Novel heterocyclic compounds and pharmaceutical composition comprising the same as DNA polymerase theta inhibitors for the prevention or treatment of cancer

Abstract

The present disclosure relates to a novel heterocyclic compound represented by the Chemical Formula 1 and a pharmaceutical composition comprising the same, and the compound according to the present disclosure can be usefully used for the prevention or treatment of cancer.

Description

NOVEL HETEROCYCLIC COMPOUNDS AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME AS DNA POLYMERASE THETA INHIBITORS FOR THE PREVENTION OR TREATMENT OF CANCER

[0001] The present disclosure relates to a novel heterocyclic compound useful as Pol-theta (DNA Polymerase-theta, Polθ) inhibitor and a pharmaceutical composition comprising the same.

[0002] Targeting DNA repair deficiencies has become a proven and effective strategy in cancer treatment. However, DNA repair deficient cancers often become dependent on backup DNA repair pathways, which present an "Achilles heel" that can be targeted to eliminate cancer cells, and is the basis of synthetic lethality. Synthetic lethality is exemplified by the success of Poly ADP-ribose polymerase (PARP) inhibitors in treating BRCA-deficient breast and ovarian cancers.

[0003]

[0004] Robust repair of DNA double-strand breaks (DSBs) is essential for the maintenance of genome stability and cell viability. DSBs can be repaired by 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 well characterized alt-NHEJ mechanism.

[0005]

[0006] Numerous genetic studies have highlighted a role for polymerase theta (Polθ) in stimulating MMEJ in higher organisms. It has been shown that cancer cells with deficiency in HR, NHEJ, or ATM (Ataxia-telangiectasia mutated; A-T mutated) are highly dependent on Polθ expression. The expression of Polθ is largely absent in normal cells but upregulated in breast, lung, and ovarian cancers. Additionally, the increase of Polθ expression correlates with poor prognosis in breast cancer. Importantly, Polθ is largely repressed in normal tissues but has been shown to be upregulated in matched cancer samples thus correlating elevated expression with disease. Its suppression or inhibition confers radio-sensitivity in tumor cells. Polθ inhibition could conceivably prevent the MMEJ-dependent functional reversion of BRCA2 mutations that underlies the emergence of cisplatin and PARPi (PARP inhibitor) resistance in tumors. Therefore, Polθ is an attractive target for novel synthetic lethal therapy in cancers containing DNA repair defects and there is a need to provide effective Polθ inhibitors for the treatment of cancer.

[0007]

[0008] In view of the above, as a result of studying novel compounds, the present inventors found that a compound having a chemical structure different from Polθ inhibitors reported so far has an excellent Polθ inhibitory effect, thereby completing the present disclosure. The compounds belonging to the present disclosure mainly have Polθ inhibitory activity on their own, but do not exclude a possibility of exhibiting a pharmacological action as an efficacious agent by a special body environment or by products of metabolic process, after absorption into the body.

[0009] It is one object of the present disclosure to provide a novel heterocyclic compound useful as a Pol-theta (Polθ) inhibitor, and a pharmaceutical composition comprising the same.

[0010] In order to achieve the above objects, there is provided a compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof:

[0011] [Chemical Formula 1]

[0012]

[0013] in Chemical Formula 1,

[0014] X is CH, or N,

[0015] Y is O, or S,

[0016] Z1and Z2are each independently N, or CH, with the proviso that at least one of Z1and Z2is N,

[0017] Z3is O, or S,

[0018] R1is C1-4alkyl, C3-6cycloalkyl, C1-4haloalkyl, or halogen,

[0019] R2is C1-4haloalkyl,

[0020] R3is hydrogen, C1-4alkyl, C3-6cycloalkyl, or halogen,

[0021] L is a single bond; or a divalent linker selected from the group consisting of a 5-membered or 6-membered heteroaromatic ring containing one or two nitrogens, unsubstituted or substituted with C1-4alkyl, halogen, C1-4haloalkyl, C1-4haloalkoxy, C1-4alkoxy, hydroxy, or amino; 2-oxa-6-azaspiro[3.3]heptane; thiomorpholinedioxide; 1H-pyrrolo[2,3-b]pyridine; and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine; and

[0022] R4is hydrogen; C1-4alkyl; (C1-4alkyl)sulfonyl(C1-4alkyl); C2-4alkynyl; C1-4alkoxy; C3-6cycloalkyl, unsubstituted or substituted with hydroxy, or C1-4alkoxy; halogen; amino; morpholino; morpholinocarbonyl; 4-membered, 5-membered or 6-membered heterocycloalkyl containing one nitrogen, unsubstituted or substituted with hydroxy, C1-4alkyl, (C1-4alkyl)carbonyl, (C3-6cycloalkyl)carbonyl, or (C1-4alkyl)sulfonyl; 5-membered or 6-membered heterocycloalkyl containing one oxygen, unsubstituted or substituted with hydroxy, C1-4alkyl, (C1-4alkyl)carbonyl, (C3-6cycloalkyl)carbonyl, or (C1-4alkyl)sulfonyl; (5-membered or 6-membered heterocycloalkyl containing one oxygen)methyl; (5-membered or 6-membered heterocycloalkyl containing one oxygen)oxy; 1-(aminocarbonyl)ethan-1-yl; 1-oxoisoindolinyl; 2-azabicyclo[2.2.1]heptan-7-yl; 2-oxa-6-azaspiro[3.3]heptan-6-yl; 4-oxaspiro[2.4]heptan-6-yl; or 5-oxopyrrolidinyl.

[0023]

[0024] Further, in order to achieve the above objects, there is provided a pharmaceutical composition comprising the compound, or, a pharmaceutically acceptable salt thereof.

[0025]

[0026] Further, in order to achieve the above objects, there is provided a pharmaceutical composition for the prevention or treatment of cancer, comprising the compound, or a pharmaceutically acceptable salt thereof.

[0027] The compound represented by Chemical Formula 1 according to the present disclosure, or a pharmaceutically acceptable salt thereof can be usefully used for the prevention or treatment of cancers.

[0028] Hereinafter, embodiments of the present disclosure will be described in more detail to facilitate understanding of the invention.

[0029]

[0030] Meanwhile, the present disclosure provides a compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof.

[0031]

[0032] Preferably, R1is methyl, cyclopropyl, trifluoromethyl, or chloro. More preferably, R1is trifluoromethyl.

[0033]

[0034] Preferably, R2is trifluoromethyl.

[0035]

[0036] Preferably, R1and R2are trifluoromethyl.

[0037]

[0038] Preferably, R3is hydrogen, methyl, cyclopropyl, fluoro, or chloro. More preferably, R3is fluoro, or chloro.

[0039]

[0040] 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, thiomorpholinedioxide, 1H-pyrrolo[2,3-b]pyridine, and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.

[0041]

[0042] Preferably, R4is 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)ethan-1-yl; 1-oxoisoindolinyl; 2-azabicyclo[2.2.1]heptan-7-yl; 2-oxa-6-azaspiro[3.3]heptan-6-yl; 4-oxaspiro[2.4]heptan-6-yl; 5-oxopyrrolidinyl; or methylsulfonylmethyl.

[0043]

[0044] Preferably, the Chemical Formula 1 is represented by Chemical Formula 2 below:

[0045] [Chemical Formula 2]

[0046]

[0047] in Chemical Formula 2,

[0048] Y is O, or S,

[0049] Z1and Z2are each independently N, or CH, with the proviso that at least one of Z1and Z2is N,

[0050] Z3is O, or S,

[0051] L is 5-membered or 6-membered heteroaromatic ring containing one or two nitrogens, and

[0052] R4is hydrogen; C1-4alkoxy; C3-6cycloalkyl; halogen; amino; morpholino; 4-membered, 5-membered or 6-membered heterocycloalkyl containing one nitrogen, unsubstituted or substituted with C1-4alkyl, or (C1-4alkyl)carbonyl; or 5-membered or 6-membered heterocycloalkyl containing one oxygen.

[0053]

[0054] Preferably, in Chemical Formulas 1 and 2, Z1and Z2are N and Z3is O.

[0055]

[0056] Preferably, in Chemical Formulas 1 and 2, L is pyrazine, pyridazine, pyridine, or pyrimidine.

[0057]

[0058] Preferably, in Chemical Formulas 1 and 2, R4is hydrogen; methoxy; cyclopropyl; cyclopentyl; bromo; chloro; amino; morpholino; piperidinyl; pyrrolidinyl; methylpyrrolidinyl; acetylpyrrolidinyl; tetrahydrofuranyl; or tetrahydropyranyl.

[0059]

[0060] Representative examples of the compound represented by Chemical Formula 1 are as follows:

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

[0062] 2) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-methoxypyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0063] 3) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-morpholinopyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0064] 4) N-((5-(6-aminopyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0065] 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,

[0066] 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,

[0067] 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,

[0068] 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,

[0069] 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,

[0070] 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,

[0071] 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)ethanethioamide,

[0072] 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,

[0073] 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,

[0074] 14) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-cyclopentylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0075] 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,

[0076] 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,

[0077] 17) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0078] 18) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-bromopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0079] 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,

[0080] 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,

[0081] 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,

[0082] 22) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-cyclopropylpyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0083] 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,

[0084] 24) N-((5-(5-aminopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0085] 25) N-((5-(5-aminopyrazin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0086] 26) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)oxazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0087] 27) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((2-(5-chloropyrimidin-2-yl)oxazol-5-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0088] 28) N-((5-(5-aminopyrazin-2-yl)-1,3,4-thiadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0089] 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,

[0090] 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,

[0091] 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,

[0092] 32) N-((5-(5-(2-azabicyclo[2.2.1]heptan-7-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0093] 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,

[0094] 34) N-((5-(5-(4-oxaspiro[2.4]heptan-6-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0095] 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,

[0096] 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,

[0097] 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,

[0098] 38) 2-(3,5-bis(trifluoromethyl)pyridin-2-yl)-N-phenyl-N-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0099] 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,

[0100] 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,

[0101] 41) N-((5-(1H-pyrrol-3-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0102] 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,

[0103] 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,

[0104] 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,

[0105] 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,

[0106] 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,

[0107] 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,

[0108] 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,

[0109] 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,

[0110] 50) 2-(4-chloro-2-(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0111] 51) 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-chlorophenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide,

[0112] 52) N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)-2-(4-methyl-2-(trifluoromethyl)phenyl)acetamide,

[0113] 53) N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(4-cyclopropyl-2-(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0114] 54) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-p-tolylacetamide,

[0115] 55) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-chloropyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-cyclopropylphenyl)acetamide,

[0116] 56) N-((5-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0117] 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,

[0118] 58) N-((5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0119] 59) N-((5-(1,1-dioxidothiomorpholin-4-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,

[0120] 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,

[0121] 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,

[0122] 62) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-ethynyl-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0123] 63) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((5-(5-ethynylpyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-N-(4-fluorophenyl)acetamide,

[0124] 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,

[0125] 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,

[0126] 66) 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-{[5-(2-methoxypyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}acetamide,

[0127] 67) 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[5-(5-chloropyrazin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-N-(4-fluorophenyl)acetamide,

[0128] 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

[0129] 69) 2-(2,4-bis(trifluoromethyl)phenyl)-N-((2-(5-chloropyridin-2-yl)oxazol-5-yl)methyl)-N-(4-fluorophenyl)acetamide.

[0130]

[0131] In addition, the compounds of the present disclosure may exist in the form of salts, especially pharmaceutically acceptable salts. As salts, salts commonly used in the art, such as acid addition salts formed by pharmaceutically acceptable free acids can be used without limitation. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound represented by Chemical Formula 1, whose concentration is relatively non-toxic and harmless to a patient and activates effectively and whose side effects do not degrade the beneficial efficacy of the above compound.

[0132]

[0133] As the free acid, an organic acid and an inorganic acid can be used. Examples of the inorganic acids include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, and the like. Examples of the 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, and the like, but are not limited thereto. Preferably, the salt may be a hydrochloride salt.

[0134]

[0135] Further, a pharmaceutically acceptable metal salt can be obtained by a conventional method using a base. For example, the compound represented by Chemical Formula 1 is dissolved in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, the non-soluble salt is filtered, and then the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt. At this time, it is particularly preferable to prepare a sodium salt, a potassium salt, or a calcium salt as the metal salt.

[0136]

[0137] In addition, a pharmaceutically unacceptable salt or solvate of the compound of Chemical Formula 1 may be used as an intermediate when preparing the compound of Chemical Formula 1, or the pharmaceutically acceptable salt or the solvate thereof.

[0138]

[0139] In one embodiment, the compound represented by Chemical Formula 1 may be prepared through Reaction Formula 1 below.

[0140] [Reaction Scheme 1]

[0141]

[0142]

[0143] In Reaction Scheme 1, X, and R1to R6are as defined above, and X1and X2are each independently halogen. Preferably, X1and X2are each independently bromo, or chloro.

[0144]

[0145] 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', in which an amine group is substituted while a 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'.

[0146]

[0147] The above preparation method will be more specifically described in the Examples described hereinafter.

[0148]

[0149] According to a further embodiment of the present disclosure, there is provided a pharmaceutical composition comprising the compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof.

[0150]

[0151] According to a further embodiment of the present disclosure, there is provided a pharmaceutical composition for the prevention or treatment of cancer diseases, which is effective for Polθ inhibitory actions, comprising the compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0152]

[0153] In this case, the cancer may be blood cancer, extranodal marginal zone B-cell lymphoma, glioblastoma, lymphoplasmacytic lymphoma, acute myelogenous leukemia, macroglobulinemia, B cell lymphoma, chronic lymphocytic leukemia, follicular lymphoma, non-Hodgkin's lymphoma, diffuse large B cell lymphoma, hairy cell leukemia, mantle cell lymphoma, glioblastoma, bladder cancer, pancreatic cancer, ovarian cancer, colorectal cancer, renal cancer, gastric cancer, transitional cell carcinoma, a carcinoid tumor, breast cancer, non-small cell lung cancer, or multiple myeloma.

[0154]

[0155] As used herein, the term "prevention" refers to any act to delay or inhibit occurrence, spread, or recurrence of the above-mentioned diseases by administration of the composition of the present disclosure, and "treatment" refers to any act to improve or change the symptoms of the above diseases for the better by administration of the composition of the present disclosure.

[0156]

[0157] The pharmaceutical composition according to the present disclosure can be formulated in types for oral or parenteral administrations according to a standard pharmaceutical practice. These formulations may contain additives such as a pharmaceutically acceptable carrier, an adjuvant, or a diluent in addition to the active ingredient.

[0158]

[0159] Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil, isopropyl myristate, and the like. Diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and the like, but are not limited thereto. Further, the compounds of the present disclosure can be dissolved in oils, propylene glycol, or other solvents commonly used in the preparation of injection solutions. Furthermore, the compounds of the present disclosure can be formulated in ointments or creams for topical application.

[0160]

[0161] A preferred dose of the compound of the present disclosure may be varied according to the condition and weight of a patient, the severity of a disease, the type of a drug, and the route and duration of administration, but it may be suitably selected by those skilled in the art. In order to achieve the desirable effects, however, the compound of the present disclosure may be administrated daily at a dose of 0.0001 to 100 mg / kg (body weight), and preferably 0.001 to 100 mg / kg (body weight). The administration may be performed once a day or in divided doses each day through an oral or parenteral route.

[0162]

[0163] Depending on the method of administration, the pharmaceutical composition may contain the compound of the present disclosure in an amount of 0.001 to 99 % by weight, preferably 0.01 to 60 % by weight.

[0164]

[0165] The pharmaceutical composition according to the present disclosure may be administered to mammals such as a rat, a mouse, a domestic animal, or a human, through various routes. The administration may be carried out through all possible methods, for example, oral, rectal, intravenous, intramuscular, subcutaneous, intra-endometrial, intracerebroventricular injection.

[0166]

[0167] Below, the present disclosure will be described in more detail by way of examples. However, these examples are provided for illustrative purposes only, and should not be construed as limiting the scope of the present disclosure to these examples.

[0168]

[0169] 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

[0170]

[0171]

[0172] Step A:N'-(2-chloroacetyl)nicotinohydrazide (2)

[0173] To a solution of pyridine-3-carbohydrazide (1.0 g, 7.29 mmol) in acetonitrile (10 mL) were added TEA (2.21 g, 21.88 mmol) and chloroacetyl chloride (0.6 mL, 7.29 mmol) at 0℃ under N2, the reaction was stirred at 25℃ for 16 h. Upon 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 Na2SO4, filtered and concentrated to dryness under reduced pressure to give crude N'-(2-chloroacetyl)nicotinohydrazide (800 mg, 3.09 mmol, 42.44%) as yellow oil, which was used in next step without further purification.

[0174] LCMS: m / z (M+H)+= 214.1.

[0175]

[0176] Step B:2-(chloromethyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole (3)

[0177] N'-(2-chloroacetyl)nicotinohydrazide (800 mg, 3.74 mmol) in POCl3(5.0 mL) was stirred at 80℃ under N2for 18 h. Upon completion, the reaction mixture was concentrated to dryness under reduced pressure to give the 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 yellow oil.

[0178] LCMS: m / z (M+H)+=196.0.

[0179]

[0180] Step C:4-fluoro-N-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)aniline (4)

[0181] To a solution of 2-(chloromethyl)-5-(pyridin-3-yl)-1,3,4-oxadiazole (170 mg, 0.87 mmol) in DMSO (5.0 mL) were added 4-fluoroaniline (96 mg, 0.99 mmol), potassium carbonate (360 mg, 2.60 mmol), potassium iodide (144 mg, 0.87 mmol) at 25℃ under N2, the reaction was stirred at 25℃ for 18 h. Upon 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 the 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 yellow oil.

[0182] LCMS: m / z (M+H)+= 271.0.

[0183]

[0184] Step D: 2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0185] 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) were added TEA (44 mg, 0.45 mmol) and [2,4-bis(trifluoromethyl) phenyl]acetyl chloride (43 mg, 0.15 mmol) at 25℃, the reaction was stirred at 25℃ under N2for 2 h. Upon 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 white solid.

[0186] 1H NMR (400 MHz, CDCl3) 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).

[0187] LCMS: m / z (M+H)+=525.1.

[0188]

[0189] 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

[0190]

[0191]

[0192] Step A:6-methoxy-1,2-diazine-3-carbohydrazide (2)

[0193] To a solution of methyl 6-methoxy-1,2-diazine-3-carboxylate (2 g, 11.89 mmol) in MeOH (20 mL) was added N2H4.H2O (3.81 g, 95.15 mmol) (80% purity), the reaction was stirred at 25℃ for 16 h. Upon 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 white solid.

[0194] LCMS: m / z (M+H)+= 169.0.

[0195]

[0196] Step B:N'-(2-chloroacetyl)-6-methoxy-1,2-diazine-3-carbohydrazide (3)

[0197] To a solution of 6-methoxy-1,2-diazine-3-carbohydrazide (1800 mg, 10.70 mmol) in DCM (20 mL) were added TEA (2.97 mL, 21.41 mmol) and chloroacetyl chloride (0.85 mL, 10.70 mmol) at 0°C, the reaction was stirred at 25℃ for 16 h. Upon completion, the reaction was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.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.

[0198] LCMS: m / z (M+H)+=245.0.

[0199]

[0200] Step C:6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-3-methoxy-1,2-diazine (4)

[0201] To a solution of N'-(2-chloroacetyl)-6-methoxy-1,2-diazine-3-carbohydrazide (1600 mg, 6.54 mmol) in DCM (20 mL) were added TEA (5.44 mL, 39.24 mmol) and 4-methylbenzenesulfonyl chloride (1620.94 mg, 8.50 mmol) at 25℃, the reaction was stirred at 25℃ for 16 h. Upon 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.

[0202] LCMS: m / z (M+H)+= 227.0.

[0203]

[0204] Step D:4-fluoro-N-((5-(6-methoxypyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)aniline (5)

[0205] To a solution of 6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-3-methoxy-1,2-diazine (200 mg, 0.66 mmol) in DMSO (2 mL) were added TEA (0.28 mL, 1.99 mmol) and 4-fluoroaniline (0.06 mL, 0.66 mmol), the reaction was stirred at 40℃ for 16 h. Upon 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 yellow solid.

[0206] LCMS: m / z (M+H)+= 302.2.

[0207]

[0208] 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

[0209] 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) were added TEA (0.03 mL, 0.20 mmol) and [2,4-bis(trifluoromethyl)phenyl]acetyl chloride (19.29 mg, 0.07 mmol) at 25℃, the reaction was stirred at 25℃ for 16 h. Upon completion, the mixture was concentrated under reduced pressure, the residue was purified by pre-HPLC (FA condition) 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 white solid.

[0210] 1H NMR (400 MHz, CDCl3) 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).

[0211] LCMS: m / z (M+H)+=556.2.

[0212]

[0213] 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

[0214]

[0215]

[0216] Step A:methyl 6-(1,4-oxazinan-4-yl)-1,2-diazine-3-carboxylate (2)

[0217] To a solution of methyl 6-chloro-1,2-diazine-3-carboxylate (1 g, 5.79 mmol) in dioxane (10 mL) were added TEA (2.41 mL, 17.38 mmol) and 1,4-oxazinane (0.61 g, 6.95 mmol) at 25℃, the reaction was stirred at 100℃ for 16 h. Upon completion, the reaction was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 2:1 to 1:1) to give methyl 6-(1,4-oxazinan-4-yl)-1,2-diazine-3-carboxylate (620 mg, 2.69 mmol, 46.40%) as yellow solid.

[0218] LCMS: m / z (M+H)+= 224.2.

[0219]

[0220] Step B:6-(1,4-oxazinan-4-yl)-1,2-diazine-3-carbohydrazide (3)

[0221] To a solution of methyl 6-(1,4-oxazinan-4-yl)-1,2-diazine-3-carboxylate (0.6 g, 2.69 mmol) in MeOH (5 mL) was added N2H4.H2O (0.86 g, 21.50 mmol) (80% purity) at 25℃, the reaction was stirred at 25°C for 16 h. Upon completion, the reaction was concentrated under reduced pressure. The residue was washed with Pet.ether (30 mL) and concentrated under reduced pressure to give 6-(1,4-oxazinan-4-yl)-1,2-diazine-3-carbohydrazide (550 mg, 2.37 mmol, 88.00%) as white solid.

[0222] LCMS: m / z (M+H)+= 224.2.

[0223]

[0224] Step C:N'-(2-chloroacetyl)-6-(1,4-oxazinan-4-yl)-1,2-diazine-3-carbohydrazide (4)

[0225] To a solution of 6-(1,4-oxazinan-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) at 25°C, the reaction was stirred at 25℃ for 16 h. Upon completion, the reaction was diluted with water (10 mL) and extracted with DCM (10 mL*2), the organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure to give N'-(2-chloroacetyl)-6-(1,4-oxazinan-4-yl)-1,2-diazine-3-carbohydrazide (550 mg, 1.71 mmol, 76.20%) as a black solid.

[0226] LCMS: m / z (M+H)+= 300.2.

[0227]

[0228] Step D:6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-3-(1,4-oxazinan-4-yl)-1,2-diazine (5)

[0229] To a solution of N'-(2-chloroacetyl)-6-(1,4-oxazinan-4-yl)-1,2-diazine-3-carbohydrazide (600 mg, 2.00 mmol) in DCM (10 mL) were added TEA (1.67 mL, 12.01 mmol) and 4-methylbenzenesulfonyl chloride (496.14 mg, 2.60 mmol) at 25℃, the reaction was stirred at 25℃ for 16 h. Upon completion, the reaction was concentrated under reduced pressure, the residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 1:1 to 0:1) to give 6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-3-(1,4-oxazinan-4-yl)-1,2-diazine (390 mg, 1.22 mmol, 60.86%) as a yellow solid.

[0230] LCMS: m / z (M+H)+= 282.0.

[0231]

[0232] Step E:6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-3-(1,4-oxazinan-4-yl)-1,2-diazine (6)

[0233] To a solution of 6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-3-(1,4-oxazinan-4-yl)-1,2-diazine (80 mg, 0.28 mmol) in DMSO (1 mL) were added TEA (0.12 mL, 0.85 mmol) and 4-fluoroaniline (0.03 mL, 0.28 mmol) at 25℃, the reaction was stirred at 25℃ for 16 h. Upon completion, the reaction was diluted with water (20 mL), and extracted with EtOAc (20 mL*2), the organic layers were concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 0:1) to give 6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-3-(1,4-oxazinan-4-yl)-1,2-diazine (30 mg, 0.08 mmol, 26.68%) as a white solid.

[0234] LCMS: m / z (M+H)+= 357.2.

[0235]

[0236] Step F: 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[6-(1,4-oxazinan-4-yl)-1,2-diazin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide

[0237] To a solution of 6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-3-(1,4-oxazinan-4-yl)-1,2-diazine (20 mg, 0.06 mmol) in THF (1 mL) were added 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) at 0℃, The reaction was stirred at 25℃ for 16 h. Upon completion, the mixture was quenched with water (5 mL) and extracted with EtOAc (10 mL*2), the organic layers were concentrated under reduced pressure. The residue was purified by pre-HPLC (FA condition) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[6-(1,4-oxazinan-4-yl)-1,2-diazin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide (2.35 mg, 6.72%) as a white solid.

[0238] 1H NMR (400 MHz, CDCl3) 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).

[0239] LCMS: m / z (M+H)+=611.2.

[0240]

[0241] 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

[0242]

[0243]

[0244] Step A:methyl 6-{bis[(4-methoxyphenyl)methyl]amino}-1,2-diazine-3-carboxylate (2)

[0245] 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) was added TEA (1.20 mL, 8.69 mmol) at 25℃. The mixture was stirred at 100℃ for 18 h to give a yellow solution. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 0 to 50%) to give methyl 6-{bis[(4-methoxyphenyl)methyl]amino}-1,2-diazine-3-carboxylate (0.97 g, 2.47 mmol, 42.54%) as white solid.

[0246] LCMS: m / z (M+H)+=394.2.

[0247]

[0248] Step B:6-{bis[(4-methoxyphenyl)methyl]amino}-1,2-diazine-3-carbohydrazide (3)

[0249] To a solution of methyl 6-{bis[(4-methoxyphenyl)methyl]amino}-1,2-diazine-3-carboxylate (970.00 mg, 2.47 mmol) in MeOH (20 mL) was added N2H4.H2O (1452.00 mg, 24.65 mmol) (80% purity) at 25℃, the mixture was stirred at 25℃ for 18 h under N2to give a brown solution. Upon 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 white solid.

[0250] LCMS: m / z (M+H)+= 394.2.

[0251]

[0252] Step C:6-{bis[(4-methoxyphenyl)methyl]amino}-N'-(2-chloroacetyl)-1,2-diazine-3-carbohydrazide (4)

[0253] 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) was added chloroacetyl chloride (0.10 mL, 1.27 mmol) in an ice bath, the mixture was stirred at 25℃ for 18 h to give a brown solution. Upon 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 white solid.

[0254] LCMS: m / z (M+H)+= 470.2.

[0255]

[0256] Step D:6-{bis[(4-methoxyphenyl)methyl]amino}-3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazine (5)

[0257] 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) was added 4-methylbenzenesulfonyl chloride (462.47 mg, 2.43 mmol) in an ice bath, the mixture was stirred at 25℃ for 18 h under N2to give a brown solution. Upon 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 6-{bis[(4-methoxyphenyl)methyl]amino}-3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazine (490 mg, 1.08 mmol, 89.39%) as white solid.

[0258] LCMS: m / z (M+H)+= 452.2.

[0259]

[0260] Step E:6-{bis[(4-methoxyphenyl)methyl]amino}-3-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazine (6)

[0261] 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) were added K2CO3(311.93 mg, 2.26 mmol) and KI (249.00 mg, 1.50 mmol) at 25℃, the mixture was stirred at 25℃ under N2for 18 h to give a brown solution. Upon completion, the mixture was concentrated 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 (280 mg, 0.43 mmol, 56.54%) as white solid.

[0262] LCMS: m / z (M+H)+= 527.4.

[0263]

[0264] 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)

[0265] To a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (25.84 mg, 0.09 mmol) in DCM (2 mL) were added oxoacetyl chloride (0.01 mL, 0.09 mmol) and a drop DMF in an ice bath, the mixture was stirred at 0℃ under N2for 1 h. The mixture was concentrated under reduced pressure and dissolved in THF (2 mL). The solution was added 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 stirred at 25℃ for 18 h to give a brown solution. Upon completion, the reaction mixture was quenched with H2O (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by prep-TLC (Pet.ether: EtOAc = 1:1) to give 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 white solid.

[0266] LCMS: m / z (M+H)+=781.3.

[0267]

[0268] 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

[0269] 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) was stirred at 25℃ for 18 h to give a brown solution. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by high performance liquid phase (trifluoroacetic acid / acetonitrile / water) to give 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 white solid.

[0270] LCMS: m / z (M+H)+=541.2.

[0271]

[0272] Example 5: Synthesis of 2-(2,4-bis(trifleoromethyl)phenyl)-N-(4-fluorophenyl)-N-((5-(6-(pyrrolidin-3-yl)pyridazin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)acetamide

[0273]

[0274]

[0275] Step A:methyl 6-(1-{[(2-methylprop-2-yl)oxy]carbonyl}-2,5-dihydro-1H-pyrrol-3-yl)-1,2-diazine-3-carboxylate (2)

[0276] To a solution of methyl 6-chloro-1,2-diazine-3-carboxylate (1 g, 5.79 mmol) in DMF (50 mL) were 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), K2CO3(2.40 g, 17.38 mmol), Pd(dppf)Cl2(0.42 g, 0.58 mmol) at 25℃ under N2. The mixture was stirred at 100℃ under N2for 3 h. Upon completion, the mixture was concentrated under reduced pressure to give a crude product. The residue was purified by silica-gel column chromatography (EtOAc: Pet.ether =1:10 to 1:1) to give methyl 6-(1-{[(2-methylprop-2-yl)oxy]carbonyl}-2,5-dihydro-1H-pyrrol-3-yl)-1,2-diazine-3-carboxylate (300 mg, 0.93 mmol, 16.1%) as white solid.

[0277] LCMS: m / z (M+H)+= 306.0.

[0278]

[0279] Step B:methyl 6-(1-{[(2-methylprop-2-yl)oxy]carbonyl}hexahydropyridin-3-yl)-1,2-diazine-3-carboxylate (3)

[0280] To a solution of methyl 6-(1-{[(2-methylprop-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 Pd / C 10% (30.0 mg) at 25℃, the mixture was stirred at 25℃ under H2(15 Psi) for 16h. After filtration, the filtrate was concentrated under reduced pressure to give methyl 6-(tetrahydro-1H-pyrrol-3-yl)-1,2-diazine-3-carboxylate (250 mg, 1.21 mmol, 83.73%) as yellow oil, which was used in next step without further purification.

[0281] LCMS: m / z (M+H-100)+= 208.3.

[0282]

[0283] Step C:2-methylpropan-2-yl 3-[6-(diazanylcarbonyl)-1,2-diazin-3-yl]tetrahydropyrrole-1-carboxylate (4)

[0284] To a solution of methyl 6-(1-{[(2-methylprop-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)-1,2-diazine-3-carboxylate (200 mg, 0.62 mmol) in MeOH (10 mL) was added N2H4.H2O (0.5 mL)(80% purity) at 25℃. The mixture was stirred at 25℃ for 16 h. Upon completion, the mixture was concentrated under reduced pressure to give 2-methylpropan-2-yl 3-[6-(diazanylcarbonyl)-1,2-diazin-3-yl]tetrahydropyrrole-1-carboxylate (150.0 mg, 0.46 mmol, 75.0%) as white solid.

[0285] LCMS: m / z (M+H)+= 308.0.

[0286]

[0287] Step D:2-methylpropan-2-yl 3-(6-{[2-(2-chloroacetyl)diazanyl]carbonyl}-1,2-diazin-3-yl)tetrahydropyrrole-1-carboxylate (5)

[0288] To a solution of 2-methylpropan-2-yl 3-[6-(diazanylcarbonyl)-1,2-diazin-3-yl]tetrahydropyrrole-1-carboxylate (700 mg, 2.28 mmol) and TEA (0.63 mL, 4.56 mmol) in DCM (100 mL) was added chloroacetyl chloride (0.20 mL, 2.51 mmol) in an ice bath, the mixture was stirred at 25℃ under N2for 18 h to give a brown solution. Upon 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-(6-{[2-(2-chloroacetyl)diazanyl]carbonyl}-1,2-diazin-3-yl)tetrahydropyrrole-1-carboxylate (700 mg, 1.46 mmol, 64.06%) as white solid.

[0289] LCMS: m / z (M+H-56)+= 328.0.

[0290]

[0291] Step E:2-methylpropan-2-yl 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}tetrahydropyrrole-1-carboxylate (6)

[0292] To a solution of 2-methylpropan-2-yl 3-(6-{[2-(2-chloroacetyl)diazanyl]carbonyl}-1,2-diazin-3-yl)tetrahydropyrrole-1-carboxylate (700 mg, 1.46 mmol) and TEA (1.52 mL, 10.94 mmol) in DCM (100 mL) was added 4-methylbenzenesulfonyl chloride (695.35 mg, 3.65 mmol) in an ice bath, the mixture was stirred at 25℃ for 18 h to give a brown solution. 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-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}tetrahydropyrrole-1-carboxylate (300 mg, 0.74 mmol, 40.47%) as white solid.

[0293] LCMS: m / z (M-56+H)+=310.0.

[0294]

[0295] Step F:2-methylpropan-2-yl 3-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazin-3-yl]tetrahydropyrrole-1-carboxylate (7)

[0296] To a solution of 2-methylpropan-2-yl 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}tetrahydropyrrole-1-carboxylate (270 mg, 0.74 mmol) and 4-fluoroaniline (0.07 mL, 0.74 mmol) in DMSO (20 mL) were added K2CO3(204.00 mg, 1.48 mmol) and KI (122.52 mg, 0.74 mmol) at 25℃, the mixture was stirred at 25℃ for 18 h to give a brown solution. Upon completion, the reaction mixture was diluted with EtOAc (200 mL) and washed with H2O (200 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica-gel column chromatography (DCM: MeOH=0 to 10%) to give 2-methylpropan-2-yl 3-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazin-3-yl]tetrahydropyrrole-1-carboxylate (290 mg, 0.53 mmol, 71.36%) as white solid.

[0297] LCMS: m / z (M+H-56)+= 385.2.

[0298]

[0299] 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}-1,2-diazin-3-yl)tetrahydropyrrole-1-carboxylate (8)

[0300] To a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (111.21 mg, 0.41 mmol) in CH3CN (2 mL) was added (1-chloro-2-methylprop-1-enyl)dimethylamine (0.05 mL, 0.41 mmol) in an ice bath under N2, the mixture was stirred at 0℃ for 1 h. Then 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)-1,2-diazin-3-yl]tetrahydropyrrole-1-carboxylate (150 mg, 0.34 mmol) and DMAP (62.41 mg, 0.51 mmol) in CH3CN (2 mL) at 0℃. The mixture was stirred at 25℃ for 2 h to give a yellow solution. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 0 to 100%) 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}-1,2-diazin-3-yl)tetrahydropyrrole-1-carboxylate (80 mg, 0.10 mmol, 30.44%) as white solid.

[0301] LCMS: m / z (M+H-56)+= 639.4.

[0302]

[0303] 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

[0304] 2-methylpropan-2-yl 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)tetrahydropyrrole-1-carboxylate (60 mg, 0.09 mmol) in TFA (3 mL) was stirred at 25℃ for 18 h to give a brown solution. Upon completion, the mixture was concentrated under reduced pressure. The residue was 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 white solid.

[0305] 1H NMR (400 MHz, CDCl3) 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).

[0306] LCMS: m / z (M+H)+= 595.4.

[0307]

[0308] 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

[0309]

[0310]

[0311] Step A:methyl 5-(1-{[(2-methylprop-2-yl)oxy]carbonyl}-2,5-dihydro-1H-pyrrol-3-yl)pyrid ine-2-carboxylate (2)

[0312] To a solution of methyl 5-chloropyridine-2-carboxylate (1 g, 5.83 mmol) in DMF (10 mL) was added 2-methylpropan-2-yl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrr ole-1-carboxylate (1.72 g, 5.83 mmol), Pd(dppf)Cl2(0.43 g, 0.58 mmol) and K2CO3(1.61 g, 11.66 mmol) at 25℃, the reaction was stirred at 100℃ for 3 h under N2. Upon completion, the mixture was concentrated under vacuum. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 0 to 40%) to give methyl 5-(1-{[(2-methylprop-2-yl)oxy]carbonyl}-2,5-dihydro-1H-pyrrol-3-yl)pyridine-2-carboxylate (900 mg, 2.96 mmol, 50.85%) as white solid.

[0313] LCMS: m / z (M+H)+= 305.2.

[0314]

[0315] Step B:methyl 5-(1-{[(2-methylprop-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)pyridine -2-carboxylate (3)

[0316] To a solution of methyl 5-(1-{[(2-methylprop-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 Pd / C 10% (100 mg) at 25℃ under H2, the reaction was stirred at 25℃ for 16 h under H2(15 Psi). 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-methylprop-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)pyridine-2-carboxylate (950 mg, 2.79 mmol, 84.65%) as white solid.

[0317] LCMS: m / z (M+H)+= 307.0.

[0318]

[0319] Step C:2-methylpropan-2-yl 3-[2-(diazanylcarbonyl)pyridin-5-yl]tetrahydropyrrole-1-carboxylate (4)

[0320] To a solution of methyl 5-(1-{[(2-methylprop-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)pyridine-2-carboxylate (0.95 g, 3.10 mmol) in MeOH (10 mL) was added hydrazine hydrate (0.94 mL, 15.50 mmol) (80% purity) at 25℃, the reaction was stirred at 25℃ for 18 h under N2. Upon 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-(diazanylcarbonyl)pyridin-5-yl]tetrahydropyrrole-1-carboxylate (900 mg, 2.64 mmol, 85.26%) as white solid.

[0321] LCMS: m / z (M+H)+= 307.2.

[0322]

[0323] Step D:2-methylpropan-2-yl 3-(2-{[2-(2-chloroacetyl)diazanyl]carbonyl}pyridin-5-yl)tetra hydropyrrole-1-carboxylate (5)

[0324] To a solution of 2-methylpropan-2-yl 3-[2-(diazanylcarbonyl)pyridin-5-yl]tetrahydropyrrole-1-carboxylate (900 mg, 2.94 mmol) in DCM (10 mL) were added chloroacetyl chloride (0.26 mL, 3.23 mmol) and triethylamine (1.63 mL, 11.75 mmol) at 0℃, the reaction was stirred at 25℃ for 18 h under N2. Upon 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)diazanyl]carbonyl}pyridin-5-yl)tetrahydropyrrole-1-carboxylate (850 mg, 2.22 mmol, 75.58%) as yellow oil.

[0325] LCMS: m / z (M+H)+=383.2.

[0326]

[0327] Step E:2-methylpropan-2-yl 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridin-3-yl}tetrah ydropyrrole-1-carboxylate (6)

[0328] To a solution of 2-methylpropan-2-yl 3-(2-{[2-(2-chloroacetyl)diazanyl]carbonyl}pyridin-5-yl)tetrahydropyrrole-1-carboxylate (850 mg, 2.22 mmol) in DCM (10 mL) were added TEA (1.23 mL, 8.88 mmol) and 4-methylbenzenesulfonyl chloride (0.85 mL, 4.44 mmol) at 0℃, the reaction was stirred at 25℃ for 18 h. Upon 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-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridin-3-yl}tetrahydropyrrole-1-carboxylate (700 mg, 1.92 mmol, 86.42%) as yellow oil.

[0329] LCMS: m / z (M-56+H)+=309.0.

[0330]

[0331] Step F:2-methylpropan-2-yl 3-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyridin-3-yl]tetrahydropyrrole-1-carboxylate (7)

[0332] To a solution of 2-methylpropan-2-yl 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridin-3-yl}tetrahydropyrrole-1-carboxylate (650 mg, 1.78 mmol) and 4-fluoroaniline (0.21 mL, 0.22 mmol) in DMF (3 mL) were added potassium iodide (295.75 mg, 1.78 mmol) and K2CO3(492.45 mg, 3.56 mmol) at 25℃, the reaction was stirred at 25℃ under N2for 18 h. Upon completion, the reaction mixture was concentrated under vacuum. The crude product was purified by silica-gel column chromatography (DCM: MeOH= 0 to 10%) to give 2-methylpropan-2-yl 3-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyridin-3-yl]tetrahydropyrrole-1-carboxylate (480 mg, 0.98 mmol, 55.17%) as yellow oil.

[0333] LCMS: m / z (M+H)+= 440.2.

[0334]

[0335] 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)tetrahydropyrrole-1-carboxylate (8)

[0336] To a solution of [2,4-bis(trifluoromethyl) phenyl] acetic acid (61.92 mg, 0.23 mmol) in CH3CN (2 mL) was added (1-chloro-2-methylprop-1-enyl) dimethylamine (0.04 mL, 0.27 mmol) in an ice bath under N2, the mixture was stirred at 0℃ for 1 h. Then 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]tetrahydropyrrole-1-carboxylate (100 mg, 0.23 mmol) and DMAP (62.41 mg, 0.51 mmol) in CH3CN (2 mL) at 0℃. The mixture was stirred at 25℃ for 16 h to give a yellow solution. Upon 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)tetrahydropyrrole-1-carboxylate (82 mg, 0.12 mmol, 51.96%) as yellow oil.

[0337] LCMS: m / z (M+H-56)+= 638.3.

[0338]

[0339] 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

[0340] 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)tetrahydropyrrole-1-carboxylate (100 mg, 0.14 mmol) in DCM (2 mL) was added TFA (0.5 mL, 6.71 mmol) at 0℃ and the mixture was stirred at 25℃ for 3 h under N2. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (NH4CO3condition) to give 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 white solid.

[0341] 1H NMR (400 MHz, CDCl3) 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).

[0342] LCMS: m / z (M+H)+= 594.2.

[0343]

[0344] 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

[0345]

[0346]

[0347] Step A:methyl 6-(1-{[(2-methylprop-2-yl)oxy]carbonyl}-1,2,3,6-tetrahydropyridin-4-yl)-1,2-diazine-3-carboxylate (2)

[0348] To a solution of 2-methylpropan-2-yl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (3583.59 mg, 11.59 mmol) in DMF (20 mL) were added K2CO3(2402.50 mg, 17.38 mmol), methyl 6-chloro-1,2-diazine-3-carboxylate (1000 mg, 5.79 mmol) and bis[5-(diphenylphosphanyl)cyclopenta-1,3-dienyl]-λ2-iron(II) palladium chloride (212.00 mg, 0.29 mmol) at 25℃, the reaction was stirred at 100℃ for 1 h under the N2. Upon completion, the reaction was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 3:1) to give methyl 6-(1-{[(2-methylprop-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.

[0349] LCMS: m / z (M+H)+= 320.2.

[0350]

[0351] Step B:methyl 6-(1-{[(2-methylprop-2-yl)oxy]carbonyl}hexahydropyridin-4-yl)-1,2-diazine-3-carboxylate (3)

[0352] To a solution of methyl 6-(1-{[(2-methylprop-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) was added 10% Pd / C (133.29 mg, 0.13 mmol) at 25℃, the mixture was stirred at 25℃ for 4 h under the H2(15 Psi). Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 3:1) to give methyl 6-(1-{[(2-methylprop-2-yl)oxy]carbonyl}hexahydropyridin-4-yl)-1,2-diazine-3-carboxylate (90 mg, 0.28 mmol, 22.36%) as a white solid.

[0353] LCMS: m / z (M+H-56)+= 266.0.

[0354]

[0355] Step C:2-methylpropan-2-yl 4-[3-(diazanylcarbonyl)-1,2-diazin-6-yl]hexahydropyridine-1-carboxylate (4)

[0356] To a solution of methyl 6-(1-{[(2-methylprop-2-yl)oxy]carbonyl}hexahydropyridin-4-yl)-1,2-diazine-3-carboxylate (90 mg, 0.28 mmol) in MeOH (3 mL) were added hydrazine hydrate (0.08 mL, 1.40 mmol) (80% purity) at 25℃, the mixture was stirred at 25℃ for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 1:1) to give 2-methylpropan-2-yl 4-[3-(diazanylcarbonyl)-1,2-diazin-6-yl]hexahydropyridine-1-carboxylate (80 mg, 0.24 mmol, 84.45%) as a white solid.

[0357] LCMS: m / z (M+H-56)+= 266.0.

[0358]

[0359] Step D:2-methylpropan-2-yl 4-(6-{[2-(2-chloroacetyl)diazanyl]carbonyl}-1,2-diazin-3-yl)he xahydropyridine-1-carboxylate (5)

[0360] To a solution of 2-methylpropan-2-yl 4-[3-(diazanylcarbonyl)-1,2-diazin-6-yl]hexahydropyridine-1-carboxylate (100 mg, 0.31 mmol) in DCM (4 mL) were added TEA (0.06 mL, 0.47 mmol) and chloroacetyl chloride (0.02 mL, 0.31 mmol) at 0℃, the mixture was stirred at 25℃ for 1 h. Upon 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 2-methylpropan-2-yl 4-(6-{[2-(2-chloroacetyl)diazanyl]carbonyl}-1,2-diazin-3-yl)hexahydropyridi ne-1-carboxylate (110 mg, 0.26 mmol, 84.41%) as yellow oil.

[0361] LCMS: m / z (M+H-56)+= 342.0.

[0362]

[0363] Step E:2-methylpropan-2-yl 4-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}hexahydropyridine-1-carboxylate (6)

[0364] To a solution of 2-methylpropan-2-yl 4-(6-{[2-(2-chloroacetyl)diazanyl]carbonyl}-1,2-diazin-3-yl)hexahydropyridine-1-carboxylate (20 mg, 0.05 mmol) in DCM (5 mL) were added TEA (0.03 mL, 0.20 mmol) and 4-methylbenzenesulfonyl chloride (19.17 mg, 0.10 mmol) at 20℃, the mixture was stirred at 20℃ for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 1:2) to give 2-methylpropan-2-yl 4-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}hexahydropyridine-1-carboxylate (10 mg, 0.03 mmol, 49.76%) as a white solid.

[0365] LCMS: m / z (M+H-56)+= 324.0.

[0366]

[0367] Step F:2-methylpropan-2-yl 4-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazin-3-yl]hexahydropyridine-1-carboxylate (7)

[0368] To a solution of 2-methylpropan-2-yl 4-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}hexahydropyridine-1-carboxylate (100 mg, 0.26 mmol) in DMF (4 mL) were added K2CO3(72.77 mg, 0.53 mmol), 4-fluoroaniline (0.03 mL, 0.26 mmol) and potassium iodide (43.70 mg, 0.26 mmol) at 20℃, the mixture was stirred at 20℃ for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 1:2) to give 2-methylpropan-2-yl 4-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazin-3-yl]hexahydropyridine-1-carboxylate (60 mg, 0.13 mmol, 47.63%) as a white solid.

[0369] LCMS: m / z (M+H-56)+= 399.2.

[0370]

[0371] Step G:2-methylpropan-2-yl 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)hexahydropyridine-1-carboxylate (8)

[0372] To a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (5.99 mg, 0.02 mmol) in acetonitrile (2 mL) was added (1-chloro-2-methylprop-1-enyl)dimethylamine (0.01 mL, 0.03 mmol) at 0℃, the mixture was stirred at 0℃ for 1 h. Then the mixture was added to a solution of 2-methylpropan-2-yl 4-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazin-3-yl]hexahydropyridine-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℃ for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 1:1) to give 2-methylpropan-2-yl 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)hexahydropyridine-1-carboxylate (4 mg, 0.01 mmol, 24.37%) as a yellow solid.

[0373] LCMS: m / z (M+H-56)+= 653.0.

[0374]

[0375] Step H: 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[6-(hexahydropyridin-4-yl)-1,2-diazin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide

[0376] To a solution of 2-methylpropan-2-yl 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)hexahydropyridine-1-carboxylate (30 mg, 0.04 mmol) in DCM (2 mL) was added the TFA (0.5 mL, 6.71 mmol) at 20℃, the mixture was stirred at 20℃ for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by p-HPLC (FA condition) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[6-(hexahydropyridin-4-yl)-1,2-diazin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide (1.16 mg, 4.50%) as a white solid.

[0377] 1H 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).

[0378] LCMS: m / z (M+H)+=609.4.

[0379]

[0380] 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

[0381]

[0382]

[0383] Step A:methyl 6-(1-{[(2-methylprop-2-yl)oxy]carbonyl}-1,2,5,6-tetrahydropyridin-3-yl)-1,2-diazine-3-carboxylate (2)

[0384] To a solution of methyl 6-chloro-1,2-diazine-3-carboxylate (3 g, 17.38 mmol) in DMF (50 mL) were added 2-methylpropan-2-yl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahyd ropyridine-1-carboxylate (5.91 g, 19.12 mmol), K2CO3(7.21 g, 52.15 mmol) and Pd(dppf)Cl2(0.64 g, 0.87 mmol) at 25℃. The reaction was degassed with N2three times and stirred at 100℃ for 4 h under N2. Upon completion, the mixture was concentrated in vacuum. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 1:1) to give methyl 6-(1-{[(2-methylprop-2-yl)oxy]carbonyl}-1,2,5,6-tetrahydropyridin-3-yl)-1,2-diazine-3-carboxylate (1000 mg, 2.29 mmol, 13.15%) as black solid.

[0385] LCMS: m / z (M+H)+= 320.0.

[0386]

[0387] Step B:methyl 6-(1-{[(2-methylprop-2-yl)oxy]carbonyl}hexahydropyridin-3-yl)-1,2-diazine-3-carboxylate (3)

[0388] To a solution of methyl 6-(1-{[(2-methylprop-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) was added 10% Pd / C (100 mg) at 25℃, the reaction was degassed with H2three times and stirred at 25℃ for 4 h under H2(15 psi). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 1:1) to give methyl 6-(1-{[(2-methylprop-2-yl)oxy]carbonyl}hexahydropyridin-3-yl)-1,2-diazine-3-carboxylate (510 mg, 1.54 mmol, 49.23%) as white solid.

[0389] LCMS: m / z (M+H)+= 322.2.

[0390]

[0391] Step C:2-methylpropan-2-yl 3-[6-(diazanylcarbonyl)-1,2-diazin-3-yl]hexahydropyridine-1-carboxylate (4)

[0392] To a solution of methyl 6-(1-{[(2-methylprop-2-yl)oxy]carbonyl}hexahydropyridin-3-yl)-1,2-diazine-3-carboxylate (530 mg, 1.65 mmol) in MeOH (5 mL) was added N2H4.H2O (515.97 mg, 8.25 mmol)(80% purity) at 25℃, the reaction was stirred at 25℃ for 16 h under N2. Upon completion, the mixture was evaporated under reduced pressure to give 2-methylpropan-2-yl 3-[6-(diazanylcarbonyl)-1,2-diazin-3-yl]hexahydropyridine-1-carboxylate (460 mg, 1.37 mmol, 82.96%) as black oil, which was used in next step without further purification.

[0393] LCMS: m / z (M+H)+= 322.2.

[0394]

[0395] Step D:2-methylpropan-2-yl 3-(6-{[2-(2-chloroacetyl)diazanyl]carbonyl}-1,2-diazin-3-yl)hexahydropyridine-1-carboxylate (5)

[0396] To a solution of 2-methylpropan-2-yl 3-[6-(diazanylcarbonyl)-1,2-diazin-3-yl]hexahydropyridine-1-carboxylate (450 mg, 1.40 mmol) in DCM (5 mL) were added TEA (0.29 mL, 2.10 mmol) and chloroacetyl chloride (0.11 mL, 1.40 mmol) at 25℃, the reaction was stirred at 25℃ for 16 h. Upon 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 3-(6-{[2-(2-chloroacetyl)diazanyl]carbonyl}-1,2-diazin-3-yl)hexahydropyridine-1-carboxylate (460 mg, 1.02 mmol, 73.11%) as yellow oil.

[0397] LCMS: m / z (M+H-56)+= 342.2.

[0398]

[0399] Step E:2-methylpropan-2-yl 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}hexahydropyridine-1-carboxylate (6)

[0400] To a solution of 2-methylpropan-2-yl 3-(6-{[2-(2-chloroacetyl)diazanyl]carbonyl}-1,2-diazin-3-yl)hexahydropyridine-1-carboxylate (400 mg, 1.01 mmol) in DCM (5 mL) were added TEA (0.56 mL, 4.02 mmol) and 4-methylbenzenesulfonyl chloride (383.33 mg, 2.01 mmol at 25℃, the reaction was stirred at 25℃ for 16 h under N2. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 1:2) to give 2-methylpropan-2-yl 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}hexahydropyridine-1-carboxylate (280 mg, 0.71 mmol, 70.39%) as a yellow solid.

[0401] LCMS: m / z (M+H)+= 380.2.

[0402]

[0403] Step F:2-methylpropan-2-yl 3-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazin-3-yl]hexahydropyridine-1-carboxylate (7)

[0404] To a solution of 2-methylpropan-2-yl 3-{6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1,2-diazin-3-yl}hexahydropyridine-1-carboxylate (260 mg, 0.68 mmol) in DMSO (5 mL) were added K2CO3(189.19 mg, 1.37 mmol), 4-fluoroaniline (0.07 mL, 0.68 mmol) and potassium iodide (0.08 mL, 0.68 mmol) at 25℃, the reaction was stirred at 25℃ for 4 h under N2. Upon completion, the mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL*2), the organic layers were concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 1:2) to give 2-methylpropan-2-yl 3-[6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,2-diazin-3-yl]hexahydropyridine-1-carboxylate (280 mg, 0.52 mmol, 76.29%) as a yellow solid.

[0405] LCMS: m / z (M+H)+= 455.2.

[0406]

[0407] 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)

[0408] To a solution of 2-(2,4-bis(trifluoromethyl)phenyl)acetic acid (30 mg, 0.11 mmol) in acetonitrile (1 mL) was added 1-Chloro-N,N,2-trimethylpropenylamine (0.02 mL, 0.17 mmol) at 0℃, the mixture was stirred at 0℃ for 30 min, then the mixture was added in 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 mL) at 0℃, the reaction was stirred at 25℃ for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 1:1) to give 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 yellow oil.

[0409] LCMS: m / z (M+H-56)+= 653.3.

[0410]

[0411] 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

[0412] 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) was added TFA (0.3 mL, 4.03 mmol) at 25℃, the reaction was stirred at 25℃ for 3 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA condition) 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.

[0413] 1H NMR (400 MHz, CDCl3) 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).

[0414] LCMS: m / z (M+H)+=609.2.

[0415]

[0416] 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

[0417]

[0418]

[0419] Step A:2-methylpropan-2-yl 3-[5-(methoxycarbonyl)pyrazin-2-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate (2)

[0420] To a solution of 2-methylpropan-2-yl 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 H2O (0.15 mL) were added K2CO3(1910.42 mg, 13.82 mmol), methyl 5-bromopyrazine-2-carboxylate (1000 mg, 4.61 mmol) and bis[5-(diphenylphosphanyl)cyclopenta-1,3-dienyl]-λ2-iron(II) palladium chloride (168.58 mg, 0.23 mmol) at 25℃, the mixture was stirred at 100℃ for 1 h under the N2. Upon completion, the mixture was concentrated in vacuum. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 1:1) to give 2-methylpropan-2-yl 3-[5-(methoxycarbonyl)pyrazin-2-yl]-2,5-dihydro-1H-pyrrole-1-carboxylate (800 mg, 2.62 mmol, 56.86%) as a white solid.

[0421] LCMS: m / z (M+H)+= 306.2.

[0422]

[0423] Step B:2-methylpropan-2-yl 3-[5-(methoxycarbonyl)pyrazin-2-yl]tetrahydropyrrole-1-carboxylate (3)

[0424] 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) was added 10% Pd / C (348.54 mg, 0.33 mmol) at 25℃, the reaction was degassed with H2three times and stirred at 25℃ for 4 h under H2(15 psi). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 3:1) to give 2-methylpropan-2-yl 3-[5-(methoxycarbonyl)pyrazin-2-yl]tetrahydropyrrole-1-carboxylate (600 mg, 1.85 mmol, 56.63%) as a white solid.

[0425] LCMS: m / z (M+H-56)+= 252.0.

[0426]

[0427] Step C:tert-butyl 3-(5-(hydrazinecarbonyl)pyrazin-2-yl)pyrrolidine-1-carboxylate (4)

[0428] To a solution of 2-methylpropan-2-yl 3-[5-(methoxycarbonyl)pyrazin-2-yl]tetrahydropyrrole-1-carboxylate (480 mg, 1.56 mmol) in MeOH (8 mL) were added hydrazine hydrate (0.45 mL, 7.81 mmol)(80% purity) at 25℃, the mixture was stirred at 25℃ for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give tert-butyl 3-(5-(hydrazinecarbonyl)pyrazin-2-yl)pyrrolidine-1-carboxylate (400 mg, 1.24 mmol, 79.17%) as a white solid.

[0429] LCMS: m / z (M+H-56)+= 252.0.

[0430]

[0431] Step D:tert-butyl 3-(5-(2-(2-chloroacetyl)hydrazine-1-carbonyl)pyrazin-2-yl)pyrrolidine-1-carboxylate (5)

[0432] To a solution of tert-butyl 3-(5-(hydrazinecarbonyl)pyrazin-2-yl)pyrrolidine-1-carboxylate (500 mg, 1.56 mmol) in DCM (10 mL) were added TEA (0.32 mL, 2.33 mmol) and chloroacetyl chloride (0.16 mL, 2.02 mmol) at 0℃, the mixture was stirred at 25℃ for 2 h. Upon 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.

[0433] LCMS: m / z (M+H-56)+= 328.0.

[0434]

[0435] Step E:2-methylpropan-2-yl 3-{5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl}tetra hydropyrrole-1-carboxylate (6)

[0436] 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) were added TEA (0.87 mL, 6.25 mmol) and 4-methylbenzenesulfonyl chloride (596.01 mg, 3.13 mmol) at 0℃, the mixture was stirred at 25℃ for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 1:2) to give 2-methylpropan-2-yl 3-{5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl}tetrahydrop yrrole-1-carboxylate (460 mg, 1.19 mmol, 76.42%) as a white solid.

[0437] LCMS: m / z (M+H-56)+= 310.0.

[0438]

[0439] Step F:2-methylpropan-2-yl 3-[5-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]tetrahydropyrrole-1-carboxylate (7)

[0440] To a solution of 2-methylpropan-2-yl 3-{5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl}tetrahydropyrrole-1-carboxylate (450 mg, 1.23 mmol) in DMF (4 mL) were added K2CO3(340.00 mg, 2.46 mmol), 4-fluoroaniline (0.12 mL, 1.23 mmol) and potassium iodide (204.20 mg, 1.23 mmol) at 20℃, the mixture was stirred at 20℃ for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 1:1) to give 2-methylpropan-2-yl 3-[5-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]tetrahydropyrrole-1-carboxylate (200 mg, 0.43 mmol, 35.07%) as a white solid.

[0441] LCMS: m / z (M+H-56)+= 385.2.

[0442]

[0443] Step G:2-methylpropan-2-yl 3-(5-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrazin-2-yl)tetrahydropyrrole-1-carboxylate (8)

[0444] To a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (61.78 mg, 0.23 mmol) in ACN (2 mL) was added (1-chloro-2-methylprop-1-enyl)dimethylamine (0.05 mL, 0.34 mmol) at 0℃, the mixture was stirred at 0℃ for 1 h. Then the mixture was added to a solution of 2-methylpropan-2-yl 3-[5-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]tetrahydropyrrole-1-carboxylate (100 mg, 0.23 mmol) and DMAP (41.60 mg, 0.34 mmol) in acetonitrile (2 mL) , the mixture was stirred at 25℃ for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 10:1 to 1:1) to give 2-methylpropan-2-yl 3-(5-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrazin-2-yl)tetrahydropyrrole-1-carboxylate (40 mg, 0.05 mmol, 24.10%) as a yellow solid.

[0445] LCMS: m / z (M+H-56)+= 639.4.

[0446]

[0447] 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

[0448] To a solution of 2-methylpropan-2-yl 3-(5-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrazin-2-yl)tetrahydropyrrole-1-carboxylate (40 mg, 0.06 mmol) in DCM (2 mL) was added TFA (0.5 mL, 6.71 mmol) at 25℃, the mixture was stirred at 25℃ for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by p-HPLC (FA condition) 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.

[0449] 1H 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).

[0450] LCMS: m / z (M+H)+=595.4.

[0451]

[0452] 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

[0453]

[0454]

[0455] Step A:methyl 2-(1-{[(2-methylprop-2-yl)oxy]carbonyl}-2,5-dihydro-1H-pyrrol-3-yl)pyrimidine-5-carboxylate (2)

[0456] 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 H2O (7 mL) were added bis[5-(diphenylphosphanyl)cyclopenta-1,3-dienyl]-λ2-iron(II) palladium chloride (0.42 g, 0.58 mmol) and K2CO3(4.81 g, 34.77 mmol) at 25℃, the mixture was stirred at 100℃ for 1 h under N2to give a brown solution. Upon completion, the mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL * 2). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc= 0 to 40%) to give methyl 2-(1-{[(2-methylprop-2-yl)oxy]carbonyl}-2,5-dihydro-1H-pyrrol-3-yl)pyrimidine-5-carboxylate (2 g, 6.42 mmol, 55.39%) as white solid.

[0457] LCMS: m / z (M+H)+= 250.0.

[0458]

[0459] Step B:methyl 2-(1-{[(2-methylprop-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)pyrimidine-5-carboxylate (3)

[0460] To a solution of methyl 2-(1-{[(2-methylprop-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) under H2at 25℃, the mixture was stirred at 25℃ for 18 h under H2(15 Psi) to give 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-methylprop-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)pyrimidine-5-carboxylate (530 mg, 1.69 mmol, 25.79%) as white solid.

[0461] LCMS: m / z (M-56+H)+=252.2.

[0462]

[0463] Step C:2-methylpropan-2-yl 3-[5-(diazanylcarbonyl)pyrimidin-2-yl]tetrahydropyrrole-1-carboxylate (4)

[0464] To a solution of methyl 2-(1-{[(2-methylprop-2-yl)oxy]carbonyl}tetrahydro-1H-pyrrol-3-yl)pyrimidine-5-carboxylate (530 mg, 1.72 mmol) in MeOH (20 mL) was added N2H4.H2O (405.19 mg, 6.88 mmol) (80% purity) at 25℃, the mixture was stirred at 25℃ for 18 h to give a yellow solution. Upon 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]tetrahydropyrrole-1-carboxylate (500 mg, 1.30 mmol, 75.47%) as white solid.

[0465] LCMS: m / z (M-56+H)+=252.2.

[0466]

[0467] Step D:2-methylpropan-2-yl 3-(5-{[2-(2-chloroacetyl)diazanyl]carbonyl}pyrimidin-2-yl)tetrahydropyrrole-1-carboxylate (5)

[0468] To a solution of 2-methylpropan-2-yl 3-[5-(diazanylcarbonyl)pyrimidin-2-yl]tetrahydropyrrole-1-carboxylate (500 mg, 1.63 mmol) and TEA (0.45 mL, 3.25 mmol) in DCM (100 mL) was added chloroacetyl chloride (0.14 mL, 1.79 mmol) in an ice bath, the mixture was stirred at 25℃ for 18 h to give a brown solution. Upon 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-(5-{[2-(2-chloroacetyl)diazanyl]carbonyl}pyrimidin-2-yl)tetrahydropyrrole-1-carboxylate (240 mg, 0.54 mmol, 33.38%) as white solid.

[0469] LCMS: m / z (M+H-56)+= 328.0.

[0470]

[0471] Step E:2-methylpropan-2-yl 3-{5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl}tetrahydropyrrole-1-carboxylate (6)

[0472] To a solution of 2-methylpropan-2-yl 3-(5-{[2-(2-chloroacetyl)diazanyl]carbonyl}pyrimidin-2-yl)tetrahydropyrrole-1-carboxylate (240 mg, 0.63 mmol) and TEA (0.52 mL, 3.75 mmol) in DCM (100 mL) was added 4-methylbenzenesulfonyl chloride (238.41 mg, 1.25 mmol) in an ice bath, the mixture was stirred at 25℃ for 18 h to give a brown solution. Upon 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-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl}tetrahydropyrrole-1-carboxylate (155 mg, 0.42 mmol, 67.76%) as white solid.

[0473] LCMS: m / z (M-56+H)+=310.2.

[0474]

[0475] Step F:2-methylpropan-2-yl 3-[5-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]tetrahydropyrrole-1-carboxylate (7)

[0476] To a solution of 2-methylpropan-2-yl 3-{5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrimidin-2-yl}tetrahydropyrrole-1-carboxylate (155 mg, 0.42 mmol) and 4-fluoroaniline (0.04 mL, 0.42 mmol) in DMSO (3 mL) were added K2CO3(117.11 mg, 0.85 mmol) and potassium iodide (70.34 mg, 0.42 mmol) at 25℃, the mixture was stirred at 25℃ for 18 h to give a brown solution. Upon completion, the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL * 2). The combined organic layers were dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by prep-TLC (Pet.ether: EtOAc = 1:1) to give 2-methylpropan-2-yl 3-[5-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]tetrahydropyrrole-1-carboxylate (40 mg, 0.09 mmol, 21.43%) as white solid.

[0477] LCMS: m / z (M+H-56)+= 385.2.

[0478]

[0479] Step G:2-methylpropan-2-yl 3-(5-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrimidin-2-yl)tetrahydropyrrole-1-carboxylate (8)

[0480] To a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (29.66 mg, 0.11 mmol) in CH3CN (2 mL) was added (1-chloro-2-methylprop-1-enyl)dimethylamine (0.01 mL, 0.11 mmol) in an ice bath under N2. The mixture was stirred at 0℃ for 0.5 h. Then the mixture was added to a solution of 2-methylpropan-2-yl 3-[5-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]tetrahydropyrrole-1-carboxylate (40 mg, 0.09 mmol) and DMAP (16.64 mg, 0.14 mmol) in CH3CN (2 mL) at 0℃. The mixture was stirred at 25℃ for 2 h to give a yellow solution. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by prep-TLC (Pet.ether: EtOAc=1:1) to give 2-methylpropan-2-yl 3-(5-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrimidin-2-yl)tetrahydropyrrole-1-carboxylate (40 mg, 0.06 mmol, 63.41%) as white solid.

[0481] LCMS: m / z (M-56+H)+=639.3.

[0482]

[0483] 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

[0484] 2-methylpropan-2-yl 3-(5-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrimidin-2-yl)tetrahydropyrrole-1-carboxylate (40 mg, 0.06 mmol) in TFA (3 mL) was stirred at 25℃ for 2 h to give a brown solution. Upon completion, the mixture was concentrated under reduced pressure. The crude product was purified by HPLC (TFA / ACN / 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 white solid.

[0485] 1H NMR (400 MHz, CDCl3) 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).

[0486] LCMS: m / z (M+H)+=595.2.

[0487]

[0488] 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)ethanethioamide

[0489]

[0490]

[0491] 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

[0492] 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) was added 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-2λ5,4λ5-1,3,2,4-dithiadiphosphetane (2.72 mg, 0.01 mmol) at 25℃, the mixture was stirred at 120℃ under N2for 18 h to give a yellow solution. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by HPLC (TFA / ACN / H2O) 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 white solid.

[0493] LCMS: m / z (M+H)+=611.2.

[0494]

[0495] Examples 12 and 13: Synthesis of i) 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) 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

[0496]

[0497]

[0498] 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

[0499] 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 iodomethane (0.01 mL , 0.03 mmol) at 25℃, the reaction was stirred at 25℃ under N2for 1 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA condition) to give 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 (1.5 mg, 24.43%) as white solid 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 (2 mg, 22.47%) as white solid.

[0500] Example 12

[0501] LCMS: m / z (M+H)+= 608.2.

[0502] 1H NMR (400 MHz, CDCl3) 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).

[0503]

[0504] Example 13

[0505] LCMS: m / z (M+H)+=622.2.

[0506]

[0507] 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

[0508]

[0509]

[0510] Step A:methyl 5-(cyclopent-1-enyl)pyridine-2-carboxylate (2)

[0511] To a solution of methyl 5-chloropyridine-2-carboxylate (2 g, 11.66 mmol) in H2O (4 mL) and dioxane (40 mL) were added 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.31 g, 11.66 mmol), Pd(dppf)Cl2.CH2Cl2(0.95 g, 1.17 mmol) and K2CO3(4.83 g, 34.97 mmol) at 25℃, the mixture was stirred at 95℃ under N2for 3h. Upon 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 (Pet.ether: EtOAc= 0 to 70%) to give methyl 5-(cyclopent-1-enyl)pyridine-2-carboxylate (1.8 g, 8.41 mmol, 72.1%) as yellow solid.

[0512] LCMS: m / z (M+H)+= 204.1.

[0513]

[0514] Step B:methyl 5-cyclopentylpyridine-2-carboxylate (3)

[0515] 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) was added Pd / C 10% (20.0 mg) at 25℃, the suspension was purged with H2several times and stirred at 25℃ under H2balloon 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 yellow solid.

[0516] LCMS: m / z (M+H)+=206.2.

[0517]

[0518] Step C:5-cyclopentylpyridine-2-carbohydrazide (4)

[0519] To a solution of methyl 5-cyclopentylpyridine-2-carboxylate (1.6 g, 7.79 mmol) in MeOH (10 mL) was added N2H4.H2O (0.49 mL, 7.79 mmol) (80% purity) at 25℃, the mixture was stirred at 25℃ for 2 h. Upon completion, the mixture was concentrated under reduced pressure to give 5-cyclopentylpyridine-2-carbohydrazide (98 mg, 0.45 mmol, 62.91%) as yellow oil.

[0520] LCMS: m / z (M+H)+=206.2.

[0521]

[0522] Step D:N'-(2-chloroacetyl)-5-cyclopentylpyridine-2-carbohydrazide (5)

[0523] 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), chloroacetyl chloride (0.14 mL, 1.75 mmol) at 25℃. The mixture was stirred at 25℃ 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 give N'-(2-chloroacetyl)-5-cyclopentylpyridine-2-carbohydrazide (300 mg, 1.01 mmol, 69.21%) as yellow oil.

[0524] LCMS: m / z (M+H)+= 281.7.

[0525]

[0526] Step E:2-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-5-cyclopentylpyridine (6)

[0527] To a solution of N'-(2-chloroacetyl)-5-cyclopentylpyridine-2-carbohydrazide (100 mg, 0.34 mmol) in DCM (10.0 mL) were added TEA (0.19 mL, 1.35 mmol) and TsCl (128.81 mg, 0.67 mmol) at 25℃, the mixture was stirred at 25℃ under N2for 2 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (MeCN: H2O (0.1% FA)) to give 2-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-5-cyclopentylpyridine (50 mg, 0.189 mmol, 55.7%) as yellow oil.

[0528] LCMS: m / z (M+H)+=264.7.

[0529]

[0530] Step F:5-cyclopentyl-2-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyridine (7)

[0531] 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) were added 4-fluoroaniline (0.01 mL, 0.08 mmol), K2CO3(20.96 mg, 0.15 mmol) and KI (12.59 mg, 0.08 mmol) at 25℃, the mixture was stirred at 25℃ for 2h. Upon completion, the mixture was diluted with EtOAc (50 mL) and washed with water (100 mL). The organic layer was concentrated reduced pressure. he residue was purified by silica-gel column chromatography (Pet.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%).

[0532] LCMS: m / z (M+H)+= 339.3.

[0533]

[0534] 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

[0535] To a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (12.06 mg, 0.04 mmol) in MeCN (0.5 mL) was added (1-chloro-2-methylprop-1-enyl)dimethylamine (0.01 mL, 0.05 mmol) dropwise at 0°C under N2atmosphere, the mixture was stirred at 0℃ for 30 min. Then 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) at 0℃, The resulting mixture was stirred at 0℃ for 18 h under N2atmosphere. Upon completion, the mixture was evaporated. The residue was purified by reverse-phase HPLC (MeCN: H2O (0.1% FA)) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[5-(5-cyclopentylpyridin-2-yl)-1,3,4-oxadiaz ol-2-yl]methyl}-N-(4-fluorophenyl)acetamide (10.0 mg, 0.02 mmol, 36.18%).

[0536] 1H 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).

[0537] LCMS: m / z (M+H)+=593.4.

[0538]

[0539] 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

[0540]

[0541]

[0542] Step A:methyl 5-(2,5-dihydrofuran-3-yl)picolinate (2)

[0543] To a stirred solution of 2-(2,5-dihydro-3-furyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (548.46 mg, 2.80 mmol) in dioxane (20 mL), H2O (4 mL) were added methyl 5-chloropyridine-2-carboxylate (400 mg, 2.33 mmol)), Pd(dppf)Cl2(170.58 mg, 0.23 mmol) and K2CO3(723.86 mg, 5.25 mmol) at 25℃ under N2, the resulting solution was stirred at 80℃ for 18 h under N2. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc= 0 to 70%) to give methyl 5-(2,5-dihydrofuran-3-yl)picolinate (210 mg, 1.02 mmol, 43.90%) as a yellow oil.

[0544] LCMS: m / z (M+H)+= 205.9.

[0545]

[0546] Step B:methyl 5-(tetrahydrofuran-3-yl)picolinate (3)

[0547] To a solution of methyl 5-(2,5-dihydrofuran-3-yl)picolinate (210 mg, 1.02 mmol) in MeOH (10 mL) was added Pd / C 10% (10.89 mg, 0.10 mmol) under H2. The suspension was purged with H2several times and stirred at 25℃ under H2balloon 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 yellow solid.

[0548] LCMS: m / z (M+H)+=208.0.

[0549]

[0550] Step C:5-(tetrahydrofuran-3-yl)picolinohydrazide (4)

[0551] To a solution of the methyl 5-(tetrahydrofuran-3-yl)picolinate (148 mg, 0.71 mmol) in EtOH (2 mL) was added 80% solution of hydrazine hydrate (5 mL) dropwised at 25℃, the mixture was stirred at 80℃ under N2for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with MeOH in DCM (1 / 100 to 1 / 10) to give 5-(tetrahydrofuran-3-yl)picolinohydrazide (98 mg, 0.45 mmol, 62.91%) as yellow oil.

[0552] LCMS: m / z (M+H)+=207.9.

[0553]

[0554] Step D:N'-(2-chloroacetyl)-5-(tetrahydrofuran-3-yl)picolinohydrazide (5)

[0555] 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) was added chloroacetyl chloride (53.08 mg, 0.47 mmol) at 0℃, the mixture was stirred at 25℃ for 2 h. Upon completion, the reaction was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (DCM: MeOH = 100:1to 10: 1) to give N'-(2-chloroacetyl)-5-(tetrahydrofuran-3-yl)picolinohydrazide (130 mg, 0.37 mmol, 77.51%) as yellow oil.

[0556] LCMS: m / z (M+H)+= 284.0.

[0557]

[0558] Step E:2-(chloromethyl)-5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-oxadiazole (6)

[0559] To a solution of N'-(2-chloroacetyl)-5-(tetrahydrofuran-3-yl)picolinohydrazide (130 mg, 0.37 mmol) and TEA (0.10 mL, 0.73 mmol) in DCM (5 mL) was added 4-methylbenzenesulfonyl chloride (83.86 mg, 0.44 mmol) at 0℃, the reaction was stirred at 25℃ for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (MeCN: H2O (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 white solid.

[0560] LCMS: m / z (M+H)+=266.0.

[0561]

[0562] Step F:4-fluoro-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-oxadiazol-2-yl)methyl) aniline (7)

[0563] 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) were added K2CO3(52.52 mg, 0.38 mmol) and potassium iodide (31.54 mg, 0.19 mmol) at 0℃, the reaction mixture stirred at 25℃ for 18 h. Upon 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 (Pet.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 yellow oil.

[0564] LCMS: m / z (M+H)+= 341.2.

[0565]

[0566] 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

[0567] To a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (39.98 mg, 0.15 mmol) in MeCN (0.5 mL) was added (1-chloro-2-methylprop-1-enyl)dimethylamine (29.44 mg, 0.22 mmol) dropwise at 0℃ under N2atmosphere, the mixture was stirred at 0℃ for 30 min. Then 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) at 0℃, The resulting mixture was stirred at 0℃ for 18 h under N2atmosphere. Upon completion, the mixture was evaporated. The residue was purified by reverse-phase HPLC (MeCN: H2O (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.

[0568] 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).

[0569] LCMS: m / z (M+H)+=595.2.

[0570]

[0571] 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

[0572]

[0573]

[0574] 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

[0575] 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) was added DIEA (0.01 mL, 0.03 mmol) and acetyl chloride (0.01 mL, 0.03 mmol) at 0℃, the reaction was stirred at 25℃ for 1 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA condition) 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 white solid.

[0576] 1H NMR (400 MHz, CDCl3) 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).

[0577] LCMS: m / z (M+H)+=636.4.

[0578]

[0579] 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

[0580]

[0581]

[0582] Step A:5-chloropyrimidine-2-carbohydrazide (2)

[0583] To a solution of methyl 5-chloropyrimidine-2-carboxylate (100 mg, 0.58 mmol) in MeOH (10.0 mL) was added N2H4.H2O (0.2 mL) (80% purity) at 25℃, the mixture was stirred at 25℃ for 2 h. Upon completion, the mixture was concentrated under reduced pressure to give 5-chloropyrimidine-2-carbohydrazide (90 mg, 0.5 mmol, 85.4%) as white solid.

[0584] LCMS: m / z (M+H)+= 173.2.

[0585]

[0586] Step B:5-chloro-N'-(2-chloroacetyl)pyrimidine-2-carbohydrazide (3)

[0587] To a solution of 5-chloropyrimidine-2-carbohydrazide (800 mg, 4.64 mmol) in DCM (10 mL) was added TEA (1.93 mL, 13.91 mmol), chloroacetyl chloride (0.44 mL, 5.56 mmol) at 0℃, the mixture was stirred at 25℃ for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted 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 yellow oil.

[0588] LCMS: m / z (M+H)+=249.1.

[0589]

[0590] Step C:5-chloro-2-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrimidine (4)

[0591] To a solution of 5-chloro-N'-(2-chloroacetyl)pyrimidine-2-carbohydrazide (100 mg, 0.40 mmol) in DCM (10.0 mL) was added TEA (0.22 mL, 1.61 mmol) and TsCl (153.38 mg, 0.80 mmol) at 25℃, the mixture was stirred at 25℃ under N2for 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 give 5-chloro-2-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrimidine (80.0 mg, 0.342 mmol, 90.2%) as yellow oil.

[0592] LCMS: m / z (M+H)+= 231.0.

[0593]

[0594] Step D:5-chloro-2-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrimidine (5)

[0595] 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) were added 4-fluoroaniline (0.03 mL, 0.35 mmol), KI (57.48 mg, 0.35 mmol) and K2CO3(95.71 mg, 0.69 mmol) at 25°C, The mixture was stirred at 25°C under N2for 16h. 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 give 5-chloro-2-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrimidine (50 mg, 0.16 mmol, 44.87%) as yellow oil.

[0596] LCMS: m / z (M+H)+= 306.2.

[0597]

[0598] 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

[0599] To a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (39.98 mg, 0.15 mmol) in MeCN (0.5 mL) was added (1-chloro-2-methylprop-1-enyl)dimethylamine (29.44 mg, 0.22 mmol) dropwise at 0℃ under N2atmosphere, the mixture was stirred at 0℃ for 30 min. Then 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) at 0℃, the mixture was stirred at 25℃ under N2for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (MeCN: H2O (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%).

[0600] 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).

[0601] LCMS: m / z (M+H)+=560.2.

[0602]

[0603] 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

[0604]

[0605]

[0606] Step A:5-bromopyrimidine-2-carbohydrazide (2)

[0607] To a solution of the methyl 5-bromopyrimidine-2-carboxylate (1 g, 4.61 mmol) in EtOH (2 mL) was added hydrazine hydrate (5 mL) (80% purity) at 25℃, the mixture was stirred at 80℃ for 16 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 give 5-bromopyrimidine-2-carbohydrazide (900 mg, 4.15 mmol) as yellow solid.

[0608] LCMS: m / z (M+H)+= 217.0 / 219.0.

[0609]

[0610] Step B:5-bromo-N'-(2-chloroacetyl)pyrimidine-2-carbohydrazide (3)

[0611] 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) was added chloroacetyl chloride (0.33 mL, 4.15 mmol) at 25℃, the mixture was stirred at 25℃ for 2 h under N2. 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 give 5-bromo-N'-(2-chloroacetyl)pyrimidine-2-carbohydrazide (600 mg, 1.02 mmol) as yellow oil.

[0612] LCMS: m / z (M+H)+= 293.0 / 295.0.

[0613]

[0614] Step C:2-(5-bromopyrimidin-2-yl)-5-(chloromethyl)-1,3,4-oxadiazole (4)

[0615] To a solution of 5-bromo-N'-(2-chloroacetyl)pyrimidine-2-carbohydrazide (1.2 g, 4.09 mmol) in DCM (50 mL) were added TEA (1.13 mL, 8.18 mmol) and 4-methylbenzenesulfonyl chloride (0.94 g, 4.91 mmol) at 25℃, the mixture was stirred at 25℃ for 2 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (TFA condition) to give 2-(5-bromopyrimidin-2-yl)-5-(chloromethyl)-1,3,4-oxadiazole (300 mg, 1.08 mmol) as white solid.

[0616] LCMS: m / z (M+H)+= 274.8 / 276.8.

[0617]

[0618] Step D:N-((5-(5-bromopyrimidin-2-yl)-1,3,4-oxadiazol-2-yl)methyl)-4-fluoroaniline (5)

[0619] To a solution 4-fluoroaniline (0.13 mL, 1.31 mmol) in DMF (5 mL) were added K2CO3(300.99 mg, 2.18 mmol) and 2-(5-bromopyrimidin-2-yl)-5-(chloromethyl)-1,3,4-oxadiazole (300 mg, 1.09 mmol) at 25℃, the mixture was stirred at 25℃ for 16 h. Upon completion, the mixture was diluted with EtOAc (100 mL), 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 next step without further purification.

[0620] LCMS: m / z (M+H)+= 350.2 / 352.2.

[0621]

[0622] 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

[0623] To a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (87.09 mg, 0.32 mmol) in MeCN (0.5 mL) was added (1-chloro-2-methylprop-1-enyl)dimethylamine (31.48 mg, 0.24 mmol) dropwise at 0℃ under N2atmosphere, the mixture was stirred at 0℃ for 30 min to give a clear solution. Then the mixture was added into 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) at 0℃, the mixture was stirred at 25℃ for 16 h under N2atmosphere. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by prep-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.

[0624] 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).

[0625] LCMS: m / z (M+H)+= 604.2 / 606.2.

[0626]

[0627] 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

[0628]

[0629]

[0630] Step A:2-[5-(chloromethyl)-1,3,4-thiadiazol-2-yl]-5-(tetrahydro-3-furyl)pyridine (2)

[0631] To a solution of N'-(2-chloroacetyl)-5-(tetrahydro-3-furyl)pyridine-2-carbohydrazide (20 mg, 0.07 mmol) in Tol (2 mL) was added 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-2λ5,4λ5-1,3,2,4-dithiadiphosphetane (56.62 mg, 0.14 mmol) at 25℃, the mixture was stirred at 110℃ for 16 h under N2. Upon 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 layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by pre-HPLC (TFA condition) to give 2-[5-(chloromethyl)-1,3,4-thiadiazol-2-yl]-5-(tetrahydro-3-furyl)pyridine (9 mg, 0.03 mmol) as a black solid.

[0632] LCMS: m / z (M+H)+= 282.0.

[0633]

[0634] Step B:4-fluoro-N-((5-(5-(tetrahydrofuran-3-yl)pyridin-2-yl)-1,3,4-thiadiazol-2-yl)methyl) aniline (3)

[0635] To a solution of 2-[5-(chloromethyl)-1,3,4-thiadiazol-2-yl]-5-(tetrahydro-3-furyl)pyridine (9 mg, 0.03 mmol) in DMF (4 mL) were added K2CO3(8.83 mg, 0.06 mmol), 4-fluoroaniline (0.001 mL, 0.03 mmol) and potassium iodide (5.30 mg, 0.03 mmol) at 25℃, the mixture was stirred at 25℃ for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified silica-gel column chromatography (Pet.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 white solid.

[0636] LCMS: m / z (M+H)+= 357.2.

[0637]

[0638] 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

[0639] To a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (11 mg, 0.04 mmol) in MeCN (0.5 mL) was added (1-chloro-2-methylprop-1-enyl)dimethylamine (6 mg, 0.05 mmol) dropwise at 0℃ under N2atmosphere, the mixture was stirred at 0℃ for 30 min to give a clear solution. Then the mixture was added into 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)　at 0℃, the mixture was stirred at 25℃ for 16 h under N2. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA　condition) 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 white solid.

[0640] 1H 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).

[0641] LCMS: m / z (M+H)+= 611.0.

[0642]

[0643] 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

[0644]

[0645]

[0646] 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

[0647] To a solution of 2-[2,4-bis(trifluoromethyl)phenyl]-N-{[2-(5-chloropyrimidin-2-yl)-1,3,4-oxadia zol-5-yl]methyl}-N-(4-fluorophenyl)acetamide (10 mg, 0.02 mmol) in DMA (2.0 mL) were added 3-bromotetrahydropyran (2.95 mg, 0.02 mmol), {6-[amino(azanylidene)methyl]pyridin-2-yl}(azanylidene)methanamine (1.17 mg, 0.01 mmol), NiI2(2.23 mg, 0.01 mmol), Zn (0.00 mL, 0.07 mmol) and NaI (1.00 mg, 0.01 mmol) at 25℃, the mixture was stirred at 80℃ under N2for 18 h. After filtration, the filtrate was purified by reverse-phase HPLC (MeCN: H2O (0.1% FA)) to give 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%) as white solid.

[0648] 1H 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).

[0649] LCMS: m / z (M+H)+=610.2.

[0650]

[0651] 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

[0652]

[0653] 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 sequentially added　H2O (0.5 mL),　cyclopropylboranediol (35.54 mg, 0.41 mmol),　PdCl2(dppf) (1.82 mg, 0.008 mmol)　and　K2CO3(20.55 mg, 0.15 mmol)　at 25℃. The resulting solution was stirred at 80℃ for 3 h under nitrogen. The reaction was complete detected by LC-MS.The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was dissolved in DCM (3 mL) and purified by Combi Flash (Biotage Isolera Prime) which applied to a 10 g silica gel column, eluted 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.

[0654] 1H 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).

[0655] LCMS: m / z (M+H)+= 566.3

[0656]

[0657] 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

[0658]

[0659] 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 sequentially added　3-bromotetrahydrofuran (10.50 mg, 0.07 mmol),　Nickeliodide (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)　at 23℃. The resulting solution was stirred at 80℃ for 18 h under nitrogen. The reaction mixture was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was dissolved in DCM (3 mL) and purified by Combi Flash (Biotage Isolera Prime) which applied to a 10 g silica gel column, eluted with 0-30% DCM in PE within 30 min to afford　2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-({5-[5-(tetrahydro-3-furyl)pyrimidin-2-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide (1.1 mg, 0.002 mmol, 5.21%)　as a white powder.

[0660] 1H 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).

[0661] LCMS: m / z (M+H)+= 596.4

[0662]

[0663] 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

[0664]

[0665]

[0666] 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)

[0667] 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),　Pd2(dba)3(4.55 mg, 0.002 mmol), Xantphos (5.75 mg, 0.01 mmol)　and　Cs2CO3(16.18 mg, 0.05 mmol) in　dioxane (2 mL)　was degassed and purged 3 times with N2　and then stirred at 120°C for 2 h.　The reaction was complete detected by　LC-MS. The reaction mixture was evaporated. crude residue purified by column chromatography (50% EtOAc in PE) to afford　2-methylpropan-2-yl [(2-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrimidin-5-yl)amino]methanoate (9 mg, 0.01 mmol, 25.47%)　as a yellow oil.

[0668]

[0669] 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

[0670] To a solution of　2-methylpropan-2-yl [(2-{5-[({2-[2,4-bis(trifluoromethyl)phenyl]acetyl}(4-fluorophenyl)amino)methyl]-1,3,4-oxadiazol-2-yl}pyrimidin-5-yl)amino]methanoate (10 mg, 0.02 mmol)　in　DCM (5 mL)　was added　TFA (2 mL, 26.84 mmol). the mixture was stirred for 30 min at 25℃. The reaction was complete detected by　LCMS. After removal of solvent by　concentration,　the residue was purified by reverse-phase HPLC to afford　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, 0.01mmol, 10.90%)　as a white solid.

[0671] 1H NMR (400 MHz, MeOD) δ 8.05 (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).

[0672] LCMS: m / z (M+H)+= 540.1

[0673]

[0674] 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

[0675]

[0676]

[0677] 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]methanoate (2)

[0678] 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 Cs2CO3(23.28 mg, 0.07 mmol),　tert-Butyl carbamate (8.37 mg, 0.07 mmol),　Xantphos (4.13 mg, 0.01 mmol)　and　Pd2(dba)3(3.27 mg, 0.004 mmol). The reaction was degassed N2three time and stirred at 100℃ for 4 h. LCMS showed the reaction was complete. The reaction was evaporated under vacuum directly. The crude product was purified by silica-gel column chromatography (PET: EtOAc = 5:1 to 3:1) to give　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]methanoate (20 mg, 0.02 mmol, 61.19%)　as yellow oil.

[0679] LCMS: m / z (M+H)+= 641.2.

[0680]

[0681] 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

[0682] To a solution of　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]methanoate (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 the reaction was complete. The reaction was evaporated under vacuum directly. The crude product was purified by pre-HPLC (FA condition) to give 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.

[0683] 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).

[0684] LCMS: m / z (M+H)+= 541.2

[0685]

[0686] 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

[0687]

[0688] 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) was added cyclopropanecarbonyl chloride (0.002 mL, 0.01 mmol) in an ice bath, the mixture was stirred at 25°C for 18 h to give a brown solution. The mixture was quenched with H2O (30 mL) and extracted with EA (50 mL*3). The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude product was purified by high performance liquid phase (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 white solid.

[0689] 1H 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).

[0690] LCMS: m / z (M+H)+= 663.4

[0691]

[0692] Example 30: Synthesis of 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[(5-{2-[1-(methyldioxo-λ6-sulfanyl)tetrahydro-1H-pyrrol-3-yl]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)methyl]acetamide

[0693]

[0694] 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 TEA (0.002 mL, 0.02 mmol) in DCM (2 mL) was added MsCl (0.0014 mL, 0.01 mmol) in an ice bath, the mixture was stirred at 25°C for 18 h to give a brown solution. The mixture was quenched with H2O (30 mL) and extracted with EA (50 mL*3). The combined organic layer was dried over anhydrous Na2SO4and concentrated under reduced pressure. The crude product was purified by high performance liquid phase (Trifluoroacetic acid / acetonitrile / water) to give 2-[2,4-bis(trifluoromethyl)phenyl]-N-(4-fluorophenyl)-N-[(5-{2-[1-(methyldioxo-λ6-sulfanyl)tetrahydro-1H-pyrrol-3-yl]pyrimidin-5-yl}-1,3,4-oxadiazol-2-yl)methyl]acetamide (1.58 mg, 0.002 mmol, 43.79%) as white solid.

[0695] 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).

[0696] LCMS: m / z (M+H)+= 673.3.

[0697]

[0698] 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

[0699]

[0700]

[0701] Step A:N'-(2-chloroacetyl)-6-methoxypyridine-2-carbohydrazide (2)

[0702] 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 white solid.

[0703] LCMS: m / z (M+H)+= 244.0.

[0704]

[0705] Step B:6-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-2-methoxypyridine (3)

[0706] 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 white solid.

[0707] LCMS: m / z (M+H)+= 226.0.

[0708]

[0709] Step C:6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-2-methoxypyridine (4)

[0710] 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, 3.28 mmol) in DMF (15 mL) were added K2CO3(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 H2O (100 mL) and extracted with EA (100 mL * 3). The combined organic layer was dried over anhydrous Na2SO4and concentrated 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 (800 mg, 2.20 mmol, 67.10%) as white solid.

[0711] LCMS: m / z (M+H)+= 301.0.

[0712]

[0713] Step D:6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyridin-2-ol (5)

[0714] To a solution of 6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-2-methoxypyridine (100 mg, 0.33 mmol) in CH3CN (20 mL) were 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 phase (TFA / acetonitrile / water) to give 6-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyridin-2-ol (50 mg, 0.15 mmol, 45.02%)as white solid.

[0715] LCMS: m / z (M+H)+= 287.1.

[0716]

[0717] 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

[0718] 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 phase (TFA / acetonitrile / water) to give 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 white solid.

[0719] 1H 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).

[0720] LCMS: m / z (M+H)+= 541.3.

[0721]

[0722] 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

[0723]

[0724]

[0725] Step A:3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentan-1-ol (2)

[0726] To a solution of cyclopentane-1,3-diol (2 g, 19.58 mmol) in　DMF (18 mL)　were added　1H-imidazole (2.67 g, 39.16 mmol)　and　chlorodimethyl(2-methylprop-2-yl)silane (3.25 g, 21.54 mmol)　at 0　°C, after the 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 organic layers were combined, 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-methylprop-2-yl)silyl]oxy}cyclopentan-1-ol (1.5 g, 6.59 mmol, 33.63%)　as a yellow solid.

[0727] LCMS: m / z (M+H)+= 217.0.

[0728]

[0729] Step B: [(3-methoxycyclopentyl)oxy]dimethyl(2-methylprop-2-yl)silane (3)

[0730] To a solution of　3-{[dimethyl(2-methylprop-2-yl)silyl]oxy}cyclopentan-1-ol (1.9 g, 8.78 mmol) in　THF (15 mL)　were added　potassium 2-methylpropan-2-olate (1.97 g, 17.56 mmol)　and　iodomethane (1.09 mL, 17.56 mmol)　at 20　°C, after the 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 organic layers were combined, 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-methylprop-2-yl)silane (500 mg, 2.06 mmol, 23.48%)　as a yellow solid.

[0731] LCMS: m / z (M+H)+= 231.0.

[0732]

[0733] Step C:3-methoxycyclopentan-1-ol (4)

[0734] To a solution of　[(3-methoxycyclopentyl)oxy]dimethyl(2-methylprop-2-yl)silane (300 mg, 1.30 mmol) in　THF (8 mL)　was added　tetrabutylammonium fluoride (2.60 mL, 2.60 mmol)　at 20　°C, after the addition, the mixture was stirred at 20　°C for 3 h. 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.

[0735] LCMS: m / z (M+H)+= 117.0.

[0736]

[0737] Step D:1-bromo-3-methoxycyclopentane (5)

[0738] To a solution of　3-methoxycyclopentan-1-ol (350 mg, 3.01 mmol)　in　DCM (12　mL)　was added　triphenylphosphane (1185.45 mg, 4.52 mmol)　and　tetrabromomethane (1199.08 mg, 3.62 mmol) at 0　°C, after the 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 organic layers were combined, 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.

[0739] LCMS: m / z (M+H)+= 180.0.

[0740]

[0741] 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

[0742] To a solution of　1-bromo-3-methoxycyclopentane (11.85 mg, 0.07 mmol)　in　DMA (3 mL)　were added the　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(azanylidene)methyl]pyridin-2-yl}(azanylidene)methanamine (1.62 mg, 0.01 mmol)　and　Nickeliodide (2.07 mg, 0.01 mmol)　at 20　°C, after the 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　condition) to give　Example 64-P1 and Example 64-P2　as a white solid.

[0743] LCMS: m / z (M+H)+= 624.4.

[0744]

[0745] 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

[0746]

[0747]

[0748] Step A:2-methoxypyridine-3-carbohydrazide (2)

[0749] 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 white solid.

[0750] LCMS: m / z (M+H)+= 168.0.

[0751]

[0752] Step B:N'-(2-chloroacetyl)-2-methoxypyridine-3-carbohydrazide (3)

[0753] 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 white solid.

[0754] LCMS: m / z (M+H)+= 244.0

[0755]

[0756] Step C:3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-2-methoxypyridine (4)

[0757] 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 white solid.

[0758] LCMS: m / z (M+H)+= 226.0.

[0759]

[0760] Step D:3-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-2-methoxypyridine (5)

[0761] To a solution of 3-(5-{[(4-fluorophenyl)amino]methyl}-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) were added K2CO3(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 H2O (100 mL) and extracted with EA (100 mL * 3). The combined organic layer was dried over anhydrous Na2SO4and 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 (400 mg, 1.33 mmol, 79.09%) as white solid.

[0762] LCMS: m / z (M+H)+= 301.0.

[0763]

[0764] 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)

[0765] To a solution of [2,4-bis(trifluoromethyl)phenyl]acetic acid (54.38 mg, 0.20 mmol) in CH3CN (4 mL) was added (1-chloro-2-methylprop-1-enyl)dimethylamine (0.03 mL, 0.20 mmol) in an ice bath under N2. The mixture was stirred at 0°C for 0.5 h. The mixture was added to a solution of 2-methylpropan-2-yl 3-[5-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrimidin-2-yl]tetrahydropyrrole-1-carboxylate (40 mg, 0.09 mmol) and DMAP (30.51 mg, 0.25 mmol) in CH3CN (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 (85 mg) as white solid. The crude product (20 mg) was purified by high performance liquid phase (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 (9.2 mg) as white solid.

[0766] 1H 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).

[0767] LCMS: m / z (M+H)+= 555.2.

[0768]

[0769] 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)

[0770] 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) were 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 phase (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 white solid.

[0771] 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).

[0772] LCMS: m / z (M+H)+= 541.2.

[0773]

[0774] 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

[0775]

[0776]

[0777] Step A: 5-bromopyrazine-2-carbohydrazide (2)

[0778] To a solution of　methyl 5-bromopyrazine-2-carboxylate (1000 mg, 4.61 mmol)　in　MeOH (10 mL)　was added　Hydrazine hydrate (1042.94 mg, 27.66 mmol).　The reaction was stirred　at 25°C for 2 h.　LCMS showed the reaction was complete. The mixture was evaporated under vacuum directly. 5-bromopyrazine-2-carbohydrazide (720 mg, 3.18 mmol, 69.08%)　as a white solid.

[0779] LCMS: m / z (M+H)+= 207.0

[0780]

[0781] Step B: 5-bromo-N'-(2-chloroacetyl)pyrazine-2-carbohydrazide (3)

[0782] To a solution of　5-bromopyrazine-2-carbohydrazide (720 mg, 3.32 mmol)　in　DCM (5 mL)　were added　TEA (0.69 mL, 4.98 mmol)　and　chloroacetyl chloride (0.53 mL, 6.64 mmol).　The reaction was stirred at 25°C for 16 h. LCMS showed the reaction was complete. The mixture was evaporated under vacuum directly. 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.

[0783] LCMS: m / z (M+H)+= 293.0

[0784]

[0785] Step C: 5-bromo-2-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyrazine (4)

[0786] To a solution of　5-bromo-N'-(2-chloroacetyl)pyrazine-2-carbohydrazide (360 mg, 1.23 mmol)　in　DCM (5 mL)　were 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 under vacuum directly. 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 (120 mg, 0.38 mmol, 31.25%)　as a yellow solid.

[0787] LCMS: m / z (M+H)+= 275.2.

[0788]

[0789] Step D:5-bromo-2-(5-{[(4-fluorophenyl)amino]methyl}-1,3,4-oxadiazol-2-yl)pyrazine (5)

[0790] 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) were added K2CO3(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 water 20mL, extracted with EA 20mL*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 (60 mg, 0.10 mmol, 24.00%)　as a yellow solid.

[0791] LCMS: m / z (M+H)+= 316.0.

[0792]

[0793] 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

[0794] To a solution of　2-(2,4-bis(trifluoromethyl)phenyl)acetic acid (40 mg, 0.15 mmol) in　acetonitrile (1 mL) was dropped 1-Chloro-N,N,2-trimethylpropenylamine (0.03 mL, 0.22 mmol). Then the mixture was added in　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 under vacuum directly. The mixture was purified by pre-HPLC (FA condition) 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.

[0795] 1H 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).

[0796] LCMS: m / z (M+H)+= 560.1.

[0797]

[0798] 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

[0799]

[0800] 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 phase (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 white solid.

[0801] 1H 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).

[0802] LCMS: m / z (M+H)+= 555.2.

[0803]

[0804] Example 69: Synthesis of 2-(2,4-bis(trifluoromethyl)phenyl)-N-((2-(5-chloropyridin-2-yl)oxazol-5-yl)methyl)-N-(4-fluorophenyl)acetamide

[0805]

[0806]

[0807] Step A:methyl 2-(5-chloropyridin-2-yl)oxazole-5-carboxylate (2)

[0808] To a solution of　ethyl 1,3-oxazole-5-carboxylate (0.43 mL, 3.54 mmol)　in　DMF (2　mL)　was added　2-bromo-5-chloropyridine (886.32 mg, 4.61 mmol),　Pd(OAc)2(79.54 mg, 0.35 mmol),　Cs2CO3(2308.65 mg, 7.09 mmol),　CuI (674.73 mg, 3.54 mmol)　. The mixture was stirred at 100℃ under N2for 1 h. The mixture was concentrated under reduced pressure to give a 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%).

[0809] LCMS: m / z (M+H)+=253.7.

[0810]

[0811] Step B: (2-(5-chloropyridin-2-yl)oxazol-5-yl)methanol (3)

[0812] 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　NaBH4(8.98 mg, 0.24 mmol). The mixture was stirred at 60℃ under N2for 1 h. The mixture was filtered, the filtrate was concentrated under reduced pressure to give a 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%).

[0813] LCMS: m / z (M+H)+= 211.6.

[0814]

[0815] Step C:5-(chloromethyl)-2-(5-chloropyridin-2-yl)oxazole (4)

[0816] 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)　at 0℃ was added　SOCl2(0.01 mL, 0.14 mmol). The mixture was stirred at 25℃ for 2 h. The mixture was concentrated under reduced pressure to give a 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%).

[0817] LCMS: m / z (M+H)+= 230.1.

[0818]

[0819] Step D:N-((2-(5-chloropyridin-2-yl)oxazol-5-yl)methyl)-4-fluoroaniline (5)

[0820] 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),　K2CO3(36.20 mg, 0.26 mmol). The mixture was stirred at 25℃ for 18 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a 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%).

[0821] LCMS: m / z (M+H)+= 304.7.

[0822]

[0823] Step E:2-(2,4-bis(trifluoromethyl)phenyl)-N-((2-(5-chloropyridin-2-yl)oxazol-5-yl)methyl)-N-(4-fluorophenyl)acetamide

[0824] 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 mg, 0.05 mmol),　DMAP (9.05 mg, 0.07 mmol),　EDCI (14.20 mg, 0.07 mmol). The mixture was stirred at 25℃ for 18 h. The mixture was concentrated under reduced pressure to give a 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%).

[0825] LCMS: m / z (M+H)+= 558.9.

[0826]

[0827] Experimental example: Inhibitory activity against Polθ

[0828] Inhibitory activities against Polθ were measured for the compounds prepared in the above examples as follows.

[0829]

[0830] A PicoGreen assay was used to measure the ability of compounds to inhibit the activity of Ροlθ in vitro. A Recombinant Polθ-polymerase domain (aa1819-2590) was produced by ChemPartner and stored at -80 ºC in aliquots. Assay measurements were performed with a 1X buffer including 25 mM tris HCL pH 7.5, 12.5 mM NaCl, 0.5 mM MgCl2, 5 % glycerol, 0.01 % Triton X-100, 0.01 % BGG, and 1 mM DTT. Test compounds were prepared by dilution in 100 % DMSO to give the correct dose range for 10 point concentration response and appropriate volume (20 nL) dispensed into 384 well microassay plates (Greiner small volume black plate product code 784076) using a Labcyte Echo 655 acoustic dispenser. The DMSO concentration was maintained at 0.2 % by back filling with DMSO solution. 5 μL purified recombinant Polθ was diluted in assay buffer to a 2X working concentration (6 nM Polθ). This was dispensed into each well of the compound plate using a VIAFLO 16 channel manual pipette (Integra) and preincubated at RT for 15 min. 5 μL of 2X working solution of dNTPs (40 μM) ( Thermo#R1121) and Primer (60 nM PTD) (5' - GCG GCT GTC ATA AG - 3' (SEQ5 ID NO: 1)): template (5' - GCT ACA TTG ACA ATG GCA TCA AAT CTC AGA TTG CGT CTT ATG ACA GCC GCG - 3' (SEQ ID NO: 2)) duplex (1:1.1) diluted in assay buffer was then added and the reaction incubated for 60 min at RT. The reaction was stopped by addition of 10 mM EDTA, 25 mM tris pH 7.5 and 1:80 dilution of PicoGreen dye (Invitrogen P7581). After 90 minutes at RT in the dark, fluorescence was read on a 2105-0020 EnVision Multilabel Reader using a 485 / 535 nm module and raw data analyzed using log(inhibitor) vs. response - variable slope (four parameters) to generate IC50values. The results are shown in Tables 1 and 2 below.

[0831] Example No.Polθ / IC50(nM)Example No.Polθ / IC50(nM)Example 187.32Example 102.08Example 2293.8Example 117.82Example 397.68Example 1211.94Example 4154.7Example 1311.4Example 527.5Example 1449.18Example 67.03Example 1518.93Example 710.61Example 1611.04Example 82.54Example 1778.64Example 95.5Example 1836.52

[0832]

[0833] Example No.Polθ / IC50(nM)Example No.Polθ / IC50(nM)Example 19>1000Example 49151.9Example 20>1000Example 64-P1>1000Example 22>1000Example 64-P2123.3Example 2361.01Example 65154.4Example 24>1000Example 66108.4Example 2536.58Example 6719.96Example 3026.48Example 68223.8Example 299.89Example 6961.69

Claims

1.A compound represented by Chemical Formula 1 below, or a pharmaceutically acceptable salt thereof:[Chemical Formula 1]in Chemical Formula 1,X is CH, or N,Y is O, or S,Z1and Z2are each independently N, or CH, with the proviso that at least one of Z1and Z2is N,Z3is O, or S,R1is C1-4alkyl, C3-6cycloalkyl, C1-4haloalkyl, or halogen,R2is C1-4haloalkyl,R3is hydrogen, C1-4alkyl, C3-6cycloalkyl, or halogen,L is a single bond; or a divalent linker selected from the group consisting of a 5-membered or 6-membered heteroaromatic ring containing one or two nitrogens, unsubstituted or substituted with C1-4alkyl, halogen, C1-4haloalkyl, C1-4haloalkoxy, C1-4alkoxy, hydroxy, or amino; 2-oxa-6-azaspiro[3.3]heptane; thiomorpholinedioxide; 1H-pyrrolo[2,3-b]pyridine; and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine; andR4is hydrogen; C1-4alkyl; (C1-4alkyl)sulfonyl(C1-4alkyl); C2-4alkynyl; C1-4alkoxy; C3-6cycloalkyl, unsubstituted or substituted with hydroxy, or C1-4alkoxy; halogen; amino; morpholino; morpholinocarbonyl; 4-membered, 5-membered or 6-membered heterocycloalkyl containing one nitrogen, unsubstituted or substituted with hydroxy, C1-4alkyl, (C1-4alkyl)carbonyl, (C3-6cycloalkyl)carbonyl, or (C1-4alkyl)sulfonyl; 5-membered or 6-membered heterocycloalkyl containing one oxygen, unsubstituted or substituted with hydroxy, C1-4alkyl, (C1-4alkyl)carbonyl, (C3-6cycloalkyl)carbonyl, or (C1-4alkyl)sulfonyl; (5-membered or 6-membered heterocycloalkyl containing one oxygen)methyl; (5-membered or 6-membered heterocycloalkyl containing one oxygen)oxy; 1-(aminocarbonyl)ethan-1-yl; 1-oxoisoindolinyl; 2-azabicyclo[2.2.1]heptan-7-yl; 2-oxa-6-azaspiro[3.3]heptan-6-yl; 4-oxaspiro[2.4]heptan-6-yl; or 5-oxopyrrolidinyl.2.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinR1is methyl, cyclopropyl, trifluoromethyl, or chloro.3.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinR2is trifluoromethyl.4.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinR3is hydrogen, methyl, cyclopropyl, fluoro, or chloro.5.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinL 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, thiomorpholinedioxide, 1H-pyrrolo[2,3-b]pyridine, and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.6.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinR4is 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)ethan-1-yl; 1-oxoisoindolinyl; 2-azabicyclo[2.2.1]heptan-7-yl; 2-oxa-6-azaspiro[3.3]heptan-6-yl; 4-oxaspiro[2.4]heptan-6-yl; 5-oxopyrrolidinyl; or methylsulfonylmethyl.7.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinthe Chemical Formula 1 is represented by Chemical Formula 2 below:[Chemical Formula 2]in Chemical Formula 2,Y is O, or S,Z1and Z2are each independently N, or CH, with the proviso that at least one of Z1and Z2is N,Z3is O, or S,L is 5-membered or 6-membered heteroaromatic ring containing one or two nitrogens, andR4is hydrogen; C1-4alkoxy; C3-6cycloalkyl; halogen; amino; morpholino; 4-membered, 5-membered or 6-membered heterocycloalkyl containing one nitrogen, unsubstituted or substituted with C1-4alkyl, or (C1-4alkyl)carbonyl; or 5-membered or 6-membered heterocycloalkyl containing one oxygen.8.The compound or a pharmaceutically acceptable salt thereof according to claim 7, whereinL is pyrazine, pyridazine, pyridine, or pyrimidine.9.The compound or a pharmaceutically acceptable salt thereof according to claim 7, whereinR4is hydrogen; methoxy; cyclopropyl; cyclopentyl; bromo; chloro; amino; morpholino; piperidinyl; pyrrolidinyl; methylpyrrolidinyl; acetylpyrrolidinyl; tetrahydrofuranyl; or tetrahydropyranyl.10.The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein1) 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)ethanethioamide,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]heptan-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]heptan-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]heptan-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]heptan-6-yl)-1,3,4-oxadiazol-2-yl)methyl)-2-(2,4-bis(trifluoromethyl)phenyl)-N-(4-fluorophenyl)acetamide,59) N-((5-(1,1-dioxidothiomorpholin-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, and69) 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 the prevention or treatment of cancer, comprising the compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof.

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