109)(1R,3S,4S)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid 110)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-((1-(4-fluorophenyl)-6-oxo-1,6-dihydropyrimidin-2-yl)methyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide 111)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbohydrazide 112)(E)-N'-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbonyl)-N,N-dimethylformohydrazonamide 113)2-((1R,3S,4S)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile 114)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 115)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 116)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-isopropyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 117)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 118)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(p-tolyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 119)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 120)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 121)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 122)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-chlorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 123)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3,4-difluorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 124)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-chloro-4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 125)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3,4-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 126)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluoro-3-methylphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 127)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 128)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluoro-3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 129)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-chloro-3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 130)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-methoxy-4-methylphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 131)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 132)3-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)phenol 133)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(6-methylpyridin-2-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 134)(1R,3S,4S)-3-(4-benzyl-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane 135)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(pyridin-2-ylmethyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 136)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(1-phenylethyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 137)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(prop-2-yn-1-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 138)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-cyclohexyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 139)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 140)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(1-methylpiperidin-4-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 141)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(1-methylpiperidin-3-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 142)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(1-methyl-1H-imidazol-4-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 143)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(1-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 144)5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)quinoline 145)5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)-1H-indole 146)(1R,3S,4S)-3-(4-(benzofuran-5-yl)-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane 147)(1R,3S,4S)-3-(4-(benzofuran-6-yl)-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane 148)5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)benzo[d]thiazole 149)7-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)benzo[d]thiazole 150)(1R,3S,4S)-3-(4-(benzo[b]thiophen-5-yl)-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane 151)5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)-3-methylbenzo[d]isoxazole 152)5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)benzo[d]thiazole 153)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(2,3-dihydrobenzofuran-6-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 154)5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine 155)6-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)benzo[d]oxazol-2(3H)-one 156)6-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)-2,3-dimethyl-2H-indazole 157)5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)-2-methyl-2H-indazole 158)(1S,3S,4S,5R)-3-(4-(benzo[d]thiazol-5-yl)-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-5-ol 159)(1S,3S,4S,5S,6R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluoro-3-methylphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane-5,6-diol 160)(1S,3S,4S,5S,6R)-3-(4-(benzofuran-6-yl)-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-5,6-diol 161)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 162)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-chloro-4-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane 163)3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepine 164)1-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-5,6,8,9-tetrahydro-7H-[1,2,4]triazolo[4,3-d][1,4]diazepin-7-yl)ethan-1-one 165)3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(methylsulfonyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepine 166)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane 167)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(3-chloro-4-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane 168)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane 169)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-phenyl-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane 170)5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one 171)5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-(m-tolyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 172)5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-(3,4-difluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one 173)5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-2,4-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one 174)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane 175)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-methyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane 176)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-isopropyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane 177)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(prop-2-yn-1-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane 178)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(3-methylbenzyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane 179)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(m-tolyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane 180)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane 181)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(5-chloro-1-(2-chloro-5-methylphenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane 182)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(5-chloro-1-(m-tolyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane 183)2-((1R,3S,4S)-3-(5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile 184)6-methyl-2-((1R,3S,4S)-3-(5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4-(trifluoromethyl)nicotinonitrile 185)2-((1R,3S,4S)-3-(1-isopropyl-5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile 186)2-((1R,3S,4S)-3-(1-methyl-5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile 187)2-((1R,3S,4S)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile 188)5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-phenyl-1,2,4-oxadiazole 189)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-phenylpyrimidin-4(3H)-one 190)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(p-tolyl)pyrimidin-4(3H)-one 191)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(m-tolyl)pyrimidin-4(3H)-one 192)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(o-tolyl)pyrimidin-4(3H)-one 193)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(4-fluorophenyl)pyrimidin-4(3H)-one 194)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-chlorophenyl)pyrimidin-4(3H)-one 195)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(4-fluoro-3-methylphenyl)pyrimidin-4(3H)-one 196)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3,4-difluorophenyl)pyrimidin-4(3H)-one 197)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-chloro-4-fluorophenyl)pyrimidin-4(3H)-one 198)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(4-fluoro-3-methoxyphenyl)pyrimidin-4(3H)-one 199)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(4-chloro-3-methoxyphenyl)pyrimidin-4(3H)-one 200)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3,4-dichlorophenyl)pyrimidin-4(3H)-one 201)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-methoxyphenyl)pyrimidin-4(3H)-one 202)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin-4(3H)-one 203)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(6-methylpyridin-2-yl)pyrimidin-4(3H)-one 204)3-(benzofuran-7-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one 205)3-(benzofuran-6-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one 206)3-(benzofuran-5-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one 207)3-(benzo[d]oxazol-5-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one 208)3-(benzo[d]thiazol-7-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one 209)3-(benzo[d]thiazol-6-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one 210)3-((1H-1,2,3-triazol-4-yl)methyl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one 211)2-((1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-chloro-4-fluorophenyl)pyrimidin-4(3H)-one 212)3-(benzofuran-5-yl)-2-((1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one 213)2-((1S,3S,4S,5S,6R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5,6-dihydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-chloro-4-fluorophenyl)pyrimidin-4(3H)-one 214)2-((1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-azatricyclo[3.2.1.02,4]octan-7-yl)-3-(m-tolyl)pyrimidin-4(3H)-one 215)2-((1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-azatricyclo[3.2.1.02,4]octan-7-yl)-3-(4-fluorophenyl)pyrimidin-4(3H)-one 216)3-(benzofuran-6-yl)-2-((1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-azatricyclo[3.2.1.02,4]octan-7-yl)pyrimidin-4(3H)-one 217)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-(trifluoromethyl)-3-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin-4(3H)-one 218)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-(trifluoromethyl)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin-4(1H)-one 219)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(6-methylpyridin-2-yl)-6-(trifluoromethyl)pyrimidin-4(3H)-one 220)2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-methyl-3-(m-tolyl)pyrimidin-4(3H)-one 221)3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-(3-methylbenzyl)-4H-1,2,4-oxadiazin-5(6H)-one 222)3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-1,2,4-oxadiazol-5(4H)-one 223)3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-phenyl-1,2,4-oxadiazol-5(4H)-one 224)3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-(3-methylbenzyl)-1,2,4-oxadiazol-5(4H)-one 225)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane 226)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)pyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane 227)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-methylpiperazin-1-yl)pyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane 228)2-((1R,3S,4S)-3-(benzo[d]oxazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile 229)2-((1R,3S,4S)-3-(benzo[d]thiazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile 230)2-((1R,3S,4S)-3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile 231)2-((1R,3S,4S)-3-(1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile 232)2-((1R,3S,4S)-3-(1-methyl-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile 233)2-((1R,3S,4S)-3-(1-isopropyl-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile 234)((1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)methyl 3-methylbenzoate 235)2-((1R,3S,4S)-3-((m-tolyloxy)methyl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile 236)N-(((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)methyl)-N,3-dimethylbenzamide 237)1-(((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine 238)(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-((4-phenyl-1H-imidazol-1-yl)methyl)-2-azabicyclo[2.2.1]heptane

[0046] As used herein, the terms “alkyl” and “substituted alkyl” are intended to include both branched and straight-chain saturated hydrocarbon groups having specified number of carbon atoms. For example, “C1-3alkyl” means a linear saturated hydrocarbon radical of one to three carbon atoms e.g. methyl, ethyl, propyl,iso-propyl and the like. Alkyl groups can be unsubstituted or substituted so that one or more of its hydrogens are replaced by another chemical group.

[0047] As used herein, the term “alkenyl” and “substituted alkenyl” are intended to include both branched and straight-chain hydrocarbon groups having specified number of carbon atoms and having one or more double carbon-carbon bonds that may occur in any stable point along the chain. For example, “C3-C5alkenyl is intended to include, but are not limited to, C3(1-propenyl, 2-propenyl, allyl), C4(1-butenyl, 2-butenyl, 3-butenyl, isobutenyl), C5(1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1,3-pentadienyl, 2,4-pentadienyl) alkenyl group. Alkenyl groups can be unsubstituted or substituted so that one or more of its hydrogens are replaced by another chemical group.

[0048] As used herein, the terms “alkynyl” and “substituted alkynyl” are intended to include both branched and straight-chain hydrocarbon groups having specified number of carbon atoms and having one or more triple carbon-carbon bonds that may occur in any stable point along the chain. For example, “C3-C5alkynyl” is intended to include, but are not limited to, C3(1-propynyl, 2-propynyl, propargyl), C4(1-butynyl, 2-butynyl, 3-butynyl), C5(1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3-methyl-1-butynyl, 1,3-pentadiynyl, 2,4-pentadiynyl) alkynyl group. Alkynyl groups can be unsubstituted or substituted so that one or more of its hydrogens are replaced by another chemical group.

[0049] In some instances, the number of carbon atoms in a moiety is indicated by the prefix "Cx-Cy", wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, "C1-C6alkyl" means an alkyl substituent containing from 1 to 6 carbon.

[0050] As used herein, the term “halo” “halogen”, and “halide(s)” include fluoro, chloro, bromo and iodo.

[0051] As used herein, the “haloalkyl” refers to an alkyl group substituted with one or more halogen atom, and the alkyl group is defined as above. The “halo” refers to F, Cl, Br, or I, and the term is compatibly used with the term “halogen”. For example, the haloalkyl refers to fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl or 2,2,2-trifluoromethyl.

[0052] As used herein, the term "alkoxy" refers to -O-alkyl or alkyl-O- group, and the alkyl group is defined as shown above. For example, it includes methoxy, ethoxy, n-propoxy, n-butoxy and t-butoxy.

[0053] As used herein, the “alkoxyalkyl” refers to alkyl-O-alkyl group, and the alkyl group is defined as above. The unlimited example is methoxymethyl, ethoxymethyl, methoxyethyl or isopropoxymethyl.

[0054] As used herein, the term “hydroxy” or “hydroxyl” alone or in combination with other terms means -OH.

[0055] As used herein, “oxo” refers to =O group.

[0056] As used herein, “cyano” refers to -CN, “cyanoalkyl” refers to alkyl substituted with -CN, wherein the alkyl group is as defined above.

[0057] As used herein, “amino” refers to -NH2; and "nitro" refers to -NO2.

[0058] As used herein, “carboxy” refers to -C(=O)-OH group.

[0059] As used herein, “ester” refers to a group of -C(=O)-OR, where R is alkyl, for example C1-10, C1-8, C1-6or C1-4alkyl.

[0060] In some instances, the number of ring atoms in a moiety is indicated by the prefix "x-y membered", wherein x is the minimum and y is the maximum number of ring atoms in the substituent. Thus, for example, the term "5-10-membered heteroaryl" may include a heteroaryl containing 5 to 6 ring atoms or a bicyclic heteroaryl with 9 to 10 ring atoms, and "6-10 membered aryl" may means phenyl or a bicyclic aryl with 6 to 10 carbon atoms.

[0061] As used herein, the terms “cycloalkyl” refers to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring in which all atoms of all ring are carbon. In addition, the carbocycle may also be a fused or bridged carbocycle. For example, “cycloalkyl” is intended to include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl (for example, bicyclopentyl such as bicyclo[1.1.1]pentyl, bicyclo[2.1.0]pentyl, or [1.1.1]propellane), cyclohexyl, cycloheptyl, cyclooctyl and the like.

[0062] As used herein, the terms “heterocycle” refers to a saturated or unsaturated monocyclic, bicyclic, or tricyclic ring in which at least one of the rings has at least one heteroatom, for example, N, O, or S. In addition, the heterocycle may also be a fused or bridged heterocycloalkyl. Examples of heterocycle include azetidinyl, oxetanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, oxapiperazinyl, oxapiperidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroisothiazolyl,tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, indolinyl, indolinylmethyl, thiomorpholinyl, azepanyl, diazepanyl, N-oxide, azabicycloheptanyl, azabicyclo[2.2.1]heptanyl, azaadamantanyl, diazamantanyl, and the like, but are not limited thereto. Attachment of a heterocycloalkyl substituent can occur via a carbon atom or a heteroatom.

[0063] As used herein, the terms “aryl” refers to substituted or unsubstituted monocyclic, bicyclic, or tricyclic aromatic hydrocarbon groups. The aryl may include a bicyclic radical containing an aromatic ring fused to a saturated or partially unsaturated ring. Exemplary aryl groups may include radicals derived from benzene (phenyl), substituted phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, fluorenyl, indenyl, indanyl, tetralinyl, and the like.

[0064] As used herein, the terms “heteroaryl” refers to substituted or unsubstituted monocyclic, bicyclic, or tricyclic aromatic groups which have at least one heteroatom, for example, N, O or S, in at least one of the rings. Examples of the heteroaryl include, but are not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiophenyl, pyridyl, pyrazinyl, pyrimidinyl, pyrimidonyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, oxadiazinyl, oxadiazinonyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, triazolonyl, dihydrotriazolonyl, tetrazolyl, triazinyl, and the like. Examples of the bicyclic heteroaryl include indolyl, indolinyl, isoindolinyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolyl, dihydrobenzimidazolyl, benzimidazolonyl, dihydrobenzimidazolonyl, benzoxazolyl, dihydrobenzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, indazolyl, quinolinyl, isoquinolinyl, furinyl, furopyridinyl, octahydropyranopyridine, benzodioxolyl, triazolodiazepinyl and similar groups thereof, but are not limited thereto. Examples of the tricyclic heteroaryl include dibenzothiophenyl, dibenzofuranyl, carbazolyl and similar groups thereof, but are not limited thereto.

[0065] Unless otherwise specified herein, the term "substituted” means that at least one hydrogen atom is substituted by one or more substituents. Examples of the substituents include, but are not limited to, a halogen atom (e.g., F, Cl, Br, or I), a cyano group, a hydroxyl group, a thiol group, a nitro group, an amino group, an imino group, an azido group, an amidino group, a hydrazino group, a hydrazono group, an oxo group, a carbonyl group, a carbamyl group, an ester group, an ether group, a carboxyl group or a salt thereof, a sulfonic acid group or a salt thereof, phosphoric acid or a salt thereof, a C1-6alkyl group, a halo C1-6alkyl group, a hydroxy C1-6alkyl group, a C2-6alkenyl group, a halo C2-6alkenyl group, a C2-6alkynyl group, a halo C2-6alkynyl group, a C1-6alkoxy group, a halo C1-6alkoxy group, a hydroxy C1-6alkoxy group, a C1-20alkylthio group, a C1-6alkylsulfonyl group, a C1-6alkylcarbonyl group, a C1-6alkoxycarbonyl group, a C3-20carbocyclic group (e.g., a C3-9cycloalkyl group, a halo C3-9cycloalkyl group, a C3-9cycloalkenyl group, a halo C3-9cycloalkenyl group), a C3-20heterocyclic group (a C1-9heterocycloalkyl group, a halo C1-9heterocycloalkyl group, a C2-9heterocycloalkenyl group, a halo C2-9heterocycloalkenyl group), a C1-20aryl group (e.g., a C6-20aryl group, a C6-20aryloxy group, a C6-20arylthio group), and a C1-20heteroaryl group (a C2-20heteroaryl group, a C2-20heteroaryloxygroup, a C2-20heteroarylthio group).

[0066] If a moiety is described as being "optionally substituted," the moiety may be either (1) not substituted or (2) substituted. If a moiety is described as being optionally substituted with up to a particular number of substituents, that moiety may be either (1) not substituted; or (2) substituted by up to that particular number of substituents or by up to the maximum number of substitutable positions on the moiety, whichever is less.

[0067] METHOD FOR PREPARING POLYMERASE THETA INHIBITOR COMPOUND

[0068] Hereinafter, a method for preparing the compound represented by Formula (I), is described on the basis of an exemplary reaction formula for better understanding of the present disclosure. However, it should be interpreted by those skilled in the art, to which the present disclosure pertains, that the compound of Formula (I) may be prepared by means of various methods based on a structure of Formula (I), and such methods are all included in the scope of the present disclosure. In other words, it should be appreciated that the compound according to the present disclosure may be prepared by arbitrarily combining various synthesis methods which are described in the present specification or disclosed in the prior art and this belongs to the scope of the present disclosure. In the following reaction formulas, all the substituents are the same as defined above, unless indicated otherwise.

[0069] [Reaction Formula 1]

[0070]

[0071] wherein, A, B, X, Y and m are as defined in the Formula (I); LG represents -Cl, -Br or -OTf.

[0072] In the Reaction Formula 1 above, X may be synthesized through methods of following reaction formulas 1-1, 1-2, 1-3, 1-4 and 1-5:

[0073] [Reaction Formula 1-1]

[0074]

[0075] [Reaction Formula 1-2]

[0076]

[0077] [Reaction Formula 1-3]

[0078]

[0079]

[0080]

[0081] [Reaction Formula 1-4]

[0082]

[0083] [Reaction Formula 1-5]

[0084]

[0085] wherein, LG’ represents -Br or -I;

[0086] V represents carbonyl or sulfonyl;

[0087] W1represents -H or -CH3;

[0088] W2represents -H or -Ph;

[0089] W3represents -H, -CH3or -CF3;

[0090] W4represents -O- or -S-;

[0091] W5represents -H or -Br;

[0092] W6represents (3-methylbenzoyl)oxy, m-tolyloxy, N,3-dimethylbenzamido, 1H-pyrrolo[2,3-b]pyridin-1-yl or 4-phenyl-1H-imidazol-1-yl;

[0093] The compound of Formula (I) according to the present disclosure may be separated or purified from products of the reaction formulas 1 above by means of several methods such as crystallization, silica gel column chromatography, etc. In this way, the compound according to the present disclosure, as well as an initiation, an intermediate, etc., for preparing the same may be synthesized by means of various methods, and it should be understood that such methods are included in the scope of the present disclosure with regard to a preparation for the compound of the Formula (I).

[0094] COMPOSITION COMPRISING POLYMERASE THETA INHIBITOR COMPOUND, AND USE THEREOF

[0095] The present disclosure provides a pharmaceutical composition and a use of treating or preventing Polymerase theta activation-related diseases, wherein the composition comprises the compound of the present disclosure, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof as an active ingredient.

[0096] The compound of Formula (I), the tautomer, the stereoisomer, the solvate, and the pharmaceutically acceptable salt thereof have a remarkable effect on preventing or treating Polymerase theta activation-related diseases by showing Polymerase theta inhibitory activity.

[0097] In the present disclosure, the said Polymerase theta activation-related diseases mean diseases associated with enhanced activity of Polymerase theta. The polymerase theta activation-related diseases may be chronic proliferative diseases characterized by persistent and unregulated angiogenesis, and / or metastasis or metastatic disease characterized by the spread of a disease from one organ or part to another non-adjacent organ or part.

[0098] Specifically, polymerase theta activation-related diseases may comprise a cancer.

[0099] The cancer may be polymerase theta activation-related cancer, or a cancer influenced by inhibition of polymerase theta. Specifically, the cancer may be polymerase theta overexpressed cancer.

[0100] The cancer may comprise diseases or conditions characterized by a deficiency or loss of function of genes related to homologous recombination (HR) or non-homologous end joining (NHEJ) mechanism. Specifically, the cancer may be homologous recombination (HR) deficient cancer.

[0101] Homologous recombination (HR) related genes are selected from any one or more of: ATM, ATR, BRCA1, BRCA2, BARD1, RAD51C, RAD50, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBD12), ERCC4 (FANCQ), PTEN, CDK12, MRE11, NBS1, NBN, CLASPIN, BLM, WRN, SMARCA2, SMARCA4, LIG1, RPA1, RPA2, BRIP1 and PTEN.

[0102] Non-homologous end joining (NHEJ) related genes are selected from any one or more of: LIG4, NHEJ1, POLL, POLM, PRKDC, XRCC4, XRCC5, XRCC6, and DCLRE1C.

[0103] More specifically, the cancer may comprise one or more selected from the group consisting of various types carcinomas, melanomas, sarcomas, adenocarcinomas, leukemias, lymphomas, prostate cancer, thyroid cancer, endocrine system cancer, brain cancer, breast cancer, cervix cancer, colon cancer, head & neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterus cancer, medulloblastoma, colorectal cancer, pancreatic cancer, Hodgkin's disease, Non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumor, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, prostate cancer, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanomajuvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, superficial spreading melanoma, nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, undifferentiated cell leukemia, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, Schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, carcinoma villosum, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abernethy’s sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, telangiectatic sarcoma, and symptoms related thereto.

[0104] In the present disclosure, pharmaceutically acceptable salt mean the salt conventionally used in a pharmaceutical industry, for example, acid salt prepared from 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, L-ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, L-malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, L-pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, L-tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid or other compounds that can be used as acids, and the like.

[0105] For its administration, the pharmaceutical composition of the present disclosure may further comprise at least one type of a pharmaceutically acceptable carrier, in addition to the compound represented by Formula (I), the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof, and may be also used with the addition of other conventional additives such as antioxidants, buffer solutions, bacteriostatic agents, etc., if needed. Also, such pharmaceutical composition may be formulated such a way that diluents, dispersing agents, surfactants, binders and lubricants are additionally added thereto.

[0106] The composition of the present disclosure may be orally or parenterally administered (for example, applied intravenously, hypodermically, intraperitoneally or locally) according to an intended method, in which a dosage thereof varies in a range thereof depending on a patient’s weight, age, gender, health condition and diet, an administration time, an administration method, an excretion rate, a severity of a disease and the like. A daily dosage of the compound represented by the formula (I) may be about 0.001 to 1000 mg / kg and may be administered once a day or divided into several times.

[0107] In addition to the compound represented by Formula (I), the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof, said pharmaceutical composition may further comprise at least one therapeutic agent as an active ingredient which show a medicinal effect the same thereto or similar thereto. Therapeutic agents may be selected from the group consisting of chemotherapy agent, radiotherapy agent, immunotherapy agent and tumor microenvironment modulating agent.

[0108] According to one specific embodiment of the present disclosure, the present disclosure provides a method for preventing or treating Polymerase theta activation-related diseases, comprising administering a therapeutically effective amount of the compound represented by Formula (I), the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof into a subject. The method for preventing or treating Polymerase theta activation-related diseases according to the present disclosure comprises not only dealing with the cancer themselves before expression of their symptoms, but also inhibiting or avoiding such symptoms by administering the compound represented by Formula (I), the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof.

[0109] According to one specific embodiment of the present disclosure, the present disclosure provides a use of the compound represented by the formula (I), the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof in preparation of a medicament for treating Polymerase theta activation-related diseases. For preparing a medicament, the compound represented by Formula (I), the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof may be combined with acceptable adjuvants, diluents, carriers, etc., and may be prepared into a complex preparation together with other active agents (therapeutic agents) and thus have a synergy action of active components.

[0110] According to one specific embodiment of the present disclosure, the present disclosure also provides a method for inhibiting Polymerase theta activity, wherein the method comprises administering a therapeutically effective dose of the formula (I), the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof into a subject.

[0111] As used herein, the “subject” means mammals including humans, and the “administration” means providing a predetermined material to a patient by means of any appropriate method.

[0112] As used herein, the term “therapeutically effective amount” refers to an amount of the compound represented by Formula (I), the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof, which are effective in preventing or treating Polymerase theta activation-related diseases.

[0113] The novel compounds according to the present disclosure effectively inhibit polymerase theta activity, and they are useful as a therapeutic or prophylactic drug for various disease associated with polymerase theta activity, such as cancer.

[0114] Hereinafter, preferred Examples will be suggested for better understanding of the present disclosure. However, the following Examples are provided only for the purpose of illustrating the present disclosure, and thus the present disclosure is not limited thereto.

[0115] All chemical reagents were commercially available. Flash column chromatography means silica gel chromatography unless specified otherwise, which was performed on Teledyne Combiflash-RF200 System. 1H NMR spectra (δ, ppm) are recorded on 400 MHz or 600 MHz instrument. Mass spectroscopy data (ESI, m / z) for a positive ionization method were measured from Agilent technologies single quadrupole G6120B equipped with Agilent technologies 1260 Infinity system. Preparative HPLC (Prep HPLC) was performed on Agilent technologies G1361A.

[0116] Hereinafter, the following Examples may be appropriately changed and modified by those skilled in the art within the scope of the present disclosure.

[0117]

[0118]

[0119] [General Method A]

[0120]

[0121] [Step a] Preparation of methyl (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylate hydrochloride. In an oven-dried 250mL round bottom flask containing a magnetic attiring bar, acetyl chloride (4.06 eq, 12 mL, 168 mmol) was slowly added to a solution of (1R,3S,4S)-2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.00 eq, 10000 mg, 41.4 mmol) in methyl alcohol (80 mL). The solution was stirred 18 hours and concentrated in reduced pressure to give the desired product as a white solid (yield, 99%)

[0122] MS (ESI, m / z): 156.1 [M+H]+

[0123] 1H NMR (400 MHz, cdcl3)4.35 (s, 1H), 4.22 (d,J= 5.0 Hz, 1H), 3.89 (s, 3H), 3.01 (s, 1H), 2.00 (dd,J= 18.2, 9.4 Hz, 1H), 1.93 - 1.75 (m, 4H), 1.67 (d,J= 11.8 Hz, 1H).

[0124] [Step b] Preparation of methyl (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylate. In an oven-dried 250mL round bottom flask containing a magnetic attiring bar, triethylamine (5.0 eq, 8.0 mL, 57.3 mmol) was slowly added to a solution of methyl (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylate hydrochloride (1.0 eq, 2200 mg, 11.5 mmol) and [4,6-bis(trifluoromethyl)-2-pyridyl] trifluoromethanesulfonate (0.8 eq, 3332 mg, 9.18 mmol) in Dimethylformamide (23mL). The reaction mixture was stirred under 25oC for 2 hours. After completion of the reaction, the mixture was evaporated under reduced pressure, and extracted with EA (50 mL) and water (50 mL). The organic extracts was concentrated in vacuo and purified with column chromatography (0~100% EA in Hx) to give the desired product as yellow oil (yield, 68%).

[0125] MS (ESI, m / z): 369.1 [M+H]+

[0126] 1H NMR (400 MHz, cd3od) δ 7.08 (s, 1H), 4.59 (s, 1H), 4.05 (s, 1H), 3.73 (s, 3H), 2.83 (s, 1H), 2.05 (s, 1H), 1.94 - 1.74 (m, 2H), 1.64 (d,J= 12.3 Hz, 1H), 1.54 (d,J= 9.9 Hz, 2H).

[0127] [Step b’] Preparation of methyl (1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylate. In an oven-dried 100mL round bottom flask containing a magnetic attiring bar, N,N-Diisopropylethylamine (5.0 eq, 2.6 mL, 15 mmol) was slowly added to a solution of methyl (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-3-carboxylate hydrochloride (1.0 eq, 595 mg, 3 mmol) and 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile (1.1 eq, 728 mg, 3.3 mmol) in Dimethylformamide (15mL). The reaction mixture was stirred under 80oC for 2 hours. After completion of the reaction, the mixture was evaporated under reduced pressure, and extracted with EA (50 mL) and water (50 mL). The organic extracts was concentrated in vacuo and purified with column chromatography (0~50% EA in Hx) to give the desired product as yellow oil (yield, 50%).

[0128] MS (ESI, m / z): 399.1 [M+H]+

[0129] 1H NMR (600 MHz, cdcl3) δ 6.72 (d,J= 7.2 Hz, 1H), 5.36 (s, 1H), 4.19 (s, 1H), 3.77 - 3.68 (m, 3H), 2.77 (s, 1H), 2.38 (d,J= 7.0 Hz, 3H), 2.15 (s, 1H), 1.86 (s, 2H), 1.62 (s, 1H), 1.54 (s, 1H), 1.48 (d,J= 7.8 Hz, 1H).

[0130]

[0131] Example 1: (1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0132]

[0133] Synthesis of (1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid. To a solution of methyl (1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.0 eq, 399 mg, 1.0 mmol) in Methyl alcohol (1.0mL) was added 1N NaOH (2 mL) and stirred at 25oC for 1 hour. The solution was neutralized with 1N HCl to give the desired product quantitatively.

[0134] Synthesis of (1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide. To a solution of (1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.0 eq, 65 mg, 0.2 mmol) and HATU (1.1 eq, 84 mg, 0.22 mmol) in dimethylformamide (0.5 mL) was added N-methyl-m-toluidine (1.3 eq, 33 μL, 0.26 mmol) and triethylamine (3 eq, 84 μL, 0.6 mmol) and stirred at 25oC for 1 hour. The reaction mixture was poured into water (3 mL), extracted with DCM (3 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified by the Prep HPLC to give the desired product.

[0135] MS (ESI, m / z): 429.2 [M+H]+

[0136] 1H NMR (600 MHz, cd3od) δ 7.40 (dd,J= 15.7, 8.0 Hz, 2H), 7.32 (d,J= 7.7 Hz, 1H), 7.26 (d,J= 7.6 Hz, 1H), 6.88 (s, 1H), 5.29 (d,J= 15.9 Hz, 1H), 4.14 (s, 1H), 3.27 (s, 3H), 2.67 (s, 1H), 2.55 - 2.51 (m, 3H), 2.42 (d,J= 9.2 Hz, 3H), 2.29 (d,J= 8.5 Hz, 1H), 1.76 (t,J= 13.2 Hz, 1H), 1.67 - 1.60 (m, 2H), 1.46 (d,J= 9.9 Hz, 1H), 0.92 (t,J= 13.2 Hz, 1H).

[0137]

[0138] Example 2: (1R,3S,4S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0139]

[0140] The title product was afforded by a procedure similar to that described for the synthesis of Example 1 using 2-chloro-6-methyl-4-(trifluoromethyl)pyridine instead of 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile in step b’.

[0141] MS (ESI, m / z): 404.2 [M+H]+

[0142] 1H NMR (400 MHz, cd3od) δ 7.37 (t,J= 7.6 Hz, 1H), 7.27 (s, 1H), 7.23 (d,J= 6.7 Hz, 2H), 6.74 (s, 1H), 6.43 (s, 1H), 3.93 (s, 1H), 3.24 (s, 3H), 2.69 (s, 1H), 2.47 (s, 3H), 2.36 (s, 3H), 2.22 (d,J= 8.8 Hz, 1H), 1.62 (s, 2H), 1.44 (s, 2H), 1.24 (d,J= 16.8 Hz, 1H), 0.87 (d,J= 30.0 Hz, 1H).

[0143]

[0144] Example 3: (1R,3S,4S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0145]

[0146] The title product was afforded by a procedure similar to that described for the synthesis of Example 1 using 2-chloro-4,6-bis(trifluoromethyl)nicotinonitrile instead of 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile in step b’.

[0147] MS (ESI, m / z): 483.2 [M+H]+

[0148] 1H NMR (400 MHz,cd3od) δ 7.39 (t,J = 7.7 Hz, 1H), 7.34 (s, 1H), 7.31 - 7.23 (m, 3H), 5.38 (s, 1H), 4.14 (s, 1H), 3.24 (s, 3H), 2.72 (s, 1H), 2.38 (s, 3H), 2.32 (d,J = 17.9 Hz, 1H), 1.86 - 1.59 (m, 4H), 1.51 (d,J = 10.0 Hz, 1H), 0.97 (dd,J = 15.2, 8.5 Hz, 1H).

[0149]

[0150] Example 4: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0151]

[0152] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 using m-toluidine instead of N-methyl-m-toluidine.

[0153] MS (ESI, m / z): 469.1 [M+H]+

[0154] 1H NMR (400 MHz,cd3od) δ 7.32 (s, 1H), 7.27 (d,J = 6.6 Hz, 2H), 7.18 (t,J = 7.8 Hz, 1H), 6.94 (d,J = 7.4 Hz, 1H), 5.43 (s, 1H), 4.44 - 4.29 (m, 1H), 2.87 (s, 1H), 2.31 (s, 3H), 1.93 (s, 3H), 1.68 (d,J = 10.1 Hz, 1H), 1.61 (d,J = 9.6 Hz, 1H), 1.29 (s, 1H).

[0155]

[0156] Example 5: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-ethyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0157]

[0158] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 using N-ethyl-3-methylaniline instead of N-methyl-m-toluidine.

[0159] MS (ESI, m / z): 497.2 [M+H]+

[0160] 1H NMR (400 MHz,cd3od) δ 7.40 (t,J = 7.7 Hz, 1H), 7.33 (s, 1H), 7.28 (d,J = 5.0 Hz, 3H), 5.39 (s, 1H), 4.13 (s, 1H), 3.96 - 3.85 (m, 1H), 3.60 - 3.50 (m, 1H), 2.68 (s, 1H), 2.39 (s, 3H), 2.27 (s, 1H), 1.76 (d,J = 28.2 Hz, 2H), 1.64 (s, 1H), 1.50 (d,J = 10.3 Hz, 1H), 1.31 (d,J = 14.3 Hz, 2H), 1.12 (t,J = 7.2 Hz, 3H), 0.91 (d,J = 8.9 Hz, 1H).

[0161]

[0162] Example 6: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-isopropyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0163]

[0164] The title product was afforded by a procedure similar to that described for the synthesis of Example 1 using N-isopropyl-3-methylaniline instead of N-methyl-m-toluidine.

[0165] MS (ESI, m / z): 511.2 [M+H]+

[0166] 1H NMR (400 MHz,cd3od) δ 7.42 (s, 1H), 7.32 (s, 1H), 7.27 (d,J = 4.4 Hz, 1H), 7.20 (s, 2H), 5.41 - 5.36 (m, 1H), 5.36 - 5.33 (m, 1H), 3.96 - 3.94 (m, 1H), 2.70 (s, 1H), 2.43 (s, 1H), 2.36 (s, 1H), 2.31 (s, 1H), 2.18 (d, J = 7.4 Hz, 1H), 2.06 - 2.01 (m, 1H), 1.52 - 1.47 (m, 2H), 1.13 - 1.05 (m, 5H), 0.90 (s, 2H).

[0167]

[0168] Example 7: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-propyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0169]

[0170] The title product was afforded by a procedure similar to that described for the synthesis of Example 1 using 3-methyl-N-propylaniline instead of N-methyl-m-toluidine.

[0171] MS (ESI, m / z): 511.2 [M+H]+

[0172] 1H NMR (400 MHz,cd3od) δ 7.39 (t,J = 7.7 Hz, 1H), 7.33 (s, 1H), 7.27 (s, 2H), 7.26 (s, 1H), 5.39 (s, 1H), 4.14 (s, 1H), 3.79 - 3.69 (m, 1H), 3.59 - 3.49 (m, 1H), 2.69 (d,J = 3.9 Hz, 1H), 2.24 (d,J = 15.4 Hz, 1H), 1.75 (dd,J = 22.3, 9.5 Hz, 2H), 1.64 (dd,J = 16.5, 12.5 Hz, 1H), 1.54 (ddd,J = 17.0, 12.1, 6.1 Hz, 3H), 0.92 (s, 1H), 0.89 (t,J = 7.4 Hz, 3H).

[0173]

[0174] Example 8: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-cyclopropyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0175]

[0176] The title product was afforded by a procedure similar to that described for the synthesis of Example 1 using N-cyclopropyl-3-methylaniline instead of N-methyl-m-toluidine.

[0177] MS (ESI, m / z): 509.2 [M+H]+

[0178] 1H NMR (400 MHz,cd3od) δ 7.37 (t,J = 7.7 Hz, 1H), 7.28 - 7.21 (m, 3H), 7.16 (s, 1H), 5.38 (s, 1H), 4.06 (s, 1H), 3.15 - 3.08 (m, 1H), 2.66 (s, 1H), 2.37 (s, 3H), 2.32 (s, 2H), 2.00 (s, 1H), 1.75 (s, 2H), 1.62 (s, 1H), 1.50 (d,J = 9.2 Hz, 1H), 0.91 (d,J = 7.0 Hz, 2H), 0.75 (d,J = 11.7 Hz, 1H), 0.71 (d,J = 6.2 Hz, 1H), 0.54 (s, 1H), 0.42 (s, 1H).

[0179]

[0180] Example 9: (1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0181]

[0182] The title product was afforded by a procedure similar to that described for the synthesis of Example 1 using 4-fluoro-N-methylaniline instead of N-methyl-m-toluidine.

[0183] MS (ESI, m / z): 433.2 [M+H]+

[0184] 1H NMR (400 MHz,cd3od) δ 7.58 (dd,J = 8.7, 4.8 Hz, 2H), 7.27 (t,J = 8.7 Hz, 2H), 6.88 (s, 1H), 5.30 (s, 1H), 4.11 (s, 1H), 3.27 (s, 3H), 2.65 (s, 1H), 2.52 (s, 3H), 2.27 (d,J = 8.9 Hz, 1H), 1.77 (t,J = 12.5 Hz, 1H), 1.69 - 1.59 (m, 2H), 1.46 (d,J = 9.9 Hz, 1H), 1.00 - 0.91 (m, 1H).

[0185]

[0186] Example 10: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0187]

[0188] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 using 4-fluoro-N-methylaniline instead of N-methyl-m-toluidine.

[0189] MS (ESI, m / z): 487.1 [M+H]+

[0190] 1H NMR (400 MHz, cd3od) δ 7.53 (s, 2H), 7.26 (dd,J = 11.4, 5.7 Hz, 3H), 5.37 (s, 1H), 4.09 (s, 1H), 3.23 (d,J = 14.2 Hz, 3H), 2.70 (s, 1H), 2.30 (s, 1H), 1.85 - 1.74 (m, 2H), 1.67 (s, 1H), 1.52 (d,J = 10.2 Hz, 1H), 1.02 (d,J = 6.8 Hz, 1H).

[0191]

[0192] Example 11:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0193]

[0194] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1] heptane-3-carboxylic acid. To a solution of methyl (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.0 eq, 354mg, 1.0 mmol) in Methyl alcohol (1.0mL) was added 1N NaOH (2 mL) and stirred at 25oC for 1 hour. The solution was neutralized with 1N HCl to give the desired product quantitatively.

[0195] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide. To a solution of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.0 eq, 71 mg, 0.4 mmol) and HATU (1.1 eq, 168 mg, 0.44 mmol) in dimethylformamide (1.0 mL) was added n-methyl-m-toluidine (1.3 eq, 56 μL, 0.52 mmol) and triethylamine (3 eq, 168 μL, 1.2 mmol) and stirred at 25 oC for 12 hour. The reaction mixture was poured into water (3 mL), extracted with DCM (3 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified by the Prep HPLC to give the desired product. (yield, 50%)

[0196] MS (ESI, m / z): 458.16 [M+H]+

[0197] 1H NMR (600 MHz, cdcl3) δ 7.32 (s, 1H), 7.27 (s, 1H), 7.17 (s, 2H), 6.98 (s, 1H), 6.74 (s, 1H), 4.32 (s, 1H), 3.91 (s, 1H), 3.28 (s, 3H), 2.63 (s, 1H), 2.51 (s, 1H), 2.39 (s, 3H), 1.69 (s, 1H), 1.62 (s, 1H), 1.48 (s, 1H), 1.41 (s, 1H), 0.97 (s, 1H).

[0198]

[0199] Example 12:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2,5-difluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0200]

[0201] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1] heptane-3-carboxylic acid. To a solution of methyl (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.0 eq, 354mg, 1.0 mmol) in Methyl alcohol (1.0mL) was added 1N NaOH (2 mL) and stirred at 25oC for 1 hour. The solution was neutralized with 1N HCl to give the desired product quantitatively.

[0202] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2,5-difluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide. To a solution of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.0 eq, 26 mg, 0.07 mmol) and HATU (1.1 eq, 31 mg, 0.08 mmol) in dimethylformamide (1.0 mL) was added 2,5-difluoroaniline (1.1 eq, 10 mg, 0.08 mmol) and triethylamine (3 eq, 39 μL, 2.2 mmol) and stirred at 25 oC for 12 hour. The reaction mixture was poured into water (3 mL), extracted with DCM (3 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified by the Prep HPLC to give the desired product. (yield, 50%)

[0203] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2,5-difluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide. To a solution of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2,5-difluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (1.0 eq, 8.4 mg, 0.02 mmol) and iodomethane (3.0 eq, 3.4 μL, 0.05 mmol) in Dimethyl sulfoxide (0.5 mL) was added NaH (2.0 eq, 1.5 mg, 0.04 mmol) at 0oC and stirred at 25oC for 12 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography give the desired product. (yield, 70%)

[0204] MS (ESI, m / z): 480.12 [M+H]+

[0205] 1H NMR (400 MHz, cdcl3) δ 7.45 (s, 1H), 7.19 (d, J = 5.0 Hz, 1H), 7.09 (s, 1H), 7.01 (s, 1H), 6.77 (s, 1H), 4.33 (s, 1H), 3.93 (s, 1H), 3.25 (s, 3H), 2.63 (s, 1H), 2.47 (d, J = 9.7 Hz, 1H), 1.74 - 1.63 (m, 2H), 1.50 (d, J = 10.0 Hz, 1H), 1.41 (d, J = 9.8 Hz, 1H), 0.99 (t, J = 10.7 Hz, 1H).

[0206]

[0207] Example 13: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0208]

[0209] Synthesis of 3-chloro-4-fluoro-N-methylaniline. To a solution of 3-chloro-4-fluoroaniline (1.0 eq, 0.622 mL, 1.0 mmol) and iodomethane (1.1 eq, 68 μL, 1.1 mmol) in tetrahydrofuran (2.0mL) was added NaH (2.0 eq, 48 mg, 2.0 mmol) and stirred at 0oC for 12 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography give the desired product. (yield, 50%)

[0210] MS (ESI, m / z): 160.0 [M+H]+

[0211] 1H NMR (600 MHz, cdcl3) δ 6.95 (t,J= 8.9 Hz, 1H), 6.58 (dd,J= 6.1, 2.9 Hz, 1H), 6.49 - 6.34 (m, 1H), 3.65 (s, 1H), 2.80 (s, 3H).

[0212] The title product was afforded by a procedure similar to that described for the synthesis of Example 11 using 3-chloro-4-fluoro-N-methylaniline instead of N-methyl-m-toluidine.

[0213] MS (ESI, m / z): 496.1 [M+H]+

[0214] 1H NMR (400 MHz, cdcl3) δ 7.52 (s, 1H), 7.33 (s, 1H), 7.22 (d,J= 8.6 Hz, 1H), 7.01 (s, 1H), 6.76 (s, 1H), 4.34 (s, 1H), 3.87 (s, 1H), 3.27 (s, 3H), 2.59 (s, 1H), 2.49 (s, 1H), 1.71 (t,J= 13.1 Hz, 2H), 1.52 (t,J= 9.9 Hz, 1H), 1.44 (d,J= 9.8 Hz, 1H), 1.04 (t,J= 9.5 Hz, 1H).

[0215]

[0216] Example 14:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-2-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0217]

[0218] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 3-chloro-2-fluoroaniline instead of 2,5-difluoroaniline.

[0219] MS (ESI, m / z): 496.09 [M+H]+

[0220] 1H NMR (400 MHz, cdcl3) δ 7.75 (s, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.12 (s, 1H), 6.89 (s, 1H), 4.45 (s, 1H), 4.04 (s, 1H), 3.38 (s, 3H), 2.73 (s, 1H), 2.58 (d, J = 9.6 Hz, 1H), 1.84 (s, 2H), 1.61 (d, J = 11.0 Hz, 1H), 1.53 (d, J = 9.4 Hz, 1H), 1.07 (d, J = 12.1 Hz, 1H).

[0221]

[0222] Example 15:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(p-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0223]

[0224] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using p-toluidine instead of 2,5-difluoroaniline.

[0225] MS (ESI, m / z): 458.16 [M+H]+

[0226] 1H NMR (400 MHz, cdcl3) δ 7.29 (s, 2H), 7.24 (s, 1H), 6.99 (s, 1H), 6.74 (s, 1H), 4.32 (s, 1H), 3.92 (s, 1H), 3.28 (s, 3H), 2.62 (s, 1H), 2.49 (d, J = 9.4 Hz, 1H), 2.39 (s, 3H), 1.70 - 1.58 (m, 2H), 1.47 (s, 1H), 1.40 (d, J = 9.9 Hz, 1H), 0.96 (d, J = 8.9 Hz, 1H).

[0227]

[0228] Example 16:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0229]

[0230] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 3-chloro-2,4-difluoroaniline instead of 2,5-difluoroaniline.

[0231] MS (ESI, m / z): 514.09 [M+H]+

[0232] 1H NMR (600 MHz, cdcl3) δ 8.86 (s, 1H), 8.02 (dd, J = 14.4, 8.7 Hz, 1H), 7.24 (s, 1H), 6.95 (dd, J = 18.0, 9.2 Hz, 2H), 4.40 (s, 1H), 4.21 (s, 1H), 3.13 (d, J = 2.5 Hz, 1H), 2.11 (d, J = 9.5 Hz, 1H), 1.95 - 1.87 (m, 1H), 1.81 (t, J = 12.4 Hz, 1H), 1.71 (t, J = 10.7 Hz, 1H), 1.65 (d, J = 10.4 Hz, 1H), 1.51 (d, J = 8.2 Hz, 1H).

[0233]

[0234] Example 17:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(o-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0235]

[0236] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using o-toluidine instead of 2,5-difluoroaniline.

[0237] MS (ESI, m / z): 458.16 [M+H]+

[0238] 1H NMR (400 MHz, dmso) δ 7.49 - 7.17 (m, 6H), 4.68 (s, 1H), 3.75 (d, J = 157.3 Hz, 1H), 3.07 (d, J = 12.9 Hz, 3H), 2.11 (d, J = 15.9 Hz, 1H), 1.96 (d, J = 9.8 Hz, 1H), 1.65 - 1.30 (m, 5H).

[0239]

[0240] Example 18:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3,4-difluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0241]

[0242] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 3,4-difluoroaniline instead of 2,5-difluoroaniline.

[0243] MS (ESI, m / z): 480.12 [M+H]+

[0244] 1H NMR (400 MHz, dmso) δ 7.58 (s, 2H), 7.37 (s, 1H), 7.28 (s, 1H), 7.17 (s, 1H), 4.69 (s, 1H), 3.74 (s, 1H), 3.13 (s, 3H), 2.73 (s, 1H), 2.18 (s, 1H), 1.61 (s, 3H), 1.38 (d, J = 9.7 Hz, 2H).

[0245]

[0246] Example 19:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0247]

[0248] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 2-fluoroaniline instead of 2,5-difluoroaniline.

[0249] MS (ESI, m / z): 462.13 [M+H]+

[0250] 1H NMR (400 MHz, cdcl3) δ 7.68 (d, J = 8.2 Hz, 1H), 7.40 (dd, J = 13.1, 6.0 Hz, 1H), 7.26 - 7.19 (m, 2H), 7.02 (s, 1H), 6.76 (s, 1H), 4.32 (s, 1H), 3.96 (s, 1H), 3.28 (s, 3H), 2.64 (s, 1H), 2.42 (d, J = 9.8 Hz, 1H), 1.64 (ddd, J = 15.8, 13.3, 10.0 Hz, 2H), 1.52 - 1.44 (m, 1H), 1.41 (d, J = 9.9 Hz, 1H), 0.96 - 0.85 (m, 1H).

[0251]

[0252] Example 20:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-bromophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0253]

[0254] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 3-bromoaniline instead of 2,5-difluoroaniline.

[0255] MS (ESI, m / z): 522.05 [M+H]+

[0256] 1H NMR (600 MHz, cdcl3) δ 7.60 (s, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.39 (d, J = 4.1 Hz, 1H), 7.36 - 7.31 (m, 1H), 6.99 (s, 1H), 6.76 (s, 1H), 4.34 (s, 1H), 3.88 (s, 1H), 3.28 (s, 3H), 2.62 (s, 1H), 2.50 (d, J = 9.3 Hz, 1H), 1.72 (s, 1H), 1.69 - 1.64 (m, 1H), 1.59 (s, 2H), 1.43 (dd, J = 7.6, 3.2 Hz, 1H).

[0257]

[0258] Example 21:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-methoxy-4-methylphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0259]

[0260] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 3-methoxy-4-methylaniline instead of 2,5-difluoroaniline.

[0261] MS (ESI, m / z): 488.17 [M+H]+

[0262] 1H NMR (400 MHz, cdcl3) δ 7.19 (d, J = 7.7 Hz, 1H), 7.00 (s, 1H), 6.88 (s, 2H), 6.74 (s, 1H), 4.31 (s, 1H), 3.98 (s, 1H), 3.85 (s, 3H), 3.31 (s, 3H), 2.67 (s, 1H), 2.40 (d, J = 9.7 Hz, 1H), 2.24 (s, 3H), 1.66 (ddd, J = 12.9, 11.6, 7.9 Hz, 2H), 1.50 (t, J = 10.3 Hz, 1H), 1.42 (d, J = 10.2 Hz, 1H), 1.02 (t, J = 10.0 Hz, 1H).

[0263]

[0264] Example 22:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0265]

[0266] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 4-fluoro-3-(trifluoromethyl)aniline instead of 2,5-difluoroaniline.

[0267] MS (ESI, m / z): 530.12 [M+H]+

[0268] 1H NMR (400 MHz, cdcl3) δ 7.67 (s, 2H), 7.32 (t, J = 9.3 Hz, 1H), 7.02 (s, 1H), 6.76 (s, 1H), 4.35 (s, 1H), 3.78 (s, 1H), 3.31 (s, 3H), 2.61 (s, 1H), 2.47 (d, J = 9.6 Hz, 1H), 1.72 (t, J = 12.5 Hz, 2H), 1.56 - 1.48 (m, 1H), 1.46 (d, J = 9.8 Hz, 1H), 1.00 (d, J = 10.3 Hz, 1H).

[0269]

[0270] Example 23:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-hydroxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0271]

[0272] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 3-aminophenol instead of 2,5-difluoroaniline.

[0273] MS (ESI, m / z): 460.14 [M+H]+

[0274] 1H NMR (400 MHz, cdcl3) δ 7.30 (t, J = 8.0 Hz, 1H), 6.99 (s, 1H), 6.95 (s, 2H), 6.84 (d, J = 9.4 Hz, 1H), 6.75 (s, 1H), 4.33 (s, 1H), 3.98 (s, 1H), 3.27 (s, 3H), 2.62 (s, 1H), 2.51 (s, 1H), 1.71 (s, 2H), 1.49 (s, 1H), 1.41 (d, J = 9.5 Hz, 1H), 1.01 (s, 1H).

[0275]

[0276] Example 24:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-methoxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0277]

[0278] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 3-aminophenol instead of 2,5-difluoroaniline.

[0279] MS (ESI, m / z): 474.15 [M+H]+

[0280] 1H NMR (400 MHz, cdcl3) δ 7.35 (t, J = 7.5 Hz, 1H), 6.99 (d, J = 5.5 Hz, 3H), 6.92 (d, J = 7.9 Hz, 1H), 6.74 (s, 1H), 4.32 (s, 1H), 3.96 (s, 1H), 3.84 (s, 3H), 3.29 (s, 3H), 2.65 (s, 1H), 2.46 (s, 1H), 1.69 (d, J = 11.3 Hz, 2H), 1.50 (s, 1H), 1.41 (d, J = 10.1 Hz, 1H), 1.01 (s, 1H).

[0281]

[0282] Example 25:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-hydroxy-4-methylphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0283]

[0284] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 5-amino-2-methylphenol instead of 2,5-difluoroaniline.

[0285] MS (ESI, m / z): 474.15 [M+H]+

[0286] 1H NMR (400 MHz, cdcl3) δ 7.21 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 6.83 (dd, J = 7.9, 2.0 Hz, 1H), 4.35 (s, 1H), 4.17 (s, 1H), 3.81 (s, 2H), 3.14 (s, 1H), 2.15 (s, 2H), 1.89 (dd, J = 14.3, 10.0 Hz, 1H), 1.78 (d, J = 12.0 Hz, 1H), 1.70 (s, 1H), 1.66 (s, 1H), 1.46 (s, 1H).

[0287]

[0288] Example 26:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-phenyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0289]

[0290] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using aniline instead of 2,5-difluoroaniline.

[0291] MS (ESI, m / z): 444.14 [M+H]+

[0292] 1H NMR (400 MHz, cdcl3) δ 7.49 - 7.38 (m, 5H), 7.02 (s, 1H), 6.74 (s, 1H), 4.31 (s, 1H), 3.93 (s, 1H), 3.32 (s, 3H), 2.62 (s, 1H), 2.43 (d, J = 9.9 Hz, 1H), 1.64 (ddd, J = 13.2, 12.2, 8.1 Hz, 2H), 1.48 (d, J = 9.8 Hz, 1H), 1.42 (d, J = 10.2 Hz, 1H), 0.93 (t, J = 10.2 Hz, 1H).

[0293]

[0294] Example 27:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-4-methylphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0295]

[0296] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 3-chloro-4-methylaniline instead of 2,5-difluoroaniline.

[0297] MS (ESI, m / z): 4922 [M+H]+

[0298] 1H NMR (400 MHz, cdcl3) δ 7.44 (s, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.24 (s, 1H), 7.01 (s, 1H), 6.74 (s, 1H), 4.32 (s, 1H), 3.92 (s, 1H), 3.28 (s, 3H), 2.63 (s, 1H), 2.45 (s, 1H), 2.41 (s, 3H), 1.74 - 1.65 (m, 2H), 1.49 (t, J = 10.2 Hz, 1H), 1.43 (d, J = 9.8 Hz, 1H), 1.03 (t, J = 9.9 Hz, 1H).

[0299]

[0300] Example 28: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3,4-dichlorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0301]

[0302] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 3,4-dichloroaniline instead of 2,5-difluoroaniline.

[0303] MS (ESI, m / z): 512.07 [M+H]+

[0304] 1H NMR (400 MHz, cdcl3) δ 7.77 (d, J = 8.3 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.36 (dd, J = 8.5, 2.3 Hz, 1H), 7.03 (s, 1H), 6.78 (s, 1H), 4.33 (s, 1H), 3.91 (s, 1H), 3.22 (s, 2H), 2.71 (s, 1H), 2.44 (d, J = 9.9 Hz, 1H), 1.68 (t, J = 13.3 Hz, 2H), 1.51 (d, J = 9.9 Hz, 1H), 1.40 (d, J = 9.9 Hz, 1H), 0.98 (d, J = 10.6 Hz, 1H).

[0305]

[0306] Example 29: methyl 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamido)-4-chloro-5-fluorobenzoate

[0307]

[0308] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using methyl 2-amino-4-chloro-5-fluorobenzoate instead of 2,5-difluoroaniline.

[0309] MS (ESI, m / z): 554.10 [M+H]+

[0310] 1H NMR (600 MHz, cdcl3) δ 7.93 (d, J = 5.4 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.01 (s, 1H), 6.77 (s, 1H), 4.33 (s, 1H), 3.95 (s, 3H), 3.80 (s, 1H), 3.52 (s, 1H), 3.20 (s, 3H), 2.50 - 2.43 (m, 2H), 1.70 (d, J = 13.9 Hz, 1H), 1.37 (d, J = 10.4 Hz, 1H), 0.96 (s, 1H), 0.87 (d, J = 7.2 Hz, 1H).

[0311]

[0312] Example 30: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluoro-3-methoxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0313]

[0314] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 4-fluoro-3-methoxyaniline instead of 2,5-difluoroaniline.

[0315] MS (ESI, m / z): 492.14 [M+H]+

[0316] 1H NMR (600 MHz, cdcl3) δ 7.17 - 7.12 (m, 1H), 7.05 (s, 1H), 6.99 (s, 1H), 6.92 (s, 1H), 6.76 (s, 1H), 4.34 (s, 1H), 3.98 (t, J = 1.8 Hz, 1H), 3.91 (s, 3H), 3.28 (s, 3H), 2.62 (s, 1H), 2.45 (d, J = 9.7 Hz, 1H), 1.72 (d, J = 11.3 Hz, 1H), 1.65 (t, J = 12.2 Hz, 1H), 1.52 (s, 1H), 1.42 (d, J = 9.6 Hz, 1H), 1.03 (s, 1H).

[0317]

[0318] Example 31: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2,4-dichlorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0319]

[0320] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 2,4-dichloroaniline instead of 2,5-difluoroaniline.

[0321] MS (ESI, m / z): 512.07 [M+H]+

[0322] 1H NMR (400 MHz, cdcl3) δ 7.54 (s, 5H), 7.52 (s, 3H), 7.32 (s, 4H), 7.00 (s, 4H), 6.76 (s, 4H), 4.34 (s, 5H), 3.88 (s, 5H), 3.27 (s, 11H), 2.61 (s, 5H), 2.50 (d, J = 8.7 Hz, 5H), 1.71 (s, 9H), 1.44 (d, J = 9.5 Hz, 6H), 1.08 (s, 8H).

[0323]

[0324] Example 32: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chlorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0325]

[0326] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 3-chloroaniline instead of 2,5-difluoroaniline.

[0327] MS (ESI, m / z): 478.10 [M+H]+

[0328] 1H NMR (400 MHz, cdcl3) δ 7.45 (s, 1H), 7.42 - 7.28 (m, 3H), 6.99 (s, 1H), 6.75 (s, 1H), 4.33 (s, 1H), 3.89 (s, 1H), 3.28 (s, 3H), 2.62 (s, 1H), 2.50 (d, J = 9.5 Hz, 1H), 1.69 (t, J = 13.3 Hz, 2H), 1.50 (t, J = 9.7 Hz, 1H), 1.43 (d, J = 9.7 Hz, 1H), 1.02 (t, J = 9.5 Hz, 1H).

[0329]

[0330] Example 33: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3,5-difluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0331]

[0332] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 3,5-difluoroaniline instead of 2,5-difluoroaniline.

[0333] MS (ESI, m / z): 480.12 [M+H]+

[0334] 1H NMR (600 MHz, cdcl3) δ 7.01 (d, J = 3.6 Hz, 3H), 6.85 (s, 1H), 6.77 (s, 1H), 4.35 (s, 1H), 3.95 (s, 1H), 3.28 (s, 3H), 2.62 (s, 1H), 2.49 (s, 1H), 1.85 - 1.66 (m, 4H), 1.45 (d, J = 9.8 Hz, 1H).

[0335]

[0336] Example 34: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-chloro-3-methoxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0337]

[0338] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 4-chloro-3-methoxyaniline instead of 2,5-difluoroaniline.

[0339] MS (ESI, m / z): 508.11 [M+H]+

[0340] 1H NMR (600 MHz, cdcl3) δ 7.45 (d, J = 8.3 Hz, 1H), 7.00 (s, 2H), 6.94 (s, 1H), 6.76 (s, 1H), 4.33 (s, 1H), 3.93 (s, 4H), 3.30 (s, 3H), 2.64 (s, 1H), 2.42 (d, J = 9.6 Hz, 1H), 1.74 (t, J = 12.0 Hz, 1H), 1.70 - 1.62 (m, 1H), 1.52 (s, 1H), 1.43 (d, J = 9.7 Hz, 1H), 1.05 (s, 1H).

[0341]

[0342] Example 35: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-bromo-2-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0343]

[0344] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 4-bromo-2-fluoroaniline instead of 2,5-difluoroaniline.

[0345] MS (ESI, m / z): 540.04 [M+H]+

[0346] 1H NMR (400 MHz, cdcl3) δ 7.59 (t, J = 8.4 Hz, 1H), 7.41 (t, J = 6.8 Hz, 2H), 7.02 (s, 1H), 6.77 (s, 1H), 4.33 (s, 1H), 3.92 (s, 1H), 3.24 (s, 3H), 2.60 (s, 1H), 2.45 (d, J = 10.0 Hz, 1H), 1.67 (dt, J = 11.7, 9.6 Hz, 2H), 1.55 - 1.46 (m, 1H), 1.42 (d, J = 10.2 Hz, 1H), 1.01 (t, J = 9.8 Hz, 1H).

[0347]

[0348] Example 36: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-hydroxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0349]

[0350] Example 36’ was afforded by a procedure similar to that described for the synthesis of Example 12 using 2-((4-methoxybenzyl)oxy)aniline instead of 2,5-difluoroaniline.

[0351] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-hydroxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide. To a solution of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-((4-methoxybenzyl)oxy)phenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide (1.0 eq, 18 mg, 0.03 mmol) in Trifluoroacetic acid (1 mL) was added water (0.05 mL) and stirred at 25oC for 3 h. The reaction mixture was concentrated in reduced pressure and purified by the Prep HPLC to give the desired product. (yield, 40%)

[0352] MS (ESI, m / z): 460.14 [M+H]+

[0353] 1H NMR (400 MHz, cdcl3) δ 7.30 (t, J = 8.2 Hz, 1H), 7.16 (d, J = 7.3 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 10.2 Hz, 2H), 6.82 (s, 1H), 4.37 (s, 1H), 3.74 (s, 1H), 3.24 (s, 3H), 2.51 (s, 1H), 2.38 (d, J = 10.2 Hz, 1H), 1.72 (d, J = 12.0 Hz, 1H), 1.58 (dd, J = 12.4, 7.8 Hz, 3H), 1.38 (d, J = 10.0 Hz, 1H).

[0354]

[0355] Example 37: (1R,3S,4S)-N-([1,1'-biphenyl]-4-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0356]

[0357] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using [1,1'-biphenyl]-4-amine instead of 2,5-difluoroaniline.

[0358] MS (ESI, m / z): 520.17 [M+H]+

[0359] 1H NMR (600 MHz, cdcl3) δ 7.68 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 7.7 Hz, 2H), 7.50 (d, J = 5.4 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.37 (t, J = 7.3 Hz, 1H), 6.99 (s, 1H), 6.76 (s, 1H), 4.34 (s, 1H), 3.99 (s, 1H), 3.33 (s, 3H), 2.67 (s, 1H), 2.54 (d, J = 8.8 Hz, 1H), 1.75 - 1.67 (m, 1H), 1.65 - 1.60 (m, 1H), 1.49 (s, 1H), 1.42 (d, J = 9.5 Hz, 1H), 1.02 (d, J = 10.9 Hz, 1H).

[0360]

[0361] Example 38: (1R,3S,4S)-N-([1,1'-biphenyl]-2-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0362]

[0363] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using [1,1'-biphenyl]-2-amine instead of 2,5-difluoroaniline.

[0364] MS (ESI, m / z): 520.17 [M+H]+

[0365] 1H NMR (400 MHz, cdcl3) δ 7.75 (s, 1H), 7.50 - 7.35 (m, 8H), 6.97 (s, 1H), 6.68 (s, 1H), 4.19 (s, 1H), 3.71 (s, 1H), 3.35 (s, 3H), 3.12 (s, 1H), 2.27 (d, J = 10.0 Hz, 1H), 1.56 (s, 2H), 1.43 - 1.35 (m, 2H), 1.08 (d, J = 9.4 Hz, 1H).

[0366]

[0367] Example 39: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-chlorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0368]

[0369] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 2-chloroaniline instead of 2,5-difluoroaniline.

[0370] MS (ESI, m / z): 478.10 [M+H]+

[0371] 1H NMR (400 MHz, cdcl3) δ 7.80 (s, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.36 (dd, J = 6.9, 2.7 Hz, 2H), 7.02 (s, 1H), 6.95 (s, 1H), 4.41 (s, 1H), 4.33 (s, 1H), 3.25 (s, 3H), 2.74 (s, 1H), 2.53 (s, 1H), 1.66 - 1.48 (m, 5H).

[0372]

[0373] Example 40: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0374]

[0375] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 3-fluoroaniline instead of 2,5-difluoroaniline.

[0376] MS (ESI, m / z): 462.13 [M+H]+

[0377] 1H NMR (400 MHz, cdcl3) δ 7.47 - 7.39 (m, 1H), 7.24 (s, 1H), 7.19 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 7.00 (s, 1H), 6.75 (s, 1H), 4.34 (s, 1H), 3.93 (s, 1H), 3.29 (s, 2H), 2.61 (s, 1H), 2.49 (d, J = 9.6 Hz, 1H), 1.67 (d, J = 15.2 Hz, 2H), 1.50 (s, 1H), 1.43 (d, J = 9.8 Hz, 1H), 1.00 (s, 1H).

[0378]

[0379] Example 41: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0380]

[0381] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using pyridin-2-amine instead of 2,5-difluoroaniline.

[0382] MS (ESI, m / z): 445.14 [M+H]+

[0383] 1H NMR (400 MHz, cdcl3) δ 8.38 (d, J = 8.2 Hz, 1H), 8.28 - 8.24 (m, 1H), 8.22 (d, J = 5.7 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.07 (s, 1H), 6.90 (s, 1H), 4.43 (d, J = 12.0 Hz, 2H), 4.31 (s, 3H), 3.03 (s, 1H), 2.24 (d, J = 9.9 Hz, 1H), 1.84 (d, J = 11.5 Hz, 2H), 1.70 (d, J = 6.4 Hz, 2H), 1.57 (d, J = 10.6 Hz, 1H).

[0384]

[0385] Example 42: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(6-(dimethylamino)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0386]

[0387] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using pyridine-2,6-diamine instead of 2,5-difluoroaniline.

[0388] MS (ESI, m / z): 488.18 [M+H]+

[0389] 1H NMR (400 MHz, cdcl3) δ 7.64 (s, 1H), 6.98 (s, 1H), 6.72 (d, J = 22.7 Hz, 2H), 6.52 (s, 1H), 4.34 (s, 1H), 3.39 (s, 2H), 3.14 (s, 4H), 2.96 (s, 6H), 2.49 (s, 1H), 1.76 (s, 2H), 1.60 - 1.43 (m, 2H), 1.27 (s, 1H).

[0390]

[0391] Example 43: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluoropyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0392]

[0393] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 4-fluoropyridin-2-amine instead of 2,5-difluoroaniline.

[0394] MS (ESI, m / z): 463.13 [M+H]+

[0395] 1H NMR (600 MHz, cdcl3) δ 8.43 (dd, J = 8.8, 5.7 Hz, 1H), 7.26 - 7.20 (m, 1H), 6.96 (d, J = 9.8 Hz, 2H), 6.76 (s, 1H), 4.35 (s, 1H), 3.98 (s, 1H), 3.42 (s, 3H), 3.00 (s, 1H), 2.56 (d, J = 7.8 Hz, 1H), 1.77 (t, J = 10.1 Hz, 2H), 1.57 (dd, J = 21.4, 15.2 Hz, 2H), 1.46 (d, J = 9.7 Hz, 1H).

[0396]

[0397] Example 44: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(6-fluoropyridin-3-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0398]

[0399] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 6-fluoropyridin-3-amine instead of 2,5-difluoroaniline.

[0400] MS (ESI, m / z): 463.13 [M+H]+

[0401] 1H NMR (400 MHz, cdcl3) δ 8.27 (s, 1H), 7.96 (s, 1H), 7.06 (d, J = 5.4 Hz, 1H), 7.01 (s, 1H), 6.77 (s, 1H), 4.36 (s, 1H), 3.79 (s, 1H), 3.29 (s, 3H), 2.62 (s, 1H), 2.52 (d, J = 10.0 Hz, 1H), 1.71 (t, J = 12.8 Hz, 2H), 1.49 (dd, J = 26.7, 10.0 Hz, 2H), 1.04 (s, 1H).

[0402]

[0403] Example 45: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(5-methylpyridin-3-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0404]

[0405] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 5-methylpyridin-3-amine instead of 2,5-difluoroaniline.

[0406] MS (ESI, m / z): 459.15 [M+H]+

[0407] 1H NMR (600 MHz, cdcl3) δ 8.44 (d, J = 7.8 Hz, 2H), 7.69 (s, 1H), 7.00 (s, 1H), 6.76 (s, 1H), 4.34 (s, 1H), 3.80 (s, 1H), 3.29 (s, 3H), 2.66 (s, 1H), 2.52 (d, J = 9.6 Hz, 1H), 2.40 (s, 3H), 1.69 (dd, J = 23.7, 12.3 Hz, 2H), 1.46 (dd, J = 23.6, 10.1 Hz, 2H), 1.02 (d, J = 10.7 Hz, 1H).

[0408]

[0409] Example 46: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(6-methylpyridin-3-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0410]

[0411] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 6-methylpyridin-3-amine instead of 2,5-difluoroaniline.

[0412] MS (ESI, m / z): 459.15 [M+H]+

[0413] 1H NMR (400 MHz, cdcl3) δ 8.56 (s, 1H), 7.77 (s, 1H), 7.31 (s, 1H), 6.99 (s, 1H), 6.76 (s, 1H), 4.35 (s, 1H), 3.86 (s, 1H), 3.32 (s, 3H), 2.64 (d, J = 5.0 Hz, 4H), 2.51 (d, J = 9.2 Hz, 1H), 1.71 (s, 1H), 1.63 - 1.59 (m, 1H), 1.46 (s, 1H), 1.40 - 1.35 (m, 1H), 0.95 - 0.92 (m, 1H).

[0414]

[0415] Example 47: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(6-methylpyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0416]

[0417] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 6-methylpyridin-2-amine instead of 2,5-difluoroaniline.

[0418] MS (ESI, m / z): 459.15 [M+H]+

[0419] 1H NMR (400 MHz, cdcl3) δ 7.75 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.96 (s, 1H), 6.74 (s, 1H), 4.34 (s, 1H), 3.91 (s, 1H), 3.40 (s, 3H), 3.08 (s, 1H), 2.58 (s, 3H), 2.53 (s, 1H), 1.77 (s, 2H), 1.51 (d, J = 10.0 Hz, 1H), 1.45 (d, J = 10.0 Hz, 1H), 1.20 (d, J = 12.7 Hz, 1H).

[0420]

[0421] Example 48: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(5-methylpyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0422]

[0423] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 5-methylpyridin-2-amine instead of 2,5-difluoroaniline.

[0424] MS (ESI, m / z): 459.15 [M+H]+

[0425] 1H NMR (400 MHz, cdcl3) δ 8.42 (d, J = 5.2 Hz, 1H), 7.42 (s, 1H), 7.15 (d, J = 4.7 Hz, 1H), 6.98 (s, 1H), 6.76 (s, 1H), 4.34 (s, 1H), 3.87 (s, 1H), 3.39 (s, 3H), 2.94 (s, 1H), 2.49 (s, 1H), 2.44 (s, 3H), 1.74 (d, J = 9.0 Hz, 2H), 1.53 (d, J = 10.3 Hz, 1H), 1.44 (d, J = 9.4 Hz, 1H), 1.13 (s, 1H).

[0426]

[0427] Example 49: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(4-methylpyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0428]

[0429] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 4-methylpyridin-2-amine instead of 2,5-difluoroaniline.

[0430] MS (ESI, m / z): 459.15 [M+H]+

[0431] 1H NMR (400 MHz, cdcl3) δ 8.43 (s, 1H), 7.77 (d, J = 6.7 Hz, 1H), 7.57 (d, J = 6.9 Hz, 1H), 7.00 (s, 1H), 6.77 (s, 1H), 4.34 (s, 1H), 3.93 (s, 1H), 3.41 (s, 3H), 2.90 (s, 1H), 2.52 - 2.44 (m, 1H), 2.43 (s, 3H), 1.75 (d, J = 8.3 Hz, 2H), 1.53 (d, J = 9.1 Hz, 1H), 1.45 (d, J = 10.2 Hz, 1H), 1.14 (s, 1H).

[0432]

[0433] Example 50: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0434]

[0435] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 6-(trifluoromethyl)pyridin-2-amine instead of 2,5-difluoroaniline.

[0436] MS (ESI, m / z): 513.13 [M+H]+

[0437] 1H NMR (400 MHz, cdcl3) δ 7.97 (t, J = 7.9 Hz, 1H), 7.57 (dd, J = 11.7, 7.9 Hz, 2H), 6.93 (s, 1H), 6.74 (s, 1H), 4.34 (s, 1H), 3.90 (s, 1H), 3.44 (s, 3H), 3.17 (s, 1H), 2.62 (s, 1H), 1.84 - 1.74 (m, 2H), 1.48 (d, J = 9.8 Hz, 2H), 1.35 - 1.28 (m, 1H).

[0438]

[0439] Example 51: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0440]

[0441] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using pyrimidin-4-amine instead of 2,5-difluoroaniline.

[0442] MS (ESI, m / z): 446.13 [M+H]+

[0443] 1H NMR (400 MHz, cdcl3) δ 9.00 (s, 1H), 8.66 (d, J = 5.8 Hz, 1H), 7.49 (d, J = 6.0 Hz, 1H), 6.96 (s, 1H), 6.77 (s, 1H), 4.38 (d, J = 14.8 Hz, 2H), 3.51 (s, 3H), 3.05 (s, 1H), 2.56 (s, 1H), 1.87 (t, J = 12.1 Hz, 2H), 1.63 (d, J = 7.0 Hz, 1H), 1.51 (d, J = 9.4 Hz, 1H), 0.96 - 0.92 (m, 1H).

[0444]

[0445] Example 52: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0446]

[0447] The title product was afforded by a procedure similar to that described for the synthesis of Example 11 using 4-fluoro-N-methylaniline instead of n-methyl-m-toluidine.

[0448] MS (ESI, m / z): 462.13 [M+H]+

[0449] 1H NMR (400 MHz, cdcl3) δ 7.41 (s, 2H), 7.14 (t, J = 8.3 Hz, 2H), 6.99 (s, 1H), 6.76 (s, 1H), 4.33 (s, 1H), 3.88 (s, 1H), 3.27 (s, 3H), 2.59 (s, 1H), 2.51 (d, J = 9.6 Hz, 1H), 1.72 - 1.62 (m, 2H), 1.49 (t, J = 10.2 Hz, 1H), 1.42 (d, J = 9.7 Hz, 1H), 0.98 (t, J = 9.9 Hz, 1H).

[0450]

[0451] Example 53: (1R,3S,4S)-N-(4-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0452]

[0453] The title product was afforded by a procedure similar to that described for the synthesis of Example 9 using 2-chloro-6-methyl-4-(trifluoromethyl)pyridine instead of 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile.

[0454] MS (ESI, m / z): 408.2 [M+H]+

[0455] 1H NMR (400 MHz,cd3od) δ 7.57 (s, 2H), 7.28 (t,J = 8.8 Hz, 2H), 6.69 (s, 1H), 6.50 (s, 1H), 3.93 (s, 1H), 3.28 (s, 3H), 2.66 (s, 1H), 2.48 (s, 3H), 2.25 (d,J = 8.5 Hz, 1H), 1.64 (d,J = 12.9 Hz, 3H), 1.44 (d,J = 9.9 Hz, 2H), 0.90 (s, 1H).

[0456]

[0457] Example 54: (1R,3S,4S)-N-(4-fluorophenyl)-N-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0458]

[0459] The title product was afforded by a procedure similar to that described for the synthesis of Example 9 using 2-chloro-4-(trifluoromethyl)pyridine instead of 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile.

[0460] MS (ESI, m / z): 394.1 [M+H]+

[0461] 1H NMR (400 MHz,cd3od) δ 8.22 (d,J = 6.0 Hz, 1H), 7.56 (s, 2H), 7.28 (t,J = 8.1 Hz, 2H), 6.88 (s, 1H), 6.76 (s, 1H), 4.51 (s, 1H), 4.02 (s, 1H), 2.67 (s, 1H), 2.23 (d,J = 9.5 Hz, 1H), 1.65 (d,J = 19.7 Hz, 2H), 1.48 (d,J = 9.0 Hz, 2H), 0.95 (s, 1H).

[0462]

[0463] Example 55: (1R,3S,4S)-2-(6-chloro-4-(trifluoromethyl) pyridin-2-yl)-N-(4-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0464]

[0465] The title product was afforded by a procedure similar to that described for the synthesis of Example 9 using 2,6-dichloro-4-(trifluoromethyl)pyridine instead of 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile.

[0466] MS (ESI, m / z): 394.1 [M+H]+

[0467] 1H NMR (600 MHz,cd3od) δ 7.64 (s, 2H), 7.26 (t,J = 8.6 Hz, 2H), 6.75 (s, 1H), 6.72 (d,J = 10.3 Hz, 1H), 4.40 (s, 1H), 3.84 (s, 1H), 3.27 (s, 3H), 2.64 (s, 1H), 2.31 (d,J = 9.2 Hz, 1H), 1.73 - 1.59 (m, 2H), 1.43 (d,J = 9.4 Hz, 2H), 0.90 (t,J = 9.2 Hz, 1H).

[0468]

[0469] Example 56: (1R,3S,4S)-N-(4-fluorophenyl)-2-(6-methoxy-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0470]

[0471] The title product was afforded by a procedure similar to that described for the synthesis of Example 9 using 2-chloro-6-methoxy-4-(trifluoromethyl)pyridine instead of 2-chloro-6-methyl-4-(trifluoromethyl)nicotinonitrile.

[0472] MS (ESI, m / z): 394.1 [M+H]+

[0473] 1H NMR (400 MHz,cd3od) δ 7.52 (dd,J = 8.8, 4.9 Hz, 2H), 7.28 (t,J = 8.6 Hz, 2H), 6.14 (s, 2H), 4.40 (s, 2H), 3.92 (s, 3H), 3.29 (s, 3H), 2.64 (s, 1H), 2.15 (d,J = 9.7 Hz, 1H), 1.68 - 1.58 (m, 2H), 1.52 (s, 1H), 1.40 (d,J = 9.6 Hz, 1H), 0.90 (s, 1H).

[0474]

[0475] Example 57: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0476]

[0477] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 1H-indol-6-amine instead of 2,5-difluoroaniline.

[0478] MS (ESI, m / z): 498.17 [M+H]+

[0479] 1H NMR (400 MHz, cdcl3) δ 8.00 (d, J = 8.1 Hz, 1H), 7.23 (s, 2H), 6.95 (s, 1H), 6.70 (s, 1H), 6.49 (d, J = 3.3 Hz, 1H), 4.31 (s, 1H), 3.87 (s, 4H), 3.43 (s, 3H), 3.23 (s, 1H), 2.58 (s, 1H), 1.69 (s, 2H), 1.46 (s, 2H), 1.06 (s, 1H).

[0480]

[0481] Example 58:(1R,3S,4S)-N-(benzofuran-6-yl)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0482]

[0483] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using benzofuran-6-amine instead of 2,5-difluoroaniline.

[0484] MS (ESI, m / z): 484.14 [M+H]+

[0485] 1H NMR (400 MHz, cdcl3) δ 7.72 (d, J = 2.1 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.62 (s, 1H), 7.33 (s, 1H), 7.02 (s, 1H), 6.82 (d, J = 1.4 Hz, 1H), 6.74 (s, 1H), 4.31 (s, 1H), 3.98 (s, 1H), 3.36 (s, 3H), 2.66 (s, 1H), 2.46 (d, J = 9.9 Hz, 1H), 1.71 - 1.54 (m, 2H), 1.43 (t, J = 10.2 Hz, 2H), 1.31 (s, 1H).

[0486]

[0487] Example 59: (1R,3S,4S)-N-(benzo[d]thiazol-5-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0488]

[0489] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using benzo[d]thiazol-5-amine instead of 2,5-difluoroaniline.

[0490] MS (ESI, m / z): 501.11 [M+H]+

[0491] 1H NMR (400 MHz, cdcl3) δ 9.14 (s, 1H), 8.18 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H), 7.01 (s, 1H), 6.75 (s, 1H), 4.33 (s, 1H), 3.94 (s, 1H), 3.38 (s, 3H), 2.71 (s, 1H), 2.51 (d, J = 9.0 Hz, 1H), 1.64 (dt, J = 35.6, 11.4 Hz, 2H), 1.44 (d, J = 9.6 Hz, 2H), 1.31 (s, 1H).

[0492]

[0493] Example 60: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0494]

[0495] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 5-amino-1,3-dihydro-2H-benzo[d]imidazol-2-one instead of 2,5-difluoroaniline.

[0496] MS (ESI, m / z): 528.18 [M+H]+

[0497] 1H NMR (400 MHz, cdcl3) δ 7.25 - 6.89 (m, 5H), 6.75 (s, 1H), 4.33 (s, 1H), 3.93 (s, 1H), 3.45 (d, J = 5.9 Hz, 6H), 3.32 (s, 3H), 2.66 (s, 1H), 2.48 (d, J = 9.7 Hz, 1H), 1.74 - 1.59 (m, 2H), 1.46 (dd, J = 26.6, 9.7 Hz, 2H), 0.96 (t, J = 9.9 Hz, 1H).

[0498]

[0499] Example 61: (1R,3S,4S)-N-(benzo[d]oxazol-2-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0500]

[0501] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using benzo[d]oxazol-2-amine instead of 2,5-difluoroaniline.

[0502] MS (ESI, m / z): 485.13 [M+H]+

[0503] 1H (400 MHz, cdcl3) δ 7.61 (dd, J = 7.5, 1.0 Hz, 1H), 7.52 - 7.47 (m, 1H), 7.36 - 7.27 (m, 2H), 6.95 (s, 1H), 6.75 (s, 1H), 4.86 (s, 1H), 4.40 (s, 1H), 3.55 (s, 3H), 3.09 (s, 1H), 2.45 (s, 1H), 1.97 - 1.81 (m, 2H), 1.71 (dd, J = 18.7, 9.1 Hz, 2H), 1.51 (s, 1H).

[0504]

[0505] Example 62: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-methyl-1H-indol-5-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0506]

[0507] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 1H-indol-5-amine instead of 2,5-difluoroaniline.

[0508] MS (ESI, m / z): 497.17 [M+H]+

[0509] 1H NMR (400 MHz, cdcl3) δ 7.66 (s, 2H), 7.36 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 2.6 Hz, 1H), 6.97 (s, 1H), 6.72 (s, 1H), 6.52 (d, J = 2.9 Hz, 1H), 4.30 (s, 1H), 3.99 (s, 1H), 3.82 (s, 3H), 3.34 (s, 3H), 2.67 (s, 1H), 2.54 (d, J = 8.8 Hz, 1H), 1.67 - 1.51 (m, 3H), 1.40 (dd, J = 14.3, 6.2 Hz, 2H).

[0510]

[0511] Example 63: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-methyl-1H-indol-4-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0512]

[0513] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 1H-indol-4-amine instead of 2,5-difluoroaniline.

[0514] MS (ESI, m / z): 497.17 [M+H]+

[0515] 1H NMR (400 MHz, cdcl3) δ 7.44 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.15 (d, J = 16.6 Hz, 1H), 7.01 (dd, J = 23.8, 10.0 Hz, 2H), 6.74 (s, 1H), 6.43 (d, J = 2.7 Hz, 1H), 4.29 (s, 1H), 4.22 (s, 1H), 3.85 (d, J = 7.4 Hz, 3H), 3.39 (d, J = 11.3 Hz, 3H), 2.45 (s, 1H), 2.41 (s, 1H), 1.45 - 1.28 (m, 5H).

[0516]

[0517] Example 64: (1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-6-azatricyclo[3.2.1.02,4]octane-7-carboxamide

[0518]

[0519] The title product was afforded by a procedure similar to that described for the synthesis of Example 11 using (1R,5S,7S)-6-(tert-butoxycarbonyl)-6-azatricyclo[3.2.1.02,4]octane-7-carboxylic acid instead of (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid.

[0520] MS (ESI, m / z): 470.2 [M+H]+

[0521] 1H NMR (600 MHz,cd3od) δ 7.41 (dd,J = 14.4, 6.7 Hz, 2H), 7.32 (d,J = 7.8 Hz, 1H), 7.28 (d,J = 6.9 Hz, 1H), 7.18 (s, 1H), 7.07 (s, 1H), 4.56 (s, 1H), 3.99 (s, 1H), 3.26 (s, 3H), 2.76 (s, 1H), 2.41 (s, 3H), 2.21 - 2.17 (m, 1H), 1.81 (d,J = 11.1 Hz, 1H), 1.60 (s, 1H), 0.66 - 0.62 (m, 1H), 0.47 (s, 1H), 0.21 (dd,J = 14.1, 7.1 Hz, 1H).

[0522]

[0523] Example 65: (1S,3R,4R)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0524]

[0525] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 using (1S,3R,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid instead of (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid.

[0526] MS (ESI, m / z): 483.1 [M+H]+

[0527] 1H NMR (400 MHz,cd3od) δ 7.39 (t,J = 7.7 Hz, 1H), 7.34 (s, 1H), 7.31 - 7.25 (m, 3H), 5.38 (s, 1H), 4.14 (s, 1H), 3.25 (s, 3H), 2.72 (s, 1H), 2.38 (s, 3H), 2.29 (s, 1H), 1.72 (dd,J = 30.1, 15.2 Hz, 2H), 1.51 (d,J = 9.9 Hz, 1H), 1.31 (d,J = 18.8 Hz, 1H), 0.97 (s, 1H).

[0528]

[0529] Example 66: (1S,3R,4R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0530]

[0531] The title product was afforded by a procedure similar to that described for the synthesis of Example 11 using (1S,3R,4R)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid instead of (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid.

[0532] MS (ESI, m / z): 458.1 [M+H]+

[0533] 1H NMR (400 MHz,cd3od) δ 7.41 - 7.34 (m, 2H), 7.31 - 7.23 (m, 2H), 7.07 (s, 2H), 4.49 (s, 1H), 3.95 (s, 1H), 3.25 (s, 3H), 2.69 (s, 1H), 2.39 (s, 3H), 2.28 (d,J = 9.8 Hz, 1H), 1.70 (d,J = 11.5 Hz, 1H), 1.63 (dd,J = 9.9, 5.8 Hz, 1H), 1.45 (d,J = 9.1 Hz, 2H), 0.89 (d,J = 7.1 Hz, 1H).

[0534]

[0535] Example 67: (1S,3R,4R)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(3-methyl-5-(trifluoromethyl)phenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0536]

[0537] The title product was afforded by a procedure similar to that described for the synthesis of Example 66 using N,3-dimethyl-5-(trifluoromethyl)anilineinstead of N-methyl-m-toluidine.

[0538] MS (ESI, m / z): 551.1 [M+H]+

[0539]

[0540] Example 68: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(methyl-d3)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0541]

[0542] Synthesis of 3-methyl-N-(methyl-d3)aniline. To a solution of m-toluidine (1.0 eq, 0.107 mL, 1.0 mmol) and iodomethane-d3(1.1 eq, 68 μL, 1.1 mmol) in tetrahydrofuran (2.0mL) was added NaH (2.0 eq, 48 mg, 2.0 mmol) and stirred at 0oC for 12 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography give the desired product. (yield, 50%)

[0543] MS (ESI, m / z): 125.1 [M+H]+

[0544] The title product was afforded by a procedure similar to that described for the synthesis of Example 11 using 3-methyl-N-(methyl-d3)aniline instead of N-methyl-m-toluidine.

[0545] MS (ESI, m / z): 486.2 [M+H]+

[0546]

[0547] Example 69: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(methyl-d3)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0548]

[0549] The title product was afforded by a procedure similar to that described for the synthesis of Example 68 using (1R,3S,4S)-2-(3,5-bis(trifluoromethyl)phenyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid instead of (1R,3S,4S)-2-(2-cyano-3,5-bis(trifluoromethyl)phenyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid.

[0550] MS (ESI, m / z): 461.2 [M+H]+

[0551]

[0552] Example 70: (1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(methyl-d3)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0553]

[0554] The title product was afforded by a procedure similar to that described for the synthesis of Example 68 using (1R,3S,4S)-2-(2-cyano-5-methyl-3-(trifluoromethyl)phenyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid instead of (1R,3S,4S)-2-(2-cyano-3,5-bis(trifluoromethyl)phenyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid.

[0555] MS (ESI, m / z): 432.2 [M+H]+

[0556]

[0557] Example 71: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carbothioamide

[0558]

[0559] To a solution of example 11 (1.0 eq, 228 mg, 0.5 mmol) in toluene (3mL) was added Lewesson’s reagent (1.1 eq, 222 mg, 0.55 mmol) and stirred at 90oC for 2 hours. The reaction mixture was poured into water (3 mL), extracted with ethyl acetate (3 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography give the desired product.

[0560] MS (ESI, m / z): 474.1 [M+H]+

[0561] 1H NMR (600 MHz, cdcl3) δ 10.16 (s, 1H), 8.34 (s, 1H), 7.43 (t,J= 7.8 Hz, 1H), 7.32 - 7.29 (m, 1H), 7.09 (s, 1H), 6.65 (s, 1H), 4.26 (s, 2H), 3.76 (s, 3H), 2.49 (s, 1H), 2.43 (s, 3H), 2.19 (d,J= 11.3 Hz, 1H), 1.83 - 1.76 (m, 1H), 1.68 - 1.59 (m, 1H), 1.48 - 1.40 (m, 2H), 0.96 (ddd,J= 9.1, 5.4, 2.4 Hz, 1H).

[0562]

[0563] Example 72: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-cyclohexyl-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0564]

[0565] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using cyclohexanamine instead of 2,5-difluoroaniline.

[0566] MS (ESI, m / z): 450.2 [M+H]+

[0567] 1H NMR (400 MHz, cdcl3) δ 7.00 (d, J = 2.4 Hz, 1H), 6.78 (s, 1H), 4.44 - 4.25 (m, 2H), 4.12 (q, J = 7.1 Hz, 1H), 2.97 (d, J = 74.0 Hz, 3H), 2.62 (d, J = 17.5 Hz, 1H), 2.44 (d, J = 49.9 Hz, 1H), 1.97 - 1.30 (m, 13H), 1.20 - 1.06 (m, 1H).

[0568]

[0569] Example 73: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-cyclopentyl-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0570]

[0571] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using cyclopentanamine instead of 2,5-difluoroaniline.

[0572] MS (ESI, m / z): 436.2 [M+H]+

[0573] 1H NMR (400 MHz, cdcl3) δ 6.98 (s, 1H), 6.78 (s, 1H), 5.06 - 4.85 (m, 1H), 4.42 - 4.23 (m, 2H), 2.96 (d, J = 83.4 Hz, 3H), 2.64 (d, J = 12.1 Hz, 1H), 2.47 (d, J = 54.8 Hz, 1H), 2.13 - 1.41 (m, 13H).

[0574]

[0575] Example 74: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0576]

[0577] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using tetrahydro-2H-pyran-4-amine instead of 2,5-difluoroaniline.

[0578] MS (ESI, m / z): 452.2 [M+H]+

[0579] 1H NMR (400 MHz, cdcl3) δ 7.00 (s, 1H), 6.79 (s, 1H), 4.71 (tt, J = 12.1, 3.9 Hz, 1H), 4.46 - 4.19 (m, 2H), 4.17 - 3.92 (m, 2H), 3.54 - 3.43 (m, 2H), 3.13 - 2.87 (m, 3H), 2.62 (d, J = 23.3 Hz, 1H), 2.55 - 2.40 (m, 1H), 2.05 - 1.45 (m, 9H).

[0580]

[0581] Example 75:(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2,5-difluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0582]

[0583] The title product was afforded by a procedure similar to that described for the synthesis of Example 11 using 2,5-difluoroaniline instead of N-methyl-m-toluidine.

[0584] MS (ESI, m / z): 466.1 [M+H]+

[0585] 1H NMR (600 MHz, cdcl3) δ 8.87 (s, 1H), 8.13 - 8.06 (m, 1H), 7.23 (s, 1H), 7.01 - 6.87 (m, 2H), 6.72 (s, 1H), 4.30 (d, J = 132.0 Hz, 2H), 3.13 (s, 1H), 2.10 (s, 1H), 1.90 (dd, J = 14.7, 9.2 Hz, 1H), 1.80 (t, J = 12.1 Hz, 1H), 1.71 (s, 1H), 1.64 (d, J = 9.9 Hz, 1H), 1.49 (s, 1H).

[0586]

[0587] Example 76: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0588]

[0589] The title product was afforded by a procedure similar to that described for the synthesis of Example 11 using 3-chloro-4-fluoroaniline instead of N-methyl-m-toluidine.

[0590] MS (ESI, m / z): 482.1 [M+H]+

[0591] 1H NMR (600 MHz, cdcl3) δ 9.31 (s, 1H), 7.71 (dd, J = 6.6, 2.6 Hz, 1H), 7.26 - 7.22 (m, 2H), 7.04 (t, J = 8.8 Hz, 1H), 6.93 (d, J = 4.5 Hz, 1H), 4.26 (d, J = 85.7 Hz, 2H), 3.14 (d, J = 3.9 Hz, 1H), 2.17 (d, J = 7.6 Hz, 1H), 1.90 (tt, J = 12.4, 4.4 Hz, 1H), 1.81 (tdd, J = 12.1, 4.5, 2.3 Hz, 1H), 1.71 - 1.66 (m, 2H), 1.49 - 1.41 (m, 1H).

[0592]

[0593] Example 77: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-2-fluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0594]

[0595] The title product was afforded by a procedure similar to that described for the synthesis of Example 11 using 3-chloro-2-fluoroaniline instead of N-methyl-m-toluidine.

[0596] MS (ESI, m / z): 482.1 [M+H]+

[0597] 1H NMR (400 MHz, cdcl3) δ 8.83 (s, 1H), 8.15 - 8.08 (m, 1H), 7.24 (s, 1H), 7.14 - 7.02 (m, 2H), 6.92 (s, 1H), 4.43 (s, 1H), 4.19 (s, 1H), 3.13 (d, J = 3.5 Hz, 1H), 2.11 (d, J = 10.4 Hz, 1H), 1.97 - 1.86 (m, 1H), 1.86 - 1.75 (m, 1H), 1.71 (t, J = 10.5 Hz, 1H), 1.64 (d, J = 10.4 Hz, 1H), 1.55 - 1.45 (m, 1H).

[0598]

[0599] Example 78: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(o-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0600]

[0601] The title product was afforded by a procedure similar to that described for the synthesis of Example 11 using o-toluidine instead of N-methyl-m-toluidine.

[0602] MS (ESI, m / z): 444.1 [M+H]+

[0603] 1H NMR (600 MHz, cdcl3) δ 8.14 (s, 1H), 7.58 (d, J = 6.9 Hz, 1H), 7.23 (s, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 7.12 - 7.08 (m, 1H), 6.92 (s, 1H), 4.29 (d, J = 113.2 Hz, 2H), 3.14 (d, J = 3.6 Hz, 1H), 2.13 (s, 1H), 2.07 (s, 3H), 1.91 (tt, J = 12.4, 4.4 Hz, 1H), 1.84 - 1.78 (m, 1H), 1.73 (s, 1H), 1.63 (d, J = 10.3 Hz, 1H), 1.55 - 1.50 (m, 1H).

[0604]

[0605] Example 79: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(p-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0606]

[0607] The title product was afforded by a procedure similar to that described for the synthesis of Example 11 using p-toluidine instead of N-methyl-m-toluidine.

[0608] MS (ESI, m / z): 444.1 [M+H]+

[0609] 1H NMR (600 MHz, cdcl3) δ 8.99 (s, 3H), 7.35 (d, J = 8.4 Hz, 9H), 7.22 (s, 4H), 7.10 (d, J = 8.3 Hz, 9H), 6.90 (s, 4H), 4.26 (d, J = 84.7 Hz, 8H), 3.13 (s, 5H), 2.29 (s, 14H), 1.88 (tt, J = 12.3, 4.4 Hz, 5H), 1.79 (tdd, J = 12.0, 4.5, 2.3 Hz, 5H), 1.69 (t, J = 10.4 Hz, 5H), 1.65 - 1.59 (m, 7H), 1.46 (dd, J = 14.6, 6.9 Hz, 5H), 1.31 - 1.24 (m, 5H).

[0610]

[0611] Example 80: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-2,4-difluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0612]

[0613] The title product was afforded by a procedure similar to that described for the synthesis of Example 11 using 3-chloro-2,4-difluoroaniline instead of N-methyl-m-toluidine.

[0614] MS (ESI, m / z): 500.1 [M+H]+

[0615] 1H NMR (600 MHz, cdcl3) δ 8.86 (s, 1H), 8.02 (dd, J = 14.4, 8.7 Hz, 1H), 7.24 (s, 1H), 6.95 (dd, J = 18.0, 9.2 Hz, 2H), 4.40 (s, 1H), 4.21 (s, 1H), 3.13 (d, J = 2.5 Hz, 1H), 2.11 (d, J = 9.5 Hz, 1H), 1.95 - 1.87 (m, 1H), 1.81 (t, J = 12.4 Hz, 1H), 1.71 (t, J = 10.7 Hz, 1H), 1.65 (d, J = 10.4 Hz, 1H), 1.51 (d, J = 8.2 Hz, 1H).

[0616]

[0617] Example 81: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3,4-difluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0618]

[0619] The title product was afforded by a procedure similar to that described for the synthesis of Example 11 using 3,4-difluoroaniline instead of N-methyl-m-toluidine.

[0620] MS (ESI, m / z): 466.1 [M+H]+

[0621] 1H NMR (400 MHz, cdcl3) δ 9.28 (s, 1H), 7.64 - 7.53 (m, 1H), 7.24 (s, 1H), 7.10 - 6.99 (m, 2H), 6.93 (s, 1H), 4.26 (d, J = 66.8 Hz, 2H), 3.14 (d, J = 3.9 Hz, 1H), 2.17 (d, J = 9.8 Hz, 1H), 1.95 - 1.75 (m, 2H), 1.69 (dd, J = 14.9, 8.0 Hz, 2H), 1.49 - 1.40 (m, 1H).

[0622]

[0623] Example 82: (1R,3S,4S)-N-((1H-indol-3-yl)methyl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0624]

[0625] The title product was afforded by a procedure similar to that described for the synthesis of Example 11 using 1H-indol-3-ylmethanamine instead of N-methyl-m-toluidine.

[0626] MS (ESI, m / z): 483.2 [M+H]+

[0627] 1H NMR (600 MHz, cdcl3) δ 8.03 (s, 1H), 7.51 - 7.48 (m, 1H), 7.34 (dt, J = 8.3, 1.0 Hz, 1H), 7.18 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 7.12 (s, 1H), 7.10 (d, J = 2.4 Hz, 1H), 7.05 (ddd, J = 7.9, 7.0, 0.9 Hz, 1H), 6.74 (s, 1H), 5.39 - 5.30 (m, 1H), 4.62 (d, J = 5.3 Hz, 2H), 3.04 (d, J = 4.3 Hz, 1H), 2.01 (dd, J = 12.8, 6.2 Hz, 1H), 1.84 (ddd, J = 16.8, 8.5, 4.5 Hz, 1H), 1.71 (d, J = 12.6 Hz, 1H), 1.63 (d, J = 8.3 Hz, 2H), 1.56 (s, 3H).

[0628]

[0629] Example 83: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0630]

[0631] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid. To a solution of methyl (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.0 eq, 368 mg, 1.0 mmol) in Methyl alcohol (1.0 mL) was added 1N NaOH (2 mL) and stirred at 25oC for 1 hour. The solution was neutralized with 1N HCl to give the desired product quantitatively.

[0632] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide. To a solution of　(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.00 eq, 185 mg, 0.522 mmol) in　Tetrahydrofuran (5mL) was added　triethylamine (1.00 eq, 73 μL, 0.522 mmol) at rt. After 15min,　ethyl chloroformate (1.00 eq, 0.050 mL, 0.522 mmol) was added. After 1hour,　ammonia solution (2M in MeOH) (1.50 eq, 0.39 mL, 0.783 mmol) was added. After 16h, the reaction mixture was concentrated under reduced pressure. The resulting crude was diluted with DCM and washed with distilled water. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography to afford　the desired product (yield, 54%).

[0633] MS (ESI, m / z): 354.1 [M+H]+

[0634]

[0635] Example 84: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-(1-cyanocyclopropyl)-N-(4-fluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0636]

[0637] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 and Example 13 using 4-fluoroaniline and 1-bromocyclopropane-1-carbonitrile instead of 3-chloro-4-fluoroaniline and methyl iodide.

[0638] MS (ESI, m / z): 538.1 [M+H]+

[0639] 1H NMR (600 MHz,cd3od) δ 7.44 (s, 1H), 7.29 (dd,J = 16.7, 9.6 Hz, 3H), 7.15 (s, 1H), 5.40 (s, 1H), 3.70 (d,J = 44.5 Hz, 1H), 2.69 (d,J = 63.0 Hz, 1H), 2.30 (s, 1H), 2.04 (s, 1H), 1.82 (s, 2H), 1.61 (s, 2H), 1.53 (s, 1H), 1.49 - 1.40 (m, 1H), 1.11 (d,J = 32.0 Hz, 1H), 1.02 (s, 1H).

[0640]

[0641] Example 85: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-((1-cyanocyclopropyl)methyl)-N-(4-fluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0642]

[0643] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 and Example 13 using 4-fluoroaniline and 1-(bromomethyl)cyclopropane-1-carbonitrile instead of 3-chloro-4-fluoroaniline and methyl iodide.

[0644] MS (ESI, m / z): 552.2 [M+H]+

[0645] 1H NMR (600 MHz, cd3od) δ 7.64 (s, 2H), 7.29 (s, 3H), 5.41 (s, 1H), 4.35 (d,J = 14.1 Hz, 1H), 4.11 (s, 1H), 3.39 (d,J = 14.1 Hz, 1H), 2.80 (s, 1H), 2.31 (s, 1H), 1.83 (s, 1H), 1.79 - 1.66 (m, 2H), 1.54 (s, 1H), 1.25 - 1.14 (m, 2H), 1.01 (s, 2H), 0.86 (s, 1H).

[0646]

[0647] Example 86: ((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)(isoindolin-2-yl)methanone

[0648]

[0649] The title product was afforded by a procedure similar to that described for the synthesis of Example 11 using isoindoline instead of N-methyl-m-toluidine.

[0650] MS (ESI, m / z): 456.1 [M+H]+

[0651] 1H NMR (600 MHz, cdcl3) δ 7.34 - 7.29 (m, 4H), 6.96 (s, 1H), 6.82 (s, 1H), 5.35 (d, J = 12.2 Hz, 1H), 4.93 - 4.77 (m, 4H), 4.41 (s, 1H), 4.27 - 4.19 (m, 1H), 2.73 (d, J = 10.9 Hz, 2H), 1.88 (dtdd, J = 15.5, 12.3, 8.8, 2.8 Hz, 2H), 1.73 - 1.67 (m, 1H), 1.57 (ddt, J = 10.7, 7.8, 2.4 Hz, 1H), 1.51 (d, J = 9.7 Hz, 1H).

[0652]

[0653] Example 87: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-(dimethylamino)ethyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0654]

[0655] The title product was afforded by a procedure similar to that described for the synthesis of Example 11 using N1,N1,N2-trimethylethane-1,2-diamine instead of N-methyl-m-toluidine.

[0656] MS (ESI, m / z): 439.2 [M+H]+

[0657] 1H NMR (400 MHz, cdcl3) δ 6.98 (s, 1H), 6.76 (s, 1H), 4.34 (s, 1H), 4.06 (s, 1H), 3.40 (s, 3H), 3.14 (s, 4H), 2.95 (s, 7H), 2.49 (s, 1H), 1.76 (s, 2H), 1.55 (s, 2H), 1.49 - 1.43 (m, 1H).

[0658]

[0659] Example 88: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-(prop-2-yn-1-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0660]

[0661] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 and Example 13 using m-toluidine and propargyl bromide instead of 3-chloro-4-fluoroaniline and methyl iodide in step e.

[0662] MS (ESI, m / z): 507.2 [M+H]+

[0663] 1H NMR (400 MHz,cd3od) δ 7.42 (s, 1H), 7.40 (d,J = 7.6 Hz, 1H), 7.35 (d,J = 7.5 Hz, 1H), 7.30 (d,J = 7.2 Hz, 1H), 7.28 (s, 1H), 5.40 (s, 1H), 4.46 (s, 2H), 4.15 (s, 1H), 2.71 (d,J = 3.7 Hz, 1H), 2.61 (t,J = 2.5 Hz, 1H), 2.39 (s, 3H), 2.26 (s, 1H), 1.72 (ddd,J = 28.0, 18.8, 11.4 Hz, 3H), 1.52 (d,J = 9.8 Hz, 1H), 0.94 (t,J = 12.7 Hz, 1H).

[0664]

[0665] Example 89: (1R,3S,4S)-N-(3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0666]

[0667] To a solution of Example 88 (1.0 eq, 101 mg, 0.2 mmol) and 6-bromopyridazin-3-amine (1.5 eq, 52 mg, 1.5 mmol) in triethylamine (3.0mL) was added Pd(PPh3)Cl2 (0.1 eq, 14 mg, 0.02 mmol) and CuI (0.2eq, 7.6mg, 0.04mmol) and stirred at 60oC for 4 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography give the desired product.

[0668] MS (ESI, m / z): 600.2 [M+H]+

[0669] 1H NMR (600 MHz,cd3od) δ 7.68 (d,J = 9.6 Hz, 1H), 7.47 - 7.39 (m, 4H), 7.33 (d,J = 7.3 Hz, 1H), 7.28 (s, 1H), 5.41 (s, 1H), 4.85 (s, 1H), 4.68 (d,J = 17.8 Hz, 1H), 4.18 (s, 1H), 2.75 (d,J = 4.0 Hz, 1H), 2.40 (s, 3H), 2.28 (s, 1H), 1.84 - 1.71 (m, 2H), 1.67 (s, 1H), 1.53 (d,J = 10.0 Hz, 1H), 0.97 (s, 1H).

[0670]

[0671] Example 90: (1R,3S,4S)-N-((1H-1,2,3-triazol-4-yl)methyl)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0672]

[0673] To a solution of Example 88 (1.0 eq, 51 mg, 0.1 mmol) and CuI (0.05 eq, 1 mg, 0.005 mmol) in DMF (0.9 mL) and Methanol (0.1 mL) was added azido(trimethyl)silane (1.5 eq, 17 mg, 0.15 mmol) and stirred at 100oC for 2 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography give the desired product.

[0674] MS (ESI, m / z): 550.2 [M+H]+

[0675] 1H NMR (400 MHz,cd3od) δ 7.81 (s, 1H), 7.34 (t,J = 7.8 Hz, 1H), 7.28 (s, 1H), 7.25 (d,J = 7.6 Hz, 1H), 7.21 (s, 1H), 7.16 (s, 1H), 5.41 (s, 1H), 4.99 (s, 2H), 4.28 - 4.20 (m, 1H), 2.73 (s, 1H), 2.35 (d,J = 11.2 Hz, 3H), 2.32 - 2.25 (m, 1H), 1.82 - 1.70 (m, 2H), 1.65 (s, 1H), 1.53 (s, 1H), 0.92 (d,J = 18.2 Hz, 1H).

[0676]

[0677] Example 91: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0678]

[0679] To a solution of Example 88 (1.0 eq, 51 mg, 0.1 mmol) and CuI (0.1 eq, 2 mg, 0.01 mmol) in DMF (1 mL) was added azidobenzene (1 eq, 12 mg, 0.1 mmol) and diisopropylethylamine (2.0 eq, 19 uL, 0.2 mmol) and stirred at 50oC for 2 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography give the desired product.

[0680] MS (ESI, m / z): 626.2 [M+H]+

[0681] 1H NMR (400 MHz,cd3od) δ 8.31 (s, 1H), 7.80 - 7.75 (m, 2H), 7.56 (t,J = 7.6 Hz, 2H), 7.48 (t,J = 7.4 Hz, 1H), 7.37 (t,J = 7.7 Hz, 1H), 7.30 - 7.20 (m, 4H), 5.41 (s, 1H), 5.00 (dd,J = 30.0, 14.7 Hz, 2H), 4.16 (s, 1H), 2.77 (s, 1H), 2.35 (s, 3H), 2.33 - 2.28 (m, 1H), 1.82 - 1.64 (m, 3H), 1.53 (d,J = 9.7 Hz, 1H), 0.95 (s, 1H).

[0682]

[0683] Example 92: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(pyridin-2-yl)prop-2-yn-1-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0684]

[0685] The title product was afforded by a procedure similar to that described for the synthesis of Example 89 using 2-bromopyridine instead of 6-bromopyridazin-3-amine.

[0686] MS (ESI, m / z): 584.2 [M+H]+

[0687] 1H NMR (400 MHz,cd3od) δ 8.56 (d,J = 4.5 Hz, 1H), 8.02 (dd,J = 7.8, 6.3 Hz, 1H), 7.61 (d,J = 7.9 Hz, 1H), 7.58 - 7.54 (m, 1H), 7.48 (s, 1H), 7.43 (d,J = 4.7 Hz, 2H), 7.31 (d,J = 10.0 Hz, 1H), 7.27 (s, 1H), 5.40 (s, 1H), 4.79 (s, 2H), 4.18 (s, 1H), 2.77 (s, 1H), 2.38 (d,J = 11.1 Hz, 3H), 2.28 (s, 1H), 1.81 - 1.66 (m, 3H), 1.53 (d,J = 10.6 Hz, 1H), 0.97 (s, 1H).

[0688]

[0689] Example 93: (1R,3S,4S)-N-allyl-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane -3-carboxamide

[0690]

[0691] The title product was afforded by a procedure similar to that described for the synthesis of Example 88 using allyl bromide instead of propargyl bromide.

[0692] MS (ESI, m / z): 509.2 [M+H]+

[0693] 1H NMR (400 MHz,cd3od) δ 7.37 (t,J = 7.8 Hz, 1H), 7.30 (s, 1H), 7.28 (s, 1H), 7.25 (d,J = 6.9 Hz, 2H), 5.90 - 5.79 (m, 1H), 5.39 (s, 1H), 5.12 - 5.02 (m, 2H), 4.39 (dd,J = 14.6, 5.9 Hz, 1H), 4.15 (dd,J = 14.6, 6.9 Hz, 2H), 2.71 (s, 1H), 2.37 (s, 3H), 2.28 (s, 1H), 1.71 (dd,J = 37.5, 22.2 Hz, 3H), 1.51 (d,J = 10.6 Hz, 1H), 0.92 (d,J = 16.5 Hz, 1H).

[0694]

[0695] Example 94: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-((E)-3-(pyridin-2-yl)allyl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0696]

[0697] To a solution of Example 93 (1.0 eq, 51 mg, 0.1 mmol) and Grubbs catalyst (0.01 eq, 0.2 mg, 0.001 mmol) in Toluene (1 mL) was added 2-vinylpyridine (2 eq, 21 mg, 0.2 mmol) and stirred at 40oC for 16 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography give the desired product.

[0698] MS (ESI, m / z): 586.2 [M+H]+

[0699] 1H NMR (400 MHz,cd3od) δ 8.62 (d,J = 5.9 Hz, 1H), 8.35 (t,J = 7.8 Hz, 1H), 8.02 (d,J = 8.3 Hz, 1H), 7.77 - 7.72 (m, 1H), 7.39 (d,J = 7.7 Hz, 1H), 7.34 (s, 1H), 7.28 (s, 1H), 7.02 - 6.93 (m, 1H), 6.69 (d,J = 16.2 Hz, 1H), 5.40 (s, 1H), 4.57 (s, 2H), 4.23 - 4.13 (m, 1H), 2.78 (s, 1H), 2.37 (s, 2H), 2.33 - 2.27 (m, 1H), 1.78 (s, 2H), 1.72 - 1.60 (m, 2H), 1.52 (s, 1H), 1.01 - 0.94 (m, 1H).

[0700]

[0701] Example 95: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(prop-2-yn-1-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0702]

[0703] The title product was afforded by a procedure similar to that described for the synthesis of Example 88 using 2-chloro-4,6-bis(trifluoromethyl)pyridine instead of 2-chloro-4,6-bis(trifluoromethyl)nicotinonitrile.

[0704] MS (ESI, m / z): 482.2 [M+H]+

[0705] 1H NMR (600 MHz,cd3od) δ 7.41 (d,J = 42.8 Hz, 3H), 7.28 (s, 1H), 7.07 (s, 2H), 4.46 (s, 2H), 3.95 (s, 1H), 3.32 (s, 1H), 2.68 (s, 1H), 2.60 (s, 1H), 2.40 (s, 3H), 2.26 (s, 1H), 1.74 - 1.58 (m, 2H), 1.44 (s, 2H), 0.86 (s, 1H).

[0706]

[0707] Example 96: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0708]

[0709] The title product was afforded by a procedure similar to that described for the synthesis of Example 91 using (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(prop-2-yn-1-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide instead of Example 88.

[0710] MS (ESI, m / z): 536.2 [M+H]+

[0711] 1H NMR (400 MHz,cd3od) δ 8.22 (s, 1H), 7.79 - 7.74 (m, 2H), 7.60 - 7.54 (m, 2H), 7.53 - 7.46 (m, 1H), 7.13 (s, 1H), 7.11 - 6.97 (m, 1H), 4.57 (d,J = 15.2 Hz, 2H), 4.46 (d,J = 15.2 Hz, 1H), 3.99 (s, 1H), 2.83 (s, 1H), 2.04 (d,J = 7.3 Hz, 1H), 1.86 (ddd,J = 14.3, 11.1, 7.1 Hz, 1H), 1.78 (d,J = 11.3 Hz, 1H), 1.64 (d,J = 12.1 Hz, 1H), 1.53 (dd,J = 17.8, 10.9 Hz, 2H).

[0712]

[0713] Example 97: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-methyl-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0714]

[0715] To a solution of Example 96 (1.0 eq, 51 mg, 0.1 mmol) and methyliodide (2.0 eq, 28 mg, 0.2 mmol) in DMSO (1.0mL) was added sodium hydride (3.0 eq, 39 mg, 0.3 mmol) and stirred at 50oC for 3 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography give the desired product.

[0716] MS (ESI, m / z): 550.2 [M+H]+

[0717] 1H NMR (400 MHz,cd3od) δ 8.25 (s, 1H), 7.85 (d,J = 7.8 Hz, 1H), 7.78 (d,J = 7.9 Hz, 1H), 7.56 (dt,J = 13.5, 5.4 Hz, 2H), 7.49 (dd,J = 11.7, 4.3 Hz, 1H), 7.10 (s, 1H), 7.00 (d,J = 4.5 Hz, 1H), 4.57 (d,J = 15.0 Hz, 2H), 4.40 (s, 1H), 3.35 (s, 3H), 3.09 (s, 1H), 2.78 (s, 1H), 2.28 (s, 1H), 1.86 (dd,J = 18.9, 8.0 Hz, 2H), 1.69 - 1.59 (m, 2H), 1.51 (t,J = 9.6 Hz, 1H).

[0718]

[0719] Example 98: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-isopropyl-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0720]

[0721] To a solution of Example 96 (1.0 eq, 51 mg, 0.1 mmol) and 2-iodopropane (2.0 eq, 34 mg, 0.2 mmol) in DMSO (1.0mL) was added sodium hydride (3.0 eq, 39 mg, 0.3 mmol) and stirred at 25oC for 3 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography give the desired product.

[0722] MS (ESI, m / z): 578.2 [M+H]+

[0723] 1H NMR (400 MHz,cd3od) δ 8.10 (s, 1H), 7.84 (d,J = 7.7 Hz, 1H), 7.71 (d,J = 8.1 Hz, 2H), 7.58 (d,J = 8.1 Hz, 1H), 7.53 (t,J = 7.6 Hz, 2H), 7.47 (d,J = 7.3 Hz, 1H), 7.13 (s, 1H), 7.01 (s, 1H), 4.69 (d,J = 15.3 Hz, 1H), 4.56 (s, 1H), 4.48 (s, 1H), 4.43 (d,J = 6.7 Hz, 1H), 2.72 (s, 1H), 2.19 (s, 1H), 1.86 (s, 2H), 1.67 - 1.62 (m, 2H), 1.54 (d,J = 9.6 Hz, 1H), 1.45 (d,J = 6.6 Hz, 3H), 1.38 (d,J = 6.8 Hz, 3H), 1.21 (s, 1H).

[0724]

[0725] Example 99: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-methyl-N-(2-(methyl(m-tolyl)amino)-2-oxoethyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0726]

[0727] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 using N-methyl-2-(methylamino)-N-(m-tolyl)acetamide instead of N-methyl m-toluidine.

[0728] MS (ESI, m / z): 554.2 [M+H]+

[0729] 1H NMR (400 MHz,cd3od) δ 7.35 (dd,J = 15.9, 8.0 Hz, 1H), 7.28 - 7.11 (m, 4H), 5.39 (s, 1H), 4.58 (s, 1H), 4.41 (s, 1H), 3.35 (d,J = 12.7 Hz, 1H), 3.23 (d,J = 10.0 Hz, 3H), 3.20 (s, 2H), 2.90 (s, 1H), 2.37 (d, J = 5.3 Hz, 3H), 1.91 (s, 4H), 1.69 (s, 1H), 1.54 (s, 1H).

[0730]

[0731] Example 100: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-(2-(methyl(m-tolyl)amino)-2-oxoethyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0732]

[0733] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 using 2-amino-N-methyl-N-(m-tolyl)acetamide instead of N-methyl m-toluidine.

[0734] MS (ESI, m / z): 540.2 [M+H]+

[0735] 1H NMR (600 MHz,cd3od) δ 7.35 (t,J = 7.7 Hz, 1H), 7.28 (s, 1H), 7.24 (d,J = 7.5 Hz, 1H), 7.16 (s, 1H), 7.11 (d,J = 7.6 Hz, 1H), 5.34 (d,J = 4.9 Hz, 1H), 4.27 (s, 1H), 3.66 (dd,J = 40.1, 16.9 Hz, 2H), 3.23 (s, 3H), 2.86 (s, 1H), 2.37 (s, 3H), 2.27 (s, 1H), 1.92 - 1.86 (m, 2H), 1.85 (s, 1H), 1.58 (dd,J = 15.8, 9.5 Hz, 2H).

[0736]

[0737] Example 101: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-((R)-1-(methyl(m-tolyl)amino)-1-oxopropan-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0738]

[0739] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 using (R)-N-methyl-2-(methylamino)-N-(m-tolyl)propanamide instead of N-methyl m-toluidine.

[0740] MS (ESI, m / z): 568.2 [M+H]+

[0741] 1H NMR (600 MHz,cd3od) δ 7.35 (t,J = 7.7 Hz, 1H), 7.31 (s, 1H), 7.23 (d,J = 7.6 Hz, 1H), 7.19 (s, 1H), 7.14 (d,J = 7.7 Hz, 1H), 5.36 (s, 1H), 4.53 (d,J = 6.6 Hz, 1H), 4.23 (s, 1H), 3.23 (s, 3H), 2.76 (s, 1H), 2.37 (s, 3H), 2.18 (d,J = 18.0 Hz, 1H), 1.90 (dd,J = 14.8, 9.6 Hz, 3H), 1.59 (t,J = 12.0 Hz, 2H), 1.06 (d,J = 6.7 Hz, 3H).

[0742]

[0743] Example 102: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(2-methyl-1-(methyl(m-tolyl)amino)-1-oxopropan-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0744]

[0745] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 using N,2-dimethyl-2-(methylamino)-N-(m-tolyl)propanamide instead of N-methyl m-toluidine.

[0746] MS (ESI, m / z): 582.2 [M+H]+

[0747] 1H NMR (600 MHz,cd3od) δ 7.31 (s, 1H), 7.28 (t,J = 7.7 Hz, 1H), 7.14 (d,J = 7.4 Hz, 1H), 7.10 (s, 1H), 7.05 (d,J = 7.5 Hz, 1H), 5.46 (s, 1H), 4.24 (s, 1H), 3.38 (s, 3H), 2.80 (d,J = 20.9 Hz, 1H), 2.35 (s, 3H), 2.14 (d,J = 14.9 Hz, 1H), 1.88 (t,J = 21.7 Hz, 3H), 1.59 (s, 2H), 1.49 - 1.38 (m, 6H).

[0748]

[0749] Example 103: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-methyl-N-(1-(methyl(m-tolyl)carbamoyl)cyclopropyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0750]

[0751] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 using N-methyl-1-(methylamino)-N-(m-tolyl)cyclopropane-1-carboxamide instead of N-methyl m-toluidine.

[0752] MS (ESI, m / z): 580.2 [M+H]+

[0753] 1H NMR (600 MHz,cd3od) δ 7.74 (s, 1H), 7.33 (t,J = 7.7 Hz, 1H), 7.25 (s, 1H), 7.15 (d,J = 8.0 Hz, 1H), 7.13 (s, 1H), 7.10 (d,J = 8.0 Hz, 1H), 5.33 (dd,J = 18.7, 14.0 Hz, 1H), 3.26 (s, 3H), 2.39 (s, 3H), 2.11 (s, 1H), 1.75 (d,J = 12.0 Hz, 5H), 1.49 (s, 1H), 1.45 - 1.28 (m, 4H), 1.09 (s, 1H).

[0754]

[0755] Example 104: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl) pyridin-2-yl)-N-methyl-N-(1-(methyl(m-tolyl)carbamoyl)cyclobutyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0756]

[0757] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 using 1-amino-N-methyl-N-(m-tolyl)cyclobutane-1-carboxamide instead of N-methyl m-toluidine.

[0758] MS (ESI, m / z): 594.2 [M+H]+

[0759] 1H NMR (400 MHz,cd3od) δ 7.28 (t,J = 8.3 Hz, 2H), 7.13 (d,J = 7.4 Hz, 1H), 7.02 (s, 1H), 6.98 (d,J = 8.3 Hz, 1H), 5.41 (s, 1H), 4.29 - 4.16 (m, 1H), 3.38 (s, 1H), 3.22 (s, 3H), 2.95 (d,J = 9.1 Hz, 1H), 2.77 (d,J = 11.2 Hz, 1H), 2.35 (s, 3H), 2.19 (s, 1H), 2.03 (s, 1H), 2.03 - 1.95 (m, 2H), 1.84 (s, 4H), 1.55 (s, 2H).

[0760]

[0761] Example 105: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-(methyl(m-tolyl) carbamoyl)cyclopentyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0762]

[0763] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 using N-methyl-1-(methylamino)-N-(m-tolyl)cyclopentane-1-carboxamide instead of N-methyl m-toluidine.

[0764] MS (ESI, m / z): 608.2 [M+H]+

[0765] 1H NMR (600 MHz,cd3od) δ 7.30 (s, 1H), 7.27 (t,J = 7.7 Hz, 1H), 7.12 (d,J = 6.7 Hz, 1H), 7.07 (s, 1H), 7.03 (d,J = 6.1 Hz, 1H), 5.45 (s, 1H), 4.23 (s, 1H), 2.43 - 2.38 (m, 1H), 2.35 (d,J = 11.6 Hz, 3H), 2.25 (s, 1H), 1.93 (dd,J = 117.0, 25.6 Hz, 9H), 1.64 (d,J = 49.8 Hz, 7H).

[0766]

[0767] Example 106: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-(methyl(m-tolyl)carbamoyl)cyclohexyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0768]

[0769] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 using N-methyl-1-(methylamino)-N-(m-tolyl)cyclohexane-1-carboxamide instead of N-methyl m-toluidine.

[0770] MS (ESI, m / z): 622.3 [M+H]+

[0771] 1H NMR (600 MHz, dmso) δ 7.42 (s, 1H), 7.22 (t,J = 7.7 Hz, 1H), 7.03 (d,J = 7.6 Hz, 1H), 6.91 (s, N 2H), 5.31 (d,J = 10.2 Hz, 1H), 4.33 (s, 1H), 3.28 (d,J = 30.6 Hz, 3H), 2.80 (s, 1H), 2.73 (s, 1H), 2.25 (d, J = 18.6 Hz, 3H), 2.02 - 1.99 (m, 1H), 1.98 (d,J = 5.8 Hz, 1H), 1.80 (s, 3H), 1.57 (s, 1H), 1.47 (d,J = 26.3 Hz, 5H), 1.23 (s, 4H).

[0772]

[0773] Example 107: (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(3-(methyl(m-tolyl)carbamoyl)oxetan-3-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0774]

[0775] The title product was afforded by a procedure similar to that described for the synthesis of Example 3 using N-methyl-3-(methylamino)-N-(m-tolyl)oxetane-3-carboxamide instead of N-methyl m-toluidine.

[0776] MS (ESI, m / z): 596.2 [M+H]+

[0777] 1H NMR (600 MHz,cd3od) δ 7.31 (dd,J = 16.2, 8.3 Hz, 2H), 7.19 (s, 1H), 6.98 (s, 1H), 6.90 (s, 1H), 5.36 (d,J = 23.8 Hz, 2H), 5.16 (d,J = 6.7 Hz, 1H), 4.41 (s, 1H), 3.31 (s, 5H), 3.23 (s, 2H), 2.37 (s, 3H), 1.85 (s, 3H), 1.57 (d,J = 9.1 Hz, 1H), 1.49 (s, 1H).

[0778]

[0779] Example 108: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(4H-1,2,4-triazol-4-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0780]

[0781] The title product was afforded by a procedure similar to that described for the synthesis of Example 12 using 4H-1,2,4-triazol-4-amine instead of 2,5-difluoroaniline.

[0782] MS (ESI, m / z): 435.1 [M+H]+

[0783] 1H NMR (600 MHz, cdcl3) δ 8.68 (s, 1H), 8.48 (s, 1H), 7.07 (s, 1H), 6.82 (s, 1H), 5.15 (s, 1H), 4.38 (s, 1H), 3.50 (d,J= 8.7 Hz, 3H), 2.59 (s, 1H), 2.40 (d,J= 9.5 Hz, 1H), 1.80 (s, 2H), 1.68 - 1.55 (m, 2H), 1.51 (d,J= 9.8 Hz, 1H).

[0784]

[0785] Example 109: (1R,3S,4S)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid

[0786]

[0787] To a stirred solution of (1R,3S,4S)-2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.00 eq, 1.00 g, 4.14 mmol) in dichloromethane (20mL), was added trifluoroacetic acid (10.0 eq, 4.73 g, 41.4 mmol) at 23 　oC. After 3h, the reaction mixture was concentrated under reduced pressure. The crude residue was diluted with dimethylformamide (20mL).　Then cesium carbonate (2.40 eq, 3.24 g, 9.95 mmol) and 2-chloro-4,6-bis(trifluoromethyl)pyridine-3-carbonitrile (1.20 eq, 1.36 g, 4.97 mmol) were added. The mixture was heated and stirred at 80 　oC. After 16h, the reaction mixture　concentrated　under reduced pressure　and the residue was taken up in ethyl acetate (100 ml). The organics washed with　saturated aqueous NH4Cl solution (50mL x 2). The organics were then separated and dried (MgSO4) before concentration to dryness. The crude was then purified by flash column chromatography (0% to 100%　ethyl acetate in n-hexane)　The desired fractions were concentrated to dryness in vacuo to afford (1R,3S,4S)-2-[(1R,3S,4S)-2-[3-cyano-4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptane-3-carbonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylic acid. (300 mg,0.597 mmol, 29 % yield).

[0788] MS (ESI, m / z): 503.1 [M+H]+

[0789] 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 5.49 (s, 1H), 4.22 (s, 1H), 4.17 (s, 1H), 4.08 (s, 1H), 3.11 (s, 1H), 2.75 (s, 1H), 2.32 (d,　J　= 10.9 Hz, 1H), 2.09 (s, 1H), 1.90 (ddd,　J　= 38.2, 29.1, 13.8 Hz, 6H), 1.60 (dd,　J　= 23.7, 9.9 Hz, 4H).

[0790]

[0791] Example 110: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-N-((1-(4-fluorophenyl)-6-oxo-1,6-dihydropyrimidin-2-yl)methyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide

[0792]

[0793] Preparation of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(cyanomethyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide. To a solution of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.0 eq, 50 mg, 0.14 mmol) and HATU (1.2 eq, 64 mg, 0.17 mmol) in dimethylformamide (0.5 mL) was added 2-aminoacetonitrile (1.1 eq, 14.4 mg, 0.15 mmol) and triethylamine (3.5 eq, 69 μL, 0.49 mmol) and stirred at 25oC for 16 hour. The reaction mixture was poured into water (3 mL), extracted with DCM (3 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified by the column chromatography to give the desired product. (yield, 54%).

[0794] MS (ESI, m / z): 393.1 [M+H]+

[0795] Preparation of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-((4-fluorophenyl)amino)-2-iminoethyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide. To a stirred solution of methyl (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(cyanomethyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (1.0eq, 30 mg 0.09 mmol) and 4-fluoroaniline (2.0 eq, 17 mg, 0.18 mmol) in toluene (1.0mL) was added AlMe3 (2.0 eq, 34 μL , 0.18 mmol) and stirred at 90oC for 16 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography (0~10% MeOH in MC) to give the desired product. (yield, 79%).

[0796] MS (ESI, m / z): 504.1 [M+H]+

[0797] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-((1-(4-fluorophenyl)-6-oxo-1,6-dihydropyrimidin-2-yl)methyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide. To a stirred solution (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-((4-fluorophenyl)amino)-2-iminoethyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (1.0eq, 30 mg 0.06 mmol) in ethanol (1.0mL) was added ethyl propiolate (1.5 eq, 9 μL, 0.09 mmol) and stirred at 90oC for 16 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified prep-HPLC to give the desired product. (yield, 45%).

[0798] MS (ESI, m / z): 556.1 [M+H]+

[0799] 1H NMR (600 MHz, cdcl3) δ 8.85 (s, 1H), 7.79 (s, 1H), 7.76 (s, 1H), 7.66 (s, 1H), 7.21 (s, 4H), 6.21 (s, 1H), 4.44 (d, J = 7.1 Hz, 2H), 3.23 (dd, J = 7.3, 1.6 Hz, 2H), 2.85 (s, 2H), 2.22 (d, J = 7.6 Hz, 2H), 2.01 (d, J = 6.3 Hz, 2H), 1.82 (s, 1H).

[0800]

[0801] Example 111: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbohydrazide

[0802] Example 112: (E)-N'-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbonyl)-N,N-dimethylformohydrazonamide

[0803]

[0804] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid. To a solution of methyl (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.0 eq, 368 mg, 1.0 mmol) in Methyl alcohol (1.0 mL) was added 1N NaOH (2 mL) and stirred at 25oC for 1 hour. The solution was neutralized with 1N HCl to give the desired product quantitatively.

[0805] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbohydrazide (Example 111). To a solution of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.0 eq, 71 mg, 0.2 mmol) and triethylamine (1.2 eq, 34 μL, 0.24 mmol) in tetrahydrofuran (2 mL) was added ethyl chloroformate (1.2 eq, 23 μL, 0.24 mmol) and stirred the mixture for 15 minutes at 0oC to form the insoluable salt. Filter the resulting salt and wash with tetrahydrofuran. Add the filtrate slowly to a solution of hydrazine monohydrate (5 eq, 500 μL, 1mmol) under 0oC and stirred for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, extracted with EA and water, dried over anhydrous Na2SO4, and concentrated in vacuo. Then, the residue was purified by the column chromatography to give the desired product (yield, 75%).

[0806] MS (ESI, m / z): 369.1 [M+H]+

[0807] 1H NMR (400 MHz, cdcl3) δ 7.26 (s, 1H), 7.16 (s, 1H), 6.86 (s, 1H), 4.35 (s, 1H), 4.06 (s, 1H), 2.92 (s, 1H), 2.00 (d,J= 10.0 Hz, 1H), 1.91 - 1.74 (m, 2H), 1.66 (t,J= 9.9 Hz, 1H), 1.56 (d,J= 10.3 Hz, 1H), 1.49 (d,J= 7.6 Hz, 1H).

[0808] Synthesis of (E)-N'-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbonyl)-N,N-dimethylformohydrazonamide (Example 112). To a solution of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbohydrazide (1.0 eq, 932 mg, 2.5 mmol) in acetonitrile (25 mL) was added N,N-dimethylformamide dimethyl acetal (2.4 eq, 794 μL, 6 mmol) at rt. The reaction mixture was stirred at 55oC for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by the column chromatography to give the desired product(yield, 88%).

[0809] MS (ESI, m / z): 424.2 [M+H]+

[0810] 1H NMR (400 MHz, cdcl3) δ 9.12 (s, 1H), 7.61 (s, 1H), 7.14 (s, 1H), 6.80 (s, 1H), 4.30 (s, 1H), 3.99 (s, 1H), 3.03 (s, 1H), 2.87 (s, 5H), 2.15 (s, 1H), 1.81 (d,J= 11.9 Hz, 1H), 1.73 (t,J= 12.4 Hz, 1H), 1.63 (s, 1H), 1.54 (d,J= 9.7 Hz, 1H), 1.42 (s, 1H).

[0811]

[0812] Example 113: 2-((1R,3S,4S)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile

[0813]

[0814] [Step c] Preparation of (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbohydrazide. To a solution of　(1R,3S,4S)-2-[3-cyano-4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.00 eq, 236 mg, 0.622 mmol) and　triethylamine (3.00 eq, 260 uL, 1.87 mmol)　in tetrahydrofuran (6 mL), was added　ethyl chloroformate (1.20 eq, 71 uL, 0.747 mmol) at 0 °C. The mixture was stirred for 15 min to form　the insoluble Et3N·HCl salt. The resulting salt was filtered and washed with THF (5 x 6 mL) and the filtrate was added　slowly to a 50-60 % solution of hydrazine monohydrate (10.0 eq, 3.1 mL, 6.22 mmol)　in　at 0 °C. The reaction mixture was stirred　for 30 minutes at 0 °C and warmed to 23 °C. After 16h, the reaction mixture was concentrated under reduced pressure. The crude was dissolved in ethyl acetate (30 mL) and washed with saturated aqueous NaHCO3 solution (20 mL x 2). Then, the mixture was extracted　with EtOAc (20 mL x 2) and washed with　brine (10 mL x 2). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was used without further purification.

[0815] [Step d] Preparation of (E)-N'-((1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbonyl)-N,N-dimethylformohydrazonamide. To a stirred solution of (1R,3S,4S)-2-[3-cyano-4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptane-3-carbohydrazide (1.00 eq, 130 mg, 0.331 mmol) in acetonitrile (2 mL), was added N,N-Dimethylformamide dimethyl acetal (10.0 eq, 394 mg, 3.31 mmol) at 23 　oC. The mixture was heated to 55 　oC. After 2h , the solution was concentrated under reduced pressure. The crude residue used directly without further purification.

[0816] [Step e] Synthesis of 2-((1R,3S,4S)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile. To a solution of (1R,3S,4S)-2-[3-cyano-4,6-bis(trifluoromethyl)-2-pyridyl]-N-[(E)-dimethylaminomethyleneamino]-2-azabicyclo[2.2.1]heptane-3-carboxamide (1.00 eq, 40 mg, 0.0890 mmol) in toluene (2mL) were added and 3-methylaniline (10.0 eq, 95 mg, 0.890 mmol) and acetic acid (50 μL) The reaction mixture was stirred at 110 　oC under microwave radiation. After 4h , the solution was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0% to 20% MeOH in EtOAc) to afford 2-[(1R,3S,4S)-3-[4-(m-tolyl)-1,2,4-triazol-3-yl]-2-azabicyclo[2.2.1]heptan-2-yl]-4,6-bis(trifluoromethyl)pyridine-3-carbonitrile (2.5 mg,0.00508 mmol, 6 % yield) as a yellow solid.

[0817] MS (ESI, m / z): 493.1 [M+H]+

[0818] 1H NMR (600 MHz, CDCl3) δ 8.88 (s, 1H), 7.52 (d, J = 6.9 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.32 (s, 2H), 7.17 (s, 1H), 5.59 (s, 1H), 4.69 (s, 1H), 2.76 - 2.57 (m, 2H), 2.00 (d, J = 12.9 Hz, 1H), 1.96 - 1.84 (m, 3H), 1.68 (s, 1H), 1.39 (s, 1H).

[0819]

[0820] Example 114: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0821] Example 115: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0822]

[0823] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane (Example 114). To a solution of　(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide (1.00 eq, 123 mg, 0.35 mmol) in toluene was added N,N-dimethylformamide dimethyl acetal (10.0 eq, 460 μL, 3.48 mmol) at rt. The mixture was stirred at 100oC for 1 hour. The mixture was concentrated under reduced pressure and the residue was dissovled in ethyl acetate. The organic layer was washed with NaHCO3(aq) and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was dissolved in Acetic acid (2mL) and hydrazine;dihydrochloride (3.00 eq, 110 mg, 1.04 mmol) was added. The reaction mixture was sitrred at 90 　oC for 1.5 hours, the mixture was neutralized with NaHCO3(aq) and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography to afford the desired product (yield, 66%).

[0824] MS (ESI, m / z): 378.1 [M+H]+

[0825] 1H NMR(400 MHz,cdcl3) δ 7.92 (s, 1H), 7.16 (s, 1H), 6.85 (s, 1H), 4.69 (s, 1H), 4.32 (s, 1H), 3.33 (s, 1H), 2.30 (d,J = 8.7 Hz, 1H), 2.01 - 1.91 (m, 1H), 1.86 (t,J = 13.2 Hz, 1H), 1.75 (dd,J = 11.7, 8.7 Hz, 2H), 1.62 - 1.52 (m, 1H).

[0826] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane (Example 115). To a stirred solution of (3S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-3-(4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane (1.00 eq, 20 mg, 0.0530 mmol) in Dimethylformamide (2mL) was added iodomethane (2.00 eq, 7 μL, 0.106 mmol) and NaH (3.00 eq, 3.8 mg, 0.159 mmol) at rt. The mixture was heated and stirred at 50 　oC.　After 1h, the solution was concentrated under reduced pressure. The resulting crude was purified by prep-HPLC to afford the desired product (yield, 24%).

[0827] MS (ESI, m / z): 392.1 [M+H]+

[0828] 1H NMR (400 MHz, cdcl3) δ 7.96 (s, 1H), 7.00 (s, 1H), 6.69 (s, 1H), 4.88 (s, 1H), 4.39 (s, 1H), 3.88 (s, 3H), 2.78 (s, 1H), 2.32 (d,　J　= 9.7 Hz, 1H), 2.01 (d,　J　= 6.2 Hz, 1H), 1.92 - 1.81 (m, 1H), 1.81 - 1.73 (m, 2H), 1.47 (d,　J　= 9.7 Hz, 1H).

[0829]

[0830] Example 116: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-isopropyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0831]

[0832] The title product was afforded by a procedure similar to that described for the synthesis of Example 115 using 2-iodopropane instead of iodomethane.

[0833] MS (ESI, m / z): 420.2 [M+H]+

[0834] 1H NMR (400 MHz, cdcl3) δ 7.98 (s, 1H), 6.97 (s, 1H), 6.75 (s, 1H), 4.49 (dt,　J　= 13.3, 6.7 Hz, 1H), 4.34 (s, 1H), 2.81 (s, 1H), 2.41 (d,　J　= 10.1 Hz, 1H), 1.91 - 1.81 (m, 1H), 1.79 (dd,　J　= 8.1, 5.6 Hz, 2H), 1.59 (s, 2H), 1.55 - 1.48 (m, 6H), 1.47 (s, 1H).

[0835]

[0836] Example 117: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0837]

[0838] To a solution of Example 112 (1.00 eq, 37 mg, 0.0874 mmol)　in Toluene (2mL)　was added aniline (10.0 eq, 0.080 mL, 0.874 mmol)　and acetic acid (10.0 eq, 0.050 mL, 0.874 mmol)　at rt.　The reaction mixture was stirred at 130oC.　After 2 hours, the solution was concentrated under reduced pressure. The resulting crude was purified by prep-HPLC to afford　the desired product (yield, 38%).

[0839] MS (ESI, m / z): 454.1 [M+H]+

[0840] 1H NMR (400 MHz, cdcl3) δ 8.21 (s, 1H), 7.61 - 7.52 (m, 3H), 7.49 (d,　J　= 6.9 Hz, 2H), 6.98 (s, 1H), 6.82 (s, 1H), 4.60 (s, 1H), 4.48 (s, 1H), 2.89 (d,　J　= 8.8 Hz, 1H), 2.55 (s, 1H), 1.80 (t,　J　= 7.2 Hz, 2H), 1.64 (t,　J　= 8.1 Hz, 1H), 1.57 (d,　J　= 10.2 Hz, 1H), 1.33 (t,　J　= 8.4 Hz, 1H).

[0841]

[0842] Example 118: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(p-tolyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0843]

[0844] The title product was afforded by a similar procedure to that described for the synthesis of Example 117 usingp-toluidine instead of aniline.

[0845] MS (ESI, m / z): 468.1 [M+H]+

[0846] 1H NMR (600 MHz, CDCl3) δ 8.32 (s, 1H), 7.36 (s, 4H), 7.00 (s, 1H), 6.83 (s, 1H), 4.59 (s, 1H), 4.47 (s, 1H), 2.75 (s, 1H), 2.54 (s, 1H), 2.45 (d,　J　= 2.3 Hz, 3H), 1.85 - 1.75 (m, 1H), 1.67 - 1.54 (m,　J　= 32.3, 10.1 Hz, 2H), 1.37 - 1.29 (m,　J　= 11.2 Hz, 2H).

[0847]

[0848] Example 119: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0849]

[0850] The title product was afforded by a similar procedure to that described for the synthesis of Example 117 usingm-toluidine instead of aniline.

[0851] MS (ESI, m / z): 468.1 [M+H]+

[0852] 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.54 (s, 1H), 7.48 (t,　J　= 7.7 Hz, 1H), 7.41 (d,　J　= 7.6 Hz, 1H), 7.32 (s, 1H), 7.28 (d,　J　= 8.0 Hz, 1H), 7.05 (s, 1H), 6.86 (s, 1H), 4.61 (s, 1H), 4.49 (s, 1H), 2.63 (d,　J　= 10.1 Hz, 1H), 2.57 (s, 1H), 2.46 (s, 3H), 1.89 - 1.76 (m,　J　= 10.3 Hz, 2H), 1.70 - 1.57 (m,　J　= 15.2, 10.8 Hz, 2H), 1.38 - 1.28 (m,　J　= 8.5 Hz, 1H).

[0853]

[0854] Example 120: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0855]

[0856] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 4-fluoroaniline instead of aniline.

[0857] MS (ESI, m / z): 472.1 [M+H]+

[0858] 1H NMR (400 MHz, cdcl3) δ 8.19 (s, 1H), 7.50 (dd,　J　= 8.7, 4.6 Hz, 2H), 7.28 (s, 1H), 7.24 (s, 1H), 7.00 (s, 1H), 6.84 (s, 1H), 4.55 (s, 1H), 4.49 (s, 1H), 2.90 (d,　J　= 10.1 Hz, 1H), 2.53 (s, 1H), 1.88 - 1.76 (m, 2H), 1.69 - 1.61 (m, 1H), 1.58 (d,　J　= 10.1 Hz, 1H), 1.35 (d,　J　= 5.7 Hz, 1H).

[0859]

[0860] Example 121: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0861]

[0862] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 3-fluoroaniline instead of aniline.

[0863] MS (ESI, m / z): 472.1 [M+H]+

[0864] 1H NMR (400 MHz, cdcl3) δ 8.21 (s, 1H), 7.60 - 7.52 (m, 1H), 7.32 (d,　J　= 8.2 Hz, 1H), 7.28 (d,　J　= 9.0 Hz, 1H), 7.26 - 7.23 (m, 1H), 7.00 (s, 1H), 6.84 (s, 1H), 4.61 (s, 1H), 4.49 (s, 1H), 2.92 (s, 1H), 2.55 (s, 1H), 2.36 (d,　J　= 10.6 Hz, 1H), 1.84 (d,　J　= 8.1 Hz, 2H), 1.65 (d,　J　= 11.2 Hz, 2H).

[0865]

[0866] Example 122: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-chlorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0867]

[0868] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 3-chloroaniline instead of aniline.

[0869] MS (ESI, m / z): 488.1 [M+H]+

[0870] 1H NMR (400 MHz, cdcl3) δ 8.20 (s, 1H), 7.56 - 7.48 (m, 3H), 7.43 (d,　J　= 7.0 Hz, 1H), 7.00 (s, 1H), 6.83 (s, 1H), 4.59 (s, 1H), 4.49 (s, 1H), 2.89 (d,　J　= 9.5 Hz, 1H), 2.56 (s, 1H), 1.86 - 1.81 (m, 2H), 1.67 (dd,　J　= 9.5, 7.5 Hz, 1H), 1.59 (d,　J　= 10.2 Hz, 1H).

[0871]

[0872] Example 123: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3,4-difluorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0873]

[0874] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 3,4-difluoroaniline instead of aniline.

[0875] MS (ESI, m / z): 490.1 [M+H]+

[0876] 1H NMR (400 MHz, cdcl3) δ 8.34 (s, 1H), 7.45 - 7.39 (m, 1H), 7.33 (dd,J= 21.7, 8.9 Hz, 1H), 7.08 (s, 1H), 7.01 (s, 1H), 6.84 (s, 1H), 4.82 (s, 1H), 4.56 (s, 1H), 4.50 (s, 1H), 2.92 (s, 1H), 2.36 (d,J= 10.4 Hz, 1H), 2.01 - 1.88 (m, 2H), 1.88 - 1.82 (m, 2H).

[0877]

[0878] Example 124: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-chloro-4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0879]

[0880] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 3-chloro-4-fluoro-aniline instead of aniline.

[0881] MS (ESI, m / z): 506.1 [M+H]+

[0882] 1H NMR (400 MHz, cdcl3) δ 8.18 (s, 1H), 7.59 (dd,　J　= 6.2, 2.4 Hz, 1H), 7.48 - 7.41 (m, 1H), 7.34 (t,　J　= 8.5 Hz, 1H), 7.01 (s, 1H), 6.84 (s, 1H), 4.55 (s, 1H), 4.49 (s, 1H), 2.89 (d,　J　= 10.0 Hz, 1H), 2.54 (s, 1H), 1.85 (d,　J　= 8.5 Hz, 2H), 1.67 (t,　J　= 8.5 Hz, 1H), 1.61 (t,　J　= 9.3 Hz, 2H).

[0883]

[0884] Example 125: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3,4-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0885]

[0886] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 3,4-dichloroaniline instead of aniline.

[0887] MS (ESI, m / z): 522.1 [M+H]+

[0888] 1H NMR (400 MHz, cdcl3) δ 8.25 (s, 1H), 7.66 (s, 1H), 7.64 (s, 1H), 7.43 (d,　J　= 8.2 Hz, 1H), 7.00 (s, 1H), 6.84 (s, 1H), 4.55 (s, 1H), 4.49 (s, 1H), 2.86 (d,　J　= 9.9 Hz, 1H), 2.58 (s, 1H), 1.84 (d,　J　= 8.6 Hz, 3H), 1.69 - 1.63 (m, 1H), 1.60 (d,　J　= 10.1 Hz, 1H).

[0889]

[0890] Example 126: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluoro-3-methylphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0891]

[0892] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 4-fluoro-3-methyl-aniline instead of aniline.

[0893] MS (ESI, m / z): 486.2 [M+H]+

[0894] 1H NMR (400 MHz, cdcl3) δ 8.17 (s, 1H), 7.35 (d,　J　= 5.4 Hz, 1H), 7.28 (s, 1H), 7.18 (t,　J　= 8.7 Hz, 1H), 6.99 (s, 1H), 6.84 (s, 1H), 4.56 (s, 1H), 4.48 (s, 1H), 2.88 (d,　J　= 9.3 Hz, 1H), 2.52 (s, 1H), 2.36 (d,　J　= 1.5 Hz, 3H), 1.88 - 1.75 (m, 2H), 1.66 (d,　J　= 10.8 Hz, 2H), 1.57 (d,　J　= 10.1 Hz, 1H).

[0895]

[0896] Example 127: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0897]

[0898] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 4-fluoro-3-(trifluoromethyl)aniline instead of aniline. MS (ESI, m / z): 540.1 [M+H]+

[0899] 1H NMR (400 MHz, cdcl3) δ 8.22 (s, 1H), 7.77 (d,　J　= 8.9 Hz, 1H), 7.73 - 7.69 (m, 1H), 7.43 (t,　J　= 9.1 Hz, 1H), 7.01 (s, 1H), 6.84 (s, 1H), 4.50 (d,　J　= 6.8 Hz, 2H), 2.91 (d,　J　= 9.8 Hz, 1H), 2.60 (s, 1H), 2.27 (s, 1H), 1.86 (d,　J　= 9.2 Hz, 2H), 1.55 (s, 2H).

[0900]

[0901] Example 128: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluoro-3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0902]

[0903] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 4-fluoro-3-methoxy-aniline instead of aniline.

[0904] MS (ESI, m / z): 502.1 [M+H]+

[0905] 1H NMR (400 MHz, cdcl3) δ 8.19 (s, 1H), 7.25 - 7.21 (m, 1H), 7.10 - 7.02 (m, 1H), 7.01 (dd,　J　= 5.5, 2.9 Hz, 1H), 6.98 (s, 1H), 6.84 (s, 1H), 4.57 (s, 1H), 4.50 (s, 1H), 3.94 (s, 3H), 2.85 (d,　J　= 9.4 Hz, 1H), 2.54 (s, 1H), 1.83 (t,　J　= 6.9 Hz, 2H), 1.66 (dd,　J　= 16.3, 10.5 Hz, 2H), 1.58 (d,　J　= 10.1 Hz, 1H).

[0906]

[0907] Example 129: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-chloro-3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0908]

[0909] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 4-chloro-3-methoxy-aniline instead of aniline.

[0910] MS (ESI, m / z): 518.1 [M+H]+

[0911] 1H NMR (400 MHz, cdcl3) δ 8.20 (s, 1H), 7.54 (d,　J　= 8.0 Hz, 1H), 7.02 (d,　J　= 2.1 Hz, 1H), 6.99 (d,　J　= 5.9 Hz, 2H), 6.84 (s, 1H), 4.59 (s, 1H), 4.50 (s, 1H), 3.96 (s, 3H), 2.85 (d,　J　= 9.8 Hz, 1H), 2.55 (s, 1H), 1.91 - 1.77 (m, 2H), 1.66 (dd,　J　= 16.9, 10.5 Hz, 1H), 1.58 (d,　J　= 10.1 Hz, 1H).

[0912]

[0913] Example 130: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-methoxy-4-methylphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0914]

[0915] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 3-methoxy-4-methyl-aniline instead of aniline.

[0916] MS (ESI, m / z): 498.2 [M+H]+

[0917] 1H NMR (400 MHz, cdcl3) δ 8.19 (s, 1H), 7.27 (d,　J　= 7.8 Hz, 1H), 6.96 (s, 1H), 6.92 (d,　J　= 7.7 Hz, 1H), 6.85 (s, 1H), 6.82 (s, 1H), 4.62 (s, 1H), 4.48 (s, 1H), 3.87 (s, 3H), 2.84 (d,　J　= 9.0 Hz, 1H), 2.57 (s, 1H), 2.28 (s, 3H), 1.82 (d,　J　= 8.1 Hz, 2H), 1.66 (d,　J　= 10.8 Hz, 1H), 1.56 (d,　J　= 10.0 Hz, 1H).

[0918]

[0919] Example 131: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0920]

[0921] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 3-methoxyaniline instead of aniline.

[0922] MS (ESI, m / z): 484.2 [M+H]+

[0923] 1H NMR (400 MHz, cdcl3) δ 8.21 (s, 1H), 7.46 (t,　J　= 8.1 Hz, 1H), 7.06 (dd,　J　= 8.1, 2.8 Hz, 2H), 6.97 (s, 2H), 6.83 (s, 1H), 4.64 (s, 1H), 4.48 (s, 1H), 3.87 (s, 3H), 2.86 (d,　J　= 9.0 Hz, 1H), 2.56 (s, 1H), 1.82 (d,　J　= 8.3 Hz, 2H), 1.67 (dd,　J　= 20.8, 10.1 Hz, 2H), 1.57 (d,　J　= 10.1 Hz, 1H).

[0924]

[0925] Example 132: 3-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)phenol

[0926]

[0927] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 3-aminophenol instead of aniline.

[0928] MS (ESI, m / z): 470.1 [M+H]+

[0929] 1H NMR (400 MHz, cdcl3) 8.93 (s, 1H), 8.26 (s, 1H), 7.87 (s, 1H), 7.19 (s, 1H), 6.99 (d,J= 9.4 Hz, 2H), 6.87 (s, 1H), 6.85 - 6.75 (m, 1H),4.59 (s, 1H), 4.49 (s, 1H), 2.89 (d,　J　= 9.5 Hz, 1H), 2.56 (s, 1H), 1.86 - 1.81 (m, 2H), 1.67 (dd,　J　= 9.5, 7.5 Hz, 1H), 1.59 (d,　J　= 10.2 Hz, 1H).

[0930]

[0931] Example 133 (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(6-methylpyridin-2-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0932] The title product was afforded by a similar procedure to that described for the synthesis of Example 117 using 2-amino-6-methylpyridine instead of aniline.

[0933] MS (ESI, m / z): 469.1 [M+H]+

[0934] 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.83 (t,　J　= 7.8 Hz, 1H), 7.36 (d,　J　= 8.1 Hz, 1H), 7.27 (d,　J　= 7.8 Hz, 1H), 6.91 (s, 1H), 6.78 (s, 1H), 4.88 (s, 1H), 4.51 (s, 1H), 2.94 (s, 2H), 2.11 - 1.47 (m, 5H).

[0935]

[0936] Example 134: (1R,3S,4S)-3-(4-benzyl-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane

[0937]

[0938] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using phenylmethanamine instead of aniline.

[0939] MS (ESI, m / z): 468.2 [M+H]+

[0940] 1H NMR (400 MHz, cdcl3) δ 8.13 (s, 1H), 7.43 - 7.32 (m, 3H), 7.18 (d,　J　= 6.7 Hz, 2H), 7.02 (s, 1H), 6.81 (s, 1H), 5.51 (d,　J　= 15.8 Hz, 1H), 5.34 (d,　J　= 16.0 Hz, 1H), 4.44 (d,　J　= 17.4 Hz, 2H), 3.05 (s, 1H), 2.19 (s, 1H), 1.80 - 1.74 (m, 1H), 1.66 - 1.59 (m, 3H), 1.53 (d,　J　= 10.2 Hz, 1H).

[0941]

[0942] Example 135: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(pyridin-2-ylmethyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0943]

[0944] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 2-pyridylmethanamine instead of aniline.

[0945] MS (ESI, m / z): 469.2 [M+H]+

[0946] 1H NMR (400 MHz, cdcl3) δ 8.59 (d,　J　= 4.1 Hz, 1H), 8.17 (s, 1H), 7.73 (td,　J　= 7.7, 1.8 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.19 (d,　J　= 7.8 Hz, 1H), 7.00 (s, 1H), 6.81 (s, 1H), 5.73 (d,　J　= 15.5 Hz, 1H), 5.35 (d,　J　= 16.2 Hz, 1H), 4.66 (s, 1H), 4.43 (s, 1H), 3.09 (s, 1H), 2.44 (d,　J　= 6.1 Hz, 1H), 1.89 - 1.71 (m, 2H), 1.71 - 1.63 (m, 1H).

[0947]

[0948] Example 136: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(1-phenylethyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0949]

[0950] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 1-phenylethanamine instead of aniline.

[0951] MS (ESI, m / z): 482.2 [M+H]+

[0952] 1H NMR (400 MHz, cdcl3) δ 8.35 (s, 1H), 7.39 - 7.29 (m, 3H), 7.10 (d,　J　= 1.6 Hz, 1H), 7.08 (s, 1H), 7.01 (s, 1H), 6.79 (s, 1H), 5.90 (q,　J　= 7.1 Hz, 1H), 4.36 (s, 1H), 4.35 (s, 1H), 3.05 (d,　J　= 9.5 Hz, 1H), 1.95 (d,　J　= 7.0 Hz, 3H), 1.80 (s, 1H), 1.78 - 1.67 (m, 1H), 1.59 (s, 1H).

[0953]

[0954] Example 137: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(prop-2-yn-1-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0955]

[0956] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using prop-2-yn-1-amine instead of aniline.

[0957] MS (ESI, m / z): 416.1 [M+H]+

[0958] 1H NMR (400 MHz, cdcl3) δ 8.16 (s, 1H), 7.00 (s, 1H), 6.83 (s, 1H), 5.16 (d,　J　= 17.8 Hz, 1H), 4.93 (dd,　J　= 17.9, 2.5 Hz, 1H), 4.65 (s, 1H), 4.47 (s, 1H), 3.20 (s, 1H), 2.78 (s, 1H), 2.53 (t,　J　= 2.6 Hz, 1H), 2.26 - 2.18 (m, 1H), 2.00 (d,　J　= 12.6 Hz, 1H), 1.97 - 1.84 (m, 2H).

[0959]

[0960] Example 138: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-cyclohexyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0961]

[0962] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using cyclohexanamine instead of aniline.

[0963] MS (ESI, m / z): 460.2 [M+H]+

[0964] 1H NMR (400 MHz, cdcl3) δ 8.13 (s, 1H), 6.99 (s, 1H), 6.84 (s, 1H), 4.49 (s, 1H), 4.24 (t,　J　= 11.6 Hz, 1H), 3.09 (s, 1H), 2.58 (s, 1H), 2.35 (d,　J　= 12.1 Hz, 1H), 2.02 (d,　J　= 10.0 Hz, 2H), 1.97 - 1.92 (m, 1H), 1.92 (s, 1H), 1.90 - 1.84 (m, 1H), 1.84 - 1.76 (m, 1H), 1.74 (d,　J　= 3.2 Hz, 1H), 1.72 - 1.66 (m, 2H), 1.62 (d,　J　= 9.2 Hz, 2H), 1.58 (s, 1H), 1.55 (d,　J　= 3.7 Hz, 1H), 1.54 - 1.41 (m, 2H).

[0965]

[0966] Example 139: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0967]

[0968] Synthesis of tert-butyl 4-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)piperidine-1-carboxylate. The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using tert-butyl 4-aminopiperidine-1-carboxylate instead of aniline. Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane. To a solution of tert-butyl 4-[3-[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptan-3-yl]-1,2,4-triazol-4-yl]piperidine-1-carboxylate (1.00 eq, 202 mg, 0.360 mmol)　in Dichloromethane (5mL) was added 2,2,2-trifluoroacetic acid (48.2 eq, 1.3 mL, 17.4 mmol) at rt. After being stirred for 2h at 40 　oC, the reaction mixture was basified with 2N-NaOH and organic layers were concentrated to dryness.　The resulting crude was purified by prep-HPLC to afford the desired product (yield, 30%).

[0969] MS (ESI, m / z): 461.2 [M+H]+

[0970] 1H NMR (400 MHz, cdcl3) δ 8.16 (s, 1H), 6.99 (s, 1H), 6.85 (s, 1H), 4.61 (s, 1H), 4.49 (s, 1H), 4.36 (t,　J　= 11.9 Hz, 1H), 3.32 (d,　J　= 12.4 Hz, 1H), 3.26 (d,　J　= 12.6 Hz, 1H), 3.11 (d,　J　= 8.3 Hz, 1H), 2.81 (dd,　J　= 15.9, 7.7 Hz, 2H), 2.58 (s, 1H), 2.31 (d,　J　= 12.1 Hz, 1H), 1.94 (ddd,　J　= 21.8, 16.4, 7.7 Hz, 4H), 1.87 - 1.69 (m, 3H), 1.63 (d,　J　= 10.3 Hz, 2H).

[0971]

[0972] Example 140: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(1-methylpiperidin-4-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0973]

[0974] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 1-methylpiperidin-4-amine instead of aniline.

[0975] MS (ESI, m / z): 475.2 [M+H]+

[0976] 1H NMR (400 MHz, cdcl3) δ 8.14 (s, 1H), 6.99 (s, 1H), 6.84 (s, 1H), 4.60 (s, 1H), 4.49 (s, 1H), 4.26 (d,　J　= 8.8 Hz, 1H), 3.07 (d,　J　= 11.1 Hz, 2H), 3.00 (dd,　J　= 11.5, 2.0 Hz, 1H), 2.58 (s, 1H), 2.35 (s, 3H), 2.32 - 2.26 (m, 1H), 2.22 - 2.07 (m, 3H), 2.01 - 1.93 (m, 2H), 1.89 (dt,　J　= 11.7, 3.2 Hz, 2H), 1.74 (d,　J　= 5.8 Hz, 1H).

[0977]

[0978] Example 141: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(1-methylpiperidin-3-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0979]

[0980] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 1-methylpiperidin-3-amine instead of aniline.

[0981] MS (ESI, m / z): 475.2 [M+H]+

[0982] 1H NMR (400 MHz, cdcl3) δ 8.52 (s, 1H), 8.33 (s, 1H), 6.98 (s, 1H), 6.85 (s, 1H), 4.66 (d,J= 9.9 Hz, 1H), 4.50 (s, 2H), 3.07 (s, 1H), 2.99 (s, 1H), 2.91 (d,J= 9.7 Hz, 1H), 2.75 (s, 1H), 2.60 (s, 1H), 2.56 (s, 1H), 2.48 (s, 1H), 2.35 (d,J= 2.0 Hz, 3H), 2.21 (dd,J= 10.6, 4.6 Hz, 1H), 1.99 (d,J= 13.8 Hz, 1H), 1.90 (t,J= 8.9 Hz, 2H), 1.79 (d,J= 10.3 Hz, 1H), 1.76 - 1.67 (m, 3H).

[0983]

[0984] Example 142: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(1-methyl-1H-imidazol-4-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0985]

[0986] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 1-methylimidazol-4-amine instead of aniline.

[0987] MS (ESI, m / z): 458.1 [M+H]+

[0988] 1H NMR (400 MHz, cdcl3) δ 8.11 (s, 1H), 7.74 (s, 1H), 7.64 (s, 1H), 6.98 (s, 1H), 6.83 (s, 1H), 4.58 (s, 1H), 4.48 (s, 1H), 3.99 (s, 3H), 2.96 - 2.86 (m, 1H), 2.54 (s, 1H), 1.89 - 1.78 (m, 2H), 1.66 (dd,　J　= 13.0, 6.2 Hz, 1H), 1.58 (d,　J　= 10.1 Hz, 1H), 1.41 (t,　J　= 8.6 Hz, 1H).

[0989]

[0990] Example 143: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(1-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[0991]

[0992] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 1-methylpyrazol-3-amine instead of aniline.

[0993] MS (ESI, m / z): 458.1 [M+H]+

[0994] 1H NMR (400 MHz, cdcl3) δ 8.29 (s, 1H), 7.47 (d,　J　= 2.3 Hz, 1H), 6.95 (s, 1H), 6.76 (s, 1H), 6.45 (s, 1H), 4.80 (s, 1H), 4.52 (s, 1H), 3.96 (s, 3H), 2.84 (s, 1H), 2.73 (s, 1H), 1.92 - 1.79 (m, 2H), 1.68 (d,　J　= 11.5 Hz, 1H), 1.62 - 1.54 (m, 2H).

[0995]

[0996] Example 144: 5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)quinoline

[0997]

[0998] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using quinolin-5-amine instead of aniline.

[0999] MS (ESI, m / z): 505.2 [M+H]+

[1000] 1H NMR (400 MHz, cdcl3) δ 9.07 (s, 1H), 8.36 (d,　J　= 8.6 Hz, 1H), 8.28 (d,　J　= 4.0 Hz, 1H), 7.72 (d,　J　= 8.1 Hz, 1H), 7.62 (dd,　J　= 8.5, 4.3 Hz, 1H), 7.58 - 7.50 (m, 1H), 7.18 (d,　J　= 3.9 Hz, 1H), 7.05 (d,　J　= 3.2 Hz, 1H), 6.86 (s, 1H), 4.48 (s, 1H), 4.40 (s, 1H), 3.85 (s, 1H), 3.01 (s, 1H), 2.48 (s, 2H), 2.20 (dd,　J　= 16.9, 9.2 Hz, 3H).

[1001]

[1002] Example 145: 5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)-1H-indole

[1003]

[1004] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 1H-indol-5-amine instead of aniline.

[1005] MS (ESI, m / z): 493.2 [M+H]+

[1006] 1H NMR (400 MHz, cdcl3) δ 9.67 (s, 1H), 8.26 (s, 1H), 7.74 (s, 1H), 7.46 (d,J = 8.5 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.21 (d,J = 7.4 Hz, 1H), 6.95 (s, 1H), 6.69 (s, 1H), 6.63 - 6.56 (m, 1H), 4.69 (s, 1H), 4.41 (s, 1H), 2.93 - 2.77 (m, 1H), 2.56 (s, 1H), 1.83 - 1.67 (m, 2H), 1.57 (t,J = 12.8 Hz, 2H), 1.26 (d,J = 6.0 Hz, 1H)

[1007]

[1008] Example 146: (1R,3S,4S)-3-(4-(benzofuran-5-yl)-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane

[1009]

[1010] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using benzofuran-5-amine instead of aniline.

[1011] MS (ESI, m / z): 494.1 [M+H]+

[1012] 1H NMR (400 MHz, cdcl3) δ 8.24 (s, 1H), 7.78 (d,　J　= 2.1 Hz, 2H), 7.66 (d,　J　= 8.7 Hz, 1H), 7.39 (d,　J　= 8.4 Hz, 1H), 7.01 (s, 1H), 6.88 (d,　J　= 1.3 Hz, 1H), 6.84 (s, 1H), 4.63 (s, 1H), 4.48 (s, 1H), 2.90 (d,　J　= 8.6 Hz, 1H), 2.53 (s, 1H), 1.85 - 1.71 (m, 2H), 1.63 (s, 3H).

[1013]

[1014] Example 147: (1R,3S,4S)-3-(4-(benzofuran-6-yl)-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane

[1015]

[1016] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using benzofuran-6-amine instead of aniline.

[1017] MS (ESI, m / z): 494.1 [M+H]+

[1018] 1H NMR (400 MHz, cdcl3) δ 8.24 (s, 1H), 7.79 (d,　J　= 2.2 Hz, 1H), 7.76 (d,　J　= 8.2 Hz, 1H), 7.68 (s, 1H), 7.38 (d,　J　= 7.6 Hz, 1H), 7.00 (s, 1H), 6.89 (dd,　J　= 2.2, 0.9 Hz, 1H), 6.82 (s, 1H), 4.65 (s, 1H), 4.49 (s, 1H), 2.90 (d,　J　= 9.3 Hz, 1H), 2.57 (s, 1H), 1.86 - 1.71 (m, 2H), 1.64 (d,　J　= 11.1 Hz, 1H), 1.59 (s, 1H), 1.56 (s, 1H).

[1019]

[1020] Example 148: 5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)benzo[d]thiazole

[1021]

[1022] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 1,3-benzothiazol-5-amine instead of aniline.

[1023] MS (ESI, m / z): 511.1 [M+H]+

[1024] 1H NMR (400 MHz, cdcl3) δ 9.18 (s, 1H), 8.29 (s, 1H), 8.23 (d,　J　= 1.6 Hz, 1H), 8.17 (d,　J　= 8.5 Hz, 1H), 7.67 (d,　J　= 8.3 Hz, 1H), 7.00 (s, 1H), 6.83 (s, 1H), 4.66 (s, 1H), 4.49 (s, 1H), 2.93 (d,　J　= 9.9 Hz, 1H), 2.62 (s, 1H), 1.80 (dd,　J　= 10.4, 4.6 Hz, 2H), 1.65 - 1.58 (m, 3H).

[1025]

[1026] Example 149: 7-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)benzo[d]thiazole

[1027]

[1028] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 1,3-benzothiazol-7-amine instead of aniline.

[1029] MS (ESI, m / z): 511.1 [M+H]+

[1030] 1H NMR (400 MHz, cdcl3) δ 9.17 (s, 1H), 8.34 - 8.25 (m, 2H), 8.21 (s, 1H), 7.63 (dd,　J　= 8.6, 2.0 Hz, 1H), 7.01 (s, 1H), 6.84 (s, 1H), 4.64 (s, 1H), 4.50 (s, 1H), 2.93 (d,　J　= 9.9 Hz, 1H), 2.57 (s, 1H), 1.86 - 1.74 (m, 2H), 1.62 (dd,　J　= 20.4, 11.0 Hz, 3H).

[1031]

[1032] Example 150: (1R,3S,4S)-3-(4-(benzo[b]thiophen-5-yl)-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane

[1033]

[1034] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using benzothiophen-5-amine instead of aniline.

[1035] MS (ESI, m / z): 510.1 [M+H]+

[1036] 1H NMR (400 MHz, cdcl3) δ 8.40 (s, 1H), 8.06 (d,　J　= 8.4 Hz, 1H), 7.99 (s, 1H), 7.66 (d,　J　= 5.4 Hz, 1H), 7.43 (d,　J　= 5.5 Hz, 2H), 7.02 (s, 1H), 6.84 (s, 1H), 4.66 (s, 1H), 4.48 (s, 1H), 2.76 (d,　J　= 9.1 Hz, 1H), 2.55 (s, 1H), 1.86 - 1.70 (m, 2H), 1.59 (t,　J　= 12.4 Hz, 2H), 1.26 (d,　J　= 11.8 Hz, 1H).

[1037]

[1038] Example 151: 5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)-3-methylbenzo[d]isoxazole

[1039]

[1040] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 3-methyl-1,2-benzoxazol-5-amine instead of aniline.

[1041] MS (ESI, m / z): 509.1 [M+H]+

[1042] 1H NMR (400 MHz, cdcl3) δ 8.23 (s, 1H), 7.82 (s, 1H), 7.72 (d,　J　= 8.8 Hz, 1H), 7.62 (dd,　J　= 8.8, 1.8 Hz, 1H), 7.00 (s, 1H), 6.84 (s, 1H), 4.50 (d,　J　= 15.8 Hz, 2H), 2.89 (d,　J　= 9.7 Hz, 1H), 2.63 (s, 3H), 2.53 (s, 1H), 1.87 - 1.72 (m, 2H), 1.61 (s, 2H), 1.28 (d,　J　= 5.8 Hz, 1H).

[1043]

[1044] Example 152: 5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)benzo[d]thiazole

[1045]

[1046] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using thiazolo[5,4-b]pyridin-6-amine instead of aniline.

[1047] MS (ESI, m / z): 511.1 [M+H]+

[1048] 1H NMR (400 MHz, cdcl3) δ 8.81 (d,　J　= 2.2 Hz, 1H), 8.64 (d,　J　= 13.0 Hz, 1H), 8.55 (d,　J　= 2.1 Hz, 1H), 8.42 (s, 1H), 7.01 (s, 1H), 6.83 (s, 1H), 4.59 (s, 1H), 4.50 (s, 1H), 2.81 (d,　J　= 13.0 Hz, 3H), 2.65 (s, 1H), 1.83 (d,　J　= 8.5 Hz, 2H), 1.65 (s, 1H).

[1049]

[1050] Example 153: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(2,3-dihydrobenzofuran-6-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[1051]

[1052] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 2,3-dihydrobenzofuran-6-amine instead of aniline.

[1053] MS (ESI, m / z): 496.2 [M+H]+

[1054] 1H NMR (400 MHz, cdcl3) δ 8.20 (s, 1H), 7.32 (d,　J　= 7.3 Hz, 1H), 6.98 (s, 1H), 6.95 (s, 1H), 6.87 (s, 1H), 6.82 (s, 1H), 4.69 (t,　J　= 8.8 Hz, 2H), 4.64 (s, 1H), 4.48 (s, 1H), 3.29 (t,　J　= 8.6 Hz, 2H), 2.84 (s, 1H), 2.54 (s, 1H), 1.80 (s, 3H), 1.75 (s, 2H).

[1055]

[1056] Example 154: 5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine

[1057]

[1058] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 1-methylpyrrolo[2,3-b]pyridin-5-amine instead of aniline.

[1059] MS (ESI, m / z): 508.2 [M+H]+

[1060] 1H NMR (400 MHz, cdcl3) δ 8.35 (d,　J　= 2.2 Hz, 1H), 8.22 (s, 1H), 8.09 (s, 1H), 7.36 (d,　J　= 3.5 Hz, 1H), 6.98 (s, 1H), 6.79 (s, 1H), 6.57 (d,　J　= 3.5 Hz, 1H), 4.58 (s, 1H), 4.47 (s, 1H), 3.95 (s, 3H), 2.87 (d,　J　= 9.0 Hz, 1H), 2.59 (s, 1H), 1.84 - 1.70 (m, 2H), 1.59 (t,　J　= 11.2 Hz, 2H), 1.31 - 1.23 (m, 1H).

[1061]

[1062] Example 155: 6-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)benzo[d]oxazol-2(3H)-one

[1063]

[1064] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 6-amino-3H-1,3-benzoxazol-2-one instead of aniline.

[1065] MS (ESI, m / z): 511.1 [M+H]+

[1066] 1H NMR (600 MHz, cdcl3) δ 8.21 (s, 1H), 7.41 (s, 1H), 7.35 (d,J= 7.1 Hz, 1H), 7.21 (d,J= 8.2 Hz, 1H), 7.01 (s, 1H), 6.85 (s, 1H) ), 4.65 (s, 1H), 4.49 (s, 1H), 2.90 (d,　J　= 9.3 Hz, 1H), 2.57 (s, 1H), 1.86 - 1.71 (m, 2H), 1.64 (d,　J　= 11.1 Hz, 1H), 1.59 (s, 1H), 1.56 (s, 1H).

[1067]

[1068] Example 156: 6-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)-2,3-dimethyl-2H-indazole

[1069]

[1070] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 2,3-dimethylindazol-6-amine instead of aniline.

[1071] MS (ESI, m / z): 511.1 [M+H]+

[1072] 1H NMR (600 MHz, cdcl3) δ 8.64 (s, 1H), 7.84 (d,　J　= 8.7 Hz, 2H), 7.19 (d,　J　= 9.1 Hz, 1H), 7.05 (s, 1H), 6.87 (s, 1H), 4.70 (s, 1H), 4.49 (s, 1H), 4.21 (s, 3H), 2.72 (s, 3H), 2.65 (s, 1H), 2.61 (d,　J　= 9.4 Hz, 1H), 1.87 - 1.73 (m, 2H), 1.64 - 1.56 (m, 2H), 1.29 (t,　J　= 9.2 Hz, 1H).

[1073]

[1074] Example 157: 5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)-2-methyl-2H-indazole

[1075]

[1076] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 2-methylindazol-5-amine instead of aniline.

[1077] MS (ESI, m / z): [M+H]+

[1078] 1H NMR (600 MHz, cdcl3) δ 8.60 (s, 1H), 8.13 (s, 1H), 7.92 (d,　J　= 8.5 Hz, 2H), 7.34 (d,　J　= 9.0 Hz, 1H), 7.06 (s, 1H), 6.88 (s, 1H), 4.66 (s, 1H), 4.49 (s, 1H), 2.63 (d,　J　= 10.0 Hz, 1H), 2.59 (s, 1H), 1.85 - 1.74 (m, 2H), 1.60 (d,　J　= 9.9 Hz, 2H), 1.30 - 1.21 (m, 1H).

[1079]

[1080] Example 158: (1S,3S,4S,5R)-3-(4-(benzo[d]thiazol-5-yl)-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-5-ol

[1081]

[1082] The title product was afforded by a procedure similar to that described for the synthesis of Example 117 using 1,3-benzothiazole-5-amine instead of aniline.

[1083] MS (ESI, m / z): 527.1 [M+H]+

[1084]

[1085] Example 159: (1S,3S,4S,5S,6R)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-3-(4-(4-fluoro-3-methylphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane-5,6-diol

[1086]

[1087] Synthesis of ethyl (3aR,4S,6S,7S,7aS)-5-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2,2-dimethylhexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine-6-carboxylate. To a stirred solution of ethyl (1S,2S,6R,7S,9S)-4,4-dimethyl-3,5-dioxa-8-azatricyclo[5.2.1.02,6]decane-9-carboxylate (1.00 eq, 480 mg, 1.99 mmol)　in Dimethylformamide (5mL)　was added [4,6-bis(trifluoromethyl)-2-pyridyl] trifluoromethanesulfonate (1.30 eq, 939 mg, 2.59 mmol) and　DIPEA (3.00 eq, 1.0 mL, 5.97 mmol)　at rt. The reaction was strirred at　110 　oC for　12h.　The resulting crude was concentrated to the dryness and purified by flash column chromatography to afford　the desired product (yield, 55%).

[1088] Synthesis of (3aR,4S,6S,7S,7aS)-5-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2,2-dimethylhexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine-6-carboxylic acid. To a solution of ethyl (3aR,4S,6S,7S,7aS)-5-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2,2-dimethylhexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine-6-carboxylate (1.00 eq, 460 mg, 1.01 mmol) in Methyl alcohol (2 mL) was added 1N NaOH (2 mL) and stirred at 25oC for 3 hour. The solution was neutralized with 1N HCl to give the desired product quantitatively.

[1089] Synthesis of (3aR,4S,6S,7S,7aS)-5-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2,2-dimethylhexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine-6-carbohydrazide. To a solution of (3aR,4S,6S,7S,7aS)-5-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2,2-dimethylhexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine-6-carboxylic acid (1.0 eq, 191 mg, 0.448 mmol) and triethylamine (1.2 eq, 75 μL, 0.538 mmol) in tetrahydrofuran (5 mL) was added ethyl chloroformate (1.2 eq, 53 μL, 0.538 mmol) and stirred the mixture for 15 minutes at 0oC to form the insoluable salt. Filter the resulting salt and wash with tetrahydrofuran. Add the filtrate slowly to a solution of hydrazine monohydrate (5 eq, 1.1 mL, 2.24 mmol) under 0oC and stirred for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, extracted with EA and water, dried over anhydrous Na2SO4, and concentrated in vacuo. Then, the residue was purified by the column chromatography to give the desired product (yield, 71%).

[1090] Synthesis of (E)-N'-((3aR,4S,6S,7S,7aS)-5-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2,2-dimethylhexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine-6-carbonyl)-N,N-dimethylformohydrazonamide. To a solution of (3aR,4S,6S,7S,7aS)-5-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2,2-dimethylhexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine-6-carbohydrazide (1.00 eq, 140 mg, 0.318 mmol) in acetonitrile (5 mL) was added N,N-dimethylformamide dimethyl acetal (2.4 eq, 100 μL, 0.763 mmol) at rt. The reaction mixture was stirred at 55oC for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by the column chromatography to give the desired product (yield, 82%).

[1091] Synthesis of (3aR,4S,6S,7S,7aS)-5-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-(4-(4-fluoro-3-methylphenyl)-4H-1,2,4-triazol-3-yl)-2,2-dimethylhexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine. To a solution of (E)-N'-((3aR,4S,6S,7S,7aS)-5-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2,2-dimethylhexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine-6-carbonyl)-N,N-dimethylformohydrazonamide (1.00 eq, 30 mg, 0.0606 mmol)　in Toluene (2mL)　was added 4-fluoro-3-methyl-aniline (10.0 eq, 76 mg, 0.606 mmol)　and acetic acid (10.0 eq, 0.035 mL, 0.606 mmol)　at rt.　The reaction mixture was stirred at 130oC.　After 2 hours, the solution was concentrated under reduced pressure to give the desired product quantitatively.

[1092] Synthesis of (1S,3S,4S,5S,6R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluoro-3-methylphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane-5,6-diol. To a solution of (3aR,4S,6S,7S,7aS)-5-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-(4-(4-fluoro-3-methylphenyl)-4H-1,2,4-triazol-3-yl)-2,2-dimethylhexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine (1.00 eq, 34 mg, 0.0610 mmol) in Ethanol (3mL) was added 2N HCl solution(5.00 eq, 0.011 mL, 0.305 mmol) at rt. The reaction mixture was stirred at rt. After 12 hours, the solution was concentrated under reduced pressure. The resulting crude was purified by prep-HPLC to give the desired product (yield, 22%).

[1093] MS (ESI, m / z): 518.1 [M+H]+

[1094] 1H NMR (400 MHz, cdcl3) δ 8.24 (s, 1H), 7.36 (s, 2H), 7.21 (s, 1H), 7.02 (s, 2H), 4.87 (s, 3H), 4.47 (s, 1H), 3.85 (s, 2H), 2.72 (s, 2H), 2.36 (s, 3H), 2.20 (s, 1H).

[1095]

[1096] Example 160: (1S,3S,4S,5S,6R)-3-(4-(benzofuran-6-yl)-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-5,6-diol

[1097]

[1098] The title product was afforded by a procedure similar to that described for the synthesis of Example 159 using benzofuran-6-amine instead of 4-fluoro-3-methyl-aniline.

[1099] MS (ESI, m / z): 526.1 [M+H]+

[1100] 1H NMR (400 MHz, cdcl3) δ 8.25 (s, 1H), 7.77 (d,J= 14.2 Hz, 2H), 7.66 (s, 1H), 7.35 (d,J= 7.3 Hz, 1H), 7.02 (s, 1H), 6.97 (s, 1H), 6.89 (s, 1H), 4.33 (s, 1H), 4.24 - 4.08 (m, 2H), 3.81 (s, 1H), 3.75 (s, 1H), 2.70 (d,J= 9.5 Hz, 1H), 2.46 (s, 1H), 2.34 (d,J= 7.9 Hz, 1H), 2.24 (d,J= 7.2 Hz, 1H).

[1101]

[1102] Example 161: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[1103]

[1104] Synthesis of N-(4-fluorophenyl)acetamide. To a stirred solution of 4-fluoroaniline (1.00 eq, 500 mg, 4.50 mmol) in Dichloromethane (50 mL) was added acetyl acetate (1.20 eq, 0.51 mL, 5.40 mmol) at 0oC. The mixture was stirred at rt. After 12h, the reaction mixture was concentrated to dryness and the crude was then purified by flash column chromatography to give the desired product (yield, 55%).

[1105] Synthesis of (Z)-N-(4-fluorophenyl)-1-(1H-imidazol-1-yl)ethan-1-imine. To a stirred solution of N-(4-fluorophenyl)acetamide (1.00 eq, 191 mg, 1.25 mmol)　in Acetonitrile (12 mL)　was added imidazole (12.0 eq, 1.0 g, 15.0 mmol) at rt. The reaction mixture was cooled to 0 　oC prior to the dropwise addition of POCl3 (2.00 eq, 0.23 mL, 2.49 mmol). The reaction mixture was allowed to stir for 30min at 0 　oC. After removal of the ice bath, the reaction mixture was heated to 60 　oC for 12h. After cooling the reaction mixture to rt, the crude was purified by　flash column chromatography to give the desired product (yield, 32%).

[1106] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane. To a solution of (1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptane-3-carbohydrazide (1.00 eq, 30 mg, 0.0815 mmol) in Tetrahydrofuran (2mL) was added (Z)-N-(4-fluorophenyl)-1-(1H-imidazol-1-yl)ethan-1-imine (1.00 eq, 17 mg, 0.0815 mmol) and TFA (3.00 eq, 19 μL, 0.244 mmol) at rt. The reaction mixture was stirred at　70 　oC.　After 12h, the solution was concentrated under reduced pressure. The resulting crude was purified by prep-HPLC to give the desired product (yield, 30%).

[1107] MS (ESI, m / z): 486.2 [M+H]+

[1108] 1H NMR (400 MHz, cdcl3) δ 7.52 (s, 1H), 7.28 (d,　J　= 7.8 Hz, 2H), 7.25 (s, 1H), 6.99 (s, 1H), 6.82 (s, 1H), 4.46 (s, 1H), 4.35 (s, 1H), 2.83 (d,　J　= 8.9 Hz, 1H), 2.46 (s, 1H), 2.26 (s, 3H), 1.87 (s, 1H), 1.80 - 1.73 (m, 2H), 1.65 - 1.50 (m, 2H).

[1109]

[1110] Example 162: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-chloro-4-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane

[1111]

[1112] The title product was afforded by a procedure similar to that described for the synthesis of Example 161 using 3-chloro-4-fluoro-aniline instead of 4-fluoroaniline.

[1113] MS (ESI, m / z): 520.1 [M+H]+

[1114] 1H NMR (400 MHz, cdcl3) δ 8.18 (s, 1H), 7.59 (dd,　J　= 6.2, 2.4 Hz, 1H), 7.48 - 7.41 (m, 1H), 7.34 (t,　J　= 8.5 Hz, 1H), 7.01 (s, 1H), 6.84 (s, 1H), 4.55 (s, 1H), 4.49 (s, 1H), 2.89 (d,　J　= 10.0 Hz, 1H), 2.54 (s, 1H), 1.85 (d,　J　= 8.5 Hz, 2H), 1.67 (t,　J　= 8.5 Hz, 1H), 1.61 (t,　J　= 9.3 Hz, 2H).

[1115]

[1116] Example 163: 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepine

[1117] Example 164: 1-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-5,6,8,9-tetrahydro-7H-[1,2,4]triazolo[4,3-d][1,4]diazepin-7-yl)ethan-1-one

[1118]

[1119] Synthesis of tert-butyl 5-ethoxy-2,3,6,7-tetrahydro-1H-1,4-diazepine-1-carboxylate. To a stirred solution of　tert-butyl 5-oxo-1,4-diazepane-1-carboxylate (1.00 eq, 1.00 g, 4.67 mmol) in　Dichloromethane (47mL) was added　Triethyl oxonium tetrafluoroborate (3.50 eq, 2.3 mL, 16.3 mmol) at rt. The mixture was stirred at rt. After 2 hours, the reaction mixture was concentrated to dryness and the crude was then purified by flash column chromatography to give the desired product (yield, 70%).

[1120] Synthesis of tert-butyl 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-5,6,8,9-tetrahydro-7H-[1,2,4]triazolo[4,3-d][1,4]diazepine-7-carboxylate. To a stirred solution of　tert-butyl 7-ethoxy-2,3,5,6-tetrahydro-1,4-diazepine-4-carboxylate (1.00 eq, 178 mg, 0.733 mmol) in　Ethanol (7mL) was added　(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptane-3-carbohydrazide (1.00 eq, 270 mg, 0.733 mmol) at room temperature. The mixture was stirred at　85 　oC. After 12 hours, the reaction mixture was concentrated to dryness and the crude was then purified by flash column chromatography to give the desired product.　(yield, 75%)

[1121] Synthesis of 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepine (Example 163). To　a solution of tert-butyl 3-[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptan-3-yl]-5,6,8,9-tetrahydro-[1,2,4]triazolo[4,3-d][1,4]diazepine-7-carboxylate (1.00 eq, 491 mg, 0.898 mmol) in Dichloromethane (10mL) wad added TFA (20.0 eq, 1.4 mL, 18.0 mmol) at room temp. After being stirred for 2 hours , the reaction mixture was concentrated in vacuo. The residue was treated with dichloromethane and washed with 2N-NaOH. The organic layer was dried over anhydrous MgSO4, filtered and evaporated under reduced pressure. The resiude was purified by flash column chromatography to give the desired product (yield, 75%).

[1122] MS (ESI, m / z): 447.2 [M+H]+

[1123] 1H NMR (600 MHz, cdcl3) δ 7.11 (s, 1H), 6.95 (s, 1H), 4.58 (s, 2H), 4.53 (s, 2H), 4.32 - 4.26 (m, 1H), 4.24 - 4.19 (m, 1H), 4.12 (dd,　J　= 11.9, 5.3 Hz, 1H), 4.02 (s, 1H), 3.97 (dd,　J　= 9.0, 6.3 Hz, 1H), 2.38 - 2.32 (m, 2H), 2.28 (t,　J　= 7.7 Hz, 2H), 2.03 (d,　J　= 11.2 Hz, 2H), 1.72 (s, 2H).

[1124] Synthesis of 1-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-5,6,8,9-tetrahydro-7H-[1,2,4]triazolo[4,3-d][1,4]diazepin-7-yl)ethan-1-one (Example 164). To a solution of 3-[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptan-3-yl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepine (1.00 eq, 100 mg, 0.224 mmol) in Ethanol (5mL) was added acetyl acetate (1.00 eq, 0.023 mL, 0.224 mmol) and triethylamine (1.50 eq, 0.047 mL, 0.336 mmol) at 0 　oC. The reaction mixture was stirred at 25 　oC. After 12h,　the reaction mixture　was　concentrated to dryness, purified by　prep-HPLC　to give the desired product (yield, 19%).

[1125] MS (ESI, m / z): 489.2 [M+H]+

[1126] 1H NMR (600 MHz, cdcl3) δ 7.07 (s, 1H), 6.90 (s, 1H), 4.59 (s, 1H), 4.50 (s, 1H), 4.47 (d,　J　= 10.3 Hz, 1H), 4.38 (s, 1H), 4.25 (s, 1H), 3.95 (s, 1H), 3.73 (s, 1H), 3.67 (s, 1H), 3.58 (s, 1H), 3.41 (s, 1H), 2.77 (s, 1H), 2.70 (s, 1H), 2.26 (s, 1H), 2.24 (s, 2H), 1.94 - 1.89 (m, 1H), 1.78 - 1.72 (m, 1H), 1.67 (d,　J　= 9.7 Hz, 1H), 1.64 - 1.59 (m, 1H).

[1127]

[1128] Example 165: 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(methylsulfonyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepine

[1129]

[1130] The title product was afforded by a procedure similar to that described for the synthesis of Example 164 using methanesulfonyl chloride instead of acetyl acetate.

[1131] MS (ESI, m / z): 525.1 [M+H]+

[1132] 1H NMR (600 MHz, cdcl3) δ 7.10 (s, 1H), 6.93 (s, 1H), 4.62 (s, 1H), 4.58 - 4.50 (m, 2H), 4.45 (dd,　J　= 14.9, 8.3 Hz, 1H), 4.06 (d,　J　= 10.0 Hz, 1H), 3.94 (d,　J　= 6.1 Hz, 1H), 3.66 - 3.52 (m, 2H), 3.50 - 3.36 (m, 2H), 2.95 (s, 3H), 2.78 (s, 1H), 2.72 (d,　J　= 9.9 Hz, 1H), 1.99 (t,　J　= 12.2 Hz, 1H), 1.93 (t,　J　= 12.3 Hz, 1H), 1.74 (t,　J　= 10.3 Hz, 1H), 1.68 (d,　J　= 10.4 Hz, 1H), 1.61 (d,　J　= 9.6 Hz, 1H).

[1133]

[1134] Example 166: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane

[1135]

[1136] Preparation of tert-butyl (1R,3S,4S)-3-(((E)-1-aminoethylidene)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To a solution of (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.0 eq, 50 mg, 0.21 mmol) and HATU (1.1 eq, 86.7 mg, 0.23 mmol) in dimethylformamide (1.0 mL) was added acetimidamide (1.5 eq, 18 mg, 0.31 mmol) and Diisopropylethylamine (3.0 eq, 108 μL, 0.62 mmol) and stirred at 25oC for 2 hour. The intermediate was used in-situ.

[1137] MS (ESI, m / z): 282.1 [M+H]+

[1138] Preparation of tert-butyl (1R,3S,4S)-3-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To a stirred solution of intermediate (methyl tert-butyl (1R,3S,4S)-3-(((E)-1-aminoethylidene)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate) in dimethylformamide (1.0mL) was added (4-(trifluoromethyl)phenyl)hydrazine (1.5 eq, 54.7 mg, 0.31 mmol) and acetic acid (10.0 eq, 124.4 mg , 2.1 mmol) at 25oC and stirred at 80oC for 2 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography to give the desired product. (yield, 46%).

[1139] MS (ESI, m / z): 423.2 [M+H]+

[1140] Synthesis of (1R,3S,4S)-3-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane. To a stirred solution tert-butyl (1R,3S,4S)-3-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.0eq, 40 mg 0.09 mmol) in DCM (1.0mL) was added Trifluoro acetic acid (3.0 eq, 32 mg, 0.28 mmol) and stirred at 25oC for 3 hour. The reaction mixture was concentrated in vacuo and purified prep-HPLC to give the desired product. (yield, 83%).

[1141] MS (ESI, m / z): 323.1 [M+H]+

[1142] Preparation of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane. To a solution of (1R,3S,4S)-3-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane (1.0 eq, 23 mg, 0.07 mmol) in dimethylformamide (1.0 mL) was added 4,6-bis(trifluoromethyl)pyridin-2-yl trifluoromethanesulfonate (1.0 eq, 25.9 mg, 0.07 mmol) and Triethylamine (3.0 eq, 29 μL, 0.21 mmol) and stirred at 25oC for 16 hour. The reaction mixture was poured into water (3 mL), extracted with DCM (3 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified by the column chromatography to give the desired product. (yield, 100%).

[1143] MS (ESI, m / z): 536.1 [M+H]+

[1144] 1H NMR (600 MHz, cdcl3) δ 7.80 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 1.1 Hz, 1H), 6.83 (s, 1H), 4.69 (s, 1H), 4.49 (s, 1H), 2.84 (d, J = 10.0 Hz, 1H), 2.68 - 2.56 (m, 1H), 2.38 (s, 3H), 1.85 (dd, J = 9.3, 4.7 Hz, 2H), 1.66 (t, J = 8.7 Hz, 1H), 1.60 (s, 1H).

[1145]

[1146] Example 167: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-3-(1-(3-chloro-4-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane

[1147]

[1148] The title product was afforded by a procedure similar to that described for the synthesis of Example 166 using (3-chloro-4-fluorophenyl)hydrazine instead of (4-(trifluoromethyl)phenyl)hydrazine.

[1149] MS (ESI, m / z): 520.1 [M+H]+

[1150] 1H NMR (600 MHz, cdcl3) δ 7.66 (d,　J　= 6.2 Hz, 1H), 7.52 (s, 1H), 7.29 (d,　J　= 3.0 Hz, 2H), 7.00 (d,　J　= 1.2 Hz, 1H), 6.82 (s, 1H), 4.63 (s, 1H), 4.48 (s, 1H), 2.79 (d,　J　= 10.1 Hz, 1H), 2.59 (s, 1H), 2.37 (s, 4H), 1.90 - 1.80 (m, 3H), 1.67 (t,　J　= 8.6 Hz, 2H), 1.43 (t,　J　= 8.8 Hz, 1H).

[1151]

[1152] Example 168: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane

[1153]

[1154] Preparation of tert-butyl (1R,3S,4S)-3-(((E)-aminomethylene)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To a solution of (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.0 eq, 50 mg, 0.21 mmol) and HATU (1.1 eq, 86.7 mg, 0.23 mmol) in dimethylformamide (1.0 mL) was added formimidamide (1.5 eq, 13.7 mg, 0.31 mmol) and Diisopropylethylamine (3.0 eq, 108 μL, 0.62 mmol) and stirred at 25oC for 2 hour. The intermediate was used in-situ.

[1155] MS (ESI, m / z): 268.1 [M+H]+

[1156] Preparation of tert-butyl (1R,3S,4S)-3-(1-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To a stirred solution of intermediate (tert-butyl (1R,3S,4S)-3-(((E)-aminomethylene)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate) in dimethylformamide (1.0mL) was added (4-fluorophenyl)hydrazine (1.5 eq, 39 mg, 0.31 mmol) and acetic acid (10.0 eq, 124.4 mg , 2.1 mmol) at 25oC and stirred at 80oC for 2 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography to give the desired product. (yield, 47%).

[1157] MS (ESI, m / z): 359.2 [M+H]+

[1158] Synthesis of (1R,3S,4S)-3-(1-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane. To a stirred solution tert-butyl (1R,3S,4S)-3-(1-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.0eq, 35 mg 0.10 mmol) in DCM (1.0mL) was added Trifluoro acetic acid (3.0 eq, 33 mg, 0.29 mmol) and stirred at 25oC for 3 hour. The reaction mixture was concentrated in vacuo and purified by prep-HPLC to give the desired product. (yield, 100%).

[1159] MS (ESI, m / z): 259.1 [M+H]+

[1160] Preparation of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane. To a solution of (1R,3S,4S)-3-(1-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane (1.0 eq, 26 mg, 0.07 mmol) in dimethylformamide (1.0 mL) was added 4,6-bis(trifluoromethyl)pyridin-2-yl trifluoromethanesulfonate (1.0 eq, 25.9 mg, 0.07 mmol) and Triethylamine (3.0 eq, 29 μL, 0.21 mmol) and stirred at 25oC for 16 hour. The reaction mixture was poured into water (3 mL), extracted with DCM (3 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified by prep-HPLC to give the desired product. (yield, 15%).

[1161] MS (ESI, m / z): 472.1 [M+H]+

[1162] 1H NMR (600 MHz, cdcl3) δ 7.98 (s, 1H), 7.59 (dd,　J　= 8.8, 4.6 Hz, 2H), 7.28 - 7.26 (m, 1H), 7.25 (d,　J　= 2.2 Hz, 1H), 7.02 (d,　J　= 1.2 Hz, 1H), 6.86 (s, 1H), 4.69 (s, 1H), 4.49 (s, 1H), 2.66 (d,　J　= 10.2 Hz, 2H), 2.60 (s, 1H), 1.88 - 1.81 (m, 2H), 1.67 (td,　J　= 8.9, 2.4 Hz, 1H), 1.59 (d,　J　= 10.2 Hz, 1H), 1.41 (td,　J　= 8.7, 2.3 Hz, 1H), 1.36 - 1.28 (m, 1H).

[1163]

[1164] Example 169: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-3-(1-phenyl-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane

[1165]

[1166] The title product was afforded by a procedure similar to that described for the synthesis of Example 167 using phenylhydrazine instead of (4-fluorophenyl)hydrazine.

[1167] MS (ESI, m / z): 454.1 [M+H]+

[1168] 1H NMR (600 MHz, cdcl3) δ 8.08 (s, 1H), 7.62 - 7.52 (m, 5H), 7.04 (s, 1H), 6.86 (s, 1H), 4.75 (s, 1H), 4.50 (s, 1H), 2.64 (s, 1H), 2.53 (d, J = 10.4 Hz, 1H), 1.84 (d, J = 8.6 Hz, 2H), 1.70 - 1.56 (m, 3H), 1.41 (t, J = 9.1 Hz, 1H)..

[1169]

[1170] Example 170: 5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1171] Preparation of 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbonyl)hydrazine-1-carboxamide. To a stirred solution of　(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.00 eq, 100 mg, 0.282 mmol) in　dichloromethane (4 mL), were added　semicarbazide (1.50 eq, 32 mg, 0.423 mmol),　EDCI (2.00 eq, 88 mg, 0.565 mmol),　1-hydroxybenzotriazole (2.00 eq, 76 mg, 0.565 mmol) and　triethylamine (2.00 eq, 77 μl, 0.565 mmol) at　23 　oC. After 16h, the mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography (100% EtOAc to 20% MeOH in EtOAc) to afford　[[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptane-3-carbonyl]amino]urea (101 mg,0.246 mmol, 87 % yield) as a white solid.

[1172] MS (ESI, m / z): 421.1 [M+H]+

[1173] 1H NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 7.14 (s, 1H), 6.88 (s, 1H), 4.32 (s, 1H), 4.01 (s, 1H), 2.91 (s, 1H), 2.07 (d, J = 10.4 Hz, 1H), 1.89 - 1.40 (m, 5H).

[1174] Synthesis of 5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one. To a solution of　　[[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptane-3-carbonyl]amino]urea (1.00 eq, 101 mg, 0.246 mmol) in distilled water (4 mL), was added　NaOH (20% aq, solution) (1.00 eq, 4.0 mL, 0.246 mmol)　at　23 　oC. The mixture was stirred at　100 　oC. After 16h, the mixture was concentrated under reduced pressure. The crude residue was purified by prep HPLC to afford　3-[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptan-3-yl]-1,4-dihydro-1,2,4-triazol-5-one (22 mg,0.0559 mmol, 23 % yield).

[1175] MS (ESI, m / z): 394.1 [M+H]+

[1176] 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 2H), 7.16 (s, 1H), 6.86 (s, 1H), 4.46 (s, 1H), 4.33 (s, 1H), 3.17 (s, 1H), 2.16 (d, J = 10.3 Hz, 1H), 1.92 (ddd, J = 16.0, 7.9, 4.1 Hz, 1H), 1.83 (t, J = 12.9 Hz, 1H), 1.75 - 1.64 (m, 2H), 1.57 - 1.47 (m, 1H).

[1177]

[1178] Example 171: 5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-(m-tolyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1179]

[1180] Preparation of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbohydrazide. To a stirred solution of　methyl (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.00 eq, 200 mg, 0.54 mmol) in　Methyl alcohol (5 mL), were added　hydrazine;hydrate (17.0 eq, 0.56 mL, 9.2 mmol)　at　23 　oC. After 12h, the mixture was concentrated under reduced pressure. Then, the residue was purified by the column chromatography to give the desired product. (yield, 65%).

[1181] MS (ESI, m / z): 369.1 [M+H]+

[1182] Synthesis of 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbonyl)-N-(m-tolyl)hydrazine-1-carboxamide. To a solution of　　(1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbohydrazide (1.00 eq, 50 mg, 0.14 mmol) in diethyl ether (1.0 mL), was added　1-isocyanato-3-methylbenzene (1.00 eq, 23 mg, 0.14 mmol)　at　23 　oC. The mixture was stirred at　23 　oC. After 48h, the obtained product was filtered and washed with diethyl ether (2mL). The crude residue was used for next step without further purification. (yield , 95 %).

[1183] MS (ESI, m / z): 524.1 [M+H]+

[1184] Synthesis of 5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-(m-tolyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. To a stirred solution 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbonyl)-N-(m-tolyl)hydrazine-1-carboxamide (1.0eq, 65 mg 0.13 mmol) in water (1.0mL) was added 2N NaOH(excess) and stirred at 130oC for 12 hour. The reaction mixture was neutralized with 1N HCl to adjust pH=7-9. The precipitate was filtered off and extracted extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified by the column chromatography to give the desired product. (yield, 3%).

[1185] MS (ESI, m / z): 484.1 [M+H]+

[1186] 1H NMR (600 MHz, cdcl3) δ 8.60 (s, 1H), 7.42 (t,　J　= 7.8 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.08 (d,　J　= 3.1 Hz, 1H), 6.83 (s, 1H), 5.34 (dd,　J　= 4.2, 1.4 Hz, 1H), 2.54 (s, 1H), 2.46 (s, 1H), 2.43 (s, 3H), 2.24 - 2.20 (m, 3H), 2.01 (q,　J　= 6.5 Hz, 3H).

[1187]

[1188] Example 172: 5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-(3,4-difluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[1189]

[1190] The title product was afforded by a procedure similar to that described for the synthesis of Example 171 using 1,2-difluoro-4-isocyanatobenzene instead of 1-isocyanato-3-methylbenzene.

[1191] MS (ESI, m / z): 506.1 [M+H]+

[1192] 1H NMR (600 MHz, cdcl3) δ 9.26 (s, 1H), 7.40 (ddd,　J　= 9.5, 6.6, 2.4 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.30 (d,　J　= 8.9 Hz, 1H), 7.09 (d,　J　= 1.2 Hz, 1H), 6.85 (s, 1H), 4.41 (s, 1H), 4.33 (s, 1H), 2.52 (s, 1H), 2.48 (d,　J　= 10.2 Hz, 1H), 1.80 (ddt,　J　= 6.5, 4.5, 2.6 Hz, 3H), 1.62 (t,　J　= 8.5 Hz, 2H), 1.58 - 1.54 (m, 1H).

[1193]

[1194] Example 173: 5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-2,4-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (SB9630)

[1195]

[1196] To a stirred　solution of Example 170 (1.00 eq, 20 mg, 0.0509 mmol) in dimethylformamide (2mL), were added iodomethane (3.00 eq, 22 mg, 0.153 mmol) and potassium carbonate (5.00 eq, 35 mg, 0.254 mmol) at 23 　oC. After 16h, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by prep HPLC to afford 5-[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptan-3-yl]-2,4-dimethyl-1,2,4-triazol-3-one (4.9 mg, 0.0116 mmol, 23 % yield) as a white solid.

[1197] MS (ESI, m / z): 422.1 [M+H]+

[1198] 1H NMR (400 MHz, CDCl3) δ 7.06 (s, 1H), 6.80 (s, 1H), 4.43 (s, 1H), 4.40 (s, 1H), 3.43 (s, 3H), 3.40 (s, 3H), 2.64 (s, 1H), 2.54 (d,　J　= 7.7 Hz, 1H), 1.96 - 1.80 (m, 2H), 1.73 - 1.65 (m,　J　= 9.9 Hz, 1H), 1.62 - 1.50 (m,　J　= 12.7, 10.7, 7.6 Hz, 2H).

[1199]

[1200] Example 174: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane

[1201]

[1202] Preparation of tert-butyl (1R,3S,4S)-3-(1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To a stirred solution of tert-butyl (1R,3S,4S)-3-formyl-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.00 eq, 730 mg, 3.24 mmol) and glyoxal (4.00 eq, 1881 mg, 13.0 mmol) in methyl alcohol (10mL)　was added 25% aqueous ammonium hydroxide (8.00 eq, 3634 mg, 25.9 mmol) at 23 　oC. After　16h , the reaction mixture was concentrated under reduced pressure. The crude was diluted with ethyl acetate (30 mL) and washed with DI water (20 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude was purified by flash column chromatography　(100% EtOAc to 10% MeOH in EtOAc)　to afford tert-butyl (1R,3S,4S)-3-(1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (720 mg,2.73 mmol, 84% yield) as a colorless oil.

[1203] MS (ESI, m / z): 264.1 [M+H]+

[1204] 1H NMR (400 MHz, CDCl3) δ 7.32 - 7.15 (m,　J　= 21.3 Hz, 2H), 4.64 (d,　J　= 32.6 Hz, 1H), 4.33 - 4.19 (m, 1H), 3.12 - 2.66 (m,　J　= 69.0 Hz, 1H), 1.91 - 1.52 (m, 6H), 1.50 - 1.29 (m, 9H).

[1205] Preparation of (1R,3S,4S)-3-(1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane. To a stirred solution of tert-butyl (1R,3S,4S)-3-(1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.00 eq, 150 mg, 0.570 mmol) in dichloromethane (6mL), was added 2,2,2-trifluoroacetic acid (68.8 eq, 3.0 mL, 39.2 mmol) at 23 　oC. After 2h, the reaction mixture was concentrated under reduced pressure. The crude was neutralized with saturated NaHCO3 aqueous solution (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was used without further purification.

[1206] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane. The crude was re-dissolved in ethanol (6mL) and [4,6-bis(trifluoromethyl)-2-pyridyl] trifluoromethanesulfonate (1.00 eq, 207 mg, 0.570 mmol) and cesium carbonate (3.00 eq, 557 mg, 1.71 mmol) were added to the solution. The mixture was heated to 80 　oC and stirred at same temperature. After 12h, the reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography (100% n-hexane to 100% EtOAc) to afford (1R,3S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-3-(1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane (63 mg,0.167 mmol, 29% yield).

[1207] MS (ESI, m / z): 377.1 [M+H]+

[1208] 1H NMR (600 MHz, CDCl3) δ 7.10 (s, 1H), 6.97 - 6.92 (m,　J　= 13.0 Hz, 2H), 6.81 (s, 1H), 4.63 (s, 1H), 4.23 (s, 1H), 3.41 (s, 1H), 2.40 (s, 1H), 1.96 - 1.89 (m,　J　= 12.1 Hz, 1H), 1.81 (t,　J　= 11.3 Hz, 1H), 1.74 - 1.66 (m,　J　= 9.2 Hz, 2H), 1.54 - 1.49 (m, 1H).

[1209]

[1210] Example 175: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane

[1211]

[1212] To a solution of (1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-3-(1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane (1.00 eq, 15 mg, 0.0399 mmol) in tetrahydrofuran (1mL), was added sodium hydride (60 wt%, 1.50 eq, 2.4 mg, 0.0598 mmol) at 23 　oC. The mixture was stirred at 23 　oC for 15 min, then a solution of　iodomethane (1.20 eq, 0.0030 mL, 0.0478 mmol) in tetrahydrofuran (1mL) was added. After 16h, the mixture was concentrated under reduced pressure. The crude was purified by prep HPLC to afford (1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-3-(1-methylimidazol-2-yl)-2-azabicyclo[2.2.1]heptane (14 mg,0.0364 mmol, 91% yield) as a white solid.

[1213] MS (ESI, m / z): 391.1 [M+H]+

[1214] 1H NMR (600 MHz, CDCl3) δ 7.27 (s, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 7.01 (s, 1H), 4.70 (s, 1H), 4.61 (s, 1H), 3.93 (s, 3H), 2.75 (d,　J　= 3.2 Hz, 1H), 2.34 (d,　J　= 10.9 Hz, 1H), 2.02 - 1.96 (m, 1H), 1.91 (t,　J　= 12.5 Hz, 1H), 1.74 - 1.65 (m, 2H), 1.65 - 1.57 (m,　J　= 12.2 Hz, 1H).

[1215]

[1216] Example 176: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-isopropyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane

[1217]

[1218] The title product was afforded by a similar procedure to that described for the synthesis of example 175 using isopropyl iodide instead of methyl iodide.

[1219] MS (ESI, m / z): 419.1 [M+H]+

[1220] 1H NMR (400 MHz, CDCl3) δ 7.55 - 6.90 (m, 4H), 4.85 - 4.60 (m, 4H), 2.70 - 2.55 (m, 1H), 2.40 - 1.85 (m, 5H), 1.64 (d, J = 6.5 Hz, 6H).

[1221]

[1222] Example 177: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(prop-2-yn-1-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane

[1223]

[1224] The title product was afforded by a similar procedure to that described for the synthesis of example 175 using propargyl bromide instead of methyl iodide.

[1225] MS (ESI, m / z): 415.1 [M+H]+

[1226] 1H NMR (400 MHz, CDCl3) δ 6.98 - 6.89 (m, 3H), 6.81 (s, 1H), 5.19 (s, 1H), 4.78 (dd,　J　= 18.0, 2.5 Hz, 1H), 4.61 (s, 1H), 4.44 (s, 1H), 3.11 (s, 1H), 2.68 (s, 1H), 2.45 (s, 1H), 1.94 - 1.49 (m,　J　= 51.7, 25.6, 7.2 Hz, 5H).

[1227]

[1228] Example 178: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(3-methylbenzyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane

[1229]

[1230] The title product was afforded by a similar procedure to that described for the synthesis of example 175 using 1-(bromomethyl)-3-methylbenzene instead of methyl iodide.

[1231] MS (ESI, m / z): 480.2 [M+H]+

[1232] 1H NMR (400 MHz, CDCl3) δ 7.37 - 7.29 (m,　J　= 7.6 Hz, 2H), 7.25 (s, 1H), 7.11 (s, 1H), 7.09 - 6.98 (m,　J　= 18.8, 11.4 Hz, 4H), 5.34 (d,　J　= 15.1 Hz, 1H), 5.22 (d,　J　= 15.1 Hz, 1H), 4.68 (s, 1H), 4.57 (s, 1H), 2.38 (s, 3H), 2.33 (d,　J　= 10.7 Hz, 1H), 2.21 (s, 1H), 1.89 - 1.72 (m, 2H), 1.64 (t,　J　= 10.3 Hz, 1H), 1.55 (d,　J　= 10.8 Hz, 1H), 1.35 (t,　J　= 9.2 Hz, 1H).

[1233]

[1234] Example 179: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(m-tolyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane

[1235]

[1236] To a solution of Example 83 (1.00 eq, 104 mg, 0.294 mmol) in dimethylformamide (2mL), was added cyanuric chloride (0.700 eq, 38 mg, 0.206 mmol) at 23 　oC. The　mixture was stirred at 23 　oC. After 1h, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0% to 25% EtOAc in n-hexane) to afford (1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptane-3-carbonitrile (85 mg,0.254 mmol, 86% yield) as a white　crystalline solid.

[1237] MS (ESI, m / z): 336.1 [M+H]+

[1238] 1H NMR (400 MHz, CDCl3) δ 7.17 (s, 1H), 6.80 (s, 1H), 4.44 (s, 1H), 4.25 (s, 1H), 2.99 (d,　J　= 4.0 Hz, 1H), 2.27 (d,　J　= 10.6 Hz, 1H), 1.94 - 1.72 (m, 3H), 1.70 - 1.61 (m,　J　= 12.4, 7.2, 2.9 Hz, 1H), 1.50 - 1.42 (m, 1H).

[1239] Preparation of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboximidamide. To a solution of (1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptane-3-carbonitrile (1.00 eq, 110 mg, 0.328 mmol) andm-toluidine (1.20 eq, 42 mg, 0.394 mmol) in toluene (2mL), was added trimethylaluminum (1.20 eq, 0.20 mL, 0.394 mmol) at 0oC. The mixture was heated and stirred at 90　oC. After 16h, the reaction mixture was quenched with distilled water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (100% DCM to 50% MeOH in DCM) to afford　(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamidine (66 mg,0.149 mmol, 45% yield) as a yellow oil.

[1240] MS (ESI, m / z): 443.2 [M+H]+

[1241] 1H NMR (400 MHz, CDCl3) δ 7.20 (br, d, J = 7.7 Hz, 1H), 7.15 (s, 1H), 6.98 - 6.71 (m, J = 24.4 Hz, 4H), 4.63 - 4.16 (m, J = 68.1 Hz, 1H), 2.97 (s, 1H), 2.30 (s, 3H), 2.22 - 2.11 (m, 1H), 1.85 - 1.38 (m, 5H).

[1242] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(m-tolyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane. To a solution of (1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamidine (1.00 eq, 32 mg, 0.0727 mmol) in 2-propanol (2 mL), were added sodium carbonate (3.00 eq, 23 mg, 0.218 mmol) and 2-chloroacetaldehyde (2.00 eq, 25 mg, 0.145 mmol) at 23oC. The reaction mixture was heated and stirred at 100 　oC. After 12 h, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by prep HPLC to afford (1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-3-[1-(m-tolyl)imidazol-2-yl]-2-azabicyclo[2.2.1]heptane (6.0 mg,0.0129 mmol, 18 % yield) as a white solid.

[1243] MS (ESI, m / z): 467.2 [M+H]+

[1244] 1H NMR (400 MHz, CDCl3) δ 7.38 (t,　J　= 7.6 Hz, 1H), 7.31 - 7.24 (m,　J　= 7.9 Hz, 3H), 7.07 - 6.98 (m,　J　= 13.2 Hz, 2H), 6.93 (s, 1H), 6.81 (s, 1H), 4.55 (s, 1H), 4.46 (s, 1H), 2.84 (s, 1H), 2.54 (s, 1H), 2.42 (s, 4H), 1.82 - 1.41 (m, 5H).

[1245]

[1246] Example 180: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane

[1247]

[1248] The title product was afforded by a procedure similar to that described for the synthesis of Example 179 using 4-(trifluoromethyl)pyridin-2-amine instead ofm-toluidine.

[1249] MS (ESI, m / z): 522.1 [M+H]+

[1250] 1H NMR (400 MHz, CDCl3) δ 8.30 (t,　J　= 7.8 Hz, 1H), 7.94 (d,　J　= 7.7 Hz, 1H), 7.78 (d,　J　= 8.1 Hz, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 6.99 (s, 1H), 6.95 (s, 1H), 4.70 (s, 1H), 4.64 (s, 1H), 3.22 (s, 1H), 2.64 (d,　J　= 10.5 Hz, 1H), 2.05 - 1.51 (m, 5H).

[1251]

[1252] Example 181: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(5-chloro-1-(2-chloro-5-methylphenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane

[1253] Example 182: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(5-chloro-1-(m-tolyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane

[1254]

[1255] To a stirred solution of example 179 (1.00 eq, 18 mg, 0.0386 mmol) in dichloromethane (1 mL), were added N-chlorosuccinimide (1.50 eq, 7.7 mg, 0.0579 mmol) and acetic acid (2.00 eq, 4.6 mg, 0.0772 mmol) at 23 °C. The mixture was heated to 60 　°C. After 12h, the mixture was concentrated under reduced pressure. The crude residue was purified by preparative HPLC to afford example 181 (5.5 mg,0.0103 mmol, 27 % yield) and example 182 (2.0 mg,0.00399 mmol, 10% yield).

[1256] MS (ESI, m / z): 535.1 [M+H]+

[1257] 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.5 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.41 - 7.32 (m, J = 6.5 Hz, 3H), 7.17 - 7.13 (m, 1H), 7.11 (s, 1H), 7.02 (s, 1H), 2.66 (s, 1H), 2.57 (s, 1H), 2.49 (s, 3H), 1.85 - 1.14 (m, 5H).

[1258] MS (ESI, m / z): 501.1 [M+H]+

[1259] 1H NMR (400 MHz, CDCl3) δ 7.49 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.35 (s, 1H), 7.12 (s, 1H), 7.08 (s, 1H), 6.85 (s, 1H), 4.45 (s, 1H), 4.40 (s, 1H), 2.50 (s, 1H), 2.46 (s, 3H), 2.41 (d, J = 9.9 Hz, 1H), 1.80 - 1.66 (m, 2H), 1.54 (t, J = 9.3 Hz, 2H), 1.16 (t, J = 8.8 Hz, 1H).

[1260]

[1261] Example 183: 2-((1R,3S,4S)-3-(5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile

[1262]

[1263] Synthesis of 2-(tert-butyl) 3-(2-oxo-2-phenylethyl) (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate. To a stirred solution of　(1R,3S,4S)-2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.0 eq, 241 mg, 1.0 mmol) and　2-bromo-1-phenyl-ethanone (1.0 eq, 199 mg, 1.0 mmol) in　dimethylformamide (5 mL) was added　Et3N (2.0 eq, 0.28 mL, 2.00 mmol). The reaction was stirred at　30 　oC for　1 h . Then, the reaction mixture was diluted with EtOAc (20 mL), washed with brine (2 X 20 mL), dried over anhydrous MgSO4, filtered with the Celite cake, concentrated under reduced pressure, and dried in vacuo to give the desired product as a pale brown solid (yield, 99%). The crude product was then used for the next step reaction without further purifications.

[1264] MS (ESI, m / z): 360.1 [M+H]+

[1265] Synthesis of tert-butyl (1R,3S,4S)-3-(5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. A stirred mixture of　O2-tert-butyl O3-phenacyl (1R,3S,4S)-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (1.0 eq, 355 mg, 1.0 mmol) and　NH4OAc (3.0 eq, 228 mg, 3.0 mmol) in　toluene (5 mL) was heated to　110　oC for　12 h . After cooling to room temperature, the reaction mixture was diluted with water (10 mL), extracted with EtOAc (15 mL X 2), washed with brine, dried over anhydrous MgSO4, filtered with the Celite cake, concentrated under reduced pressure, separated from the flash column chromatography (EtOAc / n-Hex, 1 / 3), and dried in vacuo to give the desired product as a white solid (yield, 76%).

[1266] MS (ESI, m / z): 340.1 [M+H]+

[1267] Synthesis of (1R,3S,4S)-3-(5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane. To a mixture of　tert-butyl (1R,3S,4S)-3-(5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.0 eq, 120 mg, 0.35 mmol) in　dichloromethane (3.5 mL) was added　2,2,2-trifluoroacetic acid (5.0 eq, 202 mg, 1.77 mmol) slowly. The reaction was stirred at　25 　oC　for　5 h . And the reaction mixture was concentrated under reduced pressure and dried in vacuo to give the desired product as a pale yellow solid (yield, 99%). The product was then used for the next step reaction without further purifications.

[1268] MS (ESI, m / z): 240.1 [M+H]+

[1269] Synthesis of 2-((1R,3S,4S)-3-(5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile. A mixture of (1R,3S,4S)-3-(5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane (1.0 eq, 24 mg, 0.1 mmol), 2-chloro-4,6-bis(trifluoromethyl)pyridine-3-carbonitrile (1.0 eq, 27 mg, 0.1 mmol), and K2CO3 (2.0 eq, 28 mg, 0.2 mmol) in dimethylformamide (0.5 mL) was heated to 60oC with stirring for 2 h . After cooling to room temperature, the reaction mixture was quenched with NaHCO3 (aq.), diluted with MeOH, separated from the Prep HPLC, and dried in vacuo to give the desired product as a white solid (yield, 63%).

[1270] MS (ESI, m / z): 478.1 [M+H]+

[1271] 1H NMR (400 MHz, cd3od) δ 7.78 (s, 1H), 7.74 - 7.61 (m, 2H), 7.49 (ddd,J= 12.0, 8.0, 3.3 Hz, 4H), 5.53 (s, 1H), 5.18 (s, 1H), 2.98 (s, 1H), 2.16 - 1.93 (m, 4H), 1.83 (m, 2H).

[1272]

[1273] Example 184: 6-methyl-2-((1R,3S,4S)-3-(5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4-(trifluoromethyl)nicotinonitrile

[1274]

[1275] The title product was afforded by a procedure similar to that described for the synthesis of Example 184 using 2-chloro-6-methyl-4-(trifluoromethyl)pyridine-3-carbonitrile instead of 2-chloro-4,6-bis(trifluoromethyl)pyridine-3-carbonitrile in step d.

[1276] MS (ESI, m / z): 424.1 [M+H]+

[1277] 1H NMR (400 MHz, cd3od) δ 7.76 (d,　J　= 5.8 Hz, 1H), 7.74 - 7.65 (m, 2H), 7.57 - 7.37 (m, 3H), 7.06 (s, 1H), 5.49 (s, 1H), 5.21 (s, 1H), 2.93 (s, 1H), 2.31 (s, 3H), 1.97 (m, 4H), 1.85 - 1.70 (m, 2H).

[1278]

[1279] Example 185: 2-((1R,3S,4S)-3-(1-isopropyl-5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile

[1280]

[1281] To a stirred mixture of　2-[(1R,3S,4S)-3-(5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl]-4,6-bis(trifluoromethyl)pyridine-3-carbonitrile (1.0 eq, 22 mg, 0.05 mmol) and　NaH (2.0 eq, 20 mg, 0.1 mmol) in　dimethylformamide (0.9 mL) was added　2-iodopropane (1.2 eq, 9.4 mg, 0.055 mmol) slowly. The reaction was stirred at　60 　oC for overnight. After cooling to room temperature, the reaction mixture was quenched with NaHCO3 (aq.), concentrated under reduced pressure, separated from the Prep HPLC, and dried in vacuo to give the desired product as a pale yellow solid (yield, 62%).

[1282] MS (ESI, m / z): 520.1 [M+H]+

[1283] 1H NMR (600 MHz, cd3od) δ 7.67 (t,　J　= 7.0 Hz, 2H), 7.51 (t,　J　= 7.4 Hz, 2H), 7.49 - 7.43 (m, 1H), 6.43 (s, 1H), 5.41 (s, 1H), 5.10 (s, 1H), 2.87 (d,　J　= 3.6 Hz, 1H), 2.01 - 1.86 (m, 4H), 1.74 - 1.62 (m, 2H).

[1284]

[1285] Example 186: 2-((1R,3S,4S)-3-(1-methyl-5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile

[1286]

[1287] The title product was afforded by a procedure similar to that described for the synthesis of Example 185 using iodomethane instead of 2-iodopropane.

[1288] MS (ESI, m / z): 492.1 [M+H]+

[1289] 1H NMR (600 MHz, cd3od) δ 7.69 (m, 2H), 7.50 (m, 2H), 7.48 - 7.42 (m, 1H), 6.41 (s, 1H), 5.40 (s, 1H), 5.08 (s, 1H), 2.78 (s, 3H), 2.00 - 1.88 (m, 4H), 1.72 - 1.60 (m, 2H).

[1290]

[1291]

[1292] Example 187: 2-((1R,3S,4S)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile

[1293]

[1294] Synthesis of tert-butyl (1R,3S,4S)-3-((imino(phenyl)methyl)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To a solution of (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.0 eq, 240 mg, 1 mmol), benzimidamide (1.2 eq, 144 mg, 1.2 mmol) and HATU (1.1 eq, 419 mg, 1.1 mmol) in DMF (1.0mL) was added DBU (1.2 eq, 288 uL, 0.12 mmol) and stirred at 60oC for 4 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography (0~50% EA in Hx) to give the desired product. (yield, 57%).

[1295] Synthesis of tert-butyl (1R,3S,4S)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To a solution of tert-butyl (1R,3S,4S)-3-((imino(phenyl)methyl)carbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.0 eq, 34 mg, 0.1 mmol), NBS (1.2 eq, 21 mg, 0.12 mmol) in Ethyl acetate (1.0mL) was added DIPEA (3 eq, 18 mg, 3 mmol) and stirred at 25oC for 3 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography (0~50% EA in Hx) to give the desired product. (yield, 59%).

[1296] Synthesis of 5-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-3-phenyl-1,2,4-oxadiazole

[1297] To a solution of tert-butyl (1R,3S,4S)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1 eq, 40 mg, 0.11 mmol) in dichloromethane (1.0mL) was added TFA (10 eq, 84 uL, 1.1 mmol) and stirred at 25oC for 2 hour. The reaction mixture was concentrated in vacuo and used without further purification.

[1298] Synthesis of 2-((1R,3S,4S)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.1] heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile. To a solution of 5-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-3-phenyl-1,2,4-oxadiazole (1.0 eq, 24 mg, 0.1 mmol) and Cesium carbonate (2.0 eq, 65 mg, 0.2 mmol) in DMF (1.0mL) was added of 2-chloro-4,6-bis(trifluoromethyl)nicotinonitrile. (1.2 eq, 33 mg, 0.12 mmol) and stirred at 80oC for 16 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography give the desired product.

[1299] MS (ESI, m / z): 480.1 [M+H]+

[1300] 1H NMR (400 MHz,cd3od) δ 7.99 (dd,J = 8.1, 1.6 Hz, 2H), 7.54 - 7.47 (m, 3H), 7.31 (s, 1H), 5.51 (s, 1H), 5.17 (s, 1H), 2.94 (s, 1H), 2.41 (d,J = 11.2 Hz, 1H), 2.03 (t,J = 10.9 Hz, 3H), 1.80 (dd,J = 23.9, 10.6 Hz, 2H).

[1301]

[1302] Example 188: 5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-phenyl-1,2,4-oxadiazole

[1303]

[1304] The title product was afforded by a procedure similar to that described for the synthesis of Example 187 using 2-chloro-4,6-bis(trifluoromethyl)pyridine instead of 2-chloro-4,6-bis(trifluoromethyl)nicotinonitrile.

[1305] MS (ESI, m / z): 455.1 [M+H]+

[1306] 1H NMR (400 MHz,cd3od) δ 8.02 (d,J = 7.5 Hz, 2H), 7.54 - 7.47 (m, 3H), 7.20 (s, 1H), 7.15 (s, 1H), 4.94 (s, 1H), 4.75 (s, 1H), 2.96 (s, 1H), 2.29 (s, 1H), 1.95 (dt,J = 29.2, 11.1 Hz, 2H), 1.77 (d,J = 15.1 Hz, 1H), 1.71 (d,J = 10.1 Hz, 2H)

[1307]

[1308] Example 189: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-phenylpyrimidin-4(3H)-one

[1309]

[1310] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbonitrile. To a stirred solution of Example 83 (1.0eq, 100 mg 0.23 mmol) in pyridine (2.0mL) was added trifluoroacetic anhydride (3.0 eq, 100 μL, 0.71 mmol) and stirred at 25oC for 2 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography (0~50% EA in Hx) to give the desired product. (yield, 56%).

[1311] MS (ESI, m / z): 336.1 [M+H]+

[1312] Synthesis of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-phenyl-2-azabicyclo[2.2.1]heptane-3-carboximidamide. To a stirred solution of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbonitrile (1.0eq, 50 mg 0.15 mmol) and aniline (2.0 eq, 30 mg, 0.29 mmol) in toluene (1.0mL) was added AlMe3 (2.0 eq, 0.15 mL, 0.29 mmol) and stirred at 90oC for 2 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography (0~20% MeOH in MC) to give the desired product. (yield, 68%).

[1313] MS (ESI, m / z): 429.1 [M+H]+

[1314] Synthesis of 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-phenylpyrimidin-4(3H)-one. To a stirred solution of (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-phenyl-2-azabicyclo[2.2.1]heptane-3-carboximidamide (1.0eq, 32 mg 0.07 mmol) in ethanol (1.0mL) was added ethyl propiolate (1.5 eq, 10 mg, 0.11 mmol) and stirred at 90oC for 16 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified by prep-HPLC to give the desired product. (yield, 28%).

[1315] MS (ESI, m / z): 481.1 [M+H]+

[1316] 1H NMR (600 MHz, cdcl3) δ 7.69 (s, 1H), 7.57 (d,　J　= 4.5 Hz, 3H), 7.31 (d,　J　= 7.6 Hz, 2H), 6.98 (s, 1H), 6.76 (s, 1H), 6.19 (d,　J　= 7.5 Hz, 1H), 4.39 (s, 1H), 4.02 (s, 1H), 2.90 (d,　J　= 9.8 Hz, 1H), 2.66 - 2.59 (m, 1H), 1.79 - 1.64 (m, 3H), 1.51 (d,　J　= 11.4 Hz, 1H), 1.43 (t,　J　= 10.1 Hz, 1H).

[1317]

[1318] Example 190: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(p-tolyl)pyrimidin-4(3H)-one

[1319]

[1320] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 usingp-toluidine instead of aniline.

[1321] MS (ESI, m / z): 495.1 [M+H]+

[1322] 1HNMR(600 MHz,cdcl3) δ 7.53 (s, 1H), 7.38 (d,J = 8.1 Hz, 1H), 7.34 (d,J = 8.2 Hz, 1H), 7.28 (d,J = 7.6 Hz, 1H), 7.19 (s, 1H), 6.96 (s, 1H), 6.74 (s, 1H), 6.17 (d,J = 7.6 Hz, 1H), 4.38 (s, 1H), 4.03 (s, 1H), 2.90 (d,J = 9.1 Hz, 1H), 2.62 (s, 1H), 2.44 (s, 3H), 2.23 - 2.19 (m, 1H), 2.00 (d, J = 6.4 Hz, 1H), 1.72 (d,J = 8.2 Hz, 1H), 1.62 (d,J = 7.3 Hz, 1H), 1.52 (d,J = 9.3 Hz, 1H)

[1323]

[1324] Example 191: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(m-tolyl)pyrimidin-4(3H)-one

[1325]

[1326] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 usingm-toluidine instead of aniline.

[1327] MS (ESI, m / z): 495.1 [M+H]+

[1328] 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 7.4 Hz, 1H), 7.53 - 7.44 (m, J = 12.3, 4.6 Hz, 2H), 7.41 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 7.02 (s, 1H), 6.81 (s, 1H), 6.63 (d, J = 7.4 Hz, 1H), 4.39 (s, 1H), 4.10 (d, J = 18.2 Hz, 1H), 2.70 (s, 2H), 2.45 (d, J = 10.7 Hz, 3H), 1.83 - 1.66 (m, 2H), 1.53 (t, J = 9.6 Hz, 1H), 1.46 (d, J = 9.7 Hz, 1H), 1.00 (s, 1H).

[1329]

[1330] Example 192: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(o-tolyl)pyrimidin-4(3H)-one

[1331]

[1332] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 usingo-toluidine instead of aniline.

[1333] MS (ESI, m / z): 495.1 [M+H]+

[1334] 1H NMR (600 MHz, cdcl3) δ 7.49 - 7.35 (m, 4H), 7.18 (d, J = 3.3 Hz, 1H), 7.00 (s, 1H), 6.78 (s, 1H), 6.22 (d, J = 7.5 Hz, 1H), 4.39 (s, 1H), 2.76 (d, J = 123.4 Hz, 1H), 2.49 (s, 2H), 2.27 - 2.20 (m, 3H), 2.01 (s, 1H), 1.72 (s, 1H), 1.67 - 1.57 (m, 3H).

[1335]

[1336] Example 193: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(4-fluorophenyl) pyrimidin-4(3H)-one

[1337]

[1338] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using 4-fluoroaniline instead of aniline.

[1339] MS (ESI, m / z): 495.1 [M+H]+

[1340] 1H NMR (600 MHz, cdcl3) δ 7.70 (s, 1H), 7.32 (s, 1H), 7.27 (s, 2H), 6.99 (s, 1H), 6.77 (s, 1H), 6.19 (d,　J　= 7.6 Hz, 1H), 4.40 (s, 1H), 3.99 (s, 1H), 2.91 (d,　J　= 9.8 Hz, 1H), 2.60 (s, 1H), 1.74 (dt,　J　= 11.8, 9.6 Hz, 2H), 1.43 (d,　J　= 9.6 Hz, 1H), 1.02 (t,　J　= 10.5 Hz, 1H).

[1341]

[1342] Example 194: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-chlorophenyl) pyrimidin-4(3H)-one

[1343]

[1344] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using 3-chloroaniline instead of aniline.

[1345] MS (ESI, m / z): 515.1[M+H]+

[1346] 1H NMR (600 MHz, cdcl3) δ 7.56 (td, J = 8.9, 5.7 Hz, 2H), 7.27 (ddddd, J = 6.5, 2.4, 1.8, 1.2, 0.6 Hz, 2H), 7.25 (ddq, J = 3.5, 1.8, 0.6 Hz, 1H), 6.99 (s, 1H), 6.77 (s, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.40 (s, 1H), 3.99 (d, J = 21.9 Hz, 1H), 2.90 (d, J = 9.9 Hz, 1H), 2.64 (s, 1H), 1.77 (d, J = 9.8 Hz, 2H), 1.44 (d, J = 10.0 Hz, 1H), 1.05 (s, 1H).

[1347]

[1348] Example 195: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(4-fluoro-3-methylphenyl) pyrimidin-4(3H)-one

[1349]

[1350] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using 4-fluoro-3-methylaniline instead of aniline.

[1351] MS (ESI, m / z): 513.1 [M+H]+

[1352] 1H NMR (600 MHz, cdcl3) δ 7.52 (d,　J　= 6.9 Hz, 1H), 7.26 - 7.25 (m, 1H), 7.20 - 7.09 (m, 2H), 6.98 (s, 1H), 6.77 (s, 1H), 6.18 (d,　J　= 7.5 Hz, 1H), 4.40 (s, 1H), 4.02 (d,　J　= 27.2 Hz, 1H), 2.90 (d,　J　= 10.1 Hz, 1H), 2.62 (s, 1H), 2.36 (d,　J　= 17.3 Hz, 3H), 1.80 - 1.69 (m, 3H), 1.63 (d,　J　= 6.8 Hz, 1H), 1.53 (s, 1H), 1.43 (d,　J　= 10.0 Hz, 1H).

[1353]

[1354] Example 196: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3,4-difluorophenyl) pyrimidin-4(3H)-one

[1355]

[1356] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using 3,4-difluoroaniline instead of aniline.

[1357] MS (ESI, m / z): 517.1 [M+H]+

[1358] 1HNMR(600 MHz,cdcl3) δ 7.56 (d,J = 58.9 Hz, 1H), 7.41 (dd,J = 17.5, 9.0 Hz, 1H), 7.26 -7.25 (m, 1H), 7.19 (d,J = 60.5 Hz, 1H), 7.00 (s, 1H), 6.78 (s, 1H), 6.19 (d,J = 7.6 Hz, 1H), 4.41 (s, 1H), 3.98 (d,J = 19.3 Hz, 1H), 2.89 (s, 1H), 2.61 (s, 1H), 1.79 (t,J = 10.5 Hz, 2H), 1.56 - 1.53 (m, 1H), 1.45 (d,J = 9.9 Hz, 1H), 1.30 (s, 1H).

[1359]

[1360] Example 197: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-chloro-4-fluorophenyl) pyrimidin-4(3H)-one

[1361]

[1362] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using 3-chloro-4-fluoroaniline instead of aniline.

[1363] MS (ESI, m / z): 533.1 [M+H]+

[1364] 1HNMR(600 MHz,cdcl3) δ 7.72 (d,J = 107.0 Hz, 1H), 7.40 - 7.33 (m, 1H), 7.26 (s, 1H), 7.25 (s, 1H), 7.00 (s, 1H), 6.78 (s, 1H), 6.20 (d,J = 7.6 Hz, 1H), 4.41 (s, 1H), 3.97 (d,J = 24.2 Hz, 1H), 2.90 (d,J = 9.7 Hz, 1H), 2.63 (s, 1H), 1.79 (d,J = 8.7 Hz, 2H), 1.56 (s, 1H), 1.46 (d,J = 9.7 Hz, 1H), 1.31 (s, 1H).

[1365]

[1366] Example 198: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(4-fluoro-3-methoxyphenyl)pyrimidin-4(3H)-one

[1367]

[1368] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using 4-fluoro-3-methoxyaniline instead of aniline.

[1369] MS (ESI, m / z): 529.1 [M+H]+

[1370] 1H NMR (600 MHz, cdcl3) δ 7.29 (t,　J　= 7.7 Hz, 1H), 7.26 (s, 1H), 7.25 - 7.20 (m, 1H), 6.97 (d,　J　= 14.4 Hz, 1H), 6.92 - 6.84 (m, 1H), 6.77 (s, 1H), 6.18 (dd,　J　= 7.5, 3.6 Hz, 1H), 4.40 (s, 1H), 4.03 (d,　J　= 23.8 Hz, 1H), 3.94 (d,　J　= 12.5 Hz, 3H), 2.88 (dd,　J　= 38.4, 9.7 Hz, 1H), 2.65 (s, 1H), 2.04 - 1.97 (m, 1H), 1.82 - 1.70 (m, 2H), 1.67 - 1.60 (m, 1H), 1.43 (t,　J　= 8.6 Hz, 1H).

[1371]

[1372] Example 199: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(4-chloro-3-methoxyphenyl)pyrimidin-4(3H)-one

[1373]

[1374] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using 4-chloro-3-methoxyaniline instead of aniline.

[1375] MS (ESI, m / z): 545.1 [M+H]+

[1376] 1H NMR (600 MHz, cdcl3) δ 7.57 (dd, J = 16.3, 8.4 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.15 (s, 1H), 6.97 (d, J = 17.7 Hz, 1H), 6.87 (dd, J = 8.6, 6.2 Hz, 1H), 6.77 (s, 1H), 6.19 (d, J = 7.6 Hz, 1H), 4.40 (d, J = 2.4 Hz, 1H), 4.04 (d, J = 27.8 Hz, 1H), 3.96 (s, 1H), 3.95 (s, 2H), 3.49 (d, J = 4.3 Hz, 3H), 2.66 (d, J = 14.3 Hz, 1H), 1.82 - 1.71 (m, 2H), 1.45 - 1.42 (m, 1H).

[1377]

[1378] Example 200: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3,4-dichlorophenyl) pyrimidin-4(3H)-one

[1379]

[1380] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using 3,4-dichloroaniline instead of aniline.

[1381] MS (ESI, m / z): 549.0 [M+H]+

[1382] 1H NMR (400 MHz, cdcl3) δ 7.86 - 7.42 (m, 3H), 7.22 (d, J = 13.4 Hz, 2H), 6.99 (s, 1H), 6.78 (s, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.41 (s, 1H), 3.97 (d, J = 15.3 Hz, 1H), 2.90 (d, J = 10.1 Hz, 1H), 2.64 (s, 1H), 1.79 (d, J = 9.4 Hz, 2H), 1.46 (d, J = 10.1 Hz, 1H), 1.30 (s, 2H).

[1383]

[1384] Example 201: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-methoxyphenyl) pyrimidin-4(3H)-one

[1385]

[1386] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using 3-methoxyaniline instead of aniline.

[1387] MS (ESI, m / z): 511.1 [M+H]+

[1388] 1H NMR (600 MHz, cdcl3) δ 7.44 (d,　J　= 12.9 Hz, 1H), 7.31 (d,　J　= 7.5 Hz, 1H), 7.15 (s, 1H), 7.08 (d,　J　= 6.1 Hz, 1H), 6.96 (d,　J　= 9.5 Hz, 1H), 6.91 - 6.82 (m, 1H), 6.76 (s, 1H), 6.18 (d,　J　= 7.5 Hz, 1H), 4.39 (s, 1H), 4.07 (d,　J　= 25.9 Hz, 1H), 3.87 (d,　J　= 13.1 Hz, 3H), 2.88 (s, 1H), 2.67 (s, 1H), 2.01 (d,　J　= 6.1 Hz, 1H), 1.76 (d,　J　= 12.1 Hz, 2H), 1.62 (s, 1H), 1.42 (d,　J　= 9.8 Hz, 1H).

[1389]

[1390] Example 202: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin-4(3H)-one

[1391]

[1392] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using 6-(trifluoromethyl)pyridin-2-amine instead of aniline.

[1393] MS (ESI, m / z): 550.1 [M+H]+

[1394] 1H NMR (400 MHz, CDCl3) δ 8.26 (t,　J　= 7.9 Hz, 1H), 7.91 (d,　J　= 7.8 Hz, 1H), 7.78 (d,　J　= 8.0 Hz, 1H), 7.53 (d,　J　= 7.7 Hz, 1H), 6.92 (s, 1H), 6.75 (s, 1H), 6.43 (d,　J　= 7.6 Hz, 1H), 4.37 (s, 1H), 3.69 (s, 1H), 3.19 (s, 1H), 2.96 (d,　J　= 10.5 Hz, 1H), 1.90 - 1.09 (m, 5H).

[1395]

[1396] Example 203: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(6-methylpyridin-2-yl)pyrimidin-4(3H)-one

[1397]

[1398] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using 6-methylpyridin-2-amine instead of aniline.

[1399] MS (ESI, m / z): 496.1 [M+H]+

[1400] 1H NMR (600 MHz, cdcl3) δ 7.87 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 6.74 (s, 1H), 6.20 (d, J = 7.6 Hz, 1H), 5.34 (dd, J = 4.2, 1.4 Hz, 1H), 3.93 (p, J = 5.3 Hz, 1H), 3.72 - 3.68 (m, 1H), 3.60 (dd, J = 11.5, 5.7 Hz, 1H), 3.14 (s, 1H), 2.62 (s, 3H), 2.34 (d, J = 7.6 Hz, 2H), 2.21 (d, J = 7.7 Hz, 2H).

[1401]

[1402] Example 204: 3-(benzofuran-7-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one

[1403]

[1404] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using benzofuran-7-amine instead of aniline.

[1405] MS (ESI, m / z): 521.1 [M+H]+

[1406] 1H NMR (600 MHz, cdcl3) δ 7.79 (d,　J　= 7.2 Hz, 1H), 7.74 (d,　J　= 2.1 Hz, 1H), 7.64 (d,　J　= 7.6 Hz, 1H), 7.43 (dd,　J　= 9.7, 5.9 Hz, 1H), 7.34 (d,　J　= 7.6 Hz, 1H), 7.00 - 6.94 (m, 2H), 6.75 (s, 1Hf), 6.25 (d,　J　= 7.6 Hz, 1H), 4.35 (s, 1H), 4.02 (s, 1H), 2.89 (d,　J　= 9.3 Hz, 1H), 2.61 (s, 1H), 2.24 - 2.18 (m, 2H), 2.01 (dd,　J　= 12.1, 6.3 Hz, 2H).

[1407]

[1408] Example 205: 3-(benzofuran-6-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one

[1409]

[1410] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using benzofuran-6-amine instead of aniline.

[1411] MS (ESI, m / z): 521.1 [M+H]+

[1412] 1H NMR (400 MHz, cdcl3) δ 7.88 - 7.73 (m, 3H), 7.61 - 7.48 (m, 1H), 7.38 - 7.16 (m, 2H), 6.98 (s, 1H), 6.89 (dd, J = 5.4, 2.2 Hz, 1H), 6.74 (s, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.38 (s, 1H), 4.06 (d, J = 20.9 Hz, 1H), 2.91 (t, J = 11.2 Hz, 1H), 2.68 (s, 1H), 1.75 - 1.59 (m, 3H), 1.48 (t, J = 10.4 Hz, 1H), 1.44 - 1.36 (m, 1H).

[1413]

[1414] Example 206: 3-(benzofuran-5-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one

[1415]

[1416] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using benzofuran-5-amine instead of aniline.

[1417] MS (ESI, m / z): 521.1 [M+H]+

[1418] 1H NMR (400 MHz, cdcl3) δ 7.94 (s, 1H), 7.79 (s, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.56 (s, 1H), 7.37 - 7.32 (m, 1H), 7.22 (d, J = 6.6 Hz, 1H), 6.98 (s, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.20 (d, J = 7.6 Hz, 1H), 4.38 (s, 1H), 4.09 - 4.01 (m, 2H), 2.91 (s, 1H), 2.65 (s, 1H), 2.20 (dd, J = 16.8, 9.3 Hz, 1H), 2.01 (s, 1H), 1.47 (s, 1H), 1.41 (d, J = 9.6 Hz, 1H).

[1419]

[1420] Example 207: 3-(benzo[d]oxazol-5-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one

[1421]

[1422] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using benzo[d]oxazol-5-amine instead of aniline.

[1423] MS (ESI, m / z): 522.1 [M+H]+

[1424] 1H NMR (600 MHz, cdcl3) δ 8.27 (d,　J　= 6.7 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.35 (dd,　J　= 10.5, 7.4 Hz, 1H), 6.99 (s, 1H), 6.76 (d,　J　= 12.4 Hz, 1H), 6.23 (d,　J　= 7.6 Hz, 1H), 4.39 (s, 1H), 4.01 (d,　J　= 5.2 Hz, 1H), 2.91 (t,　J　= 11.5 Hz, 1H), 2.67 (d,　J　= 8.0 Hz, 1H), 2.27 - 2.20 (m, 1H), 2.00 (q,　J　= 6.0 Hz, 1H), 1.73 (d,　J　= 12.2 Hz, 1H), 1.48 (s, 2H), 1.43 (d,　J　= 10.1 Hz, 1H).

[1425]

[1426] Example 208: 3-(benzo[d]thiazol-7-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one

[1427]

[1428] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using benzo[d]thiazol-7-amine instead of aniline.

[1429] MS (ESI, m / z): 538.1 [M+H]+

[1430] 1H NMR (600 MHz, cdcl3) δ 9.01 (d, J = 9.6 Hz, 1H), 8.34 (d, J = 8.2 Hz, 1H), 8.00 - 7.95 (m, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.03 (s, 1H), 6.79 (s, 1H), 6.28 (d, J = 7.6 Hz, 1H), 4.37 (s, 1H), 2.85 (d, J = 9.4 Hz, 1H), 2.39 (s, 1H), 2.25 - 2.20 (m, 1H), 2.01 (s, 1H), 1.74 - 1.60 (m, 3H), 1.51 - 1.41 (m, 3H).

[1431]

[1432] Example 209: 3-(benzo[d]thiazol-6-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one

[1433]

[1434] The title product was afforded by a procedure similar to that described for the synthesis of Example 189 using benzo[d]thiazol-6-amine instead of aniline.

[1435] MS (ESI, m / z): 538.1 [M+H]+

[1436] 1H NMR (600 MHz, cdcl3) δ 9.19 (d,　J　= 1.6 Hz, 1H), 8.35 - 8.29 (m, 2H), 7.48 (dd,　J　= 8.6, 2.2 Hz, 1H), 7.36 (dd,　J　= 7.6, 4.9 Hz, 1H), 7.00 (d,　J　= 5.1 Hz, 1H), 6.76 (s, 1H), 6.23 (d,　J　= 7.6 Hz, 1H), 4.39 (s, 1H), 4.02 (d,　J　= 43.2 Hz, 1H), 2.96 - 2.87 (m, 1H), 2.73 - 2.62 (m, 1H), 1.77 - 1.65 (m, 2H), 1.46 (dd,　J　= 23.0, 10.8 Hz, 2H), 1.35 - 1.27 (m, 1H).

[1437]

[1438] Example 210: 3-((1H-1,2,3-triazol-4-yl)methyl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one

[1439]

[1440] Preparation of (1R,3S,4S)-2-(4,6-bis(trifleoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboximidamide. To a stirred solution of (1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptane-3-carbonitrile (1.00 eq, 70 mg, 0.209 mmol) and ammonium chloride (2.00 eq, 22 mg, 0.418 mmol) in toluene (4 mL), was added trimethyl aluminum (2.00 eq, 0.21 mL, 0.418 mmol) at 0oC. The reaction mixture was heated at 90 　oC under microwave radiation. After 2h, the reaction mixture was quenched with DI water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0% to 20% MeOH in dichloromethane) to afford (1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptane-3-carboxamidine (90 mg,0.255 mmol, 99 % yield) as a colorless oil.

[1441] MS (ESI, m / z): 353.1 [M+H]+

[1442] 1H NMR (400 MHz, CDCl3) δ 9.36 (s, 2H), 8.22 (s, 2H), 6.91 (s, 1H), 4.55 (s, 1H), 4.46 (s, 1H), 1.99 - 1.84 (m, 2H), 1.84 - 1.74 (m, 1H), 1.73 - 1.59 (m, J = 11.5 Hz, 3H).

[1443] Preparation of 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one. To a stirred solution of ethyl 3-ethoxyacrylate (3.00 eq, 12 mg, 0.0852 mmol) in ethanol (3mL),　was added (1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptane-3-carboxamidine (1.00 eq, 10 mg, 0.0284 mmol) at 23oC. The reaction mixture was heated to 100 　oC. After 16h, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with brine (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was used without further purification.

[1444] Preparation of 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(prop-2-yn-1-yl)pyrimidin-4(3H)-one. To a stirred solution of 2-[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptan-3-yl]-1H-pyrimidin-6-one (1.00 eq, 60 mg, 0.148 mmol) in dimethylformamide (3 mL), were added potassium carbonate (3.00 eq, 62 mg, 0.445 mmol) and　1-(bromomethyl)-3-methyl-benzene (2.00 eq, 11 mg, 0.0609 mmol) at 23　oC. The mixture was heated to　60 　oC. After 16h , the reaction mixture was concentrated under reduced　pressure. The crude residue was purified by　prep HPLC to afford 2-[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptan-3-yl]-3-prop-2-ynyl-pyrimidin-4-one (27 mg,0.0610 mmol, 41% yield) as a yellow oil.

[1445] MS (ESI, m / z): 443.1 [M+H]+

[1446] 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 6.6 Hz, 1H), 7.02 (s, 1H), 6.88 (s, 1H), 6.37 (d, J = 6.5 Hz, 1H), 5.56 (d, J = 11.8 Hz, 1H), 5.02 - 4.89 (m, 1H), 4.68 (s, 1H), 4.49 (s, 1H), 2.83 (s, 2H), 2.36 (s, 1H), 1.95 - 1.88 (m, 2H).

[1447] Synthesis of 3-((1H-1,2,3-triazol-4-yl)methyl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one. To a stirred solution of　2-[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptan-3-yl]-3-prop-2-ynyl-pyrimidin-4-one (1.00 eq, 8.0 mg, 0.0181 mmol) in　dimethylformamide (1 mL), were added　ammonium chloride (5.00 eq, 4.8 mg, 0.0904 mmol),　sodium azide (5.00 eq, 5.9 mg, 0.0904 mmol), and　copper iodide (1.00 eq, 3.4 mg, 0.0181 mmol) at 23oC. The solution was heated to　100 　oC. After　16 h ,　The reaction mixture was concentrated under reduced pressure.　　The crude residue was purified by prep HPLC to afford　2-[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptan-3-yl]-3-(1H-triazol-4-ylmethyl)pyrimidin-4-one (1.3 mg,0.00268 mmol, 15 % yield) as a white solid.

[1448] MS (ESI, m / z): 486.1 [M+H]+

[1449] 1H NMR (400 MHz, CDCl3) δ 7.96 - 7.83 (m, 1H), 7.28 - 7.22 (m, J = 13.1 Hz, 1H), 7.03 (s, 1H), 6.90 (s, 1H), 6.49 (d, J = 6.6 Hz, 1H), 5.78 (d, J = 13.8 Hz, 1H), 5.48 - 5.36 (m, 1H), 5.05 (s, 1H), 4.51 (s, 1H), 2.97 - 2.44 (m, J = 103.7 Hz, 5H), 2.01 - 1.76 (m, J = 54.4 Hz, 2H).

[1450]

[1451] Example 211: 2-((1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-chloro-4-fluorophenyl)pyrimidin-4(3H)-one

[1452]

[1453] Synthesis of methyl (1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylate. To a stirred solution of methyl (1S,3S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.0eq, 250 mg 1.3 mmol) in DMF (2.0mL) was added [4,6-bis(trifluoromethyl)-2-pyridyl] trifluoromethanesulfonate (1.0eq, 490 mg 1.3 mmol), DIPEA (3 eq, 0.7 mL, 4.0 mmol) and stirred at 110 oC for 12 hour. The reaction mixture was filtered and the organic layer was concentrated in vacuo and purified with column chromatography (0~80% EA in Hx) to give the desired product. (yield, 42%).

[1454] MS (ESI, m / z): 385.1 [M+H]+

[1455] Synthesis of (1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid. To a stirred solution of methyl (1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylate (1.0eq, 230 mg 0.58 mmol) in Methyl alcohol (2.5mL), Water (2.5mL) was added 2N NaOH solution (3 eq, 0.87 mL, 1.74 mmol) and stirred at 25 oC for 16 hour. The reaction mixture was concentrated in vacuo and adjusted pH=1~2 in water then solidified to give the desired product. (yield, 84%).

[1456] MS (ESI, m / z): 371.1 [M+H]+

[1457] Synthesis of (1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxamide. To a stirred solution of (1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.0eq, 70 mg 0.19 mmol), NH4Cl (6.0 eq, 60 mg, 1.1 mmol) and HATU (1.5 eq, 108 mg, 0.28 mmol) in DMF (2.0mL) was added DIPEA (3 eq, 99 uL, 0.56 mmol) and stirred at 60 oC for 4 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography (0~50% EA in Hx) to give the desired product. (yield, quant).

[1458] MS (ESI, m / z): 370.1 [M+H]+

[1459] Synthesis of (1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carbonitrile. To a stirred solution of (1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxamide (1.0eq, 90 mg, 0.24 mmol) in pyridine (2.0mL) was added Trifluoroacetic anhydride (3.0 eq, 103 μL, 0.73 mmol) and stirred at 25oC for 2 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography (0~50% EA in Hx) to give the desired product. (yield, 60%).

[1460] MS (ESI, m / z): 352.1 [M+H]+

[1461] Synthesis of (1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboximidamide. To a stirred solution of (1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carbonitrile (1.0eq, 20 mg 0.06 mmol) and 3-chloro-4-fluoroaniline (2.0 eq, 16 mg, 0.11 mmol) in toluene (1.0mL) was added AlMe3 (2.0 eq, 57 μL, 0.11 mmol) and stirred at 90oC for 2 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography (0~20% MeOH in MC) to give the desired product. (yield, 88%).

[1462] MS (ESI, m / z): 497.1 [M+H]+

[1463] Synthesis of 2-((1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-chloro-4-fluorophenyl)pyrimidin-4(3H)-one. To a stirred solution of (1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-5-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboximidamide (1.0eq, 25 mg 0.05 mmol) in ethanol (1.0mL) was added ethyl propiolate (1.5 eq, 7.5 mg, 0.08 mmol) and stirred at 90oC for 16 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified by prep-HPLC to give the desired product. (yield, 36%).

[1464] MS (ESI, m / z): 549.1 [M+H]+

[1465] 1H NMR (600 MHz, cdcl3) δ 7.70 (dd,　J　= 78.7, 7.4 Hz, 1H), 7.53 - 7.26 (m, 3H), 7.00 (s, 1H), 6.78 (d,　J　= 8.7 Hz, 1H), 6.20 (dd,　J　= 7.6, 2.1 Hz, 1H), 4.41 (s, 1H), 3.63 (d,　J　= 7.7 Hz, 1H), 2.84 - 2.78 (m, 1H), 2.60 (s, 1H), 2.02 - 1.96 (m, 1H), 1.92 (t,　J　= 8.3 Hz, 1H), 1.64 (d,　J　= 3.8 Hz, 3H), 1.60 (d,　J　= 13.6 Hz, 1H).

[1466]

[1467] Example 212: 3-(benzofuran-5-yl)-2-((1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one

[1468]

[1469] MS (ESI, m / z): 537.1 [M+H]+

[1470] The title product was afforded by a procedure similar to that described for the synthesis of Example 211 using o-toluidine instead of aniline.

[1471] 1H NMR (600 MHz, cdcl3) δ 7.92 (d,　J　= 2.2 Hz, 1H), 7.79 (dd,　J　= 4.0, 2.2 Hz, 1H), 7.68 (dd,　J　= 8.6, 4.8 Hz, 1H), 7.63 - 7.58 (m, 1H), 7.36 (dd,　J　= 7.5, 6.1 Hz, 1H), 7.00 (s, 1H), 6.89 (dd,　J　= 37.2, 2.2 Hz, 1H), 6.75 (s, 1H), 6.21 (dd,　J　= 7.6, 1.4 Hz, 1H), 4.39 (s, 1H), 3.92 (d,　J　= 32.1 Hz, 1H), 3.47 (dd,　J　= 15.8, 6.6 Hz, 1H), 2.84 (t,　J　= 11.9 Hz, 1H), 2.62 (d,　J　= 4.8 Hz, 1H), 2.11 - 1.97 (m, 1H), 1.95 - 1.86 (m, 2H), 1.54 (d,　J　= 13.6 Hz, 1H).

[1472]

[1473] Example 213: 2-((1S,3S,4S,5S,6R)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-5,6-dihydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-chloro-4-fluorophenyl)pyrimidin-4(3H)-one

[1474]

[1475] Synthesis of ethyl (3aR,4S,6S,7S,7aS)-5-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2,2-dimethylhexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine-6-carboxylate. To a stirred solution of ethyl (1S,2S,6R,7S,9S)-4,4-dimethyl-3,5-dioxa-8-azatricyclo[5.2.1.02,6]decane-9-carboxylate (1.00 eq, 480 mg, 1.99 mmol)　in Dimethylformamide (5mL)　was added [4,6-bis(trifluoromethyl)-2-pyridyl] trifluoromethanesulfonate (1.30 eq, 939 mg, 2.59 mmol) and　DIPEA (3.00 eq, 1.0 mL, 5.97 mmol)　at rt. The reaction was strirred at　110 　oC for　12h.　The resulting crude was concentrated to the dryness and purified by flash column chromatography to afford　the desired product (yield, 55%).

[1476] MS (ESI, m / z): 455.1 [M+H]+

[1477] Synthesis of (3aR,4S,6S,7S,7aS)-5-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2,2-dimethylhexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine-6-carboxylic acid. To a solution of ethyl (3aR,4S,6S,7S,7aS)-5-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2,2-dimethylhexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine-6-carboxylate (1.00 eq, 460 mg, 1.01 mmol) in Methyl alcohol (2 mL) was added 1N NaOH (2 mL) and stirred at 25oC for 3 hour. The solution was neutralized with 1N HCl to give the desired product quantitatively.

[1478] MS (ESI, m / z): 427.1 [M+H]+

[1479] Synthesis of (3aR,4S,6S,7S,7aS)-5-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2,2-dimethylhexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine-6-carboxamide. To a solution of (3aR,4S,6S,7S,7aS)-5-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2,2-dimethylhexahydro-4,7-methano[1,3]dioxolo[4,5-c]pyridine-6-carboxylic acid (1.0eq, 120 mg 0.28 mmol), NH4Cl (6.0 eq, 90 mg, 1.7 mmol) and HATU (1.5 eq, 160 mg, 0.42 mmol) in DMF (2.5mL) was added DIPEA (3 eq, 140 uL, 0.84 mmol) and stirred at 25 oC for 4 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography (0~50% EA in Hx) to give the desired product. (yield, 83%).

[1480] MS (ESI, m / z): 426.1 [M+H]+

[1481] Synthesis of (1S,2S,6R,7S,9S)-8-[4,6-bis(trifluoromethyl)-2-pyridyl]-4,4-dimethyl-3,5-dioxa-8-azatricyclo[5.2.1.02,6]decane-9-carbonitrile. To a stirred solution of (1S,2S,6R,7S,9S)-8-[4,6-bis(trifluoromethyl)-2-pyridyl]-4,4-dimethyl-3,5-dioxa-8-azatricyclo[5.2.1.02,6]decane-9-carboxamide (1.0eq, 100 mg, 0.24 mmol) in pyridine (2.0mL) was added Trifluoroacetic anhydride (3.0 eq, 100 μL, 0.70 mmol) and stirred at 25oC for 2 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography (0~50% EA in Hx) to give the desired product. (yield, 56%).

[1482] MS (ESI, m / z): 408.2 [M+H]+

[1483] Synthesis of (1S,2S,6R,7S,9S)-8-[4,6-bis(trifluoromethyl)-2-pyridyl]-N-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-3,5-dioxa-8-azatricyclo[5.2.1.02,6]decane-9-carboxamidine. To a stirred solution of (1S,2S,6R,7S,9S)-8-[4,6-bis(trifluoromethyl)-2-pyridyl]-4,4-dimethyl-3,5-dioxa-8-azatricyclo[5.2.1.02,6]decane-9-carbonitrile (1.0eq, 25 mg 0.06 mmol) and 3-chloro-4-fluoroaniline (2.0 eq, 17 mg, 0.12 mmol) in toluene (1.0mL) was added AlMe3 (2.0 eq, 61 μL, 0.12 mmol) and stirred at 90oC for 2 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography (0~20% MeOH in MC) to give the desired product. (yield, 88%).

[1484] MS (ESI, m / z): 553.1 [M+H]+

[1485] Synthesis of 2-[(1S,2S,6R,7S,9S)-8-[4,6-bis(trifluoromethyl)-2-pyridyl]-4,4-dimethyl-3,5-dioxa-8-azatricyclo[5.2.1.02,6]decan-9-yl]-3-(3-chloro-4-fluoro-phenyl)pyrimidin-4-one. To a stirred solution of (1S,2S,6R,7S,9S)-8-[4,6-bis(trifluoromethyl)-2-pyridyl]-N-(3-chloro-4-fluoro-phenyl)-4,4-dimethyl-3,5-dioxa-8-azatricyclo[5.2.1.02,6]decane-9-carboxamidine (1.0eq, 28 mg 0.05 mmol) in ethanol (1.0mL) was added ethyl propiolate (1.5 eq, 7.5 mg, 0.08 mmol) and stirred at 90oC for 16 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified by prep-HPLC to give the desired product. (yield, 58%).

[1486] MS (ESI, m / z): 605.1 [M+H]+

[1487] Synthesis of 2-((1S,3S,4S,5S,6R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5,6-dihydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-chloro-4-fluorophenyl)pyrimidin-4(3H)-one. To a solution of 2-[(1S,2S,6R,7S,9S)-8-[4,6-bis(trifluoromethyl)-2-pyridyl]-4,4-dimethyl-3,5-dioxa-8-azatricyclo[5.2.1.02,6]decan-9-yl]-3-(3-chloro-4-fluoro-phenyl)pyrimidin-4-one (1.00 eq, 33 mg, 0.05 mmol) in Ethanol (1mL) was added 2N HCl solution(5.00 eq, 10 μL, 0.25 mmol) at rt. The reaction mixture was stirred at rt. After 12 hours, the solution was concentrated under reduced pressure. The resulting crude was purified by prep-HPLC to give the desired product (yield, 26%)

[1488] MS (ESI, m / z): 565.1 [M+H]+

[1489] 1H NMR (600 MHz, cdcl3) δ 7.82 - 7.69 (m, 1H), 7.50 - 7.27 (m, 3H), 6.86 (d,　J　= 13.9 Hz, 1H), 6.76 (d,　J　= 7.4 Hz, 1H), 6.33 (dd,　J　= 7.7, 1.5 Hz, 1H), 5.85 (d,　J　= 20.4 Hz, 1H), 5.71 (s, 1H), 4.05 (d,　J　= 69.4 Hz, 1H), 3.75 - 3.64 (m, 2H), 3.49 (s, 1H), 2.76 (d,　J　= 10.8 Hz, 1H), 2.49 (d,　J　= 18.9 Hz, 1H), 2.21 (t,　J　= 9.1 Hz, 1H).

[1490]

[1491] Example 214: 2-((1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-azatricyclo[3.2.1.02,4]octan-7-yl)-3-(m-tolyl)pyrimidin-4(3H)-one

[1492]

[1493] Synthesis of (1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-azatricyclo[3.2.1.02,4]octane-7-carboxamide. To a stirred solution of (1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-azatricyclo[3.2.1.02,4]octane-7-carboxylic acid (1.0eq, 220 mg 0.6 mmol), NH4Cl (6.0 eq, 192 mg, 3.6 mmol) and HATU (1.5 eq, 342 mg, 0.9 mmol) in DMF (2.0mL) was added DIPEA (3 eq, 172 uL, 1.8 mmol) and stirred at 60oC for 4 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography (0~50% EA in Hx) to give the desired product. (yield, 75%).

[1494] Synthesis of (1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-azatricyclo[3.2.1.02,4]octane-7-carbonitrile. To a stirred solution of (1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-azatricyclo[3.2.1.02,4]octane-7-carboxamide (1.0eq, 180 mg 0.5 mmol) in pyridine (2.0mL) was added Trifluoroacetic anhydride (3.0 eq, 315 mg, 1.5 mmol) and stirred at 25oC for 16 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography (0~50% EA in Hx) to give the desired product. (yield, 72%).

[1495] Synthesis of (1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-6-azatricyclo[3.2.1.02,4]octane-7-carboximidamide. To a stirred solution of (1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-azatricyclo[3.2.1.02,4]octane-7-carbonitrile (1.0eq, 30 mg 0.09 mmol) and m-toluidine (2.0 eq, 19 mg, 0.18 mmol) in toluene (1.0mL) was added AlMe3 (2.0 eq, 13 mg, 0.18 mmol) and stirred at 90oC for 16 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography (0~10% MeOH in MC) to give the desired product. (yield, 54%).

[1496] Synthesis of 2-((1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-azatricyclo[3.2.1.02,4]octan-7-yl)-3-(m-tolyl)pyrimidin-4(3H)-one. To a stirred solution of (1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-6-azatricyclo[3.2.1.02,4]octane-7-carboximidamide (1.0eq, 20 mg 0.05 mmol) in ethanol (1.0mL) was added ethyl propiolate (1.5 eq, 7 mg, 0.075 mmol) and stirred at 90oC for 16 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL) and dried over anhydrous MgSO4. The organic extract was concentrated in vacuo and purified with column chromatography (0~10% EA in Hx) to give the desired product. (yield, 56%).

[1497] MS (ESI, m / z): 507.2 [M+H]+

[1498] 1H NMR (400 MHz,cd3od) δ 7.83 (s, 1H), 7.50 (s, 4H), 7.23 (s, 1H), 7.08 (s, 1H), 6.28 (s, 1H), 4.65 (s, 1H), 4.12 (s, 1H), 2.93 (s, 1H), 2.48 (d,J = 30.0 Hz, 3H), 2.21 - 2.17 (m, 1H), 1.63 - 1.58 (m, 1H), 1.29 (s, 2H), 0.90 (s, 1H), 0.72 (s, 1H), 0.55 (s, 1H), 0.31 - 0.25 (m, 1H).

[1499]

[1500] Example 215: 2-((1R,5S,7S)-6-(4,6-bis(trifluoromethyl) pyridin-2-yl)-6-azatricyclo[3.2.1.02,4]octan-7-yl)-3-(4-fluorophenyl) pyrimidin-4(3H)-one

[1501]

[1502] The title product was afforded by a procedure similar to that described for the synthesis of Example 214 using 4-fluoroaniline instead of m-toluidine.

[1503] MS (ESI, m / z): 511.1 [M+H]+

[1504] 1H NMR (400 MHz,cd3od) δ 7.89 (d,J = 7.7 Hz, 1H), 7.77 (s, 1H), 7.68 (s, 1H), 7.51 - 7.38 (m, 2H), 7.25 (s, 1H), 7.09 (s, 1H), 6.31 (d,J = 7.1 Hz, 1H), 4.68 (s, 1H), 4.12 (s, 1H), 2.94 (s, 1H), 2.18 (d,J = 11.4 Hz, 1H), 1.34 (d,J = 10.8 Hz, 1H), 1.29 (s, 1H), 0.73 (s, 1H), 0.60 (s, 1H), 0.30 (d,J = 6.4 Hz, 1H).

[1505]

[1506] Example 216: 3-(benzofuran-6-yl)-2-((1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-azatricyclo[3.2.1.02,4]octan-7-yl)pyrimidin-4(3H)-one

[1507]

[1508] The title product was afforded by a procedure similar to that described for the synthesis of Example 214 using benzofuran-6-amine instead of m-toluidine.

[1509] MS (ESI, m / z): 533.1 [M+H]+

[1510] 1H NMR (400 MHz,cd3od) δ 8.02 - 7.77 (m, 4H), 7.55 (s, 1H), 7.22 (s, 1H), 7.08 (s, 1H), 7.03 (s, 1H), 6.33 (d,J = 7.3 Hz, 1H), 4.64 (s, 1H), 4.16 (d,J = 18.3 Hz, 1H), 2.97 (s, 1H), 2.21 - 2.09 (m, 1H), 1.32 (d,J = 10.6 Hz, 1H), 1.24 (d,J = 25.4 Hz, 1H), 0.68 (s, 1H), 0.42 (d,J = 36.2 Hz, 1H), 0.22 (s, 1H).

[1511]

[1512] Example 217: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-(trifluoromethyl)-3-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin-4(3H)-one

[1513] Example 218: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-(trifluoromethyl)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin-4(1H)-one

[1514]

[1515] The title products were afforded by a similar procedure to that described for the synthesis of example 202 using ethyl 4,4,4-trifluorobut-2-ynoate instead of ethyl propiolate.

[1516] MS (ESI, m / z): 618.1 [M+H]+

[1517] 1H NMR (400 MHz, CDCl3) δ 8.22 (t,　J　= 7.9 Hz, 1H), 7.96 (d,　J　= 7.7 Hz, 1H), 7.92 (d,　J　= 7.9 Hz, 1H), 6.98 (s, 1H), 6.76 (s, 1H), 6.70 (s, 1H), 4.36 (s, 1H), 3.33 (s, 1H), 3.01 (s, 1H), 2.78 (d,　J　= 10.0 Hz, 1H), 1.80 - 1.36 (m, 5H).

[1518] MS (ESI, m / z): 618.1 [M+H]+

[1519] 1H NMR (400 MHz, CDCl3) δ 8.16 (t,　J　= 7.9 Hz, 1H), 7.86 (d,　J　= 7.7 Hz, 1H), 7.82 (d,　J　= 8.1 Hz, 1H), 6.96 (s, 1H), 6.79 (s, 1H), 6.76 (s, 1H), 4.37 (s, 1H), 3.46 (s, 1H), 3.20 (s, 1H), 2.73 (d,　J　= 9.8 Hz, 1H), 1.80 - 1.45 (m, 5H).

[1520]

[1521] Example 219: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(6-methylpyridin-2-yl)-6-(trifluoromethyl)pyrimidin-4(3H)-one

[1522]

[1523] The title product was afforded by a similar procedure to that described for the synthesis of example 217 using 6-methylpyridin-2-amine instead of 6-(trifluoromethyl)pyridin-2-amine.

[1524] MS (ESI, m / z): 564.1 [M+H]+

[1525] 1H NMR (400 MHz, CDCl3) δ 7.51 (d,　J　= 6.8 Hz, 1H), 7.43 (ddd,　J　= 16.7, 10.8, 5.1 Hz, 2H), 7.12 (d,　J　= 6.9 Hz, 1H), 6.99 (s, 1H), 6.78 (d,　J　= 1.9 Hz, 1H), 6.75 (s, 1H), 4.35 (s, 1H), 3.89 (s, 1H), 2.71 (d,　J　= 10.1 Hz, 1H), 2.57 (s, 1H), 2.43 (d,　J　= 15.1 Hz, 3H), 1.68 (tdd,　J　= 16.0, 11.2, 6.1 Hz, 2H), 1.50 (d,　J　= 6.1 Hz, 1H), 1.40 (s, 1H), 0.87 - 0.78 (m, 1H).

[1526]

[1527] Example 220: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-methyl-3-(m-tolyl)pyrimidin-4(3H)-one

[1528]

[1529] The title product was afforded by a similar procedure to that described for the synthesis of example 191 using ethyl 2-butynoate instead of ethyl propiolate.

[1530] MS (ESI, m / z): 509.2 [M+H]+

[1531] 1H NMR (400 MHz, CDCl3) δ 7.51 (t,　J　= 7.7 Hz, 1H), 7.41 (t,　J　= 7.1 Hz, 2H), 7.10 (d,　J　= 7.8 Hz, 1H), 7.00 (s, 1H), 6.78 (s, 1H), 6.60 (s, 1H), 4.38 (s, 1H), 3.99 (s, 1H), 2.73 (s, 1H), 2.61 (s, 1H), 2.47 (s, 1H), 2.43 (s, 2H), 2.06 (d,　J　= 4.8 Hz, 3H), 1.70 (dt,　J　= 25.8, 11.1 Hz, 2H), 1.50 (s, 1H), 1.40 (d,　J　= 10.0 Hz, 1H), 0.87 (d,　J　= 6.9 Hz, 1H).

[1532]

[1533] Example 221: 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-(3-methylbenzyl)-4H-1,2,4-oxadiazin-5(6H)-one

[1534]

[1535] Preparation of (1R,3S,4S,Z)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N'-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboximidamide. To a stirred solution of (1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptane-3-carbonitrile (1.00 eq, 150 mg, 0.447 mmol) in ethanol (3 mL), was added hydroxylamine (5.00 eq, 74 mg, 2.24 mmol) at 23 　oC. After completion of SM consumption, the reaction mixture was concentrated under reduced pressure. The crude was used directly to next step without further purification.

[1536] Preparation of 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-oxadiazin-5(6H)-one. To a stirred solution of　(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-N'-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxamidine (1.00 eq, 23 mg, 0.0625 mmol) in　dichloromethane (2 mL) and　tetrahydrofuran (2 mL), were added　2-chloroacetyl chloride (2.50 eq, 18 mg, 0.156 mmol),　sodium carbonate (3.50 eq, 23 mg, 0.219 mmol), and　sodium hydride (3.00 eq, 7.5 mg, 0.187 mmol) at 23oC. After 16h, the mixture was concentrated under reduced pressure. The crude residue was purified by prep HPLC to afford　3-[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptan-3-yl]-4H-1,2,4-oxadiazin-5-one (26 mg,0.0637 mmol, 99 % yield) as a white solid.

[1537] MS (ESI, m / z): 409.1 [M+H]+

[1538] 1H NMR (400 MHz, CDCl-3) δ 9.80 (s, 1H), 7.21 (s, 1H), 6.89 (s, 1H), 4.37 - 4.19 (m, 5H), 3.18 (s, 1H), 2.23 (d, J = 10.6 Hz, 1H), 1.94 - 1.75 (m, 3H), 1.71 - 1.63 (m, 3H), 1.46 - 1.39 (m, 1H).

[1539] Synthesis of 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-(3-methylbenzyl)-4H-1,2,4-oxadiazin-5(6H)-one.

[1540] To a stirred solution of 3-[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptan-3-yl]-4H-1,2,4-oxadiazin-5-one (1.00 eq, 13 mg, 0.0318 mmol) in dimethylformamide (1 mL), were added 1-(bromomethyl)-3-methyl-benzene (2.00 eq, 12 mg, 0.0637 mmol) and potassium carbonate (2.00 eq, 8.8 mg, 0.0637 mmol) at 23oC. The mixture was heated to 60 　oC. After 16 h , the mixture was concentrated under reduced pressure and purified by prep HPLC to afford 3-[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptan-3-yl]-4-(m-tolylmethyl)-1,2,4-oxadiazin-5-one (7.3 mg,0.0142 mmol, 44.74 % yield) as a white solid.

[1541] MS (ESI, m / z): 513.2 [M+H]+

[1542] 1H NMR (400 MHz, CDCl3) δ 7.26 - 7.21 (m, 2H), 7.10 (d,　J　= 7.5 Hz, 1H), 7.07 - 7.01 (m,　J　= 6.0 Hz, 3H), 5.56 (s, 1H), 4.83 (s, 1H), 4.44 - 4.07 (m, 4H), 2.45 (s, 1H), 2.33 (s, 3H), 1.97 (s, 1H), 1.69 (t,　J　= 11.4 Hz, 1H), 1.58 - 1.44 (m, 2H), 1.35 (d,　J　= 10.0 Hz, 1H).

[1543]

[1544] Example 222: 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-1,2,4-oxadiazol-5(4H)-one

[1545]

[1546] To a stirred solution of　(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-N'-hydroxy-2-azabicyclo[2.2.1]heptane-3-carboxamidine (1.00 eq, 50 mg, 0.136 mmol)　in acetonitrile (3 mL), were added　c1,1'-Carbonyldiimidazole (1.10 eq, 24 mg, 0.149 mmol) and　1,8-Diazabicyclo[5.4.0]undec-7-ene (3.00 eq, 62 mg, 0.407 mmol) at 23　oC. The mixture was heated to　35 　oC. After 16h, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by flash column chromatography (0 to 15% MeOH in dichloromethane) to afford　3-[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptan-3-yl]-4H-1,2,4-oxadiazol-5-one (61 mg,0.155 mmol, 113.96 % yield) as a white solid.

[1547] MS (ESI, m / z): 395.1 [M+H]+

[1548]

[1549] Example 223: 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-phenyl-1,2,4-oxadiazol-5(4H)-one

[1550]

[1551] To a stirred solution of　Example 222 (1.00 eq, 26 mg, 0.0659 mmol) in　1,2-dichloroethane (2mL), were added diphenyliodonium trifluoromethanesulfonate (1.50 eq, 43 mg, 0.0989 mmol),　N,N-Diisopropylethylamine (1.50 eq, 10 mg, 0.0989 mmol) and　copper(I) iodide (1.50 eq, 19 mg, 0.0989 mmol) at 23　oC. The mixture was heated to　60 　oC. After 16h, the mixture was concentrated under reduced pressure. The crude was purified prep HPLC to afford　3-[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptan-3-yl]-4-phenyl-1,2,4-oxadiazol-5-one (5 mg, 0.016 mmol, 16% yield) as a white solid.

[1552] MS (ESI, m / z): 471.1 [M+H]+

[1553] 1H NMR (400 MHz, cdcl3) δ 7.59 - 7.47 (m, 5H), 7.11 (s, 1H), 6.82 (s, 1H), 4.39 (s, 1H), 4.32 (s, 1H), 2.60 (s, 1H), 2.47 (d, J = 10.6 Hz, 1H), 1.79 (d, J = 8.5 Hz, 2H), 1.61 (d, J = 10.3 Hz, 2H), 1.23 (s, 1H).

[1554]

[1555] Example 224: 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-(3-methylbenzyl)-1,2,4-oxadiazol-5(4H)-one

[1556]

[1557] To a stirred solution of Example 222 (1.00 eq, 13 mg, 0.0318 mmol) in dimethylformamide (1 mL), were added 1-(bromomethyl)-3-methyl-benzene (2.00 eq, 12 mg, 0.0637 mmol) and potassium carbonate (2.00 eq, 8.8 mg, 0.0637 mmol) at 23oC. The mixture was heated to 60 　oC. After 16 h , the mixture was concentrated under reduced pressure and purified by prep HPLC to afford a desired product.

[1558] MS (ESI, m / z): 471.1 [M+H]+

[1559] 1H NMR (400 MHz, cdcl3) δ 7.27 (t,　J　= 7.5 Hz, 1H), 7.16 (d,　J　= 7.7 Hz, 1H), 7.13 - 7.07 (m, 3H), 6.78 (s, 1H), 5.11 (d,　J　= 15.8 Hz, 1H), 4.80 (d,　J　= 15.6 Hz, 1H), 4.27 (d,　J　= 43.6 Hz, 2H), 2.38 (d,　J　= 10.4 Hz, 1H), 2.34 (s, 3H), 1.98 (s, 1H), 1.80 - 1.70 (m, 1H), 1.61 (dd,　J　= 12.1, 7.4 Hz, 2H), 1.47 (d,　J　= 10.5 Hz, 1H), 1.09 (d,　J　= 10.8 Hz, 1H).

[1560]

[1561] Example 225: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane

[1562]

[1563] To a stirred solution of　2-[(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-2-azabicyclo[2.2.1]heptan-3-yl]-1H-pyrimidin-6-one (1.00 eq, 10 mg, 0.0247 mmol) in　toluene (2 mL), was added　phosphoryl trichloride (20.0 eq, 76 mg, 0.495 mmol) at 23oC. The solution was heated to　100 　oC. After 16h, the mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography (0% to 20% MeOH in dichloromethane) to afford　(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-3-(4-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane (4.0 mg,0.00946 mmol, 38.25 % yield) as a yellow solid.

[1564] MS (ESI, m / z): 423.1 [M+H]+

[1565] 1H NMR (400 MHz, CDCl3) δ 8.62 - 8.44 (m, 1H), 7.24 (s, 2H), 6.96 (s, 1H), 4.65 (s, 2H), 2.87 (s, 1H), 2.25 (s, 1H), 1.98 - 0.96 (m, 5H).

[1566]

[1567] Example 226: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)pyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane

[1568]

[1569] To a stirred solution of　Example 225 (1.00 eq, 15 mg, 0.0355 mmol) in　dimethylformamide (2 mL), were added　m-tolylboronic acid (1.50 eq, 7.2 mg, 0.0532 mmol),　XPhos (0.100 eq, 1.7 mg, 0.00355 mmol),　potassium carbonate (2.00 eq, 9.8 mg, 0.0710 mmol), and　Pd(OAc)2(0.100 eq, 0.80 mg, 0.00355 mmol) at 23oC.

[1570] The mixture was heated to　100 　oC. After 16h, the mixture was concentrated under reduced pressure and purified by preparative HPLC to afford　(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-3-[4-(m-tolyl)pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptane (2.0 mg,0.00418 mmol, 12 % yield) as a yellow solid.

[1571] MS (ESI, m / z): 479.2 [M+H]+

[1572] 1H NMR (400 MHz, cdcl3) δ 8.97 - 8.91 (m, J = 6.2 Hz, 1H), 8.05 - 8.00 (m, J = 5.8 Hz, 2H), 7.95 (d, J = 6.2 Hz, 1H), 7.50 - 7.46 (m, J = 4.9 Hz, 2H), 4.97 (s, 1H), 4.58 (s, 1H), 3.06 (d, J = 3.6 Hz, 1H), 2.49 (s, 3H), 2.16 (d, J = 10.3 Hz, 1H), 2.06 - 1.98 (m, J = 11.0 Hz, 1H), 1.92 (d, J = 11.3 Hz, 1H), 1.86 - 1.78 (m, 2H), 1.59 (d, J = 10.9 Hz, 1H).

[1573]

[1574] Example 227: (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-methylpiperazin-1-yl)pyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane

[1575]

[1576]

[1577] To a stirred　solution of Example 225 (1.00 eq, 11 mg, 0.0260 mmol)　in dimethylformamide (1 mL) and ethanol (1mL),　was added 1-methylpiperazine (5.00 eq, 14 uL, 0.130 mmol) at　23　oC. The reaction mixture was heated to 80 　oC. After 16h, the mixture was concentrated under reduced pressure. The crude residue was purified by preparative HPLC to afford　(1R,3S,4S)-2-[4,6-bis(trifluoromethyl)-2-pyridyl]-3-[4-(4-methylpiperazin-1-yl)pyrimidin-2-yl]-2-azabicyclo[2.2.1]heptane (2.0 mg,0.00411 mmol, 16 % yield) as a white solid.

[1578] MS (ESI, m / z): 487.2 [M+H]+

[1579] 1H NMR (400 MHz, CD3OD) δ 8.20 (d, J = 7.5 Hz, 1H), 7.33 (s, 1H), 7.29 (s, 1H), 7.21 (d, J = 7.5 Hz, 1H), 4.93 - 4.87 (m, 4H), 4.70 (s, 1H), 4.66 (s, 1H), 3.51 (s, 4H), 2.06 - 1.63 (m, 5H)

[1580]

[1581] Example 228: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)benzo[d]oxazole

[1582]

[1583] Preparation of tert-butyl (1R,3S,4S)-3-(1H-benzo[d][1,2,3]triazole-1-carbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To a stirred solution of (1R,3S,4S)-2-tert-butoxycarbonyl-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.00 eq, 300 mg, 1.24 mmol), 1H-benzotriazole (1.20 eq, 178 mg, 1.49 mmol) and DMAP (0.100 eq, 15 mg, 0.124 mmol) in dichloromethane (7.5 mL), was added DCC (1.00 eq, 257 mg, 1.24 mmol) at 23oC. After 24h , the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to afford tert-butyl (1R,3S,4S)-3-(benzotriazole-1-carbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (303 mg,0.885 mmol, 71 % yield) as a white solid.

[1584] MS (ESI, m / z): 343.2 [M+H]+

[1585] 1H NMR (600 MHz, CDCl3) δ 8.27 (dt,　J　= 14.7, 7.4 Hz, 1H), 8.11 (dt,　J　= 24.1, 7.1 Hz, 1H), 7.65 (dt,　J　= 28.5, 7.4 Hz, 1H), 7.50 (dt,　J　= 15.3, 7.3 Hz, 1H), 5.26 (dd,　J　= 10.6, 7.0 Hz, 1H), 4.43 (d,　J　= 76.6 Hz, 1H), 2.91 (d,　J　= 26.5 Hz, 1H), 2.02 (t,　J　= 10.5 Hz, 1H), 1.90 - 1.65 (m, 4H), 1.61 (d,　J　= 6.3 Hz, 1H), 1.46 (d,　J　= 6.8 Hz, 4.5H), 1.21 (d,　J　= 6.8 Hz, 4.5H).

[1586] Preparation of tert-butyl (1R,3S,4S)-3-(benzo[d]oxazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To a stirred solution of tert-butyl (1R,3S,4S)-3-(benzotriazole-1-carbonyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.00 eq, 100 mg, 0.292 mmol) in dimethylformamide (2mL) was added 2-aminophenol (1.50 eq, 48 mg, 0.438 mmol) at 23oC. The mixture heated to 110 　oC under microwave radiation.　After 4h, the reaction mixture was concentrated under reduced pressure. The crude residue was used without further purification.

[1587] Synthesis of 2-((1R,3S,4S)-3-(benzo[d]oxazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile. To a stirred solution of (1R,3S,4S)-3-(benzo[d]oxazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.00 eq, 47 mg, 0.150 mmol) in dichloromethane (1.5 mL), was added trifluoroacetic acid (1 mL) at 23 　oC. After 2h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in dimethylformamide (1.5 mL).　Then, 2-chloro-4,6-bis(trifluoromethyl)pyridine-3-carbonitrile (1.50 eq, 62 mg, 0.225 mmol) and　cesium carbonate (2.00 eq, 98 mg, 0.3 mmol) were added to the solution.　The mixture was stirred at 120 　oC under microwave radiation. After 2h, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by prep HPLC to afford 2-((1R,3S,4S)-3-(benzo[d]oxazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile (5.0 mg,0.011 mmol, 7 % yield) as a yellow solid.

[1588] MS (ESI, m / z): 453.1 [M+H]+

[1589] 1H NMR (400 MHz, cdcl3) δ 8.10 (d,　J　= 22.8 Hz, 2H), 7.31 (d,　J　= 15.6 Hz, 1H), 7.15 - 6.83 (m, 4H), 5.48 (s, 1H), 4.43 (s, 1H), 3.03 (s, 1H), 2.33 (s, 1H), 2.03 - 1.79 (m, 3H), 1.67 (d,　J　= 10.7 Hz, 2H).

[1590]

[1591] Example 229: 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl) pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)benzo[d]thiazole

[1592]

[1593] The title product was afforded by a similar procedure to that described for the synthesis of example 228 using 2-aminobenzenethiol instead of 2-aminophenol in step b.

[1594] MS (ESI, m / z): 468.2 [M+H]+

[1595] 1H NMR (400 MHz, CDCl3) δ 7.96 (d,　J　= 8.2 Hz, 1H), 7.80 (d,　J　= 7.9 Hz, 1H), 7.44 (dd,　J　= 11.3, 4.1 Hz, 1H), 7.35 (t,　J　= 7.1 Hz, 1H), 5.56 (s, 1H), 5.33 (s, 1H), 3.03 (s, 1H), 2.38 (d,　J　= 10.9 Hz, 1H), 2.03 - 1.51 (m, 5H).

[1596]

[1597] Example 230: 2-((1R,3S,4S)-3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile

[1598]

[1599] Synthesis of 2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-6-bromo-1H-benzo[d]imidazole. To a solution of tert-butyl (1R,3S,4S)-3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.0 eq, 784 mg, 2.0 mmol) in Dichloromethane (12 mL) was added trifluoroacetic acid (4 mL) and stirred at 25oC for 1 hour. The reaction mixture was concentrated in reduced pressure to give the desired product.

[1600] Synthesis of 2-((1R,3S,4S)-3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile. To a solution of 2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-6-bromo-1H-benzo[d]imidazole (1.0 eq, 438 mg, 1.5 mmol) in acetonitrile (15 mL) was added 2-chloro-4,6-bis(trifluoromethyl)nicotinonitrile (1.2 eq, 494 mg, 1.8 mmol) and Cesium carbonate (2.0 eq, 652 mg, 3.0 mmol) and stirred at 80oC for 12 hour. The reaction mixture was poured into water (50 mL), extracted with DCM (50 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified by column chromatography (0~30% EA in Hx) to give the desired product (yield, 55%).

[1601] MS (ESI, m / z): 530.03 [M+H]+

[1602] 1H NMR (600 MHz, cdcl3) δ 9.91 (s, 3H), 7.88 (s, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 1.7 Hz, 2H), 7.35 (dt, J = 4.6, 2.7 Hz, 4H), 7.23 (d, J = 8.4 Hz, 2H), 5.52 (s, 4H), 5.05 (d, J = 7.6 Hz, 4H), 3.31 (s, 4H), 2.65 (t, J = 10.8 Hz, 5H), 2.02 (dd, J = 6.2, 3.3 Hz, 8H), 1.90 (s, 4H), 1.81 (d, J = 10.7 Hz, 4H), 1.67 - 1.62 (m, 7H).

[1603]

[1604] Example 231: 2-((1R,3S,4S)-3-(1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile

[1605]

[1606] Synthesis of 2-((1R,3S,4S)-3-(1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile. To a solution of 2-((1R,3S,4S)-3-(6-bromo-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile (1.0 eq, 132 mg, 0.25 mmol) in Methyl alcohol (5 mL) was added 10% Pd / C (15 mg) at 25oC. The reaction mixture was stirred at 25oC under 1 atm of hydrogen gas. The reaction mixture was filtered by celite and purified column chromatography (0~30% EA in Hx) to give the desired product. (yield, 90%)

[1607] MS (ESI, m / z): 452.12 [M+H]+

[1608] 1H NMR (400 MHz, cdcl3) δ 9.90 (s, 1H), 7.77 - 7.70 (m, 1H), 7.39 - 7.32 (m, 1H), 7.24 (t, J = 4.6 Hz, 3H), 5.52 (s, 1H), 5.09 (s, 1H), 3.33 (s, 1H), 2.69 (d, J = 10.5 Hz, 1H), 2.04 - 1.98 (m, 2H), 1.89 (t, J = 8.7 Hz, 1H), 1.80 (d, J = 10.5 Hz, 1H), 1.64 (d, J = 6.4 Hz, 2H).

[1609]

[1610] Example 232: 2-((1R,3S,4S)-3-(1-methyl-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile

[1611]

[1612] Synthesis of 2-((1R,3S,4S)-3-(1-methyl-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile. To a solution of 2-((1R,3S,4S)-3-(1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile (1.0 eq, 26 mg, 0.05 mmol) and iodomethane (1.3 eq, 4.0 μL, 0.06 mmol) in Dimethylformamide (1.0 mL) was added NaH (1.3 eq, 1.0 mg, 0.06 mmol) and stirred at 0oC for 12 hour. The reaction mixture was poured into water (5 mL), extracted with ethyl acetate (5 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography (0~30% EA in Hx) to give the desired product. (yield, 85%)

[1613] MS (ESI, m / z): 466.14 [M+H]+

[1614] 1H NMR (400 MHz, cdcl3) δ 7.68 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 7.22 (t, J = 7.2 Hz, 1H), 7.01 (s, 1H), 5.66 (s, 1H), 4.95 (s, 1H), 3.89 (s, 3H), 3.15 (s, 1H), 2.68 (s, 1H), 2.03 (dd, J = 10.8, 6.3 Hz, 3H), 1.72 (s, 2H).

[1615]

[1616] Example 233: 2-((1R,3S,4S)-3-(1-isopropyl-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile

[1617]

[1618] The title product was afforded by a procedure similar to that described for the synthesis of Example 232 using 2-iodopropane instead of iodomethane.

[1619] MS (ESI, m / z): 494.17 [M+H]+

[1620] 1H NMR (400 MHz, cdcl3) δ 7.68 (d, J = 7.0 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.24 - 7.16 (m, 2H), 7.04 (s, 1H), 5.70 (s, 1H), 5.03 (s, 1H), 4.78 (s, 1H), 2.77 (s, 1H), 2.61 (s, 1H), 2.05 - 1.98 (m, 3H), 1.75 (d, J = 6.9 Hz, 6H), 1.69 - 1.55 (m, 4H).

[1621]

[1622] Example 234: ((1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)methyl 3-methylbenzoate

[1623]

[1624] Synthesis of tert-butyl (1R,3S,4S)-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To a solution of (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.0 eq, 482 mg, 2.0 mmol) in tetrahydrofuran (20 mL) was added Lithium aluminum hydride (2.0 eq, 152 mg, 4.0 mmol) and stirred at 0oC for 2 hour. The reaction mixture was poured into cold water (60 mL), extracted with ethyl acetate (60 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography (0~30% EA in Hx) to give the desired product. (yield, 35%)

[1625] Synthesis of tert-butyl (1R,3S,4S)-3-(((3-methylbenzoyl)oxy)methyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To a solution of tert-butyl (1R,3S,4S)-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.0 eq, 50 mg, 0.22 mmol), 3-methylbenzoic acid (1.50 eq, 45 mg, 0.33 mmol) and Triphenylphosphine (2.00 eq, 115 mg, 0.440 mmol) in Tetrahydrofuran (2 mL) was added slowly Diisopropyl azodicarboxylate (2.00 eq, 0.087 mL, 0.440 mmol) at 0oC. The reaction mixture was stirred at 0oC. The reaction mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography (0~30% EA in Hx) to give the desired product. (yield, 50%)

[1626] Synthesis of ((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)methyl 3-methylbenzoate. To a solution of tert-butyl (1R,3S,4S)-3-(((3-methylbenzoyl)oxy)methyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.0 eq, 35 mg, 0.1 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.3 mL) and stirred at 25oC for 1 hour. The reaction mixture was concentrated in reduced pressure to give the desired product.

[1627] Synthesis of ((1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)methyl 3-methylbenzoate. To a solution of ((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)methyl 3-methylbenzoate ( 1.0 eq, 25 mg, 0.1 mmol) in acetonitrile (1 mL) was added 2-chloro-4,6-bis(trifluoromethyl)pyridine-3-carbonitrile (1.2 eq, 33 mg, 0.12 mmol) and Cesium carbonate (3.0 eq, 98 mg, 0.3 mmol). The reaction mixture was stirred at 80oC for 12 hour. The reaction mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography (0~30% EA in Hx) to give the desired product. (yield, 45%)

[1628] MS (ESI, m / z): 484.14 [M+H]+

[1629] 1H NMR (600 MHz, cdcl3) δ 7.85 (s, 2H), 7.39 (s, 1H), 7.35 (s, 1H), 7.19 (s, 1H), 5.40 (s, 1H), 4.58 (d, J = 7.8 Hz, 1H), 4.33 (s, 1H), 4.27 (s, 1H), 2.74 (s, 1H), 2.42 (s, 3H), 2.18 (s, 1H), 1.89 (s, 2H), 1.72 (s, 1H), 1.60 (s, 1H), 1.52 (s, 1H).

[1630]

[1631] Example 235: 2-((1R,3S,4S)-3-((m-tolyloxy)methyl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile

[1632]

[1633] Synthesis of tert-butyl (1R,3S,4S)-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To a solution of (1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid (1.0 eq, 482 mg, 2.0 mmol) in tetrahydrofuran (20 mL) was added Lithium aluminum hydride (2.0 eq, 152 mg, 4.0 mmol) and stirred at 0oC for 2 hour. The reaction mixture was poured into cold water (60 mL), extracted with ethyl acetate (60 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography (0~30% EA in Hx) to give the desired product. (yield, 35%)

[1634] Synthesis of tert-butyl (1R,3S,4S)-3-(((methylsulfonyl)oxy)methyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate. To a solution of tert-butyl (1R,3S,4S)-3-(hydroxymethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.0 eq, 114 mg, 0.5 mmol) in dichloromethane (5 mL) was added slowly methanesulfonyl chloride (1.2 eq, 47 μg, 0.6 mmol) and TEA (2.0 eq, 140 μL, 1.0 eq) at 0oC. The reaction mixture was stirred at 25oC for 2 hour. The reaction mixture was poured into cold water (20 mL), extracted with dichloromethane (20 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography (0~30% EA in Hx) to give the desired product. (yield, 75%)

[1635] Synthesis of (1R,3S,4S)-3-((m-tolyloxy)methyl)-2-azabicyclo[2.2.1]heptane. To a solution of tert-butyl (1R,3S,4S)-3-(((methylsulfonyl)oxy)methyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate ( 1.0 eq, 31 mg, 0.1 mmol) in Dimethylformamide (1 mL) was added m-cresol (1.1 eq, 12 mg, 0.11 mmol) and Cesium carbonate (3.0 eq, 98 mg, 0.3 mmol). The reaction mixture was stirred at 80oC for 12 hour. The reaction mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL), dried over anhydrous MgSO4, and concentrated in vacuo. Then, the residue was purified column chromatography (0~30% EA in Hx) to give the desired product...

Claims

1.A compound represented by a following formula (I), a tautomer, a stereoisomer, a solvate, or a pharmaceutically acceptable salt thereof:[Formula (I)]whereinA and B are independently -H, hydroxyl, or joined to form a 3-membered ring;m is 0,1, or 2;Each Y is independently selected from the group consisting of halo, C1-3 alkyl, C1-3 haloalkyl, cyano, and C1-3 alkoxy;X is selected from the group consisting of -C(O)NR1R2, -C(S)NR1R2, -R4, -R4-R5, or -L1-R7;R1is selected from the group consisting of -H, C1-3alkyl, C1-3 alkenyl, C1-3 alkynyl, methyl-d3, 3 to 10-membered cycloalkyl unsubstituted or substituted with cyano, -C1-3 alkyl-3 to 10-membered cycloalkyl unsubstituted or substituted with cyano, allyl unsubstituted or substituted with pyridine, propargyl unsubstituted or substituted with pyridine, aminopyridine, pyridazine, aminopyridazine, pyrimidine, or aminopyrimidine, -C1-3 alkyl-indole, -C1-3 alkyl-triazole, and -C1-3 alkyl-triazole-phenyl;R2is selected from the group consisting of -H, C1-3alkyl, amino, C1-3 aminoalkyl, propargyl, 3 to 10-membered cycloalkyl, phenyl, -L2-phenyl, pyridine, -C1-3 alkyl-pyridine, pyrimidine, -C1-3 alkyl-pyrimidine, benzyl, C1-3 alkylbenzyl, triazole, -C1-3 alkyl-triazole, imidazole, -C1-3 alkyl-imidazole, tetrahydropyran, benzofuran, dihydrobenzofuran, benzothiophene, indole, -C1-3 alkyl-indole, benzoxazole, dihydrobenzoxazole, benzisoxazole, benzothiazole, thiazolopyridine, pyrrolopyridine, benzimidazole, benzimidazolone, dihydrobenzimidazole, dihydrobenzimidazolone, indazole, piperidine, -methyleneamino-C1-3 alkylamino, pyrazole, -C1-3 alkyl-pyrazole, and quinoline, wherein R2is unsubstituted or substituted with one or more substituents selected from R3;or R1and R2are joined to form isoindolinyl or azabicycloheptanyl, unsubstituted or substituted with COOH;each R3is independently selected from the group consisting of C1-3alkyl, phenyl, halogen, C1-3 haloalkyl, hydroxyl, C1-3 alkoxy, C1-3 alkoxycarbonyl, and C1-3 alkylamino;R4is selected from the group consisting of triazole, dihydrotriazolone, imidazole, oxadiazine, oxadiazinone, oxadiazole, oxadiazolone, pyrimidine, pyrimidinone, benzimidazole, benzoxazole, benzothiazole, and triazolodiazepine, unsubstituted or substituted with one or more substituents selected from halo, C1-3 alkyl, C1-3 alkenyl, and C1-3 alkynyl, C1-3 haloalkyl, acetyl, and sulfonyl;R5is selected from the group consisting of 3 to 10-membered cycloalkyl, 3 to 10-membered heterocycloalkyl, 6 to 20-membered aryl, and 6 to 20-membered heteroaryl, wherein R5is unsubstituted or substituted with one or more substituents selected from R6;each R6is independently selected from the group consisting of halo, hydroxy, C1-3 alkyl, C1-3 haloalkyl, and C1-3 alkoxy;R7is selected from the group consisting of phenyl, azabicycloheptane, imidazole, isoindoline, and pyrrolopyridine, unsubstituted or substituted with C1-3 alkyl, COOH, or phenyl;L1 is selected from the group consisting of C1-3 alkyl, C1-3 alkoxy, -CO-, -C1-3 alkoxy-CO-, -C1-3 alkyl-NH-CO-, and -C1-3 alkyl-N(C1-3 alkyl)-CO-; andL2 is selected from the group consisting of C1-3 alkyl, -C1-3 alkyl-CONH-, -C1-3 alkyl-CO-N(C1-3 alkyl)-, -C1-3 alkyl-pyrimidine-, -C1-3 alkyl-dihydropyrimidine-, -C1-3 alkyl-pyrimidinone-, 3 to 10-membered cycloalkyl, -3 to 10-membered cycloalkyl-CONH-, -3 to 10-membered cycloalkyl-CO-N(C1-3 alkyl)-, 3 to 10-membered heterocycloalkyl, -3 to 10-membered heterocycloalkyl-CONH-, and -3 to 10-membered heterocycloalkyl-CO-N(C1-3 alkyl)-.2.The compound, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof according to claim 1,wherein R2is selected from the group consisting of -H, C1-3alkyl, amino, C1-3 aminoalkyl, phenyl, -L2-phenyl, pyridine, - pyrimidine, 3 to 10-membered cycloalkyl, triazole, tetrahydropyran, benzofuran, indole, -C1-3 alkyl-indole, benzoxazole, benzothiazole, pyrrolopyridine, dihydrobenzimidazolone, and -methyleneamino-C1-3 alkylamino, wherein R2is unsubstituted or substituted with one or more substituents selected from R3.3.The compound, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof according to claim 1,wherein L2 is selected from the group consisting of -C1-3 alkyl-CONH-, -C1-3 alkyl-CO-N(C1-3 alkyl)-, -C1-3 alkyl-pyrimidinone-, 3 to 6-membered cycloalkyl, -3 to 6-membered cycloalkyl-CONH-, -3 to 6-membered cycloalkyl-CO-N(C1-3 alkyl)-, oxetane, -oxetane -CONH-, and -oxetane-CO-N(C1-3 alkyl)-.4.The compound, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof according to claim 1,wherein R4is selected from the group consisting of triazole, dihydrotriazolone, imidazole, oxadiazine, oxadiazinone, oxadiazole, oxadiazolone, pyrimidine, pyrimidinone, benzimidazole, benzoxazole, benzothiazole, and triazolodiazepine,wherein the triazole is unsubstituted or substituted with C1-3 alkyl, C1-3 alkenyl, or C1-3 alkynyl,wherein the imidazole is unsubstituted or substituted with one or more substituents selected from halo, C1-3 alkyl, C1-3 alkenyl, and C1-3 alkynyl,wherein the pyrimidine is unsubstituted or substituted with halo,wherein the pyrimidinone is unsubstituted or substituted with C1-3 alkyl, or C1-3 haloalkyl,wherein the benzimidazole is unsubstituted or substituted with one or more substituents selected from halo, C1-3 alkyl, C1-3 alkenyl, and C1-3 alkynyl, andwherein the triazolodiazepine is unsubstituted or substituted with acetyl, or sulfonyl,5.The compound, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof according to claim 1,wherein R5is selected from the group consisting of 3 to 10-membered monocyclic cycloalkyl, 3 to 10-membered monocyclic heterocycloalkyl comprising one or more heteroatoms selected from N, O and S, 6 to 20-membered monocyclic aryl, and 6 to 20-membered monocyclic or bicyclic heteroaryl comprising one or more heteroatoms selected from N, O and S, wherein R5is unsubstituted or substituted with one or more substituents selected from R6.6.The compound, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof according to claim 1,wherein R5is selected from the group consisting of cyclohexyl, phenyl, piperidine, piperazine, imidazole, pyridine, pyrazole, triazole, benzofuran, dihydrobenzofuran, benzoxazole, benzoxazolone, benzoisoxazole, benzothiazole, benzothiophene, indazole, indole, pyrrolopyridine, and quinoline, wherein R5is unsubstituted or substituted with one or more substituents selected from R6.7.The compound, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof according to claim 1,wherein R7is selected from the group consisting of phenyl, azabicycloheptane, imidazole, isoindoline, and pyrrolopyridine,wherein azabicycloheptane is unsubstituted or substituted with COOH,wherein imidazole is unsubstituted or substituted with phenyl, andwherein phenyl is unsubstituted or substituted with C1-3 alkyl.8.The compound, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof according to claim 1,wherein the formula (I) is a following formula (Ia):[Formula (Ia)]wherein n is 0 or 1.9.The compound, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof according to claim 1,wherein X is -R4or -R4-R5.10.The compound, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is one selected from the group consisting of the following compounds:(1) (1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(2) (1R,3S,4S)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(3) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(4) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(5) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-ethyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(6) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-isopropyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(7) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-propyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(8) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-cyclopropyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(9) (1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(10) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(11) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(12) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2,5-difluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(13) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(14) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-2-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(15) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(p-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(16) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-2,4-difluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(17) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(o-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(18) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3,4-difluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(19) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(20) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-bromophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(21) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-methoxy-4-methylphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(22) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluoro-3-(trifluoromethyl)phenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(23) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-hydroxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(24) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-methoxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(25) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-hydroxy-4-methylphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(26) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-phenyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(27) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-4-methylphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(28) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3,4-dichlorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(29) methyl 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamido)-4-chloro-5-fluorobenzoate(30) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluoro-3-methoxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(31) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2,4-dichlorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(32) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chlorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(33) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3,5-difluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(34) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-chloro-3-methoxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(35) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-bromo-2-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(36) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-hydroxyphenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(37) (1R,3S,4S)-N-([1,1'-biphenyl]-4-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(38) (1R,3S,4S)-N-([1,1'-biphenyl]-2-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(39) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-chlorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(40) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(41) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(42) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(6-(dimethylamino)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(43) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluoropyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(44) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(6-fluoropyridin-3-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(45) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(5-methylpyridin-3-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(46) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(6-methylpyridin-3-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(47) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(6-methylpyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(48) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(5-methylpyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(49) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(4-methylpyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(50) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(6-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(51) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(pyrimidin-4-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(52) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(53) (1R,3S,4S)-N-(4-fluorophenyl)-N-methyl-2-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(54) (1R,3S,4S)-N-(4-fluorophenyl)-N-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(55) (1R,3S,4S)-2-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(56) (1R,3S,4S)-N-(4-fluorophenyl)-2-(6-methoxy-4-(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(57) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(58) (1R,3S,4S)-N-(benzofuran-6-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(59) (1R,3S,4S)-N-(benzo[d]thiazol-5-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(60) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(61) (1R,3S,4S)-N-(benzo[d]oxazol-2-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(62) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-methyl-1H-indol-5-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(63) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-methyl-1H-indol-4-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(64) (1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-6-azatricyclo[3.2.1.02,4]octane-7-carboxamide(65) (1S,3R,4R)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(66) (1S,3R,4R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(67) (1S,3R,4R)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(3-methyl-5-(trifluoromethyl)phenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(68) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(methyl-d3)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(69) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(methyl-d3)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(70) (1R,3S,4S)-2-(3-cyano-6-methyl-4-(trifluoromethyl)pyridin-2-yl)-N-(methyl-d3)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(71) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carbothioamide(72) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-cyclohexyl-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(73) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-cyclopentyl-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(74) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(75) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2,5-difluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(76) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-4-fluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(77) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-2-fluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(78) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(o-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(79) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(p-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(80) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-chloro-2,4-difluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(81) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3,4-difluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(82) (1R,3S,4S)-N-((1H-indol-3-yl)methyl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(83) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(84) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(1-cyanocyclopropyl)-N-(4-fluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(85) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-((1-cyanocyclopropyl)methyl)-N-(4-fluorophenyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(86) ((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)(isoindolin-2-yl)methanone(87) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-(dimethylamino)ethyl)-N-methyl-2-azabicyclo[2.2.1]heptane-3-carboxamide(88) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(prop-2-yn-1-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(89) (1R,3S,4S)-N-(3-(6-aminopyridazin-3-yl)prop-2-yn-1-yl)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(90) (1R,3S,4S)-N-((1H-1,2,3-triazol-4-yl)methyl)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(91) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(92) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(3-(pyridin-2-yl)prop-2-yn-1-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(93) (1R,3S,4S)-N-allyl-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(94) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-((E)-3-(pyridin-2-yl)allyl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(95) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(prop-2-yn-1-yl)-N-(m-tolyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(96) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(97) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(98) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-isopropyl-N-((1-phenyl-1H-1,2,3-triazol-4-yl)methyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(99) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(2-(methyl(m-tolyl)amino)-2-oxoethyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(100) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-(2-(methyl(m-tolyl)amino)-2-oxoethyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(101) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-((R)-1-(methyl(m-tolyl)amino)-1-oxopropan-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(102) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(2-methyl-1-(methyl(m-tolyl)amino)-1-oxopropan-2-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(103) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-(methyl(m-tolyl)carbamoyl)cyclopropyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(104) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-(methyl(m-tolyl)carbamoyl)cyclobutyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(105) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-(methyl(m-tolyl)carbamoyl)cyclopentyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(106) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(1-(methyl(m-tolyl)carbamoyl)cyclohexyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(107) (1R,3S,4S)-2-(3-cyano-4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(3-(methyl(m-tolyl)carbamoyl)oxetan-3-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(108) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-methyl-N-(4H-1,2,4-triazol-4-yl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(109) (1R,3S,4S)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid(110) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-N-((1-(4-fluorophenyl)-6-oxo-1,6-dihydropyrimidin-2-yl)methyl)-2-azabicyclo[2.2.1]heptane-3-carboxamide(111) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbohydrazide(112) (E)-N'-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-3-carbonyl)-N,N-dimethylformohydrazonamide(113) 2-((1R,3S,4S)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile(114) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(115) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(116) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-isopropyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(117) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-phenyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(118) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(p-tolyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(119) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(120) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(121) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(122) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-chlorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(123) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3,4-difluorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(124) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-chloro-4-fluorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(125) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3,4-dichlorophenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(126) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluoro-3-methylphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(127) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(128) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluoro-3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(129) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-chloro-3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(130) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-methoxy-4-methylphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(131) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-methoxyphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(132) 3-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)phenol(133) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(6-methylpyridin-2-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(134) (1R,3S,4S)-3-(4-benzyl-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane(135) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(pyridin-2-ylmethyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(136) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(1-phenylethyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(137) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(prop-2-yn-1-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(138) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-cyclohexyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(139) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(piperidin-4-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(140) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(1-methylpiperidin-4-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(141) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(1-methylpiperidin-3-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(142) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(1-methyl-1H-imidazol-4-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(143) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(1-methyl-1H-pyrazol-3-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(144) 5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)quinoline(145) 5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)-1H-indole(146) (1R,3S,4S)-3-(4-(benzofuran-5-yl)-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane(147) (1R,3S,4S)-3-(4-(benzofuran-6-yl)-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane(148) 5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)benzo[d]thiazole(149) 7-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)benzo[d]thiazole(150) (1R,3S,4S)-3-(4-(benzo[b]thiophen-5-yl)-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane(151) 5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)-3-methylbenzo[d]isoxazole(152) 5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)benzo[d]thiazole(153) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(2,3-dihydrobenzofuran-6-yl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(154) 5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)-1-methyl-1H-pyrrolo[2,3-b]pyridine(155) 6-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)benzo[d]oxazol-2(3H)-one(156) 6-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)-2,3-dimethyl-2H-indazole(157) 5-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4H-1,2,4-triazol-4-yl)-2-methyl-2H-indazole(158) (1S,3S,4S,5R)-3-(4-(benzo[d]thiazol-5-yl)-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-5-ol(159) (1S,3S,4S,5S,6R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluoro-3-methylphenyl)-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane-5,6-diol(160) (1S,3S,4S,5S,6R)-3-(4-(benzofuran-6-yl)-4H-1,2,4-triazol-3-yl)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptane-5,6-diol(161) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(162) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(3-chloro-4-fluorophenyl)-5-methyl-4H-1,2,4-triazol-3-yl)-2-azabicyclo[2.2.1]heptane(163) 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepine(164) 1-(3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-5,6,8,9-tetrahydro-7H-[1,2,4]triazolo[4,3-d][1,4]diazepin-7-yl)ethan-1-one(165) 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-7-(methylsulfonyl)-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepine(166) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(3-methyl-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane(167) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(3-chloro-4-fluorophenyl)-3-methyl-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane(168) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane(169) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-phenyl-1H-1,2,4-triazol-5-yl)-2-azabicyclo[2.2.1]heptane(170) 5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-2,4-dihydro-3H-1,2,4-triazol-3-one(171) 5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-(m-tolyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(172) 5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-(3,4-difluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one(173) 5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-2,4-dimethyl-2,4-dihydro-3H-1,2,4-triazol-3-one(174) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane(175) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-methyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane(176) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-isopropyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane(177) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(prop-2-yn-1-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane(178) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(3-methylbenzyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane(179) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(m-tolyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane(180) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(1-(6-(trifluoromethyl)pyridin-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane(181) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(5-chloro-1-(2-chloro-5-methylphenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane(182) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(5-chloro-1-(m-tolyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane(183) 2-((1R,3S,4S)-3-(5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile(184) 6-methyl-2-((1R,3S,4S)-3-(5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4-(trifluoromethyl)nicotinonitrile(185) 2-((1R,3S,4S)-3-(1-isopropyl-5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile(186) 2-((1R,3S,4S)-3-(1-methyl-5-phenyl-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile(187) 2-((1R,3S,4S)-3-(3-phenyl-1,2,4-oxadiazol-5-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-4,6-bis(trifluoromethyl)nicotinonitrile(188) 5-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-phenyl-1,2,4-oxadiazole(189) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-phenylpyrimidin-4(3H)-one(190) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(p-tolyl)pyrimidin-4(3H)-one(191) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(m-tolyl)pyrimidin-4(3H)-one(192) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(o-tolyl)pyrimidin-4(3H)-one(193) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(4-fluorophenyl)pyrimidin-4(3H)-one(194) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-chlorophenyl)pyrimidin-4(3H)-one(195) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(4-fluoro-3-methylphenyl)pyrimidin-4(3H)-one(196) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3,4-difluorophenyl)pyrimidin-4(3H)-one(197) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-chloro-4-fluorophenyl)pyrimidin-4(3H)-one(198) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(4-fluoro-3-methoxyphenyl)pyrimidin-4(3H)-one(199) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(4-chloro-3-methoxyphenyl)pyrimidin-4(3H)-one(200) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3,4-dichlorophenyl)pyrimidin-4(3H)-one(201) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-methoxyphenyl)pyrimidin-4(3H)-one(202) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin-4(3H)-one(203) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(6-methylpyridin-2-yl)pyrimidin-4(3H)-one(204) 3-(benzofuran-7-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one(205) 3-(benzofuran-6-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one(206) 3-(benzofuran-5-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one(207) 3-(benzo[d]oxazol-5-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one(208) 3-(benzo[d]thiazol-7-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one(209) 3-(benzo[d]thiazol-6-yl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one(210) 3-((1H-1,2,3-triazol-4-yl)methyl)-2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one(211) 2-((1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-chloro-4-fluorophenyl)pyrimidin-4(3H)-one(212) 3-(benzofuran-5-yl)-2-((1S,3S,4S,5R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5-hydroxy-2-azabicyclo[2.2.1]heptan-3-yl)pyrimidin-4(3H)-one(213) 2-((1S,3S,4S,5S,6R)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-5,6-dihydroxy-2-azabicyclo[2.2.1]heptan-3-yl)-3-(3-chloro-4-fluorophenyl)pyrimidin-4(3H)-one(214) 2-((1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-azatricyclo[3.2.1.02,4]octan-7-yl)-3-(m-tolyl)pyrimidin-4(3H)-one(215) 2-((1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-azatricyclo[3.2.1.02,4]octan-7-yl)-3-(4-fluorophenyl)pyrimidin-4(3H)-one(216) 3-(benzofuran-6-yl)-2-((1R,5S,7S)-6-(4,6-bis(trifluoromethyl)pyridin-2-yl)-6-azatricyclo[3.2.1.02,4]octan-7-yl)pyrimidin-4(3H)-one(217) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-(trifluoromethyl)-3-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin-4(3H)-one(218) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-(trifluoromethyl)-1-(6-(trifluoromethyl)pyridin-2-yl)pyrimidin-4(1H)-one(219) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-3-(6-methylpyridin-2-yl)-6-(trifluoromethyl)pyrimidin-4(3H)-one(220) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-methyl-3-(m-tolyl)pyrimidin-4(3H)-one(221) 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-(3-methylbenzyl)-4H-1,2,4-oxadiazin-5(6H)-one(222) 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-1,2,4-oxadiazol-5(4H)-one(223) 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-phenyl-1,2,4-oxadiazol-5(4H)-one(224) 3-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-4-(3-methylbenzyl)-1,2,4-oxadiazol-5(4H)-one(225) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-chloropyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane(226) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(m-tolyl)pyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane(227) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-(4-(4-methylpiperazin-1-yl)pyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane(228) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)benzo[d]oxazole(229) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)benzo[d]thiazole(230) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-6-bromo-1H-benzo[d]imidazole(231) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-benzo[d]imidazole(232) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-1-methyl-1H-benzo[d]imidazole(233) 2-((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)-1-isopropyl-1H-benzo[d]imidazole(234) ((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)methyl 3-methylbenzoate(235) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-((m-tolyloxy)methyl)-2-azabicyclo[2.2.1]heptane(236) N-(((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)methyl)-N,3-dimethylbenzamide(237) 1-(((1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-2-azabicyclo[2.2.1]heptan-3-yl)methyl)-1H-pyrrolo[2,3-b]pyridine(238) (1R,3S,4S)-2-(4,6-bis(trifluoromethyl)pyridin-2-yl)-3-((4-phenyl-1H-imidazol-1-yl)methyl)-2-azabicyclo[2.2.1]heptane11.A pharmaceutical composition for preventing or treating Polymerase theta activation-related diseases, comprising the compound, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.12.The pharmaceutical composition according to claim 11, wherein the composition further comprises one or more therapeutic agent selected from the group consisting of chemotherapy agent, radiotherapy agent, immunotherapy agent and tumor microenvironment modulating agent.13.The pharmaceutical composition according to claim 11, wherein the Polymerase theta activation-related diseases comprise a cancer.14.A method for preventing or treating Polymerase theta activation-related diseases, comprising administering a therapeutically effective amount of the compound, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof according to claim 1 into a subject.15.The method according to claim 14, wherein the Polymerase theta-related diseases comprise a cancer.16.A method for inhibiting Polymerase theta activity, comprising administering a therapeutically effective amount of the compound, the tautomer, the stereoisomer, the solvate, or the pharmaceutically acceptable salt thereof according to claim 1 into a subject.

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