Six-membered ring fused thiazole compounds and their applications

Abstract

The present disclosure provides a 6-membered ring fused thiazole compound represented by formula (I) or a pharma- ceutically acceptable salt thereof, a pharmaceutical composition containing the same, and the application of the same in the prevention or treatment of DNA polymerase θ-mediated diseases. [Formula 1] JPEG2025504426000147.jpg28160

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of and priority to Chinese invention patent applications Nos. 202210038783.7 and 202211207114.4, filed with the State Intellectual Property Office of the People's Republic of China on January 13, 2022 and September 30, 2022, respectively, the entire contents of which are hereby incorporated by reference.

[0002] The present application relates to a six-membered ring-fused thiazole compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the compound, and its use as a DNA polymerase θ inhibitor in the prevention or treatment of associated diseases. [Background technology]

[0003] DNA double-strand break repair is crucial for maintaining genome stability and cell viability. There are three main repair pathways for DNA double-strand breaks: homologous recombination (HR), non-homologous end joining (NHEJ), and non-conventional non-homologous end joining (alt-MEJ). Microhomology-mediated end joining (MMEJ) is the most common non-homologous end joining and non-conventional non-homologous end joining. Homologous recombination is a high-fidelity and accurate repair mechanism that can maintain genome stability and avoid cancer induction. On the other hand, non-homologous end joining and microhomology-mediated end joining are error-prone repair pathways, which can result in the appearance of mutations at the repair site.

[0004] Unlike normal cells, tumor cell survival typically depends on misregulated DNA double-strand break repair. At the same time, aberrant DNA double-strand break repair can make tumor cells more sensitive to certain types of DNA damage. Therefore, targeted tumor therapies can be developed to repair defects using DNA double-strand breaks. Repair of damaged tumor cells by homologous recombination or nonhomologous end joining relies more on microhomology-mediated end joining repair. Multiple lines of evidence from genetics, cell biology, and biochemistry indicate that DNA polymerase θ (POLQ or POLθ) is a key protein in the microhomology-mediated end joining repair process (Kent et al. Nature Structural & Molecular Biology (2015), 22(3), 230-237, Mateos-Gomez et al. Nature (2015), 518(7538), 254-257).

[0005] POLQ is a multifunctional enzyme consisting of an N-terminal helicase domain (SF2 HEL308-type) and a C-terminal low-fidelity DNA polymerase domain (A-type) (Wood & Doublie DNA Repair (2016), 44, 22-32). The helicase domain mediates the removal of RPA proteins from single-stranded DNA and promotes annealing, while the polymerase domain extends single-stranded DNA ends and fills gaps. The two domains cooperate to perform the microhomology-mediated end-joining repair process.

[0006] Studies have shown that POLQ is crucial for homologous recombination-deficient cells (e.g., synthetic lethality with FA / BRCA deficiency), and that POLQ protein levels are upregulated in homologous recombination-deficient tumor cells (Ceccaldi et al. Nature (2015), 518 (7538), 258-262). In vivo studies have also revealed that POLQ is overexpressed in a range of homologous recombination-deficient, poorly prognostic ovarian, uterine, and breast cancers (Higgins et al. Oncotarget (2010), 1, 175-184, Lemee et al. PNAS (2010), 107 (30), 13390-13395, Ceccaldi et al. (2015), supra). More importantly, POLQ expression is inhibited in normal tissues compared to tumor tissues (Kawamura et al. International Journal of Cancer (2004), 109(1), 9-16).

[0007] In summary, POLQ is crucial for homologous recombination-deficient cells, and there is currently an unmet market demand for the treatment of homologous recombination-deficient tumors. Inhibiting POLQ function can inhibit microhomology-mediated end-joining repair in cells, and the development of POLQ inhibitors could provide a novel strategy for targeted treatment of homologous recombination-deficient tumors. Summary of the Invention

[0008] In one aspect, the present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] where: X1, X2, and X3 are independently selected from CH or N; X4 is selected from C or N; Z is selected from C(=O) or CH2; Ring A is a 5- to 10-membered heteroaryl group, C6-C 14an aryl group or a 4- to 12-membered heterocyclyl group, wherein the 5- to 10-membered heteroaryl group, C6-C 14 The aryl group or the 4- to 12-membered heterocyclyl group may optionally be R 1a is replaced by Each R 1a are independently halogen, hydroxyl group, -NRR', cyano group, carboxyl group, ═O, -C(═O)NRR', C1-C 10 Alkyl groups, C1-C 10 Alkoxy groups, C1-C 10 Alkoxyacyl group, C3-C 10 Cycloalkyl groups, C2-C 10 Alkynyl groups, C2-C 10 alkenyl group, a 4- to 12-membered heterocyclyl group, or a 5- to 10-membered heteroaryl group; 10 Alkyl groups, C1-C 10 Alkoxy groups, C1-C 10 Alkoxyacyl group, C3-C 10 Cycloalkyl groups, C2-C 10 Alkynyl groups, C2-C 10 The alkenyl group, the 4- to 12-membered heterocyclyl group, or the 5- to 10-membered heteroaryl group may optionally be R 1b is replaced by R 1 is C6-C 14 an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 18-membered heterocyclyl group, or a C4-C 10 cycloalkenyl groups, wherein the C6-C 14 an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 18-membered heterocyclyl group, or a C4-C 10 The cycloalkenyl group is optionally R 2a is replaced by Each R 2a are independently halogen, cyano group, =O, hydroxyl group, -NRR', -C(=O)NRR', C1-C 10 Alkyl groups, C1-C 10 Alkoxy groups, C3-C 10 Cycloalkyloxy group, C1-C 10 Alkyl acyl groups, C1-C 10Alkylsulfonyl group, C2-C 10 Alkynyl groups, C2-C 10 Alkenyl groups, C3-C 10 a cycloalkyl group, a 4- to 12-membered heterocyclyl group, a 4- to 8-membered heterocyclylalkyl group, or a 4- to 8-membered heterocyclyloxy group, 10 Alkyl groups, C1-C 10 Alkoxy groups, C3-C 10 Cycloalkyloxy group, C1-C 10 Alkyl acyl groups, C1-C 10 Alkylsulfonyl group, C2-C 10 Alkynyl groups, C2-C 10 Alkenyl groups, C3-C 10 The cycloalkyl group, the 4- to 12-membered heterocyclyl group, the 4- to 8-membered heterocyclylalkyl group, or the 4- to 8-membered heterocyclyloxy group may optionally be R 2b is replaced by R 2 is C6-C 14 Aryl groups, 5-10 membered heteroaryl groups, C3-C 10 a cycloalkyl group or a 4- to 12-membered heterocyclyl group, 14 Aryl groups, 5-10 membered heteroaryl groups, C3-C 10 The cycloalkyl group or the 4- to 12-membered heterocyclyl group may optionally be R 3a is replaced by Each R 3a are independently halogen, -NRR', hydroxyl group, cyano group, =O, C1-C 10 Alkyl groups, C1-C 10 Alkoxy groups, C3-C 10 Cycloalkyl groups, C2-C 10 Alkynyl groups, C2-C 10 alkenyl group, a 5- to 10-membered heteroaryl group, or a 4- to 8-membered heterocyclyl group; 10 Alkyl groups, C1-C 10 Alkoxy groups, C3-C 10 Cycloalkyl groups, C2-C 10 Alkynyl groups, C2-C 10The alkenyl group, 5- to 10-membered heteroaryl group, or 4- to 8-membered heterocyclyl group may optionally be R 3b is replaced by R and R' are independently hydrogen, C3-C 10 Cycloalkyl groups, C1-C 10 Alkylcarbonyl group, 4- to 8-membered heterocyclyl group or C1-C 10 alkyl groups, wherein the C3-C 10 Cycloalkyl groups, C1-C 10 Alkylcarbonyl group, 4- to 8-membered heterocyclyl group or C1-C 10 The alkyl group may optionally be R 4b is replaced by Each R 1b , R 2b , R 3b , R 4b are independently deuterium, halogen, carboxyl group, hydroxyl group, =O, cyano group, -C(=O)NRR', sulfonyl group, -S(=O)2NRR', -NRR', C1-C 10 Alkyl group or C1-C 10 The alkoxy group is selected from the group consisting of alkoxy groups.

[0009] In another aspect, the present application provides a pharmaceutical composition, which comprises a compound of formula (I) of the present application or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0010] In a further aspect, the present application provides a method for preventing or treating a mammalian DNA polymerase θ-mediated disease, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0011] In another aspect, the present application provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for preventing or treating a DNA polymerase θ-mediated disease.

[0012] In a further aspect, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of a DNA polymerase θ-mediated disease.

[0013] In another aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a DNA polymerase θ-mediated disease.

[0014] In yet another aspect, the present application provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for preventing or treating cancer. DETAILED DESCRIPTION OF THE INVENTION

[0015] The present application relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] where: X1, X2, and X3 are independently selected from CH or N; X4 is selected from C or N; Z is selected from C(=O) or CH2; Ring A is a 5- to 10-membered heteroaryl group, C6-C 14 an aryl group or a 4- to 12-membered heterocyclyl group, wherein the 5- to 10-membered heteroaryl group, C6-C 14 The aryl group or the 4- to 12-membered heterocyclyl group may optionally be R 1a is replaced by Each R 1a are independently halogen, hydroxyl group, -NRR', cyano group, carboxyl group, ═O, -C(═O)NRR', C1-C 10 Alkyl groups, C1-C 10 Alkoxy groups, C1-C 10 Alkoxyacyl group, C3-C 10 Cycloalkyl groups, C2-C 10 Alkynyl groups, C2-C 10alkenyl group, a 4- to 12-membered heterocyclyl group, or a 5- to 10-membered heteroaryl group; 10 Alkyl groups, C1-C 10 Alkoxy groups, C1-C 10 Alkoxyacyl group, C3-C 10 Cycloalkyl groups, C2-C 10 Alkynyl groups, C2-C 10 The alkenyl group, the 4- to 12-membered heterocyclyl group, or the 5- to 10-membered heteroaryl group may optionally be R 1b is replaced by R 1 is C6-C 14 an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 18-membered heterocyclyl group, or a C4-C 10 cycloalkenyl groups, wherein the C6-C 14 an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 18-membered heterocyclyl group, or a C4-C 10 The cycloalkenyl group is optionally R 2a is replaced by Each R 2a are independently halogen, cyano group, =O, hydroxyl group, -NRR', -C(=O)NRR', C1-C 10 Alkyl groups, C1-C 10 Alkoxy groups, C3-C 10 Cycloalkyloxy group, C1-C 10 Alkyl acyl groups, C1-C 10 Alkylsulfonyl group, C2-C 10 Alkynyl groups, C2-C 10 Alkenyl groups, C3-C 10 a cycloalkyl group, a 4- to 12-membered heterocyclyl group, a 4- to 8-membered heterocyclylalkyl group, or a 4- to 8-membered heterocyclyloxy group, 10 Alkyl groups, C1-C 10 Alkoxy groups, C3-C 10 Cycloalkyloxy group, C1-C 10 Alkyl acyl groups, C1-C 10 Alkylsulfonyl group, C2-C 10 Alkynyl groups, C2-C 10 Alkenyl groups, C3-C 10The cycloalkyl group, the 4- to 12-membered heterocyclyl group, the 4- to 8-membered heterocyclylalkyl group, or the 4- to 8-membered heterocyclyloxy group may optionally be R 2b is replaced by R 2 is C6-C 14 Aryl groups, 5-10 membered heteroaryl groups, C3-C 10 a cycloalkyl group or a 4- to 12-membered heterocyclyl group, 14 Aryl groups, 5-10 membered heteroaryl groups, C3-C 10 The cycloalkyl group or the 4- to 12-membered heterocyclyl group may optionally be R 3a is replaced by Each R 3a are independently halogen, -NRR', hydroxyl group, cyano group, =O, C1-C 10 Alkyl groups, C1-C 10 Alkoxy groups, C3-C 10 Cycloalkyl groups, C2-C 10 Alkynyl groups, C2-C 10 alkenyl group, a 5- to 10-membered heteroaryl group, or a 4- to 8-membered heterocyclyl group; 10 Alkyl groups, C1-C 10 Alkoxy groups, C3-C 10 Cycloalkyl groups, C2-C 10 Alkynyl groups, C2-C 10 The alkenyl group, 5- to 10-membered heteroaryl group, or 4- to 8-membered heterocyclyl group may optionally be R 3b is replaced by R and R' are independently hydrogen, C3-C 10 Cycloalkyl groups, C1-C 10 Alkylcarbonyl group, 4- to 8-membered heterocyclyl group or C1-C 10 alkyl groups, wherein the C3-C 10 Cycloalkyl groups, C1-C 10 Alkylcarbonyl group, 4- to 8-membered heterocyclyl group or C1-C 10 The alkyl group may optionally be R 4b is replaced by Each R 1b , R 2b , R 3b , R4b are independently deuterium, halogen, carboxyl group, hydroxyl group, =O, cyano group, -C(=O)NRR', sulfonyl group, -S(=O)2NRR', -NRR', C1-C 10 Alkyl group or C1-C 10 The alkoxy group is selected from the group consisting of alkoxy groups.

[0016] In some embodiments, at least one of X 1 , X 2 , and X 3 is N.

[0017] In some embodiments, X 1 , X 2 are independently selected from CH or N, and X 3 is N.

[0018] In some embodiments, X 1 , X 2 are independently CH and X 3 is N.

[0019] In some embodiments, X1, X3 are independently N and X2 is CH.

[0020] In some embodiments, X 1 is CH, and X 2 , X 3 are independently N.

[0021] In some embodiments, X 1 is N, and X 2 , X 3 are independently CH.

[0022] In some embodiments, X4 is C.

[0023] In some embodiments, Z is C(=O).

[0024] In some embodiments, ring A is a 5- to 10-membered heteroaryl group, C-C 10 an aryl group or a 4- to 10-membered heterocyclyl group, wherein the 5- to 10-membered heteroaryl group, C6-C 10 The aryl group or the 4- to 10-membered heterocyclyl group may optionally be R 1a is replaced by

[0025] In some embodiments, ring A is a 5- to 10-membered heteroaryl group, C-C 10 an aryl group or a 6- to 10-membered heterocyclyl group, wherein the 5- to 10-membered heteroaryl group, C6-C 10 The aryl group or the 6- to 10-membered heterocyclyl group may optionally be R 1a In some embodiments, ring A is selected from a 5- to 9-membered heteroaryl group, a phenyl group, or a 9-membered heterocyclyl group, wherein the 5- to 9-membered heteroaryl group, the phenyl group, or the 5- to 9-membered heterocyclyl group is optionally substituted with R 1a is replaced by

[0026] In some embodiments, ring A is selected from a 5- to 9-membered heteroaryl group having 1, 2, or 3 nitrogen atoms, a phenyl group, or a 9-membered heterocyclyl group, wherein the 5- to 9-membered heteroaryl group, phenyl group, or 9-membered heterocyclyl group is optionally selected from R 1a is replaced by

[0027] In some embodiments, ring A is selected from an imidazolyl group, a 6- to 9-membered heteroaryl group, a phenyl group, or a 9-membered heterocyclyl group, wherein the imidazolyl group, the 6- to 9-membered heteroaryl group, the phenyl group, or the 9-membered heterocyclyl group is optionally selected from R 1a is replaced by

[0028] In some embodiments, ring A is selected from a 6-membered heteroaryl group, which is optionally R 1a is replaced by

[0029] In some embodiments, ring A is selected from a pyridyl group, an imidazolyl group, an imidazo[1,2-a]pyridyl group, a pyrimidinyl group, a [1,2,4]triazolo[1,5-a]pyridyl group, a phenyl group, or a benzo[d][1,3]dioxin group, wherein the pyridyl group, the imidazolyl group, the imidazo[1,2-a]pyridyl group, the pyrimidinyl group, the [1,2,4]triazolo[1,5-a]pyridyl group, the phenyl group, or the benzo[d][1,3]dioxin group is optionally selected from R 1ais replaced by

[0030] In some embodiments, ring A is a pyridyl group, an imidazolyl group, an imidazo[1,2-a]pyridyl group, a pyrimidinyl group, a [1,2,4]triazolo[1,5-a]pyridyl group, a phenyl group, or [ka] a pyridyl group, an imidazolyl group, an imidazo[1,2-a]pyridyl group, a pyrimidinyl group, a [1,2,4]triazolo[1,5-a]pyridyl group, a phenyl group or [ka] is optionally R 1a is replaced by

[0031] In some embodiments, ring A is selected from a pyridyl group, which is optionally R 1a is replaced by

[0032] In some embodiments, ring A is [ka] where * is selected from R 1 Represents a connection with

[0033] In some embodiments, R 1a is selected from halogen, cyano, or a C1-C6 alkyl group, and the C1-C6 alkyl group is optionally selected from R 1b is replaced by

[0034] In some embodiments, R 1a is selected from a halogen, a cyano group, or a C1-C3 alkyl group, said C1-C3 alkyl group optionally substituted with a halogen.

[0035] In some embodiments, R 1ais selected from a C1-C6 alkyl group, said C1-C6 alkyl group optionally being selected from R 1b is replaced by

[0036] In some embodiments, R 1a is selected from C1-C3 alkyl groups.

[0037] In some embodiments, R 1b is selected from halogens.

[0038] In some embodiments, R 1b is selected from fluorine.

[0039] In some embodiments, R 1a is selected from fluorine, chlorine, a cyano group, CF3 or a methyl group.

[0040] In some embodiments, R 1a is selected from a methyl group or a cyano group.

[0041] In some embodiments, R 1a is selected from methyl groups.

[0042] In some embodiments, ring A is [ka] where * is selected from R 1 Represents a connection with

[0043] In some embodiments, ring A is [ka] where * is selected from R 1 Represents a connection with

[0044] In some embodiments, ring A is [ka] where * is selected from R 1 Represents a connection with

[0045] In some embodiments, R 1 is C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, a 4- to 10-membered heterocyclyl group, or a C5-C7 cycloalkenyl group; 10 The aryl group, 5- to 10-membered heteroaryl group, 4- to 10-membered heterocyclyl group, or C5-C7 cycloalkenyl group may optionally be R 2a is replaced by

[0046] In some embodiments, R 1 is C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, or a 4- to 10-membered heterocyclyl group; 10 The aryl group, 5- to 10-membered heteroaryl group, or 4- to 10-membered heterocyclyl group may optionally be R 2a is replaced by

[0047] In some embodiments, R 1 is selected from a phenyl group, a 6-membered heteroaryl group, or a 6-membered heterocyclyl group, and said phenyl group, 6-membered heteroaryl group, or 6-membered heterocyclyl group is optionally selected from R 2a is replaced by

[0048] In some embodiments, R 1 is selected from a phenyl group, a pyridyl group, or a morpholinyl group, and the phenyl group, the pyridyl group, or the morpholinyl group is optionally selected from R 2a is replaced by

[0049] In some embodiments, R 1 is selected from a phenyl group or a pyridyl group, said phenyl group or pyridyl group optionally being selected from R 2a is replaced by

[0050] In some embodiments, R 1 is selected from a phenyl group, said phenyl group optionally being selected from R 2a is replaced by

[0051] In some embodiments, R 1 teeth, [ka] is selected from.

[0052] In some embodiments, R 2a is selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyloxy groups, and the C1-C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyloxy groups are optionally selected from R 2b is replaced by

[0053] In some embodiments, R 2a is selected from halogen, cyano, C1-C3 alkyl, C2-C4 alkynyl, C3-C4 cycloalkyl, C1-C3 alkoxy, or C3-C4 cycloalkyloxy groups, and the C1-C3 alkyl, C2-C4 alkynyl, C3-C4 cycloalkyl, C1-C3 alkoxy, or C3-C4 cycloalkyloxy groups are optionally selected from R 2b is replaced by

[0054] In some embodiments, R 2a is selected from halogen, cyano, C1-C3 alkyl, C2-C4 alkynyl, C3-C4 cycloalkyl, C1-C3 alkoxy, or C3-C4 cycloalkyloxy groups, and the C1-C3 alkyl or C1-C3 alkoxy groups are optionally selected from R 2b is replaced by

[0055] In some embodiments, R 2ais selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C1-C6 alkoxy, and the C1-C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, or C1-C6 alkoxy groups are optionally selected from R 2b is replaced by

[0056] In some embodiments, R 2a is selected from halogen, cyano, C1-C3 alkyl, C2-C4 alkynyl, C3-C4 cycloalkyl or C1-C3 alkoxy, wherein the C1-C3 alkyl, C2-C4 alkynyl, C3-C4 cycloalkyl or C1-C3 alkoxy group is optionally selected from R 2b is replaced by

[0057] In some embodiments, R 2a is selected from halogen, cyano, C1-C3 alkyl, C2-C4 alkynyl, C3-C4 cycloalkyl or C1-C3 alkoxy, wherein the C1-C3 alkyl or C1-C3 alkoxy group is optionally selected from R 2b is replaced by

[0058] In some embodiments, R 2a is selected from halogen or a C1-C6 alkoxy group, said C1-C6 alkoxy group optionally being R 2b is replaced by

[0059] In some embodiments, R 2a is selected from fluorine, chlorine, bromine, iodine or a C1-C3 alkoxy group.

[0060] In some embodiments, R 2b is selected from halogen or deuterium.

[0061] In some embodiments, R 2b is selected from fluorine or deuterium.

[0062] In some embodiments, R 2b is selected from halogens.

[0063] In some embodiments, R 2b is selected from fluorine.

[0064] In some embodiments, R 2a is a fluorine, chlorine, cyano group, OCHF2, methyl group, ethynyl group, cyclopropyl group, methoxy group, CF3, OCF3, OCD3 or [ka] is selected from.

[0065] In some embodiments, R 2a is selected from fluorine, chlorine, cyano, OCHF2, methyl, ethynyl, cyclopropyl or methoxy.

[0066] In some embodiments, R 2a is selected from fluorine or a methoxy group.

[0067] In some embodiments, R 1 teeth, [ka] is selected from.

[0068] In some embodiments, R 1 teeth, [ka] is selected from.

[0069] In some embodiments, R 1 teeth, [ka] is selected from.

[0070] In some embodiments, R 2 is C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, a C3-C6 cycloalkyl group, or a 4- to 10-membered heterocyclyl group, 10 The aryl group, 5- to 10-membered heteroaryl group, C-C cycloalkyl group, or 4- to 10-membered heterocyclyl group may optionally be R 3a is replaced by

[0071] In some embodiments, R 2 is C6-C 10 an aryl group, a 5- to 10-membered heteroaryl group, or a 4- to 10-membered heterocyclyl group; 10 The aryl group, 5- to 10-membered heteroaryl group, or 4- to 10-membered heterocyclyl group may optionally be R 3a is replaced by

[0072] In some embodiments, R 2 is selected from a phenyl group, a 5- to 6-membered heteroaryl group, or a 5- to 6-membered heterocyclyl group, and the phenyl group, the 5- to 6-membered heteroaryl group, or the 5- to 6-membered heterocyclyl group is optionally selected from R 3a is replaced by

[0073] In some embodiments, R 2 is selected from a phenyl group, a 6-membered heteroaryl group, or a 5- to 6-membered heterocyclyl group, and the phenyl group, the 6-membered heteroaryl group, or the 5- to 6-membered heterocyclyl group is optionally selected from R 3a is replaced by

[0074] In some embodiments, R 2 is a phenyl group, a pyridyl group, a tetrahydrofuranyl group, or [ka] a phenyl group, a pyridyl group, a tetrahydrofuranyl group, or [ka] is optionally R 3a In some embodiments, R 2 is selected from a phenyl group, a pyridyl group, or a tetrahydrofuranyl group, and the phenyl group, the pyridyl group, or the tetrahydrofuranyl group is optionally selected from R 3a is replaced by

[0075] In some embodiments, R 2 is selected from a phenyl group or a pyridyl group, said phenyl group or pyridyl group optionally being selected from R 3a is replaced by

[0076] In some embodiments, R 2 is selected from a phenyl group, said phenyl group optionally being selected from R 3a is replaced by

[0077] In some embodiments, R 2 teeth, [ka] is selected from.

[0078] In some embodiments, each R 3a are independently halogen, -NRR', hydroxyl group, cyano group, C1-C 10 Alkyl groups, C1-C 10 Alkoxy groups, C3-C 10 Cycloalkyl groups, C2-C 10 Alkynyl groups, C2-C 10 alkenyl groups, 5- to 10-membered heteroaryl groups or 4- to 8-membered heterocyclyl groups, 10 Alkyl groups, C1-C 10 Alkoxy groups, C3-C 10 Cycloalkyl groups, C2-C 10 Alkynyl groups, C2-C 10 The alkenyl group, 5- to 10-membered heteroaryl group, or 4- to 8-membered heterocyclyl group may optionally be R 3b is replaced by

[0079] In some embodiments, each R 3a are independently selected from halogen, cyano, ═O, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl groups, and the C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl groups are optionally selected from R 3b is replaced by

[0080] In some embodiments, each R 3a are independently selected from halogen, cyano, ═O, a C1-C6 alkyl group, a C1-C6 alkoxy group, or a C3-C6 cycloalkyl group, and the C1-C6 alkyl group or C1-C6 alkoxy group is optionally selected from R 3b is replaced by

[0081] In some embodiments, each R 3a are independently selected from halogen, cyano, C1-C6 alkyl or C1-C6 alkoxy groups, and the C1-C6 alkyl or C1-C6 alkoxy groups are optionally selected from R 3b is replaced by

[0082] In some embodiments, each R 3a are independently selected from fluorine, chlorine, bromine, iodine, a cyano group, a C1-C3 alkyl group, or a C1-C3 alkoxy group.

[0083] In some embodiments, R 3b is selected from a halogen, a cyano group, or a hydroxyl group.

[0084] In some embodiments, R 3b is selected from fluorine, a cyano group, or a hydroxyl group.

[0085] In some embodiments, R 3b is selected from halogen or cyano groups.

[0086] In some embodiments, R 3b is selected from fluorine or a cyano group.

[0087] In some embodiments, each R 3a are independently fluorine, chlorine, cyano group, =O, methyl group, cyclopropyl group, OCHF2, CF3, methoxy group, [ka] , OCF3 or a tert-butyl group.

[0088] In some embodiments, each R 3a are independently selected from a cyano group, a cyclopropyl group, OCHF2, OCF3, or CF3.

[0089] In some embodiments, each R 3a are independently fluorine, chlorine, cyano, =O, methyl, cyclopropyl, OCHF2, CF3, methoxy or [ka] is selected from.

[0090] In some embodiments, each R 3a are independently selected from chlorine, a cyano group, a methyl group, or a methoxy group.

[0091] In some embodiments, R 2 teeth, [ka] is selected from.

[0092] In some embodiments, R 2 teeth, [ka] is selected from.

[0093] In some embodiments, R 2 teeth, [ka] is selected from.

[0094] In some embodiments, R 3a is selected from chlorine or cyano groups.

[0095] In some embodiments, R 3a is a cyano group.

[0096] In some embodiments, R 2 teeth, [ka] is selected from.

[0097] In some embodiments, R and R' are independently selected from hydrogen.

[0098] In some embodiments, at least one of X1, X2, and X3 is N, X4 is selected from C or N, Z is C(=O), and ring A is a 5-10 membered heteroaryl group, C6-C 10 an aryl group or a 6- to 10-membered heterocyclyl group, wherein the 5- to 10-membered heteroaryl group, C6-C 10 The aryl group or the 6- to 10-membered heterocyclyl group may optionally be R 1a Each R is replaced by 1a are independently selected from halogen, cyano, or a C1-C3 alkyl group, wherein the C1-C3 alkyl group is optionally substituted with halogen; R 1 is selected from a phenyl group, a 6-membered heteroaryl group, or a 6-membered heterocyclyl group, and said phenyl group, 6-membered heteroaryl group, or 6-membered heterocyclyl group is optionally selected from R 2a Each R is replaced by 2aare independently selected from halogen, cyano, C1-C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyloxy groups, and the C1-C6 alkyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 alkoxy, or C3-C6 cycloalkyloxy groups are optionally selected from R 2b Each R is replaced by 2b is selected from halogen or deuterium, R 2 is selected from a phenyl group, a 5- to 6-membered heteroaryl group, or a 5- to 6-membered heterocyclyl group, and the phenyl group, the 5- to 6-membered heteroaryl group, or the 5- to 6-membered heterocyclyl group is optionally selected from R 3a Each R is replaced by 3a are independently selected from halogen, cyano, ═O, C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl groups, and the C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl groups are optionally selected from R 3b is replaced by R 3b is selected from a halogen, a cyano group, or a hydroxyl group.

[0099] In some embodiments, the compound of formula (I) of the present application or a pharmaceutically acceptable salt thereof is [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0100] In another aspect, the present application provides a pharmaceutical composition, which comprises a compound of formula (I) of the present application or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0101] In another aspect, the present application provides a method for preventing or treating a mammalian DNA polymerase θ-mediated disease, the method comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0102] In another aspect, the present application provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for preventing or treating a DNA polymerase θ-mediated disease.

[0103] In another aspect, the present application provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of a DNA polymerase θ-mediated disease.

[0104] In another aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a DNA polymerase θ-mediated disease.

[0105] In some embodiments, the DNA polymerase θ-mediated disease is a disease in which DNA polymerase θ is overexpressed.

[0106] In some embodiments, the DNA polymerase θ-mediated disease is cancer.

[0107] In some embodiments, the cancer is a cancer in which there is reduced or absent expression of a BRCA gene, a defect in a BRCA gene, or reduced BRCA protein function.

[0108] In some embodiments, the cancer is colorectal adenocarcinoma.

[0109] In another aspect, the present application provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for preventing or treating cancer.

[0110] Definitions and explanations of terms Unless otherwise specified, the terms used in this application have the following meanings, and the group and term definitions described in this application include their exemplary definitions, exemplary definitions, preferred definitions, definitions described in the tables, definitions of specific compounds in the examples, etc., and may be combined with each other in any combination. Unless otherwise defined, certain terms should not be considered indefinite or unclear, but should be interpreted according to the general meaning in the art. When a trade name appears in this specification, it is intended to refer to the corresponding product or its active ingredient.

[0111] X4 is positioned ortho to the ring atom in ring A that is connected to Z.

[0112] In this specification, [ka] represents the linking site.

[0113] In this application, "*" indicates that the atom identified by it is a linking site, e.g., a linking group [ka] indicates that the N atom in the linking group is the linking site.

[0114] The representation of racemic or enantiopure compounds herein is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise noted, the wedge bond and hash wedge bond are [ka] indicates the absolute configuration of the stereocenter, and the black solid and dotted bonds [ka] indicates the relative configuration of stereocenters (e.g., cis-trans configuration in alicyclic compounds).

[0115] The term "tautomer" refers to a functional isomer produced by the rapid movement of an atom between two positions in a molecule. The compounds of the present application may exhibit the phenomenon of tautomerization. Tautomerized compounds may exist in two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually result in a mixture, whose physicochemical properties correspond to those of the mixture of compounds. The position of the equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the ketone form predominates, while in phenols, the enol form predominates. The present application includes all tautomeric forms of the compounds.

[0116] The term "stereoisomer" refers to isomers resulting from differences in the way atoms in molecules are arranged in space, and includes cis-trans isomers, enantiomers and non-enantiomers.

[0117] The compounds of the present application may have asymmetric atoms, such as carbon, sulfur, nitrogen, or phosphorus atoms, or asymmetric double bonds, so that the compounds of the present application may exist in particular geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may include cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, non-enantiomers, (D)-isomers, (L)-isomers, and racemic or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the scope of the definition of the compound of the present application. Substituents such as alkyl groups may also have additional asymmetric carbon, sulfur, nitrogen, or phosphorus atoms, and all of these isomers and mixtures thereof associated with all substituents are included within the scope of the definition of the compound of the present application. Compounds of the present application containing an asymmetric atom can be isolated in optically pure or racemic forms; optically pure forms can be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0118] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom with a substituent, provided that the valence of the particular atom is normal and the compound after substitution is stable. When the substituent is oxo (i.e., =O), this means that two hydrogen atoms are replaced.

[0119] The term "optionally" or "optionally" means that the event or circumstance described below may or may not occur, and the statement includes both the occurrence and non-occurrence of the event or circumstance. For example, an ethyl group "optionally" substituted with a halogen refers to the ethyl group being unsubstituted (CHCH), monosubstituted (CHCHF, CHCHCl, etc.), polysubstituted (CHFCHF, CHCHF, CHFCHCl, CHCHCl, etc.), or fully substituted (CFCF, CFCCl, CClCCl, etc.). As will be understood by those skilled in the art, no substitution or substitution pattern that is spatially impossible and / or synthetically impossible is introduced into any group containing one or more substituents.

[0120] Any variable (e.g., R a , R b ) appears more than once in the composition or structure of a compound, its definition is independent in each occurrence. For example, if a group is represented by two R b If replaced by, each R b Each has independent options.

[0121] C in this specification m -C n means that the group has an integer number of carbon atoms in the range of m to n. For example, "C1-C 10 " means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.

[0122] The term "alkyl group" refers to a group having the general formula C n H 2n+1 The alkyl group may be a straight chain or a branched chain. 10The term "alkyl group" may be understood to represent a straight or branched chain saturated hydrogen group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of said alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl. The term "C1-C6 alkyl group" may be understood to represent an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, and specific examples include, but are not limited to, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a neopentyl group, a hexyl group, a 2-methylpentyl group, etc. The term "C1-C3 alkyl group" may be understood to represent a linear or branched saturated alkyl group having 1, 2 or 3 carbon atoms. 10 The "alkyl group" may include ranges such as "C1-C6 alkyl group" or "C1-C3 alkyl group", and the "C1-C6 alkyl group" may further include "C1-C3 alkyl group".

[0123] The term "alkoxy group" refers to a group formed by losing a hydrogen atom on a hydroxyl group of a straight-chain or branched-chain alcohol, and may be understood as an "alkyloxy group" or an "alkyl group -O-". 10 The term "alkoxy group" refers to a group consisting of C1-C 10 Alkyloxy group" or "C1-C 10The term "C1-C6 alkoxy group" may be understood as "C1-C6 alkyloxy group" or "C1-C6 alkyl group-O-". 10 The "alkoxy group" may include ranges such as "C1-C6 alkoxy group" and "C1-C3 alkoxy group", and the "C1-C6 alkoxy group" may further include "C1-C3 alkoxy group".

[0124] The term "alkenyl group" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. 10 The term "alkenyl group" may be understood to represent a straight or branched chain unsaturated hydrogen group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and is also referred to as "C2-C 10 The "alkenyl group" is preferably a "C2-C6 alkenyl group", more preferably a "C2-C4 alkenyl group", and even more preferably a C2 or C3 alkenyl group. It can be understood that when the alkenyl group contains one or more double bonds, the double bonds may be separate or conjugated to each other. Specific examples of the alkenyl group include, but are not limited to, a vinyl group, an allyl group, an (E)-2-methylvinyl group, a (Z)-2-methylvinyl group, an (E)-but-2-alkenyl group, a (Z)-but-2-alkenyl group, an (E)-but-1-alkenyl group, a (Z)-but-1-alkenyl group, an isopropenyl group, a 2-methylpropane-2-alkenyl group, a 1-methylpropane-2-alkenyl group, a 2-methylpropane-1-alkenyl group, an (E)-1-methylpropane-1-alkenyl group, or a (Z)-1-methylpropane-1-alkenyl group.

[0125] The term "alkynyl group" refers to a straight- or branched-chain unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms with at least one triple bond. 10The term "alkynyl group" may be understood to represent a straight or branched chain unsaturated hydrogen group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. 10 Examples of "alkynyl groups" include, but are not limited to, ethynyl groups (-C≡CH), propane-1-alkynyl groups (-C≡CCH), propane-2-alkynyl groups (-CHC≡CH), buto-1-alkynyl groups, buto-2-alkynyl groups, or buto-3-alkynyl groups. 10 The "alkynyl group" is preferably a "C2-C6 alkynyl group", more preferably a "C2-C4 alkynyl group", and even more preferably a C2 or C3 alkynyl group.

[0126] The term "cycloalkyl group" refers to a carbocyclic ring that is fully saturated and exists as a monocyclic, parallel, bridged, or spirocyclic ring. Unless otherwise specified, the carbocyclic ring typically has 3 to 10 members. 10 The term "cycloalkyl group" may be understood to represent a saturated monocyclic, parallel, spiro or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of said cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like. 10 The term "cycloalkyl group" may include a "C3-C6 cycloalkyl group", which may be understood to represent a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms, and specific examples include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, etc.

[0127] The term "cycloalkyloxy group" may also be understood as "cycloalkyl group -O-".

[0128] The term "cycloalkenyl group" refers to a non-aromatic carbon ring that is not completely saturated and exists in the form of a monocyclic, parallel ring, bridged ring, or spiro ring. Unless otherwise specified, the carbon ring is typically a 4- to 10-membered ring, having 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of the cycloalkenyl group include, but are not limited to, a cyclopentenyl group, a cyclopentadienyl group, a cyclohexenyl group, a cyclohexadienyl group, a cycloheptenyl group, or a cycloheptadienyl group.

[0129] The term "heterocyclyl group" refers to a fully saturated or partially saturated monocyclic, parallel, spiro, or bridged ring group whose ring atoms contain 1, 2, 3, 4, or 5 heteroatoms or heteroatomic groups (i.e., groups of atoms containing heteroatoms), including, but not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O)-, -S(=O)-, -P(=O)-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-. The term "3- to 18-membered heterocyclyl group" refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, and the ring atoms contain 1, 2, 3, 4, or 5 heteroatoms or heteroatomic groups independently selected from the above list. The term "4- to 12-membered heterocyclyl group" refers to a heterocyclyl group having 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring atoms, and the ring atoms contain 1, 2, 3, 4, or 5 heteroatoms or heteroatomic groups independently selected from the above list. The term "4- to 10-membered heterocyclyl group" refers to a heterocyclyl group having 4, 5, 6, 7, 8, 9, or 10 ring atoms, and the ring atoms contain 1, 2, 3, 4, or 5 heteroatoms or heteroatom groups independently selected from the above list. Specific examples of 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, thietanyl, and oxetanyl groups. Specific examples of 5-membered heterocyclyl groups include tetrahydrofuranyl, dioxolyl, pyrrolidinyl, and imidazolidinyl groups. , pyrazolidinyl group, pyrrolinyl group, 4,5-dihydrooxazole group, or 2,5-dihydro-1H-pyrrolyl group; specific examples of 6-membered heterocyclyl groups include, but are not limited to, tetrahydropyranyl group, piperidinyl group, morpholinyl group, dithianyl group, thiomorpholinyl group, piperazinyl group, trithianyl group, tetrahydropyridinyl group, or 4H-[1,3,4]thiadiazinyl group; and specific examples of 7-membered heterocyclyl groups include, but are not limited to, diazacycloheptyl group.Specific examples of 8-membered heterocyclyl groups include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl. Specific examples of 9-membered heterocyclyl groups include, but are not limited to, benzo[d][1,3]dioxole. Specific examples of 10-membered heterocyclyl groups include, but are not limited to, dihydroisoquinolinyl. The heterocyclyl group may also be a bicyclic group, where specific examples of the 5,5-membered bicyclic group include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl, and specific examples of the 5,6-membered bicyclic group include, but are not limited to, hexahydropyro[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyraazinyl, or 5,6,7,8-tetrahydroimidazo[1,5-a]pyraazinyl. Optionally, the heterocyclyl group may be a benzo-fused ring group of the above 4- to 7-membered heterocyclyl group, where specific examples include, but are not limited to, dihydroisoquinolinyl, benzo[d][1,3]dioxole, etc. The term "4- to 10-membered heterocyclyl group" may encompass ranges such as "5- to 10-membered heterocyclyl group," "4- to 7-membered heterocyclyl group," "5- to 6-membered heterocyclyl group," "6- to 8-membered heterocyclyl group," "4- to 10-membered heterocycloalkyl group," "5- to 10-membered heterocycloalkyl group," "4- to 7-membered heterocycloalkyl group," "5- to 6-membered heterocycloalkyl group," "6- to 8-membered heterocycloalkyl group," and the term "4- to 7-membered heterocyclyl group" may further encompass ranges such as "4- to 6-membered heterocyclyl group," "5- to 6-membered heterocyclyl group," "4- to 7-membered heterocycloalkyl group," "4- to 6-membered heterocycloalkyl group," "5- to 6-membered heterocycloalkyl group."

[0130] The term "heterocyclyloxy group" may also be understood as "heterocyclyl group -O-".

[0131] The term "heterocycloalkyl group" refers to a cyclic group that is fully saturated and exists as a monocyclic, parallel, bridged, or spirocyclic ring, and the ring atoms of the ring contain 1, 2, 3, 4, or 5 heteroatoms or heteroatomic groups (i.e., groups of atoms containing heteroatoms), including, but not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O)-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-.

[0132] The term "aryl group" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. An aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. "C6-C 14 The term "aryl group" may be understood as an aryl group having 6 to 14 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl group"), such as a phenyl group, or a ring having 9 carbon atoms ("C9 aryl group"), such as an indanyl or indenyl group, or a ring having 10 carbon atoms ("C 10 aryl group), such as a tetralinyl group, a dihydronaphthyl group, or a naphthyl group, or a ring having 13 carbon atoms ("C 13 aryl group), such as a fluorenyl group, or a ring having 14 carbon atoms ("C 14 aryl group), for example, an anthryl group. 10 An "aryl group" may be understood as an aryl group having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl group"), such as a phenyl group, or a ring having 9 carbon atoms ("C9 aryl group"), such as an indanyl or indenyl group, or a ring having 10 carbon atoms ("C 10 aryl group), for example, a tetralinyl group, a dihydronaphthyl group, or a naphthyl group.

[0133] The term "heteroaryl group" refers to a monocyclic or fused polycyclic ring system having aromatic character, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C aromatic ring groups. The term "5-10 membered heteroaryl group" may be understood to include such monocyclic or bicyclic aromatic ring systems, which have 5, 6, 7, 8, 9 or 10 ring atoms, particularly 5 or 6 or 9 or 10 ring atoms, and which contain 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl groups and benzo derivatives thereof, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl groups, or from pyridyl, ... The heteroaryl group may be selected from azinyl, pyrimidinyl, pyrazinyl, or triazinyl groups and their benzo derivatives, such as quinolyl, quinazolinyl, or isoquinolyl groups; azocinyl, indolizinyl, or purinyl groups and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, ptenidinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl, or phenoxazinyl groups. The term "5- to 6-membered heteroaryl group" refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1, 2, or 3, preferably 1 to 2 heteroatoms independently selected from N, O, and S. The term "9- to 10-membered heteroaryl group" refers to an aromatic ring system having 9 or 10 ring atoms and which contains 1, 2, or 3, preferably 1-2 heteroatoms independently selected from N, O, and S. A "6-membered heteroaryl group" refers to an aromatic ring system having 6 ring atoms and which contains 1, 2, or 3, preferably 1-2 heteroatoms independently selected from N, O, and S.

[0134] The term "alkoxyacyl group" refers to a -COO-alkyl group. 10 The term "alkoxyacyl group" refers to -COO-C1-C 10 It refers to an alkyl group. Examples include methoxyacyl, ethoxyacyl, propoxyacyl, isopropoxyacyl, n-butoxyacyl, isobutoxyacyl, and t-butoxyacyl groups. The term "C1-C6 alkoxyacyl group" refers to a -COO-C1-C6 alkyl group. The term "C1-C3 alkoxyacyl group" refers to a -COO-C1-C3 alkyl group.

[0135] The term "alkylsulfonyl group" refers to an -S(=O)2-alkyl group, such as methylsulfonyl group, ethylsulfonyl group, 2-propylsulfonyl group, etc. 10 The term "alkylsulfonyl group" refers to -S(=O)2-C1-C 10 The term "C1-C6 alkylsulfonyl group" refers to an -S(=O)2-C1-C6 alkyl group. The term "C1-C3 alkylsulfonyl group" refers to an -S(=O)2-C1-C3 alkyl group.

[0136] The term "alkyl acyl group" refers to a -C(=O)-alkyl group, such as methyl acyl group, ethyl acyl group, etc. 10 The term "alkyl acyl group" refers to a group consisting of -C(=O)-C1-C 10 Refers to an alkyl group.

[0137] The term "heterocyclylalkyl group" refers to the group -(alkylene)-heterocyclyl.

[0138] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0139] The term "hydroxyl group" refers to an --OH group.

[0140] The term "cyano" refers to the group -CN.

[0141] The term "amino group" refers to an -NH2 group.

[0142] The term "therapeutically effective amount" is intended to mean a dose of a compound of the present application that (i) treats a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal being treated, but can be determined by one of ordinary skill in the art based on their common knowledge in the art and the present disclosure, as is routine.

[0143] The term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable risk / benefit ratio.

[0144] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, including salts formed between a compound and an inorganic or organic acid, and salts formed between a compound and an inorganic or organic base.

[0145] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof with a pharmaceutically acceptable excipient for the purpose of advantageously administering the compounds of the present application to an organism.

[0146] The term "pharmaceutically acceptable excipient" refers to an excipient that has no significant irritating effect on an organism and does not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0147] The terms "comprise" or "comprise" and their English variants, such as comprises or comprising, may be understood in an open and non-exclusive sense, i.e. "including but not limited to".

[0148] The present application further includes isotopically labeled compounds of the present application that are the same as those described herein, but in which one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature. Examples of isotopes that can be attached to compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, 123 I, 125 Iwa 36 Cl, etc.

[0149] The compounds of the present application that are labeled with several isotopes (e.g., 3 H and 14 C) may be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N, 11 C and 18 F can be used in positron emission tomography (PET) studies to measure substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures similar to those disclosed in the following schemes and / or examples, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0150] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and may be formulated as solid, semi-solid, liquid, or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

[0151] Typical routes of administration of the compounds of the present application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0152] The pharmaceutical compositions of the present application may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, emulsifying, lyophilizing and the like.

[0153] In some embodiments, the pharmaceutical composition is in oral form.For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art.These excipients can formulate the compounds of the present application into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.

[0154] The solid oral composition can be prepared by conventional blending, filling, or tableting methods. For example, it can be obtained by the following method: the active compound is mixed with a solid excipient, the resulting mixture is optionally pulverized, and if necessary, other suitable excipients are added, and the mixture is processed into granules to obtain tablets or dragee cores. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0155] The pharmaceutical compositions are also suitable for parenteral administration, eg, as sterile solutions, suspensions, or lyophilized products in appropriate unit dosage forms.

[0156] In all administration methods of the compound of general formula (I) described herein, the daily dosage is 0.1 mg / kg to 500 mg / kg body weight, preferably 0.5 mg / kg to 400 mg / kg body weight, and more preferably 1 mg / kg to 200 mg / kg body weight, in the form of a single or individual dose.

[0157] The compounds of the present application can be prepared by a number of synthetic methods well known to those skilled in the art, including the specific examples listed below, embodiments formed by combination with other chemical synthetic methods, and equivalent substitution methods well known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present application.

[0158] The chemical reactions of the specific examples of the present application are carried out in suitable solvents appropriate for the chemical transformations of the present application and the reagents and materials required therefor. To obtain the compounds of the present application, one skilled in the art may need to modify or select synthetic steps or reaction flows based on the existing examples.

[0159] The following abbreviations are used in this application:

[0160] JPEG2023134739000032.jpg223170

[0161] [Mode for Carrying Out the Invention] The present invention will be described in detail below with reference to examples, but this does not mean any adverse limitations on the present application. The present application has been described in detail and the embodiments for carrying out the invention have been disclosed herein. It will be apparent to those skilled in the art that various modifications and improvements can be made to the embodiments for carrying out the invention of the present application without departing from the spirit and scope of the present application. All reagents used in the present application are commercially available and can be used without the need for further purification.

[0162] Unless otherwise specified, the ratios shown for mixed solvents are volumetric mixture ratios. For example, "petroleum ether:ethyl acetate=1:2" indicates that the volume ratio of petroleum ether to ethyl acetate is 1:2.

[0163] Compounds are named manually or by ChemDraw® software; commercially available compounds use supplier catalog names.

[0164] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts are measured in units of 10 -6 The solvents used in the NMR assay are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS). 50 " stands for the half-maximal inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0165] In the following high-performance liquid chromatography purification, unless otherwise specified, the "%" of the amount of acid or base in mobile phase A refers to the volume fraction. For example, "water (0.05% formic acid)" indicates that the volume of formic acid is 0.05% of the total volume of formic acid and water. B% indicates the percentage of the volume of mobile phase B in the total volume of mobile phase A and mobile phase B during gradient elution, and "B%: 50% to 70%" indicates that the percentage of the volume of mobile phase B in the total volume of mobile phase A and mobile phase B during gradient elution is 50% to 70%.

[0166] Example 1, N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide (Compound 1) [ka]

[0167] Step 1: Synthesis of N-(5-bromothiazolo[5,4-b]pyridin-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide (Intermediate 1-3) Intermediate 1-1 (100 mg) was dissolved in DMF (2 mL) at 20 °C, and intermediate 1-2 (99.63 mg, synthesized according to the method described in International Publication No. WO2020243459), HATU (247.88 mg), and DIEA (112.34 mg) were added to the reaction mixture. The reaction mixture was stirred at 20 °C for 1 hour. After the reaction was completed, ethyl acetate (10 mL) and water (20 mL) were added to the reaction mixture. The organic phase was washed with water (10 mL x 2). The organic phase was then separated and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:2) to obtain the title compound (22 mg).

[0168] MS m / z(ESI):=441.3 [M+H] + .

[0169] Step 2: Synthesis of N-(5-(4-chlorophenyl)thiazolo[5,4-b]pyridin-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide (Compound 1) Intermediate 1-3 (20 mg) was dissolved in a dioxane (1 mL) / water (0.2 mL) solution at 20 °C. To the reaction mixture was added p-chlorophenylboronic acid (9.21 mg), cesium carbonate (29.53 mg), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (PdCl2(dppf)) (1.64 mg). The reaction mixture was stirred at 80 °C for 15 minutes under nitrogen gas protection. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by high-performance liquid chromatography (chromatography column: C18-2 (100 × 30 mm × 5 μm), mobile phase: A: water (0.05% aqueous ammonia), B: acetonitrile, gradient elution, B%: 19% to 59%, 10 minutes) to obtain the title compound (1.09 mg).

[0170] 1 H NMR(400MHz,Methanol-d4)δ=8.75-8.72(m,1H),8.66(s,1H),8.16-8.08(m,3H),7.99(d,J=8.6Hz,1H),7.76 -7.73(m,1H),7.54-7.50(m,2H),7.48-7.37(m,2H),7.14(t,J=7.4Hz,1H),7.00(d,J=8.0Hz,1H),3.64(s,3H) MS m / z(ESI):=473.1 [M+H] + .

[0171] Example 2, N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide (Compound 2) [ka]

[0172] Step 1: Synthesis of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide (Intermediate 2-2) Intermediate 2-1 (100 mg) was dissolved in DMF (2 mL) at 20°C, and intermediate 1-2 (66.14 mg), HATU (164.55 mg), and DIEA (74.58 mg) were added to the reaction mixture. The reaction mixture was stirred at 20°C for 1 hour. After the reaction was completed, ethyl acetate (10 mL) and water (20 mL) were added to the reaction mixture. The organic phase was washed with water (10 mL x 2). The organic phase was then separated and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:5) to obtain the title compound (25 mg).

[0173] MS m / z(ESI):=442.0 [M+H] + .

[0174] Step 2: Synthesis of N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide (compound 2) Intermediate 2-2 (25 mg) was dissolved in a dioxane (1 mL) / water (0.2 mL) solution at 20 °C, and p-chlorophenylboronic acid (11.49 mg), cesium carbonate (36.83 mg), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (2.07 mg) were added to the reaction mixture. The reaction mixture was stirred at 80 °C for 15 minutes under nitrogen gas protection. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 (150 × 30 mm × 5 μm), mobile phase: A: water (0.05% formic acid), B: acetonitrile, gradient elution, B%: 50% to 70%, 11 minutes) to obtain the title compound (2.03 mg).

[0175] 1H NMR(400MHz,Methanol-d4)δ=9.12(s,1H),8.75(d,J=5.0Hz,1H),8.67(s,1H),8.17(d,J=8.6Hz,2H),7.76( d,J=5.3Hz,1H),7.56(d,J=8.6Hz,2H),7.47-7.41(m,2H),7.17-7.11(m,1H),7.02-6.98(m,1H),3.65(s,3H) MS m / z(ESI):=474.1 [M+H] + .

[0176] Example 3, N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-fluoro-6-methoxyphenyl)pyridine-4-carboxamide (Compound 3) [ka]

[0177] Step 1: Synthesis of 3-(2-fluoro-6-methoxyphenyl)pyridine-4-carboxylic acid methyl ester (Intermediate 3-3) Intermediate 3-1 (500 mg) was dissolved in a dioxane (15 mL) / water (3 mL) solution at 20°C, and intermediate 3-2 (786.67 mg), potassium carbonate (639.75 mg), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (169.35 mg) were added to the reaction mixture. The reaction mixture was stirred at 80°C for 15 minutes under nitrogen gas protection. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (600 mg).

[0178] MS m / z(ESI):=262.1 [M+H] + .

[0179] Step 2: Synthesis of 3-(2-fluoro-6-methoxyphenyl)pyridine-4-carboxylic acid (Intermediate 3-4) At 20°C, intermediate 3-3 (300 mg) was dissolved in a methanol (5 mL) / water (5 mL) solution, and sodium hydroxide (137.79 mg) was added to the reaction solution. The reaction solution was stirred at 50°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness. The residue was dissolved in a small amount of methanol and filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the title compound (220 mg).

[0180] MS m / z(ESI):=248.1 [M+H] + .

[0181] Step 3: Synthesis of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-3-(2-fluoro-6-methoxyphenyl)pyridine-4-carboxamide (Intermediate 3-5) Intermediate 3-4 (80 mg) was dissolved in DMF (3 mL) at 20°C, and intermediate 2-1 (74.77 mg), HATU (135.35 mg), and DIEA (83.65 mg) were added to the reaction mixture. The reaction mixture was stirred at 20°C for 1 hour. After the reaction was completed, ethyl acetate (5 mL) and water (10 mL) were added, and the mixture was extracted with ethyl acetate (5 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:2) to obtain the title compound (50 mg).

[0182] MS m / z(ESI):=460.0 [M+H] + .

[0183] Step 4: Synthesis of N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-fluoro-6-methoxyphenyl)pyridine-4-carboxamide (compound 3) Intermediate 3-5 (50 mg) was dissolved in a dioxane (1 mL) / water (0.2 mL) solution at 20 °C. To the reaction mixture was added intermediate 3-6p-chlorophenylboronic acid (33.97 mg), potassium carbonate (30.03 mg), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (7.95 mg). The reaction mixture was stirred at 80 °C for 15 minutes under nitrogen gas protection. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by high-performance liquid chromatography (chromatography column: Waters Xbridge BEH C18 (100 × 30 mm × 10 μm), mobile phase: A: water (0.05% formic acid), B: acetonitrile, gradient elution, B%: 40% to 80%, 10 min) to obtain the title compound (16.4 mg).

[0184] 1 H NMR(400MHz,Methanol-d4)δ=13.62(s,1H),9.29(s,1H),8.82(d,J=5.0Hz,1H),8.70(s,1H),8.22(d,J=8.5Hz,2H),7. 85(d,J=5.3Hz,1H),7.62(d,J=8.5Hz,2H),7.46-7.40(m,1H),6.98(t,J=9.0Hz,1H),6.91(d,J=8.5Hz,1H),3.60(s,3H) MS m / z(ESI):=492.1 [M+H] + .

[0185] Example 4, N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)-6-methylpyridine-3-carboxamide (Compound 4) [ka]

[0186] Step 1: Synthesis of 4-(2-methoxyphenyl)-6-methylpyridine-3-carboxylic acid methyl ester (intermediate 4-3) Intermediate 4-1 (500 mg) was dissolved in a dioxane (15 mL) / water (3 mL) solution at 20°C, and intermediate 4-2 (818.69 mg), potassium carbonate (744.62 mg), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (197.11 mg) were added to the reaction mixture. The reaction mixture was stirred at 80°C for 15 minutes under nitrogen gas protection. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (490 mg).

[0187] MS m / z(ESI):=258.1 [M+H] + .

[0188] Step 2: Synthesis of 4-(2-methoxyphenyl)-6-methylpyridine-3-carboxylic acid (intermediate 4-4) At 20°C, intermediate 4-3 (300 mg) was dissolved in a methanol (5 mL) / water (5 mL) solution, and sodium hydroxide (139.91 mg) was added to the reaction solution. The reaction solution was stirred at 50°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness. The residue was dissolved in a small amount of methanol and filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the title compound (280 mg).

[0189] MS m / z(ESI):=244.1 [M+H] + .

[0190] Step 3: Synthesis of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)-6-methylpyridine-3-carboxamide (Intermediate 4-5) Intermediate 4-4 (100 mg) was dissolved in DMF (3 mL) at 20°C, and intermediate 2-1 (94.99 mg), HATU (187.57 mg), and DIEA (106.26 mg) were added to the reaction mixture. The reaction mixture was stirred at 20°C for 1 hour. After the reaction was completed, ethyl acetate (5 mL) and water (10 mL) were added, and the mixture was extracted with ethyl acetate (5 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by thin-layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the title compound (130 mg).

[0191] MS m / z(ESI):=456.0 [M+H] + .

[0192] Step 4: Synthesis of N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)-6-methylpyridine-3-carboxamide (compound 4) Intermediate 4-5 (50 mg) was dissolved in a dioxane (1 mL) / water (0.2 mL) solution at 20 °C, and p-chlorophenylboronic acid (34.27 mg), potassium carbonate (30.29 mg), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (8.02 mg) were added to the reaction mixture. The reaction mixture was stirred at 80 °C for 15 minutes under nitrogen gas protection. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by high-performance liquid chromatography (chromatography column: Waters Xbridge BEH C18 (100 × 30 mm × 10 μm), mobile phase: A: water (0.05% formic acid), B: acetonitrile, gradient elution, B%: 34% to 74%, 10 min) to give the title compound (15 mg).

[0193] 1H NMR(400MHz,DMSO-d6)δ=13.35(s,1H),9.27(s,1H),8.77(s,1H),8.22(d,J=8.5Hz,2H),7.62(d,J=8.8Hz, 2H),7.44-7.40(m,2H),7.36(s,1H),7.12(t,J=7.5Hz,1H),6.99(d,J=7.8Hz,1H),3.52(s,3H),2.60(s,3H) MS m / z(ESI):=488.1 [M+H] + .

[0194] Example 5, N-(6-(3-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide (Compound 5) [ka]

[0195] At 20°C, intermediate 2-2 (30 mg) and intermediate 5-1 (31.82 mg) were dissolved in dioxane (1.5 mL) and water (0.3 mL), followed by the addition of 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (2.48 mg) and cesium carbonate (44.2 mg). The mixture was stirred at 100°C for 3 hours under nitrogen gas protection. After the reaction was completed, the organic phase was concentrated under reduced pressure until dry. Ethyl acetate (10 mL) and water (10 mL) were added, and the mixture was washed with water (10 mL x 2). The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure until dry. The residue was purified by high performance liquid chromatography (chromatography column: Boston Green ODS (150*30mm*5um), mobile phase: A: water (0.05% formic acid), B: acetonitrile, gradient elution, B%: 55% to 85%, 12 min) to give the title compound (5.4mg).

[0196] 1H NMR(400MHz,DMSO-d6)δ=13.49(s,1H),9.29(s,1H),8.77(d,J=4.8Hz,1H),8.67(s,1H),8.23(s,1H),8.16(d,J=6.9Hz, 1H),7.74(d,J=4.9Hz,1H),7.66-7.51(m,2H),7.48-7.34(m,2H),7.17-7.09(m,1H),7.00(d,J=8.3Hz,1H),3.53(s,3H) MS m / z(ESI):=474.1 [M+H] + .

[0197] Example 6, 3-(2-methoxyphenyl)-N-(6-(4-methylphenyl)thiazolo[4,5-b]pyrazin-2-yl)pyridine-4-carboxamide (Compound 6) [ka]

[0198] At 25°C, intermediate 6-1 (27.67 mg) and intermediate 2-2 (30 mg) were dissolved in dioxane (1.5 mL) and water (0.3 mL), and then cesium carbonate (44.20 mg) and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (2.48 mg) were added. The reaction mixture was reacted at 100°C for 3 hours under nitrogen gas protection. After the reaction was completed, ethyl acetate (20 mL) and water (60 mL) were added, and the mixture was washed with water (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness, and the residue was purified by high-performance liquid chromatography (chromatography column: Boston Green ODS (150*30mm*5um), mobile phase: A: water (0.05% formic acid), B: acetonitrile, gradient elution, B%: 52% to 82%, 12 minutes) to obtain the title compound (4.3mg).

[0199] 1H NMR(400MHz,DMSO-d6):δ=9.16(s,1H),8.75(d,J=4.8Hz,1H),8.64(s,1H),8.07(d,J=8.0Hz,2H),7.74(d ,J=4.9Hz,1H),7.44-7.34(m,4H),7.09(t,J=7.3Hz,1H),7.00(d,J=8.0Hz,1H),3.53(s,3H),2.39(s,3H) MS m / z(ESI):=454.2 [M+H] + .

[0200] Example 7, 3-(2-methoxyphenyl)-N-(6-(4-methoxyphenyl)thiazolo[4,5-b]pyrazin-2-yl)pyridine-4-carboxamide (Compound 7) [ka]

[0201] At 25°C, intermediate 7-1 (30.92 mg) and intermediate 2-2 (30 mg) were dissolved in dioxane (1.5 mL) and water (0.3 mL), and then cesium carbonate (44.20 mg) and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (2.48 mg) were added. The reaction mixture was reacted at 100°C for 3 hours under nitrogen gas protection. After the reaction was completed, ethyl acetate (20 mL) and water (60 mL) were added, and the mixture was washed with water (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness, and the residue was purified by high-performance liquid chromatography (chromatography column: Boston Green ODS (150*30mm*5um), mobile phase: A: water (0.05% formic acid), B: acetonitrile, gradient elution, B%: 50% to 80%, 12 minutes) to obtain the title compound (4.8mg).

[0202] 1H NMR(400MHz,DMSO-d6)δ=13.38(s,1H),9.19(s,1H),8.84~8.74(m,1H),8.68(s,1H),8.14(d,J=8.9Hz,2H) ,7.73(d,J=4.8Hz,1H),7.53-7.33(m,2H),7.15-7.08(m,3H),7.03-6.95(m,1H),3.85(s,3H),3.53(s,3H). MS m / z(ESI):=470.2 [M+H] + .

[0203] Example 8: N-(5-(4-chlorophenyl)thiazolo[5,4-d]pyrimidin-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide (Compound 8) [ka]

[0204] Step 1: Synthesis of 5-chlorothiazolo[5,4-d]pyrimidin-2-amine (Intermediate 8-2) Intermediate 8-1 (5.0 g) was added to acetic anhydride (40 mL). Potassium thiocyanate (6 g) was added to the reaction mixture at 0° C. The reaction mixture was stirred at 80° C. for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into water, filtered, and the filter cake was dried to obtain the title compound (5 g).

[0205] MS m / z(ESI):187.1 [M+H] + .

[0206] Step 2: Synthesis of N-(5-chlorothiazolo[5,4-d]pyrimidin-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide (Intermediate 8-3) Intermediate 8-2 (170 mg), Intermediate 1-2 (208 mg), HATU (345.8 mg), and DIEA (236 mg) were added to DMF (2 mL), and the reaction mixture was stirred at 25 °C for 12 h under nitrogen gas protection. After completion of the reaction, the mixture was cooled to room temperature, and water (50 mL) and ethyl acetate (100 mL) were added, followed by washing the organic phase with water (50 mL × 2). The organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini NX C18 (3.5 μm × 4.6 × 100 mm), mobile phase: A: water (0.05% TFA), B: acetonitrile, gradient elution, B%: 10% to 90%, 10 min) to give the title compound (210 mg).

[0207] MS m / z(ESI):398.2 [M+H] + .

[0208] Step 3: Synthesis of N-(5-(4-chlorophenyl)thiazolo[5,4-d]pyrimidin-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide (compound 8) Intermediate 8-3 (100 mg), p-chlorophenylboronic acid (78 mg), Pd(dtbpf)Cl2 (16.35 mg), and potassium phosphate (105 mg) were added to dioxane (1 mL) and water (0.2 mL), and the reaction mixture was stirred at 100 °C for 12 h under nitrogen gas protection. After completion of the reaction, the mixture was cooled to room temperature, and water (50 mL) and ethyl acetate (100 mL) were added sequentially. The organic phase was washed with water (50 mL × 2) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini NX C18 (3.5 μm × 4.6 × 100 mm), mobile phase: A: water (0.05% TFA), B: acetonitrile, gradient elution, B%: 10% to 90%, 10 min) to give the title compound (11 mg).

[0209] MS m / z(ESI):474.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 13.33(s,1H),9.17(s,1H),8.73(d,J=5.0Hz,1H),8.61(s,1H),8.47-8.40(m,2H),7.72(d,J=5.0Hz ,1H),7.63-7.56(m,2H),7.42-7.33(m,2H),7.12-7.03(m,1H),6.99(d,J=8.1Hz,1H),3.52(s,3H).

[0210] Example 9, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-methoxyphenyl)pyridine-4-carboxamide (Compound 9) [ka]

[0211] Intermediate 2-2 (50 mg) was dissolved in a mixture of dioxane and water (dioxane:water = 10:1, 0.55 mL) at 100 °C. Intermediate 9-1 (21.59 mg), cesium carbonate (73.67 mg), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (4.14 mg) were then slowly added to the reaction mixture. Under nitrogen gas protection, the reaction mixture was stirred at 100 °C for 15 minutes. After the reaction was complete, ethyl acetate (9 mL) and water (18 mL) were added, followed by extraction with ethyl acetate (9 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high performance liquid chromatography (chromatography column: Boston Green ODS (150*30mm*5um), mobile phase: A: water (0.05% aqueous ammonia), B: acetonitrile, gradient elution, B%: 20% to 40%, 11 min) to give the title compound (13 mg).

[0212] 1H NMR(400MHz,Methanol-d4)δ=9.00-8.97(m,1H),8.62(d,J=5.0Hz,1H),8.55(s,1H),8.34~8.29(m,2H),7.88(d ,J=8.5Hz,2H),7.81(d,J=5.0Hz,1H),7.41-7.35(m,2H),7.10-7.04(m,1H),6.98(d,J=8.3Hz,1H),3.64(s,3H) MS m / z(ESI):=465.1 [M+H] + .

[0213] Example 10, N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyridin-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 10) [ka]

[0214] Step 1: Synthesis of N-(6-bromothiazolo[4,5-b]pyridin-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Intermediate 10-2) Intermediate 1-2 (200 mg), Intermediate 10-1 (200 mg), HATU (328 mg), and DIEA (225 mg) were dissolved in DMF (4 mL), and the reaction mixture was stirred at 25 °C for 12 h. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (15 mL * 3). The organic layers were combined, washed with water (15 mL * 2), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative thin layer chromatography (dichloromethane:methanol = 15:1) to obtain the title compound (160 mg).

[0215] MS m / z (ESI): 441.0 / 443.0 [M + H] + .

[0216] Step 2: Synthesis of N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyridin-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 10) Intermediate 10-2 (80 mg) and intermediate 3-6 (42 mg) were dissolved in dioxane (1.2 mL) and water (0.3 mL). Potassium carbonate (50 mg) and Pd(dtbpf)Cl2 (17 mg) were added, and the reaction mixture was incubated at 80 °C for 4 h under nitrogen gas protection. After completion of the reaction, the mixture was cooled to room temperature, poured into water (15 mL), and extracted with ethyl acetate (10 mL × 3). The organic layers were combined, washed with water (10 mL × 2), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 3.5 μm × 4.6 × 100 mm, mobile phase: A: water (0.05% TFA), B: acetonitrile, B%: 10% to 90%, 10 min) to obtain the title compound (28 mg).

[0217] MS m / z (ESI): 473.0 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ 13.24(br,s,1H),8.88(d,J=2.3Hz,1H),8.80-8.73(m,2H),8.65(s,1H),7.81(d,J=8.6Hz,2H),7.72(d,J=4 .9Hz,1H),7.58(d,J=8.6Hz,2H),7.47-7.33(m,2H),7.12-7.08(m,1H),6.99(d,J=8.1Hz,1H),3.50(s,3H).

[0218] Example 11, N-(6-(6-cyanopyridin-3-yl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 11) [ka]

[0219] Under a nitrogen gas atmosphere, intermediate 2-2 (50 mg), intermediate 11-1 (52.02 mg), Pd(dppf)Cl (8.27 mg), and potassium phosphate (47.98 mg) were dissolved in dioxane (1 mL) and water (0.2 mL) and stirred at 100 °C for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (5 mL * 2). The organic phase was concentrated under reduced pressure to dryness. The residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 5 μm * 10 * 150 mm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 30% to 50%, 11 min) to obtain the title compound (5.5 mg).

[0220] MS m / z(ESI):466.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 13.59(s,1H),9.61-9.49(m,1H),9.43(s,1H),8.84~8.74(m,2H),8.67(s,1H),8.23(d,J=8.2Hz,1H) ,7.75(d,J=5.0Hz,1H),7.48-7.35(m,2H),7.11(t,J=7.5Hz,1H),7.00(d,J=8.4Hz,1H),3.52(s,3H).

[0221] Example 12: N-(6-(4-cyano-3-fluorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 12) [ka]

[0222] Intermediate 2-2 (30 mg), Intermediate 12-1 (22.37 mg), Pd(dppf)Cl2 (4.96 mg), and potassium phosphate (28.80 mg) were added to dioxane (1 mL) and water (0.2 mL), and the reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was poured into water (5 mL) and extracted with ethyl acetate (5 mL × 3). The organic layers were combined, washed with saturated brine (10 mL × 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness. The residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 3.5 μm × 4.6 × 100 mm, mobile phase: A: water (0.05% TFA), B: acetonitrile, B%: 10% to 90%, 8 min) to obtain the title compound (13 mg).

[0223] MS m / z (ESI): 483.0 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ 13.59(br,s,1H),9.36(s,1H),8.86-8.68(m,1H),8.64(s,1H),8.36-8.28(m,1H),8.28-8.21(m,1H),8.1 5-8.06(m,1H),7.78-7.72(m,1H),7.45-7.35(m,2H),7.14-7.06(m,1H),7.03-6.96(m,1H),3.53(s,3H).

[0224] Example 13, N-(6-(4-cyano-2-fluorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 13) [ka]

[0225] Step 1: Synthesis of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (Intermediate 13-2) Under a nitrogen atmosphere, starting material 13-1 (1.0 g) was dissolved in dioxane (10 mL), and potassium acetate (981 mg), bis(pinacolato)diboron (1.52 g), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (362 mg) were added. After the addition was complete, the mixture was heated to 100 °C and stirred for 2 h. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (PE / EA = 10 / 1) to give the title compound (1.0 g).

[0226] MS m / z(ESI):248.1 [M+H] + .

[0227] Step 2: Synthesis of N-(6-(4-cyano-2-fluorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 13) Under a nitrogen atmosphere, intermediate 13-2 (80 mg) was dissolved in dioxane (1 mL), and intermediate 2-2 (54 mg), potassium phosphate (77 mg), water (0.2 mL), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium (13 mg) were added. After the addition was complete, the mixture was heated to 100 °C and stirred for 2 h. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by high-pressure preparative liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm diameter, 150 mm length, eluting with a decreasing polarity mixture of water (containing 0.05% NH4HCO3) and acetonitrile, with an acetonitrile gradient ranging from 55% to 80%, and elution time of 13 min) to give the title compound (7.71 mg).

[0228] MS m / z(ESI):483.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 13.60(s,1H),9.09(s,1H),8.78(d,J=5.0Hz,1H),8.67(s,1H),8.22-8.18(m,1H),8.12(d,J=11.0Hz,1H),7.89( d,J=8.6Hz,1H),7.75(d,J=5.0Hz,1H),7.61-7.35(m,2H),7.13-7.09(m,1H),7.00(d,J=8.2Hz,1H),3.52(s,3H).

[0229] Example 14: N-(6-(4-cyano-3-methoxyphenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 14) [ka]

[0230] Intermediate 2-2 (40 mg), Intermediate 14-1 (32 mg), Pd(dppf)Cl2 (6.60 mg), and potassium phosphate (38.40 mg) were added to dioxane (1 mL) and water (0.2 mL) and stirred at 80 °C for 3 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (8 mL × 3). The organic layers were combined, washed with saturated brine (10 mL × 2), and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 3.5 μm × 4.6 × 100 mm, mobile phase: A: water (0.05% TFA), B: acetonitrile, B%: 20% to 90%, 10 min) to obtain the title compound (8 mg).

[0231] MS m / z(ESI):495.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 13.54(br,s,1H),9.32(s,1H),8.73(d,J=4.9Hz,1H),8.62(s,1H),7.94(s,1H),7.89(s,2H),7.78 -7.71(m,1H),7.46-7.33(m,2H),7.13-7.04(m,1H),7.03-6.96(m,1H),4.06(s,3H),3.53(s,3H).

[0232] Example 15: N-(6-(4-cyano-2-methoxyphenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-methoxyphenyl)isonicotinamide (Compound 15) [ka]

[0233] Intermediate 2-2 (30 mg), Intermediate 15-1 (24 mg), Pd(dppf)Cl2 (4.96 mg), and potassium phosphate (28.80 mg) were added to dioxane (1 mL) and water (0.2 mL) and stirred at 80 °C for 3 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were combined, washed with saturated brine (10 mL x 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness. The residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 3.5 μm x 4.6 x 100 mm, mobile phase: A: 0.05% TFA v / v, B: acetonitrile, B%: 10% to 90%, 8 min) to obtain the title compound (8 mg).

[0234] MS m / z(ESI):495.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 13.51(br,s,1H),9.08(s,1H),8.77-8.71(m,1H),8.63(s,1H),8.02-7.95(m,1H),7.77-7.69(m,2H), 7.62-7.54(m,1H),7.44-7.34(m,2H),7.13-7.04(m,1H),7.03-6.96(m,1H),3.96(s,3H),3.52(s,3H).

[0235] Example 16: N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)nicotinamide (Compound 16) [ka]

[0236] Step 1: Synthesis of tert-butyl (6-bromothiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 16-1) Starting material 2-1 (790 mg), triethylamine (691.90 mg), and DMAP (41.77 mg) were dissolved in dichloromethane (10 mL). (Boc)O (820.78 mg) was added dropwise to the reaction mixture, which was then stirred at room temperature for 16 h. The reaction mixture was then washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1 g).

[0237] MS m / z (ESI): 331.2 / 333.2 [M + H] + .

[0238] Step 2: Synthesis of tert-butyl (6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 16-2) Intermediate 16-1 (1 g), 4-cyanophenylboronic acid (887.34 mg), Pd(dppf)Cl (220.93 mg), and potassium phosphate (1.28 g) were added to dioxane (10 mL) and water (2 mL) and stirred at 80 °C for 4 h. The reaction mixture was poured into water and extracted with ethyl acetate (10 mL * 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was slurried with ethyl acetate and filtered. The title compound (0.5 g) was obtained after drying the filter cake.

[0239] MS m / z (ESI): 354.0 [M + H] + .

[0240] Step 3: Synthesis of 4-(2-aminothiazolo[4,5-b]pyrazin-6-yl)benzonitrile (Intermediate 16-3) Intermediate 16-2 (0.48 g) was dissolved in trifluoroacetic acid (2 mL) and stirred at room temperature for 1 h. Ethyl acetate was added to the reaction mixture, filtered, and the filtrate was concentrated under reduced pressure to dryness to give the title compound (230 mg).

[0241] MS m / z (ESI): 254.0 [M + H] + .

[0242] Step 4: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)nicotinamide (Compound 16) Intermediate 16-4 (30 mg), HATU (52 mg), and DIEA (36 mg) were added to DMF (1 mL) and stirred at room temperature for 1 h. Intermediate 16-3 (70.00 mg) was then added and stirred at room temperature for 16 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were combined, washed with saturated brine (10 mL x 2), and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 3.5 μm x 4.6 x 100 mm, mobile phase: A: water (0.05% TFA), B: acetonitrile, B%: 10% to 90%, 8 min) to obtain the title compound (5 mg).

[0243] MS m / z (ESI): 465.0 [M + H] + . 1 H NMR(400MHz,DMSO-d6)δ 13.49(brs,1H),9.32(s,1H),8.92(s,1H),8.78(s,1H),8.41-8.34(m,1H),8.04-7.97(m,1H),7 .49-7.37(m,3H),7.21(s,1H),7.16-7.06(m,1H),7.04-6.97(m,1H),6.67(s,1H),3.53(s,3H).

[0244] Example 17: N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-cyano-4-(2-fluoro-6-methoxyphenyl)nicotinamide (Compound 17) [ka]

[0245] Step 1: Synthesis of tert-butyl (6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 17-1) Intermediate 16-1 (1 g), 4-chlorophenylboronic acid (887.34 mg), Pd(dppf)Cl (220.93 mg), and potassium phosphate (1.28 g) were added to dioxane (10 mL) and water (2 mL) and stirred at 80 °C for 4 h. The reaction mixture was poured into water, extracted with ethyl acetate (10 mL * 3), washed with saturated brine (10 mL * 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was slurried with ethyl acetate, filtered, and the filter cake was dried to give the title compound (0.5 g).

[0246] MS m / z (ESI): 363.0 [M + H] + .

[0247] Step 2: Synthesis of 6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-amine (Intermediate 17-2) Intermediate 17-1 (0.48 g) was dissolved in trifluoroacetic acid (2 mL) and stirred at room temperature for 1 h. Ethyl acetate was added to the reaction mixture, filtered, and the filtrate was concentrated under reduced pressure to dryness to give the title compound (230 mg).

[0248] MS m / z (ESI): 263.0 [M + H] + .

[0249] Step 3: Synthesis of N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-cyano-4-(2-fluoro-6-methoxyphenyl)nicotinamide (Compound 17) Intermediate 17-3 (30 mg), HATU (62.21 mg), and DIEA (28.35 mg) were added to DMF (1 mL) and reacted at room temperature for 1 h. Intermediate 17-2 (28.95 mg) was then added and reacted for 2 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (column: Gemini NX C18 3.5 μm x 4.6 x 100 mm, mobile phase: A: water (0.05% TFA), B: acetonitrile, B%: 10% to 90%, 8 min) to obtain the title compound (15 mg).

[0250] MS m / z(ESI):514.90[MH] - . 1 H NMR (400 MHz, DMSO-d6) 1 H NMR(400MHz,DMSO-d6)δ 13.78(brs,1H),9.27(s,1H),9.20(s,1H),8.29(s,1H),8.21(d,J=8.6Hz,2H),7.62(d,J=8 .5Hz,2H),7.50(q,J=8.5Hz,1H),7.01(t,J=9.1Hz,1H),6.95(d,J=8.5Hz,1H),3.62(s,3H).

[0251] Example 18: N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-cyano-4-(2-(difluoromethoxy)phenyl)nicotinamide (Compound 18) [ka]

[0252] Intermediate 18-1 (30 mg, synthesized based on the method described in International Publication No. WO2020243459). Instead of 2-(2-(difluoromethoxy)-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane), the starting material 2-(2-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane was used. The resulting mixture was dissolved in N,N-dimethylformamide (3 mL), followed by the addition of intermediate 17-2 (27 mg), N,N-diisopropylethylamine (26 mg), and HATU (39.28 mg). The reaction mixture was stirred at 30 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to dryness, and the residue was purified by column chromatography (dichloromethane:methanol = 20:1) to obtain the title compound (3 mg).

[0253] MS m / z (ESI): 535.0 [M + H] + ; 1 H NMR(400MHz,DMSO-d6)δ 13.76(brs,1H),9.22(s,1H),9.11(s,1H),8.20(s,1H),8.18-8.08(m,2H), 7.58-7.47(m,4H),7.37-7.30(m,1H),7.19-7.14(m,1H),7.25-6.86(m,1H).

[0254] Example 19, 6-cyano-4-(2-methoxyphenyl)-N-(6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiazolo[4,5-b]pyrazin-2-yl)nicotinamide (Compound 19) [ka]

[0255] Step 1: Synthesis of tert-butyl (6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 19-2) Under a nitrogen atmosphere, intermediate 16-1 (150 mg), Pd(dppf)Cl (33.11 mg), potassium phosphate (192.04 mg), and intermediate 19-1 (159.71 mg) were dissolved in dioxane (5 mL) and water (1 mL) and stirred at 100 °C for 3 h. The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative thin-layer chromatography (DCM:CHOH = 10:1) to give the title compound (140 mg).

[0256] MS m / z(ESI):360.1 [M+H] + .

[0257] Step 2: Synthesis of 5-(2-aminothiazolo[4,5-b]pyrazin-6-yl)-1-methylpyridin-2(1H)-one (Intermediate 19-3) Intermediate 19-2 (140 mg) was dissolved in trifluoroacetic acid (2 mL) and stirred at room temperature for 2 h. The reaction mixture was concentrated to dryness to give the title compound (120.0 mg).

[0258] MS m / z(ESI):260.1 [M+H] + .

[0259] Step 3: Synthesis of 6-cyano-4-(2-methoxyphenyl)-N-(6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiazolo[4,5-b]pyrazin-2-yl)nicotinamide (Compound 19) To a solution of intermediate 19-4 (10 mg) in DMF (1 mL), DIEA (10.17 mg) and HATU (17.81 mg) were added and stirred at room temperature for 30 min. After that, intermediate 19-3 (12.24 mg) was added and stirred at room temperature for 8 h. The reaction mixture was purified by preparative high-performance liquid chromatography (column: Gemini NX C18 5 μm*10*150 mm, mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile, B%: 30%-50%, 11 min) to obtain the title compound (2.0 mg).

[0260] MS m / z(ESI):496.1 [M+H] + . 1 H NMR(400MHz,Methanol-d4)δ 8.88(d,J=3.0Hz,2H),8.49(d,J=2.6Hz,1H),8.24~8.21(m,1H),7.92(s,1H),7.37(t,J=7.8Hz, 2H),7.09-7.02(m,1H),6.90(d,J=8.1Hz,1H),6.59(d,J=9.5Hz,1H),3.60(s,3H),3.53(s,3H).

[0261] Example 20, 2'-chloro-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 20) [ka]

[0262] Step 1: Synthesis of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (intermediate 20-3) Intermediate 20-1 (3.96 g) was dissolved in a dioxane (40 mL) / water (8 mL) solution at 20 °C, and intermediate 20-2 (4 g), potassium carbonate (5.90 g), and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (Pd(dtbpf)Cl2) (1.39 g) were added to the mixture. Under nitrogen gas protection, the reaction mixture was stirred at 80 °C for 1 hour. After the reaction was completed, water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (3.2 g).

[0263] MS m / z(ESI):=292.9 [M+H] + .

[0264] Step 2: Synthesis of 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (Intermediate 20-4) At 20°C, intermediate 20-3 (190 mg) was dissolved in a tetrahydrofuran (2 mL) / water (2 mL) solution, and lithium hydroxide (31.09 mg) was added to the reaction solution. The reaction solution was stirred at 20°C for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH 4 with dilute hydrochloric acid, water (5 mL) was added thereto, and the mixture was extracted with ethyl acetate (5 mL x 3). The organic phases were combined and concentrated under reduced pressure to remove the solvent, yielding the title compound (180 mg).

[0265] MS m / z(ESI):=278.9 [M+H] + .

[0266] Step 3: Synthesis of 2'-chloro-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (compound 20) Intermediate 20-4 (180 mg) was dissolved in N,N-dimethylformamide (3 mL) at 20 ° C., and intermediate 16-3 (163.59 mg), HATU (248.58 mg), and N,N-diisopropylethylamine (166.95 mg) were added to the reaction solution. The reaction solution was stirred at 20 ° C. for 1 hour. After the reaction was completed, the reaction solution was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 um, mobile phase: A: water (0.05% ammonia water), B: acetonitrile, B%: 23% to 43%, 11 minutes) to obtain the title compound (90 mg).

[0267] 1 H NMR(400MHz,DMSO-d6)δ=13.58(s,1H),9.35(s,1H),8.91(s,1H),8.38(d,J=8.5Hz,2H) ,8.19(s,1H),8.02(d,J=8.5Hz,2H),7.62(s,1H),7.49(s,1H),3.64(s,3H),2.62(s,3H) MS m / z(ESI):=514.0 [M+H] + .

[0268] Example 21, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 21) [ka]

[0269] Step 1: Synthesis of 5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (intermediate 21-2) Intermediate 20-3 (250 mg) and intermediate 21-1 (321.64 mg) were dissolved in monoethylene glycol dimethyl ether (2 mL), and potassium carbonate (295.10 mg) was added. Pd(dppf)Cl (62.49 mg) was then added to the reaction mixture. The reaction mixture was stirred at 115°C for 2 h under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica gel column chromatography (ISCO®, 12 g SepaFlash® flash silica gel column, gradient 0-40% petroleum ether / ethyl acetate, flow rate 50 mL / min) to obtain the title compound (200.0 mg).

[0270] MS m / z (ESI): 273.0 [M + H] + .

[0271] Step 2: Synthesis of 5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid (intermediate 21-3) Intermediate 21-2 (200 mg) was dissolved in anhydrous methanol (4 mL), and sodium hydroxide (88.13 mg) and water (1 mL) were added thereto. The reaction mixture was stirred at 25° C. for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the pH of the residue was adjusted to 3 with an appropriate amount of hydrochloric acid. The reaction mixture was concentrated under reduced pressure to dryness. The residue was stirred in 10 mL of dichloromethane:methanol (10:1) for 10 min, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, yielding the title compound (120.0 mg).

[0272] MS m / z (ESI): 259.0 [M + H] + .

[0273] Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (compound 21) Intermediate 21-3 (50.00 mg) was dissolved in anhydrous N,N-dimethylformamide (1 mL), and HATU (77.29 mg) and N,N-diisopropylethylamine (75.06 mg) were added. The reaction mixture was stirred at 25°C for 30 min under a nitrogen atmosphere. Intermediate 16-3 (53.94 mg) was then added, and the reaction mixture was stirred at 25°C for 2 h under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (Boston Green ODS C18 column, 5 µm silica, 30 mm diameter, 150 mm length, eluting with a decreasing polarity mixture of water (containing 0.225% carboxylic acid) and acetonitrile, with an acetonitrile gradient of 15% to 45%, for 12 min) to obtain the title compound (12 mg).

[0274] MS m / z (ESI): 494.0 [M + H] + . 1H NMR(400MHz,DMSO-d6)δ=13.56(brs,1H),9.37(s,1H),8.88(s,1H),8.39(d,J=8.4Hz,2H),8.24 (s,1H),8.02(d,J=8.4Hz,2H),7.45(s,1H),7.43(s,1H),3.62(s,3H),2.63(s,3H),2.54(s,3H)

[0275] Example 22, 4-(5-cyano-2-methoxyphenyl)-N-(6-(5-cyclopropylpyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (Compound 22) [ka]

[0276] Step 1: Synthesis of tert-butyl (6-(5-cyclopropylpyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 22-1) Intermediate 16-1 (500 mg), 2-bromo-5-cyclopropylpyridine (299.01 mg), 6,6'-dimethyl-2,2'-bipyridine (27.81 mg), tetrabutylammonium iodide (836.46 mg), manganese powder (331.76 mg), and nickel iodide (47.18 mg) were dissolved in N,N-dimethylacetamide (20 mL). The reaction mixture was stirred at 90 °C for 16 h under a nitrogen atmosphere. After the reaction was complete, the mixture was filtered. Water (60 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by flash silica gel column chromatography (ISCO®, 8 g SepaFlash® flash silica gel column, gradient 0-34% ethyl acetate / petroleum ether, flow rate 20 mL / min) to give the title compound (140 mg).

[0277] MS m / z(ESI):=370.2 [M+H] + .

[0278] Step 2: Synthesis of 6-(5-cyclopropylpyridin-2-yl)thiazolo[4,5-b]pyrazin-2-amine (Intermediate 22-2) Intermediate 22-1 (180 mg) was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL), and the reaction solution was stirred at 20° C. for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness to obtain the title compound (80 mg).

[0279] MS m / z(ESI):=270.0 [M+H] + .

[0280] Step 3: Synthesis of 4-(5-cyano-2-methoxyphenyl)-N-(6-(5-cyclopropylpyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (compound 22) Intermediate 22-3 (48.99 mg, synthesized based on the method described in International Publication No. WO2020243459) and HATU (69.43 mg) were dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at 40 ° C for 30 minutes under a nitrogen atmosphere. Then, intermediate 22-2 (70 mg) and N,N-diisopropylethylamine (47.20 mg) were added, and the reaction mixture was stirred at 40 ° C for 16 hours. After the reaction was completed, the reaction mixture was purified by high-performance liquid chromatography (chromatography column: Boston Green ODS 150 * 30 mm * 5 um, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 40% ~ 70%, 14 minutes) to obtain the title compound (5 mg).

[0281] 1H NMR(400MHz,DMSO-d6)δ=13.44(brs,1H),9.51(s,1H),8.83(s,1H),8.56(s,1H),8.25(d,J=8.0Hz,1H),7.96-7.88(m,2H),7.62(d, J=8.4Hz,1H),7.46(s,1H),7.19(d,J=9.4Hz,1H),3.61(s,3H),2.61(s,3H),2.11-2.02(m,1H),1.14-1.05(m,2H),0.90-0.80(m,2H) MS m / z(ESI):=520.2 [M+H] +

[0282] Example 23, 4-(5-chloro-2-methoxyphenyl)-N-[6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylnicotinamide (Compound 23) [ka]

[0283] Step 1: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methylpyridine-3-carboxylic acid methyl ester (intermediate 23-2) Under a nitrogen atmosphere, intermediate 23-1 (1 g) was dissolved in dioxane (20 mL) and water (5 mL). To the reaction mixture, intermediate 20-1 (995.75 mg), Pd(dppf)Cl2 (349.65 mg), and potassium carbonate (1.48 g) were added. The reaction mixture was then stirred at 90 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ISCO®, 20 g SepaFlash® Silica Flash chromatography column, gradient 0-50% ethyl acetate / petroleum ether, flow rate 20 mL / min) to obtain the title compound (870 mg).

[0284] MS m / z(ESI):292.1 [M+H]+ .

[0285] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methylpyridine-3-carboxylic acid (Intermediate 23-3) Intermediate 23-2 (870 mg) was added to tetrahydrofuran (8 mL) and water (4 mL), and lithium hydroxide (157.13 mg) was added to the reaction solution, followed by stirring at 25° C. for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH 3 and concentrated under reduced pressure to remove the solvent. The residue was washed with a dichloromethane / methanol mixed solvent (10 / 1, 20 mL) and filtered. The filtrate was then concentrated under reduced pressure to dryness to give the title compound (1.2 g).

[0286] MS m / z(ESI):277.9 [M+H] + .

[0287] Step 3: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-[6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylnicotinamide (compound 23) Under a nitrogen gas atmosphere, intermediate 23-3 (300 mg) was added to N,N-dimethylformamide (5 mL), and intermediate 16-3 (273.62 mg), HATU (410.76 mg), and N,N-diisopropylethylamine (279.24 mg) were added to the reaction mixture. The reaction mixture was then stirred at 25°C for 2 hours under a nitrogen gas atmosphere. After the reaction was completed, the reaction mixture was purified by preparative high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 µm, mobile phase: [A: water (0.225% formic acid), B: acetonitrile], B%: 48% to 68%, 11 minutes) to obtain the title compound (51.96 mg).

[0288] MS m / z(ESI):513.1 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 13.40(brs,1H),9.27(s,1H),8.84(s,1H),8.36(d,J=8.4Hz,2H),8.00(d,J=8.3Hz ,2H),7.50-7.42(m,2H),7.36(s,1H),7.03-6.99(m,1H),3.52(s,3H),2.59(s,3H) Example 24, N-(6-(5-cyclopropylpyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 24) [ka]

[0289] Intermediate 22-2 (200 mg) was dissolved in N,N-dimethylformamide (3 mL) at 20 °C, and intermediate 21-3 (230.15 mg), HATU (338.83 mg), and N,N-diisopropylethylamine (191.95 mg) were added to the mixture. The reaction mixture was stirred at 40 °C for 6 hours. After the reaction was completed, the reaction mixture was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 μm, mobile phase: A: water (0.05% ammonia water), B: acetonitrile, B%: 20% to 40%, 11 minutes) to obtain the title compound (39.9 mg).

[0290] 1 H NMR(400MHz,DMSO-d6)δ=13.54(brs,1H),9.48(s,1H),8.85(s,1H),8.55(s,1H),8.29-8.11(m,2H),7.69-7.5 5(m,1H),7.49-7.23(m,2H),3.59(s,3H),2.61(s,3H),2.16-1.99(m,1H),1.09-0.99(m,2H),0.89-0.79(m,2H) MS m / z(ESI):=510.2 [M+H] + .

[0291] Example 25, N-(6-(5-(difluoromethoxy)pyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 25) [ka]

[0292] Step 1: Synthesis of tert-butyl (6-(5-(difluoromethoxy)pyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 25-2) Intermediate 16-1 (1.33 g) was dissolved in N,N-dimethylacetamide (10 mL) at 20 °C. To the reaction mixture was added Intermediate 25-1 (900 mg), nickel(II) chloride ethylene glycol dimethyl ether complex (NiCl2glyme) (176.56 mg), 2,2'-bipyridine (62.75 mg), and manganese powder (220.73 mg). The reaction mixture was stirred at 90 °C for 4 hours under a nitrogen atmosphere. After the reaction was complete, dichloromethane (100 mL) and methanol (10 mL) were added. The filtrate was filtered and concentrated under reduced pressure to remove the solvent. Water (100 mL) was added to the residue, filtered, and the filter cake was collected, dried, and purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to obtain the title compound (140 mg).

[0293] MS m / z(ESI):=396.3 [M+H] + .

[0294] Step 2: Synthesis of 6-(5-(difluoromethoxy)pyridin-2-yl)thiazolo[4,5-b]pyrazin-2-amine (Intermediate 25-3) At 20°C, intermediate 25-2 (140 mg) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (262.17 μL) was added to the reaction solution. The reaction solution was stirred at 20°C for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. Then, saturated sodium bicarbonate solution was added to the residue to adjust the pH to 7, and the mixture was filtered to obtain the title compound (60 mg).

[0295] MS m / z(ESI):=296.1 [M+H] + .

[0296] Step 3: Synthesis of N-(6-(5-(difluoromethoxy)pyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (compound 25) Intermediate 25-3 (100 mg) was dissolved in N,N-dimethylformamide (1 mL) at 20 °C, and intermediate 21-3 (122.46 mg), HATU (180.28 mg), and N,N-diisopropylethylamine (61.28 mg) were added to the mixture. The reaction mixture was stirred at 45 °C for 6 hours. After the reaction was completed, the reaction mixture was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 um, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 23% to 43%, 11 minutes) to obtain the title compound (55 mg).

[0297] 1 H NMR(400MHz,DMSO-d6)δ=13.56(brs,1H),9.50(s,1H),8.85(s,1H),8.65(d,J=2.8Hz,1H),8.44(d, J=8.9Hz,1H),8.21(s,1H),7.86(dd,J=2.8,8.7Hz,1H),7.62-7.24(m,3H),3.60(s,3H),2.62(s,3H) MS m / z(ESI):=536.1 [M+H] + .

[0298] Example 26, 4-(5-chloro-2-methoxyphenyl)-N-(6-(5-cyanopyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (Compound 26) [ka]

[0299] Step 1: Synthesis of tert-butyl (6-(5-cyanopyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 26-2) Intermediate 16-1 (3 g) was dissolved in N,N-dimethylacetamide (25 mL) at 20 °C, and to the mixture was added Intermediate 26-1 (1.66 g), nickel(II) chloride ethylene glycol dimethyl ether complex (398.06 mg), 2,2'-bipyridine (141.48 mg), and manganese powder (497.64 mg). The reaction mixture was stirred at 90 °C for 4 hours under a nitrogen atmosphere. After the reaction was completed, dichloromethane (250 mL) and methanol (25 mL) were added. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. Water (250 mL) was added to the residue and filtered. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 15 / 1) to obtain the title compound (320 mg).

[0300] MS m / z(ESI):=355.1 [M+H] + .

[0301] Step 2: Synthesis of 6-(2-aminothiazolo[4,5-b]pyrazin-6-yl)-3-cyanopyridine (Intermediate 26-3) Intermediate 26-2 (320 mg) was dissolved in dichloromethane (5 mL) at 20°C, and trifluoroacetic acid (668.57 μL) was added to the reaction solution. The reaction solution was stirred at 20°C for 2 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure. Then, saturated sodium bicarbonate solution was added to the residue to adjust the pH to 7, and the mixture was filtered to obtain the title compound (150 mg).

[0302] MS m / z(ESI):=255.1 [M+H] + .

[0303] Step 3: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(5-cyanopyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (compound 26) Intermediate 26-3 (150 mg) was dissolved in N,N-dimethylformamide (2.5 mL) at 20 ° C., and intermediate 23-3 (327.65 mg), HATU (448.61 mg), and N,N-diisopropylethylamine (152.48 mg) were added to the reaction solution. The reaction solution was stirred at 20 ° C. for 6 hours. After the reaction was completed, the reaction solution was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 um, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 45% to 65%, 11 minutes) to obtain the title compound (53.3 mg).

[0304] 1 H NMR(400MHz,DMSO-d6)δ=13.56(brs,1H),9.58(s,1H),9.19(s,1H),8.81(s,1H), 8.60-8.44(m,2H),7.54-7.42(m,3H),7.08-6.98(m,1H),3.52(s,3H),2.61(s,3H) MS m / z(ESI):=514.1 [M+H] + .

[0305] Example 27, 5'-Methoxy-2',6-dimethyl-N-(6-(5-(trifluoromethyl)pyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 27) [ka]

[0306] Step 1: Synthesis of tert-butyl (6-(5-(trifluoromethyl)pyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 27-2) Intermediate 16-1 (3 g) was dissolved in N,N-dimethylacetamide (40 mL) at 25 °C. To the mixture was added nickel(II) chloride ethylene glycol dimethyl ether complex (199.03 mg), manganese powder (1.99 g), 2,2'-bipyridine (141.48 mg), tetrabutylammonium iodide (5.02 g), and intermediate 27-1 (2.05 g). The reaction mixture was stirred at 90 °C for 6 hours under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature and filtered. Ethyl acetate (50 mL) and water (100 mL) were added to the reaction mixture, followed by extraction twice with saturated brine (100 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (mobile phase: 0-5% tetrahydrofuran / dichloromethane, flow rate: 60 mL / min) to give the title compound (400 mg).

[0307] MS m / z(ESI):=398.0 [M+H] + .

[0308] Step 2: Synthesis of 6-(5-(trifluoromethyl)pyridin-2-yl)thiazolo[4,5-b]pyrazin-2-amine (Intermediate 27-3). Intermediate 27-2 (100 mg) was dissolved in dichloromethane (4 mL) at 20°C, and trifluoroacetic acid (860.82 mg) was added to the reaction solution. The mixture was stirred at 20°C for 0.5 hours under a nitrogen gas atmosphere. After the reaction was completed, the organic phase was concentrated under reduced pressure to remove the solvent. Saturated sodium bicarbonate solution was then added to the residue to adjust the pH to 7, and the mixture was filtered to obtain the title compound (100 mg).

[0309] MS m / z(ESI):=298.0 [M+H] + .

[0310] Step 3: Synthesis of 5'-methoxy-2',6-dimethyl-N-(6-(5-(trifluoromethyl)pyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide (compound 27). Intermediate 21-3 (100 mg) was dissolved in N,N-dimethylformamide (1 mL) at 20 °C. HATU (127.91 mg) and DIEA (86.96 mg) were added to the reaction solution, and after stirring for 1 hour, intermediate 27-3 (100 mg) was added. The mixture was stirred at 20 °C for 16 hours under a nitrogen atmosphere. After the reaction was completed, ethyl acetate (5 mL) and water (10 mL) were added to the mixture, and the mixture was extracted twice with saturated sodium chloride solution (10 mL). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.05% aqueous ammonia), B: acetonitrile, B%: 23% to 43%, 11 min) to obtain the title compound (21.7 mg).

[0311] 1 H NMR(400MHz,DMSO-d6)δ=9.56(s,1H),9.12(s,1H),8.87(s,1H),8.56(d,J=8.6Hz,1H), 8.39(d,J=8.4Hz,1H),8.19(s,1H),7.41(s,1H),7.32(s,1H),3.59(s,3H),2.61(s,3H). MS m / z(ESI):=538.1 [M+H] + .

[0312] Example 28, N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-cyano-4-(2-methoxyphenyl)pyridine-3-carboxamide (Compound 28) [ka]

[0313] Step 1: Synthesis of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-6-cyano-4-(2-methoxyphenyl)pyridine-3-carboxamide (Intermediate 28-2) Intermediate 28-1 (150 mg, synthesized according to the method described in International Publication No. WO2020243459), intermediate 2-1 (119.97 mg), HATU (148.06 mg), and DIEA (67.10 mg) were dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at 25 °C for 1 h under a nitrogen atmosphere. After completion of the reaction, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 20 g SepaFlash® flash silica gel column, gradient 0-35% ethyl acetate / petroleum ether, flow rate 30 mL / min) to obtain the title compound (75 mg).

[0314] MS m / z(ESI):=467.1 [M+H] + .

[0315] Step 2: Synthesis of N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-cyano-4-(2-methoxyphenyl)pyridine-3-carboxamide (compound 28) Intermediate 28-2 (40 mg), (4-chlorophenyl)boronic acid (26.77 mg), 1,1'-bis(di-tert-butylphosphine)ferrocenedichloropalladium (5.58 mg), and potassium phosphate (36.34 mg) were dissolved in a mixture of dioxane (0.5 mL) and water (0.1 mL), and the reaction mixture was stirred at 60 °C for 30 min under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was cooled to room temperature, slowly poured into water (20 mL), and extracted with ethyl acetate (15 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure, and the residue was purified by high-performance liquid preparative chromatography (chromatography column: Boston Prime C18 150*30mm*5um, mobile phase: [A: water (0.225% formic acid), B: acetonitrile], B%: 60%-80%, 11 min) to obtain the title compound (11 mg).

[0316] 1 H NMR(400MHz,DMSO-d6)δ=13.71-13.59(m,1H),9.28(s,1H),9.07(s,1H),8.24~8.19(m,3H),7.62(d,J=8. 7Hz,2H),7.55-7.50(m,1H),7.50-7.45(m,1H),7.15(t,J=7.5Hz,1H),7.04(d,J=8.3Hz,1H),3.55(s,3H) MS m / z(ESI):=499.0 [M+H] + .

[0317] Example 29, N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-ethynylphenyl)pyridine-4-carboxamide (Compound 29) [ka]

[0318] Step 1: Synthesis of 3-(2-ethynylphenyl)pyridine-4-carboxylic acid methyl ester (intermediate 29-3) Intermediate 29-1 (1.18 g), Intermediate 29-2 (800 mg), potassium carbonate (1.52 g), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (401.07 mg) were dissolved in a dioxane (20 mL) / water (4 mL) solution. The reaction mixture was stirred at 70 °C for 2 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 40 g SepaFlash® flash silica gel column, gradient 0-25% ethyl acetate / petroleum ether, flow rate 50 mL / min) to give the title compound (536 mg).

[0319] MS m / z(ESI):=238.1 [M+H] + .

[0320] Step 2: Synthesis of 3-(2-ethynylphenyl)pyridine-4-carboxylic acid (intermediate 29-4) Intermediate 29-3 (350 mg) was dissolved in a methanol (3 mL) / water (3 mL) solution, and sodium hydroxide (177.01 mg) was added to the mixture. The reaction mixture was stirred at 50°C for 15 minutes. After the reaction was completed, the pH of the reaction mixture was adjusted to 7 with dilute hydrochloric acid and then concentrated under reduced pressure to dryness. The residue was dissolved in methanol (1 mL) and filtered, and the filtrate was concentrated under reduced pressure to dryness to give the title compound (300 mg).

[0321] MS m / z(ESI):=224.1 [M+H] + .

[0322] Step 3: Synthesis of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-3-(2-ethynylphenyl)pyridine-4-carboxamide (Intermediate 29-5) Intermediate 29-4 (300 mg), Intermediate 2-1 (310.55 mg), HATU (562.10 mg), and DIEA (347.39 mg) were dissolved in N,N-dimethylformamide (8 mL). The reaction mixture was stirred at 25°C for 2 hours under a nitrogen atmosphere. After the reaction was complete, water (100 mL) was added and the mixture was extracted with ethyl acetate (45 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 20 g SepaFlash® flash silica gel column, gradient 0-50% ethyl acetate / petroleum ether, flow rate 50 mL / min) to give the title compound (220 mg).

[0323] MS m / z(ESI):=436.0 [M+H] + .

[0324] Step 4: Synthesis of N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-ethynylphenyl)pyridine-4-carboxamide (compound 29) Intermediate 29-5 (100 mg), (4-chlorophenyl)boronic acid (71.68 mg), potassium carbonate (63.36 mg), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (14.94 mg) were dissolved in a dioxane (1 mL) / water (0.2 mL) solution. The reaction mixture was stirred at 90°C for 1 h under a nitrogen atmosphere. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high performance liquid chromatography (chromatography column: Boston Prime C18 150*30mm*5um, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 53% to 73%, 11 minutes) to obtain the title compound (7.5mg).

[0325] 1H NMR(400MHz,DMSO-d6)δ=13.85-13.46(m,1H),9.27(s,1H),8.85(d,J=5.0Hz,1H),8.72(s,1H),8.21(d,J =8.7Hz,2H),7.87(d,J=5.0Hz,1H),7.64-7.57(m,3H),7.53-7.47(m,1H),7.46-7.40(m,2H),4.05(s,1H) MS m / z(ESI):=468.1 [M+H] + .

[0326] Example 30. N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-ethynylphenyl)pyridine-4-carboxamide (Compound 30) [ka]

[0327] Intermediate 29-5 (100 mg), (4-cyanophenyl)boronic acid (67.36 mg), 1,1'-bis(di-tert-butylphosphine)ferrocenedichloropalladium (14.94 mg), and potassium carbonate (63.36 mg) were dissolved in a mixture of dioxane (5 mL) and water (1 mL). The reaction mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high performance liquid chromatography (chromatography column: Boston Prime C18 150*30mm*5um, mobile phase: A: water (0.05% aqueous ammonia), B: acetonitrile, B%: 25% to 45%, 11 minutes) to obtain the title compound (8.5mg).

[0328] 1H NMR(400MHz,DMSO-d6)δ=13.84-13.60(m,1H),9.39(s,1H),8.86(d,J=5.0Hz,1H),8.72(s,1H),8.39(d,J=8.5Hz,2H ),8.03(d,J=8.5Hz,2H),7.88(d,J=5.1Hz,1H),7.61-7.57(m,1H),7.53-7.49(m,1H),7.46-7.41(m,2H),4.05(s,1H) MS m / z(ESI):=459.0 [M+H] + .

[0329] Example 31, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)-6-methylpyridine-3-carboxamide (Compound 31) [ka]

[0330] Step 1: Synthesis of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)-6-methylpyridine-3-carboxamide (Intermediate 31-1) Intermediate 4-4 (110 mg), HATU (189.13 mg), Intermediate 2-1 (104.49 mg), and DIEA (116.89 mg) were dissolved in N,N-dimethylformamide (2 mL) and the reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, water (50 mL) was added and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 20 g SepaFlash® flash silica gel column, gradient 0-50% ethyl acetate / petroleum ether, flow rate 30 mL / min) to give the title compound (100 mg).

[0331] MS m / z(ESI):=456.3 [M+H] + .

[0332] Step 2: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)-6-methylpyridine-3-carboxamide (compound 31) Intermediate 31-1 (90 mg), (4-cyanophenyl)boronic acid (69.55 mg), (diphenylphosphino)ferrocenedichloropalladium(II) (14.43 mg), and potassium carbonate (54.52 mg) were dissolved in a mixture of dioxane (1 mL) and water (0.2 mL). The reaction mixture was stirred at 80°C for 15 minutes under a nitrogen atmosphere. After the reaction was completed, water (50 mL) was added and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 40%-60%, 11 minutes) to obtain the title compound (9.9 mg).

[0333] 1 H NMR(400MHz,DMSO-d6)δ=13.61-13.22(m,1H),9.42-9.22(m,1H),8.79(s,1H),8.38(d,J=8.4Hz,2H),8.01(d,J=8. 3Hz,2H),7.46-7.37(m,2H),7.34(s,1H),7.11(t,J=7.3Hz,1H),7.03-6.94(m,1H),3.54-3.52(m,3H),2.60(s,3H). MS m / z(ESI):=479.1 [M+H] +

[0334] Example 32, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-carboxamide (Compound 32) [ka]

[0335] Step 1: Synthesis of (Z)-2-(2-methoxyphenyl)imino)acetic acid methyl ester (intermediate 32-2) Intermediate 32-1 (1 g) and 2-oxoacetic acid methyl ester (715.07 mg) were dissolved in dichloromethane (20 mL), and 4A molecular sieves (200 mg) were added. The reaction mixture was stirred at 20 °C for 16 h. After the reaction was completed, the mixture was filtered and concentrated to dryness under reduced pressure to give the title compound (1.57 g).

[0336] MS m / z(ESI):=194.1 [M+H] + .

[0337] Step 2: Synthesis of 1-(2-methoxyphenyl)-1H-imidazole-5-carboxylic acid methyl ester (intermediate 32-3) Intermediate 32-2 (1.57 g) was dissolved in methanol (40 mL), potassium carbonate (2.25 g) and 1-(isocyanomethylsulfonyl)-4-methylbenzene (TosMIC) (3.17 g) were added, and the reaction mixture was stirred at 20 °C for 16 h. After the reaction was complete, the mixture was filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 20 g SepaFlash® flash silica gel column, gradient 40-50% ethyl acetate / petroleum ether, flow rate 40 mL / min) to give the title compound (220 mg).

[0338] MS m / z(ESI):=233.2 [M+H] + .

[0339] Step 3: Synthesis of 1-(2-methoxyphenyl)-1H-imidazole-5-carboxylic acid (Intermediate 32-4) Intermediate 32-3 (220 mg) was dissolved in a methanol (2 mL) / water (2 mL) solution, and sodium hydroxide (113.67 mg) was added to the mixture. The reaction mixture was stirred at 50°C for 2 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 7 with dilute hydrochloric acid and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (1 mL), filtered, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (220 mg).

[0340] MS m / z(ESI):=219.0 [M+H] + .

[0341] Step 4: Synthesis of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-carboxamide (Intermediate 32-5) Intermediate 32-4 (220 mg) and Intermediate 2-1 (232.97 mg) were dissolved in N,N-dimethylformamide (5 mL), and HATU (421.69 mg) and DIEA (260.61 mg) were added. The reaction mixture was stirred at 20 °C for 1 hour. After the reaction was complete, ethyl acetate (30 mL) and water (20 mL) were added, followed by extraction with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 12 g SepaFlash® flash silica gel column, gradient 40-60% ethyl acetate / petroleum ether, flow rate 30 mL / min) to obtain the title compound (320 mg).

[0342] MS m / z(ESI):=431.0 [M+H] + .

[0343] Step 5: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-1-(2-methoxyphenyl)-1H-imidazole-5-carboxamide (compound 32) Intermediate 32-5 (60 mg), (4-cyanophenyl)boronic acid (40.89 mg), 1,1'-bis(di-tert-butylphosphine)ferrocenedichloropalladium (9.07 mg), and potassium carbonate (38.46 mg) were dissolved in a dioxane (1 mL) / water (0.2 mL) solution. The reaction mixture was stirred at 90°C for 15 minutes under a nitrogen atmosphere. After the reaction was complete, ethyl acetate (50 mL) and water (50 mL) were added, followed by extraction with ethyl acetate (15 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high performance liquid chromatography (chromatography column: Boston Prime C18 150*30mm*5um, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 40%-60%, 11 minutes) to obtain the title compound (3mg).

[0344] 1 H NMR(400MHz,DMSO-d6)δ=13.43(s,1H),9.30(s,1H),8.38-8.34(m,2H),8.27-8.20(m,1H),8.09-8.04(m,1H) ,8.03-7.98(m,2H),7.53-7.48(m,1H),7.45-7.41(m,1H),7.26-7.21(m,1H),7.14-7.07(m,1H),3.71(s,3H) MS m / z(ESI):=454.1 [M+H] +

[0345] Example 33, 6-cyano-4-(5-cyano-2-methoxyphenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)pyridine-3-carboxamide (Compound 33) [ka]

[0346] Step 1: Synthesis of 6-cyano-4-(5-cyano-2-methoxyphenyl)pyridine-3-carboxylic acid methyl ester (intermediate 33-2) Intermediate 33-1 (1 g), (5-cyano-2-methoxyphenyl)boronic acid (1.2 g), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (372.20 mg), and potassium carbonate (1.41 g, 10.17 mmol) were dissolved in a dioxane (20 mL) / water (4 mL) solution. The reaction mixture was stirred at 80 °C for 15 minutes under a nitrogen atmosphere. After the reaction was complete, water (500 mL) was added, and the mixture was extracted with ethyl acetate (300 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 40 g SepaFlash® flash silica gel column, gradient 60-100% ethyl acetate / petroleum ether, flow rate 40 mL / min) to give the title compound (1.1 g).

[0347] MS m / z(ESI):=294.2 [M+H] + Step 2: Synthesis of 6-cyano-4-(5-cyano-2-methoxyphenyl)pyridine-3-carboxylic acid (Intermediate 33-3) Intermediate 33-2 (1 g) was dissolved in tetrahydrofuran (8 mL) and a solution of lithium hydroxide (244.97 mg) in water (8 mL) was added. The reaction mixture was stirred at 20°C for 1 hour. After the reaction was completed, the pH of the reaction mixture was adjusted to 7 with dilute hydrochloric acid and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (1 mL) and filtered. The filtrate was concentrated to dryness under reduced pressure to give the title compound (1.17 g).

[0348] MS m / z(ESI):=280.2 [M+H] + .

[0349] Step 3: Synthesis of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-6-cyano-4-(5-cyano-2-methoxyphenyl)pyridine-3-carboxamide (Intermediate 33-4) Intermediate 33-3 (150 mg), HATU (204.24 mg), and DIEA (138.85 mg) were dissolved in N,N-dimethylformamide (1 mL), and Intermediate 2-1 (124.12 mg) was added. The reaction mixture was stirred at 20 ° C for 1 hour. After the reaction was completed, water (100 mL) was added, and the mixture was extracted with ethyl acetate (60 mL x 2). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness, yielding the title compound (750 mg).

[0350] MS m / z(ESI):=492.1 [M+H] +

[0351] Step 4: Synthesis of 6-cyano-4-(5-cyano-2-methoxyphenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)pyridine-3-carboxamide (compound 33) Intermediate 33-4 (600 mg), (4-cyanophenyl)boronic acid (179.08 mg), 1,1'-bis(di-tert-butylphosphine)ferrocenedichloropalladium (79.43 mg), and potassium phosphate (517.40 mg) were dissolved in N,N-dimethylformamide (6 mL). The reaction mixture was stirred at 100 °C for 1 h under a nitrogen atmosphere. After the reaction was complete, water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 45%-65%, 11 min) to obtain the title compound (50 mg).

[0352] 1 H NMR(400MHz,DMSO-d6)δ=13.79(s,1H),9.38(s,1H),9.14(s,1H),8.42-8.36 (m,2H),8.34~8.31(m,1H),8.08-7.96(m,4H),7.26-7.20(m,1H),3.63(s,3H) MS m / z(ESI):=515.1 [M+H] + .

[0353] Example 34, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-fluoro-6-methoxyphenyl)pyridine-4-carboxamide (Compound 34) [ka]

[0354] Step 1: Synthesis of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-3-(2-fluoro-6-methoxyphenyl)pyridine-4-carboxamide (Intermediate 34-1) Intermediate 3-3 (120 mg) was dissolved in N,N-dimethylformamide (3 mL) at 20°C, and intermediate 2-1 (112.16 mg), HATU (203.02 mg), and N,N-diisopropylethylamine (125.46 mg) were added to the reaction solution. The reaction solution was stirred at 20°C for 1 hour. After the reaction was completed, ethyl acetate (5 mL) and water (20 mL) were added, and the mixture was extracted with ethyl acetate (5 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 2) to obtain the title compound (160 mg).

[0355] MS m / z(ESI):=460.0 [M+H] + .

[0356] Step 2: N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-fluoro-6-methoxyphenyl)pyridine-4-carboxamide (compound 34) Intermediate 34-1 (100 mg) was dissolved in a dioxane (1 mL) / water (0.2 mL) solution at 20 °C, and intermediate 34-2 (38.31 mg), potassium carbonate (36.03 mg), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (9.54 mg) were added to the reaction solution. The reaction solution was stirred at 80 °C for 15 minutes under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.05% aqueous ammonia), B: acetonitrile, B%: 25% to 45%, 11 minutes) to obtain the title compound (21 mg).

[0357] 1 H NMR(400MHz,DMSO-d6)δ=8.99(s,1H),8.67-8.61(m,1H),8.44~8.39(m,1H),8.31-8.25(m,2 H),7.99-7.95(m,1H),7.94-7.90(m,2H),7.39-7.31(m,1H),6.91-6.83(m,2H),3.59(s,3H) MS m / z(ESI):=483.2 [M+H] + .

[0358] Example 35. 6-cyano-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)pyridine-3-carboxamide (Compound 35) [ka]

[0359] Step 1: Synthesis of 4-chloro-6-cyanopyridine-3-carboxylic acid ethyl ester (intermediate 35-2) Intermediate 35-1 (5 g) was dissolved in N,N-dimethylformamide (50 mL) at 20 °C. Zinc cyanide (1.6 g), bis(dibenzylideneacetone)palladium (130.65 mg), and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (262.95 mg) were added to the reaction mixture. The reaction mixture was stirred at 130 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, water (200 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (3.28 g).

[0360] MS m / z(ESI):=211.1 [M+H] + .

[0361] Step 2: Synthesis of 6-cyano-4-(2-methoxyphenyl)pyridine-3-carboxylic acid ethyl ester (intermediate 35-3) Intermediate 35-2 (3.28 g) was dissolved in a dioxane (40 mL) / water (8 mL) solution at 20 °C, and 2-methoxyphenylboronic acid (2.84 g), potassium carbonate (2.58 g), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (683.7 mg) were added to the reaction solution. The reaction solution was stirred at 80 °C for 15 minutes under a nitrogen gas atmosphere. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (4.4 g). MS m / z(ESI):=283.2 [M+H] +

[0362] Step 3: Synthesis of 6-cyano-4-(2-methoxyphenyl)pyridine-3-carboxylic acid (intermediate 35-4) At 20°C, intermediate 35-3 (1 g) was dissolved in a tetrahydrofuran (10 mL) / water (10 mL) solution, and lithium hydroxide (254.5 mg) was added to the reaction solution. The reaction solution was stirred at 0°C for 8 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness. The residue was dissolved in methanol (1 mL) and filtered, and the filtrate was concentrated under reduced pressure to dryness to obtain the title compound (1 g). MS m / z(ESI):=255.2 [M+H] +

[0363] Step 4: Synthesis of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-6-cyano-4-(2-methoxyphenyl)pyridine-3-carboxamide (Intermediate 35-5) Intermediate 35-4 (100 mg) was dissolved in N,N-dimethylformamide (1.5 mL) at 20 °C, and intermediate 2-1 (90.89 mg), HATU (164.51 mg), and N,N-diisopropylethylamine (101.67 mg) were added to the reaction solution. The reaction solution was stirred at 20 °C for 1 hour. After the reaction was completed, ethyl acetate (5 mL) and water (10 mL) were added, and the mixture was extracted with ethyl acetate (5 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (100 mg).

[0364] MS m / z(ESI):=467.1 [M+H] + .

[0365] Step 5: Synthesis of 6-cyano-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)pyridine-3-carboxamide (compound 35) Intermediate 35-5 (90 mg) was dissolved in a dioxane (0.5 mL) / water (0.1 mL) solution at 20 °C, and intermediate 35-6 (56.60 mg), potassium phosphate (81.76 mg), and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (12.55 mg) were added to the reaction solution. The reaction solution was stirred at 80 °C for 15 minutes under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered and concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150*30 mm*5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 48% to 68%, 11 minutes) to obtain the title compound (12.3 mg).

[0366] 1 H NMR(400MHz,DMSO-d6)δ=13.72(s,1H),9.38(s,1H),9.07(s,1H),8.39(d,J=8.6Hz,2H),8.22(s,1H),8.03(d,J= 8.4Hz,2H),7.53(dd,J=1.3,7.6Hz,1H),7.50-7.46(m,1H),7.19-7.13(m,1H),7.04(d,J=8.2Hz,1H),3.55(s,3H) MS m / z(ESI):=490.1 [M+H] + .

[0367] Example 36, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (Compound 36) [ka]

[0368] Step 1: Synthesis of 4-(2-methoxyphenyl)-6-(trifluoromethyl)pyridine-3-carboxylic acid (Intermediate 36-2) Intermediate 36-1 (250 mg) was dissolved in a dioxane (5 mL) / water (1 mL) solution at 20°C, and 2-methoxyphenylboronic acid (336.85 mg), potassium carbonate (306.37 mg), and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (72.24 mg) were added to the reaction solution. The reaction solution was stirred at 80°C for 15 minutes under a nitrogen gas atmosphere. After the reaction was completed, the solution was filtered and concentrated under reduced pressure to dryness to obtain the title compound (700 mg).

[0369] MS m / z(ESI):=297.9 [M+H] + .

[0370] Step 2: Synthesis of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (Intermediate 36-3) Intermediate 36-2 (600 mg) was dissolved in N,N-dimethylformamide (6 mL) at 20°C, and intermediate 2-1 (233.23 mg), HATU (422.15 mg), and N,N-diisopropylethylamine (260.90 mg) were added to the reaction solution. The reaction solution was stirred at 20°C for 1 hour. After the reaction was completed, water (100 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (180 mg). MS m / z(ESI):=510.1 [M+H] +

[0371] Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxyphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (compound 36) Intermediate 36-3 (170 mg) was dissolved in a dioxane (5 mL) / water (1 mL) solution at 20°C, and intermediate 34-2 (97.90 mg), potassium carbonate (92.09 mg), and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (21.71 mg) were added to the reaction solution. The reaction solution was stirred at 80°C for 15 minutes under a nitrogen gas atmosphere. After the reaction was completed, it was filtered and concentrated under reduced pressure to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (30 mg).

[0372] 1 H NMR(400MHz,DMSO-d6)δ=13.68(s,1H),9.37(s,1H),9.11(s,1H),8.39(d,J=8.3Hz,2H),8.07-7.9 5(m,3H),7.55(d,J=7.5Hz,1H),7.51-7.45(m,1H),7.15(s,1H),7.05(d,J=8.3Hz,1H),3.56(s,3H) MS m / z(ESI):=533.1 [M+H] +

[0373] Example 37, N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-2',5-dicyano-[1,1'-biphenyl]-2-carboxamide (Compound 37) [ka]

[0374] Step 1: Synthesis of 2',5-dicyano-[1,1'biphenyl]-2-carboxylic acid methyl ester (intermediate 37-3) Intermediate 37-1 (500 mg), Intermediate 37-2 (1.22 g), 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (135.75 mg), and potassium carbonate (575.73 mg) were dissolved in dioxane (5 mL) and water (1 mL) at 25 °C and stirred at 90 °C for 2 hours under a nitrogen atmosphere. After the reaction was completed, the organic phase was concentrated under reduced pressure to dryness. Ethyl acetate (200 mL) and water (100 mL) were added to the solution, and the solution was washed with water (45 mL x 3). The organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1:1) to give the title compound (540 mg).

[0375] MS m / z(ESI):=263.1 [M+H] + .

[0376] Step 2: Synthesis of 2',5-dicyano-[1,1'-biphenyl]-2-carboxylic acid (intermediate 37-4) At 20°C, intermediate 37-3 (500 mg) was dissolved in a solution of tetrahydrofuran (3 mL) and water (3 mL), and a solution of lithium hydride (136.97 mg) and water (3 mL) was added dropwise. The reaction mixture was stirred at 50°C for 2 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 7 with dilute hydrochloric acid and then concentrated under reduced pressure to dryness. The residue was dissolved in methanol (1 mL) and filtered. The filtrate was concentrated under reduced pressure to dryness to give the title compound (540 mg).

[0377] MS m / z(ESI):=249.1 [M+H] + .

[0378] Step 3: Synthesis of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-2',5-dicyano-[1,1'-biphenyl]-2-carboxamide (Intermediate 37-5) Intermediate 37-4 (100 mg) and intermediate 2-1 (93.09 mg) were dissolved in N,N-dimethylformamide (1 mL) at 20 °C, and HATU (168.49 mg) and N,N-diisopropylethylamine (104.13 mg) were added to the reaction solution. The reaction solution was stirred at 25 °C for 2 hours. After the reaction was completed, ethyl acetate (50 mL) and water (100 mL) were added, and the mixture was washed with water (25 mL x 3). The organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (120 mg). MS m / z(ESI):=463.2 [M+H] +

[0379] Step 4: Synthesis of N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-2',5-dicyano-[1,1'-biphenyl]-2-carboxamide (compound 37) Intermediate 37-5 (100 mg) and intermediate 3-6 (50.85 mg) were dissolved in dioxane (1 mL) and water (0.2 mL) at 20 °C, and potassium carbonate (59.92 mg) and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride were added to the reaction solution. Under a nitrogen gas atmosphere, the reaction solution was stirred at 90 °C for 16 hours. After the reaction was completed, ethyl acetate (50 mL) and water (100 mL) were added, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high performance liquid chromatography (chromatography column: Boston Prime C18 150*30mm*5um, mobile phase: A: water (0.05% aqueous ammonia), B: acetonitrile, B%: 60% to 80%, 11 minutes) to obtain the title compound (25.2mg).

[0380] 1H NMR(400MHz,DMSO-d6)δ=13.79(d,J=1.0Hz,1H),9.28(s,1H),8.23-8.18(m,3H),8.18-8.14(m, 2H),8.00-7.95(m,1H),7.76(dt,J=1.3,7.7Hz,1H),7.62(d,J=8.6Hz,3H),7.53(d,J=7.6Hz,1H) MS m / z(ESI):=493.0 [M+H] +

[0381] Example 38, N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-cyano-4-(2-ethynylphenyl)pyridine-3-carboxamide (Compound 38) [ka]

[0382] Step 1: Synthesis of 6-cyano-4-(2-ethynylphenyl)-pyridine-3-carboxylic acid ethyl ester (intermediate 38-2) Intermediate 38-1 (90 mg), (2-ethynylphenyl)boronic acid (124.73 mg), potassium phosphate (181.41 mg), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (27.85 mg) were dissolved in a mixture of N,N-dimethylformamide (3 mL) and water (0.2 mL). The reaction mixture was stirred at 60 °C for 15 min under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, slowly poured into water (50 mL), and extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic layer was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (ISCO®, 20 g SepaFlash® flash silica gel column, gradient 0-30% ethyl acetate / petroleum ether, flow rate 30 mL / min) to give the title compound (85 mg).

[0383] MS m / z(ESI):=277.2 [M+H] + .

[0384] Step 2: Synthesis of 6-cyano-4-(2-ethynylphenyl)-pyridine-3-carboxylic acid (intermediate 38-3) Intermediate 38-2 (85 mg) was dissolved in tetrahydrofuran (1 mL), and a solution of lithium hydroxide (22.10 mg) in water (1 mL) was added. The reaction mixture was stirred at 0°C for 16 h. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was dissolved in dichloromethane (3 mL) and filtered. The filtrate was concentrated to dryness under reduced pressure to give the title compound (50 mg).

[0385] MS m / z(ESI):=249.1 [M+H] + .

[0386] Step 3: Synthesis of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-6-cyano-4-(2-ethynylphenyl)pyridine-3-carboxamide (Intermediate 38-4) Intermediate 38-3 (250 mg) was dissolved in N,N-dimethylformamide (4 mL) at 20°C, and intermediate 2-1 (232.72 mg), HATU (382.93 mg), and N,N-diisopropylethylamine (260.32 mg) were added to the reaction solution. The reaction solution was stirred at 20°C for 1 hour. After the reaction was completed, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain the title compound (110 mg). MS m / z(ESI):=461.1 [M+H] +

[0387] Step 4: Synthesis of N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-cyano-4-(2-ethynylphenyl)pyridine-3-carboxamide (compound 38) Intermediate 38-4 (110 mg) was dissolved in a dioxane (1 mL) / water (0.2 mL) solution at 20 °C, and intermediate 3-6 (74.58 mg), potassium carbonate (65.91 mg), and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (15.54 mg) were added to the reaction solution. The reaction solution was stirred at 80 °C for 15 minutes under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 54% to 74%, 13 minutes) to obtain the title compound (13.2 mg).

[0388] 1 H NMR(400MHz,DMSO-d6)δ=13.85(s,1H),9.29-9.26(m,1H),9.25-9.22(m,1H),8.30-8. 26(m,1H),8.24~8.19(m,2H),7.64-7.59(m,3H),7.58-7.44(m,3H),4.17-4.15(m,1H) MS m / z(ESI):=493.2 [M+H] + .

[0389] Example 39, 6-cyano-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-morpholinopyridine-3-carboxamide (Compound 39) [ka]

[0390] Step 1: Synthesis of 6-chloro-4-morpholinopyridine-3-carboxylic acid ethyl ester (intermediate 39-2) Intermediate 39-1 (2 g), morpholine (870.99 mg), and triethylamine (1.84 g) were dissolved in acetonitrile (30 mL). The reaction mixture was stirred at 25°C for 16 hours under a nitrogen atmosphere. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 20 g SepaFlash® flash silica gel column, gradient 0-15% ethyl acetate / petroleum ether, flow rate 80 mL / min) to obtain the title compound (1.0 g). MS m / z(ESI):=271.2 [M+H] +

[0391] Step 2: Synthesis of 6-chloro-4-morpholinopyridine-3-carboxylic acid (intermediate 39-3) Intermediate 39-2 (1 g) was dissolved in tetrahydrofuran (12 mL) and a solution of lithium hydroxide (465.04 mg) in water (4 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. After the reaction was completed, the pH of the reaction mixture was adjusted to 7 with dilute hydrochloric acid and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (1 mL) and filtered. The filtrate was concentrated to dryness under reduced pressure to give the title compound (800 mg).

[0392] MS m / z(ESI):=243.1 [M+H] + .

[0393] Step 3: Synthesis of 6-cyano-4-morpholinopyridine-3-carboxylic acid (intermediate 39-4) Intermediate 39-3 (700 mg), zinc cyanide (0.77 mg), zinc powder (138.85 mg), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (316.61 mg) were dissolved in N,N-dimethylformamide (10 mL). The reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (60 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ISCO®, 20 g SepaFlash® flash silica gel column, gradient 0-20% acetonitrile / water, flow rate 60 mL / min) to give the title compound (220 mg). MS m / z(ESI):=234.1 [M+H] +

[0394] Step 4: Synthesis of 6-cyano-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-morpholinopyridine-3-carboxamide (compound 39) Intermediate 39-4 (50 mg), intermediate 16-3 (54.30 mg), HATU (122.27 mg), and N,N-diisopropylethylamine (27.71 mg) were dissolved in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 25 °C for 1 h under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 35% to 55%, 12 min) to obtain the title compound (30 mg).

[0395] 1 H NMR(400MHz,DMSO-d6)δ=8.98(s,1H),8.47(s,1H),8.29-8.26(m,2H),7.93-7.90(m,2H),7.47(s,1H),3.70-3.61(m,4H),3.28-3.21(m,4H) MS m / z(ESI):=469.0 [M+H]+ .

[0396] Example 40. 3-(4-cyano-2-methoxyphenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)pyridine-4-carboxamide (Compound 40) [ka]

[0397] Step 1: Synthesis of 3-(4-cyano-2-methoxyphenyl)pyridine-4-carboxylic acid methyl ester (intermediate 40-2) Intermediate 40-1 (500 mg), (4-cyano-2-methoxyphenyl)boronic acid (614.37 mg), tetrakis(triphenylphosphine)palladium (267.45 mg), and sodium carbonate (490.62 mg) were dissolved in a dioxane (20 mL) / water (4 mL) solution. The reaction mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. After the reaction was completed, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 20 g SepaFlash® flash silica gel column, gradient ∼30% ethyl acetate / petroleum ether, flow rate 40 mL / min) to give the title compound (500 mg). MS m / z(ESI):=269.4 [M+H] +

[0398] Step 2: Synthesis of 3-(4-cyano-2-methoxyphenyl)pyridine-4-carboxylic acid (Intermediate 40-3) Intermediate 40-2 (500 mg) was dissolved in tetrahydrofuran (8 mL) and a solution of lithium hydroxide (244.97 mg) in water (8 mL) was added. The reaction mixture was stirred at 20°C for 1 hour. After the reaction was completed, the pH of the reaction mixture was adjusted to 7 with dilute hydrochloric acid and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (1 mL) and filtered. The filtrate was concentrated to dryness under reduced pressure to give the title compound (400 mg).

[0399] MS m / z(ESI):=255.2 [M+H] + .

[0400] Step 3: Synthesis of 3-(4-cyano-2-methoxyphenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)pyridine-4-carboxamide (compound 40) Intermediate 40-3 (50 mg), intermediate 16-3 (49.81 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (75.40 mg), pyridine (46.67 mg), and 1-hydroxybenzotriazole (53.15 mg) were dissolved in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 25 °C for 1 h under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 43% to 63%, 2 min) to obtain the title compound (5 mg).

[0401] 1 H NMR(400MHz,DMSO-d6)δ=9.28(s,1H),8.81(s,1H),8.64(s,1H),8.37(d,J=8.5Hz,2H ),8.00(d,J=8.3Hz,2H),7.83(d,J=5.0Hz,1H),7.59(s,2H),7.49(s,1H),3.59(s,3H) MS m / z(ESI):=490.1 [M+H] + .

[0402] Example 41, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-(2-methoxyphenyl)imidazo[1,2-a]pyridine-7-carboxamide (Compound 41) [ka]

[0403] Step 1: Synthesis of 6-bromoimidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (intermediate 41-2) Intermediate 41-1 (300 mg) and 2-chloroacetaldehyde (509.62 mg) were dissolved in ethanol (5 mL) at 25 °C, and then sodium bicarbonate (218.16 mg) was added. The reaction mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the organic phase was concentrated under reduced pressure to dryness. Ethyl acetate (200 mL) and water (100 mL) were added, and the mixture was washed with water (45 mL x 3). The organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness to obtain the title compound (200 mg).

[0404] MS m / z(ESI):=255.2 [M+H] + .

[0405] Step 2: Synthesis of 6-(2-methoxyphenyl)imidazo[1,2-a]pyridine-7-carboxylic acid methyl ester (intermediate 41-3) Intermediate 41-2 (100 mg), 2-methoxyphenylboronic acid (89.36 mg), 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (25.55 mg), and potassium carbonate (108.37 mg) were dissolved in dioxane (1 mL) and water (0.2 mL) at 20 ° C., and the reaction mixture was stirred at 90 ° C. for 2 hours. After the reaction was completed, the organic phase was concentrated under reduced pressure to dryness, and ethyl acetate (200 mL) and water (100 mL) were added. The mixture was washed with water (45 mL x 3). The organic phase was concentrated under reduced pressure to dryness, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 3) to give the title compound (100 mg).

[0406] MS m / z(ESI):=282.9 [M+H] + .

[0407] Step 3: Synthesis of 6-(2-methoxyphenyl)imidazo[1,2-a]pyridine-7-carboxylic acid (intermediate 41-4) At 20°C, intermediate 41-3 (100 mg) and sodium hydroxide (141.70 mg) were dissolved in methanol (1 mL) and water (1 mL). The reaction mixture was stirred at 60°C for 2 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 7 with dilute hydrochloric acid and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (1 mL) and filtered. The filtrate was concentrated to dryness under reduced pressure to give the title compound (100 mg).

[0408] MS m / z(ESI):=269.1 [M+H] + .

[0409] Step 4: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-(2-methoxyphenyl)imidazo[1,2-a]pyridine-7-carboxamide (compound 41) Intermediate 41-4 (80 mg) and intermediate 16-3 (90.64 mg) were dissolved in N,N-dimethylformamide (1 mL) at 20 °C. HATU (124.73 mg) and diisopropylethylamine (222.60 mg) were added to the reaction solution, and the reaction solution was stirred at 25 °C for 2 hours. After the reaction was complete, ethyl acetate (50 mL) and water (100 mL) were added, and the mixture was extracted with ethyl acetate (25 mL x 3 times). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.05% aqueous ammonia), B: acetonitrile, B%: 25% to 55%, 10 min) to obtain the title compound (1 mg).

[0410] 1H NMR(400MHz,DMSO-d6)δ=13.52-13.41(m,1H),8.63(s,1H),8.41-8.35(m,2H),8.15-8.05(m,3H),8.04-7.9 9(m,2H),7.85-7.73(m,1H),7.49-7.35(m,2H),7.14-7.06(m,1H),6.97(d,J=8.3Hz,1H),3.53-3.52(m,3H). MS m / z(ESI):=504.1 [M+H] + .

[0411] Example 42, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-ethynylphenyl)-6-methylpyridine-3-carboxamide (Compound 42) [ka]

[0412] Step 1: Synthesis of 4-(2-ethynylphenyl)-6-methylpyridine-3-carboxylic acid methyl ester (intermediate 42-2) Intermediate 42-1 (4.50 g) and (2-ethynylphenyl)boronic acid (3.00 g) were dissolved in dioxane (45 mL) and water (9 mL). Sodium carbonate (4.15 g) was added, and the reaction mixture was purged with nitrogen three times. Tetrakis(triphenylphosphine)palladium (2.26 g) was then added. The reaction mixture was stirred under nitrogen at 80 °C for 2 h. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was poured into water. Ethyl acetate (30 mL) was added. The aqueous phase was washed with ethyl acetate (50 mL × 2). The washed organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by flash silica gel column chromatography (ISCO®, 25 g SepaFlash® flash silica gel column, gradient 0–30% petroleum ether / ethyl acetate, flow rate 60 mL / min) to give the title compound (2.8 g).

[0413] MS m / z (ESI): 252.0 [M + H] + .

[0414] Step 2: Synthesis of 4-(2-ethynylphenyl)-6-methylpyridine-3-carboxylic acid (intermediate 42-3) Intermediate 42-2 (2.60 g) was dissolved in anhydrous methanol (26 mL), and sodium hydroxide (1.24 g) and water (6 mL) were added thereto, and the reaction solution was stirred for 4 hours at 30° C. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove methanol, and the pH of the remaining aqueous phase was adjusted to 3 with an appropriate amount of hydrochloric acid. A large amount of solid precipitated, which was filtered, and the filter cake was dried to obtain the title compound (2.0 g).

[0415] MS m / z (ESI): 238.0 [M + H] + .

[0416] Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-ethynylphenyl)-6-methylpyridine-3-carboxamide (compound 42) Intermediate 42-3 (30.00 mg) was dissolved in anhydrous N,N-dimethylformamide (0.5 mL), and HATU (68.68 mg) and N,N-diisopropylethylamine (46.69 mg) were added. The reaction mixture was stirred at 0 °C for 30 min under a nitrogen atmosphere. Intermediate 16-3 (30.50 mg) was then added, and the reaction mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was filtered and purified by preparative high-performance liquid chromatography (Boston Prime C18 column, 5 μm silica, 30 mm diameter, 150 mm length, elution time: 9 min, acetonitrile gradient 39%-79%, water (containing 0.225% formic acid) and acetonitrile were used as the eluent). The title compound (16.0 mg) was obtained.

[0417] MS m / z(ESI):473.1 [M+H] + .

[0418] 1H NMR(400MHz,DMSO-d6)δ=13.58(s,1H),9.34(s,1H),8.95(s,1H),8.37(d,J=8.3Hz,2H) ,8.01(d,J=8.3Hz,2H),7.58-7.49(m,2H),7.48-7.36(m,3H),4.02(s,1H),2.62(s,3H)

[0419] Example 43, 6-chloro-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-ethynylphenyl)pyridine-3-carboxamide (Compound 43) [ka]

[0420] Step 1: Synthesis of 6-chloro-4-(2-ethynylphenyl)pyridine-3-carboxylic acid methyl ester (intermediate 43-3) Intermediate 43-1 (200 mg) and intermediate 43-2 (212.52 mg) were dissolved in dioxane (5 mL) and water (1 mL) at 25 °C. Sodium bicarbonate (268.33 mg) and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (63.27 mg) were added, and the reaction mixture was stirred at 90 °C for 2 hours. After the reaction was completed, the organic phase was concentrated under reduced pressure to dryness. Ethyl acetate (200 mL) and water (100 mL) were added, and the mixture was washed with water (45 mL x 3). The organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (50 mg).

[0421] MS m / z(ESI):=272.3 [M+H] + .

[0422] Step 2: Synthesis of 6-chloro-4-(2-ethynylphenyl)pyridine-3-carboxylic acid (intermediate 43-4) Intermediate 43-3 (25 mg) was dissolved in a solution of methanol (1 mL) and water (1 mL) at 20°C, and then lithium hydroxide (19.31 mg) was added to the reaction solution. The reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 7 with dilute hydrochloric acid and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (1 mL) and filtered, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (50 mg).

[0423] MS m / z(ESI):=257.9 [M+H] + .

[0424] Step 3: Synthesis of 6-chloro-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-ethynylphenyl)pyridine-3-carboxamide (compound 43) Intermediate 43-4 (30 mg) and intermediate 16-3 (29.49 mg) were dissolved in N,N-dimethylformamide (1 mL) at 20 °C. HATU (48.70 mg) and diisopropylethylamine (222.60 mg) were added to the reaction solution, and the reaction solution was stirred at 25 °C for 2 hours. After the reaction was complete, ethyl acetate (50 mL) and water (100 mL) were added, and the mixture was extracted with ethyl acetate (25 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.05% aqueous ammonia), B: acetonitrile, B%: 41% to 71%, 9 min) to obtain the title compound (1.5 mg).

[0425] 1 H NMR(400MHz,DMSO-d6)δ=13.79-13.64(m,1H),9.30(s,1H),8.97(s,1H),8.37(d,J=8.3Hz,2H),8.00(d, J=8.4Hz,2H),7.65(s,1H),7.61-7.56(m,1H),7.54-7.45(m,2H),7.45-7.40(m,1H),4.20-4.02(m,1H). MS m / z(ESI):=493.0 [M+H] + .

[0426] Example 44, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-2-methoxy-6'-methyl-[3,4'-bipyridine]-3'-carboxamide (Compound 44) [ka]

[0427] Step 1: Synthesis of 2-methoxy-6'-methyl-[3,4'-bipyridine]-3'-carboxylic acid methyl ester (intermediate 44-2) Intermediate 20-1 (1.83 g) and intermediate 44-1 (1.00 g) were dissolved in DMSO (10 mL) and water (1 mL), and cuprous chloride (1.29 g) and cesium fluoride (1.99 g) were added. 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (426.14 mg) was then added to the reaction mixture. The reaction mixture was stirred at 90°C for 16 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was poured into water. Ethyl acetate (30 mL) was added. The aqueous phase was washed with ethyl acetate (20 mL *2), and the mixture was allowed to cool to room temperature. The washed organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to dryness. The residue was purified by flash silica gel column chromatography (ISCO®, 12 g SepaFlash® flash silica gel column, gradient 0-70% petroleum ether / ethyl acetate, flow rate 60 mL / min) to give the title compound (300.0 mg).

[0428] MS m / z(ESI):259.4 [M+H] + Step 2: Synthesis of 2-methoxy-6'-methyl-[3,4'-bipyridine]-3'-carboxylic acid (Intermediate 44-3) Intermediate 44-2 (300 mg) was dissolved in anhydrous methanol (2.5 mL), and sodium hydroxide (139.38 mg) and water (0.5 mL) were added thereto. The reaction mixture was stirred at 30° C. for 3 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the methanol. The pH of the remaining aqueous phase was adjusted to 3 with an appropriate amount of hydrochloric acid. The reaction mixture was concentrated under reduced pressure. 10 mL of dichloromethane:methanol (10:1) was added to the residue, and the mixture was stirred for 10 min. The mixture was filtered. The filtrate was concentrated under reduced pressure to dryness to give the title compound (250.0 mg).

[0429] MS m / z(ESI):245.2 [M+H] + .

[0430] Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-2-methoxy-6'-methyl-[3,4'-bipyridine]-3'-carboxamide (compound 44) Intermediate 44-3 (50.00 mg) was dissolved in anhydrous N,N-dimethylformamide (1 mL), and HATU (81.73 mg) and diisopropylethylamine (79.37 mg) were added. The reaction mixture was stirred at 25°C for 30 min under a nitrogen atmosphere. Intermediate 16-3 (51.85 mg) was then added, and the reaction mixture was stirred at 25°C for 3 h under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was filtered and purified by preparative high-performance liquid chromatography (Boston Green ODS C18 column, 5 µm silica, 30 mm diameter, 150 mm length, elution with a decreasing polarity reaction mixture of water (containing 0.225% formic acid) and acetonitrile, 35% to 65% acetonitrile gradient, 14 min elution time) to obtain the title compound (20 mg).

[0431] MS m / z(ESI):480.0 [M+H] + .

[0432] 1H NMR(400MHz,DMSO-d6)δ=13.52(s,1H),9.37(s,1H),8.84(s,1H),8.39(d,J=8.4Hz,2H),8.28-8.20(m,1H),8. 03(d,J=8.5Hz,2H),7.89(d,J=5.6Hz,1H),7.45(s,1H),7.19(dd,J=5.1,7.3Hz,1H),3.62(s,3H),2.62(s,3H)

[0433] Example 45, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 45) [ka]

[0434] Step 1: Synthesis of 3'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (intermediate 45-2) Intermediate 20-1 (500 mg), Intermediate 45-1 (618.01 mg), 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (175.57 mg), cuprous chloride (33.38 mg), and cesium fluoride (818.41 mg) were dissolved in dimethyl sulfoxide (5 mL) and water (0.2 mL) at 25 °C, and the reaction mixture was stirred at 90 °C for 2 hours. After the reaction was completed, the organic phase was concentrated under reduced pressure to dryness, and ethyl acetate (200 mL) and water (100 mL) were added. The mixture was washed with water (45 mL x 3 times). The organic phase was concentrated under reduced pressure to dryness, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (80 mg).

[0435] MS m / z(ESI):=259.0 [M+H] + .

[0436] Step 2: Synthesis of 3'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (intermediate 45-3) Intermediate 45-2 (80 mg) and sodium hydroxide (37.17 mg) were dissolved in a solution of methanol (0.8 mL) and water (0.2 mL) at 25°C, and the reaction mixture was stirred at 25°C for 2 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 7 with dilute hydrochloric acid and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (1 mL) and filtered, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (70 mg).

[0437] MS m / z(ESI):=245.2 [M+H] + Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (compound 45) Intermediate 45-3 (50 mg) and intermediate 16-3 (77.77 mg) were dissolved in N,N-dimethylformamide (1 mL) at 20 °C, and HATU (93.41 mg) and diisopropylethylamine (52.92 mg) were added to the reaction solution. The reaction solution was stirred at 25 °C for 2 hours. After the reaction was completed, ethyl acetate (50 mL) and water (100 mL) were added to the mixture, and the mixture was extracted with ethyl acetate (25 mL x 3 times). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.05% aqueous ammonia), B: acetonitrile, B%: 18% to 38%, 11 min) to obtain the title compound (5.5 mg).

[0438] 1 H NMR(400MHz,DMSO-d6)δ=13.67-13.48(m,1H),9.36(s,1H),8.87(s,1H),8.42-8 .34(m,4H),8.02(d,J=8.6Hz,2H),7.49-7.40(m,2H),3.65(s,3H),2.63(s,3H).

[0439] MS m / z(ESI):=480.0 [M+H] + .

[0440] Example 46, N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylpyridine-3-carboxamide (Compound 46) [ka]

[0441] Intermediate 22-3 (71.21 mg) and HATU (100.93 mg) were dissolved in N,N-dimethylformamide (2 mL). Under a nitrogen gas atmosphere, the reaction mixture was stirred at 40 °C for 30 minutes, and then intermediate 17-2 (110 mg) and N,N-diisopropylethylamine (68.61 mg) were added. The reaction mixture was stirred at 40 °C for 16 hours. After the reaction was completed, the reaction mixture was purified by high-performance liquid chromatography (chromatography column: Boston Green ODS 150 * 30 mm * 5 um, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 52% to 82%, 12 minutes) to obtain the title compound (22 mg).

[0442] 1 H NMR(400MHz,DMSO-d6)δ=13.46-13.33(m,1H),9.31-9.25(m,1H),8.89-8.79(m,1H),8.27-8.16(m,2H),7 .98-7.88(m,2H),7.66-7.59(m,2H),7.52-7.42(m,1H),7.25-7.15(m,1H),3.61(s,3H),2.64-2.59(m,3H) MS m / z(ESI):=513.1 [M+H] + .

[0443] Example 47, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-ethynyl-4-fluorophenyl)-6-methylpyridine-3-carboxamide (Compound 47) [ka]

[0444] Step 1: Synthesis of (4-fluoro-2-((trimethylsilyl)ethynyl)phenyl)boronic acid (Intermediate 47-2) Intermediate 47-1 (2 g) and tetrahydroxydiboron (1.98 g) were dissolved in anhydrous methanol (20 mL), N,N-diisopropylethylamine (4.77 g) was added, and the reaction mixture was purged with nitrogen gas three times. Chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium(II) (493.09 mg) was then added to the reaction mixture. The reaction mixture was stirred at 25 °C for 1 h under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 12 g SepaFlash® flash silica gel column, gradient 0-30% petroleum ether / ethyl acetate, flow rate 50 mL / min) to obtain the title compound (500 mg).

[0445] MS m / z (ESI): 237.0 [M + H] + .

[0446] Step 2: Synthesis of 4-(4-fluoro-2-((trimethylsilyl)ethynyl)phenyl)-6-methylpyridine-3-carboxylic acid methyl ester (Intermediate 47-3) Intermediate 47-2 (500 mg) and intermediate 20-1 (589.55 mg) were dissolved in dioxane (5 mL) and water (1 mL). (1,1'-bis(diphenylphosphine)ferrocene)dichloropalladium (154.94 mg) and potassium carbonate (585.32 mg) were added to the reaction mixture under a nitrogen atmosphere. The mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was poured into water. Ethyl acetate (30 mL) was added. The aqueous phase was extracted with ethyl acetate (30 mL *2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 12 g SepaFlash® flash silica gel column, gradient 0-30% ethyl acetate / petroleum ether, flow rate 60 mL / min) to obtain the title compound (500 mg).

[0447] MS m / z(ESI):342.2 [M+H] + .

[0448] Step 3: Synthesis of 4-(2-ethynyl-4-fluorophenyl)-6-methylpyridine-3-carboxylic acid (Intermediate 47-4) Intermediate 47-3 (500 mg) was dissolved in anhydrous methanol (5 mL), and sodium hydroxide (175.20 mg, 4.38 mmol) and water (1 mL) were added thereto, and the reaction mixture was stirred at 25° C. for 2 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to dryness, and 10 mL of dichloromethane:methanol (10:1) was added to the residue, and the mixture was stirred for 10 min. The mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness to give the title compound (250.0 mg).

[0449] MS m / z (ESI): 256.0 [M + H] + .

[0450] Step 4: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-ethynyl-4-fluorophenyl)-6-methylpyridine-3-carboxamide (compound 47) Intermediate 47-4 (50.00 mg) was dissolved in anhydrous N,N-dimethylformamide (1 mL), and HATU (75.23 mg) and N,N-diisopropylethylamine (75.95 mg) were added. The reaction mixture was stirred under a nitrogen atmosphere for 30 min. Intermediate 16-3 (74.42 mg) was then added, and the reaction mixture was stirred at 25 °C for 3 h under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was filtered and purified by preparative high-performance liquid chromatography (Boston Green ODS C18 column, 5 μm silica, 30 mm diameter, 150 mm length, elution with water (containing 0.225% formic acid) and the reaction mixture with decreasing polarity acetonitrile, acetonitrile gradient rate 46%-76%, elution time 12 min) to obtain the title compound (10 mg).

[0451] MS m / z (ESI): 491.0 [M + H] + .

[0452] 1 H NMR(400MHz,DMSO-d6)δ=13.59(s,1H),9.36(s,1H),8.97(s,1H),8.37(d,J=8.4Hz,2H) ,8.01(d,J=8.5Hz,2H),7.49-7.43(m,2H),7.42-7.37(m,2H),4.16(s,1H),2.62(s,3H)

[0453] Example 48, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-ethynyl-5-fluorophenyl)-6-methylpyridine-3-carboxamide (Compound 48) [ka]

[0454] Step 1: Synthesis of ((2-bromo-4-fluorophenyl)ethynyl)trimethylsilane (Intermediate 48-2) Intermediate 48-1 (10 g), trimethylethynylsilane (3.26 g), cuprous iodide (253.18 mg), and dichlorobis(triphenylphosphine)palladium (466.54 mg) were dissolved in triethylamine (90 mL) at 25 °C, and the reaction mixture was stirred at 40 °C for 4 hours. After the reaction was completed, the organic phase was concentrated to dryness under reduced pressure, and ethyl acetate (200 mL) and water (100 mL) were added. The mixture was washed with water (45 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 120 g SepaFlash® flash silica gel column, 100% petroleum ether, flow rate 50 mL / min) to give the title compound (6.89 g).

[0455] 1 H NMR(400MHz,DMSO-d6)δ=7.48-7.41(m,2H),7.40-7.33(m,1H),0.28-0.20(m,9H). Step 2: Synthesis of (5-fluoro-2-((trimethylsilyl)ethynyl)phenyl)boronic acid (Intermediate 48-3) Intermediate 48-2 (1 g), tetrahydroxydiboron (991.72 mg), chloro[(n-butylbis(1-adamantyl)phosphine)-2-(2-aminobiphenyl)]palladium (246.54 mg), and N,N-diisopropylethylamine (2.38 g, 18.44 mmol) were dissolved in methanol (12 mL) at 20 °C. The reaction mixture was stirred at 25 °C for 2 h. After the reaction was complete, ethyl acetate (50 mL) and water (50 mL) were added, followed by extraction with ethyl acetate (25 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 20 g SepaFlash® flash silica gel column, gradient 0-10% ethyl acetate / petroleum ether, flow rate 50 mL / min) to give the title compound (400 mg).

[0456] 1H NMR(400MHz,DMSO-d6)δ=7.58(dd,J=5.8,8.6Hz,1H),7.52-7.35(m,1H),7.32-7.03(m,3H),0.00(s,9H).

[0457] Step 3: Synthesis of 4-(5-fluoro-2-((trimethylsilyl)ethynyl)phenyl)-6-methylpyridine-3-carboxylic acid methyl ester (compound 48-4) Intermediate 48-3 (400 mg), intermediate 20-1 (314.43 mg), potassium carbonate (468.25 mg), and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (123.95 mg) were dissolved in dioxane (10 mL) and water (1 mL) at 20 °C. The reaction mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the organic phase was concentrated under reduced pressure to dryness. Ethyl acetate (200 mL) and water (100 mL) were added and washed with water (45 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (ISCO®, 20 g SepaFlash® flash silica gel column, gradient 0-10% ethyl acetate / petroleum ether, flow rate 50 mL / min) to give the title compound (360 mg).

[0458] MS m / z(ESI):=342.3 [M+H] +

[0459] Step 4: Synthesis of 4-(2-ethynyl-5-fluorophenyl)-6-methylpyridine-3-carboxylic acid (Intermediate 48-5) Intermediate 48-4 (280 mg) and sodium hydroxide (98.40 mg) were dissolved in a solution of methanol (2 mL) and water (1 mL) at 25 °C, and the reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 7 with dilute hydrochloric acid and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (1 mL), filtered, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (200 mg).

[0460] MS m / z(ESI):=256.1 [M+H] + .

[0461] Step 5: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-ethynyl-5-fluorophenyl)-6-methylpyridine-3-carboxamide (compound 48) Intermediate 48-5 (50 mg) and intermediate 16-3 (49.62 mg) were dissolved in N,N-dimethylformamide (1 mL) at 20 °C, and HATU (74.48 mg) and N,N-diisopropylethylamine (50.63 mg) were added to the reaction solution. The reaction solution was stirred at 25 °C for 2 hours. After the reaction was completed, ethyl acetate (50 mL) and water (100 mL) were added to the mixture, and the mixture was extracted with ethyl acetate (25 mL x 3 times). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.05% aqueous ammonia), B: acetonitrile, B%: 48% to 68%, 11 min) to obtain the title compound (7.77 mg).

[0462] 1 H NMR(400MHz,DMSO-d6)δ=13.67-13.54(m,1H),9.36(s,1H),9.00(s,1H),8.38(d,J=8.3Hz,2H),8.03 (s,2H),7.61(dd,J=5.9,8.4Hz,1H),7.43(s,1H),7.37-7.29(m,2H),4.00-3.98(m,1H),2.63(s,3H).

[0463] MS m / z(ESI):=491.1 [M+H] + .

[0464] Example 49, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-ethynyl-6-fluorophenyl)-6-methylpyridine-3-carboxamide (Compound 49) [ka]

[0465] Step 1: Synthesis of ((2-bromo-3-fluorophenyl)ethynyl)trimethylsilane (Intermediate 49-2) At 25°C, intermediate 49-1 (9 g) and trimethylethynylsilane (6.00 g) were dissolved in triethylamine (60 mL), and cuprous iodide (284.83 mg) and dichlorobis(triphenylphosphine)palladium (2.10 g) were added. The reaction solution was stirred at 20°C for 1 hour. After the reaction was completed, the organic phase was concentrated under reduced pressure to dryness, and ethyl acetate (200 mL) and water (100 mL) were added thereto. The mixture was washed with water (45 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by silica gel chromatography (petroleum ether 100%) to obtain the title compound (8 g).

[0466] 1 H NMR(400MHz,Methanol-d4)δ=7.47-7.36(m,3H),0.26(s,9H) Step 2: Synthesis of ((3-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethynyl)trimethylsilane (Intermediate 49-3) Intermediate 49-2 (800 mg), bis(pinacolato)diboron (B2Pin2) (1.12 g), 1,1-bis(diphenylphosphine)ferrocenepalladium chloride (215.84 mg), and potassium acetate (579.01 mg) were dissolved in dioxane (40 mL) at 20 °C, and the reaction mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere. After the reaction was completed, the organic phase was concentrated under reduced pressure to dryness, and ethyl acetate (200 mL) and water (100 mL) were added. The mixture was washed with water (45 mL x 3 times). The separated organic phase was concentrated under reduced pressure to dryness to give the title compound (900 mg).

[0467] MS m / z(ESI):=319.4 [M+H] + .

[0468] Step 3: Synthesis of 4-(2-fluoro-6-((trimethylsilyl)ethynyl)phenyl)-6-methylpyridine-3-carboxylic acid methyl ester (Intermediate 49-4) Intermediate 49-3 (900 mg), intermediate 20-1 (524.87 mg), potassium carbonate (781.65 mg), and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (184.30 mg) were dissolved in dioxane (10 mL) and water (2 mL) at 20 °C. The reaction mixture was stirred at 90 °C under a nitrogen atmosphere for 2 hours. After the reaction was completed, the organic phase was concentrated under reduced pressure to dryness. Ethyl acetate (200 mL) and water (100 mL) were added and the mixture was washed with water (45 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (400 mg).

[0469] MS m / z(ESI):=341.9 [M+H] + .

[0470] Step 4: Synthesis of 4-(2-ethynyl-6-fluorophenyl)-6-methylpyridine-3-carboxylic acid (Intermediate 49-5) At 20°C, intermediate 49-4 (300 mg) and sodium hydroxide (210.85 mg) were dissolved in a solution of methanol (4 mL) and water (2 mL), and the reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, the reaction solution was adjusted to pH 7 with dilute hydrochloric acid and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (1 mL), filtered, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (220 mg).

[0471] MS m / z(ESI):=256.4 [M+H] + .

[0472] Step 5: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-ethynyl-6-fluorophenyl)-6-methylpyridine-3-carboxamide (compound 49) Intermediate 49-5 (70 mg) and intermediate 16-3 (83.35 mg) were dissolved in N,N-dimethylformamide (1 mL) at 20 °C, and HATU (104.28 mg) and N,N-diisopropylethylamine (88.61 mg) were added to the reaction solution. The reaction solution was stirred at 25 °C for 2 hours. After the reaction was completed, ethyl acetate (50 mL) and water (100 mL) were added to the mixture, and the mixture was extracted with ethyl acetate (25 mL x 3 times). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.05% aqueous ammonia), B: acetonitrile, B%: 45% to 65%, 11 min) to obtain the title compound (23 mg).

[0473] 1 H NMR(400MHz,DMSO-d6)δ=13.95-13.51(m,1H),9.35(s,1H),9.06(s,1H),8.37( d,J=8.3Hz,2H),8.01(d,J=8.3Hz,2H),7.46(s,4H),4.16(s,1H),2.63(s,3H). MS m / z(ESI):=491.0 [M+H] + .

[0474] Example 50: N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-2-(2-methoxyphenyl)pyridine-3-carboxamide (Compound 50) [ka]

[0475] Step 1: Synthesis of 2-(2-methoxyphenyl)pyridine-3-carboxylic acid methyl ester (intermediate 50-3) Intermediate 50-1 (1.00 g), Intermediate 50-2 (1.41 g), Pd(dppf)Cl (338 mg), and potassium phosphate (1.97 g) were added to dioxane (10 mL) and water (2 mL), and the reaction mixture was stirred at 80 °C for 4 hours. After cooling, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL * 3). The combined organic layer was washed with water (40 mL * 2), saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (1.08 g).

[0476] MS m / z(ESI):=244.1 [M+H] + .

[0477] Step 2: Synthesis of 2-(2-methoxyphenyl)pyridine-3-carboxylic acid (Intermediate 50-4) Intermediate 50-3 (1.00 g) was dissolved in tetrahydrofuran (10 mL), and 2 M aqueous sodium hydroxide solution (10 mL) was added. The reaction mixture was stirred at 60° C. for 18 hours. The pH was adjusted to 6 with 1 M aqueous HCl solution in an ice-water bath, and extracted with ethyl acetate (30 mL * 3). The organic layers were combined, washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (550 mg).

[0478] MS m / z(ESI):=230.2 [M+H] + .

[0479] Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-2-(2-methoxyphenyl)pyridine-3-carboxamide (compound 50) Intermediate 50-4 (30 mg), HATU (49 mg), and DIEA (33 mg) were added to DMF (1 mL), and the reaction mixture was stirred at 25 °C for 1 hour. Intermediate 16-3 (66 mg) was added, and the reaction mixture was stirred at 25 °C for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate (5 mL * 3). The organic layers were combined, washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini NX C18 3.5 μm * 4.6 * 100 mm, mobile phase: A: 0.05% TFA v / v, B: acetonitrile, B%: 10% to 90%, 10 min) to obtain the title compound (1 mg).

[0480] MS m / z(ESI):=465.1 [M+H] + .

[0481] 1 H NMR(400MHz,DMSO-d6)δ 8.98(s,1H),8.66-8.60(m,1H),8.30-8.22(m,3H),7.94-7.89(m,2H),7.45-7.3 8(m,2H),7.34-7.28(m,1H),7.04-6.98(m,1H),6.93-6.88(m,1H),3.46(s,3H).

[0482] Example 51: N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-methoxyphenyl)pyridine-2-carboxamide (Compound 51) [ka]

[0483] Step 1: Synthesis of 3-(2-methoxyphenyl)pyridine-2-carboxylic acid methyl ester (intermediate 51-3) Under a nitrogen gas atmosphere, intermediate 51-1 (1.00 g), intermediate 51-2 (1.41 g), Pd(dppf)Cl (338 mg), and potassium phosphate (1.97 g) were added to dioxane (10 mL) and water (2 mL) and stirred at 80 °C for 4 h. After cooling, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL * 3). The organic layers were combined, washed with water (40 mL * 2), washed with saturated brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (0.98 g).

[0484] MS m / z(ESI):=244.1 [M+H] + .

[0485] Step 2: Synthesis of 3-(2-methoxyphenyl)pyridine-2-carboxylic acid (intermediate 51-4) Intermediate 51-3 (1.00 g) was dissolved in tetrahydrofuran (10 mL), and 2 M aqueous sodium hydroxide solution (10 mL) was added. The reaction mixture was stirred at 60° C. for 18 h. The reaction mixture was concentrated under reduced pressure to dryness, and the pH was adjusted to 6 with 1 M HCl in an ice-water bath. Extraction was performed with ethyl acetate (30 mL * 3). The organic layers were combined, washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness to give the title compound (370 mg).

[0486] MS m / z(ESI):=230.2 [M+H] + .

[0487] Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-(2-methoxyphenyl)pyridine-2-carboxamide (compound 51) Intermediate 51-4 (20 mg), HATU (33 mg), and DIEA (22 mg) were added to DMF (1 mL) and stirred at room temperature for 1 h. Intermediate 16-3 (44 mg) was then added. The reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were combined, washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini NX C18 3.5 μm x 4.6 x 100 mm, mobile phase: A: 0.05% TFA v / v, B: acetonitrile, B%: 10% to 90%, 10 min) to obtain the title compound (8 mg).

[0488] MS m / z(ESI):=465.0 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=9.31(s,1H),8.74~8.64(m,1H),8.44~8.31(m,2H),8.08-7.95(m,2 H),7.95-7.84(m,1H),7.77-7.64(m,1H),7.46-7.29(m,2H),7.14-6.94(m,2H),3.57(s,3H).

[0489] Example 52: N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5-(2-methoxyphenyl)pyrimidine-4-carboxamide (Compound 52) [ka]

[0490] Step 1: Synthesis of 5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid methyl ester (intermediate 52-2) Under a nitrogen gas atmosphere, intermediate 52-1 (200 mg), 2-methoxyphenylboronic acid (323 mg), potassium carbonate (381 mg), and Pd(dppf)Cl (67 mg) were dissolved in 1,4-dioxane (3 mL) and stirred at 90 °C for 2 h. The reaction mixture was concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give the title compound (179 mg).

[0491] MS m / z(ESI):=245.2 [M+H] + .

[0492] Step 2: Synthesis of 5-(2-methoxyphenyl)pyrimidine-4-carboxylic acid (intermediate 52-3) Intermediate 52-2 (179 mg) was dissolved in methanol (3 mL), and a solution of lithium hydroxide (153 mg) in water (1 mL) was added. The mixture was stirred at room temperature for 5 hours. The pH of the reaction mixture was adjusted to 4 with dilute hydrochloric acid, and a solid precipitated. The solid was filtered and the filter cake was dried to give the title compound (90 mg).

[0493] MS m / z(ESI):=229.2 [M−H] - .

[0494] Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5-(2-methoxyphenyl)pyrimidine-4-carboxamide (compound 52) Intermediate 52-3 (20 mg) was dissolved in N,N-dimethylformamide (2 mL), HATU (33 mg), and DIEA (34 mg) were added, and the mixture was stirred at room temperature for 0.5 h. Intermediate 16-3 (22 mg) was then added and stirred at room temperature for 2 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The ethyl acetate phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the organic phase was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18 column, 5 μm silica, 30 mm diameter, 150 mm length, eluting with a decreasing polarity mixture of water (containing 0.225% formic acid) and acetonitrile, with an acetonitrile gradient of 40% to 70%, for 15 min) to obtain the title compound (20 mg).

[0495] MS m / z(ESI):=466.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 13.72(s,1H),9.36(s,2H),9.01(s,1H),8.40-8.35(m,2H),8.04~8.00(m, 2H),7.53-7.41(m,2H),7.14-7.10(m,1H),7.08-7.04(m,1H),3.57(s,3H).

[0496] Example 53: N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5-(2-methoxyphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide (Compound 53) [ka]

[0497] Step 1: Synthesis of 5-(2-methoxyphenyl)-2-(trifluoromethyl)pyridine-4-carboxylic acid methyl ester (intermediate 53-2) Under a nitrogen atmosphere, intermediate 53-1 (200 mg), 2-methoxyphenylboronic acid (247 mg), KCO (291 mg), and Pd(dppf)Cl (51 mg) were dissolved in 1,4-dioxane (3 mL) and stirred at 90 °C for 3 h. The reaction mixture was concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give the title compound (208 mg).

[0498] MS m / z(ESI):=312.2 [M+H] + . Step 2: Synthesis of 5-(2-methoxyphenyl)-2-(trifluoromethyl)pyridine-4-carboxylic acid (Intermediate 53-3) Intermediate 53-2 (200 mg) was dissolved in methanol (3 mL), and a solution of lithium hydroxide (140 mg of lithium hydroxide dissolved in 2 mL of water) was added. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to dryness, and the aqueous phase was adjusted to pH 3 with dilute hydrochloric acid. The precipitated solid was filtered, and the filter cake was dried to give the title compound (153 mg).

[0499] MS m / z(ESI):=296.2 [M−H] - .

[0500] Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5-(2-methoxyphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide (compound 53) Intermediate 53-3 (20 mg) was dissolved in N,N-dimethylformamide (2 mL), HATU (38 mg), and DIEA (35 mg) were added, and the mixture was stirred at room temperature for 0.5 h. Intermediate 16-3 (22 mg) was then added and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (YMC-Actus Triart C18 column, 5 μm silica, 30 mm diameter, 150 mm length, eluting with a decreasing polarity mixture of water (containing 0.225% formic acid) and acetonitrile, with an acetonitrile gradient of 40% to 70%, for 15 min) to obtain the title compound (25 mg).

[0501] MS m / z(ESI):=531.1 [MH] - . 1 H NMR(400MHz,DMSO-d6)δ 13.71(s,1H),9.28(s,1H),8.83(s,1H),8.36(d,J=8.2Hz,2H),8.30(s,1H),8.00(d,J =8.2Hz,2H),7.55-7.45(m,2H),7.18-7.08(m,1H),7.04(d,J=8.2Hz,1H),3.55(s,3H).

[0502] Example 54: N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-fluoro-5-(2-methoxyphenyl)pyridine-4-carboxamide (Compound 54) [ka]

[0503] Step 1: Synthesis of 3-fluoro-5-(2-methoxyphenyl)pyridine-4-carboxylic acid methyl ester (Intermediate 54-2) Intermediate 54-1 (200 mg), 2-methoxyphenylboronic acid (247 mg), potassium carbonate (352 mg), and Pd(dppf)Cl (62 mg) were dissolved in 1,4-dioxane (3 mL) and stirred at 90 °C for 3 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give the title compound (220 mg).

[0504] MS m / z(ESI):=262.2 [M+H] + .

[0505] Step 2: Synthesis of 3-fluoro-5-(2-methoxyphenyl)pyridine-4-carboxylic acid (Intermediate 54-3) Intermediate 54-2 (210 mg) was dissolved in methanol (3 mL), and a solution of lithium hydroxide (170 mg) in water (1 mL) was added. The mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure to dryness, and the aqueous phase was adjusted to pH 3 with dilute hydrochloric acid. The precipitated solid was filtered, and the filter cake was dried to give the title compound (180 mg).

[0506] MS m / z(ESI):=246.2 [M−H] - .

[0507] Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3-fluoro-5-(2-methoxyphenyl)pyridine-4-carboxamide (compound 54) Intermediate 54-3 (20 mg) was dissolved in N,N-dimethylformamide (2 mL), HATU (45 mg), and DIEA (42 mg) were added, and the mixture was stirred at room temperature for 0.5 h. Intermediate 16-3 (29 mg) was then added and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The ethyl acetate phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18 column, 5 μm silica, 30 mm diameter, 150 mm length, eluting with a decreasing polarity mixture of water (containing 0.225% formic acid) and acetonitrile, 40% to 70% acetonitrile gradient, 15 min) to obtain the title compound (15 mg).

[0508] MS m / z(ESI):=483.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ=13.80(s,1H),9.22(s,1H),8.70(s,1H),8.48(s,1H),8.35(d, J=8.1Hz,2H),7.98(d,J=8.1Hz,2H),7.45-7.31(m,2H),7.10-6.95(m,2H),3.61(s,3H).

[0509] Example 55: N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-methoxy-[1,1'-biphenyl]-2-carboxamide (Compound 55) [ka]

[0510] Step 1: Synthesis of 2'-methoxy-[1,1'-biphenyl]-2-carboxylic acid methyl ester (intermediate 55-3) Intermediate 55-1 (1 g), Intermediate 55-2 (1.42 g), Pd(dppf)Cl (343 mg), and potassium phosphate (1.98 g) were added to dioxane (10 mL) and water (2 mL). The reaction mixture was stirred at 90 °C for 18 h under a nitrogen atmosphere. After cooling, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with water (40 mL x 2), saturated brine (40 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (1.0 g).

[0511] MS m / z(ESI):=243.1 [M+H] + .

[0512] Step 2: Synthesis of 2'-methoxy-[1,1'-biphenyl]-2-carboxylic acid (intermediate 55-4) Intermediate 55-3 (1.0 g) was dissolved in methanol (10 mL), and a solution of potassium hydroxide (3.0 g) in water (10 mL) was added. The reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was concentrated under reduced pressure to dryness, and 30 mL of 1 M HCl aqueous solution was added in an ice-water bath to adjust the pH to 6. The mixture was extracted with ethyl acetate (30 mL * 3). The organic layers were combined, washed with saturated brine (20 mL * 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness to give the title compound (900 mg).

[0513] MS m / z(ESI):=229.1 [M+H] + . Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-methoxy-[1,1'-biphenyl]-2-carboxamide (compound 55) Intermediate 55-4 (40 mg), HATU (66 mg), and DIEA (45 mg) were added to DMF (1 mL) and the reaction mixture was stirred at 25 °C for 2 h. Intermediate 16-3 (44 mg) was added and the reaction mixture was stirred at 25 °C for 18 h. The reaction mixture was poured into water and extracted with ethyl acetate (5 mL * 3). The organic layers were combined, washed with saturated brine (10 mL * 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness. The residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini NX C18 3.5 μm * 4.6 * 100 mm, mobile phase: A: 0.05% TFA v / v, B: acetonitrile, B%: 10% to 90%, 10 min) to obtain the title compound (11.9 mg).

[0514] MS m / z(ESI):464.1 [M+H] + .

[0515] 1 H NMR(400MHz,DMSO-d6)δ 13.24(s,1H),9.33(s,1H),8.41-8.34(m,2H),8.05-7.98(m,2H),7.80-7.73(m,1H),7.71-7.62(m,1H),7. 58-7.49(m,1H),7.46-7.39(m,1H),7.39-7.29(m,2H),7.11-7.03(m,1H),6.98-6.91(m,1H),3.51(s,3H).

[0516] Example 56: N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-(2-methoxyphenyl)benzo[d][1,3]dioxole-5-carboxamide (Compound 56) [ka]

[0517] Step 1: Synthesis of 6-(2-methoxyphenyl)benzo[d][1,3]dioxole-5-carboxylic acid methyl ester (intermediate 56-2) Under a nitrogen atmosphere, intermediate 56-1 (400 mg), o-methoxyphenylboronic acid (280 mg), Pd(dppf)Cl (400 mg), and potassium carbonate (426 mg) were dissolved in dioxane (5 mL) and water (1 mL) and stirred at 100 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 2:1) to give the title compound (200 mg). MS m / z(ESI):=287.1 [M+H] +

[0518] Step 2: Synthesis of 6-(2-methoxyphenyl)benzo[d][1,3]dioxole-5-carboxylic acid (Intermediate 56-3) Intermediate 56-2 (100 mg) was dissolved in MeOH (1 mL) and water (0.2 mL), lithium hydroxide (42 mg) was added, and the mixture was stirred at 60° C. for 8 h. Hydrochloric acid (2 M) was added dropwise to the reaction mixture to adjust the pH to 6, and the mixture was extracted with ethyl acetate (5 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and then concentrated to dryness under reduced pressure to give the title compound (70 mg). MS m / z(ESI):=271.1 [MH] -

[0519] Step 3: Synthesis of 3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl 6-(2-methoxyphenyl)benzo[d][1,3]dioxole-5-carboxylic acid ester (Intermediate 56-4) Intermediate 56-3 (65 mg) was dissolved in DMF (1 mL), DIEA (62 mg) and HATU (99 mg) were added, and the mixture was stirred at 20 ° C for 8 h. The reaction mixture was diluted with DMF (1 mL) and then purified by preparative high-performance liquid chromatography (chromatography column: Gemini NX C18 5 μm * 10 * 150 mm, mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile, B%: 30% to 50%, 11 min) to obtain the title compound (20 mg).

[0520] MS m / z(ESI):=391.1 [M+H] + .

[0521] Step 4: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-(2-methoxyphenyl)benzo[d][1,3]dioxole-5-carboxamide (compound 56) Intermediate 56-4 (17.0 mg) and intermediate 16-3 (11.0 mg) were dissolved in DMF (0.5 mL). NaH (3.5 mg, 60% wt) was added at 0 °C, and the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was quenched with saturated ammonium chloride (5 mL) and extracted with ethyl acetate (5 mL * 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The organic phase was concentrated to dryness under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (chromatography column: Gemini NX C18 5 μm * 10 * 150 mm, mobile phase: A: water (0.225% formic acid v / v), B: acetonitrile, B%: 30% ~ 50%, 11 min) to obtain the title compound (8.0 mg).

[0522] MS m / z(ESI):508.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 13.06(s,1H),9.32(s,1H),8.42-8.33(m,2H),8.07-7.96(m,2H),7.39-7.24(m,3H),7.04 -7.00(m,1H),6.99-6.88(m,2H),6.18(s,2H),3.51(s,3H).

[0523] Example 57: N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (Compound 57) [ka]

[0524] Step 1: Synthesis of (E)-5-bromo-2-(((dimethylamino)methylene)amino)pyridine-4-carboxylic acid methyl ester (Intermediate 57-2) Intermediate 57-1 (1.3 g) was dissolved in isopropyl alcohol (20 mL), and DMF-DMA (2.0 g, 5 mL) was added. After the addition was completed, the mixture was stirred at 80°C for 3 h to react, and the reaction solution was concentrated under reduced pressure to dryness to give the title compound (1.6 g).

[0525] MS m / z(ESI):=286.1[M+H] + .

[0526] Step 2: Synthesis of (E)-5-bromo-2-(N'-hydroxyformimidoamino)pyridine-4-carboxylic acid methyl ester (Intermediate 57-3) Hydroxylamine hydrochloride (606 mg) and intermediate 57-2 (1.20 g) were dissolved in isopropyl alcohol (20 mL) and reacted with stirring for 16 h at 50° C. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was slurried with ethyl acetate (10 mL), filtered, and the filter cake was dried to give the title compound (710 mg).

[0527] MS m / z(ESI):=274.1 [M+H] + .

[0528] Step 3: Synthesis of 6-bromo-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid methyl ester (intermediate 57-4) Intermediate 57-3 (550 mg) was dissolved in tetrahydrofuran (15 mL), and trifluoroacetic anhydride (463 mg) was slowly added dropwise at 0° C. The reaction mixture was stirred at 40° C. for 4 h. The reaction mixture was concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=10:1) to give the title compound (200 mg).

[0529] MS m / z(ESI):=256.1[M+H] + .

[0530] Step 4: Synthesis of 6-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid methyl ester (Intermediate 57-5) Under a nitrogen atmosphere, 2-methoxyphenylboronic acid (178 mg) in 1,4-dioxane (3 mL) was added to intermediate 57-4 (150 mg), K2CO3 (242 mg), and Pd(dppf)Cl2 (42 mg), in that order, and stirred at 100 °C for 3 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL * 3). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to give the title compound (150 mg).

[0531] MS m / z(ESI):284.2[M+H] + .

[0532] Step 5: Synthesis of 6-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid (Intermediate 57-6) Intermediate 57-5 (120 mg) was dissolved in tetrahydrofuran (3 mL), and a solution of lithium hydroxide (30 mg) in water (1 mL) was added. The mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to dryness, and the aqueous phase was adjusted to pH 4 with dilute hydrochloric acid. The precipitated solid was filtered, and the filter cake was dried to give the title compound (75 mg).

[0533] MS m / z(ESI):=270.2 [M+H] + .

[0534] Step 6: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide (compound 57) Intermediate 57-6 (60 mg) was dissolved in N,N-dimethylformamide (2 mL), HATU (126 mg), and DIEA (58 mg) were added, and the mixture was stirred at room temperature for 0.5 h. Intermediate 16-3 (84 mg) was then added. After the addition was complete, the mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL). The ethyl acetate phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative high-performance liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm diameter, 150 mm length, eluting with a decreasingly polar mixture of water (containing 0.225% formic acid) and acetonitrile, 40% to 70% acetonitrile gradient, 15 min) to obtain the title compound (11 mg).

[0535] MS m / z(ESI):=505.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 13.67(s,1H),9.37(s,1H),9.05(s,1H),8.70(s,1H),8.43-8.36(m,2H),8.34(s,1H),8.02(d,J=8.4 Hz,2H),7.55-7.49(m,1H),7.45-7.35(m,1H),7.18-7.08(m,1H),6.99(d,J=8.2Hz,1H),3.52(s,3H).

[0536] Example 58: 4-(5-cyano-2-methoxyphenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 58) [ka]

[0537] Intermediate 22-3 (53.65 mg) was dissolved in DMF (3 mL), HATU (98.1 mg) and DIEA (77.53 mg) were added, and the reaction mixture was stirred at room temperature for 1 hour. Intermediate 16-3 (101.3 mg) was then added, and the mixture was stirred at room temperature for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to dryness and slurried with methanol to give the title compound (20 mg).

[0538] MS m / z(ESI):=504.1 [M+H] + .

[0539] 1 H NMR(400MHz,DMSO-d6)δ 9.34(s,1H),8.85(s,1H),8.42-8.36(m,2H),8.06-7.99(m,2H),7.96- 7.89(m,2H),7.45(s,1H),7.22-7.14(m,1H),3.61(s,3H),2.61(s,3H)

[0540] Example 59, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-ethynylphenyl)-2-methylpyrimidine-5-carboxamide (Compound 59) [ka]

[0541] Step 1: Synthesis of 2-methyl-4-(2-((trimethylsilyl)ethynyl)phenyl)pyrimidine-5-carboxylic acid ethyl ester (intermediate 59-3) Under a nitrogen atmosphere, intermediate 59-1 (1.0 g) was dissolved in dioxane (10 mL), and intermediate 59-2 (0.87 g), potassium carbonate (0.92 g), water (1 mL), and dichloro[1,1'-bis(di-tert-butylphosphine)ferrocenepalladium(II)] (0.22 g) were added. After the addition was complete, the mixture was heated to 70 °C and stirred for 2 h. The reaction mixture was filtered, ethyl acetate (10 mL) was added, and the mixture was extracted with water (10 mL). The organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give the title compound (380 mg).

[0542] MS m / z(ESI):=339.1 [M+H] + .

[0543] Step 2: Synthesis of 4-(2-ethynylphenyl)-2-methylpyrimidine-5-carboxylic acid (intermediate 59-4) Intermediate 59-3 (100 mg) was dissolved in ethanol (1 mL), sodium hydroxide (23.6 mg) and water (0.3 mL) were added, and the mixture was heated to 60° C. and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to dryness, and water (60 mL) was added to dissolve the mixture. The pH was adjusted to 4 with 1 M HCl, filtered, and the filter cake was dried to give the title compound (20.0 mg).

[0544] MS m / z(ESI):=239.1 [M+H] - .

[0545] Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-ethynylphenyl)-2-methylpyrimidine-5-carboxamide (compound 59) Intermediate 59-4 (12.0 mg) was dissolved in anhydrous N,N-dimethylformamide (1 mL), HATU (19.0 mg) and DIEA (13.0 mg) were added, and the mixture was stirred at room temperature for 2 h after the addition was complete. Intermediate 16-3 (21.3 mg) was added, and the mixture was stirred at room temperature for 12 h after the addition was complete. The reaction mixture was purified by high-pressure preparative liquid chromatography (YMC-Actus Triart C18 column, 5 μm silica, 30 mm diameter, 150 mm length, eluting with a decreasing polarity mixture of water (containing 0.05% NH4HCO3) and acetonitrile, with an acetonitrile gradient from 55% to 80%, and elution time of 13 min) to give the title compound (4.0 mg).

[0546] MS m / z(ESI):=474.0 [M+H] + .

[0547] 1 H NMR(400MHz,DMSO-d6)δ 9.31(s,1H),9.23(s,1H),8.38-8.36(m,2H),8.02-7.99(m,2H),7.57-7.50(m,4H),4.02(s,1H),2.77(s,3H).

[0548] Example 60: N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyridin-2-yl)-4-(2-ethynylphenyl)-6-methylpyridine-3-carboxamide (Compound 60) [ka]

[0549] Step 1: Synthesis of tert-butyl (6-chlorothiazolo[4,5-b]pyridin-2-yl)carbamate (Intermediate 60-2) Intermediate 60-1 (100 mg), BocO (129 mg), and DMAP (13 mg) were dissolved in DCM (3 mL) and stirred at 20 °C for 1 h. Ethyl acetate (10 mL) and water (20 mL) were added to the reaction mixture, and the organic phase was washed with water (10 mL * 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (130 mg).

[0550] MS m / z(ESI):=286.1 [M+H] + .

[0551] Step 2: Synthesis of tert-butyl (6-(4-cyanophenyl)thiazolo[4,5-b]pyridin-2-yl)carbamate (Intermediate 60-3) Under a nitrogen atmosphere, intermediate 60-2 (120 mg), Pd(dtbpf)Cl (57 mg), potassium carbonate (174 mg), and 4-cyanophenylboronic acid (123 mg) were dissolved in dioxane (2 mL) and water (0.5 mL), heated to 70 °C, and stirred for 16 h. The reaction mixture was cooled to room temperature, quenched by adding water (20 mL), extracted with ethyl acetate (20 mL * 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using EA / PE = (10:1) to give the title compound (90 mg).

[0552] MS m / z(ESI):=353.2 [M+H] + .

[0553] Step 3: Synthesis of 4-(2-aminothiazolo[4,5-b]pyridin-6-yl)benzonitrile (Intermediate 60-4) Intermediate 60-3 (80 mg) was dissolved in hydrogen chloride in ethyl acetate (4 M, 5 mL) and stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to dryness, and the residue was purified by silica gel column chromatography (DCM / MeOH=10:1) to give the title compound (45 mg).

[0554] MS m / z(ESI):=253.0 [M+H] + .

[0555] Step 4: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyridin-2-yl)-4-(2-ethynylphenyl)-6-methylpyridine-3-carboxamide (Compound 60) Intermediate 60-4 (30 mg), intermediate 42-3 (28 mg), DIEA (31 mg), and HATU (40 mg) were dissolved in DMF (1 mL) and heated to 80 °C and stirred for 16 h. The reaction mixture was cooled to room temperature, quenched with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative HPLC (YMC-Actus Triart C18 column, 5 μm silica, 30 mm diameter, 150 mm length, eluting with a decreasingly polar mixture of water (containing 0.05% NH4HCO3) and acetonitrile, 30% to 80% acetonitrile gradient, 20 min) to give the title compound (3.8 mg).

[0556] MS m / z(ESI):=472.0 [M+H] + .

[0557] 1 H NMR(400MHz,DMSO-d6)δ 13.32(s,1H),8.98(s,1H),8.90(s,1H),8.73(s,1H),8.05-7.90(m,4H),7.57-7.51(m, 1H),7.51-7.46(m,1H),7.45-7.38(m,1H),7.37-7.30(m,2H),3.97(s,1H),2.59(s,3H).

[0558] Example 61, N-(6-(5-cyanopyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 61) [ka]

[0559] Intermediate 26-3 (100 mg) was dissolved in N,N-dimethylformamide (5 mL) at 20 °C, and intermediate 20-4 (76.72 mg), HATU (104.68 mg), and N,N-diisopropylethylamine (71.16 mg) were added to the reaction solution. The reaction solution was stirred at 45 °C for 2 hours. After the reaction was completed, the reaction solution was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 μm, mobile phase: A: water (0.05% ammonia water), B: acetonitrile, B%: 20% to 40%, 11 minutes) to obtain the title compound (6.2 mg).

[0560] 1 H NMR(400MHz,DMSO-d6)δ=13.85-13.59(m,1H),9.57(s,1H),9.18(s,1H),8.93(s,1H),8.55-8. 51(m,1H),8.50-8.46(m,1H),8.18(s,1H),7.61(s,1H),7.48(s,1H),3.64(s,3H),2.62(s,3H) MS m / z(ESI):=515.1 [M+H] + .

[0561] Example 62, N-(6-(5-chloropyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylpyridine-3-carboxamide (Compound 62) [ka]

[0562] Step 1: Synthesis of tert-butyl (6-(5-chloropyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 62-2) At 25°C, intermediate 16-1 (3 g), intermediate 62-1 (1.74 g), 6,6'-dimethyl-2,2'-bipyridine (166.89 mg), tetrabutylammonium iodide (5.02 g), manganese powder (1.99 g), and nickel iodide (283.07 mg) were dissolved in N,N-dimethylacetamide (150 mL). The reaction mixture was stirred at 100°C for 16 hours under a nitrogen gas atmosphere. After the reaction was completed, dichloromethane (150 mL) and methanol (20 mL) were added thereto. The mixture was filtered, and the organic phase was concentrated under reduced pressure to dryness. Water (200 mL) was added to the residual liquid, which was then filtered. The filter cake was dried to obtain the title compound (1 g).

[0563] MS m / z(ESI):=363.9 [M+H] + .

[0564] Step 2: Synthesis of 6-(5-chloropyridin-2-yl)thiazolo[4,5-b]pyrazin-2-amine (Intermediate 62-3) Intermediate 62-2 (1 g) was dissolved in dichloromethane (10 mL) at 20° C., and then trifluoroacetic acid (2.04 mL) was added to the reaction solution, and the reaction solution was stirred for 2 hours at 25° C. After the reaction was completed, the mixture was concentrated under reduced pressure to dryness, and saturated sodium bicarbonate solution was added to the residue to neutralize the remaining trifluoroacetic acid, followed by filtration to obtain the title compound (700 mg).

[0565] MS m / z(ESI):=264.1 [M+H] + .

[0566] Step 3: Synthesis of N-(6-(5-chloropyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-cyano-2-methoxyphenyl)-6-methylpyridine-3-carboxamide (compound 62) Intermediate 22-3 (100 mg) was dissolved in N,N-dimethylformamide (1.5 mL) at 20 °C, and HATU (141.74 mg), N,N-diisopropylethylamine (144.53 mg), and intermediate 62-3 (117.96 mg) were added to the reaction solution. The reaction solution was stirred at 25 °C for 2 hours. After the reaction was completed, ethyl acetate (50 mL) and water (100 mL) were added, and the mixture was extracted with ethyl acetate (25 mL x 3 times). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.05% aqueous ammonia), B: acetonitrile, B%: 45% to 65%, 11 min) to obtain the title compound (30 mg).

[0567] 1 H NMR(400MHz,DMSO-d6)δ=13.61-13.43(m,1H),9.52(s,1H),8.84(s,1H),8.82-8.78(m,1H),8.42-8.37(m, 1H),8.15-8.11(m,1H),7.96-7.91(m,2H),7.49-7.46(m,1H),7.22-7.16(m,1H),3.61(s,3H),2.62(s,3H) MS m / z(ESI):=514.1 [M+H] +

[0568] Example 63, N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-cyano-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 63) [ka]

[0569] Step 1: Synthesis of 2'-cyano-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (intermediate 63-1) Intermediate 20-3 (400 mg) was dissolved in N,N-dimethylacetamide (5 mL) at 20 °C. Zinc cyanide (208.60 mg), zinc powder (17.87 mg), tris(dibenzylideneacetone)dipalladium (37.54 mg), and 1,1-bis(diphenylphosphine)ferrocene (37.88 mg) were added to the reaction mixture. The reaction mixture was stirred at 110 °C for 1 hour under a nitrogen atmosphere. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (380 mg).

[0570] MS m / z(ESI):=284.2 [M+H] + .

[0571] Step 2: Synthesis of 2'-cyano-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (intermediate 63-2) At 20°C, intermediate 63-1 (380 mg) was dissolved in a tetrahydrofuran (3 mL) / water (3 mL) solution, and lithium hydroxide (64.25 mg) was added to the reaction solution. The reaction solution was stirred at 20°C for 4 hours. After the reaction was completed, the reaction solution was adjusted to pH 4 with dilute hydrochloric acid, water (5 mL) was added thereto, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated under reduced pressure to dryness, yielding the title compound (350 mg).

[0572] MS m / z(ESI):=270.1 [M+H] + .

[0573] Step 3: Synthesis of N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-cyano-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (compound 63) Intermediate 63-2 (150 mg) was dissolved in N,N-dimethylformamide (3 mL) at 20 ° C., and intermediate 17-2 (73.18 mg), HATU (211.82 mg), and N,N-diisopropylethylamine (72.00 mg) were added to the reaction solution. The reaction solution was stirred at 45 ° C. for 4 hours. After the reaction was completed, the reaction solution was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 um, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 53% to 73%, 11 minutes) to obtain the title compound (65.5 mg).

[0574] 1 H NMR(400MHz,DMSO-d6)δ=13.55(s,1H),9.27(s,1H),8.93(s,1H),8.58(s,1H),8.2 5-8.17(m,3H),7.62(d,J=8.4Hz,2H),7.56-7.51(m,1H),3.76(s,3H),2.64(s,3H) MS m / z(ESI):=514.0 [M+H] + .

[0575] Example 64, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-ethynyl-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 64) [ka]

[0576] Step 1: Synthesis of (2,5-dichloropyridin-4-yl)boronic acid (intermediate 64-2) Intermediate 64-1 (7.0 g) was dissolved in anhydrous tetrahydrofuran (120 mL) and cooled to -78 °C. Under a nitrogen atmosphere, a tetrahydrofuran solution of lithium diisopropylamide (47.30 mL, 2 M) was slowly added to the reaction mixture. The reaction mixture was stirred at -78 °C for 1 h under a nitrogen atmosphere. Triisopropyl borate (17.79 g) was then slowly added to the reaction mixture. After the reaction was complete, the reaction mixture was quenched with water (20 mL). After extraction with ethyl acetate (50 mL * 3), the organic phase was concentrated under reduced pressure to dryness. 30 mL of petroleum ether:ethyl acetate (1:1) was added to the residue, stirred at room temperature for 30 minutes, filtered, and the filter cake was dried to obtain the title compound (7.0 g).

[0577] MS m / z(ESI):191.8 [M+H] + .

[0578] Step 2: Synthesis of 2',5'-dichloro-6-methyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (intermediate 64-3) Intermediate 64-2 (1.00 g) and Intermediate 42-1 (1.20 g) were dissolved in dioxane (10 mL) and water (2 mL), and potassium phosphate (2.21 g) was added. Under a nitrogen atmosphere, (1,1'-bis(diphenylphosphine)ferrocene)dichloropalladium (381.48 mg) was added to the reaction mixture. The reaction mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 12 g SepaFlash® flash silica gel column, gradient 0-25% tetrahydrofuran / petroleum ether, flow rate 60 mL / min) to obtain the title compound (490.0 mg).

[0579] MS m / z(ESI):296.9 [M+H] + .

[0580] Step 3: Synthesis of 5'-chloro-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (intermediate 64-5) Intermediate 64-3 (490 mg) and Intermediate 64-4 (455.43 mg) were dissolved in monoethylene glycol dimethyl ether (5 mL), potassium carbonate (455.43 mg) was added, and the reaction mixture was stirred under a nitrogen atmosphere at 110 °C for 2 h. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 12 g SepaFlash® flash silica gel column, gradient 0-40% tetrahydrofuran / petroleum ether, flow rate 50 mL / min) to obtain the title compound (350.0 mg).

[0581] MS m / z (ESI): 277.0 [M + H] + .

[0582] Step 4: Synthesis of 2',6-dimethyl-5'-((triisopropylsilyl)ethynyl)-[4,4'-bipyridine]-3-carboxylic acid methyl ester (Intermediate 64-7) Intermediate 64-5 (200 mg) and Intermediate 64-6 (263.63 mg) were dissolved in acetonitrile (2 mL), and cesium carbonate (612.27 mg) was added. Under a nitrogen atmosphere, chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (56.87 mg) was added. The reaction mixture was stirred at 90 °C for 1 h under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 12 g SepaFlash® flash silica gel column, gradient 0-30% tetrahydrofuran / petroleum ether, flow rate 50 mL / min) to obtain the title compound (200 mg).

[0583] MS m / z(ESI):423.2 [M+H] + .

[0584] Step 5: Synthesis of 5'-ethynyl-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid (intermediates 64-8) Intermediate 64-7 (200 mg) was dissolved in anhydrous methanol (2 mL), and cesium fluoride (79.07 mg) was added thereto. The reaction mixture was stirred at 65°C for 16 h. After cooling to room temperature, a solution of sodium hydroxide (56.78 mg) in water (0.5 mL) was added thereto, and the reaction mixture was stirred at 25°C for 3 h. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to dryness. 10 mL of dichloromethane:methanol (10:1) was added to the residue, and the mixture was stirred for 10 min. The mixture was filtered. The filtrate was concentrated under reduced pressure, and the solvent was removed to give the title compound (100 mg).

[0585] MS m / z (ESI): 253.0 [M + H] + .

[0586] Step 6: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-ethynyl-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (compound 64) Intermediate 64-8 (100.00 mg) was dissolved in anhydrous N,N-dimethylformamide (2 mL), and HATU (165.80 mg) and N,N-diisopropylethylamine (153.70 mg) were added. The reaction mixture was stirred under a nitrogen atmosphere for 30 min. Intermediate 16-3 (110.44 mg) was then added, and the mixture was stirred at 25 °C for 1 h under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was filtered and purified by preparative high-performance liquid chromatography (C18-1 column, 5 μm particle size, 30 mm diameter, 150 mm length, elution with water (containing 0.225% formic acid) and acetonitrile, with a gradient of 15% to 55% acetonitrile, for 9 min) to obtain the title compound (16 mg).

[0587] MS m / z(ESI):488.1 [M+H]+.

[0588] 1 H NMR(400MHz,DMSO-d6)δ=13.70(s,1H),9.34(s,1H),9.06(s,1H),8.58(s,1H),8.38(d,J=8.5H z,2H),8.02(d,J=8.5Hz,2H),7.40(s,1H),7.37(s,1H),4.15(s,1H),2.63(s,3H),2.57(s,3H)

[0589] Example 65, N-(6-(5-chloropyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-2'-cyano-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 65) [ka]

[0590] Intermediate 63-2 (150 mg) was dissolved in N,N-dimethylformamide (2 mL) at 20 °C, and intermediate 62-3 (146.91 mg), HATU (211.82 mg), and N,N-diisopropylethylamine (144.00 mg) were added to the reaction solution. The reaction solution was stirred at 40 °C for 6 hours. After the reaction was completed, the reaction solution was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 um, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 48% to 68%, 11 minutes) to obtain the title compound (40 mg).

[0591] 1 H NMR(400MHz,DMSO-d6)δ=13.61(s,1H),9.50(s,1H),8.93(s,1H),8.78(s,1H),8.57(s,1H),8.37(d,J=8.3Hz,1H),8.20(s,1H),8.15 - 8.08(m,1H),7.52(s,1H),3.76(s,3H),2.63(s,3H) MS m / z(ESI):=515.0 [M+H] + .

[0592] Example 66, N-(6-(5-chloropyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 66) [ka]

[0593] Intermediate 21-3 (100 mg) was dissolved in N,N-dimethylformamide (1.5 mL) at 20 °C, and HATU (147.22 mg), N,N-diisopropylethylamine (150.12 mg), and intermediate 62-3 (122.52 mg) were added to the reaction solution. The reaction solution was stirred at 25 °C for 2 hours. After the reaction was completed, ethyl acetate (50 mL) and water (100 mL) were added to the solution, and the mixture was extracted with ethyl acetate (25 mL x 3 times). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.05% ammonia water), B: acetonitrile, B%: 28% to 48%, 11 min) to obtain the title compound (25 mg).

[0594] 1 H NMR(400MHz,DMSO-d6)δ=13.68-13.54(m,1H),9.52(s,1H),8.86(s,1H),8.80(d,J=2.2Hz,1H),8.39(d,J=8. 7Hz,1H),8.22(s,1H),8.13(dd,J=2.4,8.6Hz,1H),7.44(s,1H),7.41-7.37(m,1H),3.61(s,3H),2.62(s,3H). MS m / z(ESI):=504.1 [M+H] + .

[0595] Example 67, N-(6-(4-chlorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 67) [ka]

[0596] Intermediate 21-3 (200 mg) was dissolved in N,N-dimethylformamide (2 mL) at 20 ° C., and intermediate 17-2 (235.94 mg), HATU (347.35 mg), and N,N-diisopropylethylamine (196.78 mg) were added to the reaction solution. The reaction solution was stirred at 70 ° C. for 6 hours. After the reaction was completed, the reaction solution was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 um, mobile phase: A: water (0.05% ammonia water), B: acetonitrile, B%: 23% to 43%, 11 minutes) to obtain the title compound (130 mg).

[0597] 1 H NMR(400MHz,DMSO-d6)δ=13.49(s,1H),9.24(s,1H),8.84(s,1H),8.23-8.17(m, 3H),7.61(d,J=8.6Hz,2H),7.42(s,1H),7.33(s,1H),3.59(s,3H),2.61(s,3H). MS m / z(ESI):=503.1 [M+H] + .

[0598] Example 68, N-[6-[5-(1-cyano-1-methyl-ethyl)pyridin-2-yl]thiazolo[4,5-b]pyrazin-2-yl]-4-(5-methoxy-2-methylpyridin-4-yl)-6-methyl-pyridine-3-carboxamide (Compound 68) [ka]

[0599] Step 1: Synthesis of tert-butyl N-[6-[5-(1-cyano-1-methyl-ethyl)pyridin-2-yl]thiazolo[4,5-b]pyrazin-2-yl]carbamate (Intermediate 68-2) Intermediate 16-1 (1.5 g) was dissolved in N,N-dimethylacetamide (15 mL) at 25 °C. To the reaction mixture was added Intermediate 68-1 (1.02 g), tetrabutylammonium iodide (2.51 g), nickel(II) chloride ethylene glycol dimethyl ether complex (199.03 mg), 2,2'-bipyridine (70.74 mg), and manganese powder (995.29 mg). The reaction mixture was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After the reaction was complete, dichloromethane (250 mL) and methanol (25 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to dryness. Water (50 mL) was added to the residue, and the mixture was extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (ISCO®, 40 g SepaFlash® Silica Flash chromatography column, gradient 0-45% tetrahydrofuran / dichloromethane @ 30 mL / min) to give the title compound (106 mg).

[0600] MS m / z (ESI): 397.0 [M + H] + .

[0601] Step 2: Synthesis of 2-[6-(2-aminothiazolo[4,5-b]pyrazin-6-yl)pyridin-3-yl]-2-methyl-propionitrile (Intermediate 68-3) At 25°C, intermediate 68-2 (100 mg) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (28.76 mg) was added to the reaction solution. The reaction solution was stirred at 20°C for 2 hours. After the reaction was completed, it was concentrated under reduced pressure to dryness. Water (1 mL) was added to the residue, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was filtered, and the filter cake was dried to obtain the title compound (65 mg).

[0602] MS m / z(ESI):297.3 [M+H] + .

[0603] Step 3: Synthesis of N-[6-[5-(1-cyano-1-methyl-ethyl)pyridin-2-yl]thiazolo[4,5-b]pyrazin-2-yl]-4-(5-methoxy-2-methylpyridin-4-yl)-6-methyl-pyridine-3-carboxamide (compound 68) Intermediate 68-3 (65 mg) was dissolved in N,N-dimethylformamide (4 mL) at 25 ° C., and intermediate 21-3 (56.65 mg), HATU (83.40 mg), and N,N-diisopropylethylamine (56.69 mg) were added to the reaction solution. The reaction solution was stirred at 20 ° C. for 16 hours. After the reaction was completed, the reaction solution was purified by preparative high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 μm, mobile phase: [A: water (0.225% formic acid), B: acetonitrile], B%: 23% to 43%, 11 minutes) to obtain the title compound (36.96 mg).

[0604] MS m / z(ESI):537.2 [M+H] + .

[0605] 1 H NMR(400MHz,DMSO-d6)δ 13.57(s,1H),9.55(s,1H),8.92(d,J=2.2Hz,1H),8.85(s,1H),8.42(d,J=8.4Hz,1H),8.20(s,1 H),8.15(dd,J=2.4,8.4Hz,1H),7.44(s,1H),7.34(s,1H),3.60(s,3H),2.62(s,3H),1.80(s,6H)

[0606] Example 69, N-(6-(tetrahydrofuran-3-yl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 69) [ka]

[0607] Step 1: Synthesis of tert-butyl N-(6-tetrahydrofuran-3-ylthiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 69-2) Intermediate 16-1 (2 g) was dissolved in N,N-dimethylacetamide (120 mL), and intermediate 69-1 (3.59 g), nickel iodide (377.43 mg), 4,4'-di-tert-butyl-2,2'-bipyridine (324.16 mg), and manganese powder (1.16 g) were added to the reaction solution. The reaction solution was stirred at 100 °C for 16 hours under a nitrogen atmosphere. After the reaction was completed, dichloromethane (250 mL) and methanol (25 mL) were added, filtered, and the filtrate was concentrated under reduced pressure to dryness. Water (50 mL) was added to the residue, and the mixture was extracted with dichloromethane (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure and the residue was purified by silica gel column chromatography (ISCO®, 80 g SepaFlash® Silica Flash chromatography column, gradient 0-15% tetrahydrofuran / dichloromethane @ 60 mL / min) to give the title compound (250 mg).

[0608] MS m / z(ESI):322.9 [M+H] + .

[0609] Step 2: Synthesis of 6-(tetrahydrofuran-3-yl)thiazolo[4,5-b]pyrazin-2-amine (Intermediate 69-3) At 25°C, intermediate 69-2 (250 mg) was dissolved in dichloromethane (4 mL), and trifluoroacetic acid (7.70 g) was added to the reaction solution. The reaction solution was stirred at 25°C for 2 hours. After the reaction was completed, it was concentrated under reduced pressure to dryness. Water (1 mL) was added to the residue, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The mixture was filtered, and the filter cake was dried to obtain the title compound (560 mg).

[0610] MS m / z(ESI):223.2 [M+H] + .

[0611] Step 3: Synthesis of N-(6-(tetrahydrofuran-3-yl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (compound 69) Intermediate 69-3 (68.85 mg) was dissolved in N,N-dimethylformamide (4 mL) at 25 °C, and intermediate 21-3 (80 mg), HATU (117.78 mg), and N,N-diisopropylethylamine (80.06 mg) were added to the reaction solution. The reaction solution was stirred at 25 °C for 16 hours. After the reaction was completed, the reaction solution was purified by preparative high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 um, mobile phase: [A: water (0.225% formic acid), B: acetonitrile], B%: 13% to 33%, 11 minutes) to obtain the title compound (40 mg).

[0612] Compound 69 was separated by supercritical fluid chromatography (DAICEL CHIRALCEL OJ column, 10 μm silica, 30 mm diameter, 250 mm length, ethanol (containing 0.1% aqueous ammonia) as the eluent) to give compound 69-P1 (12.64 mg, RT = 4.958 min) and compound 69-P2 (8.57 mg, RT = 5.209 min). Compound 69-P1: MS m / z(ESI):463.1 [M+H] + .

[0613] 1 H NMR(400MHz,DMSO-d6)δ 13.38(s,1H),8.84(s,1H),8.61(s,1H),8.21(s,1H),7.43(s,1H),7.38(s,1H),4.16-4.08(m,1H),4.01-3.93(m,1H), 3.85(q,J=7.4Hz,1H),3.80-3.72(m,2H),3.58(s,3H),2.62(s,3H),2.52(s,3H),2.40-2.30(m,1H),2.24-2.13(m,1H) Compound 69-P2: MS m / z(ESI):463.1 [M+H] + 1 H NMR(400MHz,DMSO-d6)δ 13.37(s,1H),8.84(s,1H),8.59(s,1H),8.18(s,1H),7.41(s,1H),7.32(s,1H),4.16-4.07(m,1H),4.01-3.93(m,1H),3. 85(q,J=7.6Hz,1H),3.80-3.71(m,2H),3.57(s,3H),2.61(s,3H),2.52-2.51(m,3H),2.40-2.30(m,1H),2.24-2.13(m,1H)

[0614] Example 70, N-(6-(4-cyano-2-fluorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 70) [ka]

[0615] Step 1: Synthesis of tert-butyl (6-(4-cyano-2-fluorophenyl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 70-2) Intermediate 16-1 (300 mg) and Intermediate 70-1 (246.19 mg) were dissolved in dioxane (5 mL) and water (1 mL), and cesium carbonate (590.27 mg) was added. Under a nitrogen atmosphere, (1,1'-bis(diphenylphosphine)ferrocene)dichloropalladium (66.28 mg) was added to the reaction mixture. The reaction mixture was stirred at 90°C for 2 h under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 12 g SepaFlash® flash silica gel column, gradient 0-40% petroleum ether / ethyl acetate, flow rate 50 mL / min) to obtain the title compound (170 mg).

[0616] MS m / z (ESI): 372.0 [M + H] + .

[0617] Step 2: Synthesis of 4-(2-aminothiazolo[4,5-b]pyrazin-6-yl)-3-fluorobenzonitrile (Intermediate 70-3) Intermediate 70-2 (150 mg) was dissolved in anhydrous dichloromethane (1 mL) and trifluoroacetic acid (1 mL), and the reaction mixture was stirred for 2 h at 25° C. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove dichloromethane, and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was concentrated under reduced pressure to dryness to give the title compound (100 mg).

[0618] MS m / z(ESI):271.9 [M+H] + .

[0619] Step 3: Synthesis of N-(6-(4-cyano-2-fluorophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (compound 70) Intermediate 21-3 (76.17 mg) was dissolved in anhydrous N,N-dimethylformamide (2 mL), and HATU (123.35 mg) and N,N-diisopropylethylamine (114.34 mg) were added. The reaction mixture was stirred under a nitrogen atmosphere for 30 min. Intermediate 70-3 (80 mg) was then added, and the reaction mixture was stirred at 25 °C for 2 h under a nitrogen atmosphere. After the reaction was complete, the reaction mixture was filtered and purified by preparative high-performance liquid chromatography (Boston Green ODS C18 column, 5 μm silica, 30 mm diameter, 150 mm length, elution with a decreasing polarity reaction mixture of water (containing 0.225% formic acid) and acetonitrile, 19%-49% acetonitrile gradient, 12 min elution time) to obtain the title compound (12 mg).

[0620] MS m / z(ESI):512.2 [M+H]+.

[0621] 1H NMR(400MHz,DMSO-d6)δ=13.62(s,1H),9.10(d,J=2.1Hz,1H),8.87(s,1H),8.23(s,1H),8.21-8.17(m,1 H),8.14~8.08(m,1H),7.90(dd,J=1.4,8.1Hz,1H),7.45(s,1H),7.40(s,1H),3.61(s,3H),2.63(s,3H).

[0622] Example 71, 4-(5-chloro-2-methoxyphenyl)-N-(6-(5-chloropyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 71) [ka]

[0623] Intermediate 23-3 (100 mg) was dissolved in N,N-dimethylformamide (2 mL) at 20 °C, and HATU (136.92 mg), N,N-diisopropylethylamine (46.54 mg), and intermediate 62-3 (94.96 mg) were added to the reaction solution. The reaction solution was stirred at 25 °C for 2 hours. After the reaction was completed, ethyl acetate (50 mL) and water (100 mL) were added, and the mixture was extracted with ethyl acetate (25 mL x 3 times). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.05% ammonia water), B: acetonitrile, B%: 53% to 73%, 11 min) to obtain the title compound (35 mg).

[0624] 1H NMR(400MHz,DMSO-d6)δ=13.47(s,1H),9.49(s,1H),8.81-8.76(m,2H),8.38(d,J=8.6Hz,1H),8.11(d d,J=2.4,8.6Hz,1H),7.52-7.45(m,2H),7.43(s,1H),7.02(d,J=8.9Hz,1H),3.52(s,3H),2.61(s,3H). MS m / z(ESI):=523.0 [M+H] + .

[0625] Example 72, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 72) [ka]

[0626] Step 1: Synthesis of 2'-cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (Intermediate 72-2) Under a nitrogen atmosphere, intermediate 20-3 (500 mg) was dissolved in monoethylene glycol dimethyl ether (10 mL). To the reaction mixture, intermediate 72-1 (1.47 g), 1,1-bis(diphenylphosphine)ferrocene palladium chloride (124.99 mg), and potassium carbonate (472.16 mg) were added. The reaction mixture was then stirred at 90°C under a nitrogen atmosphere for 2 hours. After the reaction was complete, water (20 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 40 g SepaFlash® Silica Flash chromatography column, gradient 0-30% tetrahydrofuran / petroleum ether @ 30 mL / min) to give the title compound (270 mg).

[0627] MS m / z(ESI):299.5 [M+H] + .

[0628] Step 2: Synthesis of 2'-cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (Intermediate 72-3) Intermediate 72-2 (250 mg) was added to tetrahydrofuran (8 mL) and water (4 mL), and sodium hydroxide (335.17 mg) was added to the reaction solution, followed by stirring at 25° C. for 16 hours. After the reaction was completed, the reaction solution was adjusted to pH 3 and concentrated to dryness under reduced pressure. The residue was washed with dichloromethane / methanol (10 / 1, 20 mL), filtered, and the filtrate was concentrated under reduced pressure to give the title compound (700 mg).

[0629] MS m / z(ESI):285.1 [M+H] + .

[0630] Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (compound 72) Under a nitrogen gas atmosphere, intermediate 72-3 (112.25 mg) was added to N,N-dimethylformamide (4 mL), and intermediate 16-3 (100 mg), HATU (150.12 mg), and N,N-diisopropylethylamine (102.05 mg) were added to the reaction mixture. The reaction mixture was then stirred at 25°C for 2 hours under a nitrogen gas atmosphere. After the reaction was completed, the reaction mixture was purified by preparative high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 µm, mobile phase: [A: water (0.225% formic acid), B: acetonitrile], B%: 30% to 50%, 11 minutes) to obtain the title compound (43.04 mg).

[0631] MS m / z(ESI):520.1 [M+H] + .

[0632] 1H NMR(400MHz,DMSO-d6)δ 13.52(s,1H),9.35(s,1H),8.85(s,1H),8.38(d,J=8.1Hz,2H),8.16(s,1H),8.01(d,J=8.2 Hz,2H),7.46(s,1H),7.35(s,1H),3.58(s,3H),2.62(s,3H),2.16(s,1H),0.98-0.87(m,4H)

[0633] Example 73, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxamide (Compound 73) [ka]

[0634] Step 1: Synthesis of 5-methoxy-2-(trifluoromethyl)pyridine (Intermediate 73-2) Intermediate 73-1 (10 g) and sodium methanol (5.95 g) were dissolved in N,N-dimethylformamide (150 mL). The reaction mixture was stirred at 80°C for 16 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (145 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 80 g SepaFlash® flash silica gel column, gradient 0-10% ethyl acetate / petroleum ether, flow rate 60 mL / min) to obtain the title compound (2.8 g).

[0635] MS m / z(ESI):=178.1 [M+H] + .

[0636] Step 2: Synthesis of 5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (Intermediate 73-3) Intermediate 73-2 (1 g), bis(pinacolato)diboron (1.72 g), bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I) ([Ir(OMe)(cod)]2) (187.12 mg, 282.29 μmol), and tris[3,5-bis(trifluoromethyl)phenyl]phosphine (378.42 mg) were dissolved in n-octane (20 mL). The reaction mixture was stirred at 80°C for 16 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (45 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (ISCO®, 40 g SepaFlash® flash silica gel column, gradient 0-15% ethyl acetate / petroleum ether, flow rate 60 mL / min) to give the title compound (400 mg).

[0637] 1 H NMR(400MHz,DMSO-d6)δ=8.61-8.51(s,1H),7.83-7.78(s,1H),4.01-3.95(d,3H),1.33-1.29(s,12H)

[0638] Step 3: Synthesis of 5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxylic acid methyl ester (Intermediate 73-4) Intermediate 73-3 (390 mg), Intermediate 42-1 (444.05 mg), 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (83.86 mg), cesium fluoride (390.93 mg), and cuprous chloride (254.78 mg) were dissolved in dimethyl sulfoxide (10 mL) and water (1 mL). The reaction mixture was stirred at 90°C for 2 hours under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by silica gel column chromatography (ISCO®, 20 g SepaFlash® flash silica gel column, gradient 0-20% ethyl acetate / petroleum ether, flow rate 50 mL / min) to give the title compound (150 mg).

[0639] MS m / z(ESI):=327.0 [M+H] + .

[0640] Step 4: Synthesis of 5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxylic acid (Intermediate 73-5) Intermediate 73-4 (150 mg) and sodium hydroxide (55.17 mg) were dissolved in methanol (1 mL) and water (0.2 mL), and the reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 7 with dilute hydrochloric acid and concentrated to dryness under reduced pressure. The residue was dissolved in methanol (1 mL), filtered, and the filtrate was concentrated to dryness under reduced pressure to give the title compound (120 mg).

[0641] MS m / z(ESI):=313.3 [M+H] +

[0642] Step 5: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxamide (compound 73) Intermediate 73-5 (100 mg), intermediate 16-3 (81.12 mg), HATU (121.77 mg), and DIEA (124.18 mg) were dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed, water (50 mL) was added and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 45% to 65%, 11 min) to obtain the title compound (43 mg).

[0643] 1 H NMR(400MHz,DMSO-d6)δ=13.70-13.53(m,1H),9.37(s,1H),8.92(s,1H),8.58-8.54(s, 1H), 8.44~8.33(d,2H),8.05-7.98(m,3H),7.58-7.52(s,1H),3.75(s,3H),2.64(s,3H). MS m / z(ESI):=548.1 [M+H] +

[0644] Example 74, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-(difluoromethoxy)-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 74) [ka]

[0645] Step 1: Synthesis of 2-chloro-5-(difluoromethoxy)-4-iodopyridine (Intermediate 74-2) Intermediate 74-1 (9.6 g), sodium difluorochloroacetate (11.46 g), and potassium carbonate (7.79 g) were dissolved in N,N-dimethylformamide (60 mL). The reaction mixture was stirred at 90°C for 3 hours under a nitrogen atmosphere. After the reaction was complete, water (200 mL) was added and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 20 g SepaFlash® flash silica gel column, gradient 0-5% ethyl acetate / petroleum ether, flow rate 80 mL / min) to obtain the title compound (8 g).

[0646] MS m / z(ESI):=305.9 [M+H] +

[0647] Step 2: Synthesis of 2'-chloro-5'-(difluoromethoxy)-6-methyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (Intermediate 74-3) Intermediate 74-2 (200 mg), intermediate 42-1 (165.74 mg), potassium acetate (192.78 mg), 1,1-bis(diphenylphosphine)ferrocene palladium chloride (95.82 mg), and bis(pinacolato)diboron (249.41 mg) were dissolved in dioxane (4 mL). The reaction mixture was stirred at 90 °C for 16 hours. After the reaction was completed, the reaction mixture was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 35% to 55%, 12 minutes) to obtain the title compound (30 mg).

[0648] MS m / z(ESI):=329.3 [M+H] + .

[0649] Step 3: Synthesis of 5'-(difluoromethoxy)-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (Intermediate 74-4) Intermediate 74-3 (30 mg), trimethylboroxane (22.91 mg), potassium carbonate (25.23 mg), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (6.68 mg) were dissolved in monoethylene glycol dimethyl ether (0.5 mL). The reaction mixture was stirred at 110°C for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to dryness to obtain the title compound (30 mg).

[0650] MS m / z(ESI):=309.3 [M+H] + .

[0651] Step 4: Synthesis of 5'-(difluoromethoxy)-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid (Intermediate 74-5) Intermediate 74-4 (30 mg) was dissolved in tetrahydrofuran (1 mL) and a solution of lithium hydroxide (244.97 mg) in water (1 mL) was added. The reaction mixture was stirred at 20 ° C for 1 hour. After the reaction was completed, the reaction mixture was adjusted to pH 7 with dilute hydrochloric acid and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness to obtain the title compound (28 mg).

[0652] MS m / z(ESI):=294.9 [M+H] +

[0653] Step 5: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-(difluoromethoxy)-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (compound 74) Intermediate 74-5 (20 mg), intermediate 16-3 (17.22 mg), HATU (31.01 mg), and DIEA (17.57 mg) were dissolved in N,N-dimethylformamide (1 mL). The reaction mixture was stirred at 25 ° C. for 1 h under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 um, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 38%-58%, 12 min) to obtain the title compound (12 mg).

[0654] 1 H NMR(400MHz,DMSO-d6)δ 9.36(s,1H),8.99(s,1H),8.42-8.32(m,3H),8.02(d,J=8.5Hz,2H),7.47(d,J =1.8Hz,2H),6.96(t,J =72Hz,1H),2.64(s,3H),2.56(s,3H) MS m / z(ESI):=530.0 [M+H] + .

[0655] Example 75, 5'-Methoxy-N-[6-(5-methoxypyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl]-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 75) [ka]

[0656] Step 1: Synthesis of lithium triisopropoxy(5-methoxypyridin-2-yl)boron ester (intermediate 75-3) Intermediate 75-2 (300 mg) and Intermediate 75-1 (330.09 mg) were dissolved in a toluene (4 mL) / tetrahydrofuran (1 mL) solution at 20 °C, and n-butyllithium (702.05 μL) was slowly added dropwise to the reaction solution at −78 °C under a nitrogen atmosphere. After the addition was complete, the reaction solution was stirred at −78 °C for 0.5 hours, then warmed to room temperature and stirred for 16 hours. After the reaction was complete, water was added to quench the reaction, and the mixture was concentrated under reduced pressure to dryness to obtain the title compound (670 mg).

[0657] Step 2: Synthesis of tert-butyl N-[6-(5-methoxypyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl]carbamate (Intermediate 75-4) Intermediate 75-3 (570 mg) was dissolved in a dioxane (2.5 mL) / water (0.5 mL) solution at 20 °C. To the mixture was added Intermediate 16-1 (622.76 mg), potassium phosphate (1.20 g), and chloro(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (147.95 mg). The reaction mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. After completion of the reaction, the mixture was filtered, and the filtrate was concentrated under reduced pressure to dryness. The residue was purified by column chromatography (dichloromethane / tetrahydrofuran = 15 / 1) to obtain the title compound (40 mg).

[0658] MS m / z(ESI):=360.1 [M+H] + .

[0659] Step 3: Synthesis of 6-(5-methoxypyridin-2-yl)thiazolo[4,5-b]pyrazin-2-amine (Intermediate 75-5) At 20°C, intermediate 75-4 (100 mg) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (206.68 μL) was added to the mixture. The reaction mixture was stirred at 20°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to dryness. The remaining trifluoroacetic acid was neutralized with saturated sodium bicarbonate solution, and the mixture was filtered to obtain the title compound (60 mg).

[0660] MS m / z(ESI):=260.0 [M+H] + .

[0661] Step 4: Synthesis of 5'-methoxy-N-[6-(5-methoxypyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl]-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (compound 75) Intermediate 75-5 (60 mg) was dissolved in N,N-dimethylformamide (1 mL) at 20 °C, and intermediate 21-3 (89.65 mg), HATU (96.79 mg), and DIEA (59.81 mg) were added to the mixture. The reaction mixture was stirred at 20 °C for 4 hours. After the reaction was completed, the reaction mixture was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 18% to 38%, 11 minutes) to obtain the title compound (15.5 mg).

[0662] MS m / z(ESI):=500.1 [M+H] + .

[0663] 1 H NMR(400MHz,DMSO-d6)δ=13.49(s,1H),9.46(s,1H),8.85(s,1H),8.45(d,J=2.9Hz,1H),8.34(d,J=9.0Hz,1H ),8.20(s,1H),7.59(dd,J=2.8,8.9Hz,1H),7.43(s,1H),7.34(s,1H),3.92(s,3H),3.60(s,3H),2.62(s,3H)

[0664] Example 76, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3'-fluoro-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 76) [ka]

[0665] Step 1: Synthesis of 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-carboxylic acid methyl ester (Intermediate 76-1) Intermediate 42-1 (2 g), potassium acetate (2.56 g), 1,1-bis(diphenylphosphine)ferrocene palladium chloride (636.10 mg), and bis(pinacolato)diboron (3.31 g) were dissolved in dioxane (20 mL). The reaction mixture was stirred at 100°C for 12 hours. After the reaction was completed, the mixture was filtered and the organic phase was concentrated under reduced pressure to dryness, yielding the title compound (2 g).

[0666] Step 2: Synthesis of 2'-chloro-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (Intermediate 76-3) Intermediate 76-1 (1.74 g), Intermediate 76-2 (1.5 g), potassium carbonate (2.16 g), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (763.63 mg) were dissolved in a mixture of dioxane (20 mL) and water (5 mL). The reaction mixture was stirred at 90 °C for 12 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 20 g SepaFlash® flash silica gel column, gradient 0-30% tetrahydrofuran / petroleum ether, flow rate 60 mL / min) to give the title compound (230 mg).

[0667] MS m / z(ESI):=311.1 [M+H] +

[0668] Step 3: Synthesis of 3'-fluoro-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (Intermediate 76-4) Intermediate 76-3 (230 mg), trimethylboroxane (185.85 mg), potassium carbonate (204.61 mg), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (54.16 mg) were dissolved in monoethylene glycol dimethyl ether (0.5 mL). The reaction mixture was stirred at 110 °C for 2 hours. After the reaction was complete, water (20 mL) was added and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 20 g SepaFlash® flash silica gel column, gradient 0-30% tetrahydrofuran / petroleum ether, flow rate 60 mL / min) to obtain the title compound (200 mg).

[0669] MS m / z(ESI):=291.0 [M+H] + .

[0670] Step 4: Synthesis of 3'-fluoro-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid (Intermediate 76-5) Intermediate 76-4 (200 mg) was dissolved in tetrahydrofuran (10 mL) and a solution of sodium hydroxide (275.57 mg) in water (5 mL) was added. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 5 with dilute hydrochloric acid, extracted with ethyl acetate (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness to give the title compound (170 mg).

[0671] MS m / z(ESI):=277.2 [M+H] +

[0672] Step 5: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-3'-fluoro-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (compound 76) Intermediate 76-5 (170 mg), intermediate 16-3 (233.79 mg), HATU (350.97 mg), and DIEA (159.06 mg) were dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at 25 ° C. for 1 h under a nitrogen atmosphere. After the reaction was completed, the reaction mixture was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 um, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 27%-57%, 8 min) to obtain the title compound (3.6 mg).

[0673] 1 H NMR(400MHz,DMSO-d6)δ=13.67(s,1H),9.35(s,1H),9.02(s,1H),8.38(d,J=8.4Hz,2H), 8.19(s,1H),8.02(d,J=8.4Hz,2H),7.45(s,1H),3.69(s,3H),2.62(s,3H),2.45(m,3H). MS m / z(ESI):=512.1 [M+H] + .

[0674] Example 77, 4-(5-chloro-2-methoxyphenyl)-N-[6-(5-cyclopropylpyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide (Compound 77) [ka]

[0675] Intermediate 22-2 (150 mg) was dissolved in N,N-dimethylformamide (2.5 mL) at 20 °C, and intermediate 23-3 (154.67 mg), HATU (211.77 mg), and DIEA (143.96 mg) were added to the mixture. The reaction mixture was stirred at 20 °C for 6 hours. After the reaction was completed, the reaction mixture was purified by high-performance liquid chromatography (chromatography column: Boston Green ODS 150 * 30 mm * 5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 55% to 85%, 14 minutes) to obtain the title compound (91 mg).

[0676] 1 H NMR(400MHz,DMSO-d6)δ=13.42(s,1H),9.49(s,1H),8.80(s,1H),8.54(s,1H),8.22(d,J=7.7Hz,1H),7.60(d,J=7.5Hz,1H), 7.54-7.39(m,3H),7.01(d,J=8.6Hz,1H),3.52(s,3H),2.61(s,3H),2.05-1.98(m,1H),1.09-1.01(m,2H),0.91-0.86(s,2H) MS m / z(ESI):=529.1 [M+H] + .

[0677] Example 78, 4-(5-chloro-2-methoxyphenyl)-N-(6-(5-(2-hydroxyprop-2-yl)pyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 78) [ka]

[0678] Step 1: Synthesis of tert-butyl (6-(5-(2-hydroxypropan-2-yl)pyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 78-2) Intermediate 16-1 (1.53 g) was dissolved in N,N-dimethylacetamide (20 mL) at 20 °C, and to the mixture was added Intermediate 78-1 (1 g), nickel iodide (144.63 mg), tetrabutylammonium iodide (2.56 g), 6,6-dimethyl-2,2'-bipyridine (85.27 mg), and manganese powder (1.02 g). The reaction mixture was stirred at 90 °C for 8 hours under a nitrogen atmosphere. After the reaction was completed, dichloromethane (200 mL) and methanol (20 mL) were added, filtered, and the organic phase was concentrated under reduced pressure to dryness. Water (200 mL) was added to the residue and filtered. The filter cake was purified by column chromatography (dichloromethane / tetrahydrofuran = 15 / 1) to obtain the title compound (60 mg).

[0679] MS m / z(ESI):=388.3 [M+H] + .

[0680] Step 2: Synthesis of 2-(6-(2-aminothiazolo[4,5-b]pyrazin-6-yl)pyridin-3-yl)propan-2-ol (Intermediate 78-3) At 20°C, intermediate 78-2 (60 mg) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (115.03 uL) was added to the mixture. The reaction mixture was stirred at 20°C for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to dryness. The pH was adjusted to 7 with saturated sodium bicarbonate solution, filtered, and the filter cake was dried to obtain the title compound (60 mg).

[0681] MS m / z(ESI):=288.3 [M+H] + .

[0682] Step 3: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(5-(2-hydroxyprop-2-yl)pyridin-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (compound 78) Intermediate 78-3 (40 mg) was dissolved in N,N-dimethylformamide (1 mL) at 20 °C, and intermediate 23-3 (42.52 mg), HATU (52.93 mg), and DIEA (35.98 mg) were added to the mixture. The reaction mixture was stirred at 20 °C for 4 hours. After the reaction was completed, the reaction mixture was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 35% to 55%, 11 minutes) to obtain the title compound (15 mg).

[0683] 1 H NMR(400MHz,DMSO-d6)δ=13.42(s,1H),9.53(s,1H),8.84(s,1H),8.80(s,1H),8.32(d,J=8.3Hz,1H),8.05(dd,J=1.9, 8.3Hz,1H),7.51-7.45(m,2H),7.42(s,1H),7.02(d,J=8.8Hz,1H),5.36(s,1H),3.53(s,3H),2.61(s,3H),1.52(s,6H) MS m / z(ESI):=547.2 [M+H] + .

[0684] Example 79, 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyclopropylphenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 79) [ka]

[0685] Step 1: Synthesis of tert-butyl (6-(4-cyclopropylphenyl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 79-2) Intermediate 16-1 (1.50 g), Intermediate 79-1 (1.10 g), potassium carbonate (1.88 g), and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (295.19 mg, 452.91 μmol) were dissolved in dioxane (15 mL) and water (3 mL). The reaction mixture was stirred at 90°C for 2 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (45 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 40 g SepaFlash® flash silica gel column, gradient 0-30% tetrahydrofuran / petroleum ether, flow rate 40 mL / min) to give the title compound (750 mg).

[0686] MS m / z(ESI):=369.4 [M+H] + .

[0687] Step 2: Synthesis of 6-(4-cyclopropylphenyl)thiazolo[4,5-b]pyrazin-2-amine (Intermediate 79-3) Intermediate 79-2 (700 mg) and trifluoroacetic acid (7.68 g) were dissolved in dichloromethane (10 mL), and the reaction solution was stirred for 16 h at 25° C. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness, adjusted to pH 7 with saturated sodium bicarbonate solution, filtered, and the filter cake was dried to obtain the title compound (600 mg).

[0688] MS m / z(ESI):=269.3 [M+H] + .

[0689] Step 3: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyclopropylphenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (compound 79) Intermediate 79-3 (150 mg), intermediate 23-3 (155.24 mg), HATU (212.55 mg), and DIEA (72.25 mg) were dissolved in N,N-dimethylformamide (1 mL) and stirred at 25 °C for 2 hours. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 60% to 80%, 11 min) to obtain the title compound (67.1 mg).

[0690] 1 H NMR(400MHz,DMSO-d6)δ=13.33-13.27(m,1H),9.19(s,1H),8.78(s,1H),8.08-8.02(m,2H),7.51-7.39(m,3H),7.28 -7.19(m,2H),7.05-6.96(m,1H),3.51(s,3H),2.60(s,3H),2.05-1.92(m,1H),1.08-0.96(m,2H),0.84-0.68(m,2H). MS m / z(ESI):=528.2 [M+H] + .

[0691] Example 80, 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-(difluoromethoxy)phenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 80) [ka]

[0692] Step 1: Synthesis of tert-butyl (6-(4-(difluoromethoxy)phenyl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 80-2) Intermediate 16-1 (1.13 g), Intermediate 80-1 (957.59 mg), potassium carbonate (1.41 g), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (248.55 mg) were dissolved in dioxane (10 mL) and water (2 mL). The reaction mixture was stirred at 90°C for 2 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, diluted with 50 mL of ethyl acetate, and extracted with ethyl acetate (45 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness, yielding the title compound (1.16 g).

[0693] MS m / z(ESI):=395.0 [M+H] + .

[0694] Step 2: Synthesis of (6-(4-(difluoromethoxy)phenyl)thiazolo[4,5-b]pyrazin-2-amine (Intermediate 80-3) Intermediate 80-2 (510 mg) was dissolved in hydrochloric acid / ethyl acetate (4 M) (8 mL), and the reaction solution was stirred at 25° C. for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to dryness to obtain the title compound (380 mg).

[0695] MS m / z(ESI):=295.1 [M+H] + .

[0696] Step 3: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-(difluoromethoxy)phenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (compound 80) Intermediate 80-3 (150 mg), intermediate 23-3 (141.55 mg), HATU (193.81 mg), and DIEA (65.88 mg) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 25 °C for 2 hours. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 53% to 73%, 11 min) to obtain the title compound (124.8 mg).

[0697] 1 H NMR(400MHz,DMSO-d6)δ=13.35(s,1H),9.25(s,1H),8.80(s,1H),8.25(d,J=8 .8Hz,2H),7.58-7.18(m,6H),7.02(d,J=8.8Hz,1H),3.52(s,3H),2.61(s,3H). MS m / z(ESI):=554.1 [M+H] + .

[0698] Example 81, 5'-Methoxy-2',6-dimethyl-N-(6-(4-(trifluoromethoxy)phenyl)thiazolo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 81) [ka]

[0699] Step 1: Synthesis of tert-butyl (6-(4-(trifluoromethoxy)phenyl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 81-2) Intermediate 16-1 (1 g), Intermediate 81-1 (932.67 mg), 1,1'-bis(di-tert-butylphosphine)ferrocenedichloropalladium (196.79 mg), and potassium carbonate (1.25 g) were dissolved in dioxane (10 mL) and water (10 mL). The reaction mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (10 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 4 g SepaFlash® flash silica gel column, gradient 0-30% ethyl acetate / petroleum ether, flow rate 30 mL / min) to give the title compound (730 mg).

[0700] MS m / z(ESI):412.9 [M+H] + .

[0701] Step 2: Synthesis of 6-(4-(trifluoromethoxy)phenyl)thiazolo[4,5-b]pyrazin-2-amine (Intermediate 81-3) Intermediate 81-2 (270 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added to the solution, and the reaction mixture was stirred at 90°C for 2 hours. After the reaction was completed, the reaction mixture was adjusted to pH 9 with sodium bicarbonate solution, extracted with ethyl acetate (33 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The title compound (350 mg) was obtained.

[0702] MS m / z(ESI):312.9 [M+H] +

[0703] Step 3: Synthesis of 5'-methoxy-2',6-dimethyl-N-(6-(4-(trifluoromethoxy)phenyl)thiazolo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide (compound 81) Intermediate 21-3 (164.87 mg), HATU (220.83 mg), and DIEA (136.47 mg) were dissolved in N,N-dimethylformamide (2 mL). The reaction mixture was stirred at 50°C for 30 minutes. Intermediate 81-3 (150 mg) was added to the reaction mixture. The reaction mixture was stirred at 50°C for 2 hours. The reaction mixture was directly purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150*30 mm*5 um, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 25% to 45%, 11 minutes) to obtain the title compound (74.7 mg).

[0704] 1 H NMR(400MHz,DMSO-d6)δ=13.43(s,1H),9.22(s,1H),8.88(s,1H),8.29(d,J=8.8Hz,2H) ,8.20(s,1H),7.54(d,J=8.1Hz,2H),7.39(s,1H),7.30(s,1H),3.60(s,3H),2.61(s,3H) MS m / z(ESI):=553.1 [M+H] +

[0705] Example 82, N-(6-(4-cyclopropylphenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 82) [ka]

[0706] Intermediate 21-3 (144.37 mg), intermediate 79-3 (150 mg), HATU (212.55 mg), and DIEA (72.25 mg) were dissolved in N,N-dimethylformamide (1 mL). The mixture was stirred at 25°C for 2 hours. After the reaction was completed, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 23% to 43%, 11 min) to obtain the title compound (94.4 mg).

[0707] 1 H NMR(400MHz,DMSO-d6)δ=13.55-13.31(m,1H),9.17(s,1H),8.86(s,1H),8.19(s,1H),8.05(d,J=8.3Hz,2H),7.41(s,1H) ,7.32(s,1H),7.24(d,J=8.3Hz,2H),3.59(s,3H),2.61(s,3H),2.06-1.94(m,1H),1.08-0.96(m,2H),0.82-0.71(m,2H). MS m / z(ESI):=509.2 [M+H] +

[0708] Example 83, 2'-cyclopropyl-N-(6-(4-cyclopropylphenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 83) [ka]

[0709] Step 1: Synthesis of 2'-cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (intermediate 83-2) Intermediate 20-3 (1 g), Intermediate 83-1 (2.93 g), potassium carbonate (944.29 mg), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (249.97 mg) were dissolved in monoethylene glycol dimethyl ether (16 mL). The reaction mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (45 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 40 g SepaFlash® flash silica gel column, gradient 0-30% tetrahydrofuran / petroleum ether, flow rate 30 mL / min) to obtain the title compound (400 mg).

[0710] MS m / z(ESI):=298.9 [M+H] + .

[0711] Step 2: Synthesis of 2'-cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (Intermediate 83-3) Intermediate 83-2 (400 mg) and sodium hydroxide (268.13 mg) were dissolved in tetrahydrofuran (5 mL) and water (3 mL), and the reaction mixture was stirred at 40° C. for 16 hours. After the reaction was completed, the reaction mixture was adjusted to pH 7 with dilute hydrochloric acid and then concentrated under reduced pressure to dryness. The residue was dissolved in a 10:1 dichloromethane / petroleum ether solution (5 mL) and filtered. The filtrate was concentrated under reduced pressure to dryness to give the title compound (330 mg).

[0712] MS m / z(ESI):=285.1 [M+H] +

[0713] Step 3: Synthesis of 2'-cyclopropyl-N-(6-(4-cyclopropylphenyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (compound 83) Intermediate 83-3 (158.93 mg), intermediate 79-3 (150 mg), HATU (212.55 mg), and DIEA (72.25 mg) were dissolved in N,N-dimethylformamide (2 mL) and stirred at 25 °C for 2 hours. After the reaction was complete, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 43% to 63%, 11 min) to obtain the title compound (66.9 mg).

[0714] 1 H NMR(400MHz,DMSO-d6)δ=13.51-13.33(m,1H),9.20(s,1H),8.84(s,1H),8.16(s,1H),8.06(d,J=8.3Hz,2H),7.46(s,1H),7.35(s,1H),7. 27-7.22(m,2H),3.58(s,3H),2.62(s,3H),2.21-2.11(m,1H),2.06-1 .95(m,1H),1.07-1.00(m,2H),0.98-0.88(m,4H),0.80-0.72(m,2H). MS m / z(ESI):=535.2 [M+H] + .

[0715] Example 84, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-cyclopropyl-2-methoxyphenyl)-6-methylpyridine-3-carboxamide (Compound 84) [ka]

[0716] Step 1: Synthesis of 4-(5-cyclopropyl-2-methoxyphenyl)-6-methylpyridine-3-carboxylic acid methyl ester (Intermediate 84-2) Intermediate 23-2 (2 g) was dissolved in a toluene (20 mL) / water (2 mL) solution at 20 °C. To the mixture was added Intermediate 84-1 (965.77 mg), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (SPhos) (230.79 mg), palladium acetate (63.11 mg), and potassium phosphate (3.58 g). The reaction mixture was stirred at 95 °C for 1 hour under a nitrogen atmosphere. After the reaction was completed, the mixture was concentrated under reduced pressure to remove toluene. Water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (40 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 1 / 1) to obtain the title compound (2.5 g).

[0717] MS m / z(ESI):=298.3 [M+H] + .

[0718] Step 2: Synthesis of 4-(5-cyclopropyl-2-methoxyphenyl)-6-methylpyridine-3-carboxylic acid (Intermediate 84-3) At 20°C, intermediate 84-2 (2.5 g) was dissolved in a tetrahydrofuran (20 mL) / water (20 mL) solution, and lithium hydroxide (503.37 mg) was added to the mixture. The reaction solution was stirred at 20°C for 6 hours. After the reaction was completed, the reaction solution was adjusted to pH 4 with 4M diluted hydrochloric acid solution, filtered, and the filter cake was dried to obtain the title compound (1.7 g).

[0719] MS m / z(ESI):=284.3 [M+H] + .

[0720] Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-cyclopropyl-2-methoxyphenyl)-6-methylpyridine-3-carboxamide (compound 84) Intermediate 84-3 (246.09 mg) was dissolved in N,N-dimethylformamide (3 mL) at 20 °C, and intermediate 16-3 (200 mg), HATU (330.27 mg), and DIEA (204.11 mg) were added to the mixture. The reaction mixture was stirred at 40 °C for 4 hours. After the reaction was completed, the reaction mixture was purified by high-performance liquid chromatography (chromatography column: Xtimate C18 150 * 40 mm * 5 μm, mobile phase: A: water (0.05% ammonia water), B: acetonitrile, B%: 30% to 90%, 9 minutes) to obtain the title compound (260 mg).

[0721] 1 H NMR(400MHz,DMSO-d6)δ=13.39(s,1H),9.33(s,1H),8.73(s,1H),8.36(d,J=8.4Hz,2H),8.00(d,J=8.4Hz,2H),7.38(s,1H), 7.15-7.08(m,2H),6.86(d,J=8.6Hz,1H),3.47(s,3H),2.60(s,3H),1.99-1.94(m,1H),0.98-0.89(m,2H),0.74-0.65(m,2H) MS m / z(ESI):=519.2 [M+H] + .

[0722] Example 85, 4-(5-cyclopropyl-2-methoxyphenyl)-N-(6-(4-(difluoromethoxy)phenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 85) [ka]

[0723] Intermediate 84-3 (158.86 mg) was dissolved in N,N-dimethylformamide (2 mL) at 20 °C, and intermediate 80-3 (150 mg), HATU (213.19 mg), and DIEA (131.76 mg) were added to the mixture. The reaction mixture was stirred at 40 °C for 4 hours. After the reaction was completed, the reaction mixture was purified by high-performance liquid chromatography (chromatography column: Xtimate C18 150 * 40 mm * 5 um, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 44%-84%, 9 minutes) to obtain the title compound (65 mg).

[0724] 1 H NMR(400MHz,DMSO-d6)δ=13.30(s,1H),9.23(s,1H),8.73(s,1H),8.23(d,J=8.7Hz,2H),7.55-7.18(m,4H),7.14-7. 07(m,2H),6.86(d,J=8.3Hz,1H),3.47(s,3H),2.60(s,3H),2.01-1.96(m,1H),0.98-0.93(m,2H),0.87-0.81(m,2H) MS m / z(ESI):=560.2 [M+H] + .

[0725] Example 86, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylpyridine-3-carboxamide (Compound 86) [ka]

[0726] Step 1: Synthesis of 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylpyridine-3-carboxylic acid methyl ester (Intermediate 86-2) Intermediate 86-1 (980 mg), Intermediate 20-1 (826.97 mg), 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (290.38 mg), and potassium carbonate (1.23 g) were dissolved in dioxane (10 mL) and water (2 mL). The reaction mixture was stirred at 90 °C for 22 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (33 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 12 g SepaFlash® flash silica gel column, gradient 0-26% ethyl acetate / petroleum ether, flow rate 36 mL / min) to give the title compound (1.28 g).

[0727] MS m / z(ESI):=326.1 [M+H] +

[0728] Step 2: Synthesis of 4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylpyridine-3-carboxylic acid (Intermediate 86-3) Intermediate 86-2 (1.08 g) was dissolved in tetrahydrofuran (10 mL) / water (10 mL), lithium hydroxide (174.94 mg) was added, and the reaction mixture was stirred at 20 ° C for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (30 mL x 3) and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness to obtain the title compound (1 g).

[0729] MS m / z(ESI):312.1 [M+H] +

[0730] Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylpyridine-3-carboxamide (compound 86) Intermediate 86-3 (400 mg), HATU (488.64 mg), and DIEA (830.44 mg) were dissolved in N,N-dimethylformamide (5 mL). The reaction mixture was stirred at 50 °C for 30 minutes, and then intermediate 16-3 (325.50 mg) was added to the reaction mixture. The reaction mixture was stirred at 50 °C for 4 hours. After the reaction was completed, the reaction mixture was directly purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 um, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 30% to 50%, 11 minutes) to obtain the title compound (49.7 mg).

[0731] 1 H NMR(400MHz,DMSO-d6)δ= 13.50(s,1H),9.36(s,1H),8.84(s,1H),8.38(d,J=8.6Hz,2H),8.02(d,J=8.4Hz,2 H),7.82-7.76(m,2H),7.46(s,1H),7.20(d,J=8.6Hz,1H),3.61(s,3H),2.62(s,3H) MS m / z(ESI):=547.1 [M+H]

[0732] Example 87, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2,5-dichlorophenyl)-6-methylpyridine-3-carboxamide (Compound 87) [ka]

[0733] Step 1: Synthesis of 4-(2,5-dichlorophenyl)-6-methylpyridine-3-carboxylic acid methyl ester (Intermediate 87-2) Intermediate 87-1 (500 mg), Intermediate 20-1 (486.34 mg), potassium carbonate (724.27 mg), and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (170.78 mg) were dissolved in dioxane (2 mL) and water (0.4 mL). The reaction mixture was stirred at 90 °C for 2 h under a nitrogen atmosphere. After the reaction was complete, the mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (15 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ISCO®, 40 g SepaFlash® flash silica gel column, gradient 0-30% ethyl acetate / petroleum ether, flow rate 40 mL / min) to obtain the title compound (800 mg).

[0734] MS m / z(ESI):=296.2 [M+H] + .

[0735] Step 2: Synthesis of 4-(2,5-dichlorophenyl)-6-methylpyridine-3-carboxylic acid (Intermediate 87-3) Intermediate 87-2 (800 mg) and lithium hydroxide (249.39 mg) were dissolved in tetrahydrofuran (6 mL) and water (3 mL), and the reaction mixture was stirred at 25° C. for 4 hours. After the reaction was completed, the reaction mixture was adjusted to pH 7 with dilute hydrochloric acid and then concentrated under reduced pressure to dryness. The residue was dissolved in a 10 / 1 dichloromethane / petroleum ether solution (5 mL), filtered, and the filtrate was concentrated under reduced pressure to dryness to give the title compound (620 mg).

[0736] MS m / z(ESI):=282.2 [M+H] + .

[0737] Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2,5-dichlorophenyl)-6-methylpyridine-3-carboxamide (compound 87) Intermediate 87-3 (150 mg), intermediate 16-3 (134.67 mg), HATU (202.16 mg), and DIEA (206.15 mg) were dissolved in N,N-dimethylformamide (3 mL) and stirred at 25 °C for 2 hours. After the reaction was complete, the mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to dryness. The residue was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 x 30 mm x 5 μm, mobile phase: A: water (0.225% formic acid), B: acetonitrile, B%: 28% to 48%, 11 min) to obtain the title compound (158.1 mg).

[0738] 1 H NMR(400MHz,DMSO-d6)δ=9.32(s,1H),9.06(s,1H),8.37(d,J=8.5Hz,2H),8.01(d,J=8.5Hz,2H),7.58-7.53(m,3H),7.43-7.34(m,1H),2.63(s,3H). MS m / z(ESI):=517.1 [M+H] + .

[0739] Example 88, 4-(5-chloro-2-(trifluoromethyl)phenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 88) [ka]

[0740] Step 1: Synthesis of 4-(5-chloro-2-(trifluoromethyl)phenyl)-6-methylpyridine-3-carboxylic acid methyl ester (Intermediate 88-2) Intermediate 88-1 (400 mg) was dissolved in a dioxane (8 mL) / water (1.6 mL) solution at 20°C, and to the mixture were added Intermediate 20-1 (330.89 mg), 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (116.19 mg), and potassium carbonate (492.77 mg). The reaction mixture was stirred at 90°C for 1 hour under a nitrogen atmosphere. After completion of the reaction, the mixture was concentrated under reduced pressure to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain the title compound (540 mg).

[0741] MS m / z(ESI):=330.2 [M+H] + .

[0742] Step 2: Synthesis of 4-(5-chloro-2-(trifluoromethyl)phenyl)-6-methylpyridine-3-carboxylic acid (Intermediate 88-3) At 20°C, intermediate 2 (540 mg) was dissolved in tetrahydrofuran (5 mL) / water (5 mL) solution, and lithium hydroxide (98.06 mg) was added to the mixture. The reaction solution was stirred at 20°C for 6 hours. After the reaction was completed, the reaction solution was adjusted to pH = 4 with 4M diluted hydrochloric acid aqueous solution, extracted with ethyl acetate (20 mL * 3), and the organic phase was concentrated under reduced pressure to dryness to obtain the title compound (500 mg).

[0743] MS m / z(ESI):=316.2 [M+H] + .

[0744] Step 3: Synthesis of 4-(5-chloro-2-(trifluoromethyl)phenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (compound 88) Intermediate 88-3 (205.65 mg) was dissolved in N,N-dimethylformamide (3 mL) at 20 °C, and intermediate 16-3 (150 mg), HATU (225.18 mg), and DIEA (153.08 mg) were added to the mixture. The reaction mixture was stirred at 40 °C for 4 hours. After the reaction was completed, the reaction mixture was purified by high-performance liquid chromatography (chromatography column: Boston Prime C18 150 * 30 mm * 5 μm, mobile phase: A: water (0.05% ammonia water), B: acetonitrile, B%: 30% to 50%, 11 minutes) to obtain the title compound (106.6 mg).

[0745] 1 H NMR(400MHz,DMSO-d6)δ=13.81-13.64(m,1H),9.35(s,1H),9.07(s,1H),8.37(d,J=8.5Hz, 2H),8.02(d,J=8.4Hz,2H),7.87-7.83(m,2H),7.81-7.77(m,1H),7.45(s,1H),2.64(s,3H) MS m / z(ESI):=551.1 [M+H] + .

[0746] Example 89, 4-(5-chloro-2-(difluoromethoxy)phenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 89) [ka]

[0747] Step 1: Synthesis of (5-methoxycarbonyl-2-methylpyridin-4-yl)boronic acid (Intermediate 89-2) Under a nitrogen gas atmosphere, intermediate 89-1 (10 g), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (3.1 g), bis(pinacolato)diboron (13.2 g), and potassium acetate (8.5 g) were added to dioxane (100 mL), and the reaction mixture was stirred at 100°C for 18 hours. After the reaction was completed (LCMS detection), the mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (22 g).

[0748] Step 2: Synthesis of 4-(5-chloro-2-(difluoromethoxy)phenyl)-6-methylpyridine-3-carboxylic acid methyl ester (Intermediate 89-4) Under a nitrogen atmosphere, intermediate 89-3 (990 mg), intermediate 89-2 (1 g), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (187 mg), and potassium phosphate (1.08 g) were added to dioxane (15 mL) and HO (5 mL), and the reaction mixture was stirred at 100 °C for 18 hours. The reaction mixture was cooled to room temperature, quenched by adding water (30 mL), and extracted with ethyl acetate (40 mL * 3). The organic layers were combined, washed with saturated brine (15 mL * 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (230 mg).

[0749] Step 3: Synthesis of 4-(5-chloro-2-(difluoromethoxy)phenyl)-6-methylpyridine-3-carboxylic acid (Intermediate 89-5) Intermediate 89-4 (200 mg) and lithium hydroxide (29 mg) were added to THF (3 mL) and HO (1 mL), and the resulting reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was cooled to room temperature, adjusted to pH 6 with 1 M hydrochloric acid, and extracted with ethyl acetate (40 mL * 3). The organic layers were combined, washed with saturated brine (15 mL * 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by column chromatography (DCM / MeOH = 10 / 1) to give the title compound (120 mg).

[0750] Step 4: Synthesis of 4-(5-chloro-2-(difluoromethoxy)phenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (compound 89) Intermediate 16-3 (121 mg), 89-5 (100 mg), HATU (132 mg), and DIEA (82 mg) were added to DMF (3 mL). The reaction mixture was stirred at 25°C for 18 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by high-performance liquid chromatography (chromatography column: Waters Xbridge BEH C18 100*30 mm*10 μm, mobile phase: A: water (0.05% formic acid), B: acetonitrile, B%: 40% to 80%, 10 min) to obtain the title compound (67 mg).

[0751] 1 H NMR(400MHz,DMSO-d6)δ 13.61(s,1H),9.34(s,1H),8.96(s,1H),8.41-8.34(m,2H),8.05-7.98( m,2H),7.63-7.55(m,2H),7.43(s,1H),7.34-6.71(m,2H),2.62(s,3H). MS m / z(ESI):=549.1 [M+H] + .

[0752] Example 90, 4-(5-chloro-2-(trifluoromethoxy)phenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 90) [ka]

[0753] Step 1: Synthesis of 4-(5-chloro-2-(trifluoromethoxy)phenyl)-6-methylpyridine-3-carboxylic acid methyl ester (Intermediate 90-2) Intermediate 90-1 (745 mg), Intermediate 89-2 (1 g), potassium phosphate (761 mg), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) (131 mg) were added to dioxane (15 mL) and HO (4 mL). The reaction mixture was stirred at 100 °C for 18 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, quenched by adding water (30 mL), and extracted with ethyl acetate (40 mL * 3). The organic layers were combined, washed with saturated brine (15 mL * 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (320 mg).

[0754] Step 2: Synthesis of 4-(5-chloro-2-(trifluoromethoxy)phenyl)-6-methylpyridine-3-carboxylic acid (Intermediate 90-3) Intermediate 90-2 (300 mg) and lithium hydroxide (83 mg) were added to a mixture of THF (3 mL) and HO (1 mL), and the reaction mixture was stirred at 50 °C for 4 h. The reaction mixture was cooled to room temperature, and 1 M hydrochloric acid was added to adjust the pH to 6. The mixture was extracted with ethyl acetate (40 mL * 3). The organic layers were combined, washed with saturated brine (15 mL * 2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to dryness, and the residue was purified by column chromatography (DCM / MeOH = 10 / 1) to give the title compound (220 mg).

[0755] Step 3: Synthesis of 4-(5-chloro-2-(trifluoromethoxy)phenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (compound 90) Intermediate 16-3 (229 mg), intermediate 90-3 (200 mg), HATU (250 mg), ...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 where: X １ , X ２ , X ３ is independently selected from CH or N; X ４ is selected from C or N, Z is C(=O) or CH ２ is selected from Ring A is a 5- to 10-membered heteroaryl group, C ６ -C １４ an aryl group or a 4- to 12-membered heterocyclyl group, wherein said 5- to 10-membered heteroaryl group, C ６ -C １４ The aryl group or the 4- to 12-membered heterocyclyl group may optionally be R １ａ is replaced by Each R １ａ are independently a halogen, a hydroxyl group, —NRR′, a cyano group, a carboxyl group, ═O, —C(═O)NRR′, C １ -C １０ Alkyl group, C １ -C １０ Alkoxy group, C １ -C １０ Alkoxyacyl group, C ３ -C １０ Cycloalkyl group, C ２ -C １０ Alkynyl group, C ２ -C １０ alkenyl group, a 4- to 12-membered heterocyclyl group, or a 5- to 10-membered heteroaryl group; １ -C １０ Alkyl group, C １ -C １０ Alkoxy group, C １ -C １０ Alkoxyacyl group, C ３ -C １０ Cycloalkyl group, C ２ -C １０ Alkynyl group, C ２ -C １０ The alkenyl group, 4- to 12-membered heterocyclyl group, or 5- to 10-membered heteroaryl group may optionally be R １ｂ is replaced by R １ is C ６ -C １４ an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 18-membered heterocyclyl group, or C ４ -C １０ cycloalkenyl groups, ６ -C １４ an aryl group, a 5- to 10-membered heteroaryl group, a 3- to 18-membered heterocyclyl group, or C ４ -C １０ The cycloalkenyl group may optionally be R ２ａ is replaced by Each R ２ａ are independently a halogen, a cyano group, ═O, a hydroxyl group, —NRR′, —C(═O)NRR′, C １ -C １０ Alkyl group, C １ -C １０ Alkoxy group, C ３ -C １０ cycloalkyloxy group, C １ -C １０ Alkyl acyl group, C １ -C １０ Alkylsulfonyl group, C ２ -C １０ Alkynyl group, C ２ -C １０ Alkenyl group, C ３ -C １０ a cycloalkyl group, a 4- to 12-membered heterocyclyl group, a 4- to 8-membered heterocyclylalkyl group, or a 4- to 8-membered heterocyclyloxy group, １ -C １０ Alkyl group, C １ -C １０ Alkoxy group, C ３ -C １０ cycloalkyloxy group, C １ -C １０ Alkyl acyl group, C １ -C １０ Alkylsulfonyl group, C ２ -C １０ Alkynyl group, C ２ -C １０ Alkenyl group, C ３ -C １０ The cycloalkyl group, 4- to 12-membered heterocyclyl group, 4- to 8-membered heterocyclylalkyl group, or 4- to 8-membered heterocyclyloxy group may optionally be R ２ｂ is replaced by R ２ is C ６ -C １４ aryl group, 5- to 10-membered heteroaryl group, C ３ -C １０ cycloalkyl group or a 4- to 12-membered heterocyclyl group, wherein said C ６ -C １４ aryl group, 5- to 10-membered heteroaryl group, C ３ -C １０ The cycloalkyl group or the 4- to 12-membered heterocyclyl group may optionally be R ３ａ is replaced by Each R ３ａ are independently a halogen, —NRR′, a hydroxyl group, a cyano group, ═O, C １ -C １０ Alkyl group, C １ -C １０ Alkoxy group, C ３ -C １０ Cycloalkyl group, C ２ -C １０ Alkynyl group, C ２ -C １０ alkenyl group, 5- to 10-membered heteroaryl group, or 4- to 8-membered heterocyclyl group, １ -C １０ Alkyl group, C １ -C １０ Alkoxy group, C ３ -C １０ Cycloalkyl group, C ２ -C １０ Alkynyl group, C ２ -C １０ The alkenyl group, 5- to 10-membered heteroaryl group, or 4- to 8-membered heterocyclyl group may optionally be R ３ｂ is replaced by R and R' are independently hydrogen, C ３ -C １０ Cycloalkyl group, C １ -C １０ an alkylcarbonyl group, a 4- to 8-membered heterocyclyl group, or C １ -C １０ alkyl group, ３ -C １０ Cycloalkyl group, C １ -C １０ an alkylcarbonyl group, a 4- to 8-membered heterocyclyl group, or C １ -C １０ The alkyl group may optionally be R ４ｂ is replaced by Each R １ｂ , R ２ｂ , R ３ｂ , R ４ｂ are independently deuterium, halogen, a carboxyl group, a hydroxyl group, ═O, a cyano group, —C(═O)NRR′, a sulfonyl group, —S(═O) ２ NRR', -NRR', C １ -C １０ Alkyl group or C １ -C １０ A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

2. X １ , X ２ and X ３ At least one of X is N, or １ and X ２ are independently selected from CH or N; X ３ is N, or X １ and X ２ are independently CH, and X ３ is N, or X １ and X ３ are independently N, and X ２ is CH, or X １ is CH, and X ２ and X ３ are independently N, or X １ is N and X ２ and X ３ The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

3. X ４ 2. The compound of formula (I) according to claim 1, wherein Z is C and / or Z is C(=O), or a pharmaceutically acceptable salt thereof.

4. Ring A is a 5- to 10-membered heteroaryl group, C ６ -C １０ an aryl group or a 4- to 10-membered heterocyclyl group, wherein said 5- to 10-membered heteroaryl group, C ６ -C １０ The aryl group or the 4- to 10-membered heterocyclyl group may optionally be R １ａ or Ring A is a 5- to 10-membered heteroaryl group, C ６ -C １０ an aryl group or a 6- to 10-membered heterocyclyl group, wherein said 5- to 10-membered heteroaryl group, C ６ -C １０ The aryl group or the 6- to 10-membered heterocyclyl group may optionally be R １ａ or Ring A is selected from a 5- to 9-membered heteroaryl group, a phenyl group, or a 9-membered heterocyclyl group, and the 5- to 9-membered heteroaryl group, phenyl group, or 5- to 9-membered heterocyclyl group is optionally selected from R １ａ or Ring A is selected from a 5- to 9-membered heteroaryl group having 1, 2, or 3 nitrogen atoms, a phenyl group, or a 9-membered heterocyclyl group, wherein the 5- to 9-membered heteroaryl group, phenyl group, or 9-membered heterocyclyl group is optionally selected from R １ａ or Ring A is selected from an imidazolyl group, a 6- to 9-membered heteroaryl group, a phenyl group, or a 9-membered heterocyclyl group, and the imidazolyl group, the 6- to 9-membered heteroaryl group, the phenyl group, or the 9-membered heterocyclyl group is optionally selected from R １ａ or Ring A is a pyridyl group, an imidazolyl group, an imidazo[1,2-a]pyridyl group, a pyrimidinyl group, a [1,2,4]triazolo[1,5-a]pyridyl group, a phenyl group, or 【Chemistry 2】 a pyridyl group, an imidazolyl group, an imidazo[1,2-a]pyridyl group, a pyrimidinyl group, a [1,2,4]triazolo[1,5-a]pyridyl group, a phenyl group or 【Transformation 3】 is optionally R １ａ 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, substituted with:

5. R １ａ is a halogen, a cyano group or C １ -C ６ alkyl group, １ -C ６ The alkyl group may optionally be R １ｂ or substituted with R １ａ is a halogen, a cyano group or C １ -C ３ alkyl group, １ -C ３ The alkyl group is optionally substituted with halogen or R １ａ is fluorine, chlorine, cyano group, CF ３ 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of methyl, ...

6. R １ｂ is a halogen, or R １ｂ The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is fluorine.

7. Ring A is 【Chemistry 4】 where * is selected from R １ or Ring A is 【Transformation 5】 where * is selected from R １ or ring A represents a bond to 【Transformation 6】 where * is selected from R １ or a pharmaceutically acceptable salt thereof.

2. The compound of formula (I) according to claim 1, wherein:

8. R １ is C ６ -C １０ an aryl group, a 5- to 10-membered heteroaryl group, a 4- to 10-membered heterocyclyl group, or C ５ -C ７ cycloalkenyl groups, ６ -C １０ an aryl group, a 5- to 10-membered heteroaryl group, a 4- to 10-membered heterocyclyl group, or C ５ -C ７ The cycloalkenyl group may optionally be R ２ａ or R １ is C ６ -C １０ an aryl group, a 5- to 10-membered heteroaryl group, or a 4- to 10-membered heterocyclyl group; ６ -C １０ The aryl group, 5- to 10-membered heteroaryl group, or 4- to 10-membered heterocyclyl group may optionally be R ２ａ or R １ is selected from a phenyl group, a 6-membered heteroaryl group, or a 6-membered heterocyclyl group, and said phenyl group, 6-membered heteroaryl group, or 6-membered heterocyclyl group is optionally selected from R ２ａ or R １ is selected from a phenyl group, a pyridyl group, or a morpholinyl group, and the phenyl group, the pyridyl group, or the morpholinyl group is optionally selected from R ２ａ 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, substituted with:

9. R ２ａ is a halogen, a cyano group, C １ -C ６ Alkyl group, C ２ -C ６ Alkynyl group, C ３ -C ６ Cycloalkyl group, C １ -C ６ Alkoxy group or C ３ -C ６ cycloalkyloxy group, １ -C ６ Alkyl group, C ２ -C ６ Alkynyl group, C ３ -C ６ Cycloalkyl group, C １ -C ６ Alkoxy group or C ３ -C ６ The cycloalkyloxy group may optionally be R ２ｂ or R ２ａ is a halogen, a cyano group, C １ -C ３ Alkyl group, C ２ -C ４ Alkynyl group, C ３ -C ４ Cycloalkyl group, C １ -C ３ Alkoxy group or C ３ -C ４ cycloalkyloxy group, １ -C ３ Alkyl group, C ２ -C ４ Alkynyl group, C ３ -C ４ Cycloalkyl group, C １ -C ３ Alkoxy group or C ３ -C ４ The cycloalkyloxy group may optionally be R ２ｂ or R ２ａ is a halogen, a cyano group, C １ -C ３ Alkyl group, C ２ -C ４ Alkynyl group, C ３ -C ４ Cycloalkyl group, C １ -C ３ Alkoxy group or C ３ -C ４ cycloalkyloxy group, １ -C ３ Alkyl group or C １ -C ３ The alkoxy group is optionally represented by R ２ｂ or R ２ａ is a halogen, a cyano group, C １ -C ６ Alkyl group, C ２ -C ６ Alkynyl group, C ３ -C ６ Cycloalkyl group or C １ -C ６ alkoxy groups, １ -C ６ Alkyl group, C ２ -C ６ Alkynyl group, C ３ -C ６ Cycloalkyl group or C １ -C ６ The alkoxy group is optionally represented by R ２ｂ or R ２ａ is a halogen, a cyano group, C １ -C ３ Alkyl group, C ２ -C ４ Alkynyl group, C ３ -C ４ Cycloalkyl group or C １ -C ３ alkoxy groups, １ -C ３ Alkyl group, C ２ -C ４ Alkynyl group, C ３ -C ４ Cycloalkyl group or C １ -C ３ The alkoxy group is optionally represented by R ２ｂ or R ２ａ is a halogen, a cyano group, C １ -C ３ Alkyl group, C ２ -C ４ Alkynyl group, C ３ -C ４ Cycloalkyl group or C １ -C ３ alkoxy groups, １ -C ３ Alkyl group or C １ -C ３ The alkoxy group is optionally represented by R ２ｂ 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, substituted with:

10. R ２ｂ is selected from halogen or deuterium, or R ２ｂ is a halogen, or R ２ｂ is fluorine, or R ２ｂ The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is selected from fluorine or deuterium.

11. R ２ is C ６ -C １０ aryl group, 5- to 10-membered heteroaryl group, C ３ -C ６ a cycloalkyl group or a 4- to 10-membered heterocyclyl group, ６ -C １０ aryl group, 5- to 10-membered heteroaryl group, C ３ -C ６ The cycloalkyl group or the 4- to 10-membered heterocyclyl group may optionally be R ３ａ or R ２ is C ６ -C １０ an aryl group, a 5- to 10-membered heteroaryl group, or a 4- to 10-membered heterocyclyl group; ６ -C １０ The aryl group, 5- to 10-membered heteroaryl group, or 4- to 10-membered heterocyclyl group may optionally be R ３ａ or R ２ is selected from a phenyl group, a 5- to 6-membered heteroaryl group, or a 5- to 6-membered heterocyclyl group, and said phenyl group, 5- to 6-membered heteroaryl group, or 5- to 6-membered heterocyclyl group is optionally selected from R ３ａ or R ２ is selected from a phenyl group, a 6-membered heteroaryl group, or a 5- to 6-membered heterocyclyl group, and said phenyl group, 6-membered heteroaryl group, or 5- to 6-membered heterocyclyl group is optionally selected from R ３ａ or R ２ is a phenyl group, a pyridyl group, a tetrahydrofuranyl group, or 【Transformation 7】 a phenyl group, a pyridyl group, a tetrahydrofuranyl group, or 【Transformation 8】 is optionally R ３ａ or R ２ is selected from a phenyl group, a pyridyl group, or a tetrahydrofuranyl group, and said phenyl group, pyridyl group, or tetrahydrofuranyl group is optionally selected from R ３ａ or R ２ is selected from a phenyl group or a pyridyl group, said phenyl group or pyridyl group optionally being selected from R ３ａ 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, substituted with:

12. Each R ３ａ are independently a halogen, —NRR′, a hydroxyl group, a cyano group, C １ -C １０ Alkyl group, C １ -C １０ Alkoxy group, C ３ -C １０ Cycloalkyl group, C ２ -C １０ Alkynyl group, C ２ -C １０ alkenyl group, 5- to 10-membered heteroaryl group, or 4- to 8-membered heterocyclyl group, １ -C １０ Alkyl group, C １ -C １０ Alkoxy group, C ３ -C １０ Cycloalkyl group, C ２ -C １０ Alkynyl group, C ２ -C １０ The alkenyl group, 5- to 10-membered heteroaryl group, or 4- to 8-membered heterocyclyl group may optionally be R ３ｂ or Each R ３ａ are independently halogen, cyano group, ═O, C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group or C ３ -C ６ cycloalkyl groups, wherein said C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group or C ３ -C ６ The cycloalkyl group may optionally be R ３ｂ or Each R ３ａ are independently halogen, cyano group, ═O, C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group or C ３ -C ６ cycloalkyl groups, wherein said C １ -C ６ Alkyl group or C １ -C ６ The alkoxy group is optionally represented by R ３ｂ or Each R ３ａ are independently a halogen, a cyano group, C １ -C ６ Alkyl group or C １ -C ６ alkoxy groups, １ -C ６ Alkyl group or C １ -C ６ The alkoxy group is optionally represented by R ３ｂ or Each R ３ａ are independently fluorine, chlorine, bromine, iodine, a cyano group, C １ -C ３ Alkyl group or C １ -C ３ 2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the aryl group is selected from the group consisting of aryl, aryl ...

13. R ３ｂ is selected from halogen, cyano or hydroxyl groups, or R ３ｂ The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein is selected from fluorine, a cyano group, or a hydroxyl group.

14. The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the compounds of formula (I) and pharmaceutically acceptable salts thereof:

15. 15. A pharmaceutical composition comprising a compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

16. The pharmaceutical composition according to claim 15 for preventing or treating a DNA polymerase θ-mediated disease.

17. The pharmaceutical composition according to claim 16, wherein the DNA polymerase θ-mediated disease is a disease in which DNA polymerase θ is overexpressed.

18. The pharmaceutical composition of claim 16, wherein the DNA polymerase θ-mediated disease is cancer.

19. The pharmaceutical composition according to claim 18, wherein the cancer is a cancer with reduced or absent expression of the BRCA gene, a defect in the BRCA gene, or a decrease in BRCA protein function.

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