Novel heterocyclic compound for preventing or treating cancer and pharmaceutical composition comprising same as DNA polymerase theta inhibitor

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 effectively used in the prevention or treatment of cancer. [Chemical Formula 1] # imgabs0 # In Chemical Formula 1, A, B, X, Y, L1, L2, and R1 to R4 are as defined in the specification.

Description

Technical Field

[0001] The present disclosure relates to a novel heterocyclic compound that can be used as an inhibitor of Polθ (DNA polymerase θ, Polθ) and a pharmaceutical composition comprising the novel heterocyclic compound. Background Art

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

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

[0004] Polθ is distinct among human DNA polymerases, exhibiting not only a C-terminal DNA polymerase domain but also an N-terminal helicase domain. Many genetic studies have highlighted the role of polymerase θ (Polθ) in stimulating MMEJ in higher organisms. Studies have shown that cancer cells lacking HR, NHEJ, or ATM (ataxia telangiectasia mutated; A-T mutated) are highly dependent on the expression of Polθ. The expression of Polθ is essentially absent in normal cells but is upregulated in breast, lung, and ovarian cancers. Additionally, an increase in Polθ expression is associated with poor prognosis in breast cancer. Importantly, Polθ is highly repressed in normal tissues but is shown to be upregulated in matched cancer samples, thus correlating elevated expression with the disease. Its repression or inhibition renders tumor cells radiosensitive. It is conceivable that Polθ inhibition can prevent the reversal of MMEJ-dependent functions of BRCA2 mutations, which are the basis for the emergence of cisplatin and PARPi (PARP inhibitor) resistance in tumors. Therefore, in cancers with DNA repair defects, Polθ is an attractive target for novel synthetic lethal therapies, and there is a need to provide effective Polθ inhibitors for treating cancer.

[0005] In view of the above, as a result of studying novel compounds, the present inventors have found that compounds having a chemical structure different from that of Polθ inhibitors reported to date have excellent Polθ inhibitory effects, thereby completing the present disclosure. The compounds belonging to the present disclosure mainly have Polθ inhibitory activity by themselves, but the possibility that they exhibit pharmacological effects as active agents through products of a special body environment or metabolic processes after being absorbed into the body cannot be excluded. Summary of the Invention

[0006] [Technical Problem]

[0007] An object of the present disclosure is to provide a novel heterocyclic compound usable as a Polθ (Polθ) inhibitor and a pharmaceutical composition including the novel heterocyclic compound.

[0008] [Technical Solution]

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

[0010] [Chemical Formula 1]

[0011]

[0012] In Chemical Formula 1,

[0013] A is a trivalent linker of a C heterocycle containing one to three heteroatoms selected from N, O, or S, 2-10

[0014] L1 is a bond; C 1-4 alkylene; C 2-4 alkenylene; C 2-4 alkynylene; -S-; or -O-,

[0015] R1 is hydrogen; C 1-4 alkyl; -CONH2; -CONH(C 1-4 alkyl); -CON(C 1-4 alkyl)2; C 3-6 cycloalkyl; a C heterocycloalkyl containing one to three heteroatoms selected from N, O, or S, which is unsubstituted or substituted with C 2-10 alkyl or C 1-4 haloalkyl; or a C heteroaryl containing one to three heteroatoms selected from N, O, or S, which is unsubstituted or substituted with C 1-4 alkyl or C 2-10 haloalkyl, 1-4 1-4 6-10

[0016]

[0016] B is a C aryl ring; a C heterocycle containing one to three heteroatoms selected from N, O, or S,​​​2-10 a heterocycloalkane ring; or a trivalent linker of a C arylheterocycle containing one to three heteroatoms selected from N, O or S 2-10

[0017] R2 and R3 are each independently hydrogen; C 1-4 alkyl; C 2-4 alkenyl; C 2-4 alkynyl; C 1-4 haloalkyl; C 1-4 alkoxy; halogen; cyano; or a C containing one oxygen 2-6 heterocycloalkoxy; or R2 and R3, when on adjacent ring vertices, combine to form a C heterocycloalkyl containing one to three heteroatoms selected from N, O or S 2-6 heterocycloalkyl; or a C heterocycloalkyl containing one to three heteroatoms selected from N, O or S 2-6 heteroaryl,

[0018] X is N; or CR’,

[0019] R’ is hydrogen; or halogen,

[0020] Y is -S-; -S(=O)-; or -S(=O)2-,

[0021] L2 is a bond; C 1-4 alkylene, which is unsubstituted or substituted with at least one deuterium; or C 3-6 cycloalkylene,

[0022] R4 is C 6-10 aryl; a C heterocycloalkyl containing one to three heteroatoms selected from N, O or S 2-10 heteroaryl; C 3-6 cycloalkyl; a C containing one oxygen 2-6 heterocycloalkyl; a C containing one oxygen 6-10 spiroheterocycloalkyl; C 7-10 bicycloalkyl; or a C containing one or two oxygens 7-10 bicycloheteroalkyl;

[0023] R4 is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of C 1-4 alkyl; C 1-4 haloalkyl; hydroxy; C 1-4 hydroxyalkyl; and halogen.

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

[0025] Further, to achieve the above object, there is provided a pharmaceutical composition for preventing or treating cancer, comprising the compound or a pharmaceutically acceptable salt thereof.​

[0026] [Advantageous effects]

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

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

[0029] Meanwhile, the present disclosure provides a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0030] Preferably, A is a trivalent linker of 1,3-benzodioxole; 2,3-dihydrobenzofuran; 2-pyridone; imidazo[1,5-a]pyridine; imidazole; pyridazine; or pyridine.

[0031] Preferably, L1 is a bond; -CH2-; -C≡C-; or -O-.

[0032] Preferably, R1 is hydrogen; CH3; -CONH2; -CONH(CH3); -CON(CH3)2; cyclopropyl; unsubstituted or monosubstituted or disubstituted with fluorine cyclobutyl; or any ring selected from the group consisting of 8-oxo-4,7-diazaspiro[2.5]oct-8-yl, 7-azaspiro[..]]

[0033] 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.

[0034] Preferably, each of R2 and R3 is independently hydrogen; CH3; CHF2; CF3; OCH3; F; Cl; cyano; or (oxetanyloxy).

[0035] Preferably, X is N; CH; or CF.

[0036] Preferably, L2 is a bond; -CH2-; -CD2-; -CH(CH3)-; -C(CH3)2-; or cyclopropene.

[0037] Preferably, R4 is 2-oxaspiro[3.3]heptyl; 4-oxaspiro[2.4]heptyl; 6-oxaspiro[3.4]octyl; bicyclo[2.2.1]heptyl; cyclopropyl; cyclobutyl; cyclohexyl; hexahydrofuro[2,3-b]furan; phenyl; piperidinyl; pyridinyl; tetrahydrofuran; or tetrahydropyranyl, and R4 is unsubstituted or substituted with one or two substituents each independently selected from the group consisting of CH3, hydroxy; CH2OH; fluoro; and chloro.

[0038] Preferably, Formula 1 is represented by the following Formula 2:

[0039] [Formula 2]

[0040]

[0041] In Formula 2,

[0042] X is N or CH,

[0043] A is 2-pyridone; or a trivalent linker of pyridine,

[0044] L1 is a bond; C 1-4 alkylene; or C 2-4 alkynylene,

[0045] R1 is C 1-4 alkyl; -CON(C 1-4 alkyl)2; C 3-6 cycloalkyl; C 2-10 heterocycloalkyl containing one to three heteroatoms selected from N, O or S, which is unsubstituted or substituted with C 1-4 alkyl or C 1-4 haloalkyl; or C 2-10 heteroaryl containing one to three heteroatoms selected from N, O or S, which is unsubstituted or substituted with C 1-4 alkyl or C 1-4 haloalkyl,

[0046] R2 is C 1-4 alkoxy,

[0047] R3 is C 1-4 haloalkyl; or halogen,

[0048] Y is -S-; -S(=O)-; or -S(=O)2-,

[0049] L2 is a bond; or C 1-4 alkylene, which is unsubstituted or substituted with at least one deuterium,

[0050] R4 is C 6-10Aryl; C having one to three heteroatoms selected from N, O, or S 2-10 Heteroaryl; or C having one oxygen 2-6 Heterocycloalkyl;

[0051] R4 is unsubstituted or substituted by halogen.

[0052] Preferably, in Chemical Formula 2,

[0053] X is N or CH,

[0054] A is 2-pyridone; or a trivalent linker of pyridine,

[0055] L1 is a bond; -CH2-; or -C≡C-,

[0056] R1 is -CH3; 2-pyridyl unsubstituted or substituted by CH3 or CF3; 8-oxo-4,7-diazaspiro[2.5]oct-7-yl unsubstituted or substituted by CH3; -CON(CH3)2; cyclopropyl; oxopyridazinyl unsubstituted or substituted by CH3; or pyrazolyl unsubstituted or substituted by CH3.

[0057] R2 is OCH3,

[0058] R3 is CHF2; CF3; or chlorine,

[0059] Y is -S-; -S(=O)-; or -S(=O)2-,

[0060] L2 is a bond; -CH2-; -CD2-; or -CH(CH3)-,

[0061] R4 is phenyl; piperidinyl; pyridyl; tetrahydrofuranyl; or tetrahydropyranyl,

[0062] R4 is unsubstituted or substituted by chlorine.

[0063] Representative examples of the compound represented by Chemical Formula 1 are as follows:

[0064] 1) 2'-Chloro-N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0065] 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,

[0066] 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,

[0067] 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,

[0068] 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]oct-7-yl)-4,4'-bipyridine-3-carboxamide,

[0069] 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,

[0070] 7) 2'-Chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,

[0071] 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,

[0072] 9) 2'-Chloro-N-(5-(4-chlorobenzylsulfinyl)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0073] 10) 2'-Chloro-N-(5-(4-chlorobenzylsulfonyl)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0074] 11) 4-(2-Chloro-5-methoxypyridin-4-yl)-N-(5-(((5-chloropyridin-2-yl)dideuteriomethyl)thioalkyl)-1,3,4-thiadiazol-2-yl)-6-methylpyridine-3-carboxamide,

[0075] 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,

[0076] 13) 5'-Methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide,

[0077] 14) 2'-(Difluoromethyl)-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,

[0078] 15) 4-(5-(Difluoromethyl)-2-methoxyphenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0079] 16) 2'-Chloro-N-(5-(5-chloropyridin-2-ylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0080] 17) 4-(2-Methoxy-5-(trifluoromethyl)phenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0081] 18) 6-(Cyclopropyl ethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0082] 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,

[0083] 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,

[0084] 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,

[0085] 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,

[0086] 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,

[0087] 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,

[0088] 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,

[0089] 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,

[0090] 27) 2'-Chloro-5'-methoxy-6-methyl-N-(5-(piperidin-4-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide,

[0091] 28) 2'-Chloro-N-(5-(cyclopropylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0092] 29) 2'-Chloro-N-(5-(4-hydroxycyclohexylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0093] 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,

[0094] 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,

[0095] 32) 2'-Chloro-N-(5-(4-chlorophenylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0096] 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,

[0097] 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,

[0098] 35) 2'-Chloro-N-(5-(4-hydroxymethyl)cyclohexylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0099] 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,

[0100] 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,

[0101] 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,

[0102] 39) 2'-Chloro-N-(5-(3-hydroxy-3-methylcyclobutylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0103] 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,

[0104] 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,

[0105] 42) 2'-Chloro-N-(5-(3-hydroxycyclopentylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0106] 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,

[0107] 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,

[0108] 45) 4-(5-(Difluoromethyl)-2-methoxyphenyl)-6-(6-oxo-7-azaspiro[3.5]non-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0109] 46) 4-(5-(Difluoromethyl)-2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-6-(thiazol-2-yloxy)nicotinamide,

[0110] 47) 6-((3,3-Difluorocyclobutyl)ethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0111] 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,

[0112] 49) N-(5-((5-Chloropyridin-2-yl)methylthio)-1,3,4-thiadiazol-2-yl)-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]oct-7-yl)-4-morpholinonicotinamide,

[0113] 50) 4-(5-(Difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]oct-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0114] 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,

[0115] 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,

[0116] 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,

[0117] 54) 5-(2-(Difluoromethyl)-5-methoxypyridin-4-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2,3-dihydrobenzofuran-6-carboxamide,

[0118] 55) 2'-Chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)thiazol-2-yl)-4,4'-bipyridine-3-carboxamide,

[0119] 56) 2'-Chloro-N-(4-fluoro-5-(tetrahydrofuran-3-ylthio)thiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0120] 57) 6-Methyl-4-morpholinyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0121] 58) 6-Methyl-4-morpholinyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0122] 59) 4-(Benzo[d]oxazol-7-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0123] 60) 4-(2,2-difluorobenzo[d][1,3]dicyclopentadien-4-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0124] 61) 4-(5-cyano-2-methoxyphenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0125] 62) 6-methyl-4-(oxetan-3-yloxy)phenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0126] 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,

[0127] 64) 4-(3,5-dimethyl-1H-pyrazol-4-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0128] 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,

[0129] 66) 1-(2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-1H-imidazole-5-carboxamide,

[0130] 67) 7-(2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)imidazo[1,5-a]pyridine-6-carboxamide,

[0131] 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,

[0132] 69) 6-methyl-4-(2-methyl-3-oxopiperazin-1-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0133] 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,

[0134] 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,

[0135] 72) 4-(5-Ethynyl-2-methoxyphenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0136] 73) 4-(Benzo[d]thiazol-7-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide,

[0137] 74) 5-(Benzo[d]thiazol-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)pyridazine-4-carboxamide,

[0138] 75) 5-(Benzo[d]thiazol-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2,3-dihydrobenzofuran-6-carboxamide, and

[0139] 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.

[0140] In addition, the compounds of the present disclosure may exist in the form of salts, particularly pharmaceutically acceptable salts. As salts, salts commonly used in the art can be used without limitation, such as acid addition salts formed from pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound represented by Chemical Formula 1, which is relatively non-toxic and harmless to patients at the concentration, and is effectively activated, and the side effects thereof do not reduce the beneficial effects of the above compounds.

[0141] As free acids, organic acids and inorganic acids can be used. Examples of inorganic acids include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. Examples of organic acids include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc., but are not limited thereto. Preferably, the salt may be a hydrochloride.

[0142] Further, pharmaceutically acceptable metal salts can be obtained by conventional methods using bases. For example, the compound represented by Chemical Formula 1 is dissolved in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, the insoluble salts are filtered off, and then the filtrate is evaporated and dried to obtain the pharmaceutically acceptable metal salt. At this time, it is particularly preferred to prepare sodium salts, potassium salts or calcium salts as the metal salts.

[0143] In addition, when preparing the compound of Chemical Formula 1 or a pharmaceutically acceptable salt or solvate thereof, a pharmaceutically unacceptable salt or solvate of the compound of Chemical Formula 1 can be used as an intermediate.

[0144] In one embodiment, the compound represented by Chemical Formula 1 can be prepared by the following Reaction Scheme 1.

[0145] [Reaction Scheme 1]

[0146]

[0147] In Reaction Scheme 1, A, B, X, Y, L1, L2 and R1 to R4 are as defined above.

[0148] This reaction is to prepare the compound represented by Chemical Formula 1 by reacting the compound represented by Chemical Formula 2 with the compound represented by Chemical Formula 3, which is an amidation reaction. The above preparation method will be described more specifically in the examples described below.

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

[0150] According to still another embodiment of the present disclosure, there is provided a pharmaceutical composition for preventing or treating cancer diseases, which is effective for Polθ inhibitory action, comprising the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0151] In this case, the cancer can be blood cancer, extranodal marginal zone B-cell lymphoma, glioblastoma, lymphoplasmacytic lymphoma, acute myeloid leukemia, Waldenström macroglobulinemia, B-cell lymphoma, chronic lymphocytic leukemia, follicular lymphoma, non-Hodgkin lymphoma, diffuse large B-cell lymphoma, hairy cell leukemia, mantle cell lymphoma, glioblastoma, bladder cancer, pancreatic cancer, ovarian cancer, colorectal cancer, renal cancer, gastric cancer, transitional cell carcinoma, carcinoid tumor, breast cancer, non-small cell lung cancer or multiple myeloma.

[0152] As used herein, the term "prevention" refers to any act of delaying or inhibiting the occurrence, spread or recurrence of the above diseases by administering the composition of the present disclosure, while "treatment" refers to any act of improving or ameliorating the symptoms of the above diseases by administering the composition of the present disclosure.

[0153] The pharmaceutical compositions according to the present disclosure can be formulated into types for oral or parenteral administration according to standard pharmaceutical practices. In addition to the active ingredient, these formulations may also contain additives such as pharmaceutically acceptable carriers, adjuvants or diluents.

[0154] Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil, isopropyl myristate, etc. Diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, etc., but are not limited thereto. Further, the compounds of the present disclosure can be dissolved in oils, propylene glycol or other solvents commonly used for preparing injection solutions. In addition, the compounds of the present disclosure can be formulated into ointments or creams for topical administration.

[0155] The preferred dosage of the compounds of the present disclosure can vary depending on the patient's condition and weight, the severity of the disease, the type of drug, as well as the route and duration of administration, but can be appropriately selected by those skilled in the art. However, in order to achieve the desired effect, the compounds of the present disclosure can be administered daily at a dose of 0.0001 to 100 mg / kg (body weight), preferably 0.001 to 100 mg / kg (body weight). The administration can be carried out once a day, or can be carried out in divided doses daily by oral or parenteral routes.

[0156] Depending on the administration method, the pharmaceutical composition may contain from 0.001 to 99% by weight, preferably from 0.01 to 60% by weight of the compounds of the present disclosure.

[0157] The pharmaceutical compositions according to the present disclosure can be administered to mammals such as rats, mice, livestock or humans by various routes. The administration can be carried out by all possible methods, such as oral, rectal, intravenous, intramuscular, subcutaneous, intrauterine, intracerebroventricular injection.

[0158] Hereinafter, 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.

[0159] Example 1: Synthesis of Compound 1

[0160]

[0161] Step A: 5-(((4-chlorophenyl)methyl)thio)-1,3,4-thiadiazol-2-amine

[0162] At 25 °C, potassium tert-butoxide (168.50 mg, 1.50 mmol) and 4-chloro-1-(chloromethyl)benzene (241.80 mg, 1.50 mmol) were added to a solution of 5-amino-1,3,4-thiadiazole-2-thiol (0.13 mL, 1.50 mmol) in THF (2 mL), and the reaction system was stirred at 25 °C under N2 for 30 minutes. After the reaction was completed, the reaction system was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:2) to obtain 5-(((4-chlorophenyl)methyl)thio)-1,3,4-thiadiazol-2-amine (240 mg, 0.88 mmol) as a white solid.

[0163] LCMS: m / z (M+H) + = 258.0.

[0164] Step B: 2'-Chloro-N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide

[0165] At 25 °C, 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) were added to a solution of 5-(((4-chlorophenyl)methyl)thio)-1,3,4-thiadiazol-2-amine (20 mg, 0.08 mmol) in DMF (1 mL), and the reaction system was stirred at 25 °C under N2 for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) to obtain 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.

[0166] 1 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).

[0167] LCMS: m / z (M+H) + = 518.2.

[0168] Example 2: Synthesis of Compound 2

[0169]

[0170] Under N2, 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-dimethylformamide (5.0 mL) were added TCFH (68 mg, 0.24 mmol), 1-methylimidazole (39 mg, 0.48 mmol), and 5-(((5-chloropyridin-2-yl)methyl)thio)-1,3,4-thiadiazol-2-amine (50 mg, 0.19 mmol) for 18 h. The mixture was poured into water (15 mL) and extracted with EtOAc (30 mL * 3). The combined organic phases were washed with brine (50 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to dryness to give the crude product. The crude product was subjected to preparative HPLC ((ACN: water (1‰ FA)) to obtain N-(5-(4-chlorobenzylthio)-1,3,4-thiadiazol-2-yl)-5-(5-(difluoromethyl)-2-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide as a white solid (15.77 mg, 17.74%).

[0171] 1 H 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).

[0172] LCMS: m / z (M + H) + = 549.2.

[0173] Example 3: Synthesis of Compound 3

[0174]

[0175] Step A: 5-(((5-chloropyridin-2-yl)methyl)thio)-1,3,4-thiadiazol-2-amine

[0176] 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) at 25 °C was added 5-chloro-2-(chloromethyl)pyridine (1094.74 mg, 6.76 mmol), NaOH (540.58 mg, 13.51 mmol), and the mixture was stirred at 25 °C for 30 minutes. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 0:1) to give 5-(((5-chloropyridin-2-yl)methyl)thio)-1,3,4-thiadiazol-2-amine as a white solid (1.2 g, 4.41 mmol, 65.2%).

[0177] LCMS: m / z (M+H) + = 259.1.

[0178] 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

[0179] To a solution of 5-(((5-chloropyridin-2-yl)methyl)thio) -1,3,4-thiadiazol-2-amine (50 mg, 0.18 mmol) in DMF (2.0 mL) at 25 °C was 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), and the mixture was stirred at 25 °C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA conditions) 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 as a white solid (10 mg, 0.02 mmol, 9.96%).

[0180] 1 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).

[0181] LCMS: m / z (M+H) + = 519.1.

[0182] Example 4: Synthesis of Compound 4

[0183]

[0184] At 25 °C, TCFH (57.13 mg, 0.20 mmol) was added 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). The mixture was stirred at 25 °C for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) 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 a white solid.

[0185] 1 H 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).

[0186] LCMS: m / z (M + H) + = 534.2.

[0187] Example 5: Synthesis of Compound 5

[0188]

[0189] To a solution of 4-(2-chloro-5-methoxypyridin-4-yl)-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]oct-7-yl)pyridine-3-carboxylic acid (40 mg, 0.10 mmol) and 5-(((5-chloropyridin-2-yl)methyl)thio)-1,3,4-thiadiazol-2-amine (25.69 mg, 0.10 mmol) in DMF (3 mL) was added TCFH (27.86 mg, 0.10 mmol) and 1-methylimidazole (0.02 mL, 0.30 mmol). The mixture was stirred at 25 °C under N2 for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA conditions) 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]oct-7-yl)-4,4'-bipyridine-3-carboxamide as a white solid (12.25 mg, 0.02 mmol, 19.17%).

[0190] 1 H 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).

[0191] LCMS: m / z (M+H) + = 643.2.

[0192] Example 6: Synthesis of Compound 6

[0193]

[0194] At 25 °C, 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) was 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), and the mixture was stirred at 25 °C under N2 for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) 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 a white solid.

[0195] LCMS: m / z (M+H) + = 605.1.

[0196] Example 7: Synthesis of Compound 7

[0197]

[0198] Step A: 5-(Tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-amine

[0199] At 25 °C, 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), and the mixture was stirred at 80 °C for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 0:1) to give 5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-amine (40 mg, 0.19 mmol, 49.19%) as a white solid.

[0200] LCMS: m / z (M+H) + = 204.2.

[0201] Step B: 2'-Chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide

[0202] At 25 °C, to a solution of 5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-amine (50 mg, 0.12 mmol) in DMF (2.0 mL) was 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), and NMI (50.42 mg, 0.61 mmol). The mixture was stirred at 25 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) to give 2'-chloro-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide as a white solid (2.02 mg, 0.01 mmol, 3.33%).

[0203] 1 H 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).

[0204] LCMS: m / z (M+H) + = 464.1.

[0205] Example 8: Synthesis of Compound 8

[0206]

[0207] 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) at 25 °C was added TCFH (68 mg, 0.24 mmol), NMI (39 mg, 0.48 mmol) and 5-(((5-chloropyridin-2-yl)methyl)thio)-1,3,4-thiadiazol-2-amine (50 mg, 0.19 mmol), and the mixture was stirred at 25 °C under N2 for 18 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) 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 as a white solid (15.77 mg, 17.74%).

[0208] 1 H 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).

[0209] LCMS: m / z (M + H) + = 550.2.

[0210] Example 9: Synthesis of Compound 9

[0211]

[0212] To a solution of 4-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(((4-chlorophenyl)methyl)thio)-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) at 25 °C was added OXONE ((3-sulfonatotrioxolato)potassium (3.56 mg, 0.0058 mmol), and the reaction system was stirred at 25 °C under N2 for 16 h. After filtration was completed, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) to give 2'-chloro-N-(5-(4-chlorobenzylsulfinyl)-1,3,4-thiadiazol-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide as a white solid (2 mg).

[0213] 1 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).

[0214] LCMS: m / z (M + H) + = 534.2.

[0215] Example 10: Synthesis of Compound 10

[0216]

[0217] Step A: 5 - ((4 - Chlorobenzyl)sulfonyl)-1,3,4 - thiadiazol - 2 - amine

[0218] To a solution of 5 - (((4 - chlorophenyl)methyl)thio) - 1,3,4 - thiadiazol - 2 - amine (70 mg, 0.27 mmol) in THF (1 mL) and water (1 mL) at 25 °C was added OXONE ((3 - sulfonatotrioxolato)potassium (331.97 mg, 0.54 mmol), and the reaction system was stirred at 25 °C for 16 h. After filtration was completed, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum 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 a yellow oil.

[0219] LCMS: m / z (M + H) + = 290.0.

[0220] Step B: 2'-Chloro - N - (5 - (4 - chlorobenzylsulfonyl)-1,3,4 - thiadiazol - 2 - yl)-5'-methoxy - 6 - methyl - 4,4'-bipyridine - 3 - carboxamide

[0221] At 25 °C, to a solution of 5-((4-chlorobenzyl)sulfonyl)-1,3,4-thiadiazol-2-amine (20 mg, 0.06 mmol) in DMF (1 mL) was 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). The mixture was stirred at 25 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) 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.

[0222] 1 H 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).

[0223] LCMS: m / z (M + H) + = 550.2.

[0224] Example 11: Synthesis of Compound 11

[0225]

[0226] Step A: (5-Chloropyridin-2-yl)dideuteriomethanol

[0227] To a solution of methyl 5-chloropyridine-2-carboxylate (1 g, 5.83 mmol) in THF (12 mL) at 25 °C was added NaBD4 (0.49 g, 11.66 mmol) and trideutero(methanolic-d3) (0.6 mL). The mixture was stirred at 70 °C for 3 h. After completion of the reaction, the reaction system mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic layer was 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.

[0228] LCMS: m / z (M + H) + = 146.0.

[0229] Step B: 5-Chloro-2-(chlorodideuteriomethyl)pyridine

[0230] At 0 °C, SOCl2 (0.2 mL, 2.75 mmol) was added to a solution of (5-chloropyridin-2-yl)dideuteriomethanol (200 mg, 1.37 mmol) in DCM (8 mL). The mixture was stirred at 25 °C for 3 h. After completion of the reaction, the mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layer was washed with aq. NaHCO3 (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc = 100:1 to 5:1) to give 5-chloro-2-(chlorodideuteriomethyl)pyridine as a white solid (120 mg, 0.69 mmol).

[0231] LCMS: m / z (M+H) + = 163.9.

[0232] Step C: 5-(((5-Chloropyridin-2-yl)dideuteriomethyl)thio)-1,3,4-thiadiazol-2-amine

[0233] At 25 °C, tBuOK (150.50 mg, 1.34 mmol) and 5-chloro-2-(chlorodideuteriomethyl)pyridine (200 mg, 1.22 mmol) were added to a solution of 5-amino-1,3,4-thiadiazole-2-thiol (243.60 mg, 1.83 mmol) in THF (6 mL). The mixture was stirred at 25 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc = 100:1 to 3:1) to give 5-(((5-chloropyridin-2-yl)dideuteriomethyl)thio)-1,3,4-thiadiazol-2-amine as a yellow solid (170 mg, 0.62 mmol).

[0234] LCMS: m / z (M+H) + = 261.0.

[0235] Step D: 4-(2-Chloro-5-methoxypyridin-4-yl)-N-(5-(((5-chloropyridin-2-yl)dideuteriomethyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylpyridine-3-carboxamide

[0236] At 25 °C, NMI (0.05 mL, 0.58 mmol), TCFH (80.70 mg, 0.29 mmol) and 5-(((5-chloropyridin-2-yl)dideuteriomethyl)thio)-1,3,4-thiadiazol-2-amine (50 mg, 0.19 mmol) were added 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), and the mixture was stirred at 25 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) to give 4-(2-chloro-5-methoxypyridin-4-yl)-N-(5-(((5-chloropyridin-2-yl)dideuteriomethyl)thio)-1,3,4-thiadiazol-2-yl)-6-methylpyridine-3-carboxamide (1.2 mg) as a white solid.

[0237] 1 H 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).

[0238] LCMS: m / z (M + H) + = 521.2.

[0239] Example 12: Synthesis of Compound 12

[0240]

[0241] Step A: 1-(5-chloropyridin-2-yl)ethanol

[0242] Sodium borohydride (0.49 g, 12.86 mmol) was added to a solution of 1-(5-chloropyridin-2-yl)ethanol (1 g, 6.43 mmol) in methanol (10 mL) at 0 °C, and the mixture was stirred at 25 °C for 1 h. After completion of the reaction, 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)ethanol (900 mg, 5.73 mmol) as a yellow oil.

[0243] LCMS: m / z (M + H) + = 158.0.

[0244] Step B: 5-Chloro-2-(1-chloroethyl)pyridine

[0245] At 0 °C, thionyl chloride (0.69 mL, 9.52 mmol) was added to a solution of 1-(5-chloropyridin-2-yl)ethanol (600 mg, 3.81 mmol) in dichloromethane (10 mL). The mixture was stirred at 25 °C for 16 h. After completion of the reaction, 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 under reduced pressure to dryness. 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 as a yellow oil (260 mg, 1.48 mmol).

[0246] LCMS: m / z (M + H) + = 176.0.

[0247] Step C: 5-((1-(5-Chloropyridin-2-yl)ethyl)thio)-1,3,4-thiadiazol-2-amine

[0248] At 25 °C, 5-amino-1,3,4-thiadiazole-2-thiol (0.26 mL, 2.95 mmol) and potassium tert-butoxide (496 mg, 4.43 mmol) were added to a solution of 5-chloro-2-(1-chloroethyl)pyridine (260 mg, 1.48 mmol) in tetrahydrofuran (8 mL). The mixture was stirred at 65 °C for 16 h. After completion of the reaction, 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 as a yellow oil (60 mg, 0.22 mmol).

[0249] LCMS: m / z (M + H) + = 273.0.

[0250] 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

[0251] 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) at 25 °C was 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), and the mixture was stirred at 25 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC ((ACN: water (1‰ FA)) to afford 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 a white solid.

[0252] 1 H 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).

[0253] LCMS: m / z (M + H) + = 533.2.

[0254] Example 13: Synthesis of Compound 13

[0255]

[0256] Step A: Methyl 5'-methoxy-6-methyl-2'-(trifluoromethyl)-(4,4'-bipyridine)-3-carboxylate

[0257] Under N2 at 25 °C, to a stirred solution of (5-methoxy-2-(trifluoromethyl)pyridin-4-yl)boronic acid pinacol ester (626.63 mg, 2.84 mmol) in dioxane (20 mL) and H2O (4 mL) was added methyl 4-bromo-6-methylnicotinate (435 mg, 1.89 mmol), Pd(dppf)Cl2 (207.81 mg, 0.28 mmol) and K2CO3 (1157.76 mg, 8.52 mmol). The mixture was stirred at 80 °C under nitrogen for 3 h. After completion of the reaction, the reaction system mixture was quenched with 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 (petroleum 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.

[0258] LCMS: m / z (M+H) + = 327.0.

[0259] Step B: 5'-Methoxy-6-methyl-2'-(trifluoromethyl)-(4,4'-bipyridine)-3-carboxylic acid

[0260] 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) at 25 °C was added LiOH (681.59 mg, 16.24 mmol). The reaction system mixture was stirred at 25 °C for 2 h. After completion of the reaction, the reaction system mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) to give 5'-methoxy-6-methyl-2'-(trifluoromethyl)-(4,4'-bipyridine)-3-carboxylic acid (420 mg, 1.35 mmol) as a white solid.

[0261] LCMS: m / z (M+H) + = 313.0.

[0262] Step C: 5'-Methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide

[0263] 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) at 25 °C was added 5-(tetrahydrofuran-3-ylthio)-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), and the mixture was stirred at 25 °C for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) 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 a white solid.

[0264] 1 H 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).

[0265] LCMS: m / z (M + H) + = 498.2.

[0266] Example 14: Synthesis of Compound 14

[0267]

[0268] Step A: Methyl 2'-(difluoromethyl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate

[0269] Under N2 at 25 °C, to a solution of (2-(difluoromethyl)-5-methoxypyridin-4-yl)boronic acid pinacol ester (200 mg, 0.87 mmol) in dioxane (8.0 mL) was 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). The mixture was stirred at 80 °C for 2 h under N2. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (eluent: petroleum ether:EtOAc = 10:1 to 5:1) to obtain methyl 2'-(difluoromethyl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylate (210 mg, 0.66 mmol) as a yellow oil.

[0270] LCMS: m / z (M + H) + = 309.2.

[0271] Step B: 2'-(Difluoromethyl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid

[0272] 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. After completion of the reaction, the pH of the mixture was adjusted to 2 with 2M HCl and extracted with EtOAc (10 mL × 3). The organic layer was washed with brine (l5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 2'-(difluoromethyl)-5'-methoxy-6-methyl-(4,4'-bipyridine)-3-carboxylic acid (133 mg, 0.46 mmol) as a white solid.

[0273] LCMS: m / z (M + H) + = 295.2.

[0274] Step C: 2'-(Difluoromethyl)-5'-methoxy-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide

[0275] 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) at 25 °C was 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), and the mixture was stirred at 25 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC ((ACN: water (1‰ FA)) to afford 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 a white solid.

[0276] 1 H 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).

[0277] LCMS: m / z (M + H) + = 480.2.

[0278] Example 15: Synthesis of Compound 15

[0279]

[0280] Step A: Methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinate

[0281] Under N2 and at 25 °C, (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) were added to a solution of methyl 4-bromo-6-methylnicotinate (200 mg, 0.87 mmol) in dioxane (8.0 mL). The mixture was stirred at 80 °C for 2 h under N2. After completion of the reaction, 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 a yellow oil.

[0282] LCMS: m / z (M+H) + = 308.2.

[0283] Step B: 4-(5-(Difluoromethyl)-2-methoxyphenyl)-6-methylnicotinic acid

[0284] Under 25 °C, lithium hydroxide (31 mg, 1.29 mmol) was added 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). The mixture was stirred at 25 °C for 3 h. After completion of the reaction, the pH of the mixture was adjusted to 2 with 2 M HCl and extracted with EtOAc (10 mL × 3). The organic layer was 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 a white solid.

[0285] LCMS: m / z (M+H) + = 294.0.

[0286] Step C: 4-(5-(Difluoromethyl)-2-methoxyphenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide

[0287] To a solution of 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinic acid (40 mg, 0.14 mmol) in DMF (3 mL) at 25 °C was 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), and the mixture was stirred at 25 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC ((ACN: water (1‰ FA)) to afford 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 a white solid.

[0288] 1 H 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).

[0289] LCMS: m / z (M + H) + = 479.2.

[0290] Example 16: Synthesis of Compound 16

[0291]

[0292] Step A: 5-((5-Nitropyridin-2-yl)thio)-1,3,4-thiadiazol-2-amine

[0293] At 25 °C, K2CO3 (2.08 g, 15.02 mmol) was added 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). The mixture was stirred at 25 °C for 16 h to obtain a yellow solution. After completion of the reaction, the mixture was diluted with H2O (200 mL) and extracted with EtOAc (200 mL * 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 3:1) to obtain 5-((5-nitropyridin-2-yl)thio)-1,3,4-thiadiazol-2-amine (880 mg, 3.40 mmol) as a white solid.

[0294] LCMS: m / z (M+H) + = 256.0.

[0295] Step B: tert-Butyl 5-((5-nitropyridin-2-yl)thio)-1,3,4-thiadiazol-2-yl)carbamate

[0296] To a solution of 5-((5-nitropyridin-2-yl)thio)-1,3,4-thiadiazol-2-amine (860 mg, 3.37 mmol) in DCM (30 mL) in an ice bath was added Boc2O (0.87 mL, 4.04 mmol) and DMAP (617.38 mg, 5.05 mmol). The mixture was stirred at 25 °C for 16 h to obtain a yellow solution. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 3:1) to obtain tert-Butyl 5-((5-nitropyridin-2-yl)thio)-1,3,4-thiadiazol-2-yl)carbamate (1.1 g, 3.10 mmol) as a white solid.

[0297] LCMS: m / z (M+H) + = 356.0.

[0298] Step C: tert-Butyl 5-((5-aminopyridin-2-yl)thio)-1,3,4-thiadiazol-2-yl)carbamate

[0299] Under H2 at 25 °C, 10% Pd / C (0.66 g, 0.62 mmol) was added 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). The mixture was stirred for 16 h at 25 °C under H2 to obtain a black solution. After filtration was completed, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 10:1) to obtain tert-butyl 5-((5-aminopyridin-2-yl)thio)-1,3,4-thiadiazol-2-yl)carbamate as a white solid (220 mg, 0.61 mmol).

[0300] LCMS: m / z (M+H) + = 326.0.

[0301] Step D: tert-butyl 5-((5-chloropyridin-2-yl)thio)-1,3,4-thiadiazol-2-yl)carbamate

[0302] At 25 °C, LiCl (26.05 mg, 0.61 mmol), copper(II) chloride (82.64 mg, 0.61 mmol) and tert-butyl nitrite (0.07 mL, 0.61 mmol) were added 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). The mixture was stirred for 2 h at 25 °C to obtain a black solution. After the reaction was completed, the mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 5:1) to obtain tert-butyl 5-((5-chloropyridin-2-yl)thio)-1,3,4-thiadiazol-2-yl)carbamate as a white solid (150 mg, 0.43 mmol).

[0303] LCMS: m / z (M+H) + = 345.0.

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

[0305] The 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 obtain a brown solution. After completion of the reaction, the mixture was concentrated under reduced pressure to give 5-((5-chloropyridin-2-yl)thioalkyl)-1,3,4-thiadiazol-2-amine (50 mg, 0.20 mmol) as a yellow solid.

[0306] LCMS: m / z (M+H) + = 325.0.

[0307] 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

[0308] 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)thioalkyl)-1,3,4-thiadiazol-2-amine (18 mg, 0.07 mmol) in DMF (2 mL) at 25 °C was added TCFH (26.18 mg, 0.09 mmol) and 1-methylimidazole (0.02 mL, 0.22 mmol). The mixture was stirred at 25 °C for 2 h to obtain a brown solution. After completion of the reaction, 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 a white solid.

[0309] 1 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).

[0310] LCMS: m / z (M+H) + = 505.1.

[0311] Example 17: Synthesis of Compound 17

[0312]

[0313] Step A: Methyl 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylpyridine-3-carboxylate

[0314] At 25 °C, to a solution of methyl 4-bromo-6-methylpyridine-3-carboxylate (0.07 mL, 0.43 mmol) in dioxane (3 mL) was added (2-methoxy-5-(trifluoromethyl)phenyl)boronic acid pinacol ester (0.07 mL, 0.43 mmol), K2CO3 (180.21 mg, 1.30 mmol) and Pd(dppf)Cl2 (35.50 mg, 0.04 mmol). The mixture was stirred at 80 °C under N2 for 3 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum 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).

[0315] LCMS: m / z (M+H) + = 326.0.

[0316] Step B: 4-(2-Methoxy-5-(trifluoromethyl)phenyl)-6-methylnicotinic acid

[0317] At 25 °C, 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). The mixture was stirred at 25 °C for 3 h. After completion of the reaction, the pH of the mixture was adjusted to pH 2 with 2 M HCl and extracted with EtOAc (10 mL×3). The organic layer was 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 as a white solid (80 mg, 0.28 mmol).

[0318] LCMS: m / z (M+H) + = 312.0.

[0319] Step C: 4-(2-Methoxy-5-(trifluoromethyl)phenyl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide

[0320] To a solution of 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylpyridine-3-carboxylic acid (22 mg, 0.07 mmol) in DMF (2 mL) at 25 °C was added 5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-amine (14.37 mg, 0.07 mmol), TCFH (39.66 mmol, 0.14 mmol) and NMI (0.03 mL, 0.35 mmol), and the mixture was stirred at 25 °C under N2 for 3 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) 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 a white solid.

[0321] 1 H 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).

[0322] LCMS: m / z (M + H) + = 497.2.

[0323] Example 18: Synthesis of Compound 18

[0324]

[0325] Step A: Methyl 6-(cyclopropyl ethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl)pyridine-3-carboxylate

[0326] Under N2 at 25 °C, Pd(PPh3)4 (42.84 mg, 0.06 mmol), CuI (23.25 mg, 0.12 mmol) and TEA (0.17 mL, 1.22 mmol) were added 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). The mixture was stirred at 70 °C for 16 h under N2 to obtain a brown solution. After filtration was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 5:1) to obtain methyl 6-(cyclopropyl ethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl)pyridine-3-carboxylate as a white solid (200 mg, 0.56 mmol).

[0327] LCMS: m / z (M+H) + = 358.2.

[0328] Step B: 6-(Cyclopropyl ethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl)pyridine-3-carboxylic acid

[0329] At 25 °C, LiOH (28.18 mg, 0.67 mmol) was added to a solution of methyl 6-(cyclopropyl ethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl)pyridine-3-carboxylate (200 mg, 0.56 mmol) in THF (3 mL) and H2O (2 mL). The mixture was stirred at 25 °C for 16 h to obtain a yellow solution. After the reaction was completed, the pH of the mixture was adjusted to 2 with 2 M HCl, and the mixture was extracted with EtOAc (10 mL * 3). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 6-(cyclopropyl ethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl)pyridine-3-carboxylic acid as a white solid (150 mg, 0.45 mmol).

[0330] LCMS: m / z (M+H) + = 344.2.

[0331] Step C: 6-(Cyclopropyl ethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide

[0332] At 25 °C, to a solution of 6-(cyclopropylethynyl)-4-(5-(difluoromethyl)-2-methoxyphenyl)nicotinic acid (30 mg, 0.09 mmol) and 5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-amine (18.30 mg, 0.09 mmol) in DMF (2 mL) was added TCFH (31.87 mg, 0.11 mmol) and 1-methylimidazole (0.02 mL, 0.26 mmol). The mixture was stirred at 25 °C for 2 h to obtain a brown solution. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative 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 as a white solid (17.35 mg, 0.03 mmol).

[0333] 1 H 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).

[0334] LCMS: m / z (M + H) + = 529.2.

[0335] Example 19: Synthesis of Compound 19

[0336]

[0337] Step A: Methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)nicotinate

[0338] Under N2 at 25 °C, to a solution of 4-ethynyl-1-methylpyrazole (0.05 mL, 0.47 mmol) in DMF (2 mL) was 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). The mixture was stirred at 50 °C for 1 h under N2. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc = 100:1 to 3:1) to give methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)nicotinate as a white solid (30 mg, 0.076 mmol).

[0339] LCMS: m / z (M+H) + = 398.0.

[0340] Step B: 4-(5-(Difluoromethyl)-2-methoxyphenyl)-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)nicotinic acid

[0341] Under N2 at 25 °C, 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). The mixture was stirred at 25 °C for 1 h under N2. After completion of the reaction, the pH of the mixture was adjusted to 2 with 2 M HCl and extracted with EtOAc (10 mL * 3). The organic layer was 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 as a white solid (140 mg, 0.37 mmol).

[0342] LCMS: m / z (M+H) + = 384.0.

[0343] 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

[0344] At 25 °C, 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) were added 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), and the mixture was stirred at 25 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) 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 a white solid.

[0345] 1 H 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).

[0346] LCMS: m / z (M + H) + = 569.2.

[0347] Example 20: Synthesis of Compound 20

[0348]

[0349] Step A: Methyl 6-chloro-4-iodopyridine-3-carboxylate

[0350] To a solution of 6-chloro-4-iodopyridine-3-carboxylic acid (1 g, 3.53 mmol) in DMF (15 mL) at 25 °C was added Cs2CO3 (3.45 g, 10.58 mmol) and methyl iodide (0.24 mL, 3.88 mmol), and the mixture was stirred at 25 °C for 16 h. After completion of the reaction, the reaction system mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL * 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum 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.

[0351] LCMS: m / z (M + H) + = 297.9.

[0352] Step B: Methyl 6-chloro-4-(2-methoxy-5-(trifluoromethyl)phenyl)pyridine-3-carboxylate

[0353] To a solution of methyl 6-chloro-4-iodopyridine-3-carboxylate (1 g, 3.36 mmol) in dioxane (3 mL) and H2O (0.5 mL) under N2 at 25 °C was added (2-methoxy-5-(trifluoromethyl)phenyl)boronic acid pinacol ester (0.74 g, 3.36 mmol), K2CO3 (1.39 g, 10.08 mmol) and Pd(dppf)Cl2 (0.25 g, 0.34 mmol), and the mixture was stirred at 80 °C under N2 for 3 h. After completion of the reaction, the mixture was diluted with water (20 mL) and extracted with EtOAc (15 mL * 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum 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.

[0354] LCMS: m / z (M + H) + = 346.0.

[0355] Step C: Methyl 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxopyridin-3-yl)pyridine-3-carboxylate

[0356] Under N2 and at 25 °C, 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) were added 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) and H2O (0.5 mL). The mixture was stirred at 80 °C under N2 for 16 h. After completion of the reaction, 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 (petroleum 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.

[0357] LCMS: m / z (M + H) + = 419.2.

[0358] Step D: 4-(2-Methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxopyridin-3-yl)pyridine-3-carboxylic acid

[0359] At 25 °C, LiOH (10.03 mg, 0.24 mmol) was added 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). The mixture was stirred at 25 °C for 2 h. After completion of the reaction, the pH of the mixture was adjusted to 2 with 2 M HCl and extracted with EtOAc (10 mL × 3). The organic layer was 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.

[0360] LCMS: m / z (M + H) + = 405.2.

[0361] 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

[0362] At 25 °C, to a solution of 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxopyridin-3-yl)picolinate (20 mg, 0.05 mmol) in DMF (2 mL) were added 1-methylimidazole (0.01 mL, 0.15 mmol), TCFH (21.04 mg, 0.08 mmol) and 5-(tetrahydro-3-furanylthio)-1,3,4-thiadiazol-2-amine (10.16 mg, 0.05 mmol), and the mixture was stirred at 25 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) 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.

[0363] 1 H 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).

[0364] LCMS: m / z (M + H) + = 590.2.

[0365] Example 21: Synthesis of Compound 21

[0366]

[0367] Step A: Methyl 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)nicotinate

[0368] Under N2 at 25 °C, 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) were added 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). The resulting mixture was stirred at 120 °C under nitrogen for 3 hours. After completion of the reaction, the reaction system was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum 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 a white solid.

[0369] LCMS: m / z (M+H) + = 401.9.

[0370] Step B: 4-(5-(Difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylic acid At 25 °C, LiOH (104.54 mg, 2.49 mmol) was added 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). The reaction mixture was stirred at 25 °C for 3 hours. After completion of the reaction, the pH of the mixture was adjusted to 2 with 2 M HCl and extracted with EtOAc (10 mL * 3). The organic layer was 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 a white solid.

[0371] LCMS: m / z (M+H) + = 388.2.

[0372] 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

[0373] 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) at 25 °C was added TCFH (32.60 mg, 0.12 mmol), NMI (6.17 μL, 0.08 mmol) and 5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-amine (15.74 mg, 0.08 mmol), and the mixture was stirred at 25 °C for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) 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 a white solid.

[0374] 1 H 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).

[0375] LCMS: m / z (M + H) + = 573.2.

[0376] Example 22: Synthesis of Compound 22

[0377]

[0378] Step A: Benzyl 4-(2-chloro-5-methoxypyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1-yl)pyridine-3-carboxylate

[0379] Under N2 at 25 °C, potassium phosphate (54.53 mg, 0.26 mmol), CuI (2.45 mg, 0.01 mmol) and 2,5-diazahexane (0.01 mL, 0.03 mmol) were added 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). The mixture was stirred at 120 °C for 2 hours under N2 to obtain a brown solution. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 2:1) to obtain benzyl 4-(2-chloro-5-methoxypyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1-yl)pyridine-3-carboxylate as a white solid (15 mg, 0.03 mmol).

[0380] LCMS: m / z (M+H) + = 516.2.

[0381] Step B: 4-(2-Chloro-5-methoxypyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1-yl)pyridine-3-carboxylic acid

[0382] At 25 °C, LiOH (1.46 mg, 0.03 mmol) was added 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). The mixture was stirred at 25 °C for 16 hours to obtain a yellow solution. After completion of the reaction, the pH of the mixture was adjusted to <4 with 2 M HCl and extracted with EtOAc (15 mL * 2). The organic layer was washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain 4-(2-chloro-5-methoxypyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1-yl)pyridine-3-carboxylic acid as a white solid (10 mg, 0.02 mmol).

[0383] LCMS: m / z (M+H) + = 426.1.

[0384] 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

[0385] At 25 °C, 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-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-amine (4.77 mg, 0.02 mmol) in DMF (2 mL) was added TCFH (9.89 mg, 0.04 mmol) and 1-methylimidazole (5.79 mg, 0.07 mmol). The mixture was stirred at 25 °C for 2 h to obtain a yellow solution. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (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 a white solid.

[0386] 1 H 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).

[0387] LCMS: m / z (M+H) + = 611.2.

[0388] Example 23: Synthesis of Compound 23

[0389]

[0390] Step A: Benzyl 4-(2-chloro-5-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylate

[0391] Under N2 at 25 °C, 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) were added 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). The mixture was stirred at 120 °C for 18 h under N2 to obtain a brown solution. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum 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 as a white solid (20 mg, 0.04 mmol).

[0392] LCMS: m / z (M+H) + = 463.2.

[0393] Step B: 4-(2-chloro-5-methoxypyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylic acid

[0394] At 25 °C, LiOH (2.18 mg, 0.05 mmol) was added 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). The mixture was stirred at 25 °C for 16 h to obtain a yellow solution. After completion of the reaction, the pH of the mixture was adjusted to <4 with 2 M HCl and extracted with EtOAc (15 mL × 2). The organic layer was 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 as a white solid (14 mg, 0.03 mmol).

[0395] LCMS: m / z (M+H) + = 373.1.

[0396] 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

[0397] At 25 °C, 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-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-amine (7.63 mg, 0.04 mmol) in DMF (2 mL) was added TCFH (15.81 mg, 0.06 mmol) and 1-methylimidazole (9.25 mg, 0.11 mmol). The mixture was stirred at 25 °C for 2 h to obtain a yellow solution. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative 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 a white solid.

[0398] LCMS: m / z (M+H) + = 558.2.

[0399] Example 24: Synthesis of Compound 24

[0400]

[0401] Step A: Methyl 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1-yl)pyridine-3-carboxylate

[0402] Under N2 at 25 °C, 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) was added 2,5-diazabutane (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). The mixture was stirred at 120 °C under N2 for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 2:1) to give 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 a white solid.

[0403] LCMS: m / z (M+H) + = 474.0.

[0404] Step B: 4-(5-Methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1-yl)pyridine-3-carboxylic acid

[0405] At 25 °C, LiOH (3.99 mg, 0.10 mmol) was added 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). The mixture was stirred at 25 °C for 3 h. After completion of the reaction, the pH of the mixture was adjusted to <4 with 2 M HCl and extracted with EtOAc (10 mL × 2). The organic layer was 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 as a white solid (10 mg, 0.02 mmol).

[0406] LCMS: m / z (M + H) + = 460.0.

[0407] 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

[0408] At 25 °C, 5-(tetrahydro-3-furanylthio)-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) were added 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). The mixture was stirred at 25 °C for 18 h. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (FA conditions) 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).

[0409] 11H 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).

[0410] LCMS: m / z (M + H) + = 645.1.

[0411] Example 25: Synthesis of Compound 25

[0412]

[0413] Step A: Methyl 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylate

[0414] 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) at 25 °C was added CuI (10.99 mg, 0.06 mmol), 2,5-diazabicyclo[2.2.1]heptane (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). The reaction system was degassed with N2 three times and stirred at 120 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum 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.

[0415] LCMS: m / z (M + H)+ = 421.2.

[0416] Step B: 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylic acid

[0417] 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, and the reaction system was stirred at 25 °C for 16 h. After completion of the reaction, the pH of the mixture was adjusted to <4 with 2 M HCl and extracted with EtOAc (10 mL * 2). The organic layer was 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-hydroxy acid as a white solid (20 mg, 0.03 mmol).

[0418] LCMS: m / z (M + H) + = 407.0.

[0419] 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

[0420] To a solution of 4-(5-methoxy-2-(trifluoromethyl)pyridin-4-yl)-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-hydroxy acid (10 mg, 0.02 mmol) in DCM (2 mL) was added 5-(tetrahydro-3-furanylthio)-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, and the reaction system was stirred at 25 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) 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 as a white solid (0.4 mg).

[0421] LCMS: m / z (M + H) + = 592.2.

[0422] Example 26: Synthesis of Compound 26

[0423]

[0424] Step A: 5-(3,4,5,6-Tetrahydro-2H-pyran-4-ylthio)-1,3,4-thiadiazol-2-amine

[0425] At 25 °C, sodium methoxide (12.96 mg, 0.24 mmol) was added 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). The mixture was stirred at 80 °C for 18 h to obtain a yellow solution. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (pure EtOAc) to give 5-(3,4,5,6-tetrahydro-2H-pyran-4-ylthio)-1,3,4-thiadiazol-2-amine as a white solid (28.07 mg, 0.13 mmol).

[0426] LCMS: m / z (M+H) + = 218.0.

[0427] 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

[0428] At 25 °C, TCFH (45.31 mg, 0.16 mmol) and 1-methylimidazole (26.52 mg, 0.32 mmol) were added 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-ylthio)-1,3,4-thiadiazol-2-amine (28.07 mg, 0.13 mmol) in DMF (2 mL). The mixture was stirred at 25 °C for 2 h to obtain a yellow solution. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (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 as a white solid (15.97 mg, 0.03 mmol).

[0429] 11H 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).

[0430] LCMS: m / z (M + H) + = 478.3.

[0431] Example 27: Synthesis of Compound 27

[0432]

[0433] Step A: 2-Methylpropan-2-yl 4-((5-amino-1,3,4-thiadiazol-2-yl)thio)piperidine-1-carboxylate

[0434] To a solution of 2-methylpropan-2-yl 4-bromopiperidine-1-carboxylate (20 mg, 0.08 mmol) in MeCN (2 mL) at 25 °C was added TEA (0.02 mL, 0.12 mmol) and 5-amino-1,3,4-thiadiazole-2-thiol (5.04 mg, 0.04 mmol). The mixture was stirred at 80 °C for 16 h. After completion of the reaction, 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)thio)piperidine-1-carboxylate as a yellow solid (9 mg, 0.03 mmol).

[0435] LCMS: m / z (M + H - 56) + = 261.0.

[0436] 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)thio)piperidine-1-carboxylate

[0437] To a solution of 2-methylpropan-2-yl 4-((5-amino-1,3,4-thiadiazol-2-yl)thio)piperidine-1-carboxylate (9.00 mg, 0.03 mmol) in DCM (2 mL) at 25 °C was 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), and the mixture was stirred at 25 °C for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 2:1) to give 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)thio)piperidine-1-carboxylate (20 mg, 0.03 mmol) as a yellow solid.

[0438] LCMS: m / z (M+H) + = 577.3.

[0439] Step C: 2'-Chloro-5'-methoxy-6-methyl-N-(5-(piperidin-4-ylthio)-1,3,4-thiadiazol-2-yl)-4,4'-bipyridine-3-carboxamide

[0440] 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)thio)piperidine-1-carboxylate (20 mg, 0.06 mmol) in DCM (5 mL) at 25 °C was added TFA (1.5 mL, 19.60 mmol), and the mixture was stirred at 25 °C for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (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.

[0441] LCMS: m / z (M+H) + = 477.2.

[0442] 11H 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).

[0443] Experimental Example 1: Inhibitory Activity against Polθ

[0444] The ability of the compound to inhibit Polθ - helicase activity in vitro was measured using the ADP - GLO assay. Recombinant Polθ - helicase domain (aa 1 - 987) was purchased from SignalChem Biotech (Catalog No. D681 - 31G) and stored in aliquots at - 80 °C. Single - stranded DNA was produced by Genscrip (30mer ssDNA(CT)15). Reactions were carried out 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 compound was dispensed at different concentrations (10 - point, 1:3 dilution) onto a 384 - well plate (PerkinElmer #6007290) using a Labcyte Echo 655. 2 μL of a 2X helicase domain Polθ and DNA mixture (3 nM helicase domain Polθ and 2 nM DNA in assay buffer) was added to the plate that had been pre - dispensed with the compound. The plate was covered and incubated at room temperature for 30 minutes, then 2 μL of a 2X substrate mixture (80 μM ATP in assay buffer) was added to the plate to initiate the enzyme reaction. Before adding the ADP - Glo TM reagent, the plate was covered and incubated at room temperature for 1 hour. 4 μL of ADP - Glo TM reagent containing 10 mM MgCl2 was added, and the plate was incubated for 40 minutes. Then 8 μL of kinase detection reagent was added to the plate and incubated for 40 minutes. Luminescence was read on a 2105 - 0020 EnVision multimode reader, and the raw data was analyzed using a log (inhibitor) vs. response variable slope (four - parameter) to generate an IC 50 value. The results are shown in Table 1 below.

[0445] [Table 1]

[0446]

[0447]

[0448] Experimental Example 2: Metabolic Stability of Human Liver Microsomes

[0449] Preheat 100 mM K-Mg buffer with 5 mM MgCl2 at pH 7.40. 0.5 mM spiked solution: Add 5 μL of 10 mM compound stock solution and reference compound to 95 μL of acetonitrile (ACN). HLM: 1.5 μM microsome spiked solution (0.5 mg / mL): Add 1.5 μL of 500 μM spiked solution and 18.75 μL of 20 mg / mL liver microsomes to 479.75 μL of K / Mg buffer. Prepare NADPH stock solution (6 mM) by dissolving NADPH in K-Mg buffer. Aliquot 30 μL of 1.5 μM spiked solution containing microsome solution into assay plates designated for different time points (0, 5, 15, 30, and 45 minutes). Pre-incubate other plates at 37 °C for 5 minutes. At 0 minute, add 200 μL of ACN containing IS to the wells before adding 15 μL of NADPH stock solution (6 mM). At other time points, add 15 μL of NADPH stock solution (6 mM) to start the reaction and timing. At 5, 15, 30, and 45 minutes, add 200 μL of ACN containing IS to the wells of the corresponding plates to stop the reaction. After quenching, shake the plates for 10 minutes (600 rpm), then centrifuge at 4000 rmp for 50 minutes. Transfer 80 μL of the supernatant from each well to 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 (Example 8) from WO 2022 / 118210 was used as a comparative example. As shown in Table 2, Compounds 7, 13, and 14 containing S showed improved metabolic stability compared to Compound A.

[0450] [Table 2]

[0451]

[0452]

Claims

1. A compound represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In Chemical Formula 1, A is a trivalent linker of a heterocycle containing one to three heteroatoms selected from N, O or S and C 2-10 heterocycle, L1 is a key; C 1-4 alkylene; C 2-4 alkenylene; C 2-4 alkynylene; -S-; or -O-, R1 is hydrogen; C 1-4 alkyl; -CONH2; -CONH(C 1-4 alkyl); -CON(C 1-4 alkyl)2; C 3-6 cycloalkyl; C 2-10 heterocycloalkyl containing one to three heteroatoms selected from N, O or S, which is unsubstituted or substituted by C 1-4 alkyl or C 1-4 haloalkyl; or C 2-10 heteroaryl containing one to three heteroatoms selected from N, O or S, which is unsubstituted or substituted by C 1-4 alkyl or C 1-4 haloalkyl, B is C 6-10 An aromatic ring; a C containing one to three heteroatoms selected from N, O or S 2-10 A cycloalkane ring; or a C containing one to three heteroatoms selected from N, O or S 2-10 A trivalent linker of an aromatic heterocycle R2 and R3 are each independently hydrogen; C 1-4 alkyl; C 2-4 alkenyl; C 2-4 alkynyl; C 1-4 haloalkyl; C 1-4 alkoxy; halogen; cyano; or C containing one oxygen 2-6 heterocyclic alkoxy; or R2 and R3, when on adjacent ring vertices, combine to form a C containing one to three heteroatoms selected from N, O or S 2-6 heteroalkyl; or C containing one to three heteroatoms selected from N, O or S 2-6 heteroaryl, X is N; or CR', R' is hydrogen; or a halogen, Y is -S-; -S(=O)-; or -S(=O)2-, L2 is a key; C 1-4 an alkylene group, which is unsubstituted or substituted by at least one deuterium; or C 3-6 a cycloalkylene group R4 is C 6-10 aryl; C having one to three heteroatoms selected from N, O or S 2-10 heteroaryl; C 3-6 cycloalkyl; C having one oxygen 2-6 heterocycloalkyl; C having one oxygen 6-10 spiroheterocycloalkyl; C 7-10 bicycloalkyl; or C having one or two oxygens 7-10 bicycloheteroalkyl; R4 is unsubstituted or substituted by one or two substituents, each of the one or two substituents being independently selected from the group consisting of C 1-4 alkyl; C 1-4 haloalkyl; hydroxy; C 1-4 hydroxyalkyl; and halogen.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein A 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, wherein L1 is a bond; -CH2-; -C≡C-; or -O-.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is hydrogen; CH3; -CONH2; -CONH(CH3); -CON(CH3)2; cyclopropyl; an unsubstituted or mono- or di-fluorine-substituted cyclobutyl; or any ring selected from the group consisting of 8-oxo-4,7-diazaspiro[2.5]oct-8-yl, 7-azaspiro[3.5]non-6-yl, 2-pyridyl, oxadiazolyl, oxopyridazinyl, pyrazolyl, or thiazolyl, and the ring is unsubstituted or substituted by CH3 or CF3.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein 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; benzod[d]oxazole; benzod[d]thiazole; morpholine; piperazin-2-one; pyrazole; or pyridine.

6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R2 and R3 are each independently hydrogen; CH3; CHF2; CF3; OCH3; F; Cl; cyano; or (oxetanyloxy).

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is N; CH; or CF.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L2 is a bond; -CH2-; -CD2-; -CH(CH3)-; -C(CH3)2-; or cyclopropene.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R4 is 2-oxaspiro[3.3]heptyl; 4-oxaspiro[2.4]heptyl; 6-oxaspiro[3.4]octyl; bicyclo[2.2.1]heptyl; cyclopropyl; cyclobutyl; cyclohexyl; hexahydrofuro[2,3-b]furan-2-yl; phenyl; piperidinyl; pyridinyl; tetrahydrofuryl; or tetrahydropyranyl, and the R4 is unsubstituted or substituted by one or two substituents, and the one or two substituents are each independently selected from the group consisting of CH3, hydroxy; CH2OH; fluorine; and chlorine.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the chemical formula 1 is represented by the following chemical formula 2: [Chemical formula 2] In chemical formula 2, X is N or CH, A is 2-pyridone; or a trivalent linker of pyridine, L1 is a key; C 1-4 an alkylene group; or C 2-4 an alkynylene group, R1 is C 1-4 alkyl; -CON(C 1-4 alkyl)2; C 3-6 cycloalkyl; C 2-10 heterocycloalkyl containing one to three heteroatoms selected from N, O or S, which is unsubstituted or substituted by C 1-4 alkyl or C 1-4 haloalkyl; or C 2-10 heteroaryl containing one to three heteroatoms selected from N, O or S, which is unsubstituted or substituted by C 1-4 alkyl or C 1-4 haloalkyl, R2 is C 1-4 alkoxy, R3 is C 1-4 a haloalkyl group; or a halogen, Y is -S-; -S(=O)-; or -S(=O)2-, L2 is a key; or C 1-4 an alkylene group which is unsubstituted or substituted with at least one deuterium R4 is C 6-10 aryl; C having one to three heteroatoms selected from N, O or S 2-10 heteroaryl; or C having one oxygen 2-6 heterocycloalkyl; R4 is unsubstituted or substituted by halogen.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound represented by chemical formula 1 is any one selected from the group consisting of: 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]oct-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]non-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]oct-7-yl)-4-morpholinonicotinamide, 50) 4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]oct-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-morpholinyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide, 58) 6-methyl-4-morpholinyl-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-(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]oct-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]oct-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-(Benz[d]thiazol-7-yl)-6-methyl-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)nicotinamide, 74) 5-(Benz[d]thiazol-7-yl)-N-(5-(tetrahydrofuran-3-ylthio)-1,3,4-thiadiazol-2-yl)pyridazine-4-carboxamide, 75) 5-(Benz[d]thiazol- ​ 12. A pharmaceutical composition for the prevention or treatment of cancer, comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

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