Novel heterocyclic compound and pharmaceutical composition comprising same

Abstract

The present invention relates to a novel heterocyclic compound represented by Chemical Formula 1 and a pharmaceutical composition comprising the same, and the compound according to the present invention can be usefully used in the prevention or treatment of cancer. In Chemical Formula 1, A, L1, R1, B, R2, R3, L2, R4 and R5 are as defined in the specification. [Chemical Formula 1] # imgabs0 #

Description

Technical Field

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

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

[0003] Powerful repair of DNA double-strand breaks (DSBs) is crucial for maintaining genomic stability and cell viability. DSBs can be repaired 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 most typical alt-NHEJ mechanism.

[0004] Polθ is unique among human DNA polymerases, exhibiting not only a C-terminal DNA polymerase domain but also an N-terminal helicase domain. A large number of genetic studies have highlighted the role of polymerase θ (Polθ) in stimulating MMEJ in higher organisms. It has been shown that cancer cells defective in HR, NHEJ, or ATM (ataxia-telangiectasia mutated; A-T mutated) are highly dependent on Polθ expression. Polθ expression is essentially absent in normal cells but is upregulated in breast, lung, and ovarian cancers. In addition, increased Polθ expression is associated with poor prognosis in breast cancer. Importantly, Polθ is largely inhibited in normal tissues but has been shown to be upregulated in matched cancer samples, thus linking elevated expression to the disease. Its suppression or inhibition confers radiosensitivity to tumor cells. Polθ inhibition may prevent the reversal of MMEJ-dependent functions of BRCA2 mutations, which is the basis for the emergence of cisplatin and PARPi (PARP inhibitor) resistance in tumors. Therefore, in cancers with DNA repair defects, Polθ is an attractive target for novel synthetic lethality 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, thus completing the present invention. The compounds belonging to the present invention mainly have Polθ inhibitory activity by themselves, but it does not exclude the possibility of exhibiting pharmacological effects as effective drugs through special body environments or metabolites of metabolic processes after being absorbed into the body. Summary of the Invention

[0006] [Technical Problem]

[0007] An object of the present invention is to provide a novel heterocyclic compound used as a Pol-θ (Polθ) inhibitor and a pharmaceutical composition comprising the same.

[0008] [Technical Solution]

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

[0010] [Chemical Formula 1]

[0011]

[0012] In Chemical Formula 1,

[0013] A is a trivalent linker of a heteroaryl ring containing one to three heteroatoms selected from N, O or S or pyridone; 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, a C containing one to three heteroatoms selected from N, O or S that is unsubstituted or substituted with C 1-4 alkyl or C 1-4 haloalkyl heterocycloalkyl, or a C containing one to three heteroatoms selected from N, O or S that is unsubstituted or substituted with C 2-10 alkyl or C 1-4 haloalkyl heteroaryl; 1-4 2-10 2-10

[0016] B is a C 6-10 aryl ring, a C containing one to three heteroatoms selected from N, O or S 2-10 ​​A heterocycloalkane ring, or a divalent linker of a heteroaryl ring 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 C containing one oxygen 2-6 heterocycloalkoxy; or, when R2 and R3 are on adjacent ring vertices, they combine to form a C 2-6 heterocycloalkyl, or a C 2-6 heteroaryl containing one to three heteroatoms selected from N, O, or S;

[0018] L2 is a bond, C 1-4 alkylene, -CO-, -CONH-, -NHCO-, -S-, or -O-;

[0019] R4 is -C≡C-R’, a C 1-4 aryl, unsubstituted or substituted with halogen or C 6-10 alkoxy, unsubstituted or substituted with hydroxy C 3-6 cycloalkyl, unsubstituted or substituted with C 1-4 alkyl, C 1-4 haloalkyl or hydroxy, containing one to three heteroatoms selected from N, O, or S C 2-10 heterocycloalkyl, or unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 haloalkyl, containing one to three heteroatoms selected from N, O, or S C 2-10 heteroaryl;

[0020] R’ is hydrogen, a C 1-4 alkyl, unsubstituted or substituted with cyano (C 1-4 alkoxy)C 1-4 alkyl, C 1-4 hydroxyalkyl, C containing one oxygen 2-6 heterocycloalkyl, unsubstituted or substituted with one or two halogens C 3-6 cycloalkyl, unsubstituted or substituted with halogen C 6-10 aryl, unsubstituted or substituted with C 1-4 alkyl, containing one to three heteroatoms selected from N, O, or S C 2-10 heteroaryl, or unsubstituted or substituted with C 1-4 alkyl, containing one to three heteroatoms selected from N, O, or S C 2-10 heterocycloalkyl; ​

[0021] R5 is hydrogen, hydroxyl, C 1-4 alkyl, C 3-6 cycloalkyl, or halogen,

[0022] provided that when L2 is a bond, R4 is -C≡C-R'.

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

[0024] In addition, for achieving the above object, there is provided a pharmaceutical composition for preventing or treating cancer, which comprises the compound or a pharmaceutically acceptable salt thereof.

[0025] [Advantageous Effects]

[0026] The compound represented by Chemical Formula 1 according to the present invention, or a pharmaceutically acceptable salt thereof, can be usefully used for preventing or treating cancer. Detailed Description of the Invention

[0027] Hereinafter, embodiments of the present invention will be described in more detail to facilitate understanding of the present invention.

[0028] Meanwhile, the present invention provides a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0029] Preferably, A is a trivalent linker of 1,3-benzodioxole, 2,3-dihydrobenzofuran, 2-pyridone, imidazo[1,5-a]pyridine, imidazole, pyridazine or pyridine.

[0030] Preferably, L1 is a bond, -CH2-, -C≡C- or -O-.

[0031] Preferably, R1 is hydrogen, CH3, -CONH2, -CONH(CH3), -CON(CH3)2, or any ring selected from the group consisting of 4,7-diazaspiro[2.5]octan-8-onyl, 7-azaspiro[3.5]nonan-6-onyl, 2-pyridonyl, oxadiazolyl, oxopyridazinyl, pyrazolyl or thiazolyl, which is unsubstituted or substituted with CH3 or CF3.

[0032] Preferably, B is a divalent 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, benz[d]oxazole, benz[d]thiazole, morpholine, piperazin-2-one, pyrazole or pyridine.

[0033] Preferably, R2 and R3 are each independently hydrogen, CH3, -C≡CH, CHF2, CF3, OCH3, F, Cl, cyano or (oxetanyl)oxy.

[0034] Preferably, L2 is a bond, -CH2-, -CO-, -CONH-, -NHCO-, -S- or -O-.

[0035] Preferably, R4 is -C≡C-R'; R' is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH(CH3)(CN), -CH2-O-CH3, 2-hydroxypropan-2-yl, 1H-pyrrolo[2,3-b]pyridinyl unsubstituted or substituted with CH3, oxetanyl, tetrahydrofuranyl, cyclopropyl unsubstituted or substituted with one or two Fs, cyclobutyl unsubstituted or substituted with one or two Fs, cyclopentyl, cyclohexyl, spiro[2.2]pentyl, phenyl unsubstituted or substituted with Cl, pyrazolyl unsubstituted or substituted with CH3, or pyridinyl.

[0036] Preferably, R4 is phenyl unsubstituted or substituted with Cl and OCH3, cyclohexyl unsubstituted or substituted with hydroxy, hexahydrofuro[2,3-b]furanyl, bicyclo[2.2.2]octanyl unsubstituted or substituted with hydroxy, 2,3-dihydrobenzofuranyl, 4-oxaspiro[2.4]heptanyl, tetrahydrofuranyl, 1,3-benzodioxolyl, or pyridinyl unsubstituted or substituted with Cl.

[0037] Preferably, R5 is hydrogen, hydroxy, CH3, cyclopropyl, or Cl.

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

[0039] [Chemical Formula 2]

[0040]

[0041] In Chemical Formula 2,

[0042] X is N or CH;

[0043] R1 is C 1-4 alkyl, or unsubstituted or substituted with C1-4 alkyl or C 1-4 C of haloalkyl containing one to three heteroatoms selected from N, O or S 2-10 heteroaryl;

[0044] R2 is C 1-4 alkoxy;

[0045] R3 is C 1-4 haloalkyl or halogen;

[0046] R' is hydrogen, C 1-4 hydroxyalkyl, C containing one oxygen 2-6 heterocycloalkyl, C unsubstituted or substituted with one or two halogens 3-6 cycloalkyl, or unsubstituted or substituted with C 1-4 C of alkyl containing one to three heteroatoms selected from N, O or S 2-10 heteroaryl, R5 is hydrogen, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl or halogen.

[0047] Representative examples of the compound represented by Chemical Formula 1 are as follows:

[0048] 1) 2'-Chloro-N-(6-ethynylthiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0049] 2) 2'-Chloro-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0050] 3) 2'-Chloro-5'-methoxy-6-methyl-N-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0051] 4) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0052] 5) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinamide,

[0053] 6) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide,

[0054] 7) 2'-Chloro-N-(6-((3,3-difluorocyclobutyl)ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0055] 8) N-(6-(Cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)nicotinamide,

[0056] 9) N-(6-(Cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)nicotinamide,

[0057] 10) N-(6-(Cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)nicotinamide,

[0058] 11) 2'-Chloro-N-(5-cyclopropyl-6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0059] 12) 2'-Chloro-N-(6-(cyclopropyl ethynyl)-5-methylthiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0060] 13) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(oxetan-3-yl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0061] 14) 2'-Chloro-5'-methoxy-N-(6-(3-methoxyprop-1-ynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-4,4'-bipyridine-3-carboxamide,

[0062] 15) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(pyridin-2-yl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0063] 16) 2'-Chloro-N-(6-((4-chlorophenyl)ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0064] 17) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(spiro[2.2]pent-1-ylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0065] 18) 2'-Chloro-5'-methoxy-6-methyl-N-(6-((tetrahydrofuran-3-yl)ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0066] 19) 2'-Chloro-5'-methoxy-6-methyl-N-(6-((1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0067] 20) 2'-Chloro-N-(5-chloro-6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0068] 21) 2'-Chloro-N-(6-(cyclopropylethynyl)-5-hydroxythiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0069] 22) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(tetrahydrofuran-3-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0070] 23) 2'-Chloro-N-(6-((5-chloropyridin-2-yl)methyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0071] 24) 2'-Chloro-5'-methoxy-6-methyl-N-(6-((tetrahydrofuran-3-yl)methyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0072] 25) N-(6-(4-oxaspiro[2.4]hept-6-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0073] 26) 2'-Chloro-N-(6-(5-chloropyridin-2-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0074] 27) 2'-Chloro-N-(6-(4-chloro-3-methoxyphenoxy)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0075] 28) 2-(2'-Chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamido)-N-(tetrahydrofuran-3-yl)thiazolo[4,5-b]pyrazine-6-carboxamide,

[0076] 29) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(tetrahydrofuran-3-carboxamido)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0077] 30) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(morpholine-4-carbonyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0078] 31) 2'-Chloro-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-4,4'-bipyridine-3-carboxamide,

[0079] 32) N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)nicotinamide,

[0080] 33) 2'-Chloro-N-(6-(5-chloropyridin-2-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-4,4'-bipyridine-3-carboxamide,

[0081] 34) 2'-Chloro-5'-methoxy-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(6-(tetrahydrofuran-3-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0082] 35) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide,

[0083] 36) 2'-Chloro-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]octan-7-yl)-4,4'-bipyridine-3-carboxamide,

[0084] 37) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-2,3-dihydrobenzofuran-6-carboxamide,

[0085] 38) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-4-carboxamide,

[0086] 39) 2'-Chloro-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-(6-oxo-7-azaspiro[3.5]nonan-7-yl)-4,4'-bipyridine-3-carboxamide,

[0087] 40) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1,2-dihydropyridine-4-carboxamide,

[0088] 41) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide,

[0089] 42) 1-(2-Amino-2-oxoethyl)-5-(2-chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-2-oxo-1,2-dihydropyridine-4-carboxamide,

[0090] 43) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-1-(2-(methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-4-carboxamide,

[0091] 44) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-1-(2-(dimethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-4-carboxamide,

[0092] 45) 2'-Chloro-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-(thiazol-2-yloxy)-4,4'-bipyridine-3-carboxamide,

[0093] 46) 2'-Chloro-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-(oxetan-3-yl ethynyl)-4,4'-bipyridine-3-carboxamide,

[0094] 47) 2'-Chloro-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4,4'-bipyridine-3-carboxamide,

[0095] 48) 7-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)imidazo[1,5-a]pyridine-6-carboxamide,

[0096] 49) 1-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-1H-imidazole-5-carboxamide,

[0097] 50) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)pyridazine-4-carboxamide,

[0098] 51) 6-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)benzo[d][1,3]dioxole-5-carboxamide,

[0099] 52) N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-4-morpholinonicotinamide,

[0100] 53) N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0101] 54) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide,

[0102] 55) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinamide,

[0103] 56) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylnicotinamide,

[0104] 57) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-ethynyl-2-methoxyphenyl)-6-methylnicotinamide,

[0105] 58) 4-(5-Cyano-2-methoxyphenyl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide,

[0106] 59) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-4-(2-(oxetan-3-yloxy)phenyl)nicotinamide,

[0107] 60) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-6-methylnicotinamide,

[0108] 61) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(3,5-dimethyl-1H-pyrazol-4-yl)-6-methylnicotinamide,

[0109] 62) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-6-methylnicotinamide,

[0110] 63) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-4-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinamide,

[0111] 64) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-4-(2-methyl-3-oxopiperazin-1-yl)nicotinamide,

[0112] 65) 4-(2-Oxa-5-azabicyclo[4.1.0]heptan-5-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide,

[0113] 66) 4-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide,

[0114] 67) 4-(Benzo[d]thiazol-7-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide,

[0115] 68) 4-(Benzo[d]oxazol-7-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide,

[0116] 69) N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-6-methylnicotinamide,

[0117] 70) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(prop-2-yn-1-yl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0118] 71) 2'-Chloro-N-(6-(3-cyclopropylprop-2-yn-1-yl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0119] 72) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(3-(oxetan-3-yl)prop-2-yn-1-yl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0120] 73) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(3-(1-methyl-1H-pyrazol-4-yl)prop-2-yn-1-yl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0121] 74) 2'-Chloro-N-(6-(3-cyanobut-1-yn-1-yl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0122] 75) 2'-Chloro-N-(5-chloro-6-((tetrahydrofuran-3-yl)methyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0123] 76) 2'-Chloro-5'-methoxy-6-methyl-N-(5-methyl-6-((tetrahydrofuran-3-yl)methyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0124] 77) 2'-Chloro-5'-methoxy-6-methyl-N-(5-methyl-6-(tetrahydrofuran-3-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0125] 78) 2'-Chloro-N-(6-((5-chloropyridin-2-yl)methyl)-5-methylthiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0126] 79) 2'-Chloro-N-(6-(5-chloropyridin-2-yloxy)-5-methylthiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0127] 80) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(tetrahydrofuran-3-ylthio)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0128] 81) 2'-Chloro-5'-methoxy-6-methyl-N-(5-methyl-6-(tetrahydrofuran-3-ylthio)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide,

[0129] 82) 2'-Chloro-N-(6-(5-chloropyridin-2-ylthio)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0130] 83) 2'-Chloro-N-(6-(5-chloropyridin-2-ylthio)-5-methylthiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0131] 84) 2'-Chloro-N-(6-(4-hydroxycyclohexyloxy)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0132] 85) 2'-Chloro-N-(6-(hexahydrofuro[2,3-b]furan-3-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0133] 86) 2'-Chloro-N-(6-(5-hydroxybicyclo[2.2.2]octan-2-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0134] 87) N-(6-(benzo[d][1,3]dioxol-4-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0135] 88) 2'-Chloro-N-(6-(2,3-dihydrobenzofuran-3-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0136] 89) 2'-Chloro-N-(6-(4-chloro-3-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0137] 90) 2'-Chloro-N-(6-((4-hydroxycyclohexyl)methyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0138] 91) N-(6-(4-oxaspiro[2.4]heptan-6-ylmethyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0139] 92) 2'-Chloro-N-(6-((hexahydrofuro[2,3-b]furan-3-yl)methyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0140] 93) 2'-Chloro-N-(6-((5-hydroxybicyclo[2.2.2]octan-2-yl)methyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0141] 94) 2'-Chloro-N-(6-(4-chloro-3-methoxyphenylthio)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0142] 95) 2'-Chloro-N-(6-(4-hydroxycyclohexylthio)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0143] 96) N-(6-(4-oxaspiro[2.4]heptan-6-ylthio)thiazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0144] 97) 2'-Chloro-N-(6-(hexahydrofuro[2,3-b]furan-3-ylthio)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0145] 98) 2'-Chloro-N-(6-(5-hydroxybicyclo[2.2.2]octan-2-ylthio)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide,

[0146] 99) 4-(2-Chloro-5-methoxypyridin-4-yl)-N-[6-(cyclopentylethynyl)[1,3]thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide,

[0147] 100) 4-(2-Chloro-5-methoxypyridin-4-yl)-N-[6-(3,3-dimethylbut-1-ynyl)[1,3]thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide,

[0148] 101) 2'-Chloro-N-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide, and

[0149] 102) 4-(2-Chloro-5-methoxypyridin-4-yl)-N-[6-(cyclohexylethynyl)[1,3]thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide.

[0150] In addition, the compounds of the present invention may exist in the form of salts, especially in the form of pharmaceutically acceptable salts. As salts, salts commonly used in the art can be used without limitation, such as acid addition salts formed from pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound represented by Chemical Formula 1, which is relatively non-toxic and harmless to the patient, effectively activated, and whose side effects do not reduce the beneficial effects of the above compound.

[0151] 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.

[0152] In addition, pharmaceutically acceptable metal salts can be obtained by conventional methods using bases. For example, the compound represented by Chemical Formula 1 is dissolved in an excessive solution of alkali metal hydroxide or alkaline earth metal hydroxide, the insoluble salt is filtered, and then the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt. At this time, it is particularly preferred to prepare sodium salt, potassium salt or calcium salt as the metal salt.

[0153] In addition, when preparing the compound of Chemical Formula 1 or its pharmaceutically acceptable salt or solvate, a pharmaceutically unacceptable salt or solvate of the compound of Chemical Formula 1 can be used as an intermediate.

[0154] In one embodiment, the compound represented by Chemical Formula 1 can be prepared by the following Reaction Scheme 1.

[0155] [Reaction Scheme 1]

[0156]

[0157] In Reaction Scheme 1, A, L1, R1, B, R2, R3, L2, R4 and R5 are as defined above, and Y is a halogen. Preferably, Y is bromine or chlorine.

[0158] Step 1 is a step of preparing the compound represented by Chemical Formula 3' by reacting the compound represented by Chemical Formula 1' with the compound represented by Chemical Formula 2', which is an amidation reaction. Step 2 is a step of preparing the compound represented by Chemical Formula 1, in which -L2-R4 is substituted and the halogen (Y) is eliminated.

[0159] The above preparation method will be described more specifically in the examples described below.

[0160] According to another embodiment of the present invention, there is provided a pharmaceutical composition comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0161] According to another embodiment of the present invention, there is provided a pharmaceutical composition for preventing or treating cancer diseases, which is effective for Polθ inhibitory action, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0162] In this case, the cancer may be blood cancer, extranodal marginal zone B-cell lymphoma, glioblastoma, lymphoplasmacytic lymphoma, acute myeloid leukemia, 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.

[0163] As used herein, the term "prevention" refers to any act of delaying or suppressing the occurrence, spread or recurrence of the above diseases by administering the composition of the present invention, while "treatment" refers to any act of better improving or altering the symptoms of the above diseases by administering the composition of the present invention.

[0164] The pharmaceutical composition according to the present invention can be formulated into a type for oral or parenteral administration according to standard pharmaceutical practice. In addition to the active ingredient, these preparations may also contain additives such as pharmaceutically acceptable carriers, adjuvants or diluents.

[0165] Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil, isopropyl myristate, etc. Diluents include, for example, lactose, glucose, sucrose, mannitol, sorbitol, cellulose and / or glycine, etc., but are not limited thereto. In addition, the compounds of the present invention can be dissolved in oils, propylene glycol or other solvents commonly used for preparing injection solutions. In addition, the compounds of the present invention can be formulated into ointments or creams for topical administration.

[0166] The preferred dose of the compound of the present invention may vary depending on the condition and weight of the patient, the severity of the disease, the type of drug, and the route and duration of administration, but can be appropriately selected by those skilled in the art. However, in order to achieve the desired effect, the compound of the present invention can be administered at a dose of 0.0001 mg / kg (body weight) to 100 mg / kg (body weight) per day, preferably at a dose of 0.001 mg / kg (body weight) to 100 mg / kg (body weight). It can be administered once a day or in divided doses per day through oral or parenteral routes.

[0167] Depending on the administration method, the pharmaceutical composition may contain from 0.001% to 99% by weight of the compound of the present invention, preferably from 0.01% to 60% by weight of the compound of the present invention.

[0168] The pharmaceutical composition according to the present invention 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.

[0169] Hereinafter, the present invention will be described in more detail by way of examples. However, these examples are for illustrative purposes only and should not be construed as limiting the scope of the present invention to these examples.

[0170] Example 1: Synthesis of Compound 1

[0171]

[0172] Step A: N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxamide

[0173] At 25 °C, to a solution of 4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (241.22 mg, 0.87 mmol) in DMF (2 mL) was added 6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-amine (200 mg, 0.87 mmol), DIEA (335.59 mg, 2.60 mmol) and HATU (493.67 mg, 1.30 mmol). The reaction was stirred at 25 °C for 16 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA conditions) to give N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxamide (40.0 mg, 0.08 mmol) as a yellow solid.

[0174] LCMS: m / z (M+H) + = 491.0 / 493.0.

[0175] Step B: 4-(2-chloro-5-methoxypyridin-4-yl)-6-methyl-N-{6-[(trimethylsilyl)ethynyl][1,3]thiazolo[4,5-b]pyrazin-2-yl}pyridine-3-carboxamide

[0176] At 25 °C, CuI (0.77 mg), ethynyltrimethylsilane (2.00 mg, 0.02 mmol), DIEA (0.01 mL, 0.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.70 mg) were added to a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxamide (10 mg, 0.02 mmol) in DMF (1 mL). The mixture was degassed three times with N2 and stirred at 70 °C for 1 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA conditions) to give 4-(2-chloro-5-methoxypyridin-4-yl)-6-methyl-N-{6-[(trimethylsilyl)ethynyl][1,3]thiazolo[4,5-b]pyrazin-2-yl}pyridine-3-carboxamide (8 mg, 0.02 mmol) as a white solid.

[0177] LCMS: m / z (M+H) + = 509.2.

[0178] Step C: 2'-Chloro-N-(6-ethynylthiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide

[0179] At 25 °C, K2CO3 (5.43 mg, 0.04 mmol) was added to a solution of 4-(2-chloro-5-methoxypyridin-4-yl)-6-methyl-N-{6-[(trimethylsilyl)ethynyl][1,3]thiazolo[4,5-b]pyrazin-2-yl}pyridine-3-carboxamide (8 mg, 0.02 mmol) in methanol (1 mL). The reaction was stirred at 25 °C for 1 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA conditions) to give 2'-chloro-N-(6-ethynylthiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide (3.1 mg, 0.01 mmol) as a white solid.

[0180] 1 1H NMR (400 MHz, MeOD) δ 8.89 (s, 1H), 8.69 (s, 1H), 8.10 (s, 1H), 7.55 (s, 1H), 7.48 (s, 1H), 4.00 (s, 1H), 3.73 (s, 3H), 2.71 (s, 3H).

[0181] LCMS: m / z (M+H) + = 437.2.

[0182] Example 2: Synthesis of Compound 2

[0183]

[0184] At 25 °C, ethynylcyclopropane (2.69 mg, 0.03 mmol), CuI (1.55 mg, 0.01 mmol), DIEA (0.01 mL, 0.08 mmol), and tetrakis(triphenylphosphine)palladium(0) (9.40 mg, 0.01 mmol) were added to a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxamide (20 mg, 0.04 mmol) in DMF (1 mL). The mixture was degassed three times with N2 and stirred at 70 °C for 1 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA conditions) to give 2'-chloro-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide (4.5 mg, 0.01 mmol) as a white solid.

[0185] 1 H NMR (400 MHz, MeOD) δ 8.85 (s, 1H), 8.54 (s, 1H), 8.08 (s, 1H), 7.53 (s, 1H), 7.48 (s, 1H), 3.71 (s, 3H), 2.69 (s, 3H), 1.63 - 1.54 (m, 1H), 1.00 (s, 2H), 0.88 (s, 2H).

[0186] LCMS: m / z (M + H) + = 477.2.

[0187] Example 3: Synthesis of Compound 3

[0188]

[0189] At 25 °C, to a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxamide (10 mg, 0.02 mmol) in DMF (1 mL) was added 4-ethynyl-1-methylpyrazole (2.55 mg, 0.02 mmol), DIEA (0.01 mL, 0.04 mmol), CuI (0.76 mg, 0.001 mmol), and tetrakis(triphenylphosphine)palladium(0) (4.62 mg). The mixture was degassed with N2 three times and stirred at 90 °C for 1 h. After completion, the filtrate was concentrated under reduced pressure. The residue was purified by pre-HPLC (NH4HCO3 conditions) to give 2'-chloro-5'-methoxy-6-methyl-N-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide (0.41 mg, 0.001 mmol) as a yellow solid.

[0190] LCMS: m / z (M+H) + = 517.2.

[0191] Example 4: Synthesis of Compound 4

[0192]

[0193] Step A: Methyl 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate

[0194] At 25 °C under N2, to a solution of [2-(difluoromethyl)-5-methoxypyridin-4-yl]boronic acid pinacol ester (200 mg, 0.99 mmol) in dioxane (8.0 mL) was added methyl 4-bromo-6-methylpyridine-3-carboxylate (249 mg, 1.08 mmol), potassium carbonate (408 mg, 2.95 mmol), and Pd(dppf)Cl2 (144 mg, 0.20 mmol). The mixture was stirred at 100 °C for 2 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether:EtOAc = 10:1 to 5:1) to give methyl 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (180 mg, 0.58 mmol) as a yellow oil.

[0195] LCMS: m / z (M+H) + = 309.1.

[0196] Step B: 2'-(Difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid

[0197] At 25 °C, lithium hydroxide (28 mg, 1.17 mmol) was added to a stirred solution of methyl 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (180 mg, 0.58 mmol) in methanol / H2O (4:1) (5.0 mL). The mixture was stirred at 25 °C for 18 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (TFA conditions) to give 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (130 mg, 0.44 mmol) as a white solid.

[0198] LCMS: m / z (M+H) + = 295.0.

[0199] Step C: N-(6-Bromothiazolo[4,5-b]pyrazin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[0200] At 25 °C, 6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-amine (122 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (127 mg, 0.66 mmol) and 4-dimethylaminopyridine (161 mg, 1.32 mmol) were added to a solution of 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (130 mg, 0.44 mmol) in DCM (5 mL). The mixture was stirred at 25 °C for 18 h. Upon completion, the reaction was concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: petroleum ether:EtOAc = 10:1 to 3:1) to give N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (70 mg) as a yellow oil.

[0201] LCMS: m / z (M+H) + = 507.0 / 509.0.

[0202] Step D: N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide

[0203] At 25 °C under N2, to a solution of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (70 mg, 0.14 mmol) in N,N-dimethylformamide (5 mL) was added ethynylcyclopropane (18 mg, 0.27 mmol), copper(I) iodide (10 mg, 0.05 mmol), tetrakis(triphenylphosphine)palladium(0) (31 mg, 0.03 mmol), and N,N-diisopropylethylamine (53 mg, 0.41 mmol). The mixture was stirred at 70 °C under N2 for 18 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by Prep-HPLC (ACN: water (1‰ FA) conditions) to give N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide (0.82 mg, 0.01 mmol) as a white solid.

[0204] 1 H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 8.40 (d, J = 21.6 Hz, 1H), 8.15 (s, 1H), 7.59 (s, 1H), 7.28 (s, 1H), 7.22–6.38 (m, 2H), 3.69 (s, 3H), 2.57 (s, 3H), 1.24 (s, 1H), 0.94–0.92 (m2H), 0.82–0.79 (m, 2H).

[0205] LCMS: m / z (M+H) + = 493.2.

[0206] Example 5: Synthesis of Compound 5

[0207]

[0208] Step A: 4-(Difluoromethyl)-2-iodo-1-methoxybenzene

[0209] At 0 °C, DAST (5.04 mL, 38.16 mmol) was added to a solution of 3-iodo-4-methoxybenzene-1-carbaldehyde (5000 mg, 19.08 mmol) in DCM (50 mL). The reaction was stirred at 25 °C for 16 h. After completion, the mixture was quenched with an aqueous NaHCO3 solution (100 mL), extracted with DCM (100 mL × 2), the organic layer was washed with brine (100 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 100:1 to 10:1) to give 4-(difluoromethyl)-2-iodo-1-methoxybenzene (3400 mg, 10.77 mmol) as a colorless oil.

[0210] Step B: 2-[5-(Difluoromethyl)-2-methoxyphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0211] At 25 °C, KOAc (3524.25 mg, 35.91 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (6079.40 mg, 23.94 mmol) and Pd(dppf)Cl2 (875.87 mg, 1.20 mmol) were added to a solution of 4-(difluoromethyl)-2-iodo-1-methoxybenzene (3400 mg, 11.97 mmol) in dioxane (40 mL). The reaction was degassed with N2 three times and stirred at 100 °C for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 5:1) to give 2-[5-(difluoromethyl)-2-methoxyphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3100 mg, 9.82 mmol) as a colorless oil.

[0212] LCMS: m / z (M + H) + = 285.2.

[0213] Step C: Methyl 4-[5-(difluoromethyl)-2-methoxyphenyl]-6-methylpyridine-3-carboxylate

[0214] At 25 °C, to a solution of methyl 4-chloro-6-methylpyridine-3-carboxylate (2200 mg, 11.85 mmol) in dioxane (30 mL) was added 2-[5-(difluoromethyl)-2-methoxyphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3704.25 mg, 13.04 mmol), KOAc (3489.70 mg, 35.56 mmol) and PdCl2(dppf) (867.28 mg, 1.19 mmol). The reaction was degassed three times with N2 and stirred at 100 °C for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:2) to give methyl 4-[5-(difluoromethyl)-2-methoxyphenyl]-6-methylpyridine-3-carboxylate (3100 mg, 10.09 mmol) as a white solid.

[0215] LCMS: m / z(M+H) + = 308.2.

[0216] Step D: 4-[5-(Difluoromethyl)-2-methoxyphenyl]-6-methylpyridine-3-carboxylic acid

[0217] To a solution of methyl 4-[5-(difluoromethyl)-2-methoxyphenyl]-6-methylpyridine-3-carboxylate (2700 mg, 8.79 mmol) in MeOH (20 mL) and water (5 mL) was added LiOH (737.66 mg, 17.58 mmol). The reaction was stirred at 25 °C for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (FA conditions) to give 4-[5-(difluoromethyl)-2-methoxyphenyl]-6-methylpyridine-3-carboxylic acid (510 mg, 1.63 mmol) as a white solid.

[0218] LCMS: m / z(M+H) + = 294.2.

[0219] Step E: N-(6-Bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-[5-(difluoromethyl)-2-methoxyphenyl]-6-methylpyridine-3-carboxamide

[0220] At 25 °C, 4-[5-(difluoromethyl)-2-methoxyphenyl]-6-methylpyridine-3-carboxylic acid (126.92 mg, 0.43 mmol), DMAP (52.87 mg, 0.43 mmol) and EDCI (165.92 mg, 0.87 mmol) were added to a solution of 6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-amine (100 mg, 0.43 mmol) in Py (2 mL). The reaction was stirred at 35 °C for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 20:1 to 10:1) to give N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-[5-(difluoromethyl)-2-methoxyphenyl]-6-methylpyridine-3-carboxamide (95 mg, 0.17 mmol) as a yellow solid.

[0221] LCMS: m / z (M+H) + = 506.0 / 508.0.

[0222] Step F: N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinamide

[0223] At 25 °C, ethynylcyclopropane (0.02 mL, 0.20 mmol), CuI (3.76 mg, 0.02 mmol), DIEA (0.03 mL, 0.20 mmol) and tetrakis(triphenylphosphine)palladium(0) (22.82 mg, 0.02 mmol) were added to a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-[5-(difluoromethyl)-2-methoxyphenyl]-6-methylpyridine-3-carboxamide (50 mg, 0.10 mmol) in DMF (1 mL). The reaction was degassed three times with N2 and stirred at 75 °C for 1 h. After filtration, the filtrate was purified by pre-HPLC (FA conditions) to give N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinamide (10 mg, 0.02 mmol) as a white solid.

[0224] 11H NMR (400 MHz, CDCl3) = 8.96 (s, 1H), 8.52 (s, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.48 (s, 1H), 7.22 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 6.68 (t, J = 56.6 Hz, 1H), 3.77 (s, 3H), 2.73 (s, 3H), 1.56 - 1.54 (m, 1H), 1.01 - 0.88 (m, 4H).

[0225] LCMS: m / z (M+H) + = 492.2.

[0226] Example 6: Synthesis of Compound 6

[0227]

[0228] Step A: N-(6-Bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-[5-methoxy-2-(trifluoromethyl)pyridin-4-yl]-6-methylpyridine-3-carboxamide

[0229] At 25 °C, to a solution of 4-[5-methoxy-2-(trifluoromethyl)pyridin-4-yl]-6-methylpyridine-3-carboxylic acid (50 mg, 0.16 mmol) and 6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-amine (37.00 mg, 0.16 mmol) in DMF (3 mL) was added TCFH (58.41 mg, 0.21 mmol) and 1-methylimidazole (0.04 mL, 0.48 mmol). The mixture was stirred at 25 °C for 2 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to give N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-[5-methoxy-2-(trifluoromethyl)pyridin-4-yl]-6-methylpyridine-3-carboxamide (63 mg, 0.07 mmol) as a white solid.

[0230] LCMS: m / z (M+H) + = 525.2 / 527.2.

[0231] Step B: N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide

[0232] At 25 °C, to a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-[5-methoxy-2-(trifluoromethyl)pyridin-4-yl]-6-methylpyridine-3-carboxamide (31 mg, 0.06 mmol) and ethynylcyclopropane (0.01 mL, 0.12 mmol) in DMF (2 mL) was added palladium(II) chloride bis(triphenylphosphine) (4.21 mg, 0.01 mmol), CuI (2.25 mg, 0.01 mmol) and TEA (0.02 mL, 0.12 mmol). The mixture was stirred at 70 °C under N2 for 2 h. After filtration, the filtrate was purified by high performance liquid chromatography (TFA / acetonitrile / water) to give N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide (4.54 mg, 0.01 mmol) as a white solid.

[0233] 1 H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 8.43 (d, J = 5.2 Hz, 2H), 7.60 (s, 1H), 7.23 (s, 1H), 3.85 (s, 3H), 2.72 (s, 3H), 1.56 (m, 1H), 0.98 (m, 4H).

[0234] LCMS: m / z (M+H) + = 511.2.

[0235] Example 7: Synthesis of Compound 7

[0236]

[0237] At 25 °C, to a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxamide (300 mg, 0.61 mmol) in DMF (4 mL) was added 3-ethynyl-1,1-difluorocyclobutane (77.92 mg, 0.67 mmol), CuI (11.62 mg, 0.06 mmol), DIEA (0.20 mL, 1.22 mmol), and tetrakis(triphenylphosphine)palladium(0) (35.25 mg, 0.03 mmol). The reaction was degassed three times with N2 and stirred at 70 °C for 1 h. After filtration, the filtrate was purified by pre-HPLC (FA conditions) to give 2'-chloro-N-(6-((3,3-difluorocyclobutyl)ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide (135 mg, 0.25 mmol) as a white solid.

[0238] 1 1H NMR (400 MHz, DMSO-d6) δ 8.91 - 8.87 (m, 1H), 8.71 (s, 1H), 8.18 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 3.63 (s, 3H), 3.27 - 2.99 (m, 3H), 2.88 - 2.74 (m, 2H), 2.61 (s, 3H).

[0239] LCMS: m / z (M+H) + = 527.2.

[0240] Example 8: Synthesis of Compound 8

[0241]

[0242] Step A: Methyl 6-chloro-4-iodopyridine-3-carboxylate

[0243] At 25 °C, to a solution of 6-chloro-4-iodopyridine-3-carboxylic acid (300 mg, 1.06 mmol) and Cs2CO3 (1034.53 mg, 3.18 mmol) in DMF (10 mL) was added iodomethane (0.07 mL, 1.06 mmol). The mixture was stirred at 25 °C for 16 h to give a yellow solution. Upon completion, the mixture was quenched 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 = 0 to 5%) to give methyl 6-chloro-4-iodopyridine-3-carboxylate (300 mg, 1.00 mmol) as a white solid.

[0244] LCMS: m / z (M+H) + = 298.0

[0245] Step B: Methyl 6-chloro-4-[2-methoxy-5-(trifluoromethyl)phenyl]pyridine-3-carboxylate

[0246] At 25 °C under N2, to a solution of methyl 6-chloro-4-iodopyridine-3-carboxylate (300 mg, 1.01 mmol) and [2-methoxy-5-(trifluoromethyl)phenyl]boronic acid pinacol ester (221.81 mg, 1.01 mmol) in dioxane (8 mL) and H2O (2 mL) was added Pd(dppf)Cl2 (73.79 mg, 0.10 mmol) and K2CO3 (418.11 mg, 3.03 mmol). The mixture was stirred at 80 °C under N2 for 2 h to give a black suspension. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 0 to 20%) to give methyl 6-chloro-4-[2-methoxy-5-(trifluoromethyl)phenyl]pyridine-3-carboxylate (290 mg, 0.69 mmol) as a white solid.

[0247] LCMS: m / z (M+H) + = 346.0

[0248] Step C: Methyl 4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylate

[0249] At 25 °C under N2, to a solution of methyl 6-chloro-4-[2-methoxy-5-(trifluoromethyl)phenyl]pyridine-3-carboxylate (270 mg, 0.78 mmol) and 5-methyl-2H,3H-1,2-diazin-3-one (172.01 mg, 1.56 mmol) in toluene (10 mL) was added tripotassium phosphate (331.56 mg, 1.56 mmol), CuI (14.87 mg, 0.08 mmol) and 2,5-diazabicyclo[2.2.1]heptane (0.02 mL, 0.16 mmol). The mixture was stirred at 120 °C under N2 for 16 h to give a brown solution. After completion, the mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (trifluoroacetic acid / acetonitrile / water) to give methyl 4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylate (100 mg, 0.21 mmol) as a white solid.

[0250] LCMS: m / z (M+H) + = 420.3

[0251] Step D: 4-[2-Methoxy-5-(trifluoromethyl)phenyl]-6-(4-methyl-6-oxo-1,2-dihydropyridazin-1-yl)pyridine-3-carboxylic acid

[0252] At 25 °C, LiOH (12.01 mg, 0.29 mmol) was added to a solution of methyl 4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-(4-methyl-6-oxo-1,2-dihydropyridazin-1-yl)pyridine-3-carboxylate (100 mg, 0.24 mmol) in THF (3 mL) and H2O (2 mL). The mixture was stirred at 25 °C for 16 h to give a yellow solution. After completion, the mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL). Under an ice bath, the aqueous phase was adjusted to pH = 3 with HCl (2 N in H2O) and extracted with EtOAc (20 mL × 2). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 0 to 10%) to give 4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-(4-methyl-6-oxo-1,2-dihydropyridazin-1-yl)pyridine-3-carboxylic acid (30 mg, 0.06 mmol) as a white solid.

[0253] LCMS: m / z (M+H) + = 406.2

[0254] Step E: N-(6-Bromo[1,3]thiazolo[4,5-b]pyridazin-2-yl)-4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-(4-methyl-6-oxo-1,2-dihydropyridazin-1-yl)pyridine-3-carboxamide

[0255] At 25 °C, DMAP (1.83 mg, 0.02 mmol) and EDCI (2.88 mg, 0.02 mmol) were added to a solution of 4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxylic acid (80 mg, 0.01 mmol) and 6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-amine (2.31 mg, 0.01 mmol) in DCM (3 mL). The mixture was stirred at 25 °C for 3 h to obtain a brown solution. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM:MeOH = 0 to 6%) to give N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxamide (30 mg, 0.03 mmol) as a white solid.

[0256] LCMS: m / z (M+H) + = 618.2 / 620.2.

[0257] Step F: N-(6-(Cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)nicotinamide

[0258] At 25 °C under N2, palladium chloride bis(triphenylphosphine) (3.41 mg), CuI (1.85 mg, 0.01 mmol), and TEA (0.01 mL, 0.10 mmol) were added to a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-(4-methyl-6-oxo-1,2-diazin-1-yl)pyridine-3-carboxamide (30 mg, 0.05 mmol) and ethynylcyclopropane (0.01 mL, 0.10 mmol) in DMF (2 mL). The mixture was stirred at 70 °C under N2 for 2 h to obtain a brown solution. After filtration, the filtrate was purified by high performance liquid chromatography (TFA / acetonitrile / water) to give N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)nicotinamide (9.34 mg, 0.01 mmol) as a white solid.

[0259] 11H NMR (400 MHz, CDCl3) δ 11.55 (s, 1H), 8.85 (s, 1H), 8.43 (s, 1H), 7.77 (d, J = 26.2 Hz, 2H), 7.60 (dd, J = 8.8, 2.2 Hz, 1H), 7.49 (s, 1H), 6.88–6.74 (m, 2H), 3.58 (s, 3H), 2.25 (s, 3H), 1.46 (m, 1H), 0.94–0.77 (m, 4H).

[0260] LCMS: m / z (M+H) + = 604.4.

[0261] Example 9: Synthesis of Compound 9

[0262]

[0263] Step A: Methyl 4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-(1-methyl-2-oxopyridin-3-yl)pyridine-3-carboxylate

[0264] At 20 °C under N2, 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) was added K2CO3 (39.98 mg, 0.29 mmol), 3-(dihydroxyboranyl)-1-methyl-1,2-dihydropyridin-2-one (44.24 mg, 0.29 mmol) and bis[5-(diphenylphosphino)cyclopent-1,3-dienyl]-λ2-iron(II) chloride palladium (21.17 mg, 0.03 mmol). The mixture was stirred at 80 °C for 16 h. After completion, the reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 3:1) 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.

[0265] LCMS: m / z (M+H) + = 419.2.

[0266] Step B: 4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-(1-methyl-2-oxopyridin-3-yl)pyridine-3-carboxylic acid

[0267] At 20 °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 20 °C for 2 h. Upon completion, the reaction 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 Na2SO4, 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 as a white solid (60 mg, 0.13 mmol).

[0268] LCMS: m / z (M + H) + = 405.2

[0269] Step C: N-(6-Bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-(1-methyl-2-oxopyridin-3-yl)pyridine-3-carboxamide

[0270] At 20 °C, DMAP (18.13 mg, 0.15 mmol), EDCI (28.45 mg, 0.15 mmol) and 6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-amine (22.86 mg, 0.10 mmol) were added to a solution of 4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-(1-methyl-2-oxopyridin-3-yl)pyridine-3-carboxylic acid (40 mg, 0.10 mmol) in DCM (3 mL). The mixture was stirred at 20 °C for 3 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:1) to give N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-(1-methyl-2-oxopyridin-3-yl)pyridine-3-carboxamide as a yellow solid (25 mg, 0.04 mmol).

[0271] LCMS: m / z (M + H) + = 617.2 / 619.2

[0272] Step D: N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)nicotinamide

[0273] At 20 °C under N2, to a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-(1-methyl-2-oxopyridin-3-yl)pyridine-3-carboxamide (40 mg, 0.06 mmol) in DMF (1.5 mL) was added DIEA (0.02 mL, 0.13 mmol), CuI (2.47 mg, 0.01 mmol), ethynylcyclopropane (0.01 mL, 0.06 mmol) and Pd(PPh3)4 (4.55 mg, 0.01 mmol). The mixture was stirred at 70 °C under N2 for 16 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (TFA / acetonitrile / water) to give N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)nicotinamide (1.55 mg) as a white solid.

[0274] LCMS: m / z (M+H) + = 603.4.

[0275] Example 10: Synthesis of Compound 10

[0276]

[0277] Step A: Methyl 4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-[2-oxo-4-(trifluoromethyl)pyridin-1-yl]pyridine-3-carboxylate

[0278] At 20 °C, to a solution of methyl 6-chloro-4-[2-methoxy-5-(trifluoromethyl)phenyl]pyridine-3-carboxylate (50 mg, 0.14 mmol) in Tol (3 mL) was added K3PO4 (92.10 mg, 0.43 mmol), CuI (5.51 mg, 0.03 mmol), 4-(trifluoromethyl)pyridin-2-ol (23.59 mg, 0.14 mmol) and methyl[2-(methylamino)cyclohexyl]amine (2.06 mg, 0.01 mmol). The mixture was stirred at 120 °C for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:1) to give methyl 4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-[2-oxo-4-(trifluoromethyl)pyridin-1-yl]pyridine-3-carboxylate (41 mg, 0.08 mmol) as a yellow solid.

[0279] LCMS: m / z (M+H) + = 473.2.

[0280] Step B: 4-[2-Methoxy-5-(trifluoromethyl)phenyl]-6-[2-oxo-4-(trifluoromethyl)pyridin-1-yl]pyridine-3-carboxylic acid

[0281] At 20 °C, to a solution of methyl 4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-[2-oxo-4-(trifluoromethyl)pyridin-1-yl]pyridine-3-carboxylate (83 mg, 0.18 mmol) in THF (4 mL), MeOH (0.5 mL) and H2O (1 mL) was added LiOH (10.03 mg, 0.24 mmol). The mixture was stirred at 20 °C for 2 h. After completion, the reaction 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 Na2SO4, filtered and concentrated under reduced pressure to give 4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-[2-oxo-4-(trifluoromethyl)pyridin-1-yl]pyridine-3-carboxylic acid (38 mg, 0.08 mmol) as a white solid.

[0282] LCMS: m / z (M+H) + = 459.2.

[0283] Step C: N-(6-Bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-[2-oxo-4-(trifluoromethyl)pyridin-1-yl]pyridine-3-carboxamide

[0284] At 20 °C, to a solution of 4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-[2-oxo-4-(trifluoromethyl)pyridin-1-yl]pyridine-3-carboxylic acid (80 mg, 0.17 mmol) in DCM (3 mL) was added DMAP (31.99 mg, 0.26 mmol), EDCI (50.19 mg, 0.26 mmol) and 6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-amine (40.33 mg, 0.17 mmol). The mixture was stirred at 20 °C for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:1) to afford N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-[2-oxo-4-(trifluoromethyl)pyridin-1-yl]pyridine-3-carboxamide (90 mg, 0.12 mmol) as a yellow solid.

[0285] LCMS: m / z (M+H) + = 671.2 / 673.2.

[0286] Step D: N-(6-(Cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)nicotinamide

[0287] At 20 °C under N2, to a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-[2-methoxy-5-(trifluoromethyl)phenyl]-6-[2-oxo-4-(trifluoromethyl)pyridin-1-yl]pyridine-3-carboxamide (90 mg, 0.15 mmol) in DMF (1.5 mL) was added DIEA (0.04 mL, 0.27 mmol), CuI (5.11 mg, 0.03 mmol), ethynylcyclopropane (0.02 mL, 0.27 mmol) and Pd(PPh3)4 (9.41 mg, 0.01 mmol). The mixture was stirred at 70 °C under N2 for 16 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by high performance liquid phase (FA / acetonitrile / water) to afford N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)nicotinamide (1.72 mg) as a white solid.

[0288] 11H NMR (400 MHz, MeOD) δ 8.99 (s, 1H), 8.56 (s, 1H), 8.30 (d, J = 7.4 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.76–7.67 (m, 1H), 7.63–7.48 (m, 1H), 7.18 (d, J = 8.6 Hz, 1H), 7.01 (s, 1H), 6.72 (dd, J = 7.4, 2.0 Hz, 1H), 3.72 (s, 3H), 1.61 (m, 1H), 1.06–0.97 (m, 2H), 0.95–0.86 (m, 2H).

[0289] LCMS: m / z (M+H) + = 657.4.

[0290] Example 11: Synthesis of Compound 11

[0291]

[0292] Step A: 6-Bromo-5-chloro-N-(4-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-amine

[0293] At 20 °C, NaOH (0.83 g, 20.71 mmol) and {[(4-methoxyphenyl)methyl]azanylidene}methanethione (1.12 mL, 6.80 mmol) were added to a solution of 3,5-dibromo-6-chloropyrazin-2-amine (1.7 g, 5.92 mmol) in THF (20 mL). The reaction was stirred at 70 °C for 2 h under microwave. After completion, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 3:1) to give 6-bromo-5-chloro-N-(4-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-amine (1.6 g, 2.66 mmol) as a white solid.

[0294] LCMS: m / z (M+H) + = 384.7 / 386.7.

[0295] Step B: 5-Chloro-6-(cyclopropylethynyl)-N-(4-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-amine

[0296] A mixture of 6-bromo-5-chloro-N-(4-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-amine (50 mg, 0.13 mmol), ethynylcyclopropane (219.74 μL, 2.59 mmol), CuI (10 mg, 0.03 mmol), DIEA (53.91 μL, 0.39 mmol) and Pd(PPh3)2Cl2 (9.10 mg, 0.01 mmol) in dioxane (3 mL) was degassed with N2 and purged three times, and then stirred at 25 °C for 2 h. After completion, the reaction mixture was evaporated and the crude residue was purified by column chromatography (20% EtOAc in PE) to give 5-chloro-6-(cyclopropylethynyl)-N-(4-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-amine (35 mg, 0.07 mmol) as a yellow oil.

[0297] LCMS: m / z (M+H) + = 370.9.

[0298] Step C: 5-cyclopropyl-6-(cyclopropylethynyl)-N-(4-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-amine

[0299] A mixture of cyclopropylboronic acid pinacol ester (231.62 mg, 2.70 mmol), 5-chloro-6-(cyclopropylethynyl)-N-(4-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-amine (50 mg, 0.13 mmol), Cs2CO3 (87.86 mg, 0.27 mmol) and Pd(PPh3)4 (31.16 mg, 0.03 mmol) in dioxane (5 mL) was degassed with N2 and purged three times, and then stirred at 120 °C under N2 for 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by p-TLC (5% EtOAc in PE) to give 5-cyclopropyl-6-(cyclopropylethynyl)-N-(4-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-amine (10 mg, 0.01 mmol) as a yellow oil.

[0300] LCMS: m / z (M+H) + = 377.2.

[0301] Step D: 5-cyclopropyl-6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-amine

[0302] At 0 °C, DDQ (18.09 mg, 0.08 mmol) was added to a stirred solution of 5-cyclopropyl-6-(cyclopropylethynyl)-N-(4-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-amine (15 mg, 0.04 mmol) in DCM (10 mL). The mixture was stirred at 25 °C for 16 h. Upon completion, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution and stirred vigorously for 10 min, then the mixture was extracted with DCM (30 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 2:1) to give 5-cyclopropyl-6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-amine (8 mg, 0.01 mmol) as a yellow solid.

[0303] LCMS: m / z (M + H) + = 257.0.

[0304] Step E: 2'-Chloro-N-(5-cyclopropyl-6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide

[0305] At 25 °C, 5-cyclopropyl-6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-amine (10 mg, 0.04 mmol), DMAP (12.33 mg, 0.10 mmol), and EDCI (19.35 mg, 0.10 mmol) were added to a solution of 4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (11.96 mg, 0.04 mmol) in DCM (2 mL). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction was concentrated under reduced pressure. The residue was purified by preparative-HPLC (FA conditions) to give 2'-Chloro-N-(5-cyclopropyl-6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide (1 mg, 0.01 mmol) as a white solid.

[0306] LCMS: m / z (M + H) + = 517.2.

[0307] Example 12: Synthesis of Compound 12

[0308]

[0309] Step A: 6-(Cyclopropylethynyl)-N-(4-methoxybenzyl)-5-methylthiazolo[4,5-b]pyrazin-2-amine

[0310] At 25 °C, to a solution of 6-bromo-N-(4-methoxybenzyl)-5-methylthiazolo[4,5-b]pyrazin-2-amine (200 mg, 0.55 mmol) in DMF (5 mL) was added ethynylcyclopropane (0.09 mL, 1.10 mmol), CuI (10 mg, 0.11 mmol), TEA (0.23 mL, 1.64 mmol) and Pd(PPh3)2Cl2 (38.43 mg, 0.05 mmol). The mixture was degassed with N2 and purged three times, and stirred at 70 °C for 2 hours. After completion, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether:EtOAc = 100:1 to 5:1) to give 6-(cyclopropylethynyl)-N-(4-methoxybenzyl)-5-methylthiazolo[4,5-b]pyrazin-2-amine (80 mg, 0.21 mmol) as a yellow oil.

[0311] LCMS: m / z (M+H) + = 351.2.

[0312] Step B: 6-(Cyclopropylethynyl)-5-methylthiazolo[4,5-b]pyrazin-2-amine

[0313] At 0 °C, to a solution of 6-(cyclopropylethynyl)-N-(4-methoxybenzyl)-5-methylthiazolo[4,5-b]pyrazin-2-amine (50 mg, 0.14 mmol) in DCM (20 mL) was added DDQ (64.78 mg, 0.29 mmol). The mixture was stirred at 25 °C for 18 hours. After completion, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution and stirred vigorously for 10 minutes, then the mixture was extracted with DCM (20 mL * 2), and the combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 2:1) to give 6-(cyclopropylethynyl)-5-methylthiazolo[4,5-b]pyrazin-2-amine (21 mg, 0.07 mmol) as a brown solid.

[0314] LCMS: m / z (M+H) + = 231.1.

[0315] Step C: 2'-Chloro-N-(6-(cyclopropylethynyl)-5-methylthiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide

[0316] At 25 °C, 6-(cyclopropyl ethynyl)-5-methyl thiazolo[4,5-b]pyrazin-2-amine (21 mg, 0.07 mmol), DMAP (12.33 mg, 0.10 mmol) and EDCI (19.35 mg, 0.10 mmol) were added to a solution of 4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (20.63 mg, 0.07 mmol) in DCM (2 mL). The mixture was stirred at 25 °C for 16 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (FA conditions) to give 2'-chloro-N-(6-(cyclopropyl ethynyl)-5-methyl thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide (9 mg, 0.02 mmol) as a white solid.

[0317] 1 H NMR (400 MHz, DMSO) δ 13.46 (s, 1H), 8.91 (s, 1H), 8.17 (s, 1H), 7.56 (s, 1H), 7.43 (s, 1H), 3.62 (s, 3H), 2.63 (s, 3H), 2.60 (s, 3H), 1.73–1.62 (m, 1H), 1.03–0.95 (m, 2H), 0.89–0.82 (m, 2H).

[0318] LCMS: m / z (M+H) + = 491.2.

[0319] Example 13: Synthesis of Compound 13

[0320]

[0321] Step A: 3-ethynyloxetane

[0322] A solution of oxetane-3-carbaldehyde (50 mg, 0.58 mmol), (1Z)-1-(diazen-1-ium-1-yl)-1-[dimethoxy(oxo)-λ5-phosphoryl]prop-1-en-2-olate (111.42 mg, 0.58 mmol) and K2CO3 (120.40 mg, 0.87 mmol) in EtOH (1 mL) was reacted at 25 °C for 3 h. The mixture was filtered and the filtrate was used for the next step without further purification.

[0323] Step B: 2'-chloro-5'-methoxy-6-methyl-N-(6-(oxetan-3-yl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide

[0324] To a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxamide (100 mg, 0.20 mmol) in DMF (2 mL) was added DIEA (78.85 mg, 0.61 mmol), 3-ethynyloxetane (20.03 mg, 0.24 mmol), CuI (2.32 mg, 0.01 mmol) and Pd(PPh3)4 (7.05 mg, 0.01 mmol). The resulting mixture was degassed and purged with N2 three times, and stirred at 60 °C for 18 h under N2 protection to obtain a brown solution. LCMS showed that the starting material was consumed and the desired product was formed. The cooled reaction was filtered. The filtrate was purified by prep-HPLC (FA conditions) to give the desired product 2'-chloro-5'-methoxy-6-methyl-N-(6-(oxetan-3-ylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide (52.47 mg, 0.11 mmol, 52.34%) as a yellow solid.

[0325] LCMS: m / z (M+H) + = 493.1.

[0326] 1 H NMR (400 MHz, DMSO-d6) δ 13.59 (s, 1H), 8.89 (s, 1H), 8.73 (s, 1H), 8.18 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 4.84 (dd, J = 8.8, 5.6 Hz, 2H), 4.67 (dd, J = 7.2, 5.6 Hz, 2H), 4.34 - 4.17 (m, 1H), 3.63 (s, 3H), 2.61 (s, 3H).

[0327] Example 14: Synthesis of Compound 14

[0328]

[0329] At 25 °C, 3-methoxyprop-1-yne (15.42 mg, 0.22 mmol), CuI (2.32 mg, 0.01 mmol), DIPEA (78.85 mg, 0.61 mmol) and Pd(PPh3)4 (37.05 mg, 0.01 mmol) were added to a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxamide (100 mg, 0.20 mmol) in DMF (10 mL). The reaction was degassed three times with N2 and stirred at 70 °C for 18 h. After filtration, the filtrate was purified by pre-HPLC (FA conditions) to give 2'-chloro-5'-methoxy-N-(6-(3-methoxyprop-1-ynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-4,4'-bipyridine-3-carboxamide (21.68 mg, 0.05 mmol) as a yellow solid.

[0330] LCMS: m / z (M+H) + = 481.0.

[0331] 1 1H NMR (400 MHz, DMSO-d6) δ 13.61 (s, 1H), 8.91 (s, 1H), 8.73 (s, 1H), 8.18 (s, 1H), 7.59 (s, 1H), 7.47 (s, 1H), 4.43 (s, 2H), 3.63 (s, 3H), 3.37 (s, 3H), 2.61 (s, 3H).

[0332] Example 15: Synthesis of Compound 15

[0333]

[0334] To a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxamide (100 mg, 0.20 mmol) in DMF (2 mL) was added DIEA (78.85 mg, 0.61 mmol), 2-ethynylpyridine (31.46 mg, 0.31 mmol), CuI (2.32 mg, 0.01 mmol), and Pd(PPh3)4 (7.05 mg, 0.01 mmol). The resulting mixture was degassed and purged with N2 three times, and then stirred at 60 °C for 18 h under N2 protection to obtain a brown solution. LCMS showed that the starting material was consumed and the desired product was formed. The cooled reaction was filtered. The filtrate was purified by prep-HPLC (FA conditions) to give the desired product 2'-chloro-5'-methoxy-6-methyl-N-(6-(pyridin-2-ylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide (73 mg, 0.14 mmol) as a yellow solid.

[0335] LCMS: m / z (M+H) + = 514.0.

[0336] 1 H NMR (400 MHz, DMSO-d6) δ 13.67 (s, 1H), 8.91 (d, J = 6.2 Hz, 2H), 8.68 (d, J = 4.8 Hz, 1H), 8.19 (s, 1H), 7.92 (dt, J = 7.8, 3.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.62 (s, 1H), 7.51 (d, J = 8.8 Hz, 2H), 3.64 (s, 3H), 2.62 (s, 3H).

[0337] Example 16: Synthesis of Compound 16

[0338]

[0339] At 25 °C, 1-chloro-4-ethynylbenzene (30.05 mg, 0.22 mmol), CuI (2.32 mg, 0.01 mmol), DIPEA (78.85 mg, 0.61 mmol) and Pd(PPh3)4 (37.05 mg, 0.01 mmol) were added to a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxamide (100 mg, 0.20 mmol) in DMF (10 mL). The reaction was degassed three times with N2 and stirred at 70 °C for 18 h. After filtration, the filtrate was purified by pre-HPLC (FA conditions) to give 2'-chloro-N-(6-((4-chlorophenyl)ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide (47.51 mg, 0.09 mmol) as a yellow solid.

[0340] LCMS: m / z (M+H) + = 547.0.

[0341] 1 1H NMR (400 MHz, DMSO-d6) δ 13.64 (s, 1H), 8.88 (d, J = 12.6 Hz, 2H), 8.19 (s, 1H), 7.72 - 7.67 (m, 2H), 7.61 (s, 1H), 7.59 - 7.54 (m, 2H), 7.49 (s, 1H), 3.64 (s, 3H), 2.61 (s, 3H).

[0342] Example 18: Synthesis of Compound 18

[0343]

[0344] To a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxamide (100 mg, 0.20 mmol) in DMF (2 mL) was added DIEA (78.85 mg, 0.61 mmol), 3-ethynyltetrahydrofuran (23.07 mg, 0.24 mmol), CuI (2.32 mg, 0.01 mmol), and Pd(PPh3)4 (7.05 mg, 0.01 mmol). The resulting mixture was degassed and purged with N2 three times, and then stirred at 60 °C for 18 h under N2 protection to obtain a brown solution. LCMS showed that the starting material was consumed and the desired product was formed. The cooled reaction was filtered. The filtrate was purified by prep-HPLC (FA conditions) to give the desired product 2'-chloro-5'-methoxy-6-methyl-N-(6-((tetrahydrofuran-3-yl)ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide (38 mg, 0.07 mmol) as a yellow solid.

[0345] LCMS: m / z (M+H) + = 507.0.

[0346] 1 H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 8.92 (s, 1H), 8.64 (s, 1H), 8.17 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 4.00 (t, J = 7.8 Hz, 1H), 3.90 - 3.83 (m, 1H), 3.80 - 3.74 (m, 1H), 3.70 - 3.65 (dm, 1H), 3.63 (s, 3H), 3.41 - 3.35 (m, 1H), 2.60 (s, 3H), 2.35 - 2.26 (m, 1H), 2.07 - 1.96 (m, 1H).

[0347] Example 20: Synthesis of Compound 20

[0348]

[0349] Step A: 6-Bromo-5-chloro-N-(4-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-amine

[0350] To a solution of 3,5-dibromo-6-chloropyrazin-2-amine (1.7 g, 5.92 mmol) in THF (20 mL) was added NaOH (0.83 g, 20.71 mmol) and {[(4-methoxyphenyl)methyl]azanylidene}methanethione (1.12 mL, 6.80 mmol). The mixture was stirred at 70 °C for 2 h (microwave). The reaction was monitored to completion by LC-MS. The solvent was removed under vacuum. The resulting residue was dissolved in DCM (3 mL) and purified by Combi Flash (Biotage Isolera Prime) equipped with a 40 g silica gel column, eluting with 0 - 40% PE in EA over 30 min to afford 6-bromo-5-chloro-N-(4-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-amine as a white solid (1.6 g, 2.66 mmol, 44.88%).

[0351] LCMS: m / z (M+H) + = 384.7, 386.7.

[0352] Step B: 5-chloro-6-(cyclopropyl ethynyl)-N-(4-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-amine

[0353] A solution of 6-bromo-5-chloro-N-(4-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-amine (50 mg, 0.13 mmol), ethynylcyclopropane (219.74 μL, 2.59 mmol), CuI (0.88 μL, 0.03 mmol), TEA (53.91 μL, 0.39 mmol) and Pd(PPh3)2Cl2 (9.10 mg, 0.01 mmol) in dioxane (3 mL) was degassed and purged with N2 three times, then stirred at 25 °C for 2 h. The reaction was monitored to completion by LC-MS. The reaction mixture was evaporated and the crude residue was purified by column chromatography (20% EtOAc in PE) to afford 5-chloro-6-(cyclopropyl ethynyl)-N-(4-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-amine as a yellow oil (35 mg, 0.07 mmol, 56.78%).

[0354] LCMS: m / z (M+H) + = 370.9.

[0355] Step C: 5-chloro-6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-amine

[0356] DDQ was added portionwise to a stirred solution of 5-chloro-6-(cyclopropyl ethynyl)-2-{[(4-methoxyphenyl)methyl]amino}[1,3]thiazolo[5,4-b]pyridine (15 mg, 0.04 mmol) in DCM (2 mL), and the mixture was stirred at 25 °C. The reaction was monitored by LC-MS until completion. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate and stirred vigorously for 10 minutes before extraction with EA. The combined organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography on silica gel (hexane:EtOAc = 2:1) to afford 5-chloro-6-(cyclopropyl ethynyl)[1,3]thiazolo[5,4-b]pyrazin-2-amine as a colorless oil (10 mg, 0.02 mmol, 56.21%).

[0357] LCMS: m / z (M+H) + = 257.0

[0358] Step D: 2'-Chloro-N-(5-chloro-6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide

[0359] EDCI (11.47 mg, 0.06 mmol) was added to a mixture of 4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxylic acid (12.23 mg, 0.04 mmol), 5-chloro-6-(cyclopropyl ethynyl)[1,3]thiazolo[5,4-b]pyrazin-2-amine (10 mg, 0.04 mmol), and DMAP (7.31 mg, 0.06 mmol) in DCM (2 mL). The mixture was then stirred at 25 °C for 2 h. The reaction was monitored by LC-MS until completion. The reaction mixture was poured into water (20 mL) and extracted with EA (3 x 50 mL). The combined ester layers were washed with water (50 mL) and sat. aq. NaCl solution (50 mL). The organic layer was dried (Na2SO4) and the solvent was removed under vacuum. The residue was purified by preparative HPLC (FA conditions) to afford 2'-Chloro-N-(5-chloro-6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide as a white solid (2 mg, 0.01 mmol, 9.22%).

[0360] LCMS: m / z (M+H) + = 510.8

[0361] Example 99: Synthesis of Compound 99

[0362]

[0363] To a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxamide (100 mg, 0.20 mmol) in DMF (2 mL) was added DIEA (78.85 mg, 0.61 mmol), ethynylcyclopentane (22.60 mg, 0.24 mmol), CuI (2.32 mg, 0.01 mmol), and Pd(PPh3)4 (7.05 mg, 0.01 mmol). The resulting mixture was degassed and purged with N2 three times, and then stirred at 60 °C for 18 h under N2 protection to obtain a brown solution. LCMS showed that the starting material was consumed and the desired product was formed. The cooled reaction was filtered. The filtrate was purified by prep-HPLC (FA conditions) to give the desired product 4-(2-chloro-5-methoxypyridin-4-yl)-N-[6-(cyclopentylethynyl)[1,3]thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide (46 mg, 0.09 mmol) as a yellow solid.

[0364] LCMS: m / z (M+H) + = 505.0.

[0365] 1 H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 8.89 (s, 1H), 8.64 (s, 1H), 8.18 (s, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 3.63 (s, 3H), 3.02 - 2.92 (m, 1H), 2.61 (s, 3H), 2.08 - 1.97 (m, 2H), 1.76 - 1.56 (m, 6H).

[0366] Example 100: Synthesis of Compound 100

[0367]

[0368] To a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxamide (100 mg, 0.20 mmol) in DMF (2 mL) was added DIEA (78.85 mg, 0.61 mmol), 3,3-dimethylbut-1-yne (33.41 mg, 0.41 mmol), CuI (2.32 mg, 0.01 mmol) and Pd(PPh3)4 (11.75 mg, 0.01 mmol). The resulting mixture was degassed and purged with N2 three times, and stirred at 60 °C for 18 h under N2 protection to obtain a brown solution. LCMS showed that the starting material was consumed and the desired product was formed. The cooled reaction was filtered. The filtrate was purified by prep-HPLC (FA conditions) to give the desired product 4-(2-chloro-5-methoxypyridin-4-yl)-N-[6-(3,3-dimethylbut-1-ynyl)[1,3]thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide (7.27 mg, 0.01 mmol) as a white solid.

[0369] LCMS: m / z (M+H) + = 493.0.

[0370] 1 1H NMR (400 MHz, DMSO-d6) δ 13.56 (s, 1H), 8.93 (s, 1H), 8.55 (s, 1H), 8.17 (s, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 3.63 (s, 3H), 2.60 (s, 3H), 1.33 (s, 9H).

[0371] Example 101: Synthesis of Compound 101

[0372]

[0373] At 25 °C, 2-methylbut-3-yn-2-ol (20.19 mg, 0.22 mmol), CuI (2.32 mg, 0.01 mmol), DIEA (78.85 mg, 0.61 mmol) and tetrakis(triphenylphosphine)palladium(0) (37.05 mg, 0.01 mmol) were added to a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-(2-chloro-5-methoxypyridin-4-yl)-6-methylpyridine-3-carboxamide (100 mg, 0.20 mmol) in DMF (10 mL). The reaction was degassed three times with N2 and stirred at 70 °C for 18 hours. After filtration, the filtrate was purified by pre-HPLC (FA conditions) to give 2'-chloro-N-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (47.26 mg, 0.10 mmol) as a yellow solid.

[0374] LCMS: m / z (M+H) + = 495.0.

[0375] 1 1H NMR (400 MHz, DMSO-d6) δ 13.59 (s, 1H), 8.89 (s, 1H), 8.65 (s, 1H), 8.18 (s, 1H), 7.60 (s, 1H), 7.47 (s, 1H), 5.68 (s, 1H), 3.63 (s, 3H), 2.61 (s, 3H), 1.51 (s, 6H).

[0376] Example 102: Synthesis of Compound 102

[0377]

[0378] To a solution of N-(6-bromo[1,3]thiazolo[4,5-b]pyrazin-2-yl)-4-(2-chloro-5-methoxypyridin-4-yl)-6-methylnicotinamide (100 mg, 0.20 mmol) in DMF (2 mL) was added DIEA (78.85 mg, 0.61 mmol), ethynylcyclohexane (25.96 mg, 0.24 mmol), CuI (2.32 mg, 0.01 mmol), and Pd(PPh3)4 (7.05 mg, 0.01 mmol). The resulting mixture was degassed and purged with N2 three times, and then stirred at 60 °C for 18 h under N2 protection to obtain a brown solution. LCMS showed that the starting material was consumed and the desired product was formed. The cooled reaction was filtered. The filtrate was purified by prep-HPLC (FA conditions) to give the desired product 4-(2-chloro-5-methoxypyridin-4-yl)-N-[6-(cyclohexylethynyl)[1,3]thiazolo[4,5-b]pyrazin-2-yl]-6-methylnicotinamide (59 mg, 0.11 mmol) as a yellow solid.

[0379] LCMS: m / z (M+H) + = 519.0.

[0380] 1 H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 8.89 (s, 1H), 8.64 (s, 1H), 8.18 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 3.63 (s, 3H), 2.81 - 2.71 (m, 1H), 2.61 (s, 3H), 1.93 - 1.81 (m, 2H), 1.76 - 1.65 (m, 2H), 1.60 - 1.46 (m, 3H), 1.44 - 1.30 (m, 3H).

[0381] Experimental Example 1: Inhibitory Activity against Polθ

[0382] The inhibitory activity of the compounds prepared in the above examples against Polθ was measured as follows.

[0383] The ADP-GLO assay was used to measure the ability of compounds to inhibit Polθ-helicase activity in vitro. The 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 generated 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). Compounds were dispensed at different concentrations (10 points, 1:3 dilution) onto a 384-well plate (PerkinElmer #6007290) using a Labcyte Echo 655. 2 μL of a 2X mixture of helicase domain Polθ and DNA (3 nM helicase domain Polθ and 2 nM DNA, in assay buffer) was added to the plate that had been pre-dispensed with the compounds. 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 Multilabel Reader, and the raw data were analyzed using log(inhibitor) versus response-variable slope (four parameters) to obtain the IC 50 value. The results are shown in Table 1 below.

[0384] [Table 1]

[0385] Example Number <![CDATA[Polθ / IC 50 (nM)]]> Example 1 22.16 Example 2 0.49 Example 3 60.51 Example 4 2.14 Example 5 0.78 Example 6 1.12 Example 7 0.5 Example 8 1.31 Example 9 9.15 Example 10 8.87 Example 11 13.93 Example 12 1.49 Example 13 3.41 Example 14 3.28 Example 15 0.42 Example 16 0.36 Example 18 1.61 Example 20 0.88 Example 99 0.22 Example 100 8.30 Example 101 9.65 Example 102 0.30

[0386] Experimental Example 2: Evaluation of Kinetic Solubility

[0387] Prepare a stock solution of the test compound at a concentration of 10 mM in DMSO. Add 8.71 g of K2HPO4 to 500 mL of deionized water to prepare a 100 mM K2HPO4 solution. Add 2.05 g of KH2PO4 to 150 mL of deionized water to prepare a 100 mM KH2PO4 solution. Mix 405 mL of 100 mM K2HPO4 and 95 mL of 100 mM KH2PO4, and adjust the mixed solution to pH 7.4 with 100 mM K2HPO4 / KH2PO4 solution. Add 16 μL of the 10 mM stock solution of the compound to 784 μL of different buffers in a 96-well plate (n = 3). Seal the plate and shake at 1000 rpm for 1.5 hours at room temperature (PBS = 7.4). After incubation, transfer the solution to a filter plate. Filter all samples using a vacuum manifold. Take 5 μL aliquots of the filtrate and 5 μL of DMSO, then add 490 μL of a mixture of H2O and acetonitrile (1:1) containing an internal standard. Dilute the diluent using a mixture of H2O and acetonitrile according to the signal response. Change the dilution factor according to the solubility value and UPLC-MS / MS signal response. Dilute the 10 mM stock solution with DMSO to obtain STDs of 2, 20, and 200 μM. Then transfer 5 μL of DMSO STD and 5 μL of buffer to the remaining empty plate, and then add 490 μL of a mixture of H2O and acetonitrile (1:1) containing an internal standard. Dilute the diluent using a certain ratio of a mixture of H2O and acetonitrile according to the signal response. Change the dilution factor according to the solubility value and UPLC-MS / MS signal response. Mix well and analyze the sample results using UPLC-MS / MS as shown in Table 2 below. For comparison, compounds A, B, and C with an aryl moiety substituted on the right side were synthesized and their solubilities were tested. As shown in Table 2, the solubilities of the substituted alkynyl analogs (Example 2 and Example 7) are much better than those of the substituted aryl analogs (compounds A, B, and C).

[0388] [Table 2]

[0389] Example Number Test System Solubility (μM) Example 2 PBS (pH = 7.4) 122.33 Example 7 PBS (pH = 7.4) 29.53 Compound A PBS (pH = 7.4) 0.41 Compound B PBS (pH = 7.4) 3.93 Compound C PBS (pH = 7.4) <0.00033

[0390]

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 that is a heteroaromatic ring containing one to three heteroatoms selected from N, O or S, or a pyridone; 2-10 ​ L1 is a bond, C 1-4 an alkylene, C 2-4 an alkenylene, C 2-4 an alkynylene, -S-, or -O-; R1 is hydrogen, C 1-4 alkyl, -CONH2, -CONH(C 1-4 alkyl), -CON(C 1-4 alkyl)2, unsubstituted or substituted with C 1-4 alkyl or C 1-4 haloalkyl, a C 2-10 heterocycloalkyl containing one to three heteroatoms selected from N, O or S, or unsubstituted or substituted with C 1-4 alkyl or C 1-4 haloalkyl, a C 2-10 heteroaryl; B is C 6-10 An aromatic ring, a C having one to three heteroatoms selected from N, O or S 2-10 A cycloalkane ring, or a C having one to three heteroatoms selected from N, O or S 2-10 A divalent linker of a heteroaromatic ring; 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, when R2 and R3 are on adjacent ring vertices, they combine to form a C 2-6 heteroalkyl containing one to three heteroatoms selected from N, O, or S, or a C 2-6 heteroaryl; L2 is a key, C 1-4 an alkylene group, -CO-, -CONH-, -NHCO-, -S-, or -O-; R4 is -C≡C-R’, unsubstituted or substituted with halogen or C 1-4 alkoxy C 6-10 aryl, unsubstituted or substituted with hydroxy C 3-6 cycloalkyl, unsubstituted or substituted with C 1-4 alkyl, C 1-4 haloalkyl or hydroxy C containing one to three heteroatoms selected from N, O or S 2-10 heterocycloalkyl, or unsubstituted or substituted with halogen, C 1-4 alkyl or C 1-4 haloalkyl C containing one to three heteroatoms selected from N, O or S 2-10 heteroaryl; R’ is hydrogen, an unsubstituted or cyano-substituted C 1-4 alkyl group, a (C 1-4 alkoxy)C 1-4 alkyl group, a C 1-4 hydroxyalkyl group, a C containing one oxygen 2-6 heterocycloalkyl group, an unsubstituted or one- or two-halogen-substituted C 3-6 cycloalkyl group, an unsubstituted or halogen-substituted C 6-10 aryl group, an unsubstituted or C-substituted C containing one to three heteroatoms selected from N, O or S 1-4 heteroaryl group, or an unsubstituted or C-substituted C containing one to three heteroatoms selected from N, O or S 2-10 heteroaryl group; 1-4 alkyl group, a C 2-10 heterocycloalkyl group; R5 is hydrogen, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl, or halogen, provided that when L2 is a bond, R4 is -C≡C-R'.

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, or any ring selected from the group consisting of 4,7-diazaspiro[2.5]oct-8-yl, 7-azaspiro[3.5]non-6-yl, 2-pyridone group, oxadiazole group, oxopyridazine group, pyrazole group or thiazole group which is unsubstituted or substituted with CH3 or CF3.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein B is a divalent linker of 1,3-benzodioxole, 2-oxa-5-azabicyclo[4.1.0]heptane, 3,4-dihydro-2H-benzo[b][1,4]oxazine, 3-oxa-8-azabicyclo[3.2.1]octane, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine, 4-oxa-7-azaspiro[2.5]octane, benzene, benzo[d]oxazole, benzo[d]thiazole, morpholine, piperazin-2-one, pyrazole or pyridine.

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

7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein L2 is a bond, -CH2-, -CO-, -CONH-, -NHCO-, -S- or -O-.

8. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R4 is -C≡C-R'; R' is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, -CH(CH3)(CN), -CH2-O-CH3, 2-hydroxypropan-2-yl, 1H-pyrrolo[2,3-b]pyridinyl which is unsubstituted or substituted with CH3, oxetanyl, tetrahydrofuranyl, cyclopropyl which is unsubstituted or substituted with one or two Fs, cyclobutyl which is unsubstituted or substituted with one or two Fs, cyclopentyl, cyclohexyl, spiro[2.2]pentyl, phenyl which is unsubstituted or substituted with Cl, pyrazolyl which is unsubstituted or substituted with CH3, or pyridinyl.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R4 is phenyl which is unsubstituted or substituted with Cl and OCH3, cyclohexyl which is unsubstituted or substituted with a hydroxyl group, hexahydrofuro[2,3-b]furanyl, bicyclo[2.2.2]octanyl which is unsubstituted or substituted with a hydroxyl group, 2,3-dihydrobenzofuranyl, 4-oxaspiro[2.4]heptanyl, tetrahydrofuranyl, 1,3-benzodioxolyl, or pyridinyl which is unsubstituted or substituted with Cl.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R5 is hydrogen, a hydroxyl group, CH3, cyclopropyl, or Cl.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, Chemical formula 1 is represented by the following chemical formula 2: [Chemical formula 2] In chemical formula 2, X is N or CH; R1 is C 1-4 alkyl, or is unsubstituted or substituted with C 1-4 alkyl or C 1-4 haloalkyl, and is a C 2-10 heteroaryl containing one to three heteroatoms selected from N, O or S; R2 is C 1-4 an alkoxy group; R3 is C 1-4 a haloalkyl or a halogen; R’ is hydrogen, C 1-4 hydroxyalkyl, C with one oxygen 2-6 heterocycloalkyl, C unsubstituted or substituted with one or two halogens 3-6 cycloalkyl, or C unsubstituted or substituted with C 1-4 C with one to three heteroatoms selected from N, O or S, and alkyl 2-10 heteroaryl; R5 is hydrogen, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl or halogen.

12. 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-(6-ethynylthiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 2) 2'-Chloro-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 3) 2'-Chloro-5'-methoxy-6-methyl-N-(6-((1-methyl-1H-pyrazol-4-yl)ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 4) N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 5) N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinamide, 6) N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide, 7) 2'-Chloro-N-(6-((3,3-difluorocyclobutyl)ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 8) N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)nicotinamide, 9) N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)nicotinamide, 10) N-(6-(Cyclopropyl ethynyl) thiazolo[4,5-b] pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-(2-oxo-4-(trifluoromethyl)pyridin-1(2H)-yl)nicotinamide, 11) 2'-Chloro-N-(5-cyclopropyl-6-(cyclopropyl ethynyl) thiazolo[4,5-b] pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 12) 2'-Chloro-N-(6-(cyclopropyl ethynyl)-5-methyl thiazolo[4,5-b] pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 13) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(oxetan-3-yl ethynyl) thiazolo[4,5-b] pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 14) 2'-Chloro-5'-methoxy-N-(6-(3-methoxyprop-1-ynyl) thiazolo[4,5-b] pyrazin-2-yl)-6-methyl-4,4'-bipyridine-3-carboxamide, 15) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(pyridin-2-yl ethynyl) thiazolo[4,5-b] pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 16) 2'-Chloro-N-(6-((4-chlorophenyl) ethynyl) thiazolo[4,5-b] pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 17) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(spiro[2.2] pent-1-yl ethynyl) thiazolo[4,5-b] pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 18) 2'-Chloro-5'-methoxy-6-methyl-N-(6-((tetrahydrofuran-3-yl) ethynyl) thiazolo[4,5-b] pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 19) 2'-Chloro-5'-methoxy-6-methyl-N-(6-((1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl) ethynyl) thiazolo[4,5-b] pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 20) 2'-Chloro-N-(5-chloro-6-(cyclopropyl ethynyl) thiazolo[4,5-b] pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 21) 2'-Chloro-N-(6-(cyclopropyl ethynyl)-5-hydroxy thiazolo[4,5-b] pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 22) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(tetrahydrofuran-3-yloxy) thiazolo[4,5-b] pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 23) 2'-Chloro-N-(6-((5-chloropyridin-2-yl)methyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 24) 2'-Chloro-5'-methoxy-6-methyl-N-(6-((tetrahydrofuran-3-yl)methyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 25) N-(6-(4-Oxaspiro[2.4]hept-6-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 26) 2'-Chloro-N-(6-(5-chloropyridin-2-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 27) 2'-Chloro-N-(6-(4-chloro-3-methoxyphenoxy)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 28) 2-(2'-Chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamido)-N-(tetrahydrofuran-3-yl)thiazolo[4,5-b]pyrazine-6-carboxamide, 29) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(tetrahydrofuran-3-carboxamido)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 30) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(morpholine-4-carbonyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 31) 2'-Chloro-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-4,4'-bipyridine-3-carboxamide, 32) N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)nicotinamide, 33) 2'-Chloro-N-(6-(5-chloropyridin-2-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-4,4'-bipyridine-3-carboxamide, 34) 2'-Chloro-5'-methoxy-6-(4-methyl-6-oxopyridazin-1(6H)-yl)-N-(6-(tetrahydrofuran-3-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 35) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide, 36) 2'-Chloro-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-(4-methyl-8-oxo-4,7-diazaspiro[2.5]octan-7-yl)-4,4'-bipyridine-3-carboxamide, 37) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-2,3-dihydrobenzofuran-6-carboxamide, 38) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-4-carboxamide, 39) 2'-Chloro-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-(6-oxo-7-azaspiro[3.5]nonan-7-yl)-4,4'-bipyridine-3-carboxamide, 40) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-1-(5-methyl-1,3,4-oxadiazol-2-yl)-2-oxo-1,2-dihydropyridine-4-carboxamide, 41) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-2-oxo-1,2-dihydropyridine-4-carboxamide, 42) 1-(2-Amino-2-oxoethyl)-5-(2-chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-2-oxo-1,2-dihydropyridine-4-carboxamide, 43) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-1-(2-(methylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-4-carboxamide, 44) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-1-(2-(dimethylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-4-carboxamide, 45) 2'-Chloro-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-(thiazol-2-yloxy)-4,4'-bipyridine-3-carboxamide, 46) 2'-Chloro-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-(oxetan-3-yl ethynyl)-4,4'-bipyridine-3-carboxamide, 47) 2'-Chloro-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-((1-methyl-1H-pyrazol-4-yl)ethynyl)-4,4'-bipyridine-3-carboxamide, 48) 7-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)imidazo[1,5-a]pyridine-6-carboxamide, 49) 1-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-1H-imidazole-5-carboxamide, 50) 5-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)pyridazine-4-carboxamide, 51) 6-(2-Chloro-5-methoxypyridin-4-yl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)benzo[d][1,3]dioxole-5-carboxamide, 52) N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-4-morpholinonicotinamide, 53) N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 54) N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-2'-(trifluoromethyl)-4,4'-bipyridine-3-carboxamide, 55) N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-(difluoromethyl)-2-methoxyphenyl)-6-methylnicotinamide, 56) N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylnicotinamide, 57) N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-ethynyl-2-methoxyphenyl)-6-methylnicotinamide, 58) 4-(5-Cyano-2-methoxyphenyl)-N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide, 59) N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-4-(2-(oxetan-3-yloxy)phenyl)nicotinamide, 60) N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl)-6-methylnicotinamide, 61) N-(6-(cyclopropyl ethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(3,5-dimethyl-1H-pyrazol-4-yl)-6-methylnicotinamide, 62) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(6,7-dihydropyrazolo[1,5-a]pyrimidin-4(5H)-yl)-6-methylnicotinamide, 63) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-4-(4-oxa-7-azaspiro[2.5]octan-7-yl)nicotinamide, 64) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-4-(2-methyl-3-oxopiperazin-1-yl)nicotinamide, 65) 4-(2-Oxa-5-azabicyclo[4.1.0]heptan-5-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide, 66) 4-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide, 67) 4-(Benzo[d]thiazol-7-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide, 68) 4-(Benzo[d]oxazol-7-yl)-N-(6-(cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide, 69) N-(6-(Cyclopropylethynyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2,2-difluorobenzo[d][1,3]dioxol-4-yl)-6-methylnicotinamide, 70) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(prop-2-ynyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 71) 2'-Chloro-N-(6-(3-cyclopropylprop-2-ynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 72) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(3-(oxetan-3-yl)prop-2-ynyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 73) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(3-(1-methyl-1H-pyrazol-4-yl)prop-2-ynyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 74) 2'-Chloro-N-(6-(3-cyanobut-1-ynyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 75) 2'-Chloro-N-(5-chloro-6-((tetrahydrofuran-3-yl)methyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 76) 2'-Chloro-5'-methoxy-6-methyl-N-(5-methyl-6-((tetrahydrofuran-3-yl)methyl)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 77) 2'-Chloro-5'-methoxy-6-methyl-N-(5-methyl-6-(tetrahydrofuran-3-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 78) 2'-Chloro-N-(6-((5-chloropyridin-2-yl)methyl)-5-methylthiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 79) 2'-Chloro-N-(6-(5-chloropyridin-2-yloxy)-5-methylthiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 80) 2'-Chloro-5'-methoxy-6-methyl-N-(6-(tetrahydrofuran-3-ylthio)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 81) 2'-Chloro-5'-methoxy-6-methyl-N-(5-methyl-6-(tetrahydrofuran-3-ylthio)thiazolo[4,5-b]pyrazin-2-yl)-4,4'-bipyridine-3-carboxamide, 82) 2'-Chloro-N-(6-(5-chloropyridin-2-ylthio)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 83) 2'-Chloro-N-(6-(5-chloropyridin-2-ylthio)-5-methylthiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 84) 2'-Chloro-N-(6-(4-hydroxycyclohexyloxy)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 85) 2'-Chloro-N-(6-(hexahydrofuro[2,3-b]furan-3-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 86) 2'-Chloro-N-(6-(5-hydroxybicyclo[2.2.2]octan-2-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 87) N-(6-(Benzo[d][1,3]dioxol-4-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 88) 2'-Chloro-N-(6-(2,3-dihydrobenzofuran-3-yloxy)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 89) 2'-Chloro-N-(6-(4-chloro-3-methoxybenzyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 90) 2'-Chloro-N-(6-((4-hydroxycyclohexyl)methyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 91) N-(6-(4-oxaspiro[2.4]heptane-6-ylmethyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 92) 2'-Chloro-N-(6-((hexahydrofuro[2,3-b]furan-3-yl)methyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 93) 2'-Chloro-N-(6-((5-hydroxybicyclo[2.2.2]octan-2-yl)methyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 94) 2'-Chloro-N-(6-(4-chloro-3-methoxyphenylthio)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 95) 2'-Chloro-N-(6-(4-hydroxycyclohexylthio)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 96) N-(6-(4-oxaspiro[2.4]hept-6-ylthio)thiazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 97) 2'-Chloro-N-(6-(hexahydrofuro[2,3-b]furan-3-ylthio)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 98) 2'-Chloro-N-(6-(5-hydroxybicyclo[2.2.2]octan-2-ylthio)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-4,4'-bipyridine-3-carboxamide, 99) 4-(2-Chloro-5-methoxypyridin-4-yl)-N-[6-(cyclopentylethynyl)[1,3]thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide, 100) 4-(2-Chloro-5-methoxypyridin-4-yl)-N-[6-(3,3-dimethylbut-1-ynyl)[1,3]thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide, 101) 2'-Chloro-N-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide, and 102) 4-(2-chloro-5-methoxypyridin-4-yl)-N-[6-(cyclohexylethynyl)[1,3]thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide.

13. A pharmaceutical composition for preventing or treating cancer, comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

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