Novel heterocyclic compound and pharmaceutical composition comprising same

Abstract

The present invention relates to a novel heterocyclic compound represented by Chemical Formula 1 and a pharmaceutical composition comprising the same, and the compound according to the present disclosure can be usefully used in the prevention or treatment of cancer. In Chemical Formula 1, X, Y, Z1, Z2, Z3, R1, R2, R3, L and R4 are as defined in the specification. [Chemical Formula 1] # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a novel heterocyclic compound used as an inhibitor of Pol-θ (DNA polymerase θ, Polθ) and a pharmaceutical composition comprising the same. Background Art

[0002] Targeting DNA repair defects has emerged as a strategy proven effective in cancer treatment. However, DNA repair-deficient cancers often rely on backup DNA repair pathways, which have a "fatal weakness" that can be targeted to eliminate cancer cells and is the basis of synthetic lethality. An example of synthetic lethality is the success of poly ADP-ribose polymerase (PARP) inhibitors in treating BRCA-deficient breast and ovarian cancers.

[0003] Powerful repair of DNA double-strand breaks (DSBs) is crucial for maintaining genomic stability and cell viability. DSBs can be repaired through one of three main pathways: homologous recombination (HR), non-homologous end joining (NHEJ), and alternative NHEJ (alt-NHEJ). Microhomology-mediated end joining (MMEJ) is the most typical alt-NHEJ mechanism.

[0004] Numerous genetic studies have highlighted the role of polymerase θ (Polθ) in stimulating MMEJ in higher organisms. It has been shown that cancer cells defective in HR, NHEJ, or ATM (ataxia-telangiectasia mutated; A-T mutated) are highly dependent on Polθ expression. Polθ expression is essentially absent in normal cells but is upregulated in breast, lung, and ovarian cancers. In addition, increased Polθ expression is associated with poor prognosis in breast cancer. Importantly, Polθ is largely inhibited in normal tissues but has been shown to be upregulated in matched cancer samples, thus linking elevated expression to the disease. Its suppression or inhibition confers radiosensitivity to tumor cells. Polθ inhibition may prevent the reversal of MMEJ-dependent functions of BRCA2 mutations, which is the basis for the emergence of cisplatin and PARPi (PARP inhibitor) resistance in tumors. Therefore, in cancers with DNA repair defects, Polθ is an attractive target for novel synthetic lethal therapies, and there is a need to provide effective Polθ inhibitors for treating cancer.

[0005] In view of the above, as a result of studying novel compounds, the present inventors found that compounds having a chemical structure different from that of Polθ inhibitors reported to date have excellent Polθ inhibitory effects, thereby completing the present invention. The compounds belonging to the present invention mainly have Polθ inhibitory activity by themselves, but do not exclude the possibility of exhibiting pharmacological effects as effective medicaments through products of a special body environment or metabolic process after being absorbed into the body. Summary of the Invention

[0006] [Technical Problem]

[0007] One object of the present invention is to provide novel heterocyclic compounds useful as Pol-θ (Polθ) inhibitors and pharmaceutical compositions comprising the same.

[0008] [Technical Solution]

[0009] To achieve the above object, there is provided a compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof:

[0010] [Chemical Formula 1]

[0011]

[0012] In Chemical Formula 1,

[0013] X is CH or N;

[0014] Y is O or S;

[0015] Z 1 and Z 2 are each independently N or CH, provided that at least one of Z 1 and Z 2 is N;

[0016] Z 3 is O or S;

[0017] R 1 is C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 haloalkyl or halogen;

[0018] R 2 is C 1-4 haloalkyl;

[0019] R 3 is hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl or halogen;

[0020] L is a single bond or a divalent linker selected from the group consisting of a 5- or 6-membered heteroaromatic ring containing one or two nitrogens unsubstituted or substituted with C 1-4 alkyl, halogen, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 alkoxy, hydroxy or amino, 2-oxa-6-azaspiro[3.3]heptane, thiomorpholine dioxide, 1H-pyrrolo[2,3-b]pyridine and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine; and

[0021] R 4 is hydrogen, C 1-4 alkyl, (C 1-4 alkyl)sulfonyl(C 1-4 alkyl), C 2-4 alkynyl, C 1-4 alkoxy, unsubstituted or substituted with hydroxy or C 1-4 alkoxy-substituted C 3-6 cycloalkyl, halogen, amino, morpholino, morpholinocarbonyl, unsubstituted or substituted with hydroxy, C 1-4 alkyl, (C 1-4 alkyl)carbonyl, (C 3-6 cycloalkyl)carbonyl or (C 1-4 alkyl)sulfonyl-containing 4-, 5- or 6-membered heterocycloalkyl with one nitrogen, unsubstituted or substituted with hydroxy, C 1-4 alkyl, (C 1-4 alkyl)carbonyl, (C 3-6 cycloalkyl)carbonyl or (C 1-4 alkyl)sulfonyl-containing 5- or 6-membered heterocycloalkyl with one oxygen, (5- or 6-membered heterocycloalkyl with one oxygen)methyl, (5- or 6-membered heterocycloalkyl with one oxygen)oxy, 1-(aminocarbonyl)eth-1-yl, 1-oxoisoindolinyl, 2-azabicyclo[2.2.1]hept-7-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 4-oxaspiro[2.4]hept-6-yl, or 5-oxopyrrolidinyl.

[0022] In addition, for achieving the above object, there is provided a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof.

[0023] In addition, for achieving the above object, there is provided a pharmaceutical composition for preventing or treating cancer, which comprises the compound or a pharmaceutically acceptable salt thereof.

[0024] [Beneficial effects]

[0025] The compound represented by Chemical Formula 1 according to the present disclosure, or a pharmaceutically acceptable salt thereof, may be usefully used for preventing or treating cancer. Detailed embodiments

[0026] Hereinafter, the embodiments of the present disclosure will be described in more detail to facilitate understanding of the present invention.

[0027] Meanwhile, the present invention provides a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0028] Preferably, R 1 is methyl, cyclopropyl, trifluoromethyl or chlorine. More preferably, R 1 is trifluoromethyl.

[0029] Preferably, R 2 is trifluoromethyl.

[0030] Preferably, R 1 and R 2 are trifluoromethyl.

[0031] Preferably, R 3 is hydrogen, methyl, cyclopropyl, fluorine or chlorine. More preferably, R 3 is fluorine or chlorine.

[0032] Preferably, L is a single bond or a divalent linker selected from the group consisting of 1-methyl-1H-pyrazole, imidazole, pyrazine, pyrazole, pyridazine, pyridin-2(1H)-one, pyridine, pyrimidine, pyrrole, 2-oxa-6-azaspiro[3.3]heptane, thiomorpholine dioxide, 1H-pyrrolo[2,3-b]pyridine, and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.

[0033] Preferably, R 4 is hydrogen, methyl, methanesulfonylmethyl, ethynyl, methoxy, cyclopropyl, cyclopentyl unsubstituted or substituted with methoxy, bromine, chlorine, amino, morpholino, morpholinocarbonyl, azetidinyl, piperidinyl or pyrrolidinyl unsubstituted or substituted with hydroxyl, methyl, acetyl, cyclopropanecarbonyl or methanesulfonyl, tetrahydrofuranyl, tetrahydropyranyl, (tetrahydrofuranyl)methyl, (tetrahydrofuranyl)oxy, 1-(aminocarbonyl)eth-1-yl, 1-oxoisoindolinyl, 2-azabicyclo[2.2.1]hept-7-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 4-oxaspiro[2.4]hept-6-yl, 5-oxopyrrolidinyl, or methanesulfonylmethyl.

[0034] Preferably, Chemical Formula 1 is represented by the following Chemical Formula 2:

[0035] [Chemical Formula 2]

[0036]

[0037] In Chemical Formula 2,

[0038] Y is O or S;

[0039] Z 1 and Z 2 are each independently N or CH, provided that at least one of Z 1 and Z 2 is N;

[0040] Z 3 is O or S;

[0041] L is a 5- or 6-membered heteroaromatic ring containing one or two nitrogens; and

[0042] R 4 is hydrogen, C 1-4 alkoxy, C 3-6 cycloalkyl, halogen, amino, morpholino, a 4-, 5- or 6-membered heterocycloalkyl containing one nitrogen unsubstituted or substituted with C 1-4 alkyl or (C 1-4 alkyl)carbonyl, or a 5- or 6-membered heterocycloalkyl containing one oxygen.

[0043] Preferably, in Formula 1 and Formula 2, Z 1 and Z 2 are N, and Z 3 is O.

[0044] Preferably, in Formula 1 and Formula 2, L is pyrazine, pyridazine, pyridine or pyrimidine.

[0045] Preferably, in Formula 1 and Formula 2, R 4 is hydrogen, methoxy, cyclopropyl, cyclopentyl, bromine, chlorine, amino, morpholino, piperidinyl, pyrrolidinyl, methylpyrrolidinyl, acetylpyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl.

[0046] Representative examples of the compounds represented by Formula 1 are as follows:

[0047] 1) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0048] 2) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-methoxypyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0049] 3) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-morpholinopyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0050] 4) N-((5-(6-Aminopyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0051] 5) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-(pyrrolidin-3-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0052] 6) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(pyrrolidin-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0053] 7) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-(piperidin-4-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0054] 8) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-(piperidin-3-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0055] 9) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(pyrrolidin-3-yl)pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0056] 10) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(pyrrolidin-3-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0057] 11) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-(pyrrolidin-3-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)thioacetamide,

[0058] 12) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(1-methylpyrrolidin-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0059] 13) 3-(6-(5-((2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamido)methyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1,1-dimethylpyrrolidinium,

[0060] 14) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-((5-(5-cyclopentylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0061] 15) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0062] 16) N-((5-(5-(1-Acetylpyrrolidin-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0063] 17) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0064] 18) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-((5-(5-bromopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0065] 19) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)acetamide,

[0066] 20) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydro-2H-pyran-3-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0067] 21) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-(1-methylpyrrolidin-3-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0068] 22) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-((5-(5-cyclopropylpyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0069] 23) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydrofuran-3-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0070] 24) N-((5-(5-Aminopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0071] 25) N-((5-(5-Aminopyrazin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0072] 26) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)oxazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0073] 27) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-((2-(5-chloropyrimidin-2-yl)oxazol-5-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0074] 28) N-((5-(5-Aminopyrazin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0075] 29) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-((5-(5-(1-(cyclopropanecarbonyl)pyrrolidin-3-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0076] 30) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(1-(methanesulfonyl)pyrrolidin-3-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0077] 31) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(3-hydroxycyclopentyl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0078] 32) N-((5-(5-(2-Azabicyclo[2.2.1]hept-7-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0079] 33) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(5-oxopyrrolidin-3-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0080] 34) N-((5-(5-(4-Oxaspiro[2.4]hept-6-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0081] 35) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-((tetrahydrofuran-3-yl)methyl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0082] 36) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydrofuran-3-yloxy)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0083] 37) 2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)-N-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0084] 38) 2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-phenyl-N-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0085] 39) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(morpholine-4-carbonyl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0086] 40) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(1-methyl-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0087] 41) N-((5-(1H-pyrrol-3-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0088] 42) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0089] 43) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0090] 44) N-((5-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0091] 45) 2-(4-(5-((2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamido)methyl)-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)propanamide,

[0092] 46) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(1-(methylsulfonylmethyl)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0093] 47) N-((5-(3-amino-1-methyl-1H-pyrazol-5-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0094] 48) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(1-methyl-1H-imidazol-5-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0095] 49) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-oxo-1,6-dihydropyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0096] 50) 2-(4-chloro-2-(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0097] 51) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-chlorophenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0098] 52) N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)-2-(4-methyl-2-(trifluoromethyl)phenyl)acetamide,

[0099] 53) N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0100] 54) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-p-tolylacetamide,

[0101] 55) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-cyclopropylphenyl)acetamide,

[0102] 56) N-((5-(5-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0103] 57) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(1-oxoisoindolin-2-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0104] 58) N-((5-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0105] 59) N-((5-(1,1-dioxothiomorpholin-4-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0106] 60) N-((5-(1H-pyrrolo[2,3-b]pyridin-6-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0107] 61) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-((5-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0108] 62) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-((5-ethynyl-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0109] 63) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-((5-(5-ethynylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0110] 64) 2-[2,4-Bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[5-(3-methoxycyclopentyl)pyrimidin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide,

[0111] 65) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(2-oxo-1,2-dihydropyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0112] 66) 2-[2,4-Bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(2-methoxypyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide,

[0113] 67) 2-[2,4-Bis(trifluoromethyl)phenyl]-N-{[5-(5-chloropyrazin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-N-(4-fluorophenyl)acetamide,

[0114] 68) 2-[2,4-Bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(6-methoxypyridin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide, and

[0115] 69) 2-(2,4-Bis(trifluoromethyl)phenyl)-N-((2-(5-chloropyridin-2-yl)oxazol-5-yl)methyl)-N-(4-fluorophenyl)acetamide.

[0116] In addition, the compounds of the present invention may exist in the form of salts, especially pharmaceutically acceptable salts. As salts, salts commonly used in the art can be used without limitation, such as acid addition salts formed from pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound represented by Chemical Formula 1, which is relatively non-toxic and harmless to the patient, is effectively activated, and whose side effects do not reduce the beneficial effects of the above compound.

[0117] As the free acid, organic acids and inorganic acids can be used. Examples of inorganic acids include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. Examples of organic acids include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc., but are not limited thereto. Preferably, the salt may be a hydrochloride.

[0118] In addition, pharmaceutically acceptable metal salts can be obtained by conventional methods using bases. For example, the compound represented by Chemical Formula 1 is dissolved in an excessive solution of an alkali metal hydroxide or an alkaline earth metal hydroxide, the insoluble salt is filtered, and then the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt. At this time, it is particularly preferred to prepare a sodium salt, a potassium salt or a calcium salt as the metal salt.

[0119] In addition, when preparing the compound of Chemical Formula 1 or its pharmaceutically acceptable salt or solvate, a pharmaceutically unacceptable salt or solvate of the compound of Chemical Formula 1 can be used as an intermediate.

[0120] In one embodiment, the compound represented by Chemical Formula 1 can be prepared by the following Reaction Scheme 1.

[0121] [Reaction Scheme 1]

[0122]

[0123] In Reaction Scheme 1, X, and R 1 to R 6 are as defined above, X 1 and X 2 are each independently a halogen. Preferably, X 1 and X 2 are each independently bromine or chlorine.

[0124] Step 1 is a step of preparing a compound represented by Chemical Formula 3’ by reacting a compound represented by Chemical Formula 1’ with a compound represented by Chemical Formula 2’, where the amino group is substituted and the halogen is eliminated. Step 2 is a step of preparing a compound represented by Chemical Formula 1 by reacting a compound represented by Chemical Formula 3’ with a compound represented by Chemical Formula 4’.

[0125] The above preparation method will be described more specifically in the examples described below.

[0126] According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0127] According to another embodiment of the present invention, there is provided a pharmaceutical composition for preventing or treating cancer diseases, which is effective for Polθ inhibitory action, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0128] In this case, the cancer can be blood cancer, extranodal marginal zone B-cell lymphoma, glioblastoma, lymphoplasmacytic lymphoma, acute myeloid leukemia, Waldenström macroglobulinemia, B-cell lymphoma, chronic lymphocytic leukemia, follicular lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, hairy cell leukemia, mantle cell lymphoma, glioblastoma, bladder cancer, pancreatic cancer, ovarian cancer, colorectal cancer, kidney cancer, gastric cancer, transitional cell carcinoma, carcinoid tumor, breast cancer, non-small cell lung cancer or multiple myeloma.

[0129] As used herein, the term "prevention" refers to any act of delaying or inhibiting the occurrence, spread or recurrence of the above diseases by administering the compositions of the present disclosure, while "treatment" refers to any act of better improving or altering the symptoms of the above diseases by administering the compositions of the present disclosure.

[0130] The pharmaceutical composition according to the present disclosure can be formulated into a type for oral or parenteral administration according to standard pharmaceutical practices. In addition to the active ingredient, these preparations may also contain additives such as pharmaceutically acceptable carriers, adjuvants or diluents.

[0131] Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil, isopropyl myristate, etc. Diluents include, for example, lactose, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine, etc., but are not limited thereto. In addition, the compounds of the present disclosure can be dissolved in oils, propylene glycol or other solvents commonly used for preparing injection solutions. In addition, the compounds of the present disclosure can be formulated into ointments or creams for topical administration.

[0132] The preferred dosage of the compounds of the present disclosure may vary depending on the condition and weight of the patient, the severity of the disease, the type of drug, and the route and duration of administration, but can be appropriately selected by those skilled in the art. However, in order to achieve the desired effect, the compounds of the present disclosure can be administered at a dosage of 0.0001 mg / kg (body weight) to 100 mg / kg (body weight) per day, preferably at a dosage of 0.001 mg / kg (body weight) to 100 mg / kg (body weight). It can be administered once a day or in divided doses per day by oral or parenteral routes.

[0133] Depending on the method of administration, the pharmaceutical composition may contain 0.001% to 99% by weight of the compounds of the present disclosure, preferably 0.01% to 60% by weight of the compounds of the present disclosure.

[0134] The pharmaceutical compositions according to the present disclosure can be administered to mammals, such as rats, mice, livestock or humans, by various routes. The administration can be carried out by all possible methods, such as oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine, intracerebroventricular injection.

[0135] Hereinafter, the present disclosure will be described in more detail by way of examples. However, these examples are for illustrative purposes only and should not be construed as limiting the scope of the present disclosure to these examples.

[0136] Example 1: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0137]

[0138] Step A: N'-(2-chloroacetyl)nicotinohydrazide (2)

[0139] At 0 °C and N 2 under, to a solution of pyridine-3-carbohydrazide (1.0 g, 7.29 mmol) in acetonitrile (10 mL) was added TEA (2.21 g, 21.88 mmol) and chloroacetyl chloride (0.6 mL, 7.29 mmol). The reaction was stirred at 25 °C for 16 h. After completion, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 and filtered and concentrated to dryness under reduced pressure to give crude N'-(2-chloroacetyl)nicotinohydrazide (800 mg, 3.09 mmol, 42.44%) in the form of a yellow oil, which was used in the next step without further purification.

[0140] LCMS: m / z (M+H) + = 214.1

[0141] Step B: 2-(Chloromethyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole (3)

[0142] At 80 °C and N 2 under, N'-(2-chloroacetyl)nicotinohydrazide (800 mg, 3.74 mmol) was stirred in POCl 3 (5.0 mL) for 18 h. After completion, the reaction mixture was concentrated to dryness under reduced pressure to give a residue. The residue was purified by silica gel chromatography (eluent: petroleum ether:EtOAc = 100:1 to 10:1) to give 2-(chloromethyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole (230 mg, 1.06 mmol, 28.26%) as a yellow oil.

[0143] LCMS: m / z (M+H) + = 196.0

[0144] Step C: 4-Fluoro-N-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)aniline (4)

[0145] At 25 °C and N 2 under, to a solution of 2-(chloromethyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole (170 mg, 0.87 mmol) in DMSO (5.0 mL) was added 4-fluoroaniline (96 mg, 0.99 mmol), potassium carbonate (360 mg, 2.60 mmol), potassium iodide (144 mg, 0.87 mmol), and the reaction was stirred at 25 °C for 18 h. After completion, the mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (eluent: petroleum ether:EtOAc = 100:1 to 10:1) to give 4-fluoro-N-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)aniline (60 mg, 0.20 mmol, 22.99%) as a yellow oil.

[0146] LCMS: m / z (M+H) + = 271.0

[0147] Step D: 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0148] At 25 °C, to a solution of 4-fluoro-N-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)aniline (40 mg, 0.15 mmol) in DCM (5.0 mL) was added TEA (44 mg, 0.45 mmol) and [2,4-bis(trifluoromethyl)phenyl]acetyl chloride (43 mg, 0.15 mmol). The reaction was stirred at 25 °C and N 2 for 2 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (ACN: water (1‰ FA)) to give 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide (6.3 mg, 0.01 mmol, 7.79%) as a white solid.

[0149] 1 1H NMR (400 MHz, CDCl 3 ) δ 9.11 (s, 1H), 8.79 (d, J = 4.8 Hz, 1H), 8.31 (d, J = 7.9 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.91 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.63 (m, 1H), 7.57 (m, 2H), 7.36 (t, J = 8.7 Hz, 2H), 5.14 (s, 2H), 3.74 (s, 2H).

[0150] LCMS: m / z (M+H) + = 525.1.

[0151] Example 2: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-methoxypyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0152]

[0153] Step A: 6-methoxy-1,2-diazine-3-carbohydrazide (2)

[0154] To a solution of methyl 6-methoxy-1,2-diazine-3-carboxylate (2 g, 11.89 mmol) in MeOH (20 mL) was added N 2 H 4 .H 2O (3.81 g, 95.15 mmol) (80% purity) was stirred at 25 °C for 16 h. After completion, the reaction was evaporated to remove MeOH, filtered and washed with MeCN (30 mL) to give 6-methoxy-1,2-diazine-3-carbohydrazide (1800 mg, 9.85 mmol, 82.80%) as a white solid.

[0155] LCMS: m / z (M+H) + = 169.0.

[0156] Step B: N'-(2-chloroacetyl)-6-methoxy-1,2-diazine-3-carbohydrazide (3)

[0157] At 0 °C, TEA (2.97 mL, 21.41 mmol) and chloroacetyl chloride (0.85 mL, 10.70 mmol) were added to a solution of 6-methoxy-1,2-diazine-3-carbohydrazide (1800 mg, 10.70 mmol) in DCM (20 mL). The reaction was stirred at 25 °C for 16 h. After completion, the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 1:1 to 0:1) to give N'-(2-chloroacetyl)-6-methoxy-1,2-diazine-3-carbohydrazide (1600 mg, 6.54 mmol, 61.10%) as a yellow solid.

[0158] LCMS: m / z (M+H) + = 245.0.

[0159] Step C: 6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-3-methoxy-1,2-diazine (4)

[0160] At 25 °C, TEA (5.44 mL, 39.24 mmol) and 4-methylbenzenesulfonyl chloride (1620.94 mg, 8.50 mmol) were added to a solution of N'-(2-chloroacetyl)-6-methoxy-1,2-diazine-3-carbohydrazide (1600 mg, 6.54 mmol) in DCM (20 mL). The reaction was stirred at 25 °C for 16 h. After completion, the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1 to 10:1) to give 6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-3-methoxy-1,2-diazine (900 mg, 3.69 mmol, 56.47%) as a yellow solid.

[0161] LCMS: m / z (M+H) + = 227.0.

[0162] Step D: 4-Fluoro-N-((5-(6-methoxypyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)aniline (5)

[0163] To a solution of 6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-3-methoxy-1,2-diazine (200 mg, 0.66 mmol) in DMSO (2 mL) was added TEA (0.28 mL, 1.99 mmol) and 4-fluoroaniline (0.06 mL, 0.66 mmol). The reaction was stirred at 40 °C for 16 h. After completion, the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1 to 10:1) to give 4-fluoro-N-((5-(6-methoxypyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)aniline (70 mg, 0.12 mmol, 18.23%) as a yellow solid.

[0164] LCMS: m / z (M+H) + = 302.2.

[0165] Step E: 2-[2,4-Bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(6-methoxy-1,2-diazin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide

[0166] At 25 °C, to a solution of 4-fluoro-N-((5-(6-methoxypyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)aniline (20 mg, 0.06 mmol) in DCM (1 mL) was added TEA (0.03 mL, 0.20 mmol) and [2,4-bis(trifluoromethyl)phenyl]acetyl chloride (19.29 mg, 0.07 mmol). The reaction was stirred at 25 °C for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA conditions) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(6-methoxy-1,2-diazin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide (1.03 mg, 2.59%) as a white solid.

[0167] 1 1H NMR (400 MHz, CDCl 3 ) δ = 8.23 (d, J = 9.2 Hz, 1H), 7.91 - 7.84 (m, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.48 - 7.43 (m, 2H), 7.18 - 7.12 (m, 3H), 5.22 (s, 2H), 4.26 (s, 3H), 3.75 - 3.73 (m, 2H).

[0168] LCMS: m / z (M+H) + = 556.2

[0169] Example 3: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-morpholinopyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0170]

[0171] Step A: Methyl 6-(1,4-oxazin-4-yl)-1,2-diazine-3-carboxylate (2)

[0172] At 25 °C, to a solution of methyl 6-chloro-1,2-diazine-3-carboxylate (1 g, 5.79 mmol) in dioxane (10 mL) was added TEA (2.41 mL, 17.38 mmol) and 1,4-oxazine (0.61 g, 6.95 mmol). The reaction was stirred at 100 °C for 16 h. After completion, the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 2:1 to 1:1) to give methyl 6-(1,4-oxazin-4-yl)-1,2-diazine-3-carboxylate as a yellow solid (620 mg, 2.69 mmol, 46.40%).

[0173] LCMS: m / z (M+H) + = 224.2

[0174] Step B: 6-(1,4-oxazin-4-yl)-1,2-diazine-3-carbohydrazide (3)

[0175] At 25 °C, to a solution of methyl 6-(1,4-oxazin-4-yl)-1,2-diazine-3-carboxylate (0.6 g, 2.69 mmol) in MeOH (5 mL) was added N 2 H 4 .H 2 O (0.86 g, 21.50 mmol) (80% purity). The reaction was stirred at 25 °C for 16 h. After completion, the reaction was concentrated under reduced pressure. The residue was washed with petroleum ether (30 mL) and concentrated under reduced pressure to give 6-(1,4-oxazin-4-yl)-1,2-diazine-3-carbohydrazide as a white solid (550 mg, 2.37 mmol, 88.00%).

[0176] LCMS: m / z (M+H) + = 224.2

[0177] Step C: N'-(2-chloroacetyl)-6-(1,4-oxazin-4-yl)-1,2-diazine-3-carbohydrazide (4)

[0178] At 25 °C, to a solution of 6-(1,4-oxazin-4-yl)-1,2-diazine-3-carbohydrazide (500 mg, 2.24 mmol) in DCM (10 mL) was added TEA (0.62 mL, 4.48 mmol) and chloroacetyl chloride (0.21 mL, 2.69 mmol). The reaction was stirred at 25 °C for 16 h. After completion, the reaction was diluted with water (10 mL) and extracted with DCM (10 mL × 2). The organic phase was washed with brine (20 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure to give N'-(2-chloroacetyl)-6-(1,4-oxazin-4-yl)-1,2-diazine-3-carbohydrazide as a black solid (550 mg, 1.71 mmol, 76.20 %).

[0179] LCMS: m / z (M+H) + = 300.2.

[0180] Step D: 6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-3-(1,4-oxazin-4-yl)-1,2-diazine (5)

[0181] At 25 °C, to a solution of N'-(2-chloroacetyl)-6-(1,4-oxazin-4-yl)-1,2-diazine-3-carbohydrazide (600 mg, 2.00 mmol) in DCM (10 mL) was added TEA (1.67 mL, 12.01 mmol) and 4-methylbenzenesulfonyl chloride (496.14 mg, 2.60 mmol). The reaction was stirred at 25 °C for 16 h. After completion, the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 1:1 to 0:1) to give 6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-3-(1,4-oxazin-4-yl)-1,2-diazine as a yellow solid (390 mg, 1.22 mmol, 60.86 %).

[0182] LCMS: m / z (M+H) + = 282.0.

[0183] Step E: 6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-3-(1,4-oxazin-4-yl)-1,2-diazine (6)

[0184] At 25 °C, TEA (0.12 mL, 0.85 mmol) and 4-fluoroaniline (0.03 mL, 0.28 mmol) were added to a solution of 6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-3-(1,4-oxazin-4-yl)-1,2-diazine (80 mg, 0.28 mmol) in DMSO (1 mL). The reaction was stirred at 25 °C for 16 h. After completion, the reaction was diluted with water (20 mL), extracted with EtOAc (20 mL × 2), and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 0:1) to give 6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl]-3-(1,4-oxazin-4-yl)-1,2-diazine as a white solid (30 mg, 0.08 mmol, 26.68%).

[0185] LCMS: m / z (M+H) + = 357.2.

[0186] Step F: 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-((5-(6-(1,4-oxazin-4-yl)-1,2-diazin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide

[0187] At 0 °C, NaH (3.60 mg, 0.09 mmol) (60% purity, in oil) and [2,4-bis(trifluoromethyl)phenyl]acetyl chloride (16.31 mg, 0.06 mmol) were added to a solution of 6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl]-3-(1,4-oxazin-4-yl)-1,2-diazine (20 mg, 0.06 mmol) in THF (1 mL). The reaction was stirred at 25 °C for 16 h. After completion, the mixture was quenched with water (5 mL), extracted with EtOAc (10 mL × 2), and the organic layer was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA conditions) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-((5-(6-(1,4-oxazin-4-yl)-1,2-diazin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide as a white solid (2.35 mg, 6.72%).

[0188] 1 H NMR (400 MHz, CDCl 3)δ = 8.07 (d, J = 9.6 Hz, 1H), 7.89 (br d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.47 - 7.41 (m, 2H), 7.13 (t, J = 8.3 Hz, 2H), 6.99 (d, J = 9.6 Hz, 1H), 5.20 (s, 2H), 3.93 - 3.87 (m, 4H), 3.86 - 3.78 (m, 4H), 3.74 (s, 2H).

[0189] LCMS: m / z (M + H) + = 611.2.

[0190] Example 4: Synthesis of N - ((5 - (6 - aminopyridazin - 3 - yl) - 1,3,4 - oxadiazol - 2 - yl)methyl) - 2 - (2,4 - bis(trifluoromethyl)phenyl) - N - (4 - fluorophenyl)acetamide

[0191]

[0192] Step A: Methyl 6 - {bis[(4 - methoxyphenyl)methyl]amino}-1,2 - diazine - 3 - carboxylate (2)

[0193] At 25 °C, TEA (1.20 mL, 8.69 mmol) was added to methyl 6 - chloro - 1,2 - diazine - 3 - carboxylate (1 g, 5.79 mmol) and bis[(4 - methoxyphenyl)methyl]amine (1.64 g, 6.37 mmol) in dioxane (100 mL). The mixture was stirred at 100 °C for 18 h to give a yellow solution. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 0 to 50%) to give methyl 6 - {bis[(4 - methoxyphenyl)methyl]amino}-1,2 - diazine - 3 - carboxylate as a white solid (0.97 g, 2.47 mmol, 42.54%).

[0194] LCMS: m / z (M + H) + = 394.2.

[0195] Step B: 6 - {bis[(4 - methoxyphenyl)methyl]amino}-1,2 - diazine - 3 - carbohydrazide (3)

[0196] At 25 °C, N 2 H 4 .H 2O (1452.00 mg, 24.65 mmol) (80% purity). The mixture was stirred at 25 °C and N 2 for 18 h to give a brown solution. After completion, the mixture was concentrated under reduced pressure. The residue was purified by C18 silica gel column chromatography (trifluoroacetic acid / acetonitrile / water) to give 6-{bis[(4-methoxyphenyl)methyl]amino}-1,2-diazine-3-carbohydrazide (500 mg, 1.27 mmol, 51.55%) as a white solid.

[0197] LCMS: m / z (M+H) + = 394.2.

[0198] Step C: 6-{bis[(4-methoxyphenyl)methyl]amino}-N'-(2-chloroacetyl)-1,2-diazine-3-carbohydrazide (4)

[0199] In an ice bath, chloroacetyl chloride (0.10 mL, 1.27 mmol) was added to a solution of 6-{bis[(4-methoxyphenyl)methyl]amino}-1,2-diazine-3-carbohydrazide (500 mg, 1.27 mmol) and TEA (0.35 mL, 2.54 mmol) in DCM (20 mL). The mixture was stirred at 25 °C for 18 h to give a brown solution. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to give 6-{bis[(4-methoxyphenyl)methyl]amino}-N'-(2-chloroacetyl)-1,2-diazine-3-carbohydrazide (570 mg, 0.95 mmol, 74.45%) as a white solid.

[0200] LCMS: m / z (M+H) + = 470.2.

[0201] Step D: 6-{bis[(4-methoxyphenyl)methyl]amino}-3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazine (5)

[0202] In an ice bath, 4-methylbenzenesulfonyl chloride (462.47 mg, 2.43 mmol) was added to a solution of 6-{bis[(4-methoxyphenyl)methyl]amino}-N'-(2-chloroacetyl)-1,2-diazine-3-carbohydrazide (570 mg, 1.21 mmol) and TEA (1.01 mL, 7.28 mmol) in DCM (30 mL). The mixture was stirred at 25 °C and N 2Stir for 18 h to obtain a brown solution. After completion, concentrate the mixture under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to give 6-{bis[(4-methoxyphenyl)methyl]amino}-3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazine as a white solid (490 mg, 1.08 mmol, 89.39%).

[0203] LCMS: m / z (M+H) + = 452.2.

[0204] Step E: 6-{bis[(4-methoxyphenyl)methyl]amino}-3-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazine (6)

[0205] At 25 °C, to a solution of 6-{bis[(4-methoxyphenyl)methyl]amino}-3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazine (340 mg, 0.75 mmol) and 4-fluoroaniline (0.07 mL, 0.75 mmol) in DMF (20 mL) was added K 2 CO 3 (311.93 mg, 2.26 mmol) and KI (249.00 mg, 1.50 mmol). The mixture was stirred at 25 °C and N 2 for 18 h to obtain a brown solution. After completion, concentrate the mixture under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to give 6-{bis[(4-methoxyphenyl)methyl]amino}-3-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazine as a white solid (280 mg, 0.43 mmol, 56.54%).

[0206] LCMS: m / z (M+H) + = 527.4.

[0207] Step F: N-{[5-(6-{bis[(4-methoxyphenyl)methyl]amino}-1,2-diazin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide (7)

[0208] In an ice bath, to a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (25.84 mg, 0.09 mmol) in DCM (2 mL) was added chloroacetyl chloride (0.01 mL, 0.09 mmol) and a drop of DMF. The mixture was stirred at 0 °C and N 2Stir for 1 hour. Concentrate the mixture under reduced pressure and dissolve in THF (2 mL). Add this solution to a solution of 6-{bis[(4-methoxyphenyl)methyl]amino}-3-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazine (50 mg, 0.09 mmol) and NaH (5.40 mg, 0.13 mmol) (60% purity, in oil) in THF (4 mL), and stir at 25 °C for 18 hours to obtain a brown solution. After completion, quench the reaction mixture with H 2 O (10 mL), and extract with EtOAc (10 mL × 3). Combine the organic layers, dry over anhydrous Na 2 SO 4 and concentrate under reduced pressure. Purify the residue by prep-TLC (petroleum ether:EtOAc = 1:1) to obtain N-{[5-(6-{bis[(4-methoxyphenyl)methyl]amino}-1,2-diazin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide (20 mg, 0.01 mmol, 5.40%) as a white solid.

[0209] LCMS: m / z (M+H) + = 781.3.

[0210] Step G: N-{[5-(6-Amino-1,2-diazin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide

[0211] Stir N-{[5-(6-{bis[(4-methoxyphenyl)methyl]amino}-1,2-diazin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide (20 mg, 0.01 mmol) in TFA (3 mL) at 25 °C for 18 hours to obtain a brown solution. After completion, concentrate the mixture under reduced pressure. Purify the residue by high performance liquid chromatography (trifluoroacetic acid / acetonitrile / water) to obtain N-{[5-(6-amino-1,2-diazin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide (1.42 mg, 30.80%) as a white solid.

[0212] LCMS: m / z (M+H) + = 541.2.

[0213] Example 5: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-(pyrrolidin-3-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0214]

[0215] Step A: Methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,5-dihydro-1H-pyrrol-3-yl)-1,2-diazine-3-carboxylate (2)

[0216] At 25 °C and N 2 under, to a solution of methyl 6-chloro-1,2-diazine-3-carboxylate (1 g, 5.79 mmol) in DMF (50 mL) was added 2-methylpropan-2-yl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.71 g, 5.79 mmol), K 2 CO 3 (2.40 g, 17.38 mmol) and Pd(dppf)Cl 2 (0.42 g, 0.58 mmol). The mixture was stirred at 100 °C and N 2 under for 3 hours. After completion, the mixture was concentrated under reduced pressure to give a crude product. The residue was purified by silica gel column chromatography (EtOAc: petroleum ether = 1:10 to 1:1) to give methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,5-dihydro-1H-pyrrol-3-yl)-1,2-diazine-3-carboxylate (300 mg, 0.93 mmol, 16.1%).

[0217] LCMS: m / z (M+H) + = 306.0.

[0218] Step B: Methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)-1,2-diazine-3-carboxylate (3)

[0219] At 25 °C, to a solution of methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,5-dihydro-1H-pyrrol-3-yl)-1,2-diazine-3-carboxylate (300 mg, 1.13 mmol) in MeOH (40 mL) was added 10% Pd / C (30.0 mg). The mixture was stirred at 25 °C and H 2(15 Psi) Stir for 16 hours. After filtration, concentrate the filtrate under reduced pressure to obtain methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)-1,2-diazine-3-carboxylate (250 mg, 1.21 mmol, 83.73%) in the form of a yellow oil, which can be used in the next step without further purification.

[0220] LCMS: m / z (M + H - 100) + = 208.3.

[0221] Step C: 2-Methylpropan-2-yl 3-[6-(diazinylcarbonyl)-1,2-diazine-3-yl]tetrahydropyrrole-1-carboxylate (4)

[0222] At 25 °C, add N 2 H 4 .H 2 O (0.5 mL) (80% purity) to a solution of methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrole-3-yl)-1,2-diazine-3-carboxylate (200 mg, 0.62 mmol) in MeOH (10 mL). Stir the mixture at 25 °C for 16 hours. After completion, concentrate the mixture under reduced pressure to obtain 2-methylpropan-2-yl 3-[6-(diazinylcarbonyl)-1,2-diazine-3-yl]tetrahydropyrrole-1-carboxylate (150.0 mg, 0.46 mmol, 75.0%) in the form of a white solid.

[0223] LCMS: m / z (M + H) + = 308.0.

[0224] Step D: 2-Methylpropan-2-yl 3-(6-{[2-(2-chloroacetyl)diazinyl]carbonyl}-1,2-diazine-3-yl)tetrahydropyrrole-1-carboxylate (5)

[0225] In an ice bath, add chloroacetyl chloride (0.20 mL, 2.51 mmol) to a solution of 2-methylpropan-2-yl 3-[6-(diazinylcarbonyl)-1,2-diazine-3-yl]tetrahydropyrrole-1-carboxylate (700 mg, 2.28 mmol) and TEA (0.63 mL, 4.56 mmol) in DCM (100 mL). Stir the mixture at 25 °C and N 2Stir for 18 hours to obtain a brown solution. After completion, concentrate the mixture under reduced pressure. The residue is purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to obtain 3-(6-{[2-(2-chloroacetyl)diazanyl]carbonyl}-1,2-diazin-3-yl)pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (700 mg, 1.46 mmol, 64.06%) in the form of a white solid.

[0226] LCMS: m / z (M + H - 56) + = 328.0.

[0227] Step E: 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (6)

[0228] In an ice bath, add 4-methylbenzenesulfonyl chloride (695.35 mg, 3.65 mmol) to a solution of 3-(6-{[2-(2-chloroacetyl)diazanyl]carbonyl}-1,2-diazin-3-yl)pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (700 mg, 1.46 mmol) and TEA (1.52 mL, 10.94 mmol) in DCM (100 mL). Stir the mixture at 25 °C for 18 hours to obtain a brown solution. Concentrate the mixture under reduced pressure. The residue is purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to obtain 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (300 mg, 0.74 mmol, 40.47%) in the form of a white solid.

[0229] LCMS: m / z (M - 56 + H) + = 310.0.

[0230] Step F: 3-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazin-3-yl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (7)

[0231] At 25 °C, add K to a solution of 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (270 mg, 0.74 mmol) and 4-fluoroaniline (0.07 mL, 0.74 mmol) in DMSO (20 mL). 2 CO 3(204.00 mg, 1.48 mmol) and KI (122.52 mg, 0.74 mmol). The mixture was stirred at 25 °C for 18 h to give a brown solution. After completion, the reaction mixture was diluted with EtOAc (200 mL) and washed with H 2 O (200 mL). The organic layer was dried over anhydrous Na 2 SO 4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to afford 3-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazin-3-yl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester as a white solid (290 mg, 0.53 mmol, 71.36%).

[0232] LCMS: m / z (M+H-56) + = 385.2.

[0233] Step G: 3-(6-{5-[({2-[2,4-Bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}-1,2-diazin-3-yl)pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (8)

[0234] Under an ice bath and N 2 2, [2,4-Bis(trifluoromethyl)phenyl]acetic acid (111.21 mg, 0.41 mmol) was added to a solution of (1-chloro-2-methylprop-1-enyl)dimethylamine (0.05 mL, 0.41 mmol) in CH 3 CN (2 mL). The mixture was stirred at 0 °C for 1 h. Then at 0 °C, the mixture was added to a solution of 3-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazin-3-yl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (150 mg, 0.34 mmol) and DMAP (62.41 mg, 0.51 mmol) in CH 3 CN (2 mL). The mixture was stirred at 25 °C for 2 h to give a yellow solution. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 0 to 100%) to afford 3-(6-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}-1,2-diazin-3-yl)pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester as a white solid (80 mg, 0.10 mmol, 30.44%).

[0235] LCMS: m / z (M + H - 56) + = 639.4

[0236] Step H: 2-[2,4-Bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[6-(tetrahydro-1H-pyrrol-3-yl)-1,2-diazin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide

[0237] At 25 °C, stir 3-(6-{5-[({2-[2,4-Bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}-1,2-diazin-3-yl)tetrahydro-1H-pyrrole-1-carboxylic acid 2-methylprop-2-yl ester (60 mg, 0.09 mmol) in TFA (3 mL) for 18 h to obtain a brown solution. After completion, concentrate the mixture under reduced pressure. The residue is purified by HPLC (TFA / acetonitrile / water) to give 2-[2,4-Bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[6-(tetrahydro-1H-pyrrol-3-yl)-1,2-diazin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide (24.77 mg, 0.04 mmol, 45.92%) as a white solid.

[0238] 1 H NMR (400 MHz, CDCl 3 ) δ 8.19 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 19.3 Hz, 3H), 7.49 (d, J = 8.0 Hz, 1H), 7.37 (dd, J = 8.6, 4.7 Hz, 2H), 7.07 (t, J = 8.2 Hz, 2H), 5.12 (s, 2H), 3.73 (d, J = 67.8 Hz, 9H), 2.52 (s, 1H).

[0239] LCMS: m / z (M + H) + = 595.4

[0240] Example 6: Synthesis of 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(pyrrolidin-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0241]

[0242] Step A: Methyl 5-(1-{[(2-Methylprop-2-yl)oxy]carbonyl}-2,5-dihydro-1H-pyrrol-3-yl)pyridine-2-carboxylate (2)

[0243] At 25 °C, to a solution of methyl 5-chloropyridine-2-carboxylate (1 g, 5.83 mmol) in DMF (10 mL) was added 2-methylpropyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1.72 g, 5.83 mmol), Pd(dppf)Cl 2 (0.43 g, 0.58 mmol) and K 2 CO 3 (1.61 g, 11.66 mmol). The reaction was stirred at 100 °C and N 2 for 3 h. After completion, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 0 to 40%) to give methyl 5-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,5-dihydro-1H-pyrrol-3-yl)pyridine-2-carboxylate (900 mg, 2.96 mmol, 50.85%) as a white solid.

[0244] LCMS: m / z (M+H) + = 305.2.

[0245] Step B: Methyl 5-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)pyridine-2-carboxylate (3)

[0246] At 25 °C and H 2 under, to a solution of methyl 5-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,5-dihydro-1H-pyrrol-3-yl)pyridine-2-carboxylate (1 g, 3.29 mmol) in MeOH (10 mL) was added 10% Pd / C (100 mg). The reaction was stirred at 25 °C and H 2 (15 Psi) for 16 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to give methyl 5-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)pyridine-2-carboxylate (950 mg, 2.79 mmol, 84.65%) as a white solid.

[0247] LCMS: m / z (M+H) + = 307.0.

[0248] Step C: 2-Methylpropyl 3-[2-(diazanylcarbonyl)pyridin-5-yl]tetrahydro-1H-pyrrole-1-carboxylate (4)

[0249] At 25 °C, hydrazine hydrate (0.94 mL, 15.50 mmol) (80% purity) was added to a solution of methyl 5-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)pyridine-2-carboxylate (0.95 g, 3.10 mmol) in MeOH (10 mL). The reaction was stirred at 25 °C for 18 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to give 2-methylpropan-2-yl 3-[2-(diazinylcarbonyl)pyridin-5-yl]tetrahydro-1H-pyrrole-1-carboxylate (900 mg, 2.64 mmol, 85.26%) as a white solid.

[0250] LCMS: m / z (M+H) + = 307.2.

[0251] Step D: 2-Methylpropan-2-yl 3-(2-{[2-(2-chloroacetyl)diazinyl]carbonyl}pyridin-5-yl)tetrahydro-1H-pyrrole-1-carboxylate (5)

[0252] At 0 °C, chloroacetyl chloride (0.26 mL, 3.23 mmol) and triethylamine (1.63 mL, 11.75 mmol) were added to a solution of 2-methylpropan-2-yl 3-[2-(diazinylcarbonyl)pyridin-5-yl]tetrahydro-1H-pyrrole-1-carboxylate (900 mg, 2.94 mmol) in DCM (10 mL). The reaction was stirred at 25 °C and N 2 for 18 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 0 to 5%) to give 2-methylpropan-2-yl 3-(2-{[2-(2-chloroacetyl)diazinyl]carbonyl}pyridin-5-yl)tetrahydro-1H-pyrrole-1-carboxylate (850 mg, 2.22 mmol, 75.58%) as a yellow oil.

[0253] LCMS: m / z (M+H) + = 383.2.

[0254] Step E: 2-Methylpropan-2-yl 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridin-3-yl}tetrahydro-1H-pyrrole-1-carboxylate (6)

[0255] At 0 °C, to a solution of 3-(2-{[2-(2-chloroacetyl)diazanyl]carbonyl}pyridin-5-yl)pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (850 mg, 2.22 mmol) in DCM (10 mL) was added TEA (1.23 mL, 8.88 mmol) and 4-methylbenzenesulfonyl chloride (0.85 mL, 4.44 mmol). The reaction was stirred at 25 °C for 18 h. After completion, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to give 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridin-3-yl}pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (700 mg, 1.92 mmol, 86.42%) as a yellow oil.

[0256] LCMS: m / z (M - 56 + H) + = 309.0.

[0257] Step F: 3-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyridin-3-yl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (7)

[0258] At 25 °C, to a solution of 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridin-3-yl}pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (650 mg, 1.78 mmol) and 4-fluoroaniline (0.21 mL, 0.22 mmol) in DMF (3 mL) was added potassium iodide (295.75 mg, 1.78 mmol) and K 2 CO 3 (492.45 mg, 3.56 mmol). The reaction was stirred at 25 °C and N 2 for 18 h. After completion, the reaction mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to give 3-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyridin-3-yl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (480 mg, 0.98 mmol, 55.17%) as a yellow oil.

[0259] LCMS: m / z (M + H) + = 440.2.

[0260] Step G: 2-Methylpropan-2-yl 3-(6-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyridin-3-yl)pyrrolidine-1-carboxylate (8)

[0261] Under an ice bath and N 2 To a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (61.92 mg, 0.23 mmol) in CH 3 CN (2 mL) was added (1-chloro-2-methylprop-1-enyl)dimethylamine (0.04 mL, 0.27 mmol). The mixture was stirred at 0 °C for 1 h. Then at 0 °C, the mixture was added to a solution of 2-methylpropan-2-yl 3-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyridin-3-yl]pyrrolidine-1-carboxylate (100 mg, 0.23 mmol) and DMAP (62.41 mg, 0.51 mmol) in CH 3 CN (2 mL). The mixture was stirred at 25 °C for 16 h to give a yellow solution. After completion, the mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to give 2-methylpropan-2-yl 3-(6-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyridin-3-yl)pyrrolidine-1-carboxylate (82 mg, 0.12 mmol, 51.96%) as a yellow oil.

[0262] LCMS: m / z (M + H - 56) + = 638.3.

[0263] Step H: 2-[2,4-Bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[5-(tetrahydro-1H-pyrrol-3-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide

[0264] At 0 °C, to a solution of 2-methylpropan-2-yl 3-(6-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyridin-3-yl)pyrrolidine-1-carboxylate (100 mg, 0.14 mmol) in DCM (2 mL) was added TFA (0.5 mL, 6.71 mmol). The mixture was stirred at 25 °C and N 2 for 3 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (NH 4 CO3 Condition) Purification gave 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[5-(tetrahydro-1H-pyrrol-3-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide (28 mg, 0.05 mmol, 31.51%) as a white solid.

[0265] 1 1H NMR (400 MHz, CDCl 3 ) δ 8.64 (d, J = 1.9 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.82 - 7.75 (m, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.46 (dd, J = 8.9, 4.8 Hz, 2H), 7.14 (dd, J = 8.7, 8.2 Hz, 2H), 5.17 (s, 2H), 3.72 (s, 2H), 3.53 - 3.44 (m, 1H), 3.41 - 3.31 (m, 1H), 3.29 - 3.13 (m, 2H), 2.94 (m, 1H), 2.36 (m, 1H), 1.97 - 1.93 (m, 1H).

[0266] LCMS: m / z (M + H) + = 594.2.

[0267] Example 7: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-((5-(6-(piperidin-4-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0268]

[0269] Step A: Methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)-1,2-diazine-3-carboxylate (2)

[0270] At 25 °C, to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (3583.59 mg, 11.59 mmol) in DMF (20 mL) was added K 2 CO 3(2402.50 mg, 17.38 mmol), methyl 6-chloro-1,2-diazine-3-carboxylate (1000 mg, 5.79 mmol) and bis[5-(diphenylphosphoryl)cyclopent-1,3-dienyl]-λ2-iron(II) palladium(II) chloride (212.00 mg, 0.29 mmol). The reaction was stirred at 100 °C and N 2 for 1 hour. After completion, the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 3:1) to give methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)-1,2-diazine-3-carboxylate (300 mg, 0.92 mmol, 15.89%) as a white solid.

[0271] LCMS: m / z (M+H) + = 320.2.

[0272] Step B: Methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-4-yl)-1,2-diazine-3-carboxylate (3)

[0273] At 25 °C, 10% Pd / C (133.29 mg, 0.13 mmol) was added to a solution of methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)-1,2-diazine-3-carboxylate (400 mg, 1.25 mmol) in MeOH (5 mL) and THF (5 mL). The mixture was stirred at 25 °C and H 2 (15 Psi) for 4 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 3:1) to give methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-4-yl)-1,2-diazine-3-carboxylate (90 mg, 0.28 mmol, 22.36%) as a white solid.

[0274] LCMS: m / z (M+H - 56) + = 266.0.

[0275] Step C: 2-Methylpropan-2-yl 4-[3-(diazinylcarbonyl)-1,2-diazin-6-yl]hexahydropyridine-1-carboxylate (4)

[0276] At 25 °C, hydrazine hydrate (0.08 mL, 1.40 mmol) (80% purity) was added to a solution of methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}piperidin-4-yl)-1,2-diazine-3-carboxylate (90 mg, 0.28 mmol) in MeOH (3 mL). The mixture was stirred at 25 °C for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:1) to give 2-methylpropan-2-yl 4-[3-(diazinylcarbonyl)-1,2-diazin-6-yl]piperidine-1-carboxylate (80 mg, 0.24 mmol, 84.45%) as a white solid.

[0277] LCMS: m / z (M+H-56) + = 266.0.

[0278] Step D: 2-Methylpropan-2-yl 4-(6-{[2-(2-chloroacetyl)diazinyl]carbonyl}-1,2-diazin-3-yl)piperidine-1-carboxylate (5)

[0279] At 0 °C, TEA (0.06 mL, 0.47 mmol) and chloroacetyl chloride (0.02 mL, 0.31 mmol) were added to a solution of 2-methylpropan-2-yl 4-[3-(diazinylcarbonyl)-1,2-diazin-6-yl]piperidine-1-carboxylate (100 mg, 0.31 mmol) in DCM (4 mL). The mixture was stirred at 25 °C for 1 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1 to 5:1) to give 2-methylpropan-2-yl 4-(6-{[2-(2-chloroacetyl)diazinyl]carbonyl}-1,2-diazin-3-yl)piperidine-1-carboxylate (110 mg, 0.26 mmol, 84.41%) as a yellow oil.

[0280] LCMS: m / z (M+H-56) + = 342.0.

[0281] Step E: 2-Methylpropan-2-yl 4-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}piperidine-1-carboxylate (6)

[0282] At 20 °C, to a solution of 4-(6-{[2-(2-chloroacetyl)diazinyl]carbonyl}-1,2-diazin-3-yl)hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (20 mg, 0.05 mmol) in DCM (5 mL) was added TEA (0.03 mL, 0.20 mmol) and 4-methylbenzenesulfonyl chloride (19.17 mg, 0.10 mmol). The mixture was stirred at 20 °C for 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:2) to give 4-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (10 mg, 0.03 mmol, 49.76%) as a white solid.

[0283] LCMS: m / z (M+H-56) + = 324.0.

[0284] Step F: 4-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazin-3-yl]hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (7)

[0285] At 20 °C, to a solution of 4-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (100 mg, 0.26 mmol) in DMF (4 mL) was added K 2 CO 3 (72.77 mg, 0.53 mmol), 4-fluoroaniline (0.03 mL, 0.26 mmol) and potassium iodide (43.70 mg, 0.26 mmol). The mixture was stirred at 20 °C for 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:2) to give 4-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazin-3-yl]hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (60 mg, 0.13 mmol, 47.63%) as a white solid.

[0286] LCMS: m / z (M+H-56) + = 399.2.

[0287] Step G: 2-Methyl-2-propanyl 4-(6-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}-1,2-diazin-3-yl)piperidine-1-carboxylate (8)

[0288] At 0 °C, (1-chloro-2-methylprop-1-enyl)dimethylamine (0.01 mL, 0.03 mmol) was added to a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (5.99 mg, 0.02 mmol) in acetonitrile (2 mL). The mixture was stirred at 0 °C for 1 hour. Then at 0 °C, the mixture was added to a solution of 2-methyl-2-propanyl 4-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazin-3-yl]piperidine-1-carboxylate (10 mg, 0.02 mmol) and DMAP (4.03 mg, 0.03 mmol) in acetonitrile (2 mL). The mixture was stirred at 20 °C for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:1) to give 2-methyl-2-propanyl 4-(6-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}-1,2-diazin-3-yl)piperidine-1-carboxylate as a yellow solid (4 mg, 0.01 mmol, 24.37%).

[0289] LCMS: m / z(M + H - 56) + = 653.0.

[0290] Step H: 2-[2,4-Bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[6-(piperidin-4-yl)-1,2-diazin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide

[0291] At 20 °C, trifluoroacetic acid (TFA, 0.5 mL, 6.71 mmol) was added to a solution of 2-methylpropyl 4-(6-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}-1,2-diazin-3-yl)piperidine-1-carboxylate (30 mg, 0.04 mmol) in DCM (2 mL). The mixture was stirred at 20 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by p-HPLC (FA conditions) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[6-(piperidin-4-yl)-1,2-diazin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide (1.16 mg, 4.50%) as a white solid.

[0292] 1 H NMR (400 MHz, MeOD) δ 8.42 (d, J = 8.7 Hz, 1H), 7.95 (s, 1H), 7.93 - 7.88 (m, 2H), 7.76 (s, 1H), 7.63 (dd, J = 8.8, 4.7 Hz, 2H), 7.29 (t, J = 8.6 Hz, 2H), 5.29 (s, 2H), 3.87 (s, 2H), 3.60 - 3.48 (m, 3H), 3.18 (d, J = 20.3 Hz, 2H), 2.24 (dd, J = 50.0, 11.3 Hz, 4H).

[0293] LCMS: m / z (M + H) + = 609.4.

[0294] Example 8: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-((5-(6-(piperidin-3-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0295]

[0296] Step A: Methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}-1,2,5,6-tetrahydropyridin-3-yl)-1,2-diazine-3-carboxylate (2)

[0297] At 25 °C, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid 2-methylpropyl ester (5.91 g, 19.12 mmol) and K2 CO 3 (7.21 g, 52.15 mmol) and Pd(dppf)Cl 2 (0.64 g, 0.87 mmol). The reaction was degassed three times with N 2 and stirred at 100 °C under N 2 for 4 h. After completion, the mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:1) to give methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}-1,2,5,6-tetrahydropyridin-3-yl)-1,2-diazine-3-carboxylate (1000 mg, 2.29 mmol, 13.15%) as a black solid.

[0298] LCMS: m / z (M+H) + = 320.0.

[0299] Step B: Methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-yl)-1,2-diazine-3-carboxylate (3)

[0300] At 25 °C, 10% Pd / C (100 mg) was added to a solution of methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}-1,2,5,6-tetrahydropyridin-3-yl)-1,2-diazine-3-carboxylate (1000 mg, 3.13 mmol) in MeOH (10 mL) and THF (10 mL). The reaction was degassed three times with H 2 and stirred at 25 °C under H 2 (15 Psi) for 4 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:1) to give methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-yl)-1,2-diazine-3-carboxylate (510 mg, 1.54 mmol, 49.23%) as a white solid.

[0301] LCMS: m / z (M+H) + = 322.2.

[0302] Step C: 2-Methylpropan-2-yl 3-[6-(diazinylcarbonyl)-1,2-diazin-3-yl]hexahydropyridine-1-carboxylate (4)

[0303] At 25 °C, N was added to a solution of methyl 6-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}hexahydropyridin-3-yl)-1,2-diazine-3-carboxylate (530 mg, 1.65 mmol) in MeOH (5 mL)2 H 4 .H 2 O (515.97 mg, 8.25 mmol) (80% purity). The reaction was stirred at 25 °C and N 2 for 16 h. After completion, the mixture was evaporated under reduced pressure to give 3-[6-(diazinylcarbonyl)-1,2-diazin-3-yl]hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (460 mg, 1.37 mmol, 82.96%) as a black oil, which was used in the next step without further purification.

[0304] LCMS: m / z (M+H) + = 322.2.

[0305] Step D: 3-(6-{[2-(2-chloroacetyl)diazinyl]carbonyl}-1,2-diazin-3-yl)hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (5)

[0306] At 25 °C, TEA (0.29 mL, 2.10 mmol) and chloroacetyl chloride (0.11 mL, 1.40 mmol) were added to a solution of 3-[6-(diazinylcarbonyl)-1,2-diazin-3-yl]hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (450 mg, 1.40 mmol) in DCM (5 mL). The reaction was stirred at 25 °C for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1 to 5:1) to give 3-(6-{[2-(2-chloroacetyl)diazinyl]carbonyl}-1,2-diazin-3-yl)hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (460 mg, 1.02 mmol, 73.11%) as a yellow oil.

[0307] LCMS: m / z (M+H - 56) + = 342.2.

[0308] Step E: 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (6)

[0309] At 25 °C, TEA (0.56 mL, 4.02 mmol) and 4-methylbenzenesulfonyl chloride (383.33 mg, 2.01 mmol) were added to a solution of 3-(6-{[2-(2-chloroacetyl)diazinyl]carbonyl}-1,2-diazin-3-yl)hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (400 mg, 1.01 mmol) in DCM (5 mL). The reaction was stirred at 25 °C and N 2Stir for 16 h. After completion, concentrate the mixture under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 10:1 to 1:2) to give 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (280 mg, 0.71 mmol, 70.39%) as a yellow solid.

[0310] LCMS: m / z (M+H) + = 380.2.

[0311] Step F: 3-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazin-3-yl]hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (7)

[0312] At 25 °C, to a solution of 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (260 mg, 0.68 mmol) in DMSO (5 mL) was added K 2 CO 3 (189.19 mg, 1.37 mmol), 4-fluoroaniline (0.07 mL, 0.68 mmol) and potassium iodide (0.08 mL, 0.68 mmol). The reaction was stirred at 25 °C and N 2 for 4 h. After completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL × 2). The organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 10:1 to 1:2) to give 3-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazin-3-yl]hexahydropyridine-1-carboxylic acid 2-methylpropan-2-yl ester (280 mg, 0.52 mmol, 76.29%) as a yellow solid.

[0313] LCMS: m / z (M+H) + = 455.2.

[0314] Step G: tert-Butyl 3-(6-(5-((2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamido)methyl)-1,3,4-oxadiazol-2-yl)pyridazin-3-yl)piperidine-1-carboxylate (8)

[0315] At 0 °C, 1-chloro-N,N,2-trimethylpropenylamine (0.02 mL, 0.17 mmol) was added to a solution of 2-(2,4-bis(trifluoromethyl)phenyl)acetic acid (30 mg, 0.11 mmol) in acetonitrile (1 mL). The mixture was stirred at 0 °C for 30 minutes, and then at 0 °C, the mixture was added to a solution of tert-butyl 3-(6-(5-(((4-fluorophenyl)amino)methyl)-1,3,4-oxadiazol-2-yl)pyridazin-3-yl)piperidine-1-carboxylate (50.10 mg, 0.11 mmol) and DMAP (20.20 mg, 0.17 mmol) in acetonitrile (1 mmol). The reaction was stirred at 25 °C for 16 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:1) to give tert-butyl 3-(6-(5-((2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamido)methyl)-1,3,4-oxadiazol-2-yl)pyridazin-3-yl)piperidine-1-carboxylate (30 mg, 0.03 mmol, 27.19%) as a yellow oil.

[0316] LCMS: m / z(M + H - 56) + = 653.3.

[0317] Step H: 2-[2,4-Bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[6-(hexahydropyridin-3-yl)-1,2-diazin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide

[0318] At 25 °C, TFA (0.3 mL, 4.03 mmol) was added to a solution of tert-butyl 3-(6-(5-((2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamido)methyl)-1,3,4-oxadiazol-2-yl)pyridazin-3-yl)piperidine-1-carboxylate (30 mg, 0.04 mmol) in DCM (1 mL). The reaction was stirred at 25 °C for 3 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA conditions) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[6-(hexahydropyridin-3-yl)-1,2-diazin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide (23.10 mg, 0.03 mmol, 81.72%) as a white solid.

[0319] 1 H NMR (400 MHz, CDCl 3)δ = 8.29 - 8.23 (m, 2H), 7.83 - 7.71 (m, 2H), 7.66 - 7.51 (m, 2H), 7.45 - 7.34 (m, 2H), 7.08 (t, J = 8.3 Hz, 2H), 5.14 (s, 2H), 3.67 (s, 2H), 3.66 - 3.37 (m, 4H), 2.99 (m, 1H), 2.17 (m, 1H), 2.06 - 1.81 (m, 3H).

[0320] LCMS: m / z (M + H) + = 609.2.

[0321] Example 9: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(pyrrolidin-3-yl)pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0322]

[0323] Step A: 2-Methylpropyl 3-[5-(methoxycarbonyl)pyrazin-2-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate (2)

[0324] At 25 °C, to a solution of 2-methylpropyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (1632.24 mg, 5.53 mmol) in dioxane (15 mL) and H 2 O (0.15 mL) was added K 2 CO 3 (1910.42 mg, 13.82 mmol), methyl 5-bromopyrazine-2-carboxylate (1000 mg, 4.61 mmol) and bis[5-(diphenylphosphino)cyclopent-1,3-dienyl]-λ2-iron(II) chloride palladium (168.58 mg, 0.23 mmol). The mixture was stirred at 100 °C and N 2 for 1 hour. After completion, the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:1) to give 2-methylpropyl 3-[5-(methoxycarbonyl)pyrazin-2-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate as a white solid (800 mg, 2.62 mmol, 56.86%).

[0325] LCMS: m / z (M + H) + = 306.2.

[0326] Step B: 2-Methylpropan-2-yl 3-[5-(methoxycarbonyl)pyrazin-2-yl]pyrrolidine-1-carboxylate (3)

[0327] At 25 °C, 10% Pd / C (348.54 mg, 0.33 mmol) was added to a solution of 2-methylpropan-2-yl 3-[5-(methoxycarbonyl)pyrazin-2-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate (1000 mg, 3.28 mmol) in MeOH (2.5 mL) and THF (2.5 mL). The reaction was degassed three times and stirred at 25 °C and H 2 for 4 h at 15 psi. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 3:1) to give 2-methylpropan-2-yl 3-[5-(methoxycarbonyl)pyrazin-2-yl]pyrrolidine-1-carboxylate as a white solid (600 mg, 1.85 mmol, 56.63%). 2 (15 psi) for 4 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 3:1) to give 2-methylpropan-2-yl 3-[5-(methoxycarbonyl)pyrazin-2-yl]pyrrolidine-1-carboxylate as a white solid (600 mg, 1.85 mmol, 56.63%).

[0328] LCMS: m / z (M + H - 56) + = 252.0.

[0329] Step C: tert-Butyl 3-(5-(hydrazinecarbonyl)pyrazin-2-yl)pyrrolidine-1-carboxylate (4)

[0330] At 25 °C, hydrazine hydrate (0.45 mL, 7.81 mmol) (80% purity) was added to a solution of 2-methylpropan-2-yl 3-[5-(methoxycarbonyl)pyrazin-2-yl]pyrrolidine-1-carboxylate (480 mg, 1.56 mmol) in MeOH (8 mL). The mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure to give tert-Butyl 3-(5-(hydrazinecarbonyl)pyrazin-2-yl)pyrrolidine-1-carboxylate as a white solid (400 mg, 1.24 mmol, 79.17%).

[0331] LCMS: m / z (M + H - 56) + = 252.0.

[0332] Step D: tert-Butyl 3-(5-(2-(2-chloroacetyl)hydrazine-1-carbonyl)pyrazin-2-yl)pyrrolidine-1-carboxylate (5)

[0333] At 0 °C, to a solution of tert-butyl 3-(5-(hydrazinecarbonyl)pyrazin-2-yl)pyrrolidine-1-carboxylate (500 mg, 1.56 mmol) in DCM (10 mL) was added TEA (0.32 mL, 2.33 mmol) and chloroacetyl chloride (0.16 mL, 2.02 mmol). The mixture was stirred at 25 °C for 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 10:1 to 5:1) to give tert-butyl 3-(5-(2-(2-chloroacetyl)hydrazine-1-carbonyl)pyrazin-2-yl)pyrrolidine-1-carboxylate (600 mg, 1.43 mmol, 92.09%) as a white solid.

[0334] LCMS: m / z (M+H-56) + = 328.0.

[0335] Step E: 2-Methylpropyl 3-{5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl}pyrrolidine-1-carboxylate (6)

[0336] At 0 °C, to a solution of tert-butyl 3-(5-(2-(2-chloroacetyl)hydrazine-1-carbonyl)pyrazin-2-yl)pyrrolidine-1-carboxylate (600 mg, 1.56 mmol) in DCM (15 mL) was added TEA (0.87 mL, 6.25 mmol) and 4-methylbenzenesulfonyl chloride (596.01 mg, 3.13 mmol). The mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:2) to give 2-methylpropyl 3-{5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl}pyrrolidine-1-carboxylate (460 mg, 1.19 mmol, 76.42%) as a white solid.

[0337] LCMS: m / z (M+H-56) + = 310.0.

[0338] Step F: 2-Methylpropyl 3-[5-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]pyrrolidine-1-carboxylate (7)

[0339] At 20 °C, to a solution of 2-methylpropyl 3-{5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl}pyrrolidine-1-carboxylate (450 mg, 1.23 mmol) in DMF (4 mL) was added K 2 CO3 (340.00 mg, 2.46 mmol), 4-fluoroaniline (0.12 mL, 1.23 mmol), and potassium iodide (204.20 mg, 1.23 mmol). The mixture was stirred at 20 °C for 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:1) to give 3-[5-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester as a white solid (200 mg, 0.43 mmol, 35.07%).

[0340] LCMS: m / z (M+H - 56) + = 385.2.

[0341] Step G: 3-(5-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrazin-2-yl)pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (8)

[0342] At 0 °C, (1-chloro-2-methylprop-1-enyl)dimethylamine (0.05 mL, 0.03 mmol) was added to a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (61.78 mg, 0.23 mmol) in ACN (2 mL). The mixture was stirred at 0 °C for 1 h. Then, at 0 °C, the mixture was added to a solution of 3-[5-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (100 mg, 0.23 mmol) and DMAP (41.60 mg, 0.34 mmol) in acetonitrile (2 mL). The mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:1) to give 3-(5-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrazin-2-yl)pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester as a yellow solid (40 mg, 0.05 mmol, 24.10%).

[0343] LCMS: m / z (M+H - 56) + = 639.4.

[0344] Step H: 2-[2,4-Bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[5-(tetrahydro-1H-pyrrol-3-yl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide

[0345] At 25 °C, TFA (0.5 mL, 6.71 mmol) was added to a solution of 3-(5-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrazin-2-yl)tetrahydro-1H-pyrrole-1-carboxylic acid 2-methylpropan-2-yl ester (40 mg, 0.06 mmol) in DCM (2 mL). The mixture was stirred at 25 °C for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by p-HPLC (FA conditions) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[5-(tetrahydro-1H-pyrrol-3-yl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide (3.2 mg, 0.01 mmol, 9.35%) as a white solid.

[0346] 1 H NMR (400 MHz, MeOD) δ 9.34 (s, 1H), 8.83 (d, J = 1.1 Hz, 1H), 8.54 (s, 1H), 7.91 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.62 (dd, J = 8.8, 4.8 Hz, 2H), 7.30 (t, J = 8.6 Hz, 2H), 5.26 (s, 2H), 4.01 (dd, J = 14.1, 7.1 Hz, 1H), 3.86 (s, 2H), 3.74 - 3.65 (m, 2H), 3.59 - 3.44 (m, 2H), 2.59 (dd, J = 13.4, 6.4 Hz, 1H), 2.27 (dd, J = 13.7, 7.0 Hz, 1H).

[0347] LCMS: m / z (M+H) + = 595.4.

[0348] Example 10: Synthesis of 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(pyrrolidin-3-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0349]

[0350] Step A: Methyl 2-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,5-dihydro-1H-pyrrol-3-yl)pyrimidine-5-carboxylate (2)

[0351] At 25 °C, to a solution of methyl 2-chloropyrimidine-5-carboxylate (2 g, 11.59 mmol) and 2-methylpropan-2-yl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (3.42 g, 11.59 mmol) in dioxane (210 mL) and H 2 O (7 mL) was added bis[5-(diphenylphosphino)cyclopent-1,3-dienyl]-λ2-iron(II) chloride palladium (0.42 g, 0.58 mmol) and K 2 CO 3 (4.81 g, 34.77 mmol). The mixture was stirred at 100 °C and N 2 for 1 h to give a brown solution. After completion, the mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 0 to 40%) to give methyl 2-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,5-dihydro-1H-pyrrol-3-yl)pyrimidine-5-carboxylate as a white solid (2 g, 6.42 mmol, 55.39%).

[0352] LCMS: m / z (M + H) + = 250.0.

[0353] Step B: Methyl 2-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)pyrimidine-5-carboxylate (3)

[0354] At 25 °C and H 2 under, to a solution of methyl 2-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}-2,5-dihydro-1H-pyrrol-3-yl)pyrimidine-5-carboxylate (2 g, 6.55 mmol) in MeOH (100 mL) and THF (100 mL) was added Pd / C (10%, 1.39 g, 1.31 mmol). The mixture was at 25 °C and H 2(15 Psi), stir for 18 hours to obtain a black solution. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to give methyl 2-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)pyrimidine-5-carboxylate (530 mg, 1.69 mmol, 25.79%) as a white solid.

[0355] LCMS: m / z (M - 56 + H) + = 252.2.

[0356] Step C: 2-Methylpropan-2-yl 3-[5-(diazanylcarbonyl)pyrimidin-2-yl]tetrahydro-1H-pyrrole-1-carboxylate (4)

[0357] At 25 °C, to a solution of methyl 2-(1-{[(2-methylpropan-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)pyrimidine-5-carboxylate (530 mg, 1.72 mmol) in MeOH (20 mL) was added N 2 H 4 .H 2 O (405.19 mg, 6.88 mmol) (80% purity). The mixture was stirred at 25 °C for 18 hours to obtain a yellow solution. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to give 2-methylpropan-2-yl 3-[5-(diazanylcarbonyl)pyrimidin-2-yl]tetrahydro-1H-pyrrole-1-carboxylate (500 mg, 1.30 mmol, 75.47%) as a white solid.

[0358] LCMS: m / z (M - 56 + H) + = 252.2.

[0359] Step D: 2-Methylpropan-2-yl 3-(5-{[2-(2-chloroacetyl)diazanyl]carbonyl}pyrimidin-2-yl)tetrahydro-1H-pyrrole-1-carboxylate (5)

[0360] In an ice bath, chloroacetyl chloride (0.14 mL, 1.79 mmol) was added to a solution of 3-[5-(diazoacetyl)pyrimidin-2-yl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (500 mg, 1.63 mmol) and TEA (0.45 mL, 3.25 mmol) in DCM (100 mL). The mixture was stirred at 25 °C for 18 h to give a brown solution. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 0 to 5%) to afford 3-(5-{[2-(2-chloroacetyl)diazo]carbonyl}pyrimidin-2-yl)pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (240 mg, 0.54 mmol, 33.38%) as a white solid.

[0361] LCMS: m / z (M + H - 56) + = 328.0.

[0362] Step E: 3-{5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl}pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (6)

[0363] In an ice bath, 4-methylbenzenesulfonyl chloride (238.41 mg, 1.25 mmol) was added to a solution of 3-(5-{[2-(2-chloroacetyl)diazo]carbonyl}pyrimidin-2-yl)pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (240 mg, 0.63 mmol) and TEA (0.52 mL, 3.75 mmol) in DCM (100 mL). The mixture was stirred at 25 °C for 18 h to give a brown solution. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to afford 3-{5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl}pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (155 mg, 0.42 mmol, 67.76%) as a white solid.

[0364] LCMS: m / z (M - 56 + H) + = 310.2.

[0365] Step F: 3-[5-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (7)

[0366] At 25 °C, to a solution of 3-{5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl}pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (155 mg, 0.42 mmol) and 4-fluoroaniline (0.04 mL, 0.42 mmol) in DMSO (3 mL) was added K 2 CO 3 (117.11 mg, 0.85 mmol) and KI (70.34 mg, 0.42 mmol). The mixture was stirred at 25 °C for 18 h to give a brown solution. Upon completion, the reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether:EtOAc = 1:1) to afford 3-[5-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (40 mg, 0.09 mmol, 21.43%) as a white solid.

[0367] LCMS: m / z (M+H-56) + = 385.2.

[0368] Step G: 3-(5-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrimidin-2-yl)pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (8)

[0369] Under an ice bath and N 2 , to a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (29.66 mg, 0.11 mmol) in CH 3 CN (2 mL) was added (1-chloro-2-methylprop-1-enyl)dimethylamine (0.01 mL, 0.11 mmol). The mixture was stirred at 0 °C for 0.5 h. Then at 0 °C, the mixture was added to a solution of 3-[5-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (40 mg, 0.09 mmol) and DMAP (16.64 mg, 0.14 mmol) in CH 3In the solution in CN (2 mL). The mixture was stirred at 25 °C for 2 h to obtain a yellow solution. After completion, the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether: EtOAc = 1:1) to give 3-(5-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrimidin-2-yl)pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (40 mg, 0.06 mmol, 63.41%) as a white solid.

[0370] LCMS: m / z (M - 56 + H) + = 639.3.

[0371] Step H: 2-[2,4-Bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[2-(tetrahydro-1H-pyrrol-3-yl)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide

[0372] At 25 °C, 3-(5-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrimidin-2-yl)pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (40 mg, 0.06 mmol) in TFA (3 mL) was stirred for 2 h to obtain a brown solution. After completion, the mixture was concentrated under reduced pressure. The crude product was purified by HPLC (TFA / acetonitrile / water) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[2-(tetrahydro-1H-pyrrol-3-yl)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide (10.32 mg, 0.02 mmol, 29.83%) as a white solid.

[0373] 1 H NMR (400 MHz, CDCl 3 ) δ 9.21 (s, 2H), 8.44 (s, 1H), 7.79 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.38 (dd, J = 8.7, 4.7 Hz, 2H), 7.11 (t, J = 8.2 Hz, 2H), 5.09 (s, 2H), 3.95 - 3.34 (m, 7H), 2.41 (d, J = 60.1 Hz, 2H).

[0374] LCMS: m / z (M + H) + = 595.2.

[0375] Example 11: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-(pyrrolidin-3-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)thioacetamide

[0376]

[0377] Step A: 2-[2,4-bis(trifluoromethyl)phenyl]-1-[(4-fluorophenyl)({5-[6-(tetrahydro-1H-pyrrol-3-yl)-1,2-diazin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)amino]ethane-1-thione

[0378] At 25 °C, 2,4-bis(4-methoxyphenyl)-2,4-dithio-2λ5,4λ5-1,3,2,4-dithiadiphosphetane (2.72 mg, 0.01 mmol) was added to a solution of 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[6-(tetrahydro-1H-pyrrol-3-yl)-1,2-diazin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide (4 mg, 0.01 mmol) in toluene (2 mL). The mixture was stirred at 120 °C and N 2 for 18 h to give a yellow solution. After completion, the mixture was concentrated under reduced pressure. The residue was purified by HPLC (TFA / ACN / H 2 O) to give 2-[2,4-bis(trifluoromethyl)phenyl]-1-[(4-fluorophenyl)({5-[6-(tetrahydro-1H-pyrrol-3-yl)-1,2-diazin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)amino]ethane-1-thione (1.05 mg, 25.55%) as a white solid.

[0379] LCMS: m / z (M+H) + = 611.2.

[0380] Examples 12 and 13: i) Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(1-methylpyrrolidin-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, and ii) Synthesis of 3-(6-(5-((2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamido)methyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1,1-dimethylpyrrolidinium

[0381]

[0382] Step A: 2-[2,4-Bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[5-(1-methyltetrahydro-1H-pyrrol-3-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide, and 3-(6-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyridin-3-yl)-1,1-dimethyltetrahydropyrrol-1-ium

[0383] At 25 °C, to a solution of 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[5-(tetrahydro-1H-pyrrol-3-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide (6 mg, 0.01 mmol) in ACN (2 mL) was added TEA (0.01 mL, 0.03 mmol) and methyl iodide (0.01 mL, 0.03 mmol). The reaction was stirred at 25 °C and N 2 for 1 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA conditions) to afford 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[5-(1-methyltetrahydro-1H-pyrrol-3-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide as a white solid (1.5 mg, 24.43%) and 3-(6-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyridin-3-yl)-1,1-dimethyltetrahydropyrrol-1-ium as a white solid (2 mg, 22.47%).

[0384] Example 12

[0385] LCMS: m / z (M + H) + = 608.2.

[0386] 1 H NMR (400 MHz, CDCl 3)δ 8.57 (d, J = 1.8 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.82 (dd, J = 8.1, 1.5 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.11 - 7.03 (m, 2H), 5.10 (s, 2H), 3.65 (s, 2H), 3.57 - 3.44 (m, 1H), 3.15 - 3.03 (m, 1H), 2.95 - 2.80 (m, 2H), 2.76 - 2.64 (m, 1H), 2.48 (s, 3H), 2.41 (m, 1H), 1.99 - 1.89 (m, 1H).

[0387] Example 13

[0388] LCMS: m / z (M + H) + = 622.2.

[0389] Example 14: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-cyclopentylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide

[0390]

[0391] Step A: Methyl 5-(cyclopent-1-enyl)pyridine-2-carboxylate (2)

[0392] At 25 °C, to a solution of methyl 5-chloropyridine-2-carboxylate (2 g, 11.66 mmol) in H 2 O (4 mL) and dioxane (40 mL) was added 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.31 g, 11.66 mmol), Pd(dppf)Cl 2 .CH 2 Cl 2 (0.95 g, 1.17 mmol) and K 2 CO 3 (4.83 g, 34.97 mmol). The mixture was stirred at 95 °C and N 2 for 3 h. After completion, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (100 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 0 to 70%) to give methyl 5-(cyclopent-1-enyl)pyridine-2-carboxylate (1.8 g, 8.41 mmol, 72.1%) as a yellow solid.

[0393] LCMS: m / z (M+H) + = 204.1

[0394] Step B: Methyl 5-cyclopentylpyridine-2-carboxylate (3)

[0395] At 25 °C, 10% Pd / C (20.0 mg) was added to a solution of methyl 5-(cyclopent-1-enyl)pyridine-2-carboxylate (200 mg, 0.98 mmol) in THF (5 mL) and MeOH (5 mL). The suspension was purged with H 2 several times and stirred under H 2 balloon at 25 °C for 16 h. After filtration, the filtrate was concentrated under reduced pressure to give methyl 5-cyclopentylpyridine-2-carboxylate (170 mg, 0.69 mmol, 70.55%) as a yellow solid.

[0396] LCMS: m / z (M+H) + = 206.2

[0397] Step C: 5-Cyclopentylpyridine-2-carbohydrazide (4)

[0398] At 25 °C, N 2 H 4 .H 2 O (0.49 mL, 7.79 mmol) (80% purity) was added to a solution of methyl 5-cyclopentylpyridine-2-carboxylate (1.6 g, 7.79 mmol) in MeOH (10 mL). The mixture was stirred at 25 °C for 2 h. After completion, the mixture was concentrated under reduced pressure to give 5-cyclopentylpyridine-2-carbohydrazide (98 mg, 0.45 mmol, 62.91%) as a yellow oil.

[0399] LCMS: m / z (M+H) + = 206.2

[0400] Step D: N'-(2-Chloroacetyl)-5-cyclopentylpyridine-2-carbohydrazide (5)

[0401] At 25 °C, to a solution of 5-cyclopentylpyridine-2-carbohydrazide (300 mg, 1.46 mmol) in DCM (10.0 mL) was added TEA (0.61 mL, 4.38 mmol) and chloroacetyl chloride (0.14 mL, 1.75 mmol). The mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to afford N'-(2-chloroacetyl)-5-cyclopentylpyridine-2-carbohydrazide (300 mg, 1.01 mmol, 69.21%) as a yellow oil.

[0402] LCMS: m / z (M+H) + = 281.7.

[0403] Step E: 2-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-5-cyclopentylpyridine (6)

[0404] At 25 °C, to a solution of N'-(2-chloroacetyl)-5-cyclopentylpyridine-2-carbohydrazide (100 mg, 0.34 mmol) in DCM (10.0 mL) was added TEA (0.19 mL, 1.35 mmol) and TsCl (128.81 mg, 0.67 mmol). The mixture was stirred at 25 °C and N 2 under for 2 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (MeCN:H 2 O (0.1% FA)) to afford 2-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-5-cyclopentylpyridine (50 mg, 0.189 mmol, 55.7%) as a yellow oil.

[0405] LCMS: m / z (M+H) + = 264.7.

[0406] Step F: 5-cyclopentyl-2-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyridine (7)

[0407] At 25 °C, to a solution of 2-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-5-cyclopentylpyridine (20 mg, 0.08 mmol) in DMSO (2.0 mL) was added 4-fluoroaniline (0.01 mL, 0.08 mmol), K 2 CO 3(20.96 mg, 0.15 mmol) and KI (12.59 mg, 0.08 mmol). The mixture was stirred at 25 °C for 2 h. After completion, the mixture was diluted with EtOAc (50 mL) and washed with water (100 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 1:1) to give 5-cyclopentyl-2-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyridine (10 mg, 0.03 mmol, 37.02%).

[0408] LCMS: m / z (M+H) + = 339.3.

[0409] Step G: 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[5-(5-cyclopentylpyridin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-N-(4-fluorophenyl)acetamide

[0410] At 0 °C and under N 2 atmosphere, (1-chloro-2-methylprop-1-enyl)dimethylamine (0.01 mL, 0.05 mmol) was added dropwise to a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (12.06 mg, 0.04 mmol) in MeCN (0.5 mL). The mixture was stirred at 0 °C for 30 min. Then at 0 °C, the mixture was added to a solution of 5-cyclopentyl-2-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyridine (15 mg, 0.04 mmol) and DMAP (16.25 mg, 0.13 mmol) in MeCN (2 mL). The resulting mixture was stirred at 0 °C and under N 2 atmosphere for 18 h. After completion, the mixture was evaporated. The residue was purified by reverse phase HPLC (MeCN:H 2 O (0.1% FA)) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[5-(5-cyclopentylpyridin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-N-(4-fluorophenyl)acetamide (10.0 mg, 0.02 mmol, 36.18%).

[0411] 11H NMR (400 MHz, MeOD) δ 8.53 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.88 - 7.70 (m, 3H), 7.61 (d, J = 7.9 Hz, 1H), 7.48 (dd, J = 8.7, 4.8 Hz, 2H), 7.16 (t, J = 8.4 Hz, 2H), 5.14 (s, 2H), 3.74 (d, J = 7.1 Hz, 2H), 3.12 - 2.99 (m, 1H), 2.06 (s, 2H), 1.89 - 1.48 (m, 6H).

[0412] LCMS: m / z (M + H) + = 593.4.

[0413] Example 15: Synthesis of 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0414]

[0415] Step A: Methyl 5-(2,5-dihydrofuran-3-yl)pyridine-2-carboxylate (2)

[0416] At 25 °C and N 2 under, to a stirred solution of 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (548.46 mg, 2.80 mmol) in dioxane (20 mL) and H 2 O (4 mL) was added methyl 5-chloropyridine-2-carboxylate (400 mg, 2.33 mmol), Pd(dppf)Cl 2 (170.58 mg, 0.23 mmol) and K 2 CO 3 (723.86 mg, 5.25 mmol). The resulting solution was stirred at 80 °C and N 2 under for 18 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: EtOAc = 0 to 70%) to give methyl 5-(2,5-dihydrofuran-3-yl)pyridine-2-carboxylate (210 mg, 1.02 mmol, 43.90%) as a yellow oil.

[0417] LCMS: m / z (M + H) + = 205.9.

[0418] Step B: Methyl 5-(tetrahydrofuran-3-yl)pyridine-2-carboxylate (3)

[0419] In H 2 Under H, to a solution of methyl 5-(2,5-dihydrofuran-3-yl)picolinate (210 mg, 1.02 mmol) in MeOH (10 mL) was added 10% Pd / C (10.89 mg, 0.10 mmol). The suspension was purged with H 2 several times and stirred under H 2 balloon at 25 °C for 16 h. After filtration, the filtrate was concentrated under reduced pressure to give methyl 5-(tetrahydrofuran-3-yl)picolinate (148 mg, 0.71 mmol, 69.79%) as a yellow solid.

[0420] LCMS: m / z (M+H) + = 208.0.

[0421] Step C: 5-(Tetrahydrofuran-3-yl)picolinohydrazide (4)

[0422] At 25 °C, 80% hydrazine hydrate (5 mL) solution was added dropwise to a solution of methyl 5-(tetrahydrofuran-3-yl)picolinate (148 mg, 0.71 mmol) in EtOH (2 mL). The mixture was stirred at 80 °C under N 2 for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with MeOH in DCM (1 / 100 to 1 / 10), to give 5-(tetrahydrofuran-3-yl)picolinohydrazide (98 mg, 0.45 mmol, 62.91%) as a yellow oil.

[0423] LCMS: m / z (M+H) + = 207.9.

[0424] Step D: N'-(2-Chloroacetyl)-5-(tetrahydrofuran-3-yl)picolinohydrazide (5)

[0425] At 0 °C, chloroacetyl chloride (53.08 mg, 0.47 mmol) was added to a solution of 5-(tetrahydrofuran-3-yl)picolinohydrazide (98 mg, 0.47 mmol) and TEA (0.10 mL, 0.70 mmol) in DCM (5 mL). The mixture was stirred at 25 °C for 2 h. After completion, the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to give N'-(2-chloroacetyl)-5-(tetrahydrofuran-3-yl)picolinohydrazide (130 mg, 0.37 mmol, 77.51%) as a yellow oil.

[0426] LCMS: m / z (M+H) + = 284.0.

[0427] Step E: 2-(Chloromethyl)-5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-oxadiazole (6)

[0428] At 0 °C, 4-methylbenzenesulfonyl chloride (83.86 mg, 0.44 mmol) was added to a solution of N'-(2-chloroacetyl)-5-(tetrahydrofuran-3-yl)pyridine hydrazide (130 mg, 0.37 mmol) and TEA (0.10 mL, 0.73 mmol) in DCM (5 mL). The reaction was stirred at 25 °C for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (MeCN:H 2 O (0.1% FA)) to give 2-(chloromethyl)-5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-oxadiazole (50 mg, 0.17 mmol, 45.69%) as a white solid.

[0429] LCMS: m / z (M+H) + = 266.0.

[0430] Step F: 4-Fluoro-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)aniline (7)

[0431] At 0 °C, K 2 CO 3 (52.52 mg, 0.38 mmol) and potassium iodide (31.54 mg, 0.19 mmol) were added to a stirred solution of 2-(chloromethyl)-5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-oxadiazole (50 mg, 0.19 mmol) and 4-fluoroaniline (0.02 mL, 0.23 mmol) in DMSO (5 mL). The reaction mixture was stirred at 25 °C for 18 h. After completion, the mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 1:1) to give 4-fluoro-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)aniline (40 mg, 0.09 mmol, 49.48%) as a yellow oil.

[0432] LCMS: m / z (M+H) + = 341.2.

[0433] Step G: 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0434] At 0 °C and under N 2 atmosphere, (1-chloro-2-methylprop-1-enyl)dimethylamine (29.44 mg, 0.22 mmol) was added dropwise to a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (39.98 mg, 0.15 mmol) in MeCN (0.5 mL). The mixture was stirred at 0 °C for 30 minutes. Then, at 0 °C, the mixture was added to a solution of 4-fluoro-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)aniline (50 mg, 0.15 mmol) and NaH (11.75 mg, 0.29 mmol) (60% purity, in oil) in THF (2 mL). The resulting mixture was stirred at 0 °C and under N 2 atmosphere for 18 hours. After completion, the mixture was evaporated. The residue was purified by reverse-phase HPLC (MeCN:H 2 O (0.1% FA)) to give 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide (10 mg, 0.02 mmol, 11.11%) as a white solid.

[0435] 1 1H NMR (400 MHz, MeOD) δ 8.69 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H), 8.00 (dd, J = 8.2, 2.1 Hz, 1H), 7.94 - 7.89 (m, 2H), 7.73 (d, J = 7.9 Hz, 1H), 7.64 - 7.57 (m, 2H), 7.28 (t, J = 8.6 Hz, 2H), 5.26 (s, 2H), 4.19 - 4.10 (m, 2H), 3.96 (dd, J = 15.9, 7.7 Hz, 1H), 3.85 (s, 2H), 3.81 (dd, J = 8.5, 6.5 Hz, 1H), 3.68 - 3.58 (m, 1H), 2.58 - 2.46 (m, 1H), 2.14 - 1.99 (m, 1H).

[0436] LCMS: m / z (M+H) + = 595.2.

[0437] Example 16: Synthesis of N-((5-(5-(1-acetylpyrrolidin-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide

[0438]

[0439] Step A: N-({5-[5-(1-acetyltetrahydro-1H-pyrrol-3-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide

[0440] At 0 °C, DIEA (0.01 mL, 0.03 mmol) and acetyl chloride (0.01 mL, 0.03 mmol) were added to a solution of 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[5-(tetrahydro-1H-pyrrol-3-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide (8 mg, 0.01 mmol) in ACN (2 mL). The reaction was stirred at 25 °C for 1 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA conditions) to give N-({5-[5-(1-acetyltetrahydro-1H-pyrrol-3-yl)pyridin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide (5 mg, 0.01 mmol, 58.34%) as a white solid.

[0441] 1 H NMR (400 MHz, CDCl 3 ) δ 8.59 (m, 1H), 8.12 (t, J = 7.7 Hz, 1H), 7.78 (s, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.68 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.40 (m, 2H), 7.11 - 7.04 (m, 2H), 5.10 (s, 2H), 3.94 - 3.74 (m, 1H), 3.66 (s, 2H), 3.59 - 3.51 (m, 1H), 3.42 (m, 2H), 2.48 - 2.30 (m, 1H), 2.04 (m, 5H).

[0442] LCMS: m / z (M + H) + = 636.4.

[0443] Example 17: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide

[0444]

[0445] Step A: 5-Chloropyrimidine-2-carbohydrazide (2)

[0446] At 25 °C, N 2 H 4 .H 2 O (0.2 mL) (80% purity) was added to a solution of methyl 5-chloropyrimidine-2-carboxylate (100 mg, 0.58 mmol) in MeOH (10.0 mL). The mixture was stirred at 25 °C for 2 hours. After completion, the mixture was concentrated under reduced pressure to give 5-chloropyrimidine-2-carbohydrazide (90 mg, 0.5 mmol, 85.4%) as a white solid.

[0447] LCMS: m / z (M+H) + = 173.2.

[0448] Step B: 5-Chloro-N'-(2-chloroacetyl)pyrimidine-2-carbohydrazide (3)

[0449] At 0 °C, TEA (1.93 mL, 13.91 mmol) and chloroacetyl chloride (0.44 mL, 5.56 mmol) were added to a solution of 5-chloropyrimidine-2-carbohydrazide (800 mg, 4.64 mmol) in DCM (10 mL). The mixture was stirred at 25 °C for 16 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with MeOH in DCM (1 / 100 to 1 / 10), to give 5-chloro-N'-(2-chloroacetyl)pyrimidine-2-carbohydrazide (700 mg, 2.67 mmol, 57.60%) as a yellow oil.

[0450] LCMS: m / z (M+H) + = 249.1.

[0451] Step C: 5-Chloro-2-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrimidine (4)

[0452] At 25 °C, TEA (0.22 mL, 1.61 mmol) and TsCl (153.38 mg, 0.80 mmol) were added to a solution of 5-chloro-N'-(2-chloroacetyl)pyrimidine-2-carbohydrazide (100 mg, 0.40 mmol) in DCM (10.0 mL). The mixture was stirred at 25 °C and N2 Stir for 2 hours. After completion, concentrate the mixture under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to give 5-chloro-2-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrimidine as a yellow oil (80.0 mg, 0.342 mmol, 90.2%).

[0453] LCMS: m / z (M+H) + = 231.0

[0454] Step D: 5-chloro-2-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrimidine (5)

[0455] At 25 °C, 4-fluoroaniline (0.03 mL, 0.35 mmol), KI (57.48 mg, 0.35 mmol) and K 2 CO 3 (95.71 mg, 0.69 mmol) were added to a solution of 5-chloro-2-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrimidine (80 mg, 0.35 mmol) in DMF (2.0 mL). The mixture was stirred at 25 °C and N 2 for 16 hours. After completion, concentrate the mixture under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to give 5-chloro-2-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrimidine as a yellow oil (50 mg, 0.16 mmol, 44.87%).

[0456] LCMS: m / z (M+H) + = 306.2

[0457] Step E: 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[2-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-5-yl]methyl}-N-(4-fluorophenyl)acetamide

[0458] At 0 °C and N 2Under an atmosphere, (1-chloro-2-methylprop-1-enyl)dimethylamine (29.44 mg, 0.22 mmol) was added dropwise to a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (39.98 mg, 0.15 mmol) in MeCN (0.5 mL). The mixture was stirred at 0 °C for 30 minutes. Then, at 0 °C, the mixture was added to a solution of 5-chloro-2-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrimidine (20 mg, 0.07 mmol) and DMAP (23.98 mg, 0.20 mmol) in MeCN (2 mL). The mixture was stirred at 25 °C and under a N 2 atmosphere for 16 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (MeCN:H 2 O (0.1% FA)) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[2-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-5-yl]methyl}-N-(4-fluorophenyl)acetamide (5.0 mg, 0.01 mmol, 12.97%).

[0459] 1 1H NMR (400 MHz, MeOD) δ 9.07 (s, 2H), 7.92 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 7.8 Hz, 1H), 7.66 - 7.57 (m, 2H), 7.29 (t, J = 8.6 Hz, 2H), 5.27 (s, 2H), 3.85 (s, 2H).

[0460] LCMS: m / z (M+H) + = 560.2.

[0461] Example 18: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-bromopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide

[0462]

[0463] Step A: 5-Bromopyrimidine-2-carbohydrazide (2)

[0464] At 25 °C, hydrazine hydrate (5 mL) (80% purity) was added to a solution of methyl 5-bromopyrimidine-2-carboxylate (1 g, 4.61 mmol) in EtOH (2 mL). The mixture was stirred at 80 °C for 16 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to give 5-bromopyrimidine-2-carbohydrazide (900 mg, 4.15 mmol) as a yellow solid.

[0465] LCMS: m / z (M+H) + = 217.0 / 219.0

[0466] Step B: 5-Bromo-N'-(2-chloroacetyl)pyrimidine-2-carbohydrazide (3)

[0467] At 25 °C, chloroacetyl chloride (0.33 mL, 4.15 mmol) was added to a solution of 5-bromopyrimidine-2-carbohydrazide (900 mg, 4.15 mmol) and TEA (0.86 mL, 6.22 mmol) in DCM (5 mL). The mixture was stirred at 25 °C and N 2 for 2 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to give 5-bromo-N'-(2-chloroacetyl)pyrimidine-2-carbohydrazide (600 mg, 1.02 mmol) as a yellow oil.

[0468] LCMS: m / z (M+H) + = 293.0 / 295.0

[0469] Step C: 2-(5-Bromopyrimidin-2-yl)-5-(chloromethyl)-1,3,4-oxadiazole (4)

[0470] At 25 °C, TEA (1.13 mL, 8.18 mmol) and 4-methylbenzenesulfonyl chloride (0.94 g, 4.91 mmol) were added to a solution of 5-bromo-N'-(2-chloroacetyl)pyrimidine-2-carbohydrazide (1.2 g, 4.09 mmol) in DCM (50 mL). The mixture was stirred at 25 °C for 2 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (TFA conditions) to give 2-(5-bromopyrimidin-2-yl)-5-(chloromethyl)-1,3,4-oxadiazole (300 mg, 1.08 mmol) as a white solid.

[0471] LCMS: m / z (M+H) + = 274.8 / 276.8

[0472] Step D: N-((5-(5-Bromopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-4-fluoroaniline (5)

[0473] At 25 °C, K 2 CO 3(300.99 mg, 2.18 mmol) and 2-(5-bromopyrimidin-2-yl)-5-(chloromethyl)-1,3,4-oxadiazole (300 mg, 1.09 mmol). The mixture was stirred at 25 °C for 16 h. After completion, the mixture was diluted with EtOAc (100 mL) and then washed with water (100 mL) and brine (100 mL). The organic layer was concentrated under reduced pressure to give N-((5-(5-bromopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-4-fluoroaniline (55 mg, 0.14 mmol) as a yellow solid, which was used in the next step without further purification.

[0474] LCMS: m / z (M+H) + = 350.2 / 352.2.

[0475] Step E: 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-bromopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide

[0476] At 0 °C and under N 2 atmosphere, (1-chloro-2-methylprop-1-enyl)dimethylamine (31.48 mg, 0.24 mmol) was added dropwise to a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (87.09 mg, 0.32 mmol) in MeCN (0.5 mL). The mixture was stirred at 0 °C for 30 min to give a clear solution. Then at 0 °C, the mixture was added to a solution of N-((5-(5-bromopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-4-fluoroaniline (55 mg, 0.16 mmol) and DMAP (19.55 mg, 0.16 mmol) in MeCN (2 mL). The mixture was stirred at 25 °C and under N 2 atmosphere for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC to give 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-bromopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide (15 mg, 0.02 mmol) as a white solid.

[0477] 1 1H NMR (400 MHz, MeOD) δ 9.16 (s, 2H), 7.94 - 7.88 (m, 2H), 7.72 (d, J = 7.8 Hz, 1H), 7.62 (dd, J = 8.9, 4.8 Hz, 2H), 7.29 (m, 2H), 5.27 (s, 2H), 3.85 (s, 2H).

[0478] LCMS: m / z (M+H) + = 604.2 / 606.2

[0479] Example 19: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)acetamide

[0480]

[0481] Step A: 2-[5-(Chloromethyl)-1,3,4-thiadiazol-2-yl]-5-(tetrahydro-3-furanyl)pyridine (2)

[0482] At 25 °C, 2,4-bis(4-methoxyphenyl)-2,4-dithio-2λ5,4λ5-1,3,2,4-dithiadiphosphetane (56.62 mg, 0.14 mmol) was added to a solution of N'-(2-chloroacetyl)-5-(tetrahydro-3-furanyl)pyridine-2-carbohydrazide (20 mg, 0.07 mmol) in toluene (2 mL). The mixture was stirred at 110 °C and N 2 for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by pre-HPLC (TFA conditions) to give 2-[5-(chloromethyl)-1,3,4-thiadiazol-2-yl]-5-(tetrahydro-3-furanyl)pyridine (9 mg, 0.03 mmol) as a black solid.

[0483] LCMS: m / z (M+H) + = 282.0

[0484] Step B: 4-Fluoro-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)aniline (3)

[0485] At 25 °C, K 2 CO 3(8.83 mg, 0.06 mmol), 4-fluoroaniline (0.001 mL, 0.03 mmol) and potassium iodide (5.30 mg, 0.03 mmol). The mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 2:1) to give 4-fluoro-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)aniline (6 mg, 0.02 mmol) as a white solid.

[0486] LCMS: m / z (M+H) + = 357.2.

[0487] Step C: 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)acetamide

[0488] At 0 °C and under N 2 atmosphere, (1-chloro-2-methylprop-1-enyl)dimethylamine (6 mg, 0.05 mmol) was added dropwise to a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (11 mg, 0.04 mmol) in MeCN (0.5 mL). The mixture was stirred at 0 °C for 30 min to give a clear solution. Then at 0 °C, the mixture was added to a solution of 4-fluoro-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)aniline (6 mg, 0.02 mmol) and DMAP (3.08 mg, 0.03 mmol) in MeCN (2 mL). The mixture was stirred at 25 °C and under N 2 atmosphere for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA conditions) to give 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)acetamide (0.91 mg, 0.001 mmol) as a white solid.

[0489] 11H NMR (400 MHz, MeOD) δ 8.61 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 8.2 Hz, 1H), 7.96 - 7.91 (m, 3H), 7.71 (d, J = 7.6 Hz, 1H), 7.43 (dd, J = 8.8, 4.8 Hz, 2H), 7.27 (m, 2H), 5.31 (s, 2H), 4.61 (s, 2H), 4.20 - 4.09 (m, 2H), 3.83 (s, 2H), 3.64 - 3.55 (m, 1H), 2.50 (m, 1H), 2.08 (m, 1H).

[0490] LCMS: m / z (M + H) + = 611.0

[0491] Example 20: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydro-2H-pyran-3-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0492]

[0493] Step A: 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({2-[5-(3,4,5,6-tetrahydro-2H-pyran-3-yl)pyrimidin-2-yl]-1,3,4-oxadiazol-5-yl}methyl)acetamide

[0494] At 25 °C, to a solution of 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[2-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-5-yl]methyl}-N-(4-fluorophenyl)acetamide (10 mg, 0.02 mmol) in DMA (2.0 mL) was added 3-bromotetrahydropyran (2.95 mg, 0.02 mmol), {6-[amino(diazanylidene)methyl]pyridin-2-yl}(diazanylidene)methanamine (1.17 mg, 0.01 mmol), NiI 2 (2.23 mg, 0.01 mmol), Zn (0.00 mL, 0.07 mmol) and NaI (1.00 mg, 0.01 mmol). The mixture was stirred at 80 °C and N 2 under for 18 h. After filtration, the filtrate was purified by reverse-phase HPLC (MeCN:H 2Purified with O(0.1% FA) to obtain 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({2-[5-(3,4,5,6-tetrahydro-2H-pyran-3-yl)pyrimidin-2-yl]-1,3,4-oxadiazol-5-yl}methyl)acetamide (1.0 mg, 0.01 mmol, 8.72%) in the form of a white solid.

[0495] 1 H NMR (400 MHz, MeOD) δ 8.69 (s, 2H), 7.77 (s, 1H), 7.58 (m, 4H), 7.04 (t, J = 8.7 Hz, 2H), 4.56 (d, J = 22.9 Hz, 3H), 3.95 - 3.80 (m, 2H), 3.51 (m, 2H), 2.91 (d, J = 9.8 Hz, 1H), 1.99 (s, 1H), 1.86 - 1.60 (m, 3H), 1.37 - 1.13 (m, 1H).

[0496] LCMS: m / z (M + H) + = 610.2.

[0497] Example 22: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-cyclopropylpyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide

[0498]

[0499] At 25 °C, to a stirred solution of 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[5-(5-bromopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-N-(4-fluorophenyl)acetamide (50 mg, 0.08 mmol) in dioxane (2 mL) were successively added H 2 O (0.5 mL), cyclopropylboronic acid pinacol ester (35.54 mg, 0.41 mmol), PdCl 2 (dppf) (1.82 mg, 0.008 mmol) and K 2 CO 3(20.55 mg, 0.15 mmol). The resulting solution was stirred under nitrogen at 80 °C for 3 h. The reaction completion was detected by LC-MS. The reaction mixture was quenched by adding water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM (3 mL) and purified by CombiFlash (Biotage Isolera Prime), including applying it onto a 10 g silica gel column and eluting with 0 - 40% PE in EA to afford 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[5-(5-cyclopropylpyrimidin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-N-(4-fluorophenyl)acetamide (1 mg, 0.01 mmol, 2.03%) as a white powder.

[0500] 1 H NMR (400 MHz, MeOD) δ 8.53 (s, 3H), 7.89 - 7.80 (m, 1H), 7.71 - 7.66 (m, 2H), 7.55 - 7.47 (m, 1H), 7.15 - 7.09 (m, 2H), 4.68 (s, 2H), 4.61 (s, 2H), 2.05 - 1.98 (m, 1H), 1.26 - 1.18 (m, 2H), 0.94 - 0.88 (m, 2H).

[0501] LCMS: m / z (M + H) + = 566.3.

[0502] Example 23: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-((5-(5-(tetrahydrofuran-3-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0503]

[0504] At 23 °C, to a stirred solution of 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[5-(5-bromopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-N-(4-fluorophenyl)acetamide (21 mg, 0.03 mmol) in DMA (1 mL) were successively added 3-bromotetrahydrofuran (10.50 mmol, 0.07 mg), nickel(II) iodide (4.34 mg, 0.01 mmol), Zn (9.09 mg, 0.14 mmol), NaI (2.60 mg, 0.02 mmol), and pyridine-2,6-dicarboximidamide (3.28 mg, 0.01 mmol). The resulting solution was stirred under nitrogen at 80 °C for 18 h. The reaction mixture was quenched by addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in DCM (3 mL) and purified by Combi Flash (Biotage Isolera Prime), including applying it to a 10 g silica gel column and eluting with 0 - 30% DCM in PE over 30 min to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[5-(tetrahydrofuran-3-yl)pyrimidin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide (1.1 mg, 0.002 mmol, 5.21%) as a white powder.

[0505] 1 H NMR (400 MHz, MeOD) δ 8.83 (s, 2H), 7.84 - 7.77 (m, 2H), 7.61 (d, J = 6.9 Hz, 1H), 7.53 - 7.47 (m, 2H), 7.20 - 7.12 (m, 2H), 5.15 (s, 2H), 4.06 - 4.00 (m, 2H), 3.87 - 3.81 (m, 1H), 3.77 - 3.71 (m, 3H), 3.53 - 3.45 (m, 1H), 2.47 - 2.38 (m, 1H), 2.04 - 1.96 (m, 1H).

[0506] LCMS: m / z (M + H) + = 596.4.

[0507] Example 24: Synthesis of N-((5-(5-aminopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide

[0508]

[0509] Step A: tert-Butyl ((2-(5-((2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamido)methyl)-1,3,4-oxadiazol-2-yl)pyrimidin-5-yl)carbamate (2)

[0510] A mixture of 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[5-(5-bromopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-N-(4-fluorophenyl)acetamide (10 mg, 0.02 mmol), tert-butyl carbamate (3.5 mg, 0.03 mmol), Pd 2 (dba) 3 (4.55 mg, 0.002 mmol), Xantphos (5.75 mg, 0.01 mmol) and Cs 2 CO 3 (16.18 mg, 0.05 mmol) in dioxane (2 mL) was degassed and purged with N 2 for 3 times, and then stirred at 120 °C for 2 h. The completion of the reaction was detected by LC-MS. The reaction mixture was evaporated. The crude residue was purified by column chromatography (50% EtOAc in PE) to give tert-butyl [(2-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrimidin-5-yl)amino]carbamate (9 mg, 0.01 mmol, 25.47%) as a yellow oil.

[0511] Step B: N-((5-(5-Aminopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide

[0512] At 25 °C, TFA (2 mL, 26.84 mmol) was added to a solution of tert-butyl [(2-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrimidin-5-yl)amino]carbamate (10 mg, 0.02 mmol) in DCM (5 mL). The mixture was stirred at 25 °C for 30 min. The completion of the reaction was detected by LCMS. After removing the solvent by concentration, the residue was purified by reverse-phase HPLC to give N-{[5-(5-aminopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide (1 mg, 0.01 mmol, 10.90%) as a white solid.

[0513] 1 H NMR (400MHz, MeOD) δ8.05(s,2H),7.89-7.82(m,1H),7.71-7.65(m,3H),7.54-7.44(m,1H),7.15-7.06(m,2H),4.65(s,2H),3.36(s,2H).

[0514] LCMS: m / z(M+H) + =540.1.

[0515] Example 25: Synthesis of N-{[5-(5-aminopyrazin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide

[0516]

[0517] Step A: 2-methylpropan-2-yl [(5-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrazin-2-yl)amino]carboxylate (2)

[0518] To a solution of 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[5-(5-chloropyrazin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-N-(4-fluorophenyl)acetamide (20 mg, 0.04 mmol) in dioxane (1 mL) was added Cs 2 CO 3 (23.28 mg, 0.07 mmol), tert-butyl carbamate (8.37 mg, 0.07 mmol), Xantphos (4.13 mg, 0.01 mmol) and Pd 2 (dba) 3 (3.27 mg, 0.004 mmol). 2 In 4- oxadiazole-2-yl} pyrazine-2-yl) amino] formic acid 2- methyl propan-2-yl ester (20mg, 0.02mmol, 61.19%).Degassing three times, and stirring at 100 ℃ for 4 hours.LCMS shows that the reaction is complete.The reaction is directly evaporated under vacuum.The crude product is purified by silica gel column chromatography (PET: EtOAc = 5: 1 to 3: 1) to obtain [(5-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazole-2-yl}pyrazine-2-yl)amino] formic acid 2-methylpropan-2-yl ester (20mg, 0.02mmol, 61.19%) as a yellow oil.

[0519] LCMS: m / z(M+H) + =641.2.

[0520] Step B: N-{[5-(5-Aminopyrazin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide

[0521] To a solution of [(5-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrazin-2-yl)amino]carbamic acid 2-methylpropan-2-yl ester (10 mg, 0.02 mmol) in DCM (1 mL) was added TFA (0.2 mL, 2.68 mmol). The reaction was stirred at 25 °C for 2 h. LCMS showed completion of the reaction. The reaction was evaporated directly under vacuum. The crude product was purified by pre-HPLC (FA conditions) to afford N-{[5-(5-aminopyrazin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)acetamide (2 mg, 0.004 mmol, 23.70%) as a white solid.

[0522] 1 1H NMR (400 MHz, chloroform-d) δ 8.83 (s, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.80 (br d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.44 (dd, J = 4.7, 8.6 Hz, 2H), 7.15 (t, J = 8.3 Hz, 2H), 5.16 (s, 4H), 3.72 (s, 2H).

[0523] LCMS: m / z (M+H) + = 541.2.

[0524] Example 29: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-N-[(5-{2-[1-(cyclopropylcarbonyl)tetrahydro-1H-pyrrol-3-yl]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide

[0525]

[0526] In an ice bath, cyclopropanecarbonyl chloride (0.002 mL, 0.01 mmol) was added to a solution of 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[2-(tetrahydro-1H-pyrrol-3-yl)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide (6 mg, 0.01 mmol) and TEA (0.003 mL, 0.03 mmol) in DCM (2 mL). The mixture was stirred at 25 °C for 18 h to give a brown solution. The mixture was quenched with H 2 O (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (trifluoroacetic acid / acetonitrile / water) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-[(5-{2-[1-(cyclopropylcarbonyl)tetrahydro-1H-pyrrol-3-yl]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)methyl]-N-(4-fluorophenyl)acetamide (3.71 mg, 0.01 mmol, 51.92%) as a white solid.

[0527] 1 H NMR (400 MHz, chloroform-d) δ 9.20 (d, J = 6.7 Hz, 2H), 7.80 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.37 (dt, J = 8.7, 4.5 Hz, 2H), 7.11 (ddd, J = 9.6, 8.3, 1.9 Hz, 2H), 5.09 (s, 2H), 4.11 - 3.64 (m, 7H), 2.48 - 2.30 (m, 1H), 2.15 (t, J = 7.6 Hz, 1H), 1.94 (d, J = 6.5 Hz, 1H), 0.85 - 0.68 (m, 4H).

[0528] LCMS: m / z (M + H) + = 663.4.

[0529] Example 30: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[(5-{2-[1-(methyldioxido-λ6-sulfanyl)tetrahydro-1H-pyrrol-3-yl]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)methyl]acetamide

[0530]

[0531] In an ice bath, methanesulfonyl chloride (MsCl, 0.0014 mL, 0.01 mmol) was added to a solution of 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[2-(tetrahydro-1H-pyrrol-3-yl)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide (3 mg, 0.01 mmol) and triethylamine (TEA, 0.002 mL, 0.02 mmol) in DCM (2 mL). The mixture was stirred at 25 °C for 18 h to give a brown solution. The mixture was quenched with H 2 O (30 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (trifluoroacetic acid / acetonitrile / water) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[(5-{2-[1-(methyldioxido-λ6-sulfanyl)tetrahydro-1H-pyrrol-3-yl]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)methyl]acetamide as a white solid (1.58 mg, 0.002 mmol, 43.79%).

[0532] 1 1H NMR (400 MHz, methanol-d4) δ 9.34 (s, 2H), 7.92 (s, 2H), 7.71 (d, J = 8.2 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.30 (s, 2H), 5.25 (s, 2H), 3.92 - 3.77 (m, 5H), 3.53 (s, 2H), 2.96 (s, 3H), 2.58 - 2.35 (m, 2H).

[0533] LCMS: m / z (M + H) + = 673.3.

[0534] Example 49: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(6-hydroxypyridin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide

[0535]

[0536] Step A: N'-(2-chloroacetyl)-6-methoxypyridine-2-carbohydrazide (2)

[0537] To a solution of 2-methoxypyridine-3-carbohydrazide (1 g, 5.98 mmol) and TEA (1.66 mL, 11.96 mmol) in DCM (100 mL) was added chloroacetyl chloride (0.52 mL, 6.58 mmol). The mixture was stirred at 25 °C for 18 h to give a brown solution. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 0 to 5%) to give N'-(2-chloroacetyl)-6-methoxypyridine-2-carbohydrazide (1.22 g, 5.01 mmol, 83.56%) as a white solid.

[0538] LCMS: m / z (M+H) + = 244.0.

[0539] Step B: 6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-2-methoxypyridine (3)

[0540] To a solution of N'-(2-chloroacetyl)-6-methoxypyridine-2-carbohydrazide (1.22 g, 5.01 mmol) and TEA (4.16 mL, 30.04 mmol) in DCM (100 mL) was added 4-methylbenzenesulfonyl chloride (1.91 g, 10.01 mmol). The mixture was stirred at 25 °C for 18 h to give a brown solution. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 0 to 10%) to give 6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-2-methoxypyridine (740 mg, 3.28 mmol, 65.50%) as a white solid.

[0541] LCMS: m / z (M+H) + = 226.0.

[0542] Step C: 6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-2-methoxypyridine (4)

[0543] To a solution of 6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-2-methoxypyridine (740 mg, 3.28 mmol) and 4-fluoroaniline (0.31 mL, 0.42 mmol) in DMF (15 mL) was added K 2 CO 3 (906.51 mg, 6.56 mmol) and potassium iodide (544.43 mg, 3.28 mmol). The mixture was stirred at 25 °C for 18 h to give a brown solution. The mixture was treated with H 2 O (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na2 SO 4 Dry and concentrate under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 0 to 30%) to give 6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-2-methoxypyridine as a white solid (800 mg, 2.20 mmol, 67.10%).

[0544] LCMS: m / z (M+H) + = 301.0.

[0545] Step D: 6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyridin-2-ol (5)

[0546] To a solution of 6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-2-methoxypyridine (100 mg, 0.33 mmol) in CH 3 CN (20 mL) was added TMSCl (0.42 mL, 3.33 mmol) and NaI (149.75 mg, 1.00 mmol). The mixture was stirred at 80 °C for 1.5 h to give a yellow solution. The mixture was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (TFA / acetonitrile / water) to give 6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyridin-2-ol as a white solid (50 mg, 0.15 mmol, 45.02%).

[0547] LCMS: m / z (M+H) + = 287.1.

[0548] Step E: 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(6-hydroxypyridin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide

[0549] To a solution of 6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyridin-2-ol (50 mg, 0.17 mmol) and [2,4-bis(trifluoromethyl)phenyl]acetic acid (57.04 mg, 0.21 mmol) in DCM (10 mL) were added DMAP (32.01 mg, 0.26 mmol) and EDCI (50.22 mg, 0.26 mmol). The mixture was stirred at 25 °C for 3 h to give a yellow solution. The mixture was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (TFA / acetonitrile / water) to afford 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(6-hydroxypyridin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide (4.94 mg, 0.01 mmol, 4.90%) as a white solid.

[0550] 1 H NMR (400 MHz, chloroform-d) δ 7.79 (d, J = 1.7 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 8.3 Hz, 2H), 7.34 (dd, J = 8.7, 4.7 Hz, 2H), 7.11 (t, J = 8.1 Hz, 2H), 6.91 (d, J = 13.4 Hz, 1H), 6.73 (s, 1H), 5.05 (s, 2H), 3.62 (s, 2H).

[0551] LCMS: m / z (M+H) + = 541.3.

[0552] Example 64: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[5-(3-methoxycyclopentyl)pyrimidin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide

[0553]

[0554] Step A: 3-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}cyclopent-1-ol (2)

[0555] At 0 °C, 1H-imidazole (2.67 g, 39.16 mmol) and chlorodimethyl(2-methylpropan-2-yl)silane (3.25 g, 21.54 mmol) were added to a solution of cyclopentane-1,3-diol (2 g, 19.58 mmol) in DMF (18 mL). After addition, the mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Flash (DCM:MeOH = 95:5) to give 3-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}cyclopentan-1-ol (1.5 g, 6.59 mmol, 33.63%) as a yellow solid.

[0556] LCMS: m / z (M+H) + = 217.0.

[0557] Step B: [(3-methoxycyclopentyl)oxy]dimethyl(2-methylpropan-2-yl)silane (3)

[0558] At 20 °C, potassium 2-methylpropan-2-olate (1.97 g, 17.56 mmol) and methyl iodide (1.09 mL, 17.56 mmol) were added to a solution of 3-{[dimethyl(2-methylpropan-2-yl)silyl]oxy}cyclopentan-1-ol (1.9 g, 8.78 mmol) in THF (15 mL). After addition, the mixture was stirred at 20 °C for 16 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Flash (PE:EA = 80:20) to give [(3-methoxycyclopentyl)oxy]dimethyl(2-methylpropan-2-yl)silane (500 mg, 2.06 mmol, 23.48%) as a yellow solid.

[0559] LCMS: m / z (M+H) + = 231.0.

[0560] Step C: 3-methoxycyclopentan-1-ol (4)

[0561] At 20 °C, tetrabutylammonium fluoride (2.60 mL, 2.60 mmol) was added to a solution of [(3-methoxycyclopentyl)oxy]dimethyl(2-methylpropan-2-yl)silane (300 mg, 1.30 mmol) in THF (8 mL). After addition, the mixture was stirred at 20 °C for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by Flash (DCM:MeOH = 92:8) to give 3-methoxycyclopentan-1-ol (110 mg, 0.90 mmol, 69.10%) as a yellow solid.

[0562] LCMS: m / z (M+H) + = 117.0.

[0563] Step D: 1-Bromo-3-methoxycyclopentane (5)

[0564] At 0 °C, triphenylphosphine (1185.45 mg, 4.52 mmol) and carbon tetrabromide (1199.08 mg, 3.62 mmol) were added to a solution of 3-methoxycyclopentan-1-ol (350 mg, 3.01 mmol) in DCM (12 mL). After addition, the mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by Flash (PE:EA = 70:30) to give 1-bromo-3-methoxycyclopentane (140 mg, 0.74 mmol, 24.65%) as a white solid.

[0565] LCMS: m / z (M+H) + = 180.0.

[0566] Step E: 2-[2,4-Bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[5-(3-methoxycyclopentyl)pyrimidin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide

[0567] At 20 °C, to a solution of 1-bromo-3-methoxycyclopentane (11.85 mg, 0.07 mmol) in DMA (3 mL) was added 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[5-(5-bromopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-N-(4-fluorophenyl)acetamide (20 mg, 0.03 mmol), NaI (2.48 mg, 0.02 mmol), Zn (8.66 mg, 0.13 mmol), {6-[amino(diazaalkylidene)methyl]pyridin-2-yl}(diazaalkylidene)methanamine (1.62 mg, 0.01 mmol) and nickel(II) iodide (2.07 mg, 0.01 mmol). After addition, the mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by p-HPLC (FA conditions) to give Example 64-P1 and Example 64-P2 as white solids.

[0568] LCMS: m / z (M+H) + = 624.4.

[0569] Examples 65 and 66: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-((5-(2-oxo-1,2-dihydropyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide and 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(2-methoxypyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide

[0570]

[0571] Step A: 2-Methoxypyridine-3-carbohydrazide (2)

[0572] To a solution of methyl 2-methoxypyridine-3-carboxylate (1 g, 5.98 mmol) in EtOH (100 mL) was added hydrazine hydrate (0.53 g, 8.97 mmol). The mixture was stirred at 85 °C for 16 h to give a white suspension. The reaction was concentrated under reduced pressure to give 2-methoxypyridine-3-carbohydrazide (1 g, 4.49 mmol, 75.00%) as a white solid.

[0573] LCMS: m / z (M+H) + = 168.0.

[0574] Step B: N'-(2-Chloroacetyl)-2-methoxypyridine-3-carbohydrazide (3)

[0575] To a solution of 2-methoxypyridine-3-carbohydrazide (1 g, 5.98 mmol) and TEA (1.66 mL, 11.96 mmol) in DCM (100 mL) was added chloroacetyl chloride (0.52 mL, 6.58 mmol). The mixture was stirred at 25 °C for 18 h to give a brown solution. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 0 to 5%) to give N'-(2-chloroacetyl)-2-methoxypyridine-3-carbohydrazide (890 mg, 3.65 mmol, 61.06%) as a white solid.

[0576] LCMS: m / z (M+H) + = 244.0.

[0577] Step C: 3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-2-methoxypyridine (4)

[0578] To a solution of N'-(2-chloroacetyl)-2-methoxypyridine-3-carbohydrazide (890 mg, 3.65 mmol) and TEA (3.04 mL, 21.92 mmol) in DCM (100 mL) was added 4-methylbenzenesulfonyl chloride (1392.73 mg, 7.31 mmol). The mixture was stirred at 25 °C for 18 h to give a brown solution. The mixture was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to give 3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-2-methoxypyridine (380 mg, 1.41 mmol, 38.64%) as a white solid.

[0579] LCMS: m / z (M+H) + = 226.0.

[0580] Step D: 3-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-2-methoxypyridine (5)

[0581] To a solution of 3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-2-methoxypyridine (400 mg, 1.33 mmol, 79.09%) and 4-fluoroaniline (0.16 mL, 1.68 mmol) in DMF (15 mL) was added K 2 CO 3 (465.51 mg, 3.37 mmol) and potassium iodide (279.57 mg, 1.68 mmol). The mixture was stirred at 25 °C for 18 h to give a brown solution. The mixture was treated with H 2Treated with O (100 mL), and extracted with EtOAc (100 mL × 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 0 to 1:1) to give 3-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-2-methoxypyridine as a white solid (400 mg, 1.33 mmol, 79.09%).

[0582] LCMS: m / z (M + H) + = 301.0.

[0583] Step E: 2-[2,4-Bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(2-methoxypyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide (Example 66)

[0584] Under an ice bath and N 2 to a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (54.38 mg, 0.20 mmol) in CH 3 CN (4 mL) was added (1-chloro-2-methylprop-1-enyl)dimethylamine (0.03 mL, 0.20 mmol). The mixture was stirred at 0 °C for 0.5 h. The mixture was added to a solution of 3-[5-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]pyrrolidine-1-carboxylic acid 2-methylpropan-2-yl ester (40 mg, 0.09 mmol) and DMAP (30.51 mg, 0.25 mmol) in CH 3 CN (4 mL). The mixture was stirred at 25 °C for 2 h to give a yellow solution. The mixture was concentrated under reduced pressure. The crude product was purified by TLC (PE:EA = 2:1) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(2-methoxypyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide as a white solid (85 mg). The crude product (20 mg) was purified by high performance liquid chromatography (TFA / acetonitrile / water) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(2-methoxypyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide as a white solid (9.2 mg).

[0585] 11H NMR (400 MHz, chloroform-d) δ 8.29 (dd, J = 5.0, 1.9 Hz, 1H), 8.16 (dd, J = 7.6, 2.0 Hz, 1H), 7.78 (s, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.40 - 7.32 (m, 2H), 7.08 (t, J = 8.4 Hz, 2H), 6.97 (dd, J = 7.5, 4.9 Hz, 1H), 5.09 (s, 2H), 4.03 (s, 3H), 3.63 (s, 2H).

[0586] LCMS: m / z (M+H) + = 555.2.

[0587] Step F: 2-(2,4-Bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(2-oxo-1,2-dihydropyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide (Example 65)

[0588] To a solution of 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(2-methoxypyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide (8 mg, 0.01 mmol) in DMF (1 mL) was added 4-methylbenzenesulfonic acid (12.42 mg, 0.07 mmol) and LiCl (3.06 mg, 0.07 mmol). The mixture was stirred at 120 °C for 0.5 h to give a colorless solution. The crude product was purified by high performance liquid chromatography (TFA / acetonitrile / water) to give 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(2-oxo-1,2-dihydropyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide (2.69 mg, 34.11%) as a white solid.

[0589] 1 1H NMR (400 MHz, chloroform-d) δ 8.19 (d, J = 7.1 Hz, 1H), 7.78 (s, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.62 (d, J = 6.2 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.36 (dd, J = 8.8, 4.7 Hz, 2H), 7.07 (t, J = 8.3 Hz, 2H), 6.41 (t, J = 6.6 Hz, 1H), 5.09 (s, 2H), 3.64 (s, 2H).

[0590] LCMS: m / z (M+H) + = 541.2.

[0591] Example 67: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[5-(5-chloropyrazin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-N-(4-fluorophenyl)acetamide

[0592]

[0593] Step A: 5-Bromopyrazine-2-carbohydrazide (2)

[0594] Hydrazine hydrate (1042.94 mg, 27.66 mmol) was added to a solution of methyl 5-bromopyrazine-2-carboxylate (1000 mg, 4.61 mmol) in MeOH (10 mL). The reaction was stirred at 25 °C for 2 h. LCMS showed the reaction was complete. The mixture was evaporated directly under vacuum to give 5-bromopyrazine-2-carbohydrazide (720 mg, 3.18 mmol, 69.08%) as a white solid.

[0595] LCMS: m / z (M+H) + = 207.0.

[0596] Step B: 5-Bromo-N'-(2-chloroacetyl)pyrazine-2-carbohydrazide (3)

[0597] Triethylamine (0.69 mL, 4.98 mmol) and chloroacetyl chloride (0.53 mL, 6.64 mmol) were added to a solution of 5-bromopyrazine-2-carbohydrazide (720 mg, 3.32 mmol) in DCM (5 mL). The reaction was stirred at 25 °C for 16 h. LCMS showed the reaction was complete. The mixture was evaporated directly under vacuum. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1 to 5:1) to give 5-bromo-N'-(2-chloroacetyl)pyrazine-2-carbohydrazide (840 mg, 2.66 mmol, 80.23%) as a yellow solid.

[0598] LCMS: m / z (M+H) + = 293.0.

[0599] Step C: 5-Bromo-2-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrazine (4)

[0600] To a solution of 5-bromo-N'-(2-chloroacetyl)pyrazine-2-carbohydrazide (360 mg, 1.23 mmol) in DCM (5 mL) was added TEA (0.68 mL, 4.91 mmol) and 4-methylbenzenesulfonyl chloride (467.67 mg, 2.45 mmol). The reaction was stirred at 25 °C for 16 h. LCMS showed the reaction was complete. The mixture was evaporated directly under vacuum. The crude product was purified by silica gel column chromatography (PET:EtOAc = 5:1 to 3:1) to give 5-bromo-2-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrazine as a yellow solid (120 mg, 0.38 mmol, 31.25%).

[0601] LCMS: m / z (M+H) + = 275.2.

[0602] Step D: 5-bromo-2-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrazine (5)

[0603] To a solution of 5-bromo-2-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrazine (120 mg, 0.44 mmol) in DMF (5 mL) was added K 2 CO 3 (120.40 mg, 0.87 mmol), 4-fluoroaniline (0.04 mL, 0.44 mmol) and potassium iodide (72.31 mg, 0.44 mmol). The reaction was stirred at 25 °C for 4 h. LCMS showed the reaction was complete. The mixture was diluted with 20 mL of water, extracted with EA (20 mL×2), washed with brine, dried and concentrated. The crude product was purified by silica gel column chromatography (PE:EtOAc = 1:1 to 1:2) to give 5-bromo-2-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrazine as a yellow solid (60 mg, 0.10 mmol, 24.00%).

[0604] LCMS: m / z (M+H) + = 316.0.

[0605] Step E: 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[5-(5-chloropyrazin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-N-(4-fluorophenyl)acetamide

[0606] To a solution of 2-(2,4-bis(trifluoromethyl)phenyl)acetic acid (40 mg, 0.15 mmol) in acetonitrile (1 mL) was added dropwise 1-chloro-N,N,2-trimethylpropenylamine (0.03 mL, 0.22 mmol). Then the mixture was added to 5-bromo-2-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrazine (51.46 mg, 0.15 mmol) and DMAP (26.93 mg, 0.22 mmol) in acetonitrile (1 mL). The reaction was stirred at 25 °C for 16 h. LCMS showed the reaction was complete. The mixture was evaporated directly under vacuum. The mixture was purified by pre-HPLC (FA conditions) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[5-(5-chloropyrazin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-N-(4-fluorophenyl)acetamide (3.8 mg, 0.01 mmol, 4.31%) as a white solid.

[0607] 1 H NMR (400 MHz, chloroform-d) δ 9.22 (d, J = 1.4 Hz, 1H), 8.73 (d, J = 1.4 Hz, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.50 - 7.46 (m, 2H), 7.17 (t, J = 8.4 Hz, 2H), 5.18 (s, 2H), 3.73 (s, 2H).

[0608] LCMS: m / z (M+H) + = 560.1.

[0609] Example 68: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(6-methoxypyridin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide

[0610]

[0611] To a solution of 6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-2-methoxypyridine (100 mg, 0.33 mmol) and [2,4-bis(trifluoromethyl)phenyl]acetic acid (108.75 mg, 0.40 mmol) in DCM (100 mL) were added DMAP (61.03 mg, 0.50 mmol) and EDCI (95.76 mg, 0.50 mmol). The mixture was stirred at 25 °C for 3 h to give a yellow solution. The mixture was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography (trifluoroacetic acid / acetonitrile / water) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(6-methoxypyridin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide (43.58 mg, 0.08 mmol, 22.86%) as a white solid.

[0612] 1 H NMR (400 MHz, chloroform-d) δ 7.87 (d, J = 1.7 Hz, 1H), 7.84 - 7.70 (m, 3H), 7.60 (d, J = 8.1 Hz, 1H), 7.52 - 7.42 (m, 2H), 7.22 - 7.11 (m, 2H), 6.94 (dd, J = 7.6, 1.6 Hz, 1H), 5.20 (s, 2H), 4.05 (s, 3H), 3.73 (s, 2H).

[0613] LCMS: m / z (M + H) + = 555.2.

[0614] Example 69: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-N-((2-(5-chloropyridin-2-yl)oxazol-5-yl)methyl)-N-(4-fluorophenyl)acetamide

[0615]

[0616] Step A: Methyl 2-(5-chloropyridin-2-yl)oxazole-5-carboxylate (2)

[0617] To a solution of ethyl 1,3-oxazole-5-carboxylate (0.43 mL, 3.54 mmol) in DMF (2 mL) were added 2-bromo-5-chloropyridine (886.32 mg, 4.61 mmol), Pd(OAc) 2 (79.54 mg, 0.35 mmol), Cs 2 CO 3 (2308.65 mg, 7.09 mmol), CuI (674.73 mg, 3.54 mmol). The mixture was at 100 °C and N2 Stir for 1 hour. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by Flash (EA:PE = 1:100 to 1:3) to give methyl 2-(5-chloropyridin-2-yl)oxazole-5-carboxylate (400 mg, 1.58 mmol, 44.7%).

[0618] LCMS: m / z (M+H) + = 253.7.

[0619] Step B: (2-(5-chloropyridin-2-yl)oxazol-5-yl)methanol (3)

[0620] To a solution of ethyl 2-(5-chloropyridin-2-yl)-1,3-oxazole-5-carboxylate (20 mg, 0.08 mmol) in MeOH (0.5 mL) and THF (5 mL) was added NaBH 4 (8.98 mg, 0.24 mmol). The mixture was stirred at 60 °C and N 2 for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by Flash (EA:PE = 1:10 to 1:0) to give (2-(5-chloropyridin-2-yl)oxazol-5-yl)methanol (10 mg, 0.05 mmol, 56.99%).

[0621] LCMS: m / z (M+H) + = 211.6.

[0622] Step C: 5-(chloromethyl)-2-(5-chloropyridin-2-yl)oxazole (4)

[0623] At 0 °C, to a solution of [2-(5-chloropyridin-2-yl)-1,3-oxazol-5-yl]methanol (15 mg, 0.07 mmol) in DCM (10.0 mL) was added SOCl 2 (0.01 mL, 0.14 mmol). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by Flash (EA:PE = 1:10 to 1:0) to give 5-(chloromethyl)-2-(5-chloropyridin-2-yl)oxazole (10.0 mg, 0.043 mmol, 62.3%).

[0624] LCMS: m / z (M+H) + = 230.1.

[0625] Step D: N-((2-(5-chloropyridin-2-yl)oxazol-5-yl)methyl)-4-fluoroaniline (5)

[0626] To a solution of 5-chloro-2-[5-(chloromethyl)-1,3-oxazol-2-yl]pyridine (15 mg, 0.07 mmol) in DMF (2.0 mL) was added 4-fluoroaniline (0.01 mL, 0.07 mmol), KI (10.87 mg, 0.07 mmol) and K 2 CO 3 (36.20 mg, 0.26 mmol). The mixture was stirred at 25 °C for 18 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by Flash (EA:PE = 1:1 to 1:0) to give N-((2-(5-chloropyridin-2-yl)oxazol-5-yl)methyl)-4-fluoroaniline (10.0 mg, 0.03 mmol, 45.25%).

[0627] LCMS: m / z (M+H) + = 304.7.

[0628] Step E: 2-(2,4-bis(trifluoromethyl)phenyl)-N-((2-(5-chloropyridin-2-yl)oxazol-5-yl)methyl)-N-(4-fluorophenyl)acetamide

[0629] To a solution of 5-chloro-2-(5-{[(4-fluorophenyl)amino]methyl}-1,3-oxazol-2-yl)pyridine (15 mg, 0.05 mmol) in DCM (2.0 mL) was added [2,4-bis(trifluoromethyl)phenyl]acetic acid (13.44 mL, 0.05 mmol), DMAP (9.05 mg, 0.07 mmol) and EDCI (14.20 mg, 0.07 mmol). The mixture was stirred at 25 °C for 18 h. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by Flash (EA:PE = 1:10 to 1:1) to give 2-(2,4-bis(trifluoromethyl)phenyl)-N-((2-(5-chloropyridin-2-yl)oxazol-5-yl)methyl)-N-(4-fluorophenyl)acetamide (10 mg, 0.02 mmol, 34.48%).

[0630] LCMS: m / z (M+H) + = 558.9.

[0631] Experimental Example: Inhibitory Activity against Polθ

[0632] The inhibitory activity of the compounds prepared in the above examples against Polθ was measured as follows.

[0633] The PicoGreen assay was used to measure the ability of compounds to inhibit Polθ activity in vitro. Recombinant Polθ-polymerase domain (aa1819-2590) was produced by ChemPartner and stored in aliquots at -80 °C. Assay measurements were performed using 1× buffer consisting of 25 mM tris HCL pH 7.5, 12.5 mM NaCl, 0.5 mM MgCl 2 , 5% glycerol, 0.01% Triton X-100, 0.01% BGG, and 1 mM DTT. Test compounds were prepared by dilution in 100% DMSO to obtain an appropriate dose range for 10-point concentration-response and dispensed in appropriate volumes (20 nL) into 384-well microtiter plates (Greiner small volume black plates, product number 784076) using a Labcyte Echo 655 acoustic dispenser. The DMSO concentration was maintained at 0.2% by backfilling with DMSO solution. 5 μL of purified recombinant Polθ was diluted to a 2× working concentration (6 nM Polθ) in assay buffer. It was dispensed into each well of the compound plate using a VIAFLO 16-channel manual pipette (Integra) and pre-incubated for 15 minutes at room temperature. Then 5 μL of 2× working solution of dNTPs (40 μM) (Thermo #R1121) diluted in assay buffer, primer (60 nM PTD) (5'-GCG GCT GTC ATA AG-3' (SEQID NO:1)):template (5'-GCT ACA TTG ACA ATG GCA TCA AAT CTC AGA TTG CGT CTT ATG ACAGCC GCG-3' (SEQ ID NO:2)) duplex (1:1.1) was added. The reaction was incubated for 60 minutes at room temperature. The reaction was stopped by adding 10 mM EDTA, 25 mM tris pH 7.5, and 1:80 diluted PicoGreen dye (Invitrogen P7581). Fluorescence was read after 90 minutes at room temperature in the dark using a 485 / 535 nm module on a 2105-0020 EnVision multimode plate reader, and the raw data were analyzed using log(inhibitor) vs response-variable slope (four parameters) to generate IC 50 values. The results are shown in Tables 1 and 2 below.

[0634] [Table 1]

[0635] Example No. <![CDATA[Polθ / IC 50 (nM)]]> Example No. <![CDATA[Polθ / IC 50 (nM)]]> Example 1 87.32 Example 10 2.08 Example 2 293.8 Example 11 7.82 Example 3 97.68 Example 12 11.94 Example 4 154.7 Example 13 11.4 Example 5 27.5 Example 14 49.18 Example 6 7.03 Example 15 18.93 Example 7 10.61 Example 16 11.04 Example 8 2.54 Example 17 78.64 Example 9 5.5 Example 18 36.52

[0636] [Table 2]

[0637] Example No. <![CDATA[Polθ / IC 50 (nM)]]> Example No. <![CDATA[Polθ / IC 50 (nM)]]> Example 19 >1000 Example 49 151.9 Example 20 >1000 Example 64 - P1 >1000 Example 22 >1000 Example 64 - P2 123.3 Example 23 61.01 Example 65 154.4 Example 24 >1000 Example 66 108.4 Example 25 36.58 Example 67 19.96 Example 30 26.48 Example 68 223.8 Example 29 9.89 Example 69 61.69

Claims

1. A compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical formula 1] In Chemical Formula 1, X is CH or N; Y is O or S; Z1 and Z2 are each independently N or CH, provided that at least one of Z1 and Z2 is N; Z3 is O or S; R1 is C 1-4 Alkyl, C 3-6 Cycloalkyl, C 1-4 Haloalkyl or halogen; R2 is C 1-4 Haloalkyl; R3 is hydrogen, C 1-4 Alkyl, C 3-6 Cycloalkyl or halogen; L is a single bond or a divalent linker; the divalent linker is selected from unsubstituted or substituted C 1-4 Alkyl, halogen, C 1-4 Haloalkyl, C 1-4 Haloalkoxy, C 1-4 The group consisting of an alkoxy, hydroxy or amino group containing one or two nitrogen-containing 5- or 6-membered heteroaromatic rings, 2-oxa-6-azaspiro[3.3]heptane, thiomorpholine dioxide, 1H-pyrrolo[2,3-b]pyridine and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine; and R4 is hydrogen, C 1-4 Alkyl, (C 1-4 Alkyl)sulfonyl (C 1-4 Alkyl), C 2-4 Alkynyl, C 1-4 Alkoxy, unsubstituted or substituted with hydroxy or C 1-4 Alkoxy C 3-6 Cycloalkyl, halogen, amino, morpholino, morpholinocarbonyl, unsubstituted or substituted with hydroxyl, C 1-4 Alkyl, (C 1-4 alkyl)carbonyl, (C 3-6 Cycloalkyl)carbonyl or (C 1-4 alkyl)sulfonyl 4-, 5- or 6-membered heterocycloalkyl containing one nitrogen, unsubstituted or substituted with hydroxyl, C 1-4 Alkyl, (C 1-4 alkyl)carbonyl, (C 3-6 Cycloalkyl)carbonyl or (C 1-4 1-(aminocarbonyl)eth-1-yl, 1-oxoisoindolinyl, 2-azabicyclo[2.2.1]hept-7-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 4-oxaspiro[2.4]hept-6-yl, or 5-oxopyrrolidinyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is methyl, cyclopropyl, trifluoromethyl or chloro.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is trifluoromethyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, methyl, cyclopropyl, fluorine or chlorine.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L is a single bond or a divalent linker selected from the group consisting of 1-methyl-1H-pyrazole, imidazole, pyrazine, pyrazole, pyridazine, pyridin-2(1H)-one, pyridine, pyrimidine, pyrrole, 2-oxa-6-azaspiro[3.3]heptane, thiomorpholine dioxide, 1H-pyrrolo[2,3-b]pyridine and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen, methyl, methylsulfonylmethyl, ethynyl, methoxy, cyclopropyl, cyclopentyl unsubstituted or substituted with methoxy, bromo, chloro, amino, morpholino, morpholinocarbonyl, azetidinyl, piperidinyl or pyrrolidinyl unsubstituted or substituted with hydroxy, methyl, acetyl, cyclopropanecarbonyl or methylsulfonyl, tetrahydrofuranyl, tetrahydropyranyl, (tetrahydrofuranyl)methyl, (tetrahydrofuranyl)oxy, 1-(aminocarbonyl)eth-1-yl, 1-oxoisoindolinyl, 2-azabicyclo[2.2.1]hept-7-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 4-oxaspiro[2.4]hept-6-yl, 5-oxopyrrolidinyl, or methylsulfonylmethyl.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Chemical formula 1 is represented by the following chemical formula 2: [Chemical formula 2] In chemical formula 2, Y is O or S; Z1 and Z2 are each independently N or CH, provided that at least one of Z1 and Z2 is N; Z3 is O or S; L is a 5- or 6-membered heteroaromatic ring containing one or two nitrogens; and R4 is hydrogen, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen, amino, morpholino, unsubstituted or substituted with C 1-4 Alkyl or (C 1-4 alkyl)carbonyl, a 4-, 5- or 6-membered heterocycloalkyl group containing one nitrogen atom, or a 5- or 6-membered heterocycloalkyl group containing one oxygen atom.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein L is pyrazine, pyridazine, pyridine or pyrimidine.

9. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen, methoxy, cyclopropyl, cyclopentyl, bromo, chloro, amino, morpholino, piperidinyl, pyrrolidinyl, methylpyrrolidinyl, acetylpyrrolidinyl, tetrahydrofuranyl or tetrahydropyranyl.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein 1) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 2) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-methoxypyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 3) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-morpholinopyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 4) N-((5-(6-aminopyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide, 5) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-(pyrrolidin-3-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 6) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(pyrrolidin-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 7) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-(piperidin-4-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 8) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-(piperidin-3-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 9) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(pyrrolidin-3-yl)pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 10) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(pyrrolidin-3-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 11) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-(pyrrolidin-3-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)thioacetamide, 12) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(1-methylpyrrolidin-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 13) 3-(6-(5-((2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamido)methyl)-1,3,4-oxadiazol-2-yl)pyridin-3-yl)-1,1-dimethylpyrrolidinium, 14) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-cyclopentylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide, 15) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 16) N-((5-(5-(1-acetylpyrrolidin-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide, 17) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide, 18) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-bromopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide, 19) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)acetamide, 20) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydro-2H-pyran-3-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 21) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-(1-methylpyrrolidin-3-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 22) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-cyclopropylpyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide, 23) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydrofuran-3-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 24) N-((5-(5-aminopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide, 25) N-((5-(5-aminopyrazin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide, 26) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)oxazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide, 27) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((2-(5-chloropyrimidin-2-yl)oxazol-5-yl)methyl)-N-(4-fluorophenyl)acetamide, 28) N-((5-(5-aminopyrazin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide, 29) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-(1-(cyclopropanecarbonyl)pyrrolidin-3-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide, 30) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(1-(methylsulfonyl)pyrrolidin-3-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 31) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(3-hydroxycyclopentyl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 32) N-((5-(5-(2-azabicyclo[ 2.2.1] hept-7-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide, 33) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(5-oxopyrrolidin-3-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 34) N-((5-(5-(4-oxaspiro[2.4]hept-6-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide, 35) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-((tetrahydrofuran-3-yl)methyl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 36) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(tetrahydrofuran-3-yloxy)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 37) 2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-(4-fluorophenyl)-N-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 38) 2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-phenyl-N-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 39) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(morpholine-4-carbonyl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 40) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(1-methyl-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 41) N-((5-(1H-pyrrol-3-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide, 42) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 43) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 44) N-((5-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide, 45) 2-(4-(5-((2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamido)methyl)-1,3,4-oxadiazol-2-yl)-1H-pyrazol-1-yl)propanamide, 46) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(1-(methylsulfonylmethyl)-1H-pyrazol-4-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 47) N-((5-(3-amino-1-methyl-1H-pyrazol-5-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide, 48) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(1-methyl-1H-imidazol-5-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 49) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-oxo-1,6-dihydropyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 50) 2-(4-chloro-2-(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide, 51) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-chlorophenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 52) N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)-2-(4-methyl-2-(trifluoromethyl)phenyl)acetamide, 53) N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide, 54) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-p-tolylacetamide, 55) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-cyclopropylphenyl)acetamide, 56) N-((5-(5-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide, 57) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(5-(1-oxoisoindolin-2-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 58) N-((5-(2-oxa-6-azaspiro[3.3]hept-6-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide, 59) N-((5-(1,1-dioxothiomorpholin-4-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide, 60) N-((5-(1H-pyrrolo[2,3-b]pyridin-6-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide, 61) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-6-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide, 62) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-ethynyl-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide, 63) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-ethynylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide, 64) 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[5-(3-methoxycyclopentyl)pyrimidin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide, 65) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(2-oxo-1,2-dihydropyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide, 66) 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(2-methoxypyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide, 67) 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[5-(5-chloropyrazin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-N-(4-fluorophenyl)acetamide, 68) 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(6-methoxypyridin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide, and 69) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((2-(5-chloropyridin-2-yl)oxazol-5-yl)methyl)-N-(4-fluorophenyl)acetamide.

11. A pharmaceutical composition for preventing or treating cancer, comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

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