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. [Chemical Formula 1] in Chemical Formula 1, A, B, X, Y, L 1 , L 2 , and R 1 to R 4 are as defined in the specification.

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]

[0003] 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.

[0004]

[0005] 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.

[0006]

[0007] Polθ is distinct among human DNA polymerases, exhibiting not only a C-terminal DNA polymerase domain but also an N-terminal helicase domain. 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.

[0008]

[0009] 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.

[0010]

[0011] 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.

[0012]

[0013] 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:

[0014] [Chemical Formula 1]

[0015]

[0016] in Chemical Formula 1,

[0017] A is a trivalent linker of C2-10heterocyclic ring containing one to three heteroatoms selected from N, O, or S,

[0018] L1is a bond; C1-4alkylene; C2-4alkenylene; C2-4alkynylene; -S-; or -O-,

[0019] R1is hydrogen; C1-4alkyl; -CONH2; -CONH(C1-4alkyl); -CON(C1-4alkyl)2; C3-6cycloalkyl; C2-10heterocycloalkyl containing one to three heteroatoms selected from N, O, or S, which is unsubstituted or substituted by C1-4alkyl, or C1-4haloalkyl; or C2-10heteroaryl containing one to three heteroatoms selected from N, O, or S, which is unsubstituted or substituted by C1-4alkyl, or C1-4haloalkyl,

[0020] B is a trivalent linker of C6-10aromatic ring; C2-10heterocycloalkane ring containing one to three heteroatoms selected from N, O, or S; or C2-10heteroaromatic ring containing one to three heteroatoms selected from N, O, or S,

[0021] R2and R3are each independently, hydrogen; C1-4alkyl; C2-4alkenyl; C2-4alkynyl; C1-4haloalkyl; C1-4alkoxy; halogen; cyano; or C2-6heterocycloalkyloxy containing one oxygen; or R2and R3when on adjacent ring vertices, combine to form a C2-6heterocycloalkyl containing one to three heteroatoms selected from N, O, or S ; or C2-6heteroaryl containing one to three heteroatoms selected from N, O, or S,

[0022] X is N; or CR’,

[0023] R’ is hydrogen; or halogen,

[0024] Y is -S-; -S(=O)-; or -S(=O)2-,

[0025] L2is a bond; C1-4alkylene, which is unsubstituted or substituted at least one deuterium; or C3-6cycloalkylene,

[0026] R4is C6-10aryl; C2-10heteroaryl containing one to three heteroatoms selected from N, O, or S; C3-6cycloalkyl; C2-6heterocycloalkyl containing one oxygen; C6-10spiro-heterocycloalkyl containing one oxygen; C7-10bicycloalkyl; or C7-10biheterocycloalkyl containing one or two oxygen;

[0027] R4is unsubstituted or substituted by one or two substituents independently selected from the group consisting of C1-4alkyl; C1-4haloalkyl; hydroxy; C1-4hydroxyalkyl; and halogen.

[0028]

[0029] Further, in order to achieve the above objects, there is provided a pharmaceutical composition comprising the compound, or, a pharmaceutically acceptable salt thereof.

[0030]

[0031] 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.

[0032]

[0033] 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.

[0034]

[0035] Hereinafter, embodiments of the present disclosure will be described in more detail to facilitate understanding of the invention.

[0036]

[0037] Meanwhile, the present disclosure provides a compound represented by Chemical Formula 1, or a pharmaceutically acceptable salt thereof.

[0038]

[0039] Preferably, A is a trivalent linker of 1,3-benzodioxole; 2,3-dihydrobenzofuran; 2-pyridone; imidazo[1,5-a]pyridine; imidazole; pyridazine; or pyridine.

[0040]

[0041] Preferably, L1is a bond; -CH2-; -C≡C-; or -O-.

[0042]

[0043] Preferably, R1is hydrogen; CH3; -CONH2; -CONH(CH3); -CON(CH3)2; cyclopropyl; cyclobutyl unsubstituted or substituted by one or two fluoro; or any ring selected from the group consisting of 8-oxo-4,7-diazaspiro[2.5]octan-8-onyl, 7-azaspiro[3.5]nonan-6-onyl, 2-pyridonyl, oxadiazolyl, oxopyridazinyl, pyrazolyl, or thiazolyl, which ring is unsubstituted or substituted by CH3, or CF3.

[0044]

[0045] Preferably, B is a trivalent linker of 1,3-benzodioxole; 2-oxa-5-azabicyclo[4.1.0]heptane; 3,4-dihydro-2H-benzo[b][1,4]oxazine; 3-oxa-8-azabicyclo[3.2.1]octane; 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine; 4-oxa-7-azaspiro[2.5]octane; benzene; benzo[d]oxazole; benzo[d]thiazole; morpholine; piperazin-2-one; pyrazole; or pyridine.

[0046]

[0047] Preferably, R2and R3are each independently, hydrogen; CH3; CHF2; CF3; OCH3; F; Cl; cyano; or (oxetanyl)oxy.

[0048]

[0049] Preferably, X is N; CH; or CF.

[0050]

[0051] Preferably, L2is a bond; -CH2-; -CD2-; -CH(CH3)-; -C(CH3)2-; or cyclopropylene.

[0052]

[0053] Preferably, R4is 2-oxaspiro[3.3]heptanyl; 4-oxaspiro[2.4]heptanyl; 6-oxaspiro[3.4]octanyl; bicyclo[2.2.1]heptanyl; cyclopropyl; cyclobutyl; cyclohexyl; hexahydrofuro[2,3-b]furanyl; phenyl; piperidinyl; pyridinyl; tetrahydrofuranyl; or tetrahydropyranyl, and the R4is unsubstituted or substituted by one or two substituents independently selected from the group consisting of CH3, hydroxy; CH2OH; fluoro; and chloro.

[0054]

[0055] Preferably, the Chemical Formula 1 is represented by Chemical Formula 2 below:

[0056] [Chemical Formula 2]

[0057]

[0058] in Chemical Formula 2,

[0059] X is N, or CH,

[0060] A is a trivalent linker of 2-pyridone; or pyridine,

[0061] L1is a bond; C1-4alkylene; or C2-4alkynylene,

[0062] R1is C1-4alkyl; -CON(C1-4alkyl)2; C3-6cycloalkyl; C2-10heterocycloalkyl containing one to three heteroatoms selected from N, O, or S, which is unsubstituted or substituted by C1-4alkyl, or C1-4haloalkyl; or C2-10heteroaryl containing one to three heteroatoms selected from N, O, or S, which is unsubstituted or substituted by C1-4alkyl, or C1-4haloalkyl,

[0063] R2is C1-4alkoxy,

[0064] R3is C1-4haloalkyl; or halogen,

[0065] Y is -S-; -S(=O)-; or -S(=O)2-,

[0066] L2is a bond; or C1-4alkylene, which is unsubstituted or substituted at least one deuterium,

[0067] R4is C6-10aryl; C2-10heteroaryl containing one to three heteroatoms selected from N, O, or S; or C2-6heterocycloalkyl containing one oxygen;

[0068] R4is unsubstituted or substituted by halogen.

[0069]

[0070] Preferably, in Chemical Formula 2,

[0071] X is N, or CH,

[0072] A is a trivalent linker of 2-pyridone; or pyridine,

[0073] L1is a bond; -CH2-; or -C≡C-,

[0074] R1is -CH3; 2-pyridonyl unsubstituted or substituted by CH3or CF3; 8-oxo-4,7-diazaspiro[2.5]octan-7-yl unsubstituted or substituted by CH3; -CON(CH3)2; cyclopropyl; oxopyridazinyl unsubstituted or substituted by CH3; or pyrazolyl unsubstituted or substituted by CH3.

[0075] R2is OCH3,

[0076] R3is CHF2; CF3; or chloro,

[0077] Y is -S-; -S(=O)-; or -S(=O)2-,

[0078] L2is a bond; -CH2-; -CD2-; or -CH(CH3)-,

[0079] R4is phenyl; piperidinyl; pyridinyl; tetrahydrofuranyl; or tetrahydropyranyl,

[0080] R4is unsubstituted or substituted by chloro.

[0081]

[0082] Representative examples of the compound represented by Chemical Formula 1 are as follows:

[0083] 1) 2'-chloro-N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0084] 2) N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-5-(5-(difluoromethyl)-2-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide,

[0085] 3) 2'-chloro-N-(5-((5-chloropyridin-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0086] 4) 5-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide,

[0087] 5) 2'-chloro-N-(5-((5-chloropyridin-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]octan-7-yl)-4,4'-bipyridine-3-carboxamide,

[0088] 6) 5-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-1-(2-(dimethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-4-carboxamide,

[0089] 7) 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,

[0090] 8) N-(5-((5-chloropyridin-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-5-(5-(difluoromethyl)-2-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide,

[0091] 9) 2'-chloro-N-(5-(4-chlorobenzylsulfinyl)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0092] 10) 2'-chloro-N-(5-(4-chlorobenzylsulfonyl)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0093] 11) 4-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(((5-chloropyridin-2-yl)dideuteriomethyl)sulfanyl)-1,3,4-thiadiazol-2-yl)-6-methylpyridine-3-carboxamide,

[0094] 12) 2'-chloro-N-(5-(1-(5-chloropyridin-2-yl)ethylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0095] 13) 5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide,

[0096] 14) 2'-(difluoromethyl)-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,

[0097] 15) 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0098] 16) 2'-chloro-N-(5-(5-chloropyridin-2-ylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0099] 17) 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0100] 18) 6-(cyclopropylethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0101] 19) 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0102] 20) 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0103] 21) 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0104] 22) 2'-chloro-5'-methoxy-6-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,

[0105] 23) 2'-chloro-5'-methoxy-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,

[0106] 24) 5'-methoxy-6-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide,

[0107] 25) 5'-methoxy-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide,

[0108] 26) 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydro-2H-pyran-4-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,

[0109] 27) 2'-chloro-5'-methoxy-6-methyl-N-(5-(piperidin-4-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,

[0110] 28) 2'-chloro-N-(5-(cyclopropylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0111] 29) 2'-chloro-N-(5-(4-hydroxycyclohexylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0112] 30) 2'-chloro-N-(5-(5-hydroxybicyclo[2.2.1]heptan-2-ylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0113] 31) 2'-chloro-N-(5-((3R,3aR,6aR)-hexahydrofuro[2,3-b]furan-3-ylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0114] 32) 2'-chloro-N-(5-(4-chlorophenylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0115] 33) 2'-chloro-N-(5-(2-(5-chloropyridin-2-yl)propan-2-ylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0116] 34) 2'-chloro-5'-methoxy-6-methyl-N-(5-(1-(tetrahydrofuran-3-yl)ethylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,

[0117] 35) 2'-chloro-N-(5-(4-(hydroxymethyl)cyclohexylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0118] 36) N-(5-(6-oxaspiro[3.4]octan-1-ylthio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0119] 37) 2'-chloro-5'-methoxy-6-methyl-N-(5-(1-(tetrahydrofuran-3-yl)cyclopropylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,

[0120] 38) N-(5-(2-oxaspiro[3.3]heptan-6-ylthio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0121] 39) 2'-chloro-N-(5-(3-hydroxy-3-methylcyclobutylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0122] 40) 2'-chloro-N-(5-(5,5-dimethyltetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0123] 41) 2'-chloro-N-(5-(4,4-difluorotetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0124] 42) 2'-chloro-N-(5-(3-hydroxycyclopentylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0125] 43) N-(5-(4-oxaspiro[2.4]heptan-6-ylthio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0126] 44) 5-(5-(difluoromethyl)-2-methoxyphenyl)-1-(2-(dimethylamino)-2-oxoethyl)-2-oxo-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-1,2-dihydropyridine-4-carboxamide,

[0127] 45) 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(6-oxo-7-azaspiro[3.5]nonan-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0128] 46) 4-(5-(difluoromethyl)-2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-6-(thiazol-2-yloxy)nicotinamide,

[0129] 47) 6-((3,3-difluorocyclobutyl)ethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0130] 48) 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0131] 49) N-(5-((5-chloropyridin-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]octan-7-yl)-4-morpholinonicotinamide,

[0132] 50) 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]octan-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0133] 51) 5-(5-(difluoromethyl)-2-methoxyphenyl)-1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-2-oxo-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-1,2-dihydropyridine-4-carboxamide,

[0134] 52) 5-(5-(difluoromethyl)-2-methoxyphenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-1,2-dihydropyridine-4-carboxamide,

[0135] 53) 5-(5-(difluoromethyl)-2-methoxyphenyl)-1-methyl-2-oxo-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-1,2-dihydropyridine-4-carboxamide,

[0136] 54) 5-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2,3-dihydrobenzofuran-6-carboxamide,

[0137] 55) 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)thiazol-2-yl)-4,4'-bipyridine-3-carboxamide,

[0138] 56) 2'-chloro-N-(4-fluoro-5-(tetrahydrofuran-3-ylthio)thiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0139] 57) 6-methyl-4-morpholino-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0140] 58) 6-methyl-4-morpholino-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0141] 59) 4-(benzo[d]oxazol-7-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0142] 60) 4-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0143] 61) 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0144] 62) 6-methyl-4-(2-(oxetan-3-yloxy)phenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0145] 63) 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0146] 64) 4-(3,5-dimethyl-1H-pyrazol-4-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0147] 65) 4-(6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0148] 66) 1-(2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-1H-imidazole-5-carboxamide,

[0149] 67) 7-(2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-carboxamide,

[0150] 68) 6-methyl-4-(4-oxa-7-azaspiro[2.5]octan-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0151] 69) 6-methyl-4-(2-methyl-3-oxopiperazin-1-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0152] 70) 4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0153] 71) 4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0154] 72) 4-(5-ethynyl-2-methoxyphenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0155] 73) 4-(benzo[d]thiazol-7-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0156] 74) 5-(benzo[d]thiazol-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)pyridazine-4-carboxamide,

[0157] 75) 5-(benzo[d]thiazol-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2,3-dihydrobenzofuran-6-carboxamide, and

[0158] 76) 6-(benzo[d]thiazol-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)benzo[d][1,3]dioxole-5-carboxamide.

[0159]

[0160] 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.

[0161]

[0162] 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.

[0163]

[0164] 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.

[0165]

[0166] 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.

[0167]

[0168] In one embodiment, the compound represented by Chemical Formula 1 may be prepared through Reaction Formula 1 below.

[0169] [Reaction Scheme 1]

[0170]

[0171]

[0172] In Reaction Scheme 1, A, B, X, Y, L1, L2, and R1to R4are as defined in the above.

[0173]

[0174] The reaction is for preparing a compound represented by Chemical Formula 1 by reacting a compound represented by Chemical Formula 2 with a compound represented by Chemical Formula 3, which is the amidation reaction. The above preparation method will be more specifically described in the Examples described hereinafter.

[0175]

[0176] 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.

[0177]

[0178] 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.

[0179]

[0180] 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.

[0181]

[0182] 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.

[0183]

[0184] 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.

[0185]

[0186] 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.

[0187]

[0188] 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.

[0189]

[0190] 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.

[0191]

[0192] 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.

[0193]

[0194] 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.

[0195]

[0196] Example 1: Synthesis of Compound 1

[0197]

[0198] Step A: 5-(((4-chlorophenyl)methyl)sulfanyl)-1,3,4-thiadiazol-2-amine

[0199] To a solution of 5-amino-1,3,4-thiadiazole-2-thiol (0.13 mL, 1.50 mmol) in THF (2 mL) were added Potassium tert-butoxide (168.50 mg, 1.50 mmol) and 4-chloro-1-(chloromethyl)benzene (241.80 mg, 1.50 mmol) at 25 °C, the reaction was stirred at 25 °C for 30 min under 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 1:2) to give 5-(((4-chlorophenyl) methyl)sulfanyl)-1,3,4-thiadiazol-2-amine (240 mg, 0.88 mmol) as a white solid.

[0200] LCMS: m / z (M+H)+= 258.0.

[0201]

[0202] Step B: 2'-chloro-N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide

[0203] To a solution of 5-(((4-chlorophenyl)methyl)sulfanyl)-1,3,4-thiadiazol-2-amine (20 mg, 0.08 mmol) in DMF (1 mL) were added 4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (21.62 mg, 0.08 mmol), DIEA (30.08 mg, 0.23 mmol) and HATU (35.41 mg, 0.09 mmol) at 25 °C, the reaction was stirred at 25 °C under N2for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA condition) to give 2'-chloro-N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide (5.4 mg, 0.01 mmol, 13.42%) as a white solid.

[0204] 1H NMR (400 MHz, MeOD) δ 8.79 (s, 1H), 8.05 (s, 1H), 7.50 (s, 1H), 7.44 (s, 1H), 7.41 - 7.36 (m, 2H), 7.33 - 7.28 (m, 2H), 4.43 (s, 2H), 3.61 (s, 3H), 2.67 (s, 3H).

[0205] LCMS: m / z (M+H)+= 518.2.

[0206]

[0207] Example 2: Synthesis of Compound 2

[0208]

[0209] To a solution of 5-(5-(difluoromethyl)-2-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (50 mg, 0.16 mmol) in N,N-dimethyl formamide (5.0 mL) was added TCFH (68 mg, 0.24 mmol), 1-Methylimidazole (39 mg, 0.48 mmol),5-(((5-chloropyridin-2-yl)methyl)sulfanyl)-1,3,4-thiadiazol-2-amine (50 mg, 0.19 mmol) under N2for 18 hours. The mixture was poured into water (15 mL) and extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine (50 mL*2), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure to give the crude product. The crude produce was subjected to Prep-HPLC ((ACN : water (1‰ FA) ) to N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-5-(5-(difluoromethyl)-2-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (15.77 mg, 17.74 %)　was obtained as a　white solid.

[0210] 1H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 7.77 (s, 1H), 7.46 (d, J = 9.2 Hz, 2H), 7.39 - 7.29 (m, 4H), 7.14 - 6.78 (m, 2H), 6.66 (s, 1H), 4.40 (s, 2H), 3.47 (s, 3H), 3.36 (s, 3H).

[0211] LCMS: m / z (M+H)+= 549.2.

[0212]

[0213] Example 3: Synthesis of Compound

[0214]

[0215] Step A: 5-(((5-chloropyridin-2-yl)methyl)thio)-1,3,4-thiadiazol-2-amine

[0216] To a solution of 5-amino-1,3,4-thiadiazole-2-thiol (0.60 mL, 6.76 mmol) in H2O (10 mL) and EtOH (20 mL) were added 5-chloro-2-(chloromethyl)pyridine (1094.74 mg, 6.76 mmol), NaOH (540.58 mg, 13.51 mmol) at 25 °C, the mixture was stirred at 25 °C for 30mins. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 100:1 to 0:1) to give 5-(((5-chloropyridin-2-yl)methyl)thio)-1,3,4-thiadiazol-2-amine (1.2 g, 4.41 mmol, 65.2%) as white solid.

[0217] LCMS: m / z (M+H)+= 259.1.

[0218]

[0219] Step B: 2'-chloro-N-(5-((5-chloropyridin-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide

[0220] To a solution of 5-(((5-chloropyridin-2-yl)methyl)sulfanyl)-1,3,4-thiadiazol-2-amine (50 mg, 0.18 mmol) in DMF (2.0 mL) were added 4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (51.16 mg, 0.18 mmol), TCFH (102.81 mg, 0.37 mmol), NMI (75.27 mg, 0.92 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA condition) to give 2'-chloro-N-(5-((5-chloropyridin-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide (10 mg, 0.02 mmol, 9.96%) as white solid.

[0221] 1H NMR (400 MHz, MeOD) δ 8.88 (s, 1H), 8.49 (d, J = 2.3 Hz, 1H), 8.11 (s, 1H), 7.91 - 7.76 (m, 1H), 7.65 - 7.44 (m, 3H), 4.57 (s, 2H), 3.68 (s, 3H), 2.73 (s, 3H).

[0222] LCMS: m / z (M+H)+= 519.1.

[0223]

[0224] Example 4: Synthesis of Compound 4

[0225]

[0226] To a solution of 5-(((5-chloropyridin-2-yl)methyl)oxy)-1,3,4-thiadiazol-2-amine (12.22 mg, 0.05 mmol), 2'-chloro-5'-methoxy-1-methyl-6-oxo-1,6-dihydro-(3,4'-bipyridine)-4-carboxylic acid (16 mg, 0.05 mmol) and NMI (10.82 μL, 0.14 mmol) in acetonitrile (5 mL) was added TCFH (57.13 mg, 0.20 mmol) at 25 °C, the mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (FA condition) to give 5-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (25 mg, 0.05 mmol) as white solid.

[0227] 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.99 (s, 1H), 7.47 (s, 1H), 7.42 - 7.35 (m, 4H), 6.77 (s, 1H), 4.46 (s, 2H), 3.51 (s, 3H), 3.47 (s, 3H).

[0228] LCMS: m / z (M+H)+= 534.2.

[0229]

[0230] Example 5: Synthesis of Compound 5

[0231]

[0232] To a solution of 4-(2-chloro-5-methoxypyridin-4-yl)-6-(4-methyl-8-oxo-4,7-diazaspiro (2.5) octan-7-yl) pyridine-3-carboxylic acid (40 mg, 0.10 mmol) and 5-(((5-chloropyridin-2-yl) methyl) sulfanyl)-1,3,4-thiadiazol-2-amine (25.69 mg, 0.10 mmol) in DMF (3 mL) were added TCFH (27.86 mg, 0.10 mmol) and 1-methylimidazole (0.02 mL, 0.30 mmol) at 25 °C, the mixture was stirred at 25 °C under N2for 2 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (TFA condition) to give 2'-chloro-N-(5-((5-chloropyridin-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]octan-7-yl)-4,4'-bipyridine-3-carboxamide (12.25 mg, 0.02 mmol, 19.17%) as white solid.

[0233] 1H NMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H),8.87 (s, 1H), 8.56 (d, J = 2.6 Hz, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.92 (dd, J = 8.4, 2.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 4.60 (s, 2H), 4.33 (s, 2H), 3.58 (s, 3H), 2.00 (m, 2H), 1.45 (s, 2H), 1.24 (s, 5H).

[0234] LCMS: m / z (M+H)+= 643.2.

[0235]

[0236] Example 6: Synthesis of Compound 6

[0237]

[0238] To a solution of 2'-chloro-1-(2-(dimethylamino)-2-oxoethyl)-5'-methoxy-6-oxo-1,6-dihydro-(3,4'-bipyridine)-4-carboxylic acid (40 mg, 0.11 mmol) in ACN (3.0 mL) were added TCFH (46 mg, 0.16 mmol), NMI (36 mg, 0.32 mmol) and 5-((4-chlorobenzyl)thio)-1,3,4-thiadiazol-2-amine (33 mg, 0.13 mmol) at 25 °C, the mixture was stirred at 25 °C under N2for 16 hours. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (FA condition) to give 5-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-1-(2-(dimethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-4-carboxamide (0.52 mg, 0.65 %) as white solid.

[0239] LCMS: m / z (M+H)+= 605.1.

[0240]

[0241] Example 7: Synthesis of Compound 7

[0242]

[0243] Step A: 5-(tetrahydro-3-furylsulfanyl)-1,3,4-thiadiazol-2-amine

[0244] To a solution of 5-amino-1,3,4-thiadiazole-2-thiol (0.03 mL, 0.38 mmol) in H2O (1 mL) and EtOH (1 mL) was added KOH (42.64 mg, 0.76 mmol), 3-bromotetrahydrofuran (57.38 mg, 0.38 mmol) at 25 °C, the mixture was stirred at 80 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 100:1 to 0:1) to give 5-(tetrahydro-3-furylsulfanyl)-1,3,4-thiadiazol-2-amine (40 mg, 0.19 mmol, 49.19%) as white solid.

[0245] LCMS: m / z (M+H)+= 204.2.

[0246]

[0247] Step B: 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide

[0248] To a solution of 5-(tetrahydro-3-furylsulfanyl)-1,3,4-thiadiazol-2-amine (50 mg, 0.12 mmol) in DMF (2.0 mL) were added 4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (34.10 mg, 0.12 mmol), TCFH (68.87 mg, 0.25 mmol), NMI (50.42 mg, 0.61 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (FA condition) to give 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide (2.02 mg, 0.01 mmol, 3.33%) as white solid.

[0249] 1H NMR (400 MHz, MeOD) δ 8.83 (s, 1H), 8.10 (s, 1H), 7.52 (s, 1H), 7.47 (s, 1H), 4.33 - 4.23 (m, 1H), 4.19 (dd, J = 9.6, 6.3 Hz, 1H), 4.01 - 3.93 (m, 1H), 3.89 - 3.80 (m, 2H), 3.70 (s, 3H), 2.70 (s, 3H), 2.50 (m, 1H), 2.09 - 1.94 (m, 1H).

[0250] LCMS: m / z (M+H)+= 464.1.

[0251]

[0252] Example 8: Synthesis of Compound 8

[0253]

[0254] To a solution of 5-(5-(difluoromethyl)-2-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (50 mg, 0.16 mmol) in DMF (3.0 mL) were added TCFH (68 mg, 0.24 mmol), NMI (39 mg, 0.48 mmol) and 5-(((5-chloropyridin-2-yl)methyl)sulfanyl)-1,3,4-thiadiazol-2-amine (50 mg, 0.19 mmol) at 25 °C, the mixture was at 25 °C under N2for 18 hours. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (FA condition) to give N-(5-((5-chloropyridin-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-5-(5-(difluoromethyl)-2-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (15.77 mg, 17.74 %) as white solid.

[0255] 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.54 (d, J = 2.5 Hz, 1H), 7.90 (dd, J = 8.4, 2.5 Hz, 1H), 7.79 (s, 1H), 7.58 - 7.42 (m, 3H), 7.25 - 6.78 (m, 2H), 6.71 (s, 1H), 4.54 (s, 2H), 3.51 (s, 3H), 3.43 (s, 3H).

[0256] LCMS: m / z (M+H)+= 550.2.

[0257]

[0258] Example 9: Synthesis of Compound 9

[0259]

[0260] To a solution of 4-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(((4-chlorophenyl)methyl)sulfanyl)-1,3,4-thiadiazol-2-yl)-6-methylpyridine-3-carboxamide (5 mg, 0.01 mmol) in THF (0.5 mL) and water (0.5 mL) was added OXONE ((3-sulfotrioxidanyl)potassium, 3.56 mg, 0.0058 mmol) at 25 °C, the reaction was stirred at 25 °C for 16 h under N2. After filtration, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA condition) to give 2'-chloro-N-(5-(4-chlorobenzylsulfinyl)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide (2 mg) as a white solid.

[0261] 1H NMR (400 MHz, MeOD) δ 8.86 - 8.80 (m, 1H), 8.09 - 8.02 (m, 1H), 7.50 - 7.47 (m, 1H), 7.44 - 7.40 (m, 1H), 7.34 - 7.27 (m, 2H), 7.20 (s, 2H), 4.65 (s, 2H), 3.62 (s, 3H), 2.67 (s, 3H).

[0262] LCMS: m / z (M+H)+= 534.2.

[0263]

[0264] Example 10: Synthesis of Compound 10

[0265]

[0266] Step A: 5-((4-chlorobenzyl)sulfonyl)-1,3,4-thiadiazol-2-amine

[0267] To a solution of 5-(((4-chlorophenyl)methyl)sulfanyl)-1,3,4-thiadiazol-2-amine (70 mg, 0.27 mmol) in THF (1 mL) and Water (1 mL) was added OXONE ((3-sulfotrioxidanyl)potassium, 331.97 mg, 0.54 mmol) at 25 °C, the reaction was stirred at 25 °C for 16 h. After filtration, the filtrate was concentrated under vacuum. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 100:1 to 1:1) to give 5-((4-chlorobenzyl)sulfonyl)-1,3,4-thiadiazol-2-amine (20 mg, 0.06 mmol) as yellow oil.

[0268] LCMS: m / z (M+H)+= 290.0.

[0269]

[0270] Step B: 2'-chloro-N-(5-(4-chlorobenzylsulfonyl)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide

[0271] To a solution of 5-((4-chlorobenzyl)sulfonyl)-1,3,4-thiadiazol-2-amine (20 mg, 0.06 mmol) in DMF (1 mL) were added 4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (19.24 mg, 0.07 mmol), DIEA (26.76 mg, 0.21 mmol) and HATU (31.50 mg, 0.08 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA condition) to give 2'-chloro-N-(5-(4-chlorobenzylsulfonyl)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide (7.5 mg, 0.01 mmol) as a white solid.

[0272] 1H NMR (400 MHz, MeOD) δ 8.83 (s, 1H), 8.05 (s, 1H), 7.51 (s, 1H), 7.47 - 7.43 (m, 1H), 7.34 (s, 2H), 7.30 (s, 2H), 4.70 - 4.50 (m, 2H), 3.59 (s, 3H), 2.68 (s, 3H).

[0273] LCMS: m / z (M+H)+= 550.2.

[0274]

[0275] Example 11: Synthesis of Compound 11

[0276]

[0277] Step A: (5-chloropyridin-2-yl)dideuteriomethanol

[0278] To a solution of methyl 5-chloropyridine-2-carboxylate (1 g, 5.83 mmol) in THF (12 mL) were added NaBD4(0.49 g, 11.66 mmol) and trideuterio(deuteriooxidanyl)methane (0.6 mL) at 25 °C, the mixture was stirred at 70 °C for 3 h. Upon completion, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL*3), the combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (DCM: MeOH = 100:1 to 10:1) to give (5-chloropyridin-2-yl)dideuteriomethanol (650 mg, 4.24 mmol) as a yellow solid.

[0279] LCMS: m / z (M+H)+= 146.0.

[0280]

[0281] Step B: 5-chloro-2-(chlorodideuteriomethyl)pyridine

[0282] To a solution of (5-chloropyridin-2-yl)dideuteriomethanol (200 mg, 1.37 mmol) in DCM (8 mL) was added SOCl2(0.2 mL, 2.75 mmol) at 0 °C, the mixture was stirred at 25 °C for 3 h. Upon completion, the mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL*3), the combined organic layers were washed with aq. NaHCO3(20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet.ether: EtOAc = 100:1 to 5:1) to give 5-chloro-2-(chlorodideuteriomethyl)pyridine (120 mg, 0.69 mmol) as a white solid.

[0283] LCMS: m / z (M+H)+= 163.9.

[0284]

[0285] Step C: 5-(((5-chloropyridin-2-yl)dideuteriomethyl)sulfanyl)-1,3,4-thiadiazol-2-amine

[0286] To a solution of 5-amino-1,3,4-thiadiazole-2-thiol (243.60 mg, 1.83 mmol) in THF (6 mL) were added tBuOK (150.50 mg, 1.34 mmol) and 5-chloro-2-(chlorodideuteriomethyl)pyridine (200 mg, 1.22 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Pet.ether: EtOAc = 100:1 to 3:1) to give 5-(((5-chloropyridin-2-yl)dideuteriomethyl)sulfanyl)-1,3,4-thiadiazol-2-amine (170 mg, 0.62 mmol) as a yellow solid.

[0287] LCMS: m / z (M+H)+= 261.0.

[0288]

[0289] Step D: 4-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(((5-chloropyridin-2-yl)dideuteriomethyl)sulfanyl)-1,3,4-thiadiazol-2-yl)-6-methylpyridine-3-carboxamide

[0290] To a solution of 4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (58.78 mg, 0.21 mmol) in DMF (2 mL) were added NMI (0.05 mL, 0.58 mmol), TCFH (80.70 mg, 0.29 mmol) and 5-(((5-chloropyridin-2-yl)dideuteriomethyl)sulfanyl)-1,3,4-thiadiazol-2-amine (50 mg, 0.19 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA condition) to give 4-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(((5-chloropyridin-2-yl)dideuteriomethyl)sulfanyl)-1,3,4-thiadiazol-2-yl)-6-methylpyridine-3-carboxamide (1.2 mg) as a white solid.

[0291] 1H NMR (400 MHz, DMSO) δ 13.22 (s, 1H), 8.84 (s, 1H), 8.56 (d, J = 2.5 Hz, 1H), 8.15 (d, J = 6.7 Hz, 1H), 7.92 (dd, J = 8.4, 2.5 Hz, 1H), 7.59 - 7.49 (m, 2H), 7.42 (s, 1H), 3.57 (s, 3H), 2.59 (s, 3H).

[0292] LCMS: m / z (M+H)+= 521.2.

[0293]

[0294] Example 12: Synthesis of Compound 12

[0295]

[0296] Step A: 1-(5-chloropyridin-2-yl)ethan-1-ol

[0297] To a solution of 1-(5-chloropyridin-2-yl)ethan-1-one (1 g, 6.43 mmol) in methanol (10 mL) was added sodium borohydride (0.49 g, 12.86 mmol) at 0 °C, the mixture was stirred at 25 °C for 1 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 1-(5-chloropyridin-2-yl)ethan-1-ol (900 mg,5.73 mmol) as yellow oil.

[0298] LCMS: m / z (M+H)+= 158.0.

[0299]

[0300] Step B: 5-chloro-2-(1-chloroethyl)pyridine

[0301] To a solution of 1-(5-chloropyridin-2-yl)ethan-1-ol (600 mg, 3.81 mmol) in dichloromethane (10 mL) was added thionyl chloride (0.69 mL, 9.52 mmol) at 0 °C, the mixture was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was poured into water (50 mL) and extracted with DCM (30 mL *3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether: EtOAc = 10: 1 to 5: 1) to give 5-chloro-2-(1-chloroethyl)pyridine (260 mg, 1.48 mmol) as yellow oil.

[0302] LCMS: m / z (M+H)+= 176.0.

[0303]

[0304] Step C: 5-((1-(5-chloropyridin-2-yl)ethyl)thio)-1,3,4-thiadiazol-2-amine

[0305] To a solution of 5-chloro-2-(1-chloroethyl)pyridine (260 mg, 1.48 mmol) in tetrahydrofuran (8 mL) was added 5-amino-1,3,4-thiadiazole-2-thiol (0.26 mL, 2.95 mmol), Potassium tert-butoxide (496 mg, 4.43 mmol) at 25 °C, the mixture was stirred at 65 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether: EtOAc = 10: 1 to 2: 1) to give 5-((1-(5-chloropyridin-2-yl)ethyl)thio)-1,3,4-thiadiazol-2-amine (60 mg, 0.22 mmol) as yellow oil.

[0306] LCMS: m / z (M+H)+= 273.0.

[0307]

[0308] Step D: 2'-chloro-N-(5-(1-(5-chloropyridin-2-yl)ethylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide

[0309] To a solution of 5-((1-(5-chloropyridin-2-yl)ethyl)thio)-1,3,4-thiadiazol-2-amine (60 mg, 0.22 mmol) in DMF (3 mL) were added 2'-chloro-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (73 mg, 0.26 mmol), TCFH (92 mg, 0.33 mmol) and NMI (54 mg, 0.66 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC ((ACN: water (1‰ FA)) to give 2'-chloro-N-(5-(1-(5-chloropyridin-2-yl)ethylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide (20.3 mg, 0.038 mmol) as white solid.

[0310] 1H NMR (400 MHz, DMSO) δ 13.25 (s, 1H), 8.82 (s, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.16 (s, 1H), 7.92 (dd, J = 8.4, 2.5 Hz, 1H), 7.55 (d, J = 3.7 Hz, 1H), 7.53 (s, 1H), 7.45 (s, 1H), 5.02 (m, 1H), 3.56 (s, 3H), 2.59 (s, 3H), 1.69 (d, J = 6.9 Hz, 3H).

[0311] LCMS: m / z (M+H)+= 533.2.

[0312]

[0313] Example 13: Synthesis of Compound 13

[0314]

[0315] Step A: methyl 5'-methoxy-6-methyl-2'-(trifluoromethyl)-(4,4'-bipyridine)-3-carboxylate

[0316] To a stirred solution of (5-methoxy-2-(trifluoromethyl)pyridin-4-yl)boranediol (626.63 mg, 2.84 mmol) in Dioxane (20 mL), H2O (4 mL) were added methyl 4-bromo-6-methylnicotinate (435 mg, 1.89 mmol)), PdCl2(dppf) (207.81 mg, 0.28 mmol) and K2CO3(1157.76 mg, 8.52 mmol) at 25 °C under N2, the mixture was stirred at 80 °C for 3 h under nitrogen. Upon completion, the reaction mixture was quenched by water (20 mL) and extracted with ethyl acetate (20 mL*2), the combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (Pet.ether: EtOAc = 100:1 to 3:1) to give methyl 5'-methoxy-6-methyl-2'-(trifluoromethyl)-(4,4'-bipyridine)-3-carboxylate (530 mg, 1.62 mmol) as a white solid.

[0317] LCMS: m / z (M+H)+= 327.0.

[0318]

[0319] Step B: 5'-methoxy-6-methyl-2'-(trifluoromethyl)-(4,4'-bipyridine)-3-carboxylic acid

[0320] To a solution of methyl 5'-methoxy-6-methyl-2'-(trifluoromethyl)-(4,4'-bipyridine)-3-carboxylate (530 mg, 1.62 mmol) in MeOH (3 mL) and H2O (3 mL) was added LiOH (681.59 mg, 16.24 mmol) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA condition) to give 5'-methoxy-6-methyl-2'-(trifluoromethyl)-(4,4'-bipyridine)-3-carboxylic acid (420 mg, 1.35 mmol) as white solid.

[0321] LCMS: m / z (M+H)+= 313.0.

[0322]

[0323] Step C: 5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide

[0324] To a solution of 5'-methoxy-6-methyl-2'-(trifluoromethyl)-(4,4'-bipyridine)-3-carboxylic acid (50 mg, 0.16 mmol) in acetonitrile (2 mL) were added 5-(tetrahydro-3-furylsulfanyl)-1,3,4-thiadiazol-2-amine (32.55 mg, 0.16 mmol), NMI (12.77 μL, 0.16 mmol) and TCFH (67.39 mg, 0.24 mmol) at 25 °C, the mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA condition) to give 5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide (11 mg, 0.02 mmol) as white solid .

[0325] 1H NMR (400 MHz, CD3OD) δ 8.85 (s, 1H), 8.45 (s, 1H), 7.86 (s, 1H), 7.49 (s, 1H), 4.30 - 4.22 (m, 1H), 4.19 (dd, J = 9.5, 6.3 Hz, 1H), 3.96 (dd, J = 14.9, 7.8 Hz, 1H), 3.89 - 3.84 (m, 1H), 3.84 - 3.77 (m, 1H), 3.81 (s, 3H), 2.70 (s, 3H), 2.55 - 2.44 (m, 1H), 2.07 - 1.93 (m, 1H).

[0326] LCMS: m / z (M+H)+= 498.2.

[0327]

[0328] Example 14: Synthesis of Compound 14

[0329]

[0330] Step A: methyl 2'-(difluoromethyl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate

[0331] To a solution of (2-(difluoromethyl)-5-methoxypyridin-4-yl)boranediol (200 mg, 0.87 mmol) in Dioxane (8.0 mL) were added methyl 4-bromo-6-methylpyridine-3-carboxylate (297 mg, 1.04 mmol), K2CO3(360 mg, 2.60 mmol) and Pd(dppf)Cl2(128 mg, 0.17 mmol) at 25 °C under N2, the mixture was stirred at 80 °C for 2 h under N2. Upon completion, the mixture was concentrated under reduced pressure to give the residue. The residue was purified by silica gel chromatography (eluent: petroleum ether: EtOAc = 10: 1 to 5: 1) to give methyl 2'-(difluoromethyl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate (210 mg, 0.66 mmol) as yellow oil.

[0332] LCMS: m / z (M+H)+= 309.2

[0333]

[0334] Step B: 2'-(difluoromethyl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid

[0335] To a solution of methyl 2'-(difluoromethyl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate (200 mg, 0.65 mmol) in MeOH / H2O (4:1) (5.0 mL) was added lithium hydroxide (31 mg, 1.29 mmol) at 25 °C, the mixture was stirred at 25 °C for 3 h. Upon completion, the mixture was adjusted pH to 2 with 2M HCl and extracted with EtOAc (10 mL*3). The organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 2'-(difluoromethyl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (133 mg, 0.46 mmol) as white solid.

[0336] LCMS: m / z (M+H)+= 295.2.

[0337]

[0338] Step C: 2'-(difluoromethyl)-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide

[0339] To a solution of 2'-(difluoromethyl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (40 mg, 0.14 mmol) in DMF (3 mL) were added 5-((tetrahydrofuran-3-yl)thio)-1,3,4-thiadiazol-2-amine (33 mg, 0.16 mmol), TCFH and NMI (33 mg, 0.40 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC ((ACN: water (1‰ FA)) to give 2'-(difluoromethyl)-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide (7.25 mg, 0.02 mmol) as white solid.

[0340] 1H NMR (400 MHz, DMSO) δ 13.29 (s, 1H), 8.85 (s, 1H), 8.45 (s, 1H), 7.68 (s, 1H), 7.42 (s, 1H), 6.98 (m, 1H), 4.31 - 4.15 (m, 1H), 4.08-4.06 (m, 1H), 3.85-3.84 (m, 1H), 3.79 - 3.71 (m, 1H), 3.70 - 3.64 (m, 1H), 3.66 (s, 3H), 2.60 (s, 3H), 2.45 - 2.26 (m, 1H), 1.91-1.83 (m, 1H).

[0341] LCMS: m / z (M+H)+= 480.2.

[0342]

[0343] Example 15: Synthesis of Compound 15

[0344]

[0345] Step A: methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinate

[0346] To a solution of methyl 4-bromo-6-methylnicotinate (200 mg, 0.87 mmol) in dioxane (8.0 mL) was added (5-(difluoromethyl)-2-methoxyphenyl)boronic acid (296 mg, 1.04 mmol), K2CO3(360 mg, 2.60 mmol) and Pd(dppf)Cl2(128 mg, 0.17 mmol) at 25 °C under N2, the mixture was stirred at 80 °C for 2 hours under N2. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether: EtOAc = 10: 1 to 5: 1) to give methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinate (200 mg, 0.65 mmol) as yellow oil.

[0347] LCMS: m / z (M+H)+= 308.2

[0348]

[0349] Step B: 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinic acid

[0350] To a solution of methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinate (200 mg, 0.65 mmol) in MeOH / H2O (4:1) (5.0 mL) was added lithium hydroxide (31 mg, 1.29 mmol) at 25 °C, the mixture was stirred at 25 °C for 3 h. Upon completion, the mixture was adjusted pH to 2 with 2M HCl and extracted with EtOAc (10 mL*3). The organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinic acid (133 mg, 0.46 mmol) as white solid.

[0351] LCMS: m / z (M+H)+= 294.0.

[0352]

[0353] Step C: 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide

[0354] To a solution of 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinic acid (40 mg, 0.14 mmol) in DMF (3 mL) were added 5-((tetrahydrofuran-3-yl)thio)-1,3,4-thiadiazol-2-amine (33 mg, 0.16 mmol), TCFH and NMI (33 mg, 0.40 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC ((ACN: water (1‰ FA)) to give 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide (22.89 mg, 0.05 mmol) as white solid.

[0355] 1H NMR (400 MHz, DMSO) δ 13.17 (s, 1H), 8.73 (s, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.57 (s, 1H), 7.35 (s, 1H), 7.25 - 6.78 (m, 2H), 4.27 - 4.16 (m, 1H), 4.08 - 4.04 (m, 1H), 3.86 - 3.80 (m, 1H), 3.77 - 3.75 (m, 1H), 3.71 - 3.61 (m, 1H), 3.52 (s, 3H), 2.59 (s, 3H), 2.45 - 2.29 (m, 1H), 1.91 - 1.84 (m, 1H).

[0356] LCMS: m / z (M+H)+= 479.2.

[0357]

[0358] Example 16: Synthesis of Compound 16

[0359]

[0360] Step A: 5-((5-nitropyridin-2-yl) sulfanyl)-1,3,4-thiadiazol-2-amine

[0361] To a solution of 5-amino-1,3,4-thiadiazole-2-thiol (1 g, 7.51 mmol) and 2-chloro-5-nitropyridine (1.19 g, 7.51 mmol) in DMF (30 mL) was added K2CO3(2.08 g, 15.02 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h to give a yellow solution. Upon completion, the mixture was diluted with H2O (200 mL) and extracted with EtOAc (200 mL * 3), 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 = 100:1 to 3:1) to give 5-((5-nitropyridin-2-yl) sulfanyl)-1,3,4-thiadiazol-2-amine (880 mg, 3.40 mmol) as white solid.

[0362] LCMS: m / z (M+H)+= 256.0.

[0363]

[0364] Step B: tert-butyl (5-((5-nitropyridin-2-yl)thio)-1,3,4-thiadiazol-2-yl)carbamate

[0365] To a solution of 5-((5-nitropyridin-2-yl) sulfanyl)-1,3,4-thiadiazol-2-amine (860 mg, 3.37 mmol) in DCM (30 mL) were added Boc2O (0.87 mL, 4.04 mmol) and DMAP (617.38 mg, 5.05 mmol) in an ice bath, the mixture was stirred at 25 °C for 16 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 = 100:1 to 3:1) to give tert-butyl (5-((5-nitropyridin-2-yl)thio)-1,3,4-thiadiazol-2-yl)carbamate (1.1 g, 3.10 mmol) as white solid.

[0366] LCMS: m / z (M+H)+= 356.0.

[0367]

[0368] Step C: tert-butyl (5-((5-aminopyridin-2-yl)thio)-1,3,4-thiadiazol-2-yl)carbamate

[0369] To a solution of tert-butyl (5-((5-nitropyridin-2-yl)thio)-1,3,4-thiadiazol-2-yl)carbamate (1.1 g, 3.10 mmol) in MeOH (100 mL) was added 10% Pd / C (0.66 g, 0.62 mmol) at 25 °C under H2, the mixture was stirred at 25 °C under H2for 16 h 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= 100:1 to 10:1) to give tert-butyl (5-((5-aminopyridin-2-yl)thio)-1,3,4-thiadiazol-2-yl)carbamate (220 mg, 0.61 mmol) as white solid.

[0370] LCMS: m / z (M+H)+= 326.0.

[0371]

[0372] Step D: tert-butyl (5-((5-chloropyridin-2-yl)thio)-1,3,4-thiadiazol-2-yl)carbamate

[0373] To a solution of tert-butyl (5-((5-aminopyridin-2-yl)thio)-1,3,4-thiadiazol-2-yl)carbamate (220 mg, 0.61 mmol) in CH3CN (30 mL) were added LiCl (26.05 mg, 0.61 mmol), cupric chloride (82.64 mg, 0.61 mmol) and tert-Butyl nitrite (0.07 mL, 0.61 mmol) at 25 °C, the mixture was stirred at 25 °C for 2 h to give a black solution. Upon completion, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL * 3), 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 = 100:1 to 5:1) to give tert-butyl (5-((5-chloropyridin-2-yl)thio)-1,3,4-thiadiazol-2-yl)carbamate (150 mg, 0.43 mmol) as white solid.

[0374] LCMS: m / z (M+H)+= 345.0.

[0375]

[0376] Step E: 5-((5-chloropyridin-2-yl) sulfanyl)-1,3,4-thiadiazol-2-amine

[0377] To a solution of tert-butyl (5-((5-chloropyridin-2-yl)thio)-1,3,4-thiadiazol-2-yl)carbamate (150 mg, 0.43 mmol) in TFA (5 mL) was stirred at 25 °C for 2 h to give a brown solution. Upon completion, the mixture was concentrated under reduced pressure to give 5-((5-chloropyridin-2-yl) sulfanyl)-1,3,4-thiadiazol-2-amine (50 mg, 0.20 mmol) as yellow solid.

[0378] LCMS: m / z (M+H)+= 325.0.

[0379]

[0380] Step F: 2'-chloro-N-(5-(5-chloropyridin-2-ylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide

[0381] To a solution of 4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (20 mg, 0.07 mmol) and 5-((5-chloropyridin-2-yl) sulfanyl)-1,3,4-thiadiazol-2-amine (18 mg, 0.07 mmol) in DMF (2 mL) were added TCFH (26.18 mg, 0.09 mmol) and 1-methylimidazole (0.02 mL, 0.22 mmol) at 25 °C, the mixture was stirred at 25 °C for 2 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'-chloro-N-(5-(5-chloropyridin-2-ylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide (9.56 mg, 0.02 mmol) as white solid.

[0382] 1H NMR (400 MHz, CDCl3) δ 9.17 (s, 1H), 8.52 (s, 1H), 8.09 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.45 - 7.30 (m, 4H), 3.77 (s, 3H), 2.86 (s, 3H).

[0383] LCMS: m / z (M+H)+= 505.1.

[0384]

[0385] Example 17: Synthesis of Compound 17

[0386]

[0387] Step A: methyl 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylpyridine-3-carboxylate

[0388] To a solution of methyl 4-bromo-6-methylpyridine-3-carboxylate (0.07 mL, 0.43 mmol) in dioxane (3 mL) were added (2-methoxy-5-(trifluoromethyl)phenyl)boranediol (0.07 mL, 0.43 mmol), K2CO3(180.21 mg, 1.30 mmol) and Pd(dppf)Cl2(35.50 mg, 0.04 mmol) at 25 °C, the mixture was stirred at 80 °C under N2for 3h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Pet.ether: EtOAc = 100:1 to 3:1) to give methyl 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylpyridine-3-carboxylate(141 mg, 0.43 mmol).

[0389] LCMS: m / z (M+H)+= 326.0.

[0390]

[0391] Step B: 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylnicotinic acid

[0392] To a solution of methyl 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylpyridine-3-carboxylate (100 mg, 0.31 mmol) in H2O (1 mL) and MeOH (3 mL) was added LiOH (0.02 mL, 0.62 mmol) at 25 °C, the mixture was stirred at 25 °C for 3 h. Upon completion, the mixture was adjusted pH to 2 with 2M HCl and extracted with EtOAc (10 mL*3). The organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylnicotinic acid (80 mg, 0.28 mmol) as white solid.

[0393] LCMS: m / z (M+H)+= 312.0.

[0394]

[0395] Step C: 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide

[0396] To a solution of 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylpyridine-3-carboxylic acid (22 mg, 0.07 mmol) in DMF (2 mL) was added 5-(tetrahydro-3-furylsulfanyl)-1,3,4-thiadiazol-2-amine (14.37 mg, 0.07 mmol), TCFH (39.66 mg, 0.14 mmol) and NMI (0.03 mL, 0.35 mmol) at 25 °C, the mixture was stirred at 25 °C under N2for 3 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA condition) to give 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide (10 mg, 0.02 mmol) as white solid.

[0397] 1H NMR (400 MHz, DMSO) δ 13.19 (s, 1H), 8.77 (s, 1H), 7.78 (dd, J = 8.7, 1.9 Hz, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.44 (s, 1H), 7.18 (d, J = 8.7 Hz, 1H), 4.28 - 4.19 (m, 1H), 4.07 (dd, J = 9.6, 6.3 Hz, 1H), 3.84 (dd, J = 14.8, 7.8 Hz, 1H), 3.78 - 3.65 (m, 2H), 3.56 (s, 3H), 2.60 (s, 3H), 2.41 (dt, J = 14.4, 7.9 Hz, 1H), 1.97 - 1.81 (m, 1H).

[0398] LCMS: m / z (M+H)+= 497.2.

[0399]

[0400] Example 18: Synthesis of Compound 18

[0401]

[0402] Step A: methyl 6-(cyclopropylethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl) pyridine-3-carboxylate

[0403] To a solution of methyl 6-chloro-4-(5-(difluoromethyl)-2-methoxyphenyl) pyridine-3-carboxylate (200 mg, 0.61 mmol) and ethynylcyclopropane (0.05 mL, 0.61 mmol) in DMF (20 mL) were added Pd(PPh3)4(42.84 mg, 0.06 mmol), CuI (23.25 mg, 0.12 mmol) and TEA (0.17 mL, 1.22 mmol) at 25 °C under N2, The mixture was stirred at 70 °C under N2for 16 h to give a brown solution. After filtration, the mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 100:1 to 5:1) to give methyl 6-(cyclopropylethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl) pyridine-3-carboxylate (200 mg, 0.56 mmol) as white solid.

[0404] LCMS: m / z (M+H)+= 358.2.

[0405]

[0406] Step B: 6-(cyclopropylethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl) pyridine-3-carboxylic acid

[0407] To a solution of methyl 6-(cyclopropylethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl) pyridine-3-carboxylate (200 mg, 0.56 mmol) in THF (3 mL) and H2O (2 mL) was added LiOH (28.18 mg, 0.67 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h to give a yellow solution. Upon completion, the mixture was adjusted pH to 2 with 2M HCI and extracted with EtOAc (10 mL*3), the organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6-(cyclopropylethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl) pyridine-3-carboxylic acid (150 mg, 0.45 mmol) as white solid.

[0408] LCMS: m / z (M+H)+= 344.2.

[0409]

[0410] Step C: 6-(cyclopropylethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide

[0411] To a solution of 6-(cyclopropylethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl) pyridine-3-carboxylic acid (30 mg, 0.09 mmol) and 5-(tetrahydro-3-furylsulfanyl)-1,3,4-thiadiazol-2-amine (18.30 mg, 0.09 mmol) in DMF (2 mL) were added TCFH (31.87 mg, 0.11 mmol) and 1-methylimidazole (0.02 mL, 0.26 mmol) at 25 °C, the mixture was stirred at 25 °C for 2 h to give a brown solution. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (TFA / acetonitrile / water) to give 6-(cyclopropylethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide (17.35 mg, 0.03 mmol) as white solid.

[0412] 1H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.78 (s, 1H), 7.65 - 7.57 (m, 2H), 7.48 (s, 1H), 7.18 - 6.85 (m, 2H), 4.22 (m, 1H), 4.07 (dd, J = 9.6, 6.3 Hz, 1H), 3.84 (m, 1H), 3.79 - 3.64 (m, 2H), 3.53 (s, 3H), 2.40 (m, 1H), 1.88 (m, 1H), 1.64 (m, 1H), 0.98 (m, 2H), 0.91 - 0.75 (m, 2H).

[0413] LCMS: m / z (M+H)+= 529.2.

[0414]

[0415] Example 19: Synthesis of Compound 19

[0416]

[0417] Step A: methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)nicotinate

[0418] To a solution of 4-ethynyl-1-methylpyrazole (0.05 mL, 0.47 mmol) in DMF (2 mL) were added methyl 6-chloro-4-(5-(difluoromethyl)-2-methoxyphenyl)pyridine-3-carboxylate (154.39 mg, 0.47 mmol), TEA (0.20 mL, 1.41 mmol), CuI (9.52 mg, 0.05 mmol) and Pd(dppf)Cl2(38.47 mg, 0.05 mmol) at 25 °C under N2, the mixture was stirred at 50 °C under N2for 1h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (Pet.ether: EtOAc = 100:1 to 3:1) to give methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)nicotinate (30 mg, 0.076 mmol) as white solid.

[0419] LCMS: m / z (M+H)+= 398.0.

[0420]

[0421] Step B: 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)nicotinic acid

[0422] To a solution of methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)nicotinate (200 mg, 0.50 mmol) in H2O (2 mL) and MeOH (2 mL) was added LiOH (0.06 mL, 2.01 mmol) at 25 °C, the mixture was stirred at 25 °C under N2for 1h. Upon completion, the mixture was adjusted pH to 2 with 2M HCl and extracted with EtOAc (10 mL*3), the organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)nicotinic acid (140 mg, 0.02 mmol) as white solid.

[0423] LCMS: m / z (M+H)+= 384.0.

[0424]

[0425] Step C: 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide

[0426] To a solution of 5-(tetrahydrothiophen-3-yloxy)-1,3,4-thiadiazol-2-amine (10.61 mg, 0.05 mmol) in DMF (3.0 mL) was added 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)nicotinic acid (20 mg, 0.05 mmol), TCFH (29.22 mg, 0.10 mmol) and NMI (0.02 mL, 0.26 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA condition) to give 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide (10 mg, 0.02 mmol, 32.03%) as white solid.

[0427] 1H NMR (400 MHz, DMSO) δ 8.89 (s, 1H), 8.20 (s, 1H), 7.80 (s, 1H), 7.62 (d, J = 9.7 Hz, 2H), 7.54 (s, 1H), 7.19 - 6.82 (m, 2H), 4.16 (d, J = 7.3 Hz, 1H), 4.10 - 4.01 (m, 1H), 3.89 (s, 3H), 3.83 (dd, J = 14.8, 7.7 Hz, 1H), 3.74 (m, 1H), 3.67 (dd, J = 9.5, 4.3 Hz, 1H), 3.54 (s, 3H), 2.39 (m, 1H), 1.91 - 1.81 (m, 1H).

[0428] LCMS: m / z (M+H)+= 569.2.

[0429]

[0430] Example 20: Synthesis of Compound 20

[0431]

[0432] Step A: methyl 6-chloro-4-iodopyridine-3-carboxylate

[0433] To a solution of 6-chloro-4-iodopyridine-3-carboxylic acid (1 g, 3.53 mmol) in DMF (15 mL) were added Cs2CO3(3.45 g, 10.58 mmol) and iodomethane (0.24 mL, 3.88 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h. Upon completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL*3), the combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet.ether: EtOAc = 100:1 to 3:1) to give methyl 6-chloro-4-iodopyridine-3-carboxylate (1 g, 3.19 mmol) as a yellow solid.

[0434] LCMS: m / z (M+H)+= 297.9

[0435]

[0436] Step B: methyl 6-chloro-4-(2-methoxy-5-(trifluoromethyl)phenyl)pyridine-3-carboxylate

[0437] To a solution of methyl 6-chloro-4-iodopyridine-3-carboxylate (1 g, 3.36 mmol) in Dioxane (3 mL), H2O (0.5 mL) were added (2-methoxy-5-(trifluoromethyl)phenyl)boranediol (0.74 g, 3.36 mmol), K2CO3(1.39 g, 10.08 mmol) and Pd(dppf)Cl2(0.25 g, 0.34 mmol) at 25 °C under N2, the mixture was stirred at 80 °C for 3 h under N2. Upon completion, the mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL*3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet.ether: EtOAc = 100:1 to 2:1) to give methyl 6-chloro-4-(2-methoxy-5-(trifluoromethyl)phenyl)pyridine-3-carboxylate (700 mg, 1.92 mmol) as a yellow solid.

[0438] LCMS: m / z (M+H)+= 346.0.

[0439]

[0440] Step C: methyl 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxopyridin-3-yl)pyri dine-3-carboxylate

[0441] To a solution of methyl 6-chloro-4-(2-methoxy-5-(trifluoromethyl)phenyl)pyridine-3-carboxylate (100 mg, 0.29 mmol) in Dioxane (2 mL), H2O (0.5 mL) were added 3-(dihydroxyboranyl)-1-methyl-1,2-dihydropyridin-2-one (44.24 mg, 0.29 mmol), K2CO3(39.98 mg, 0.29 mmol) and Pd(dppf)Cl2(21.17 mg, 0.03 mmol) at 25 °C under N2, the mixture was stirred at 80 °C under N2for 16 h. Upon completion, the mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL*3). The combined organic layers were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet.ether: EtOAc = 100:1 to 2:1) to give methyl 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxopyridin-3-yl)pyridine-3-carboxylate (100 mg, 0.24 mmol) as a yellow solid.

[0442] LCMS: m / z (M+H)+= 419.2.

[0443]

[0444] Step D: 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxopyridin-3-yl)pyridine-3-carboxylic acid

[0445] To a solution of methyl 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxopyridin-3-yl)pyridine-3-carboxylate (100 mg, 0.24 mmol) in THF (4 mL), MeOH (0.5 mL) and H2O (1 mL) were added LiOH (10.03 mg, 0.24 mmol) at 25 °C, the mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was adjusted pH to 2 with 2M HCl and extracted with EtOAc (10 mL*3). The organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxopyridin-3-yl)pyridine-3-carboxylic acid (60 mg, 0.13 mmol) as a white solid.

[0446] LCMS: m / z (M+H)+= 405.2.

[0447]

[0448] Step E: 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide

[0449] To a solution of 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxopyridin-3-yl)pyridi ne-3-carboxylic acid (20 mg, 0.05 mmol) in DMF (2 mL) were added the 1-methylimidazole (0.01 mL, 0.15 mmol), TCFH (21.04 mg, 0.08 mmol) and 5-(tetrahydro-3-furylsulfanyl)-1,3,4-thiadiazol-2-amine (10.16 mg, 0.05 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA condition) to give 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide (1.12 mg) as a white solid.

[0450] 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.73 (s, 1H), 8.62 (d, J = 5.6 Hz, 1H), 7.70 (d, J = 9.3 Hz, 1H), 7.65 (s, 1H), 7.55 (d, J = 6.1 Hz, 1H), 7.05 - 6.96 (m, 1H), 6.47 (t, J = 6.9 Hz, 1H), 4.20 (dd, J = 9.6, 6.5 Hz, 1H), 4.01 - 3.78 (m, 4H), 3.74 (s, 3H), 3.72 (s, 3H), 2.01 (m, 2H).

[0451] LCMS: m / z (M+H)+= 590.2.

[0452]

[0453] Example 21: Synthesis of Compound 21

[0454]

[0455] Step A: methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)nicotinate

[0456] To a stirred solution of methyl 6-chloro-4-(2-(difluoromethyl)-5-methoxypyridin-4-yl)pyridine-3-carboxylate (238 mg, 0.72 mmol) in Tol (2 mL) were added 2,5-diazahexane (0.02 mL, 0.14 mmol), 5-methyl-2H,3H-1,2-diazin-3-one (119.60 mg, 1.09 mmol)), CuI (13.79 mg, 0.07 mmol) and K3PO4(307.38 mg, 1.45 mmol) at 25 °C under N2, the resulting solution was stirred at 120 °C for 3 h under nitrogen. Upon completion, the reaction was concentrated under reduced pressure. The residue was purified by column chromatography (Pet.ether: EtOAc = 100:1 to 1:1) to give methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)nicotinate (100 mg, 0.25 mmol) as white solid.

[0457] LCMS: m / z (M+H)+= 401.9.

[0458]

[0459] Step B: 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylic acid

[0460] To a solution of methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)nicotinate (100 mg, 0.25 mmol) in THF (3 mL), MeOH (3 mL) and H2O (3 mL) was added LiOH (104.54 mg, 2.49 mmol) at 25 °C, the reaction mixture was stirred at 25 °C for 3 h. Upon completion, the mixture was adjusted pH to 2 with 2M HCl and extracted with EtOAc (10 mL*3), the organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylic acid (70 mg, 0.18 mmol) as white solid.

[0461] LCMS: m / z (M+H)+= 388.2.

[0462]

[0463] Step C: 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide

[0464] To a solution of 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylic acid (30 mg, 0.08 mmol) in DMF (2 mL) were added TCFH (32.60 mg, 0.12 mmol), NMI (6.17 μL, 0.08 mmol) and 5-(tetrahydro-3-furylsulfanyl)-1,3,4-thiadiazol-2-amine (15.74 mg, 0.08 mmol) at 25 °C, the mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA condition) to give 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide (7.4 mg, 0.01 mmol) as white solid.

[0465] 1H NMR (400 MHz, CD3CN) δ 8.88 (s, 1H), 7.91 (d, J = 1.9 Hz, 1H), 7.82 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.59 (s, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.83 (s, 1H), 6.80 (m, 1H), 4.26 - 4.16 (m, 1H), 4.09 (dd, J = 9.7, 6.2 Hz, 1H), 3.88 (dd, J = 14.7, 7.9 Hz, 1H), 3.79 - 3.70 (m, 2H), 3.62 (s, 3H), 2.46 - 2.37 (m, 2H), 2.28 (s, 3H).

[0466] LCMS: m / z (M+H)+= 573.2.

[0467]

[0468] Example 22: Synthesis of Compound 22

[0469]

[0470] Step A: benzyl 4-(2-chloro-5-methoxypyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1-yl)pyridine-3-carboxylate

[0471] To a solution of benzyl 6-chloro-4-(2-chloro-5-methoxypyridin-4-yl) pyridine-3-carboxylate (50 mg, 0.13 mmol) and 4-(trifluoromethyl)-1,2-dihydropyridin-2-one (20.95 mg, 0.13 mmol) in Toluene (5 mL) were added tripotassium phosphate (54.53 mg, 0.26 mmol), CuI (2.45 mg, 0.01 mmol) and 2,5-diazahexane (0.01 mL, 0.03 mmol) at 25 °C under N2, the mixture was stirred at 120 °C under N2for 2 h to give a brown solution. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 100:1 to 2:1) to give benzyl 4-(2-chloro-5-methoxypyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl) pyridin-1-yl) pyridine-3-carboxylate (15 mg, 0.03 mmol) as white solid.

[0472] LCMS: m / z (M+H)+= 516.2.

[0473]

[0474] Step B: 4-(2-chloro-5-methoxypyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl) pyridin-1-yl) pyridine-3-carboxylic acid

[0475] To a solution of benzyl 4-(2-chloro-5-methoxypyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1-yl)pyridine-3-carboxylate (15 mg, 0.03 mmol) in MeOH (3 mL) and H2O (3 mL) was added LiOH (1.46 mg, 0.03 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h to give a yellow solution. Upon completion, the mixture was adjusted pH<4 with 2 M HCl and extracted with EtOAc (15 mL*2), the organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(2-chloro-5-methoxypyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1-yl)pyridine-3-carboxylic acid (10 mg, 0.02 mmol) as white solid.

[0476] LCMS: m / z (M+H)+= 426.1.

[0477]

[0478] Step C: 2'-chloro-5'-methoxy-6-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide

[0479] To a solution of 4-(2-chloro-5-methoxypyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl) pyridin-1-yl) pyridine-3-carboxylic acid (10 mg, 0.02 mmol) and 5-(tetrahydro-3-furylsulfanyl)-1,3,4-thiadiazol-2-amine (4.77 mg, 0.02 mmol) in DMF (2 mL) were added TCFH (9.89 mg, 0.04 mmol) and 1-methylimidazole (5.79 mg, 0.07 mmol) at 25 °C, the mixture was stirred at 25 °C for 2 h to give a yellow solution. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by high performance liquid phase (TFA / acetonitrile / water) to give 2'-chloro-5'-methoxy-6-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide (4.78 mg, 0.01 mmol) as white solid.

[0480] 1H NMR (400 MHz, CDCl3) δ 9.04 (s, 1H), 8.22 (d, J = 7.5 Hz, 1H), 8.14 (s, 1H), 8.00 (s, 1H), 7.25 (s, 1H), 6.89 (s, 1H), 6.43 (dd, J = 7.6, 2.0 Hz, 1H), 4.15 (s, 1H), 4.03 (dd, J = 9.8, 6.2 Hz, 1H), 3.83 (m, 1H), 3.71 - 3.59 (m, 5H), 2.31 (m, 1H), 1.86 (m, 1H).

[0481] LCMS: m / z (M+H)+= 611.2.

[0482]

[0483] Example 23: Synthesis of Compound 23

[0484]

[0485] Step A: benzyl 4-(2-chloro-5-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylate

[0486] To a solution of benzyl 6-chloro-4-(2-chloro-5-methoxypyridin-4-yl) pyridine-3-carboxylate (50 mg, 0.13 mmol) and 5-methyl-2H,3H-1,2-diazin-3-one (14.15 mg, 0.13 mmol) in toluene (2 mL) were added tripotassium phosphate (54.53 mg, 0.26 mmol), CuI (2.45 mg, 0.01 mmol) and 2,5-diazahexane (0.01 mL, 0.03 mmol) at 25 °C under N2, the mixture was stirred at 120 °C under N2for 18 h to give a brown solution. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (Pet.ether: EtOAc = 1:1) to give benzyl 4-(2-chloro-5-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylate (20 mg, 0.04 mmol) as white solid.

[0487] LCMS: m / z (M+H)+= 463.2.

[0488]

[0489] Step B: 4-(2-chloro-5-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylic acid

[0490] To a solution of benzyl 4-(2-chloro-5-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl) pyridine-3-carboxylate (20 mg, 0.04 mmol) in MeOH (5 mL) and H2O (3 mL) was added LiOH (2.18 mg, 0.05 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h to give a yellow solution. Upon completion, the mixture was adjusted pH<4 with 2 M HCl and extracted with EtOAc (15 mL*2), the organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(2-chloro-5-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylic acid (14 mg, 0.03 mmol) as white solid.

[0491] LCMS: m / z (M+H)+= 373.1.

[0492]

[0493] Step C: 2'-chloro-5'-methoxy-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide

[0494] To a solution of 4-(2-chloro-5-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylic acid (14 mg, 0.04 mmol) and 5-(tetrahydro-3-furylsulfanyl)-1,3,4-thiadiazol-2-amine (7.63 mg, 0.04 mmol) in DMF (2 mL) were added TCFH (15.81 mg, 0.06 mmol) and 1-methylimidazole (9.25 mg, 0.11 mmol) at 25 °C, the mixture was stirred at 25 °C for 2 h to give a yellow solution. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (TFA / acetonitrile / water) to give 2'-chloro-5'-methoxy-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide (0.82 mg) as white solid.

[0495] LCMS: m / z (M+H)+= 558.2.

[0496]

[0497] Example 24: Synthesis of Compound 24

[0498]

[0499] Step A: methyl 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1-yl)pyridine-3-carboxylate

[0500] To a solution of methyl 6-chloro-4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)pyridine-3-carboxylate (100 mg, 0.29 mmol) in Toluene (3.0 mL) were added 2,5-diazahexane (0.01 mL, 0.06 mmol), 4-(trifluoromethyl)-1,2-dihydropyridin-2-one (47.04 mg, 0.29 mmol), CuI (10.99 mg, 0.06 mmol) and K3PO4(183.67 mg, 0.87 mmol) at 25 °C under N2, the mixture was stirred at 120 °C under N2for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 100:1 to 2:1) to give methyl 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1-yl)pyridine-3-carboxylate (30 mg, 0.06 mmol) as white solid.

[0501] LCMS: m / z (M+H)+= 474.0.

[0502]

[0503] Step B: 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1-yl)pyridine-3-carboxylic acid

[0504] To a solution of methyl 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1-yl)pyridine-3-carboxylate (15 mg, 0.03 mmol) in H2O (0.7 mL) and MeOH (2 mL) was added LiOH (3.99 mg, 0.10 mmol) at 25 °C, the mixture was stirred at 25 °C for 3 h. Upon completion, the mixture was adjusted pH<4 with 2 M HCl and extracted with EtOAc (10mL*2), the organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1-yl)pyridine-3-carboxylic acid (10 mg, 0.02 mmol) as white solid.

[0505] LCMS: m / z (M+H)+= 460.0.

[0506]

[0507] Step C: 5'-methoxy-6-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide

[0508] To a solution of 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl) pyridin-1-yl)pyridine-3-carboxylic acid (10 mg, 0.02 mmol) in DMF (2.0 mL) were added 5-(tetrahydro-3-furylsulfanyl)-1,3,4-thiadiazol-2-amine (4.43 mg, 0.02 mmol), TCFH (12.19 mg, 0.04 mmol) and NMI (8.93 mg, 0.11 mmol) at 25 °C, the mixture was stirred at 25 °C for 18 h. Upon completion, the mixture was concentrated under reduced pressure, the residue was purified by pre-HPLC (FA condition) to give 5'-methoxy-6-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide (1.0 mg, 0.0015 mmol).

[0509] 1H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H), 8.38 (s, 1H), 8.18 (d, J = 7.5 Hz, 1H), 7.99 (s, 1H), 7.83 (s, 1H), 6.88 (s, 1H), 6.60 (d, J = 7.4 Hz, 1H), 4.16 (s, 1H), 4.08 (dd, J = 9.6, 6.3 Hz, 1H), 3.85 (dd, J = 13.6, 6.1 Hz, 1H), 3.78 - 3.66 (m, 5H), 2.39 (dd, J = 13.5, 6.8 Hz, 1H), 1.88 (dd, J = 17.9, 12.6 Hz, 1H).

[0510] LCMS: m / z (M+H)+= 645.1.

[0511]

[0512] Example 25: Synthesis of Compound 25

[0513]

[0514] Step A: methyl 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylate

[0515] To a solution of methyl 6-chloro-4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)pyridine-3-carboxylate (100 mg, 0.29 mmol) in Tol (5 mL) were added CuI (10.99 mg, 0.06 mmol), 2,5-diazahexane (25.43 mg, 0.29 mmol), 5-methyl-3H,2H-1,2-diazin-3-one (63.53 mg, 0.58 mmol), and K3PO4(122.45 mg, 0.58 mmol) at 25 °C, the reaction was degassed N2three times and stirred at 120 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 100:1 to 1:1) to give methyl 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylate (30 mg, 0.06 mmol) as a white solid.

[0516] LCMS: m / z (M+H) + = 421.2.

[0517]

[0518] Step B: 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl) pyridine-3-carboxylic acid

[0519] To a solution of methyl 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylate (30 mg, 0.07 mmol) in MeOH (1 mL) and Water (0.2 mL) was added LiOH (5.99 mg, 0.14 mmol) at 25 °C, the reaction was stirred at 25 °C for 16 h. Upon completion, the mixture was adjusted pH<4 with 2 M HCl and extracted with EtOAc (10mL*2), the organic layers were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylic acid (20 mg, 0.03 mmol) as white solid.

[0520] LCMS: m / z (M+H)+= 407.0.

[0521]

[0522] Step C: 5'-methoxy-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide

[0523] To a solution of 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylic acid (10 mg, 0.02 mmol) in DCM (2 mL) were added 5-(tetrahydro-3-furylsulfanyl)-1,3,4-thiadiazol-2-amine (5.50 mg, 0.03 mmol), DMAP (4.51 mg, 0.04 mmol) and EDCI (7.08 mg, 0.04 mmol) at 25 °C, the reaction was stirred at 25 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA condition) to give 5'-methoxy-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide (0.4 mg) as a white solid.

[0524] LCMS: m / z (M+H)+= 592.2.

[0525]

[0526] Example 26: Synthesis of Compound 26

[0527]

[0528] Step A: 5-(3,4,5,6-tetrahydro-2H-pyran-4-ylsulfanyl)-1,3,4-thiadiazol-2-amine

[0529] To a solution of 4-bromotetrahydropyran (20 mg, 0.12 mmol) and 5-amino-1,3,4-thiadiazole-2-thiol (16.14 mg, 0.12 mmol) in MeOH (3 mL) was added sodium methanolate (12.96 mg, 0.24 mmol) at 25 °C, the mixture was stirred at 80 °C for 18 h to give a yellow solution. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (Pure EtOAc) to give 5-(3,4,5,6-tetrahydro-2H-pyran-4-ylsulfanyl)-1,3,4-thiadiazol-2-amine (28.07 mg, 0.13 mmol) as white solid.

[0530] LCMS: m / z (M+H)+= 218.0.

[0531]

[0532] Step B: 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydro-2H-pyran-4-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide

[0533] To a solution of 4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (30 mg, 0.11 mmol) and 5-(3,4,5,6-tetrahydro-2H-pyran-4-ylsulfanyl)-1,3,4-thiadiazol-2-amine (28.07 mg, 0.13 mmol) in DMF (2 mL) were added TCFH (45.31 mg, 0.16 mmol) and 1-methylimidazole (26.52 mg, 0.32 mmol) at 25 °C, the mixture was stirred at 25 °C for 2 h to give a yellow solution. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by high performance liquid phase (TFA / acetonitrile / water) to give 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydro-2H-pyran-4-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide (15.97 mg, 0.03 mmol) as white solid.

[0534] 1H NMR (400 MHz, CDCl3) δ 9.11 (s, 1H), 8.06 (s, 1H), 7.25 (d, J = 2.8 Hz, 2H), 3.98 (m, 2H), 3.90 (s, 1H), 3.73 (s, 3H), 3.54 (m, 2H), 2.75 (s, 3H), 2.14 - 2.06 (m, 2H), 1.88 - 1.74 (m, 2H).

[0535] LCMS: m / z (M+H)+= 478.3.

[0536]

[0537] Example 27: Synthesis of Compound 27

[0538]

[0539] Step A: 2-methylpropan-2-yl 4-((5-amino-1,3,4-thiadiazol-2-yl)sulfanyl)hexahydropyridine-1-carboxylate

[0540] To a solution of 2-methylpropan-2-yl 4-bromohexahydropyridine-1-carboxylate (20 mg, 0.08 mmol) in MeCN (2 mL) were added TEA (0.02 mL, 0.12 mmol) and 5-amino-1,3,4-thiadiazole-2-thiol (5.04 mg, 0.04 mmol) at 25 °C, the mixture was stirred at 80 °C 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 2-methylpropan-2-yl 4-((5-amino-1,3,4-thiadiazol-2-yl)sulfanyl)hexahydropyridine-1-carboxylate (9 mg, 0.03 mmol) as yellow solid.

[0541] LCMS: m / z (M+H-56)+= 261.0.

[0542]

[0543] Step B: 2-methylpropan-2-yl 4-((5-(((4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridin-3-yl)carbonyl)amino)-1,3,4-thiadiazol-2-yl)sulfanyl)hexahydropyridine-1-carboxylate

[0544] To a solution of 2-methylpropan-2-yl 4-((5-amino-1,3,4-thiadiazol-2-yl)sulfanyl)hexahydropyridine-1-carboxylate (9.00 mg, 0.03 mmol) in DCM (2 mL) were added DMAP (11.58 mg, 0.09 mmol), EDCI (18.17 mg, 0.09 mmol) and 4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (17.61 mg, 0.06 mmol) at 25 °C, the mixture was stirred at 25 °C for 16 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (Pet.ether: EtOAc = 100:1 to 2:1) to give 2-methylpropan-2-yl 4-((5-(((4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridin-3-yl)carbonyl)amino)-1,3,4-thiadiazol-2-yl)sulfanyl)hexahydropyridine-1-carboxylate (20 mg, 0.03 mmol) as yellow solid.

[0545] LCMS: m / z (M+H)+= 577.3.

[0546]

[0547] Step C: 2'-chloro-5'-methoxy-6-methyl-N-(5-(piperidin-4-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide

[0548] To a solution of 2-methylpropan-2-yl 4-((5-(((4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridin-3-yl)carbonyl)amino)-1,3,4-thiadiazol-2-yl)sulfanyl)hexahydropyridine-1-carboxylate (20 mg, 0.06 mmol) in DCM (5 mL) was added the TFA (1.5 mL, 19.60 mmol) at 25 °C, the mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by high performance liquid phase (TFA / acetonitrile / water) to give 2'-chloro-5'-methoxy-6-methyl-N-(5-(piperidin-4-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide (1.2 mg) as a white solid.

[0549] LCMS: m / z (M+H)+= 477.2.

[0550] 1H NMR (400 MHz, CD3OD) δ 8.86 (s, 1H), 8.06 (s, 1H), 7.48 (s, 1H), 7.40 (s, 1H), 3.82 (s, 1H), 3.70 (s, 3H), 3.47 - 3.37 (m, 2H), 3.21 - 3.04 (m, 2H), 2.67 (s, 3H), 2.34 (m, 2H), 1.92 (m, 2H).

[0551]

[0552] Experimental Example 1: Inhibitory activity against Polθ

[0553] An ADP-GLO assay was used to measure the ability of compounds to inhibit the activity of Ροlθ-Helicase in vitro. A Recombinant Polθ-Helicase domain (aa 1-987) was purchased from SignalChem Biotech (Catalog No. D681-31G) and stored at -80 ºC in aliquots, Single stranded DNA was produced by Genscrip (30mer ssDNA (CT)15). Reactions were performed at room temperature, in freshly prepared assay buffer (25 mM Tris-HCl pH 7.5, 6 mM NaCl, 1.5 mM MgCl2, 5% (v / v) glycerol, 0.01% v / v Triton x-100, 0.01% (w / v) Bovine γ-Globulin, 1 mM dithiothreitol). The compounds were dispensed on a 384-well plate (PerkinElmer# 6007290) using a Labcyte Echo 655 at varying concentrations (10 point, 1:3 dilution), 2 μL of 2 X helicase domain Polθ and DNA mix (3 nM helicase domain Polθ and 2 nM DNA in assay buffer) was added to plates that had been pre-dispensed with compound. The plates were covered and left to incubate for 30 minutes at room temperature. then 2 μL of 2 X substrate mix (80 μM ATP in assay buffer) was added to the plates to start the enzyme reaction. The plates were covered and left to incubate for 1 hour at room temperature before the addition of the ADP-Glo™ Reagent. 4 μL ADP-Glo™ Reagent containing 10mM MgCl2was added, and plates incubated for 40 minutes. 8 μL kinase detection reagent was then added to the plates and incubated for 40 minutes. The luminescence was read on a 2105-0020 EnVision Multilabel Reader and raw data analyzed using log(inhibitor) vs. response - variable slope (four parameters) to generate IC50values. The results are shown in Table 1 below.

[0554]

[0555] Polθ / IC50(nM)Compound 10.27Compound 23.74Compound 34.37Compound 43.02Compound 527.75Compound 61.41Compound 738.71Compound 844.97Compound 939.75Compound 1015.05Compound 112.31Compound 123.90Compound 137.35Compound 1428.88Compound 1518.23Compound 16106.8Compound 1713.67Compound 184.54Compound 199.89Compound 2061.36Compound 219.4Compound 2218.93Compound 2349.62Compound 2476.49Compound 2558.06Compound 2624.88Compound 27382.1

[0556]

[0557] Experimental Example 2: Metabolic Stability in Human Liver Microsomes

[0558] Preheat 100 mM K-Mg-buffer with 5 mM MgCl2pH 7.40. 0.5 mM spiking solution: Add 5 μL of 10 mM stock solution of compound and reference into 95 μL of acetonitrile (ACN). HLM: 1.5 μM spiking solution in microsomes (0.5 mg / mL): add 1.5 μL of 500 μM spiking solution and 18.75 μL of 20 mg / mL liver microsomes into 479.75 μL of K / Mg-Buffer. NADPH stock solution (6 mM) is prepared by dissolving NADPH into K-Mg-buffer. Dispense 30 μL of 1.5 μM spiking solution containing microsomes solution to the assay plates designated for different time points (0, 5, 15, 30 and 45 min). Pre-incubate other plates at 37 °C for 5 minutes. For 0-min, add 200 μL of ACN containing IS to the wells before adding 15 μL of NADPH stock solution (6 mM). For other time points, add 15 μL of NADPH stock solution (6 mM) to the wells to start the reaction and timing. At 5, 15, 30 and 45 min add 200 μL of ACN containing IS to the wells of corresponding plates, respectively, to stop the reaction. After quenching, shake the plates for 10 min (600 rpm) and then centrifuge at 4000 rmp for 50 min. Transfer 80 μL of the supernatant from each well into a 96-well sample plate containing 160 μL of pure water for UPLC / MS / MS analysis. The results are shown in Table 2 below. Further, for comparison, the following compound A from WO 2022 / 118210 (Example 8) was used as comparative example. As shown Table 2, S-containing compounds 7, 13 and 14 showed improved metabolic stability than compound A.

[0559]

[0560] T1 / 2(minute)Clint, in vitro (mL / min / mg)Clint(mL / min / kg)Clh(mL / min / kg)Eh(%)Example 786.000.0220.2110.2349.41Example 13110.16<0.0215.788.9543.26Example 14>145<0.02<0.02<0.02<0.02Compound A26.330.0566.0215.7676.13

[0561]

Claims

1.A compound represented by Chemical Formula 1 below, or a pharmaceutically acceptable salt thereof:[Chemical Formula 1]in Chemical Formula 1,A is a trivalent linker of C2-10heterocyclic ring containing one to three heteroatoms selected from N, O, or S,L1is a bond; C1-4alkylene; C2-4alkenylene; C2-4alkynylene; -S-; or -O-,R1is hydrogen; C1-4alkyl; -CONH2; -CONH(C1-4alkyl); -CON(C1-4alkyl)2; C3-6cycloalkyl; C2-10heterocycloalkyl containing one to three heteroatoms selected from N, O, or S, which is unsubstituted or substituted by C1-4alkyl, or C1-4haloalkyl; or C2-10heteroaryl containing one to three heteroatoms selected from N, O, or S, which is unsubstituted or substituted by C1-4alkyl, or C1-4haloalkyl,B is a trivalent linker of C6-10aromatic ring; C2-10heterocycloalkane ring containing one to three heteroatoms selected from N, O, or S; or C2-10heteroaromatic ring containing one to three heteroatoms selected from N, O, or S,R2and R3are each independently, hydrogen; C1-4alkyl; C2-4alkenyl; C2-4alkynyl; C1-4haloalkyl; C1-4alkoxy; halogen; cyano; or C2-6heterocycloalkyloxy containing one oxygen; or R2and R3when on adjacent ring vertices, combine to form a C2-6heterocycloalkyl containing one to three heteroatoms selected from N, O, or S ; or C2-6heteroaryl containing one to three heteroatoms selected from N, O, or S,X is N; or CR’,R’ is hydrogen; or halogen,Y is -S-; -S(=O)-; or -S(=O)2-,L2is a bond; C1-4alkylene, which is unsubstituted or substituted at least one deuterium; or C3-6cycloalkylene,R4is C6-10aryl; C2-10heteroaryl containing one to three heteroatoms selected from N, O, or S; C3-6cycloalkyl; C2-6heterocycloalkyl containing one oxygen; C6-10spiro-heterocycloalkyl containing one oxygen; C7-10bicycloalkyl; or C7-10biheterocycloalkyl containing one or two oxygen;R4is unsubstituted or substituted by one or two substituents independently selected from the group consisting of C1-4alkyl; C1-4haloalkyl; hydroxy; C1-4hydroxyalkyl; and halogen.2.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinA is a trivalent linker of 1,3-benzodioxole; 2,3-dihydrobenzofuran; 2-pyridone; imidazo[1,5-a]pyridine; imidazole; pyridazine; or pyridine.3.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinL1is a bond; -CH2-; -C≡C-; or -O-.4.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinR1is hydrogen; CH3; -CONH2; -CONH(CH3); -CON(CH3)2; cyclopropyl; cyclobutyl unsubstituted or substituted by one or two fluoro; or any ring selected from the group consisting of 8-oxo-4,7-diazaspiro[2.5]octan-8-onyl, 7-azaspiro[3.5]nonan-6-onyl, 2-pyridonyl, oxadiazolyl, oxopyridazinyl, pyrazolyl, or thiazolyl, which ring is unsubstituted or substituted by CH3, or CF3.5.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinB is a trivalent linker of 1,3-benzodioxole; 2-oxa-5-azabicyclo[4.1.0]heptane; 3,4-dihydro-2H-benzo[b][1,4]oxazine; 3-oxa-8-azabicyclo[3.2.1]octane; 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine; 4-oxa-7-azaspiro[2.5]octane; benzene; benzo[d]oxazole; benzo[d]thiazole; morpholine; piperazin-2-one; pyrazole; or pyridine.6.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinR2and R3are each independently, hydrogen; CH3; CHF2; CF3; OCH3; F; Cl; cyano; or (oxetanyl)oxy.7.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinX is N; CH; or CF.8.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinL2is a bond; -CH2-; -CD2-; -CH(CH3)-; -C(CH3)2-; or cyclopropylene.9.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinR4is 2-oxaspiro[3.3]heptanyl; 4-oxaspiro[2.4]heptanyl; 6-oxaspiro[3.4]octanyl; bicyclo[2.2.1]heptanyl; cyclopropyl; cyclobutyl; cyclohexyl; hexahydrofuro[2,3-b]furanyl; phenyl; piperidinyl; pyridinyl; tetrahydrofuranyl; or tetrahydropyranyl,the R4is unsubstituted or substituted by one or two substituents independently selected from the group consisting of CH3, hydroxy; CH2OH; fluoro; and chloro.10.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,X is N, or CH,A is a trivalent linker of 2-pyridone; or pyridine,L1is a bond; C1-4alkylene; or C2-4alkynylene,R1is C1-4alkyl; -CON(C1-4alkyl)2; C3-6cycloalkyl; C2-10heterocycloalkyl containing one to three heteroatoms selected from N, O, or S, which is unsubstituted or substituted by C1-4alkyl, or C1-4haloalkyl; or C2-10heteroaryl containing one to three heteroatoms selected from N, O, or S, which is unsubstituted or substituted by C1-4alkyl, or C1-4haloalkyl,R2is C1-4alkoxy,R3is C1-4haloalkyl; or halogen,Y is -S-; -S(=O)-; or -S(=O)2-,L2is a bond; or C1-4alkylene, which is unsubstituted or substituted by at least one deuterium,R4is C6-10aryl; C2-10heteroaryl containing one to three heteroatoms selected from N, O, or S; or C2-6heterocycloalkyl containing one oxygen;R4is unsubstituted or substituted by halogen.11.The compound or a pharmaceutically acceptable salt thereof according to claim 1, whereinthe compound represented by Chemical Formula 1 is any one selected from the group consisting of the following:1) 2'-chloro-N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,2) N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-5-(5-(difluoromethyl)-2-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide,3) 2'-chloro-N-(5-((5-chloropyridin-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,4) 5-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide,5) 2'-chloro-N-(5-((5-chloropyridin-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]octan-7-yl)-4,4'-bipyridine-3-carboxamide,6) 5-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-1-(2-(dimethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-4-carboxamide,7) 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,8) N-(5-((5-chloropyridin-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-5-(5-(difluoromethyl)-2-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide,9) 2'-chloro-N-(5-(4-chlorobenzylsulfinyl)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,10) 2'-chloro-N-(5-(4-chlorobenzylsulfonyl)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,11) 4-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(((5-chloropyridin-2-yl)dideuteriomethyl)sulfanyl)-1,3,4-thiadiazol-2-yl)-6-methylpyridine-3-carboxamide,12) 2'-chloro-N-(5-(1-(5-chloropyridin-2-yl)ethylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,13) 5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide,14) 2'-(difluoromethyl)-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,15) 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,16) 2'-chloro-N-(5-(5-chloropyridin-2-ylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,17) 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,18) 6-(cyclopropylethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,19) 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,20) 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,21) 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,22) 2'-chloro-5'-methoxy-6-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,23) 2'-chloro-5'-methoxy-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,24) 5'-methoxy-6-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide,25) 5'-methoxy-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide,26) 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydro-2H-pyran-4-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,27) 2'-chloro-5'-methoxy-6-methyl-N-(5-(piperidin-4-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,28) 2'-chloro-N-(5-(cyclopropylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,29) 2'-chloro-N-(5-(4-hydroxycyclohexylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,30) 2'-chloro-N-(5-(5-hydroxybicyclo[2.2.1]heptan-2-ylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,31) 2'-chloro-N-(5-((3R,3aR,6aR)-hexahydrofuro[2,3-b]furan-3-ylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,32) 2'-chloro-N-(5-(4-chlorophenylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,33) 2'-chloro-N-(5-(2-(5-chloropyridin-2-yl)propan-2-ylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,34) 2'-chloro-5'-methoxy-6-methyl-N-(5-(1-(tetrahydrofuran-3-yl)ethylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,35) 2'-chloro-N-(5-(4-(hydroxymethyl)cyclohexylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,36) N-(5-(6-oxaspiro[3.4]octan-1-ylthio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,37) 2'-chloro-5'-methoxy-6-methyl-N-(5-(1-(tetrahydrofuran-3-yl)cyclopropylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,38) N-(5-(2-oxaspiro[3.3]heptan-6-ylthio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,39) 2'-chloro-N-(5-(3-hydroxy-3-methylcyclobutylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,40) 2'-chloro-N-(5-(5,5-dimethyltetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,41) 2'-chloro-N-(5-(4,4-difluorotetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,42) 2'-chloro-N-(5-(3-hydroxycyclopentylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,43) N-(5-(4-oxaspiro[2.4]heptan-6-ylthio)-1,3,4-thiadiazol-2-yl)-2'-chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,44) 5-(5-(difluoromethyl)-2-methoxyphenyl)-1-(2-(dimethylamino)-2-oxoethyl)-2-oxo-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-1,2-dihydropyridine-4-carboxamide,45) 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(6-oxo-7-azaspiro[3.5]nonan-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,46) 4-(5-(difluoromethyl)-2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-6-(thiazol-2-yloxy)nicotinamide,47) 6-((3,3-difluorocyclobutyl)ethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,48) 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,49) N-(5-((5-chloropyridin-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]octan-7-yl)-4-morpholinonicotinamide,50) 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]octan-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,51) 5-(5-(difluoromethyl)-2-methoxyphenyl)-1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-2-oxo-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-1,2-dihydropyridine-4-carboxamide,52) 5-(5-(difluoromethyl)-2-methoxyphenyl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-1,2-dihydropyridine-4-carboxamide,53) 5-(5-(difluoromethyl)-2-methoxyphenyl)-1-methyl-2-oxo-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-1,2-dihydropyridine-4-carboxamide,54) 5-(2-(difluoromethyl)-5-methoxypyridin-4-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2,3-dihydrobenzofuran-6-carboxamide,55) 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)thiazol-2-yl)-4,4'-bipyridine-3-carboxamide,56) 2'-chloro-N-(4-fluoro-5-(tetrahydrofuran-3-ylthio)thiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,57) 6-methyl-4-morpholino-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,58) 6-methyl-4-morpholino-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,59) 4-(benzo[d]oxazol-7-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,60) 4-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,61) 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,62) 6-methyl-4-(2-(oxetan-3-yloxy)phenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,63) 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,64) 4-(3,5-dimethyl-1H-pyrazol-4-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,65) 4-(6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,66) 1-(2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-1H-imidazole-5-carboxamide,67) 7-(2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-carboxamide,68) 6-methyl-4-(4-oxa-7-azaspiro[2.5]octan-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,69) 6-methyl-4-(2-methyl-3-oxopiperazin-1-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,70) 4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,71) 4-(2-oxa-5-azabicyclo[4.1.0]heptan-5-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,72) 4-(5-ethynyl-2-methoxyphenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,73) 4-(benzo[d]thiazol-7-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,74) 5-(benzo[d]thiazol-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)pyridazine-4-carboxamide,75) 5-(benzo[d]thiazol-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2,3-dihydrobenzofuran-6-carboxamide, and76) 6-(benzo[d]thiazol-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)benzo[d][1,3]dioxole-5-carboxamide.12.A pharmaceutical composition for the prevention or treatment of cancer, comprising the compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.