Thiazole pyrazine compounds and use thereof

Abstract

Provided are thiazole pyrazine compounds represented by formulas (I), (II), (III) and (IV), or pharmaceutically acceptable salts or stereoisomers thereof, a pharmaceutical composition containing same, and a use thereof in the preparation of a drug for preventing or treating a DNA polymerase theta-mediated disease.

Description

Thiazolopyrazine compounds and their applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of the following Chinese patent applications filed with the State Intellectual Property Office of China: Chinese Patent Application No. 202310882781.0 filed on July 18, 2023; and Chinese Patent Application No. 202410628488.6 filed on May 21, 2024. The entire contents of the above patent applications are incorporated herein by reference in their entirety. Technical Field

[0003] The present application relates to thiazolopyrazine compounds or pharmaceutically acceptable salts or stereoisomers thereof, pharmaceutical compositions containing them, and their use as DNA polymerase θ inhibitors in preventing or treating related diseases. Background Art

[0004] DNA double-strand break repair is crucial for maintaining genomic stability and cell survival. There are three main repair pathways for DNA double-strand breaks: homologous recombination (HR), non-homologous end joining (NHEJ), and alternative non-homologous end joining (alt-NHEJ). Microhomology-mediated end joining (MMEJ) is the most common alternative non-homologous end joining. Homologous recombination is a high-fidelity, accurate repair mechanism that maintains genomic stability and avoids inducing cancer. However, non-homologous end joining and microhomology-mediated end joining are error-prone repair pathways that can lead to mutations at the repair site.

[0005] Unlike normal cells, the survival of tumor cells often depends on the misregulation of DNA double-strand break repair. At the same time, abnormal DNA double-strand break repair can make tumor cells more sensitive to specific types of DNA damage. Therefore, defects in DNA double-strand break repair can be used to develop targeted tumor treatments. Tumor cells with impaired homologous recombination or non-homologous end-joining repair are more dependent 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).

[0006] POLQ is a multifunctional enzyme composed 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 the RPA protein from single-stranded DNA and promotes annealing, while the polymerase domain can extend the ends of single-stranded DNA and fill the gaps. These two domains work together to function in the microhomology-mediated end-joining repair process.

[0007] Studies have shown that POLQ is essential for cells with homologous recombination defects (e.g., synthetic lethality with FA / BRCA defects), 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 shown that POLQ is overexpressed in a series of homologous recombination-deficient ovarian, uterine, and breast cancers with poor prognosis (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 suppressed in normal tissues compared with tumor tissues (Kawamura et al. International Journal of Cancer (2004), 109(1), 9-16).

[0008] In summary, POLQ is crucial for cells with homologous recombination defects, and there is currently an unmet need for the treatment of homologous recombination-deficient tumors. Inhibiting POLQ function can inhibit microhomology-mediated end-joining repair in cells. The development of POLQ inhibitors may provide a novel strategy for the targeted treatment of homologous recombination-deficient tumors.

[0009] Summary of the Invention

[0010] The present application relates to a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof,

[0011] wherein ring A is selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally replaced by R 1a replace;

[0012] Every R1a are independently selected from hydroxy, amino, cyano, halogen, oxo or optionally replaced by R 1b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, -(CH2) q -5-10 membered heteroaryl or -(CH2) z -C(O)NH2, -NHC(O)C1-C6 alkyl, C1-C 10 Alkoxy acyl, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl, C2-C 10 Alkenyl or -(CH2) q -4-12 membered heterocyclic group;

[0013] q and z are each independently selected from 0, 1, 2 or 3;

[0014] R 1 Selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally replaced by R 2a replace;

[0015] Every R 2a independently selected from halogen, cyano, hydroxy, amino or optionally replaced by R 2b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl or 4-12 membered heterocyclic group;

[0016] R 2S Selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, C4-C 10 Cycloalkenyl or 4-12 membered heterocyclic group;

[0017] Every R 3a are independently selected from cyano, hydroxy, halogen, oxo or optionally replaced by R 3b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C(O)NH2, C1-C 10 Alkyl acyl, C3-C10 Cycloalkyl or 5-10 membered heteroaryl;

[0018] Every R 1b 、R 2b 、R 3b independently selected from hydroxy, cyano, halogen, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 4-12 membered heterocyclyl, C1-C6 haloalkyl, C(O)NH2, C(O)NH(C1-C6 alkyl) or C(O)N(C1-C6 alkyl)2;

[0019] The condition is that R 2S Not selected from phenyl, pyridyl, The phenyl group is substituted by one or two substituents selected from cyano, halogen, methoxy, cyclopropyl, -OCHF2, methyl or OCF3, and the pyridyl group is substituted by one substituent selected from cyano, methoxy, cyclopropyl, CF3, chlorine, -C(CH3)2CN or -C(CH3)2OH.

[0020] In some embodiments, R 2S Selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted groups: C1-C6 alkyl, C1-C6 alkoxy, C4-C8 cycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl or 4-12 membered heterocyclyl;

[0021] The condition is that R 2S Not selected from phenyl, pyridyl, The phenyl group is substituted by one or two substituents selected from cyano, halogen, methoxy, cyclopropyl, -OCHF2, methyl or OCF3, and the pyridyl group is substituted by one substituent selected from cyano, methoxy, cyclopropyl, CF3, chlorine, -C(CH3)2CN or -C(CH3)2OH.

[0022] In some embodiments, R 2S Selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted: C1-C3 alkyl, C1-C3 alkoxy, C6 cycloalkenyl, phenyl, 5-10 membered heteroaryl, C3-C7 cycloalkyl or 4-10 membered heterocyclyl;

[0023] The condition is that R 2S Not selected from phenyl, pyridyl, The phenyl group is substituted by one or two substituents selected from cyano, halogen, methoxy, cyclopropyl, -OCHF2, methyl or OCF3, and the pyridyl group is substituted by one substituent selected from cyano, methoxy, cyclopropyl, CF3, chlorine, -C(CH3)2CN or -C(CH3)2OH.

[0024] In some embodiments, R 2S Selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted C1-C3 alkyl, C1-C3 alkoxy, C6 cycloalkenyl, 7-10 membered heteroaryl, C3-C7 cycloalkyl or 4-10 membered heterocyclyl;

[0025] The condition is that R 2S Not selected

[0026] In some embodiments, R 2S Selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a substituted with the following groups: C1-C3 alkyl, C1-C3 alkoxy, C6 cycloalkenyl or C3-C7 cycloalkyl. 2S is selected from hydrogen, pyridyl optionally substituted by isopropyl, phenyl optionally substituted by C(O)CH3 or C(CH3)2OH or optionally substituted by R 3a Substituted groups: methyl, methoxy, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentyl, cyclohexenyl, piperidinyl, dihydropyranyl, piperazinyl, azetidinyl, furyl,

[0027] In some embodiments, R 2S is selected from hydrogen, pyridyl optionally substituted by isopropyl, phenyl optionally substituted by C(O)CH3 or C(CH3)2OH or optionally substituted by R 3a Substituted groups: methyl, methoxy, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentyl, cyclohexenyl, piperidinyl, dihydropyranyl, piperazinyl, azetidinyl, furyl,

[0028] In some embodiments, R 2S Selected from hydrogen, methyl, methoxy,

[0029] In some embodiments, R 2S Selected from hydrogen, methyl, methoxy,

[0030] The present application also provides a compound of formula (II) or a pharmaceutically acceptable salt or a stereoisomer thereof,

[0031] wherein ring A is selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group;

[0032] n is selected from 1, 2, 3 or 4;

[0033] Every R 1Sa are independently selected from hydroxy, amino, cyano, halogen, oxo or optionally replaced by R 1b Substituted with the following groups: C1-C 10 Alkoxy, -(CH2) q -5-10 membered heteroaryl or -(CH2) z -C(O)NH2, -NHC(O)C1-C6 alkyl, C1-C 10 Alkoxy acyl, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl, C2-C 10 Alkenyl or -(CH2) q -4-12 membered heterocyclic group;

[0034] q and z are each independently selected from 0, 1, 2 or 3;

[0035] R 1 Selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally replaced by R 2a replace;

[0036] Every R 2a independently selected from halogen, cyano, hydroxy, amino or optionally replaced by R 2b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl or 4-12 membered heterocyclic group;

[0037] R 2 Selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C6-C 14Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, C4-C 10 Cycloalkenyl or 4-12 membered heterocyclic group;

[0038] Every R 3a are independently selected from cyano, hydroxy, halogen, oxo or optionally replaced by R 3b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C(O)NH2, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl or 5-10 membered heteroaryl;

[0039] Every R 1b 、R 2b 、R 3b independently selected from hydroxy, cyano, halogen, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 4-12 membered heterocyclyl, C1-C6 haloalkyl, C(O)NH2, C(O)NH(C1-C6 alkyl) or C(O)N(C1-C6 alkyl)2.

[0040] In some embodiments, n is selected from 1.

[0041] In some embodiments, each R 1Sa independently selected from oxo or optionally replaced by R 1b Substituted with the following groups: C1-C6 alkoxy, -(CH2) q -5-10 membered heteroaryl or -(CH2) z -C(O)NH2, -NHC(O)C1-C6 alkyl or -(CH2) q -4-10 membered heterocyclic group.

[0042] In some embodiments, each R 1Sa independently selected from oxo or optionally replaced by R 1b Substituted with the following groups: C1-C3 alkoxy, -(CH2) q -5-membered heteroaryl or -(CH2) z -C(O)NH2, -NHC(O)C1-C3 alkyl or 6-membered heterocyclic group.

[0043] In some embodiments, each R 1Sa independently selected from oxo or optionally replaced by R 1b Substituted with the following groups: methoxy, -NHC(O)CH3, -CH2C(O)NH2, 1-oxa-3,4-oxadiazole, pyrazolyl, morpholinyl, Piperazinyl, piperidinyl or

[0044] In some embodiments, each R 1Sa Independently selected from oxo, methoxy,

[0045] The present application also provides a compound of formula (IIa) or a pharmaceutically acceptable salt or a stereoisomer thereof,

[0046] wherein ring B is selected from the group consisting of 1b Substituted: 5-10 membered heteroaryl or 4-12 membered heterocyclyl;

[0047] Ring A, q, R 1b 、R 1 or R 2 As defined for the compound of formula (II).

[0048] In some embodiments, Ring B is selected from the group consisting of 1b Substituted: 5-10 membered heteroaryl or 4-10 membered heterocyclyl.

[0049] In some embodiments, Ring B is selected from the group consisting of 1b Substituted: 5-membered heteroaryl or 6-membered heterocyclyl.

[0050] In some embodiments, Ring B is selected from the group consisting of 1b Substituted with the following groups: 1-oxa-3,4-oxadiazole, pyrazolyl, morpholinyl, piperazinyl or piperidinyl.

[0051] In some embodiments, Ring B is selected from

[0052] The present application also provides a compound of formula (III) or a pharmaceutically acceptable salt or a stereoisomer thereof,

[0053] Among them, ring A S Selected from R 1a Substituted groups:

[0054] * indicates the same as R 1 connect;

[0055] Every R 1a are independently selected from hydroxy, amino, cyano, halogen, oxo or optionally replaced by R 1bSubstituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, -(CH2) q -5-10 membered heteroaryl or -(CH2) z -C(O)NH2, -NHC(O)C1-C6 alkyl, C1-C 10 Alkoxy acyl, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl, C2-C 10 Alkenyl or -(CH2) q -4-12 membered heterocyclic group;

[0056] q and z are each independently selected from 0, 1, 2 or 3;

[0057] R 1 Selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally replaced by R 2a replace;

[0058] Every R 2a independently selected from halogen, cyano, hydroxy, amino or optionally replaced by R 2b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl or 4-12 membered heterocyclic group;

[0059] R 2 Selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, C4-C 10 Cycloalkenyl or 4-12 membered heterocyclic group;

[0060] Every R 3a are independently selected from cyano, hydroxy, halogen, oxo or optionally replaced by R 3b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C(O)NH2, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl or 5-10 membered heteroaryl;

[0061] Every R 1b 、R 2b 、R 3b independently selected from hydroxy, cyano, halogen, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 4-12 membered heterocyclyl, C1-C6 haloalkyl, C(O)NH2, C(O)NH(C1-C6 alkyl) or C(O)N(C1-C6 alkyl)2.

[0062] In some embodiments, Ring A S Selected from * indicates the same as R 1 connect.

[0063] The present application also provides a compound of formula (IV) or a pharmaceutically acceptable salt or a stereoisomer thereof,

[0064] wherein ring A is selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally replaced by R 1a replace;

[0065] Every R 1a are independently selected from hydroxy, amino, cyano, halogen, oxo or optionally replaced by R 1b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, -(CH2) q -5-10 membered heteroaryl or -(CH2) z -C(O)NH2, -NHC(O)C1-C6 alkyl, C1-C 10 Alkoxy acyl, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl, C2-C 10 Alkenyl or -(CH2) q -4-12 membered heterocyclic group;

[0066] q and z are each independently selected from 0, 1, 2 or 3;

[0067] R 1S Selected from R 2a Substituted with the following groups: C 10 -C 14 aryl, 5-10 membered heteroaryl or 4-12 membered heterocyclyl;

[0068] Every R 2aindependently selected from halogen, cyano, hydroxy, amino or optionally replaced by R 2b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl or 4-12 membered heterocyclic group;

[0069] The conditions are: R 1S Not selected from phenyl, pyridyl or The phenyl or pyridyl group is replaced by one or two groups selected from halogen, cyano, OCHF2, methyl, ethynyl, cyclopropyl, methoxy, CF3, OCF3, OCD3 or substituted by a substituent;

[0070] R 2 Selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, C4-C 10 Cycloalkenyl or 4-12 membered heterocyclic group;

[0071] Every R 3a are independently selected from cyano, hydroxy, halogen, oxo or optionally replaced by R 3b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C(O)NH2, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl or 5-10 membered heteroaryl;

[0072] Every R 1b 、R 2b 、R 3b independently selected from hydroxy, cyano, halogen, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 4-12 membered heterocyclyl, C1-C6 haloalkyl, C(O)NH2, C(O)NH(C1-C6 alkyl) or C(O)N(C1-C6 alkyl)2.

[0073] In some embodiments, R 1S is selected from 7-10 membered heteroaryl or 4-10 membered heterocyclic group, wherein the 7-10 membered heteroaryl is optionally replaced by R 2a Substituted, the 4-10 membered heterocyclic group is R 2a replace.

[0074] In some embodiments, R 1S is selected from 9-membered heteroaryl or morpholinyl, wherein the 9-membered heteroaryl is optionally replaced by R 2a Substituted, the morpholinyl group is R 2a replace.

[0075] In some embodiments, R 1S Selected from morpholinyl, described Optional R 2a Substituted, the morpholinyl group is R 2a replace.

[0076] In some embodiments, R 1S Selected from

[0077] In some embodiments, Ring A is selected from 5-10 membered heteroaryl, C6-C 10 Aryl or 4-10 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 10 Aryl or 4-10 membered heterocyclic group is optionally replaced by R 1a replace.

[0078] In some embodiments, Ring A is selected from 6-9 membered heteroaryl, phenyl or 6 membered heterocyclyl, wherein the 6-9 membered heteroaryl, phenyl or 6 membered heterocyclyl is optionally replaced by R 1a replace.

[0079] In some embodiments, ring A is selected from pyridyl, phenyl, The pyridyl, phenyl, Optional R 1a Substitution, where * indicates that R 1 connect.

[0080] In some embodiments, ring A is selected from pyridyl, phenyl, The pyridyl, phenyl, Optional R 1a Substitution, where * indicates that R 1S connect.

[0081] In some embodiments, Ring A is selected from * indicates the same as R 1 or R 1S Connection, # indicates R 1a or R 1Sa connect.

[0082] In some embodiments, Ring A is selected from * indicates the same as R 1 or R 1S Connection, # indicates R1a or R 1Sa connect.

[0083] In some embodiments, Ring A is selected from * indicates the same as R 1 or R 1S Connection, # indicates R 1a or R 1Sa connect.

[0084] In some embodiments, R 1a Selected from oxo or optionally replaced by R 1b Substituted groups: C1-C6 alkyl, C1-C6 alkoxy, -(CH2) q -5-10 membered heteroaryl or -(CH2) z -C(O)NH2, -NHC(O)C1-C6 alkyl or -(CH2) q -4-10 membered heterocyclic group.

[0085] In some embodiments, R 1a Selected from oxo or optionally replaced by R 1b Substituted groups: C1-C3 alkyl, C1-C3 alkoxy, -(CH2) q -5-6 membered heteroaryl or -(CH2) z -C(O)NH2, -NHC(O)C1-C3 alkyl or 6-membered heterocyclic group.

[0086] In some embodiments, R 1a Selected from oxo or optionally replaced by R 1b Substituted groups: methyl, methoxy, -NHC(O)CH3, -CH2C(O)NH2, 1-oxa-3,4-oxadiazole, pyrazolyl, morpholinyl, Piperazinyl, piperidinyl or

[0087] In some embodiments, R 1b Selected from cyano, C1-C6 alkyl or oxo.

[0088] In some embodiments, R 1b Selected from cyano, methyl or oxo.

[0089] In some embodiments, R 1b Selected from C1-C6 alkyl or oxo.

[0090] In some embodiments, R 1b Selected from C1-C3 alkyl or oxo.

[0091] In some embodiments, R1b Selected from methyl or oxo.

[0092] In some embodiments, q is selected from 0 or 1.

[0093] In some embodiments, z is selected from 1.

[0094] In some embodiments, R 1a Selected from oxo, methyl, methoxy,

[0095] In some embodiments, R 1a Selected from oxo, methyl, methoxy,

[0096] In some embodiments, R 1a Selected from methyl.

[0097] In some embodiments, Ring A is selected from * indicates the same as R 1 or R 1S connect.

[0098] In some embodiments, Ring A is selected from * indicates the same as R 1 or R 1S connect.

[0099] In some embodiments, R 1 Selected from 5-10 membered heteroaryl, C6-C 10 Aryl or 5-10 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 10 Aryl or 5-10 membered heterocyclic group is optionally replaced by R 2a replace.

[0100] In some embodiments, R 1 Selected from pyridyl, phenyl, morpholinyl, The pyridyl, phenyl, morpholinyl, Optional R 2a replace.

[0101] In some embodiments, R 1 is selected from pyridyl or phenyl, wherein the pyridyl or phenyl is optionally replaced by R 2a replace.

[0102] In some embodiments, R 2ais selected from halogen, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl is optionally replaced by R 2b replace.

[0103] In some embodiments, R 2a is selected from fluorine, chlorine, methyl, methoxy or cyclopropyl, wherein the methyl, methoxy or cyclopropyl is optionally replaced by R 2b replace.

[0104] In some embodiments, R 2a is selected from halogen, C1-C6 alkyl or C1-C6 alkoxy, wherein the C1-C6 alkyl or C1-C6 alkoxy is optionally replaced by R 2b replace.

[0105] In some embodiments, R 2a is selected from halogen, C1-C3 alkyl or C1-C3 alkoxy, wherein the C1-C3 alkyl or C1-C3 alkoxy is optionally replaced by R 2b replace.

[0106] In some embodiments, R 2b Selected from halogen.

[0107] In some embodiments, R 2b Selected from fluorine.

[0108] In some embodiments, R 2a is selected from methoxy, chloro, methyl, CF3, CHF2, cyclopropyl, fluoro or OCHF2.

[0109] In some embodiments, R 2a Selected from methoxy, chlorine, methyl or CF3.

[0110] In some embodiments, R 1 Selected from

[0111] In some embodiments, R 1 Selected from

[0112] In some embodiments, R 2 Selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted groups: C1-C6 alkyl, C1-C6 alkoxy, C4-C8 cycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl or 4-12 membered heterocyclyl.

[0113] In some embodiments, R2 Selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted: C1-C3 alkyl, C1-C3 alkoxy, C6 cycloalkenyl, phenyl, 5-10 membered heteroaryl, C3-C7 cycloalkyl or 4-10 membered heterocyclyl.

[0114] In some embodiments, R 2 Selected from hydrogen or optionally replaced by R 3a Substituted groups: methyl, methoxy, phenyl, pyridyl, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentyl, cyclohexenyl, piperidinyl, dihydropyranyl, piperazinyl, azetidinyl, furyl,

[0115] In some embodiments, R 2 Selected from hydrogen or optionally replaced by R 3a Substituted groups: methyl, methoxy, phenyl, pyridyl, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentyl, cyclohexenyl, piperidinyl, dihydropyranyl, piperazinyl, azetidinyl, furyl,

[0116] In some embodiments, R 2 Selected from R 3a Substituted: phenyl or pyridyl.

[0117] In some embodiments, R 3a is selected from cyano, hydroxy, halogen, oxo, C1-C6 alkyl, C1-C6 alkoxy, C(O)NH2, C1-C6 alkylacyl, C3-C8 cycloalkyl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C(O)NH2, C1-C6 alkylacyl, C3-C8 cycloalkyl or 5-10 membered heteroaryl is optionally replaced by R 3b replace.

[0118] In some embodiments, R 3a is selected from cyano, hydroxy, halogen, oxo, C1-C3 alkyl, C1-C3 alkoxy, C(O)NH2, C1-C3 alkylacyl, C3-C6 cycloalkyl or 5-6 membered heteroaryl, wherein the C1-C3 alkyl, C1-C3 alkoxy, C(O)NH2, C1-C3 alkylacyl, C3-C6 cycloalkyl or 5-6 membered heteroaryl is optionally replaced by R 3b replace.

[0119] In some embodiments, R 3ais selected from cyano, hydroxy, F, oxo, methyl, ethyl, isopropyl, methoxy, C(O)NH2, C(O)CH3, cyclopropyl or imidazolyl, wherein the methyl, ethyl, isopropyl, methoxy, C(O)NH2, C(O)CH3, cyclopropyl or imidazolyl is optionally replaced by R 3b replace.

[0120] In some embodiments, R 3b Selected from hydroxy, cyano, halogen, oxo or C1-C3 alkoxy.

[0121] In some embodiments, R 3b is selected from hydroxy, cyano, F, oxo or methoxy.

[0122] In some embodiments, R 3a Selected from methyl, cyano, hydroxy, F, oxo, C(O)NH2, Isopropyl, methoxy, CH2CN, CH2CF3, ethyl, C(O)CH3, CF3, CH2OH, cyclopropyl, CHF2,

[0123] In some embodiments, R 2 Selected from hydrogen, methyl, methoxy,

[0124] In some embodiments, R 2 Selected from hydrogen, methyl, methoxy,

[0125] In some embodiments, R 2 Selected from hydrogen.

[0126] The present application also provides the following compounds or pharmaceutically acceptable salts or stereoisomers thereof:

[0127] On the other hand, the present application provides a pharmaceutical composition comprising the compound of formula (I) of the present application or a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable excipient.

[0128] On the other hand, the present application provides a method for preventing or treating a disease mediated by DNA polymerase θ in a mammal, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.

[0129] On the other hand, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, in the preparation of a drug for preventing or treating a disease mediated by DNA polymerase θ.

[0130] On the other hand, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, in preventing or treating diseases mediated by DNA polymerase θ.

[0131] On the other hand, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof for preventing or treating diseases mediated by DNA polymerase θ.

[0132] In some embodiments, the DNA polymerase theta-mediated disease is a disease in which DNA polymerase theta is overexpressed.

[0133] In some embodiments, the DNA polymerase theta-mediated disease is cancer.

[0134] In some embodiments, the cancer is a homologous recombination (HR)-deficient cancer.

[0135] In some embodiments, the cancer is a cancer characterized by decreased or absent BRCA gene expression, a deficiency of a BRCA gene, or reduced BRCA protein function.

[0136] In some embodiments, the cancer is colorectal adenocarcinoma.

[0137] On the other hand, the present application provides use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, in the preparation of a drug for preventing or treating cancer.

[0138] Definitions and Explanations of Terms

[0139] Unless otherwise indicated, the terms used in this application have the following meanings. The definitions of groups and terms described in this application, including their definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the examples, may be combined and coupled with each other in any manner. A specific term should not be considered as undefined or unclear unless specifically defined, but should be understood according to its common meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0140] X4 is located in the ortho position to the ring atom in ring A to which Z is attached.

[0141] In this article Indicates the attachment site.

[0142] In this application, "*" indicates that the atom it identifies is a linking site, such as a linking group It indicates that the N atom in the linking group is the linking site.

[0143] The diagrammatic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, wedge and dotted wedge keys are used. To indicate the absolute configuration of a stereocenter, use black real and imaginary bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0144] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in a molecule between two positions. The compounds of the present application may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; whereas in phenols, the enol form predominates. The present application encompasses all tautomeric forms of the compounds.

[0145] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0146] The compounds of the present application may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and therefore the compounds of the present application may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E-type and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the definition of the compounds of the present application and mixtures thereof. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of these isomers and mixtures thereof involved in the substituents are also within the definition of the compounds of the present application. The compounds of the present invention containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0147] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (ie, =O), it means that two hydrogen atoms are replaced.

[0148] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any sterically impossible and / or incomposable replacement or substitution pattern will not be introduced.

[0149] When any variable (such as R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options.

[0150] In this article, C m -C nIt means having an integer number of carbon atoms in the range mn. 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.

[0151] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10 The term "alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl radical 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, etc.; the term "C1-C6 alkyl" may be understood to mean an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, specific examples of which include but are not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C3 alkyl" may be understood to mean a straight-chain or branched saturated alkyl group having 1, 2 or 3 carbon atoms. The "C1-C 10 The term "alkyl" may include "C1-C6 alkyl" or "C1-C3 alkyl" and the like, and the "C1-C6 alkyl" may further include "C1-C3 alkyl".

[0152] The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by the same or different halogens. The term "halo" or "halogen" refers to fluorine, chlorine, bromine, or iodine. The term "C1-C6 haloalkyl" refers to a C1-C6 alkyl group in which one or more hydrogen atoms are replaced by the same or different halogens.

[0153] The term "alkoxy" refers to a group generated by the loss of a hydrogen atom from a hydroxyl group of a straight-chain or branched alcohol, and can be understood as "alkyloxy" or "alkyl-O-". The term "C1-C 10 "Alkoxy" can be understood as "C1-C 10 Alkyloxy" or "C1-C 10The term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". The "C1-C 10 The term "alkoxy" may include "C1-C6 alkoxy" and "C1-C3 alkoxy", and the "C1-C6 alkoxy" may further include "C1-C3 alkoxy".

[0154] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. 10 "Alkenyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C2-C 10 "Alkenyl" is preferably "C2-C6 alkenyl", further preferably "C2-C4 alkenyl", and further preferably C2 or C3 alkenyl. It will be understood that when the alkenyl contains more than one double bond, the double bonds may be separated from each other or conjugated. Specific examples of the alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.

[0155] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. 10 "Alkynyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C2-C 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), prop-2-ynyl (-CH2C≡CH), but-1-ynyl, but-2-ynyl, or but-3-ynyl. "C2-C 10 The "alkynyl group" is preferably a "C2-C6 alkynyl group", more preferably a "C2-C4 alkynyl group", and further preferably a C2 or C3 alkynyl group.

[0156] The term "cycloalkyl" refers to a fully saturated carbon ring that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbon ring is typically a 3- to 10-membered ring. The term "C3-C 10"Cycloalkyl" is understood to mean a saturated monocyclic, bicyclic, spirocyclic or bridged ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like. The term "C3-C 10 "Cycloalkyl" may include "C3-C6 cycloalkyl". The term "C3-C6 cycloalkyl" may be understood to mean a saturated monocyclic or bicyclic hydrocarbon ring having 3, 4, 5 or 6 carbon atoms. Specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0157] The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic 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, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, or cycloheptadienyl.

[0158] The term "heterocyclyl" refers to a fully saturated or partially saturated monocyclic, fused, spirocyclic or bridged ring group, whose ring atoms contain 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups (i.e., an atom group containing heteroatoms), and the "heteroatoms or heteroatom groups" include but are not limited to nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-, etc. The term "3-18 membered heterocyclyl" 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 containing 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms. The term "4-12 membered heterocyclyl" refers to a heterocyclyl group having 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms. The term "4-10 membered heterocyclyl" refers to a heterocyclyl having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms, wherein specific examples of 4-membered heterocyclyls include, but are not limited to, azetidinyl, thietanyl or oxetanyl; specific examples of 5-membered heterocyclyls include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclyls include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclic groups include, but are not limited to, diazepanyl. Specific examples of 8-membered heterocyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl. Specific examples of 9-membered heterocyclic groups include, but are not limited to, benzo[d][1,3]dioxolyl. Specific examples of 10-membered heterocyclic groups include, but are not limited to, dihydroisoquinolinyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5- and 5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of 5- and 6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7 membered heterocyclic group, and specific examples include but are not limited to dihydroisoquinolinyl, benzo[d][1,3]dioxolyl, etc. "4-10 membered heterocyclic group" may include "5-10 membered heterocyclic group", "4-7 membered heterocyclic group", "5-6 membered heterocyclic group", "6-8 membered heterocyclic group" and the like, and "4-7 membered heterocyclic group" may further include "4-6 membered heterocyclic group", "5-6 membered heterocyclic group", "4-7 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl" and the like.

[0159] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-10 carbon atoms. The term "C6-C 14 "Aryl" is understood to be an aromatic radical having 6 to 14 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 or a ring having 13 carbon atoms ("C 13 aryl) such as fluorenyl; or a ring having 14 carbon atoms ("C 14 The term "C6-C 10 "Aryl" is understood to be an aromatic radical having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 "aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0160] The term "heteroaryl" 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. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and containing 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, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or acinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term “5-6 membered heteroaryl” refers to an aromatic ring system having 5 or 6 ring atoms and containing 1, 2 or 3, preferably 1-2, heteroatoms independently selected from N, O and S. The term “9-10 membered heteroaryl” refers to an aromatic ring system having 9 or 10 ring atoms and containing 1, 2 or 3, preferably 1-2, heteroatoms independently selected from N, O and S. “6 membered heteroaryl” refers to an aromatic ring system having 6 ring atoms and containing 1, 2 or 3, preferably 1-2, heteroatoms independently selected from N, O and S.

[0161] The term "alkoxyacyl" refers to a -COO-alkyl group. 10 "Alkoxyacyl" refers to -COO-C1-C 10 Alkyl. For example, methoxyacyl, ethoxyacyl, propoxyacyl, isopropoxyacyl, n-butoxyacyl, isobutoxyacyl, or tert-butoxyacyl. The term "C1-C6 alkoxyacyl" refers to -COO-C1-C6 alkyl. The term "C1-C3 alkoxyacyl" refers to -COO-C1-C3 alkyl.

[0162] The term "alkylacyl" refers to -C(=O)-alkyl, for example, methylacyl, ethylacyl, etc. The term "C1-C 10 "Alkyl acyl" refers to -C(=O)-C1-C 10 alkyl.

[0163] The term "hydroxy" refers to an -OH group.

[0164] The term "cyano" refers to a -CN group.

[0165] The term "amino" refers to a -NH2 group.

[0166] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats a specific disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a specific disease, condition, or disorder described herein. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art based on their own knowledge and this disclosure.

[0167] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0168] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0169] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present application to an organism.

[0170] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0171] The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0172] The present application also includes isotopically labeled compounds of the present application that are identical to 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 usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 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 I and 36 Cl et al.

[0173] Certain isotope-labeled compounds of the present application (e.g. 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to 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 determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0174] The pharmaceutical compositions of the present application can be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0175] Typical routes of administration of the compounds of the present invention, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0176] The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, etc.

[0177] 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 enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0178] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0179] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0180] In all methods of administration of the compounds of formula (I) described herein, the dosage administered per day is 0.1 mg / kg to 500 mg / kg body weight, in the form of single or divided doses.

[0181] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific examples listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent replacement methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0182] The chemical reactions of the specific examples of this application are carried out in a suitable solvent that is compatible with the chemical transformations of this application and the reagents and materials required. In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing examples.

[0183] This application uses the following abbreviations: Specific embodiments

[0184] The invention is described in detail below by way of examples, but this is not intended to limit the present invention in any way. While the present invention has been described in detail herein, including specific examples thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific examples without departing from the spirit and scope of the present invention. All reagents used herein were commercially available and used without further purification.

[0185] Unless otherwise specified, the ratio of mixed solvents is the volume ratio. For example, "petroleum ether:ethyl acetate = 1:2" means that the volume ratio of petroleum ether to ethyl acetate is 1:2.

[0186] Compounds are manually or The software named the commercially available compounds using the supplier's catalog name.

[0187] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 (ppm). The solvents for NMR measurements are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 ” refers to the half-maximal inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

[0188] In the following purification methods using high performance liquid chromatography, unless otherwise specified, the "%" of the acid or base used in mobile phase A refers to the volume fraction. For example, "water (0.05% formic acid)" means that the volume of formic acid is 0.05% of the total volume of formic acid and water. B% represents the ratio of the volume of mobile phase B to the total volume of mobile phases A and B during gradient elution. "B%: 50%-70%" means that the volume of mobile phase B to the total volume of mobile phases A and B varies from 50% to 70% during gradient elution.

[0189] Common intermediate synthesis:

[0190] Synthesis of Intermediate Int1: tert-Butyl (6-bromothiazolo[4,5-b]pyrazin-2-yl)carbamate

[0191] Step 1: Synthesis of N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)benzamide (Intermediate Int1-3)

[0192] Dissolve the starting materials Int1-1 (140.0 g) and Int1-2 (457.5 g) in acetone (1.4 L) and heat at 60°C for 16 h. After the reaction is complete, cool the reaction mixture to room temperature, filter, and wash the filter cake with acetone and dry to obtain the title compound (107.0 g).

[0193] MS m / z(ESI):335.0[M+H] + .

[0194] Step 2: Synthesis of 6-bromothiazolo[4,5-b]pyrazin-2-amine (Intermediate Int1-4)

[0195] Intermediate Int1-3 (107.0 g) was dissolved in methanol (750 mL), and sodium hydroxide (25.8 g) and water (750 mL) were added. The mixture was heated at 65°C for 48 h. After the reaction was completed, the reaction solution was cooled in an ice-water bath with stirring, and the pH was adjusted to approximately 6-7 with 3N hydrochloric acid. The filter cake was washed with water and dried to obtain the title compound (42.0 g).

[0196] MS m / z(ESI):230.9[M+H] + .

[0197] Step 3: Synthesis of tert-butyl (6-bromothiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate Int1)

[0198] Intermediate Int1-4 (47.0 g), triethylamine (41.2 g), and 4-dimethylaminopyridine (2.5 g) were dissolved in dichloromethane (500 mL), and di-tert-butyl dicarbonate (53.3 g) was added dropwise. The mixture was reacted at room temperature for 16 h. After the reaction, the system was diluted with dichloromethane (100 mL), washed twice with water (100 mL x 2) and once with saturated brine (100 mL x 1). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was crystallized from a mixed solvent of ethyl acetate / petroleum ether (10 / 1) to obtain the title compound (50.0 g).

[0199] MS m / z(ESI):331.0 / 333.0[M+H] + .

[0200] 1 H NMR (400MHz, DMSO-d6) δ8.70 (s, 1H), 1.53 (s, 9H).

[0201] Synthesis of intermediate Int2: (4-(5-chloro-2-methoxy-phenyl)-6-methyl-pyridine-3-carboxylic acid

[0202] Step 1: Synthesis of 4-chloro-6-methyl-pyridine-3-carboxylic acid methyl ester hydrochloride (Intermediate Int2-2)

[0203] Phosphorus oxychloride (500 mL) was added to a single-necked bottle containing the starting material Int2-1 (100.0 g), heated to 95 ° C and stirred for 2 h. After the reaction was completed, the phosphorus oxychloride was removed by concentration under reduced pressure, and the concentrated residue was then added dropwise to methanol (500 mL) at 30 ° C and stirred for 2 h. After concentration under reduced pressure to dryness, ethyl acetate (300 mL) was added to the residue, stirred, filtered, and the filter cake was washed with ethyl acetate. The filter cake was dried to obtain the title compound (100.0 g). The filtrate was adjusted to pH 8-9 with 20% sodium carbonate aqueous solution, separated, and the organic phase was dried over anhydrous sodium sulfate. 4N hydrochloric acid ethyl acetate solution (100 mL) was added thereto, stirred for 1 h, filtered, and the filter cake was washed with ethyl acetate to obtain the title compound (34.0 g). The two batches were combined to obtain the title compound (134.0 g).

[0204] MS m / z(ESI):186.0[M+H] + .

[0205] Step 2: Synthesis of methyl 4-(5-chloro-2-methoxyphenyl)-6-methylnicotinate (Intermediate Int2-4)

[0206] The intermediate Int2-2 (11.2 g) was dissolved in dioxane (94 mL) and water (18.8 mL), and the intermediate Int2-3 (9.4 g), 1,1-di(tert-butylphosphino)ferrocenepalladium chloride (1.9 g) and potassium carbonate (21.0 g) were added to the reaction solution. Under nitrogen protection, the reaction was heated at 90 ° C for 16 h. After the reaction was completed, water (150 mL) was added to the reaction solution, and the product was extracted three times with ethyl acetate (150 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated to dryness under reduced pressure, and the residue was flash purified ( 220g Silica Flash column chromatography, gradient 0-50% ethyl acetate / petroleum ether @100 mL / min) to give the title compound (9.6 g).

[0207] MS m / z(ESI):292.0[M+H] + .

[0208] Step 3: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-pyridine-3-carboxylic acid (Intermediate Int2)

[0209] Intermediate Int2-4 (9.6 g) was added to tetrahydrofuran (96 mL) and water (96 mL). Lithium hydroxide (2.6 g) was added to the reaction solution, and the system was stirred at room temperature for 16 hours. After the reaction, the pH of the reaction solution was adjusted to 3, and the tetrahydrofuran was removed by concentration under reduced pressure. The mixture was filtered and the filter cake was dried to obtain the title compound (7.5 g).

[0210] MS m / z(ESI):278.1[M+H] + .

[0211] 1 H NMR (400MHz, DMSO-d6) δ12.94(s,1H),8.82(s,1H),7.45-7.43(m,1H),7.36-7.30(m,2H),7.08(d,J=8.9Hz,1H),3.67(s,3H),2.57(s,3H).

[0212] Synthesis of intermediate Int3: (4-(5-methoxy-2-methyl-4-pyridyl)-6-methyl-pyridine-3-carboxylic acid

[0213] Step 1: Synthesis of methyl 2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (Intermediate Int3-3)

[0214] The starting material Int3-2 (4.0 g) was dissolved in a solution of dioxane (40 mL) and water (8 mL). The intermediate Int3-1 hydrochloride (4.8 g), potassium carbonate (5.9 g), and 1,1-di(tert-butylphosphino)ferrocenepalladium chloride (1.4 g) were added to the system. Under nitrogen, the reaction was stirred at 90°C for 1 h. After the reaction was complete, water (100 mL) was added and the mixture was extracted three times with ethyl acetate (50 mL x 3). 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 column chromatography (ethyl acetate:petroleum ether 0-50%) to obtain the title compound (3.2 g).

[0215] MS m / z(ESI):292.9[M+H] + .

[0216] Step 2: Synthesis of 5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (Intermediate Int3-4)

[0217] The intermediate Int3-3 (12.3 g) and trimethylcyclotriboroxane (7.9 g) were dissolved in ethylene glycol dimethyl ether (100 mL), potassium carbonate (11.6 g) and (1,1'-bis(diphenylphosphino)ferrocene) palladium dichloride (3.1 g) were added, and the mixture was heated and stirred at 100 ° C under nitrogen protection for 2 h. After the reaction was completed, the mixture was naturally cooled to room temperature, the reaction solution was directly filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography ( 330g Flash silica gel column, gradient 0-50% tetrahydrofuran / petroleum ether) to give the title compound (11.0 g).

[0218] MS m / z(ESI):273.1[M+H] + .

[0219] Step 3: Synthesis of 4-(5-methoxy-2-methyl-4-pyridinyl)-6-methyl-pyridine-3-carboxylic acid (Intermediate Int3)

[0220] Intermediate Int3-4 (11.0 g) was dissolved in tetrahydrofuran (100 mL), and lithium hydroxide (1.9 g) and water (100 mL) were added. The mixture was stirred at room temperature for 4 h. After the reaction, the pH was adjusted to 3 with 4N hydrochloric acid and the mixture was concentrated to dryness under reduced pressure to obtain the title compound (11.0 g).

[0221] MS m / z(ESI):259.1[M+H] + .

[0222] 1 H NMR (400MHz, D2O) δ8.92(s,1H),8.28(s,1H),7.78(s,1H),7.72(s,1H),3.80(s,3H),2.75(s,3H),2.65(s,3H).

[0223] Synthesis of intermediate Int4: (N-(6-bromothiazolo[4,5-b]pyrazin-2-yl)-4-(5-chloro-2-methoxy-phenyl)-6-methyl-pyridine-3-carboxamide

[0224] Intermediate Int2 (1.5 g) and 1-hydroxybenzotriazole (1.1 g) were dissolved in N,N-dimethylformamide (20 mL), and N,N-diisopropylethylamine (1.4 g) was added. The mixture was stirred at room temperature for 5 min. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.6 g) and intermediate Int1-4 (1.3 g) were then added to the mixture. The mixture was reacted at room temperature for 2 h, followed by heating for 18 h. Upon completion of the reaction, the mixture was diluted with ethyl acetate (60 mL), washed twice with water (20 mL x 2) and twice with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (methanol:dichloromethane 0-10%) to obtain the title compound (1.4 g).

[0225] MS m / z(ESI):491.9[M+1] + .

[0226] 1H NMR (400MHz, DMSO-d6) δ13.45(s,1H),8.79-8.78(m,2H),7.49-7.44(m,2H),7.41(s,1H),7.02-7.00(m,1H),3.49(s,3H),2.73(s,3H).

[0227] Synthesis of intermediate Int5: 4-(2-amino-[1,3]thiazolo[4,5-b]pyrazin-6-yl)benzonitrile

[0228] Step 1: Synthesis of tert-butyl N-[6-(4-cyanophenyl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]amino ester (Intermediate Int5-2)

[0229] At 20°C, intermediate Int1 (50.0 g) was dissolved in a dioxane (300 mL) / water (60 mL) solution. To this mixture were added starting material Int5-1 (33.3 g), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (11.1 g), and potassium carbonate (41.7 g). Under nitrogen, the mixture was stirred at 80°C for 5 h. After the reaction was complete, the mixture was concentrated under reduced pressure to remove the dioxane and filtered to obtain the title compound (35.0 g).

[0230] MS m / z(ESI):=354.1[M+H] + .

[0231] Step 2: Synthesis of 4-(2-amino-[1,3]thiazolo[4,5-b]pyrazin-6-yl)benzonitrile (Intermediate Int5)

[0232] Intermediate Int5-2 (35.0 g) was dissolved in dichloromethane (300 mL) at 20°C, and trifluoroacetic acid (73.3 mL) was added to the mixture. The reaction mixture was stirred at 20°C for 2 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, and the pH was adjusted to 7 with saturated sodium bicarbonate solution. The title compound (21.0 g) was obtained by filtration.

[0233] 1 H NMR (400MHz, DMSO-d6) δ = 8.97 (s, 1H), 8.64 (s, 2H), 8.30-8.21 (m, J = 8.4Hz, 2H), 7.94 (d, J = 8.4Hz, 2H)

[0234] MS m / z(ESI):=254.1[M+H] + .

[0235] Synthesis of intermediate Int6: 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide

[0236] Weigh 269.1 mg of pinacol diboronate (269.1 mg), intermediate Int4 (400 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (99.1 mg), and potassium acetate (240.0 mg) and dissolve them in 1,4-dioxane (5 mL) under nitrogen. Heat at 100°C for 16 h. After the reaction is complete, filter the filtrate, and concentrate it to dryness under reduced pressure. The residue is purified on a C18 column (acetonitrile / water: 5% to 60%) to obtain the title compound (250 mg).

[0237] MS m / z(ESI):=456.0[M-82+H] + .

[0238] Synthesis of intermediate Int7: (2-(4-(5-chloro-2-methoxyphenyl)-6-methylnicotinamido)thiazolo[4,5-b]pyrazin-6-yl)boronic acid

[0239] Intermediate Int6 (300 mg) was dissolved in tetrahydrofuran (6 mL), and 2 M dilute hydrochloric acid (2 mL) was added to the system. The reaction was stirred at room temperature for 2 h. After the reaction was completed, water (10 mL) and ethyl acetate (20 mL) were added to the reaction solution, stirred, and the layers were separated. The aqueous layer was extracted once with ethyl acetate (10 mL x 1). The organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (200 mg), which was used directly in the next reaction.

[0240] MS m / z(ESI):=456.0[M+H] + .

[0241] Example 1, N-(6-bromo-[1,3]thiazolo[4,5-b]pyrazin-2-yl)-2'-chloro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 1)

[0242] Intermediate 1-1 (124.37 mg), intermediate 1-2 (100 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (204.65 mg), and N,N-diisopropylethylamine (139.12 mg) were dissolved in N,N-dimethylformamide (2 mL). The atmosphere was purged with nitrogen three times. Under nitrogen protection, the reaction solution was stirred at 25°C for 1 hour. After completion of the reaction, the reaction solution was purified by HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 29%-69%, over 9 minutes) to obtain the title compound (19.28 mg).

[0243] 1 H NMR(400MHz, DMSO-d6)δ=13.66-13.59(m,1H),8.90-8.89(m,1H),8.81-8.81(m, 1H),8.18(s,1H),7.63-7.62(m,1H),7.50-7.50(m,1H),3.63(s,3H),2.62(s,3H)

[0244] MS m / z(ESI):=493.0[M+H] + .

[0245] Example 2, 2'-chloro-5'-methoxy-6-methyl-N-(thiazolo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 2)

[0246] Step 1: Synthesis of tert-butyl N-([1,3]thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 2-1)

[0247] Intermediate Int1 (1.00 g) and n-butyllithium (3.62 mL, 2.5 M) were dissolved in tetrahydrofuran (20 mL) and the atmosphere was replaced with nitrogen three times. Under nitrogen, the reaction mixture was stirred at -75°C for 2 hours. After completion of the reaction, the reaction mixture was quenched with water (5 mL) at 0°C. After quenching, the reaction mixture was warmed to room temperature and diluted with water (50 mL). After filtration, the filter cake was collected to obtain the title compound (440 mg).

[0248] MS m / z(ESI):=253.2[M+H] + .

[0249] Step 2: Synthesis of [1,3]thiazolo[4,5-b]pyrazin-2-amine (Intermediate 2-2)

[0250] Intermediate 2 (100 mg) and trifluoroacetic acid (1.88 mL) were dissolved in dichloromethane (2 mL), and the reaction mixture was stirred at 25° C. for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the solvent to obtain the title compound (100 mg).

[0251] MS m / z(ESI):=153.1[M+H] + .

[0252] Step 3: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-(thiazolo[4,5-b]pyrazin-2-yl)-[4,4'-bipyridine]-3-carboxamide (Compound 2)

[0253] Intermediate 1-2 (50.00 mg) was dissolved in anhydrous N'N-dimethylformamide (1 mL). 2-(7-Azabenzotriazole)-N,N,N'N'-tetramethyluronium hexafluorophosphate (71.63 mg) and N,N-diisopropylethylamine (69.56 mg) were added. The reaction mixture was stirred under nitrogen for 30 minutes. Intermediate 2-2 (30.03 mg) was then added, and the reaction mixture was stirred at 25°C under nitrogen for 3 hours. The reaction mixture was filtered and purified by preparative HPLC (Boston Green ODS C18 column, 5 μm silica, 30 mm diameter, 150 mm length; eluent: decreasingly polar mixtures of water (containing 0.225% formic acid) and acetonitrile; acetonitrile gradient from 20% to 50% over 12 minutes) to obtain the title compound (11.0 mg).

[0254] MS m / z(ESI):412.9[M+H] + .

[0255] 1 H NMR (400MHz, DMSO-d6) δ = 13.50 (s, 1H), 8.89 (s, 1H), 8.66 (d, J = 2.4Hz, 1H), 8.53 ( d,J=2.6Hz,1H),8.18(s,1H),7.62(s,1H),7.50(s,1H),3.63(s,3H),2.62(s,3H)

[0256] Example 3, 2'-chloro-5'-methoxy-6-methyl-N-[6-(piperidin-1-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]-[4,4'-bipyridine]-3-carboxamide (Compound 3)

[0257] Step 1: Synthesis of tert-butyl (6-(piperidin-1-yl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 3-2)

[0258] The intermediate Int1 (3g), piperidine (1.16g), N'-benzyl-N-(2-methylnaphthalen-1-yl) oxalamide (288.39mg), cuprous oxide (129.62mg), and potassium hydroxide (762.33mg) were dissolved in ethanol (30mL) and replaced with nitrogen three times. Under nitrogen protection, the reaction solution was stirred at 100°C for 16 hours. After the reaction was completed, the mixture was filtered and concentrated to dryness under reduced pressure. The residue was purified by rapid silica gel column chromatography ( 40g Flash silica gel column, gradient 0-25% tetrahydrofuran / petroleum ether, flow rate 60 mL / min) to give the title compound (670 mg).

[0259] MS m / z(ESI):=336.1[M+H] +

[0260] Step 2: Synthesis of 6-(piperidin-1-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-amine (Intermediate 3-3)

[0261] Intermediate 3-2 (120 mg) was dissolved in dichloromethane (2 mL) at 20°C, and trifluoroacetic acid (265.75 μL) was added to the mixture. The reaction mixture was stirred at 20°C for 4 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure. The residual trifluoroacetic acid was neutralized with saturated sodium bicarbonate solution, and the title compound (100 mg) was obtained by filtration.

[0262] MS m / z(ESI):=236.2[M+H] + .

[0263] Step 3: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-[6-(piperidin-1-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]-[4,4'-bipyridine]-3-carboxamide (Compound 3)

[0264] At 20°C, intermediate 3-3 (100 mg) was dissolved in N,N-dimethylformamide (2 mL). To this mixture were added intermediate 3-4 (118.44 mg, synthesized according to the method reported in patent WO2022118210), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (161.59 mg), and N,N-diisopropylethylamine (109.85 mg). The reaction mixture was stirred at 20°C for 4 hours. After completion of the reaction, the reaction mixture was purified by HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: A: water (0.05% ammonium hydroxide), B: acetonitrile; B%: 30%-50%, over 11 minutes) to obtain the title compound (16.3 mg).

[0265] 1 H NMR (400MHz, DMSO-d6)δ=9.03(s,1H),8.13(s,1H),8.05(s,1H),7.38(s,1H),7.21(s,1H),3.64(s,3H),3.49(s,4H),2.55(s,3H),1.60(s,6H)

[0266] MS m / z(ESI):=496.2[M+H] + .

[0267] Example 4, 2'-chloro-5'-methoxy-6-methyl-N-[6-(4-methylpiperidin-1-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]-[4,4'-bipyridine]-3-carboxamide (Compound 4)

[0268] Step 1: Synthesis of tert-butyl N-[6-(4-methylpiperidin-1-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]carbamate (Intermediate 4-2)

[0269] The intermediate Int-1 (1g), starting material 4-1 (449.17mg), N-benzyl-N-(2-methylnaphthalen-1-yl)oxyaldehyde amide (96.13mg), cuprous oxide (43.21mg), potassium hydroxide (254.11mg) were dissolved in ethanol (15mL). Under nitrogen protection, the reaction solution was stirred at 80°C for 16 hours. After the reaction was completed, water (20mL) was added thereto, and the mixture was extracted with dichloromethane (10mL*3 times). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by rapid silica gel column chromatography ( 20g Flash silica gel column, gradient 0-7% tetrahydrofuran / petroleum ether, flow rate 80 mL / min) to give the title compound (200 mg).

[0270] MS m / z (ESI): =350.4 [M+H] +

[0271] Step 2: Synthesis of 6-(4-methylpiperidin-1-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-amine (Intermediate 4-3)

[0272] Intermediate 4-2 (150 mg) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 ml) was added. The reaction mixture was stirred at 40°C for 2 hours. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure to obtain the title compound (150 mg).

[0273] MS m / z(ESI):=250.1[M+H] +

[0274] Step 3: Synthesis of 2'-chloro-5'-methoxy-6-methyl-N-[6-(4-methylpiperidin-1-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]-[4,4'-bipyridine]-3-carboxamide (Compound 4)

[0275] Intermediate 4-3 (44.73 mg), intermediate 1-2 (50 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (68.22 mg), and N,N-diisopropylethylamine (69.56 mg) were dissolved in N,N-dimethylformamide (2 mL). The atmosphere was purged with nitrogen three times. Under nitrogen protection, the reaction solution was stirred at 25°C for 1 hour. After completion of the reaction, the reaction solution was purified by HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 50%-70%, over 11 minutes) to obtain the title compound (10 mg).

[0276] 1 H NMR (400MHz, DMSO-d6) δ=12.98(s,1H),8.84(s,1H),8.34(s,1H),8.17(s,1H),7.59(s,1H),7.47(s,1H),4.33(d,J=13.2Hz,2H) ,3.63(s,3H),2.91(t,J=11.7Hz,2H),2.61(s,3H),1.72(d,J=13.0Hz,2H),1.64(s,1H),1.22-1.09(m,2H),0.94(d,J=6.4Hz,3H)

[0277] MS m / z(ESI):=510.1[M+H] + .

[0278] Example 5, 2'-chloro-N-(6-cyclopropyl-[1,3]thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 5)

[0279] Step 1: Synthesis of N-(6-cyclopropyl-[1,3]thiazolo[4,5-b]pyrazin-2-yl)aminomethyl ester (Intermediate 5-1)

[0280] The intermediate Int1 (500 mg), cyclopropylphenylboronic acid (1.33 g), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (110.47 mg), and potassium carbonate (414.62 mg) were dissolved in ethylene glycol dimethyl ether (8 mL) solution, and the nitrogen atmosphere was replaced three times. Under nitrogen protection, the reaction solution was stirred at 110 ° C for 4 hours. After the reaction was completed, the residual catalyst was filtered and concentrated to dryness under reduced pressure. The residue was purified by rapid silica gel column chromatography ( 12g Flash silica gel column, gradient 0-5% tetrahydrofuran / dichloromethane, flow rate 40 mL / min) to obtain the title compound (80 mg)

[0281] MS m / z (ESI): =193.0 [M-100+1] +

[0282] Step 2: Synthesis of 6-cyclopropyl-[1,3]thiazolo[4,5-b]pyrazin-2-amine (Intermediate 5-2)

[0283] Dissolve intermediate 5-1 (80 mg) in dichloromethane (2 mL) at 20°C, and add trifluoroacetic acid (203.26 μL) to the mixture. Stir the reaction mixture at 20°C for 4 hours. After completion of the reaction, concentrate to dryness under reduced pressure. Neutralize the residual trifluoroacetic acid with saturated sodium bicarbonate solution, and filter to obtain the title compound (50 mg).

[0284] MS m / z(ESI):=193.0[M+H] + .

[0285] Step 3: Synthesis of 2'-chloro-N-(6-cyclopropyl-[1,3]thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 5)

[0286] At 20°C, intermediate 5-2 (50 mg) was dissolved in N,N-dimethylformamide (1 mL). To this mixture were added intermediate 1-2 (72.48 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (98.89 mg), and N,N-diisopropylethylamine (67.23 mg). The reaction mixture was stirred at 20°C for 4 hours. After completion of the reaction, the reaction mixture was purified by HPLC (column: C18-1150*30mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 27%-67%, over 9 minutes) to obtain the title compound (7 mg).

[0287] 1 H NMR (400MHz, DMSO-d6) δ = 13.33 (s, 1H), 8.86 (s, 1H), 8.62 (s, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 7 .49(s,1H),3.61(s,3H),2.61(s,3H),2.35-2.31(m,1H),1.14-1.05(m,2H),1.05-0.97(m,2H)

[0288] MS m / z(ESI):=452.9[M+H] + .

[0289] Example 6, 2'-chloro-N-[6-(5,6-dihydro-2H-pyran-3-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 6)

[0290] Step 1: Synthesis of tert-butyl N-[6-(5,6-dihydro-2H-pyran-3-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]amino ester (Intermediate 6-2)

[0291] Intermediate 6-1 (200 mg), Intermediate Int1 (301.58 mg), 1,1-di(tert-butylphosphino)ferrocenepalladium chloride (62.05 mg), and potassium carbonate (263.15 mg) were dissolved in dioxane (5 mL) and water (1 mL) at 25°C. The reaction mixture was stirred at 90°C under nitrogen for 2 hours. After the reaction, the organic phase was concentrated to dryness under reduced pressure. Ethyl acetate (20 mL) and water (10 mL) were added, and the mixture was washed with water (20 mL x 3) and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel thin-layer chromatography (petroleum ether / ethyl acetate = 1:2) to afford the title compound (260 mg).

[0292] MS m / z(ESI):=333.1[M+H] + .

[0293] Step 2: Synthesis of 6-(5,6-dihydro-2H-pyran-3-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-amine (Intermediate 6-3)

[0294] Intermediate 6-2 (260 mg) was dissolved in dichloromethane (5 mL) at 25°C. Trifluoroacetic acid (1 mL) was added to the mixture, and the reaction mixture was stirred at 25°C for 2 hours. After the reaction, the organic phase was concentrated to dryness under reduced pressure. Aqueous sodium bicarbonate was added to adjust the pH to >7. After filtration, the filter cake was collected and concentrated to dryness under reduced pressure to obtain the title compound (150 mg).

[0295] 1 H NMR (400MHz, Methanol-d4) δ = 8.42 (s, 3H), 6.75 (s, 1H), 4.54-4.46 (m, 2H), 3.75 (t, J = 5.5Hz, 2H), 2.33-2.27 (m, 2H)

[0296] MS m / z(ESI):=235.0[M+H] + .

[0297] Step 3: Synthesis of 2'-chloro-N-[6-(5,6-dihydro-2H-pyran-3-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 6)

[0298] At 20°C, intermediate 6-3 (50 mg), intermediate 1-2 (54.91 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (80.52 mg), and N,N-diisopropylethylamine (275.83 mg) were dissolved in N,N-dimethylformamide (3 mL). The reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, the organic phase was concentrated to dryness under reduced pressure. Ethyl acetate (10 mL) and water (20 mL) were added, and the mixture was washed with water (10 mL x 2). The 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 HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: A: water (0.05% ammonia), B: acetonitrile; B%: 25%-45%, 11 min) to obtain the title compound (91.4 mg).

[0299] 1H NMR (400MHz, DMSO-d6) δ = 13.50-13.38 (m, 1H), 8.89 (d, J = 5.0Hz, 2H), 8.18 (s, 1H), 7.62 (s, 1H), 7.50 (s, 1H), 6.99(s,1H),4.58(d,J=1.7Hz,2H),3.78(t,J=5.4Hz,2H),3.62(s,3H),2.64-2.61(m,3H),2.38-2.32(m,2H)

[0300] MS m / z(ESI):=495.1[M+H] + .

[0301] Example 7, 2'-chloro-5'-methoxy-N-(6-methoxy-[1,3]thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 7)

[0302] Step 1: Synthesis of tert-butyl N-(6-methoxy-[1,3]thiazolo[4,5-b]pyrazin-2-yl)aminomethyl ester (Intermediate 7-2)

[0303] At 20°C, intermediate Int1 (300 mg) was dissolved in dioxane (1.5 mL) / methanol (1.5 mL). Methanesulfonic acid-2-(di-tert-butylphosphino)-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl(2-amino-1,1-biphenyl-2-yl)palladium(II) (77.40 mg) and sodium tert-butoxide (174.11 mg) were added to the mixture. Under nitrogen, the reaction mixture was stirred at 40°C for 8 hours. After completion of the reaction, the mixture was filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (petroleum ether / tetrahydrofuran = 3 / 1) to obtain the title compound (160 mg).

[0304] MS m / z(ESI):=283.0[M+H] + .

[0305] Step 2: Synthesis of 6-methoxy-[1,3]thiazolo[4,5-b]pyrazin-2-amine (Intermediate 7-3)

[0306] Dissolve intermediate 7-2 (160 mg) in dichloromethane (5 mL) at 20°C, and add trifluoroacetic acid (420.98 μL) to the mixture. Stir the reaction mixture at 20°C for 6 hours. After completion of the reaction, concentrate to dryness under reduced pressure. Neutralize the residual trifluoroacetic acid with saturated sodium bicarbonate solution, and filter to obtain the title compound (100 mg).

[0307] MS m / z(ESI):=183.2[M+H] + .

[0308] Step 3: Synthesis of 2'-chloro-5'-methoxy-N-(6-methoxy-[1,3]thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 7)

[0309] At 20°C, intermediate 3-4 (80 mg) was dissolved in N,N-dimethylformamide (1 mL). To this mixture were added intermediate 7-3 (52.30 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (109.15 mg), and N,N-diisopropylethylamine (74.20 mg). The reaction mixture was stirred at 20°C for 6 hours. After completion of the reaction, the reaction mixture was purified by HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 35%-55%, over 11 minutes) to obtain the title compound (24.6 mg).

[0310] 1 H NMR (400MHz, DMSO-d6)δ=13.24(s,1H),8.86(s,1H),8.31(s,1H),8.18(s,1H),7.61(s,1H),7.49(s,1H),3.98(s,3H),3.62(s,3H),2.61(s,3H)

[0311] MS m / z(ESI):=443.3[M+H] + .

[0312] Example 8, 5'-methoxy-2',6-dimethyl-N-[6-(4-methylpiperidin-1-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]-[4,4'-bipyridine]-3-carboxamide (Compound 8)

[0313] At 20°C, Intermediate 8-2 (330 mg) was dissolved in N,N-dimethylformamide (2 mL). To this mixture were added Intermediate 8-1 (159.25 mg, synthesized from 4-methylpiperidine according to the synthesis method of Intermediate 3-2), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (485.83 mg), and N,N-diisopropylethylamine (330.27 mg). The reaction mixture was stirred at 20°C for 6 hours. After completion of the reaction, the reaction mixture was purified by HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 25%-45%, over 11 minutes) to obtain the title compound (42.9 mg).

[0314] 1 H NMR (400MHz, DMSO-d6) δ=12.95(s,1H),8.80(s,1H),8.34(s,1H),8.21(s,1H),7.41(s,1H),7.36(s,1H),4.33(d,J=13.0Hz,2H ),3.59(s,3H),3.40-3.38(m,3H),2.96-2.86(m,2H),2.60(s,3H),1.77-1.58(m,3H),1.23-1.07(m,2H),0.94(d,J=6.6Hz,3H)

[0315] MS m / z(ESI):=490.2[M+H] + .

[0316] Example 9, 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-[6-(4-methylpiperidin-1-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 9)

[0317] At 20°C, Intermediate Int2 (133.65 mg) was dissolved in acetonitrile (5 mL). To this mixture were added Intermediate 8-1 (120 mg), N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (675.19 mg), and N-methylimidazole (553.21 mg). The reaction mixture was stirred at 40°C for 8 hours. After completion of the reaction, the reaction mixture was purified by HPLC (column: Welch Xtimate C18 150*25mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 55%-75%, over 11 minutes) to obtain the title compound (63.4 mg).

[0318] 1 H NMR (400MHz, DMSO-d6)δ=12.79(s,1H),8.73(s,1H),8.32(s,1H),7.48-7.42(m,2H),7.38(s,1H),7.04-6.98(m,1H),4.32(d, J=13.1Hz,2H),3.51(s,3H),2.91(t,J=11.6Hz,2H),2.59(s,3H),1.75-1.60(m,3H),1.21-1.09(m,2H),0.94(d,J=6.5Hz,3H)

[0319] MS m / z(ESI):=509.2[M+H] + .

[0320] Example 10, N-[6-(4-cyanopiperidin-1-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 10)

[0321] Intermediate 10-1 (150 mg, synthesized using Intermediate Int3 as starting material, following the synthesis method of Intermediate Int4), Intermediate 10-2 (52.59 mg), sodium tert-butoxide (91.75 mg), 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (22.53 mg), and dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) (29.70 mg) were dissolved in tetrahydrofuran (5 mL). The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction, water (20 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by HPLC (column: Boston Prime C18 150*30mm*5um; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 15%-35%, 11 min) to obtain the title compound (11 mg).

[0322] 1H NMR (400MHz, DMSO-d6) δ = 13.10-12.85 (m, 1H), 8.79 (s, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 7.40 (s, 1H), 7.30 (s, 1H), 3.95-3. 88(m,2H),3.58(s,3H),3.49-3.42(m,2H),3.31(s,3H),2.60(s,3H),2.56(s,1H),2.03-1.93(m,2H),1.86-1.75(m,2H).

[0323] MS m / z(ESI):=501.2[M+H] + .

[0324] Example 11, 4-(5-chloro-2-methoxyphenyl)-N-[6-(4-cyanopiperidin-1-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide (Compound 11)

[0325] Step 1: Synthesis of tert-butyl N-[6-(4-cyanopiperidin-1-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]carbamate (Intermediate 11-1)

[0326] Intermediate Int1 (1g), intermediate 10-2 (432.39mg), dichlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine] palladium (II) (213.80mg), sodium tert-butoxide (870.50mg) and 2-dicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (281.80mg) were dissolved in tetrahydrofuran (20mL) and replaced with nitrogen 3 times. Under nitrogen protection, the reaction solution was stirred at 80°C for 2hr. After the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water (100mL), extracted with ethyl acetate (45ml*3 times), the organic phases were combined, and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by rapid silica gel column chromatography ( 40g Flash silica gel column, gradient 0-40% tetrahydrofuran / petroleum ether, flow rate 60 mL / min) to give the title compound (700 mg).

[0327] MS m / z(ESI):=361.4[M+H] +

[0328] Step 2: Synthesis of 1-(2-amino-[1,3]thiazolo[4,5-b]pyrazin-6-yl)piperidine-4-carbonitrile (Intermediate 11-2)

[0329] Dissolve intermediate 11-1 (700 mg) and trifluoroacetic acid (7.68 g) in dichloromethane (10 mL). Stir the reaction mixture at 25°C for 2 hours. After the reaction is complete, concentrate the reaction mixture under reduced pressure to remove the organic solvent to obtain the title compound (400 mg).

[0330] MS m / z(ESI):=261.3[M+H] + .

[0331] Step 3: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-[6-(4-cyanopiperidin-1-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide (Compound 11)

[0332] Intermediate 11-2 (150 mg), intermediate Int2 (480.05 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (657.29 mg), and N,N-diisopropylethylamine (74.47 mg) were dissolved in N,N-dimethylformamide (3 mL). The reaction mixture was stirred at 40°C for 2 hours. After completion of the reaction, water (50 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 phases were concentrated to dryness under reduced pressure. The residue was purified by HPLC (column: Welch Xtimate C18 150 x 25 mm x 5 μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 40%-60%, 11 minutes) to obtain the title compound (54.4 mg).

[0333] 1 H NMR (400MHz, DMSO-d6)δ=12.87(s,1H),8.75(s,1H),8.37(s,1H),7.48-7.44(m,2H),7.41(s,1H),7.03-6.99(m,1H),3.96-3.84(m, 2H),3.50(s,3H),3.47-3.42(m,2H),3.16(td,J=4.4,8.6Hz,1H),2.60(s,3H),1.98(ddd,J=3.2,6.1,9.8Hz,2H),1.84-1.74(m,2H).

[0334] MS m / z(ESI):=520.2[M+H] + .

[0335] Example 12, 4-(5-chloro-2-methoxyphenyl)-N-[6-(4-hydroxypiperidin-1-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide (Compound 12)

[0336] Intermediate Int4 (100 mg), Intermediate 12-1 (103.05 mg), cuprous iodide (3.88 mg), potassium phosphate (129.76 mg), and L-hydroxyproline (2.67 mg) were dissolved in dimethyl sulfoxide (1 mL). The reaction mixture was stirred at 120°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature. The reaction mixture was diluted with water (30 mL) 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 to dryness under reduced pressure. The residue was purified by HPLC (acidic conditions, column: Boston Prime C18 150 x 40 mm x 5 μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 28%-48%, over 9 minutes) to obtain the title compound (13 mg).

[0337] 1 H NMR (400MHz, DMSO-d6) δ=12.85-12.76(m,1H),8.73(s,1H),8.34(s,1H),7.47-7.43(m,2H),7.40-7.37(m,1H),7.01(d,J=9.5Hz,1H),4.82 -4.66(m,1H),4.12-3.96(m,2H),3.81-3.69(m,1H),3.51(s,3H),3.28-3.20(m,2H),2.59(s,3H),1.87-1.78(m,2H),1.42(d,J=9.2Hz,2H)

[0338] MS m / z(ESI):=511.1[M+H] + .

[0339] Example 13, 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-[6-(4-methylpiperazin-1-yl)-[1,3]thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 13)

[0340] Intermediate Int4 (50 mg), Intermediate 13-1 (51.02 mg), cuprous iodide (1.94 mg), and potassium phosphate (64.88 mg) were dissolved in dimethyl sulfoxide (1 mL). The reaction mixture was stirred at 120°C for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with ethyl acetate (5 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated to dryness under reduced pressure. The residue was purified by HPLC (column: Boston Prime C18 150 x 40 mm x 5 μm; mobile phase: A: water (0.225% formic acid), B: acetonitrile; B%: 20%-40%, over 9 minutes) to obtain the title compound (5.6 mg).

[0341] 1 H NMR (400MHz, DMSO-d6) δ = 13.08-12.55 (m, 1H), 8.74 (s, 1H), 8.34 (s, 1H), 7.48-7.42 (m, 2H), 7.42-7 .35(m,1H),7.01(d,J=9.5Hz,1H),3.60(s,4H),3.50(s,3H),2.59(s,3H),2.48(s,4H),2.26(s,3H)

[0342] MS m / z(ESI):=510.1[M+H] + .

[0343] Example 14, 4-(5-chloro-2-methoxy-phenyl)-N-[6-(5-isopropyl-2-pyridyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 14)

[0344] Step 1: Synthesis of tert-butyl N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazolo[4,5-b]pyrazin-2-yl]carbamate (Intermediate 14-1)

[0345] Dissolve bis(pinacol)diboronate (3.1 g), intermediate Int1 (2.0 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (876.4 mg), and potassium acetate (1.8 g) in 1,4-dioxane (20 mL). Heat at 100°C under nitrogen for 16 h. After the reaction is complete, filter the mixture, and concentrate the filtrate to dryness under reduced pressure to obtain the title compound (2.4 g).

[0346] Step 2: Synthesis of tert-butyl N-[6-(5-isopropyl-2-pyridyl)thiazolo[4,5-b]pyrazin-2-yl]carbamate (Intermediate 14-3)

[0347] Intermediate 14-1 (189.1 mg), intermediate 14-2 (150.0 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (64.6 mg), and potassium phosphate (318.3 mg) were dissolved in 1,4-dioxane (1.5 mL) and water (0.1 mL). The mixture was heated at 100°C under nitrogen for 15 h. After the reaction, the reaction solution was diluted with ethyl acetate (20 mL) and washed twice with saturated sodium chloride solution (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (ethyl acetate:petroleum ether 0-30%) to obtain the title compound (60.0 mg).

[0348] MS m / z(ESI):372.1[M+H] +

[0349] Step 3: Synthesis of 6-(5-isopropyl-2-pyridyl)thiazo[4,5-b]pyrazin-2-amine trifluoroacetate (Intermediate 14-4)

[0350] Intermediate 14-3 (120.0 mg) was dissolved in trifluoroacetic acid (2 mL) and dichloromethane (2 mL) and reacted at room temperature for 2 h. After the reaction was complete, the mixture was concentrated to dryness under reduced pressure to obtain the title compound (85.0 mg).

[0351] MS m / z(ESI):272.1[M+H] +

[0352] Step 4: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(5-isopropyl-2-pyridyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 14)

[0353] Intermediate Int2 (130.5 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90.8 mg), and 1-hydroxybenzotriazole (63.5 mg) were dissolved in N,N-dimethylformamide (1.5 mL) and stirred at room temperature for 10 min. N,N-diisopropylethylamine (121.5 mg, 939.0 μmol) and Intermediate 14-4 (85.0 mg) were then added to the mixture, and the reaction was heated at 45°C for 18 h. After the reaction was complete, the mixture was diluted with ethyl acetate (10 mL) and washed twice with saturated brine (5 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 75-95% acetonitrile) to obtain the title compound (15.0 mg).

[0354] MS m / z(ESI):531.0[M+H] + .

[0355] 1 H NMR (400MHz, DMSO-d6) δ9.49(s,1H),8.80(s,1H),8.63(d,J=2.2Hz,1H),8.29(d,J=8.2Hz,1H),7.87(m,1H),7.5 1-7.43(m,2H),7.40(s,1H),7.01(d,J=8.6Hz,1H),3.52(s,3H),3.03(m,1H),2.60(s,3H),1.28(d,J=6.9Hz,6H).

[0356] Example 15. Synthesis of 4-(6-chloro-1-methyl-1H-benzo[d]imidazol-4-yl)-N-[6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide (Compound 15)

[0357] Step 1: Synthesis of 4-bromo-6-chloro-1-methyl-1H-benzo[d]imidazole (Intermediate 15-2): Starting material 15-1 (300.0 mg), potassium carbonate (358.2 mg), and iodomethane (275.9 mg) were added to anhydrous N,N-dimethylformamide (3 mL) and reacted at room temperature for 18 h. After the reaction, ethyl acetate (30 mL) and water (30 mL) were added to the reaction solution, stirred, and the layers were separated. The organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Purification by column chromatography (ethyl acetate:petroleum ether 0-20%) afforded the title compound (213.0 mg).

[0358] MS m / z(ESI):245.0,247.0[M+H] + .

[0359] Step 2: Synthesis of 6-chloro-1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (Intermediate 15-3)

[0360] Intermediate 15-2 (210.0 mg), pinacol diboronate (434.4 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (62.1 mg), and potassium acetate (167.9 mg) were added to dioxane (3 mL) and heated at 100°C under nitrogen for 18 hours. After the reaction, the mixture was filtered through celite, and the filter cake was washed with dioxane. The filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (methanol:dichloromethane 0-5%) to obtain the title compound (132.0 mg).

[0361] MS m / z(ESI):293.1[M+H] +

[0362] Step 3: Synthesis of 4-(6-chloro-1-methyl-1H-benzo[d]imidazol-4-yl)-6-methyl-pyridine-3-carboxylic acid methyl ester (Intermediate 15-4)

[0363] Intermediate 15-3 (132.0 mg), methyl 4-chloro-6-methyl-pyridine-3-carboxylate (100.2 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (29.1 mg), and potassium carbonate (187.1 mg) were added to dioxane (1.5 mL) and water (0.3 mL). The mixture was heated at 90°C under nitrogen for 18 h. After the reaction was complete, ethyl acetate (30 mL) and water (30 mL) were added to the reaction solution, stirred, and the layers were separated. The organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the title compound (130.0 mg).

[0364] MS m / z(ESI):316.1[M+H] +

[0365] Step 4: Synthesis of 4-(6-chloro-1-methyl-1H-benzo[d]imidazol-4-yl)-6-methylpyridine-3-carboxylic acid (Intermediate 15-5)

[0366] Intermediate 15-4 (130 mg) was added to tetrahydrofuran (3 mL) and water (3 mL). Lithium hydroxide (33.0 mg) was added to the reaction system, and the reaction was stirred at room temperature for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove tetrahydrofuran. The residue was diluted with water (10 mL) and the pH was adjusted to 3-4. The mixture was then extracted twice with ethyl acetate (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the title compound (90.0 mg).

[0367] MS m / z(ESI):302.1[M+H] +

[0368] Step 5: Synthesis of 4-(6-chloro-1-methyl-1H-benzo[d]imidazol-4-yl)-N-[6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide (Compound 15)

[0369] Intermediate 15-5 (90.0 mg), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl) hexafluorophosphate (135.0 mg), and N,N-diisopropylethylamine (115.7 mg) were added to anhydrous N,N-dimethylformamide (1 mL) and stirred at room temperature for 0.5 h. Intermediate Int5 (60.4 mg) was then added and allowed to react at room temperature for 16 h. After the reaction, ethyl acetate (50 mL) and water (50 mL) were added to the reaction solution, stirred, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (methanol:dichloromethane 0-10%) and then by preparative chromatography (YMC TAR column, 0.5‰ ammonium bicarbonate-water & acetonitrile system, 25 mL / min, acetonitrile ratio 50-70%) to obtain the title compound (1.0 mg).

[0370] MS m / z(ESI):537.1[M+H] + .

[0371] 1 H NMR (400MHz, DMSO-d6) δ9.04 (s, 2H), 8.49 (s, 1H), 8.28 (d, J = 8.2Hz, 2H), 8.13 (s, 1H), 7 .85(d,J=8.2Hz,2H),7.68(s,1H),7.45(s,1H),7.11(m,1H),3.49(s,3H),2.68(s,3H).

[0372] Example 16. Synthesis of 4-(5-methoxy-2-methyl-4-pyridyl)-6-methyl-N-[6-(5-methyl-3-furyl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 16)

[0373] Step 1: Synthesis of tert-butyl N-[6-(5-formyl-3-furyl)thiazolo[4,5-b]pyrazin-2-yl]carbamate (Intermediate 16-2)

[0374] Intermediate Int1 (200.0 mg), Intermediate 16-1 (127.0 mg), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (39.0 mg), and potassium phosphate (385.0 mg) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The mixture was heated at 90°C under nitrogen for 16 hours. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-50%) to obtain the title compound (165.0 mg).

[0375] MS m / z(ESI):347.1[M+H] + .

[0376] Step 2: Synthesis of 6-(5-methyl-3-furyl)thiazolo[4,5-b]pyrazin-2-amine (Intermediate 16-3)

[0377] Intermediate 16-2 (100.0 mg) was dissolved in trifluoroacetic acid (2 mL), and triethylsilyl hydrochloride (0.3 mL) was then added to the reaction system. The reaction was allowed to react at room temperature for 4 h. Upon completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was dissolved in ethyl acetate (20 mL) and washed twice with saturated sodium bicarbonate solution. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane 0-5%) to obtain the title compound (64.0 mg).

[0378] MS m / z(ESI):233.0[M+H] + .

[0379] Step 3: Synthesis of 4-(5-methoxy-2-methyl-4-pyridinyl)-6-methyl-N-[6-(5-methyl-3-furyl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 16)

[0380] Compound Intermediate 16-3 (64.0 mg), Intermediate Int3 (142.0 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (106.0 mg), N,N-dimethyl-4-pyridinamine (67.0 mg), and 1-hydroxybenzotriazole (37.0 mg) were added to N,N-dimethylformamide (2 mL) and heated at 45°C for 16 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 45-95% acetonitrile ratio) to obtain the title compound (5.0 mg).

[0381] MS m / z(ESI):473.2[M+H] + .

[0382] 1 H NMR(400MHz,DMSO-d6)δ13.38(s,1H),8.95(s,1H),8.84(s,1H),8.34(S,1H),8.19(s ,1H),7.41(s,1H),7.32(s,1H),6.78(s,1H),3.59(s,3H),2.61(s,3H),2.34(s,3H).

[0383] Example 17. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(3-furyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 17)

[0384] Step 1: Synthesis of tert-butyl N-[6-(3-furyl)thiazolo[4,5-b]pyrazin-2-yl]carbamate (Intermediate 17-2)

[0385] Intermediate Int1 (1.3 g), Intermediate 17-1 (633.0 mg), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (247.0 mg), and potassium phosphate (2.4 g) were dissolved in 1,4-dioxane (15 mL) and water (3 mL). The mixture was heated at 90°C under nitrogen for 16 h. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-50%) to obtain the title compound (1.1 g).

[0386] MS m / z(ESI):319.0[M+H] + .

[0387] Step 2: Synthesis of 6-(3-furyl)thiazolo[4,5-b]pyrazin-2-amine (Intermediate 17-3)

[0388] Intermediate 17-2 (300.0 mg) was dissolved in dichloromethane (5 mL). Trifluoroacetic acid (5 mL) was slowly added dropwise at 0°C until the addition was complete. The system was allowed to react at room temperature for 2 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure. Saturated sodium bicarbonate solution was added to the residue, stirred, filtered, and the filter cake was washed with water and dried to obtain the title compound (200.0 mg).

[0389] MS m / z(ESI):219.0[M+H] + .

[0390] Step 3: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(3-furyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 17)

[0391] Intermediate 17-3 (128.0 mg), intermediate Int2 (326.0 mg), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (225.0 mg), and N,N-dimethyl-4-pyridinamine (143.0 mg) were added to N,N-dimethylformamide (4 mL), and the system was heated at 45°C for 16 h. After completion of the reaction, the product was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 45-95% acetonitrile) to obtain the title compound (10.0 mg).

[0392] MS m / z(ESI):478.0[M+H] + .

[0393] 1 H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.78(s,1H),8.52(s,1H),7.85-7.84(m,1H),7.49-7 .42(m,2H),7.40(s,1H),7.18-7.17(m,1H),7.02-7.00(m,1H),3.51(s,3H),2.60(s,3H).

[0394] Example 18. Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-[6-(1-methyl-1H-benzo[d]imidazol-5-yl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 18)

[0395] Step 1: Synthesis of 1-methyl-1H-benzo[d]imidazole-6-boronic acid pinacol ester (Intermediate 18-2)

[0396] Intermediate 18-1 (630.3 mg), diboron pinacol ester (1.2 g), and potassium acetate (600.2 mg) were dissolved in a mixture of dioxane and water (10 mL). 1,1-Bis(diphenylphosphino)diphenylferric palladium chloride (220.3 mg) was added and the mixture was heated at 100°C under nitrogen for 4 h. After the reaction, the reaction solution was concentrated under reduced pressure to remove some of the solvent. Water (30 mL) and dichloromethane (30 mL) were added to the residue, stirred, and the layers separated. The aqueous phase was extracted twice with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the title compound (530.0 mg).

[0397] MS m / z(ESI):259.1[M+H] + .

[0398] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-[6-(1-methyl-1H-benzo[d]imidazol-5-yl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 18)

[0399] Intermediate 18-2 (51.6 mg), intermediate Int4 (49.1 mg), and potassium carbonate (28.4 mg) were dissolved in a mixture of dioxane and water (1 mL). 1,1-Bis(diphenylphosphino)diphenylferric palladium chloride (7.3 mg) was added and the mixture was heated at 100°C under nitrogen for 6 h. After the reaction, the reaction solution was concentrated under reduced pressure to remove some of the solvent. Water (30 mL) and dichloromethane (30 mL) were added to the residue, stirred, and the layers separated. The aqueous phase was extracted twice with dichloromethane (20 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness. The residue was purified by preparative chromatography (column: YMC C18; mobile phase: B%: 20%-90%, B is acetonitrile, 25 mL / min) to obtain the title compound (10.0 mg).

[0400] MS m / z(ESI):542.0[M+H] + .

[0401] 1 H NMR(400MHz,DMSO-d6)δ9.28(s,1H),8.82(s,1H),8.47(s,1H),8.29(s,1H),8.17-8.11(m,1H), 7.76-7.71(m,1H),7.52-7.37(m,3H),7.06-6.99(m,1H),3.90(s,3H),3.53(s,3H),2.60(s,3H).

[0402] Example 19. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 19)

[0403] Step 1: Synthesis of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (Intermediate 19-2)

[0404] Dissolve starting material 19-1 (0.5 g), pinacol borate (0.9 g), 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (171.9 mg), and potassium acetate (465.0 mg) in anhydrous dioxane (5 mL). Heat the mixture at 100°C under nitrogen for 6 h. After the reaction is complete, add water (30 mL) and ethyl acetate (30 mL), stir, and separate the layers. The organic phase is dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue is purified by column chromatography (ethyl acetate:petroleum ether 0-25%) to afford the title compound (450.0 mg).

[0405] MS m / z(ESI):259.1[M+H] + .

[0406] Step 2: Synthesis of tert-butyl N-[6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-b]pyrazin-2-yl]carbamate (Intermediate 19-3)

[0407] Intermediate Int1 (500.0 mg), intermediate 19-2 (389.7 mg), 1,1-bis(di-tert-butylphosphino)diphenylferric palladium chloride (97.5 mg), and potassium carbonate (417.3 mg) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The mixture was heated at 90°C under nitrogen for 6 h. After the reaction, the reaction solution was slowly added dropwise to a mixed solvent of ethyl acetate (30 mL) and water (50 mL), stirred, and filtered. The filter cake was washed with ethyl acetate and dried to obtain the title compound (500.0 mg).

[0408] MS m / z(ESI):383.2[M+H] + .

[0409] Step 3: Synthesis of 6-(2-methyl-2-H-indazol-5-yl)thiazolo[4,5-b]pyrazin-2-amine (Intermediate 19-4)

[0410] Intermediate 19-3 (500.0 mg) was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) and allowed to react at room temperature for 18 h. After the reaction was complete, the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and slowly added dropwise to saturated sodium bicarbonate solution (30 mL). The mixture was filtered, and the filter cake was washed with ethyl acetate and dried to obtain the title compound (317.0 mg).

[0411] MS m / z(ESI):283.1[M+H] + .

[0412] Step 4: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(2-methyl-2H-indazol-5-yl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 19)

[0413] Intermediate Int2 (300.0 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (248.5 mg), 1-hydroxybenzotriazole (175.2 mg), and N,N-diisopropylethylamine (418.9 mg) were dissolved in N,N-dimethylformamide (4 mL) and stirred at room temperature for 0.5 h. Intermediate 19-4 (305.0 mg) was then added and reacted at room temperature for 4 h. After the reaction was completed, the reaction solution was added to water (50 mL), filtered, and the filter cake was washed with water. After drying, the filter cake was purified by preparative chromatography (YMC TAR column, 0.5‰ ammonium bicarbonate-water & acetonitrile system, 25 mL / min, acetonitrile ratio 30-60%) to obtain the title compound (50.0 mg).

[0414] MS m / z(ESI):542.1[M+H] + .

[0415] 1 H NMR (400MHz, DMSO-d6) δ13.31(s,1H),9.23(s,1H),8.82(s,1H),8.56(s,1H),8.50(s,1H),8.06(d,J=9.1Hz, 1H),7.73(d,J=9.1Hz,1H),7.49-7.37(m,3H),7.02(d,J=9.0Hz,1H),4.21(s,3H),3.52(s,3H),2.59(s,3H).

[0416] Example 20. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylnicotinamide (Compound 20)

[0417] Step 1: Synthesis of 4-bromo-1-cyclopropyl-pyridin-2(1H)-one (Intermediate 20-2)

[0418] The starting material 20-1 (1.8 g), cyclopropylboronic acid (2.0 g), copper acetate (2.0 g), 2,2'-bipyridine (1.7 g), and sodium carbonate (2.5 g) were dissolved in 1,2-dichloroethane (75 mL) and heated at 85°C for 18 h. After the reaction was complete, water (100 mL) and dichloromethane (100 mL) were added to the reaction solution, stirred, and filtered. The filter cake was rinsed with dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-50%) to obtain the title compound (900.0 mg).

[0419] MS m / z(ESI):214.0,216.0[M+H] + .

[0420] Step 2: Synthesis of 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (Intermediate 20-3)

[0421] Intermediate 20-2 (780.0 mg), pinacol borate (1.4 g), tris(dibenzylideneacetone)dipalladium (166.8 mg), tricyclohexylphosphine (102.2 mg), and potassium acetate (715.2 mg) were dissolved in anhydrous dioxane (8 mL) and heated at 100°C under nitrogen for 4 h. After the reaction, the reaction solution was concentrated to dryness under reduced pressure to obtain the title compound, which was used directly in the next reaction.

[0422] Step 3: Synthesis of tert-butyl (6-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 20-4)

[0423] Intermediate Int1 (780.0 mg), intermediate 20-3 (615.0 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (152.0 mg), and potassium carbonate (651.0 mg) were dissolved in 1,4-dioxane (8 mL) and water (1.6 mL). The mixture was heated at 90°C under nitrogen for 16 h. After the reaction was complete, the reaction solution was slowly added dropwise to a mixed solvent of ethyl acetate (30 mL) and water (50 mL), stirred, and filtered. The filter cake was washed with ethyl acetate and dried to obtain the title compound (900.0 mg).

[0424] MS m / z(ESI):386.1[M+H] + .

[0425] Step 4: Synthesis of 4-(2-aminothiazolo[4,5-b]pyrazin-6-yl)-1-cyclopropyl-pyridin-2(1H)-one (Intermediate 20-5)

[0426] Intermediate 20-4 (900.0 mg) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (3 mL) and allowed to react at room temperature for 3 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and washed twice with saturated sodium bicarbonate solution (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain the title compound (463.0 mg).

[0427] MS m / z(ESI):286.1[M+H] + .

[0428] Step 5: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylnicotinamide (Compound 20)

[0429] Intermediate Int2 (200.0 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (165.7 mg), 1-hydroxybenzotriazole (116.8 mg), and N,N-diisopropylethylamine (279.2 mg) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 0.5 h. Intermediate 20-5 (205.5 mg) was then added and allowed to react at room temperature for 18 h. After completion of the reaction, the reaction solution was quenched by dropwise addition into water (30 mL) and extracted twice with ethyl acetate (15 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Purification by preparative chromatography (YMC TAR column, 0.5‰ ammonium bicarbonate-water & acetonitrile system, 25 mL / min, 30-60% acetonitrile ratio) afforded the title compound (5.0 mg).

[0430] MS m / z(ESI):545.1[M+H] + .

[0431] 1 H NMR (400MHz, DMSO-d6) δ13.44(s,1H),9.18(s,1H),8.85(s,1H),7.67(d,J=7.3Hz,1H),7.44(d,J=7.1Hz,2H),7.35 (s,1H),7.15(s,1H),7.00(d,J=9.2Hz,1H),6.93(m,1H),3.50(s,3H),2.58(s,3H),1.02(m,2H),0.93-0.84(m,2H).

[0432] Example 21. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(3-methylbicyclo[1.1.1]pentan-1-yl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 21)

[0433] Step 1: Synthesis of (1,3-dioxoisoindol-2-yl) 3-methylbicyclo[1.1.1]pentane-1-carboxylate (Intermediate 21-3)

[0434] Starting material 21-1 (400.0 mg) was dissolved in dichloromethane (20 mL), cooled to 0°C, and then 4-dimethylaminopyridine (38.7 mg) and starting material 21-2 (620.7 mg) were added. The mixture was stirred at 0°C for 0.5 h. Dicyclohexylcarbodiimide (719.7 mg) was added to the system, stirred at 0°C for 2 h, then heated to 20°C and stirred for 16 h. After the reaction was completed, the mixture was filtered through silica gel (100-200 mesh), the filter cake was washed with dichloromethane, and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (800.0 mg).

[0435] 1 H NMR (400MHz, CDCl3) δ7.88 (dd, J = 5.5, 3.1Hz, 2H), 7.85-7.74 (m, 2H), 2.17 (s, 6H), 1.25 (s, 3H).

[0436] Step 2: Synthesis of tert-butyl (6-(3-methylbicyclo[1.1.1]pentan-1-yl)thiazolo[4,5-b]pyrazin-2-yl]carbamate (Intermediate 21-4)

[0437] Intermediate 21-3 (866.0 mg), intermediate Int1 (700.0 mg), dihydropyridine (1.1 g), nickel bromide trihydrate (115.2 mg), 4,4'-di-tert-butyl-2,2'-bipyridine (113.0 mg), and sodium bicarbonate (710.0 mg) were dissolved in N-dimethylacetamide (20 mL) and reacted under nitrogen at 25°C under UV irradiation for 36 h. After the reaction, the reaction solution was added to water (100 mL) and extracted twice with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (ethyl acetate:petroleum ether 0-25%) to obtain the title compound (450.0 mg).

[0438] MS m / z(ESI):333.2[M+H] + .

[0439] Step 3: Synthesis of 6-(3-methylbicyclo[1.1.1]pentan-1-yl)thiazolo[4,5-b]pyrazin-2-amine (Intermediate 21-5)

[0440] Intermediate 21-4 (450.0 mg) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) and allowed to react at room temperature for 18 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (15 mL), washed with saturated sodium bicarbonate solution (15 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain the title compound (18.0 mg).

[0441] MS m / z(ESI):233.1[M+H] + .

[0442] Step 4: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(6-(3-methylbicyclo[1.1.1]pentan-1-yl)thiazolo[4,5-b]pyrazin-2-yl)pyridine-3-carboxamide (Compound 21)

[0443] Intermediate Int2 (25.0 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.0 mg), 1-hydroxybenzotriazole (15.0 mg), and N,N-diisopropylethylamine (35.0 mg) were dissolved in anhydrous N,N-dimethylformamide (1 mL) and reacted at room temperature for 0.5 h. Intermediate 21-5 (21.0 mg) was then added and reacted at room temperature for 18 h. After the reaction, ethyl acetate (20 mL) and water (20 mL) were added to the reaction solution, stirred, and the layers separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ ammonium bicarbonate-water & acetonitrile system, 25 mL / min, acetonitrile ratio 30-60%) to obtain the title compound (2.0 mg).

[0444] MS m / z(ESI):492.1[M+H] + .

[0445] 1 H NMR (400MHz, DMSO-d6) δ13.23 (s, 1H), 8.77 (s, 1H), 8.46 (d, J = 46.3Hz, 1H), 7.49-7.38 (m, 3H),6.99(d,J=8.8Hz,1H),3.48(d,J=2.5Hz,3H),2.59(s,3H),2.06(s,6H),1.26(s,3H).

[0446] Example 22. Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(cis-3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide and 4-(5-chloro-2-methoxyphenyl)-N-(6-(trans-3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 22-P1 and Compound 22-P2)

[0447] Step 1: Synthesis of tert-butyl (6-(3-cyano-1-hydroxycyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 22-2)

[0448] Intermediate Int1 (1.0 g) was added to a dry three-necked flask. Under nitrogen, anhydrous tetrahydrofuran (10 mL) was added. The reaction solution was stirred at -78°C, and a solution of n-butyllithium in n-hexane (2.5 mL, 2.5 M) was slowly added dropwise to the system. After the addition was complete, the reaction was allowed to proceed at -78°C for 1 h. Subsequently, a solution of 3-oxocyclobutanecarbonitrile (345.0 mg) in tetrahydrofuran was slowly added to the reaction system and the reaction was continued for 2 h. After the reaction was completed, saturated ammonium chloride solution (30 mL) was added to the system to quench the reaction. The mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-50%) to obtain the title compound (330.0 mg).

[0449] MS m / z(ESI):348.1[M+H] + .

[0450] Step 2: Synthesis of tert-butyl (6-(1-chloro-3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 22-3)

[0451] Intermediate 22-2 (100.0 mg) was dissolved in dichloromethane (2 mL), and thionyl chloride (0.1 mL) was added dropwise at 0°C. The mixture was kept at 0°C for 0.5 h, and then stirred at room temperature for 4 h. After the reaction, the reaction solution was slowly added dropwise to saturated sodium bicarbonate solution (30 mL), and extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the title compound (120.0 mg).

[0452] MS m / z(ESI):366.0[M+H] + .

[0453] Step 3: Synthesis of tert-butyl (6-(cis-3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl]carbamate and tert-butyl (6-(trans-3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl]carbamate (Intermediates 22-4-P1 and 22-4-P2)

[0454] Intermediate 22-3 (100.0 mg) was dissolved in ethyl acetate (5 mL), and wet palladium carbon (palladium content 10%, 3.0 mg) was added. The reaction was allowed to react at room temperature for 16 h under a hydrogen atmosphere. After the reaction was completed, the mixture was filtered through a pad of celite and washed with ethyl acetate. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether 0-50%) to obtain the title compounds 22-4-P1 (24.0 mg) and 22-4-P2 (18.0 mg). The two isomers were analyzed by chromatographic methods:

[0455] The retention time of 22-4-P1 was 8.653 min, and the retention time of 22-4-P2 was 8.872 min.

[0456] MS m / z(ESI):332.1[M+H] + .

[0457] Step 4: Synthesis of cis-3-(2-aminothiazolo[4,5-b]pyrazin-6-yl)cyclobutane-1-carbonitrile and trans-3-(2-aminothiazolo[4,5-b]pyrazin-6-yl)cyclobutane-1-carbonitrile (Intermediates 22-5-P1 and 22-5-P2)

[0458] Intermediate 22-4-P1 (24.0 mg) was dissolved in dichloromethane (2 mL), cooled and stirred, and trifluoroacetic acid (2 mL) was slowly added dropwise at 0°C. The mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (15 mL), washed twice with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the title compound 22-5-P1 (15.0 mg).

[0459] MS m / z(ESI):232.1[M+H] + .

[0460] Intermediate 22-4-P2 (18.0 mg) was dissolved in dichloromethane (2 mL), cooled and stirred, and trifluoroacetic acid (2 mL) was slowly added dropwise at 0°C. The mixture was allowed to react at room temperature for 2 h. After the reaction was complete, the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in ethyl acetate (15 mL), washed twice with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the title compound 22-5-P2 (13.0 mg).

[0461] MS m / z(ESI):232.1[M+H] + .

[0462] Step 5: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(cis-3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide and 4-(5-chloro-2-methoxyphenyl)-N-(6-(trans-3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 22-P1 and Compound 22-P2)

[0463] Intermediate Int2 (50.0 mg) was dissolved in N,N-dimethylformamide (1 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (68.0 mg) and N,N-diisopropylethylamine (63.0 μL) were added. The mixture was allowed to react at room temperature for 2 h. After the reaction, the system was diluted with dichloromethane (10 mL), washed twice with water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1 mL). The above solution was divided into two equal portions (0.5 mL). Intermediate 22-5-P1 (15.0 mg) was added to one portion, and intermediate 22-5-P2 (13.0 mg) was added to the other portion. N,N-diisopropylethylamine (34 μL) was added to each reaction system, and the reaction was heated at 45°C for 16 h. After the reaction was completed, the product was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, acetonitrile ratio 45-95%) to obtain the title compounds 22-P1 (2.0 mg) and 22-P2 (2.0 mg). The two isomers were analyzed by chromatography:

[0464] MS m / z(ESI):491.0[M+H] + .

[0465] Compound 22-P1

[0466] Under the above chromatographic conditions, the retention time of compound 22-P1 was 8.622 min.

[0467] 1H NMR (400MHz, DMSO-d6) δ8.92(s,1H),8.22(s,1H),7.40-7.37(m,1H),7.30(s,1H),7.20(s,1H),6. 98(d,J=8.8Hz,1H),3.81-3.60(m,1H),3.50(s,3H),3.39(m,1H),2.71-2.56(m,4H),2.54(s,3H).

[0468] Compound 22-P2

[0469] Under the above chromatographic conditions, the retention time of compound 22-P2 was 8.841 min.

[0470] 1 H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.30(s,1H),7.40-7.38(m,1H),7.33(s,1H),7.23(s,1H),6.98 (d,J=8.8Hz,1H),4.05-3.94(m,1H),3.49(s,3H),3.48-3.42(m,1H),2.60-2.73(m,4H),2.55(s,3H).

[0471] Example 23. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(3-cyanoazetidin-1-yl)thiazolyl[4,5-b]pyrazin-2-yl]-6-methylnicotinamide (Compound 23)

[0472] Intermediate Int4 (102.0 mg), starting material 23-1 (37.0 mg), tris(dibenzylideneacetone)dipalladium (38.0 mg), (2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl) (19.0 mg), and cesium carbonate (203.0 mg) were added to 1,4-dioxane (2 mL) and heated at 100°C under nitrogen for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 45-80% acetonitrile ratio) to obtain the title compound (5.0 mg).

[0473] MS m / z(ESI):492.0[M+H] + .

[0474] 1H NMR(400MHz,DMSO-d6)δ8.75(s,1H),7.91(s,1H),7.45-7.42(m,2H),7.36(s,1H),7.01-6.9 8(m,1H),4.38-4.34(m,2H),4.26-4.22(m,2H),3.98-3.90(m,1H),3.49(s,3H),2.57(s,3H).

[0475] Example 24. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(4-cyanocyclohex-1-en-1-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 24)

[0476] Step 1: Synthesis of tert-butyl N-[6-(4-cyanocyclohex-1-en-1-yl)thiazolo[4,5-b]pyrazin-2-yl]carbamate (Intermediate 24-2)

[0477] Intermediate Int1 (500.0 mg), starting material 24-1 (422.3 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (109.5 mg), and potassium carbonate (417.3 mg) were dissolved in 1,4-dioxane (5 mL) and water (1 mL). The mixture was heated at 100°C under nitrogen for 16 h. After the reaction, the system was diluted with ethyl acetate (30 mL), washed twice with water (10 mL x 2), washed once with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was added to a mixed solvent (20 mL) (petroleum ether / ethyl acetate = 5 / 1), stirred, and filtered. The filter cake was washed with petroleum ether and dried to obtain the title compound (250.0 mg).

[0478] MS m / z(ESI):358.2[M+H] + .

[0479] Step 2: Synthesis of 4-(2-aminothiazolo[4,5-b]pyrazin-6-yl)cyclohex-3-ene-1-carbonitrile trifluoroacetate (Intermediate 24-3)

[0480] Intermediate 24-2 (250.0 mg) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (3 mL) was added dropwise. The mixture was reacted at room temperature for 1 h. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure to obtain the title compound (250.0 mg), which was used directly in the next reaction without further purification.

[0481] MS m / z(ESI):258.1[M+H] + .

[0482] Step 3: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(4-cyanocyclohex-1-en-1-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 24)

[0483] Intermediate Int2 (202.0 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (139.7 mg), and 1-hydroxybenzotriazole (98.5 mg) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 10 min. N,N-diisopropylethylamine (188.6 mg) and Intermediate 24-3 (180.0 mg) were then added and heated at 45°C for 18 h. After the reaction, the system was diluted with ethyl acetate (25 mL) and washed twice with saturated brine (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative chromatography (YMC TAR column, mobile phase A: 7 mmol aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile, 45-75% acetonitrile ratio, elution time: 8 min) to obtain the title compound (21.0 mg).

[0484] MS m / z(ESI):517.1[M+H] + .

[0485] 1 H NMR(400MHz,DMSO-d6)δ13.29(s,1H),8.80(m,2H),7.45(m,2H),7.38(s,1H),7.04-6.96(m,1H),6. 79(s,1H),3.50(s,3H),3.18(m,1H),2.73-2.61(m,3H),2.59(s,3H),2.54(m,1H)2.11-1.95(m,2H).

[0486] Example 25. Synthesis of 4-(2-chloro-5-methoxy-4-pyridinyl)-N-[6-(4-cyano-1-piperidinyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 25)

[0487] Step 1: Synthesis of tert-butyl N-[6-(4-cyano-1-piperidinyl)thiazolo[4,5-b]pyrazin-2-yl]carbamate (Intermediate 25-2)

[0488] Intermediate Int1 (200.0 mg), starting material Intermediate 25-1 (86.5 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (42.9 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (56.4 mg), and sodium tert-butoxide (174.1 mg) were dissolved in 1,4-dioxane (3 mL) and heated at 100°C under nitrogen for 16 h. After the reaction, the system was diluted with ethyl acetate (25 mL), washed twice with water (10 mL x 2), once with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (methanol:dichloromethane 0-10%) to obtain the title compound (160.0 mg).

[0489] MS m / z(ESI):361.1[M+H] + .

[0490] Step 2: Synthesis of 1-(aminothiazolo[4,5-b]pyrazin-6-yl)piperidine-4-carbonitrile trifluoroacetate (Intermediate 25-3)

[0491] Intermediate 25-2 (160.0 mg) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (3 mL) was added dropwise. The mixture was stirred at room temperature for 1 h. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure to obtain the title compound (165.0 mg).

[0492] MS m / z(ESI):261.2[M+H] + .

[0493] Step 3: Synthesis of 4-(2-chloro-5-methoxy-4-pyridinyl)-N-[6-(4-cyano-1-piperidinyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 25)

[0494] Intermediate Int3 (150.0 mg) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl) hexafluorophosphate (243.6 mg) were dissolved in N,N-dimethylformamide (5 mL), and N,N-diisopropylethylamine (166.9 mg) was added. The reaction was stirred at room temperature for 1 hour. Intermediate 25-3 (165.0 mg) was then added, and the reaction was heated at 45°C for 18 hours. After the reaction, the system was diluted with ethyl acetate (30 mL), washed twice with water (10 mL x 2) and once with saturated brine (10 mL x 1). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TA column, mobile phase A: 0.5‰ formic acid in water, mobile phase B: acetonitrile, 50-80% acetonitrile, elution time: 8 min) to obtain the title compound (26.0 mg).

[0495] MS m / z(ESI):521.1[M+H] + .

[0496] 1 H NMR(400MHz,DMSO-d6)δ13.01(s,1H),8.84(s,1H),8.38(s,1H),8.17(s,1H),7.58(s,1H),7.46(s,1 H),3.91(m,2H),3.62(s,3H),3.46(m,2H),3.16(m,1H),2.60(s,3H),2.03-1.93(m,2H),1.79(m,2H).

[0497] Example 26. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(4-cyano-4-methyl-1-piperidinyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 26)

[0498] Intermediate Int4 (80.0 mg), starting material Intermediate 26-1 (26.3 mg), sodium tert-butoxide (54.8 mg), (2-bicyclohexylphosphino-2',6'-diisopropoxybiphenyl) (15.2 mg), and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (11.6 mg) were added to 1,4-dioxane (1 mL) and heated at 100°C under nitrogen for 16 h. After the reaction was complete, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, acetonitrile ratio 75-95%) to obtain the title compound (20.0 mg).

[0499] MS m / z(ESI):534.0[M+H] + .

[0500] 1 H NMR (400MHz, DMSO-d6) δ12.84(s,1H),8.73(s,1H),8.38(s,1H),7.46-7.43(m,2H),7.38(s,1H),7.02-6.99(m ,1H),4.35(m,2H),3.50(s,3H),3.13-3.07(m,2H),2.58(s,3H),1.98(m,2H),1.65-1.58(m,2H),1.39(s,3H).

[0501] Example 27. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(4-cyano-4-fluoro-1-piperidinyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 27)

[0502] Intermediate Int4 (100.0 mg) and starting material 27-1 (43.6 mg) were dissolved in dioxane (2 mL). Tris(dibenzylideneacetone)dipalladium (37.3 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (19.0 mg), and cesium carbonate (199.1 mg) were added. The mixture was then stirred under nitrogen at 100°C for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to remove some of the solvent. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 75-95% acetonitrile) to obtain the title compound (16.0 mg).

[0503] MS m / z(ESI):538.1[M+H] + .

[0504] 1 H NMR(400MHz,DMSO-d6)δ12.88(s,1H),8.73(s,1H),8.44(s,1H),7.46(s,1H),7.46-7.42(m,1H),7.39(s,1H),7.06- 6.92(m,1H),3.90-3.79(m,2H),3.78-3.65(m,2H),3.50(s,3H),2.59(s,3H),2.45-2.28(m,2H),2.23-2.21(m,2H).

[0505] Example 28. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-8-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 28)

[0506] Step 1: Synthesis of 8-bromo-3,4-dihydro-2H-pyrido[1,2-a]pyrimidine (Intermediate 28-2)

[0507] Starting material 28-1 (1.0 g) was dissolved in N,N-dimethylformamide (15 mL). Sodium hydride (924.8 mg, 60% in mineral oil) was added at 0°C and stirred for 30 min. 1,3-Dibromopropane (1.3 g) was then added dropwise and allowed to react at room temperature for 1 h. Upon completion of the reaction, the reaction solution was quenched with ice water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0%-50%) to obtain the title compound (0.2 g).

[0508] Step 2: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(3,4-dihydro-2H-pyrido[1,2-a]pyrimidin-8-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 28)

[0509] Intermediate 28-2 (74.8 mg) was dissolved in dioxane (1 mL) and water (0.1 mL). Intermediate Int7 (80.0 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (27.6 mg), and potassium phosphate (111.7 mg) were added. Under nitrogen, the system was heated at 100°C for 2 h. After the reaction was complete, the mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 75-95% acetonitrile) to obtain the title compound (8.0 mg).

[0510] MS m / z(ESI):544.1[M+H] + .

[0511] 1 H NMR (400MHz, DMSO-d6) δ13.41(s,1H),9.04(s,1H),8.87(s,1H),8.08(d,J=5 .4Hz,1H),7.46-7.41(m,1H),7.41(s,1H),7.31(s,1H),7.25(s,1H),7.22-7. 16(m,1H),7.00(d,J=8.8Hz,1H),6.92-6.82(m,1H),6.02-5.88(m,1H),5.28- 5.17(m,1H),5.10-5.03(m,1H),4.00-3.92(m,2H),3.51(s,3H),2.57(s,3H).

[0512] Example 29. Synthesis of N-[6-(4-acetylphenyl)thiazolo[4,5-b]pyrazin-2-yl]-4-(5-chloro-2-methoxyphenyl)-6-methylpyridine-3-carboxamide (Compound 29)

[0513] Step 1: Synthesis of tert-butyl N-[6-(4-acetylphenyl)thiazolo[4,5-b]pyrazin-2-yl]carbamate (Intermediate 29-2)

[0514] Starting material 29-1 (2.0 g), intermediate Int1 (3.3 g), and potassium carbonate (2.9 g) were dissolved in a mixed solvent of dioxane and water (60 mL). 1,1-Bis(diphenylphosphino)diphenylferric palladium chloride (361.0 mg) was added and the mixture was heated at 90°C under nitrogen for 6 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure. The residue was added with water (60 mL) and dichloromethane (60 mL), stirred, and the layers separated. The aqueous phase was extracted twice with dichloromethane (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the title compound (3.5 g).

[0515] MS m / z(ESI):371.1[M+H] + .

[0516] Step 2: Synthesis of 1-[4-(2-aminothiazolo[4,5-b]pyrazin-6-yl)phenyl]ethanone (Intermediate 29-3)

[0517] Intermediate 29-2 (3.5 g) was dissolved in trifluoroacetic acid (50 mL) and stirred at room temperature for 4 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure. The residue was added with ethyl acetate (60 mL) and saturated aqueous sodium bicarbonate solution (60 mL), stirred, and filtered. The filter cake was washed with ethyl acetate and dried to obtain the title compound (2.1 g).

[0518] MS m / z(ESI):271.1[M+H] + .

[0519] Step 3: Synthesis of N-[6-(4-acetylphenyl)thiazolo[4,5-b]pyrazin-2-yl]-4-(5-chloro-2-methoxyphenyl)-6-methylpyridine-3-carboxamide (Compound 29)

[0520] Intermediate 29-3 (270.0 mg), intermediate Int2 (277.0 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (570.0 mg), and N,N-diisopropylethylamine (390.0 mg) were dissolved in N,N-dimethylformamide (20 mL) and stirred at room temperature for 16 h. After the reaction, the reaction solution was diluted with ethyl acetate (60 mL), washed twice with water (25 mL x 2) and once with saturated brine (25 mL x 1). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (column: YMC C18; mobile phase: B%: 10%-90%, B is acetonitrile, 25 mL / min) to obtain the title compound (15.0 mg).

[0521] MS m / z(ESI):530.1[M+H] + .

[0522] 1 H NMR(400MHz,CD3OD)δ9.15(s,1H),8.81(s,1H),8.32-8.27(m,2H),8.18 -8.13(m,2H),7.50-7.46(m,1H),7.44-7.39(m,2H),7.00-6.96(m,1H),3.63(s,3H),2.69(m,6H).

[0523] Example 30, Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(3-cyano-1-hydroxy-cyclobutyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 30)

[0524] Step 1: Synthesis of tert-butyl N-[6-(3-cyano-1-hydroxycyclobutyl)thiazolo[4,5-b]pyrazin-2-yl]carbamate (Intermediate 30-2)

[0525] Intermediate Int1 (1.0 g) was added to a dry three-necked flask. Under nitrogen, anhydrous tetrahydrofuran (10 mL) was added and the mixture was cooled to -78°C with stirring. When the internal temperature reached -78°C, a 2.5 M solution of n-butyllithium in n-hexane (2.5 mL) was slowly added dropwise. The mixture was kept at -78°C for 1 h. Subsequently, a solution of starting material 30-1 (345.0 mg) in tetrahydrofuran was slowly added to the reaction system and the reaction continued for 2 h. Upon completion of the reaction, the reaction was quenched by the addition of saturated ammonium chloride solution (30 mL). The mixture was extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-50%) to obtain the title compound (330.0 mg).

[0526] MS m / z(ESI):348.1[M+H] + .

[0527] Step 2: Synthesis of 3-(2-aminothiazolo[4,5-b]pyrazin-6-yl)-3-hydroxy-cyclobutanecarbonitrile (Intermediate 30-3)

[0528] Intermediate 30-2 (15.0 mg) was dissolved in dichloromethane (1 mL). The system was cooled and stirred. Trifluoroacetic acid (1 mL) was slowly added dropwise at 0°C and allowed to react at room temperature for 4 h. After the reaction was complete, the mixture was concentrated to dryness under reduced pressure. The residue was added to ethyl acetate (10 mL) and saturated sodium bicarbonate solution (10 mL), stirred, and filtered. The filter cake was washed with ethyl acetate and dried to obtain the title compound (10.0 mg), which was used directly in the next step without further purification.

[0529] MS m / z(ESI):248.1[M+H] + .

[0530] Step 3: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(3-cyano-1-hydroxy-cyclobutyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 30)

[0531] Intermediate Int2 (22.0 mg) was dissolved in dichloromethane (1 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (31.0 mg) and N,N-diisopropylethylamine (21 μL) were added. The mixture was allowed to react at room temperature for 2 h. After the reaction, the system was diluted with dichloromethane (20 mL) and washed twice with water (5 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1 mL), and intermediate 30-3 (10.0 mg) and N,N-diisopropylethylamine (21 μL) were added. The reaction was heated at 45°C for 16 h. After the reaction was completed, the product was concentrated to dryness under reduced pressure and the residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, acetonitrile ratio 25 mL / min, 45-95%) to give the title compound (2.0 mg).

[0532] MS m / z(ESI):507.1[M+H] + .

[0533] 1 H NMR(400MHz,DMSO-d6)δ13.30(s,1H),8.79(s,1H),8.74(s,1H),7.46-7.43(m,2H),7.38(s,1H),7.01-6.9 9(m,1H),6.58(s,1H),3.49(s,3H),3.30-3.21(m,1H),3.07-2.94(m,2H),2.68-2.63(m,2H),2.59(s,3H).

[0534] Example 31. Synthesis of N-[6-(6-azaspiro[2.5]octan-6-yl)thiazolo[4,5-b]pyrazin-2-yl]-4-(5-chloro-2-methoxy-phenyl)-6-methyl-pyridine-3-carboxamide (Compound 31)

[0535] Intermediate Int4 (100.0 mg) and starting material 31-1 (45.1 mg) were dissolved in dioxane (2 mL). Tris(dibenzylideneacetone)dipalladium (37.3 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (19.0 mg), and cesium carbonate (199.1 mg) were added. The mixture was then stirred under nitrogen at 100°C for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove some of the solvent. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 75-95% acetonitrile) to obtain the title compound (6.0 mg).

[0536] MS m / z(ESI):521.1[M+H] + .

[0537] 1 H NMR(400MHz,DMSO-d6)δ12.80(s,1H),8.73(s,1H),8.35(s,1H),7.45(s,1H),7.45-7.42(m,1H),7.38( s,1H),7.04-6.96(m,1H),3.77-3.60(m,4H),3.50(s,3H),2.58(s,3H),1.49-1.28(m,4H),0.37(s,4H).

[0538] Example 32, Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(2-oxa-7-azaspiro[3.5]non-7-yl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 32)

[0539] Intermediate Int4 (100.0 mg) and starting material 32-1 (38.9 mg) were dissolved in dioxane (2 mL). Tris(dibenzylideneacetone)dipalladium (37.3 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (19.0 mg), and cesium carbonate (199.1 mg) were added. The mixture was then stirred under nitrogen at 100°C for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove some of the solvent. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 75-95% acetonitrile) to obtain the title compound (7.5 mg).

[0540] MS m / z(ESI):537.1[M+H] + .

[0541] 1 H NMR(400MHz,DMSO-d6)δ12.82(s,1H),8.73(s,1H),8.35(s,1H),7.46 -7.45(m,1H),7.44-7.42(m,1H),7.38(s,1H),7.04-6.96(m,1H),4.36( s,4H),3.63-3.52(m,4H),3.50(s,3H),2.58(s,3H),1.96-1.78(m,4H).

[0542] Example 33. Synthesis of N-[6-(4-carbamoylpiperidin-1-yl)thiazolo[4,5-b]pyrazin-2-yl]-4-(5-chloro-2-methoxyphenyl)-6-methylnicotinamide (Compound 33)

[0543] Intermediate Int4 (30.0 mg), starting material 33-1 (78.4 mg), and N,N-diisopropylethylamine (15.8 mg) were dissolved in N-methylpyrrolidone (1 mL) and heated at 130°C for 16 h under nitrogen. After the reaction, the system was diluted with ethyl acetate (30 mL) and washed twice with saturated brine (10 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative chromatography (YMC TAR column, mobile phase A: 7 mmol / L aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile, acetonitrile ratio 30-55%) to obtain the title compound (7.0 mg).

[0544] MS m / z(ESI):538.1[M+H] + .

[0545] 1 H NMR (400MHz, DMSO-d6) δ12.76(s,1H),8.67(s,1H),8.26(s,1H),7.37(d,J=6.3Hz,2H),7.30(s,1H),7.25(s,1H),6.93(d,J=9.5Hz,1H) ,6.75(s,1H),4.28-4.25(m,2H),3.43(s,3H),2.91-2.84(m,2H),2.51(s,3H),2.37-2.25(m,1H),1.75-1.72(m,2H),1.53-1.45(m,2H).

[0546] Example 34. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-(6-(4-(2-hydroxypropane-2-yl)piperidin-1-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (Compound 34)

[0547] Intermediate Int4 (100.0 mg), starting material 34-1 (38.0 mg), cesium carbonate (166.0 mg), tris(dibenzylideneacetone)dipalladium (18.7 mg), and (2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl) (19.0 mg) were added to 1,4-dioxane (1 mL) and heated at 100°C under nitrogen for 16 h. After the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 75-95% acetonitrile) to obtain the title compound (10.0 mg).

[0548] MS m / z(ESI):553.1[M+H] + .

[0549] 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),8.74(s,1H),8.31(s,1H),7.42-7.46(m,2H),7.37(s,1H),7.01-6.99(m,1H),4.44-4.41(m,2 H),4.15(s,1H),3.50(s,3H),2.77-2.83(m,2H),2.58(s,3H),1.82-1.79(m,2H),1.43-1.49(m,1H),1.20-1.29(m,2H),1.05(s,6H).

[0550] Example 35. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-(6-(4-isopropyl-1-piperidinyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-pyridine-3-carboxamide (Compound 35)

[0551] Intermediate Int4 (70.0 mg), starting material 35-1 (36.3 mg), tris(dibenzylideneacetone)dipalladium (26.1 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (13.3 mg), and cesium carbonate (139.4 mg) were dissolved in 1,4-dioxane (3 mL) and heated at 100°C under nitrogen for 16 h. After the reaction, the system was diluted with ethyl acetate (25 mL) and washed three times with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TA column, mobile phase A: 7 mmol / L aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile, acetonitrile ratio 0-100%, elution time 8 min) to obtain the title compound (4.9 mg).

[0552] MS m / z(ESI):537.1[M+H] + .

[0553] 1 H NMR (400MHz, DMSO-d6) δ12.72(s,1H),8.66(s,1H),8.25(s,1H),7.46-7.43(m,2H),7.38(s,1H),6.98-6.89(m,1H),4.40-4.37(m, 2H),3.44(s,3H),2.87-2.81(m,2H),2.52(s,3H),1.76-1.73(m,2H),1.46-1.43(m,1H),1.21-1.14(m,3H),0.81(d,J=6.7Hz,6H).

[0554] Example 36. Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-[6-(4-methoxy-1-piperidinyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide (Compound 36)

[0555] Intermediate Int4 (49.4 mg), starting material 36-1 (23.2 mg), 2-bicyclohexylphosphino-2',6'-diisopropoxybiphenyl (5.2 mg), and sodium tert-butoxide (38.4 mg) were dissolved in dioxane (2 mL). Di-tert-butyl-(4-dimethylaminophenyl)phosphine palladium dichloride (7.1 mg) was added. The mixture was heated at 100°C under nitrogen for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (column: YMC C18; mobile phase: 0.1% aqueous ammonium bicarbonate; B%: 10%-90%, B is acetonitrile, 25 mL / min) to obtain the title compound (9.0 mg).

[0556] MS m / z(ESI):525.1[M+H] + .

[0557] 1 H NMR(400MHz, CDCl3)δ9.51(s,1H),8.92(s,1H),8.08(s,1H),7.41-7.35(m,1H),7.29-7.27(m,1H),7.14(s,1H),6.90-6.83(m, 1H),4.03-3.93(m,2H),3.71(s,3H),3.51-3.45(m,1H),3.43-3.31(m,4H),2.67(s,3H),2.04-1.93(m,2H),1.73-1.63(m,2H).

[0558] Example 37. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-[4-(cyanomethyl)-1-piperidinyl]thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 37)

[0559] Intermediate Int4 (50.0 mg), starting material 37-1 (21.3 mg), cesium carbonate (116.2 mg), tris(dibenzylideneacetone)dipalladium (9.3 mg), and (2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl) (9.5 mg) were added to 1,4-dioxane (1 mL) and heated at 100°C under nitrogen for 16 h. After the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, acetonitrile ratio 75-95%) to obtain the title compound (60.0 mg).

[0560] MS m / z(ESI):534.1[M+H] + .

[0561] 1 H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.31(s,1H),7.42-7.45(m,2H),7.35(s,1H),6.99-7.01(m,1H), 4.37-4.34(m,2H),3.50(s,3H),2.96-2.90(m,2H),2.58(s,3H),2.56-2.54(m,2H),1.89-1.95(m,1H), 1.83-1.80(m,2H),1.24-1.35(m,2H).

[0562] Example 38. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(4-methyl-3-oxo-piperazin-1-yl)thiazolyl[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 38)

[0563] Intermediate Int4 (50.0 mg), starting material 38-1 (17.0 mg), tris(dibenzylideneacetone)dipalladium (19.0 mg), (2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl) (10.0 mg), and cesium carbonate (100.0 mg) were added to 1,4-dioxane (1 mL) and heated at 100°C under nitrogen for 16 h. After the reaction, the reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, acetonitrile ratio 75-95%) to obtain the title compound (5.0 mg).

[0564] MS m / z(ESI):524.1[M+H] + .

[0565] 1 H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.32(s,1H),7.45-7.43(m,2H),7.37(s,1H),7.03-6.95(m ,1H),4.15(s,2H),3.90-3.87(m,2H),3.49(s,3H),3.48-3.45(m,2H),2.91(s,3H),2.58(s,3H).

[0566] Example 39. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 39)

[0567] Starting material 39-1 (34.3 mg), intermediate Int4 (100.0 mg), tris(dibenzylideneacetone)dipalladium (37.3 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (19.0 mg), and cesium carbonate (199.2 mg) were added to dioxane (2 mL) and heated at 100°C under nitrogen for 18 h. After the reaction, ethyl acetate (20 mL) and water (20 mL) were added to the reaction solution, stirred, and the layers separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ ammonium bicarbonate-water & acetonitrile system, 25 mL / min, 40-60% acetonitrile) to obtain the title compound (20.0 mg).

[0568] MS m / z(ESI):578.1[M+H] + .

[0569] 1 H NMR (400MHz, DMSO-d6) δ12.85(s,1H),8.73(s,1H),8.34(s,1H),7.45(d,J=7.1Hz,2H),7.38 (s,1H),7.03-6.97(m,1H),3.60(m,4H),3.50(s,3H),3.26(m,2H),2.75(m,4H),2.58(s,3H).

[0570] Example 40. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(4-ethylpiperazin-1-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide (Compound 40)

[0571] Intermediate Int4 (70.0 mg), starting material 40-1 (32.6 mg), tris(dibenzylideneacetone)dipalladium (26.1 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (13.3 mg), and cesium carbonate (139.4 mg) were dissolved in 1,4-dioxane (3 mL) and heated at 100°C under nitrogen for 16 h. After the reaction, the system was diluted with ethyl acetate (25 mL) and washed three times with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TA column, mobile phase A: 7 mmol / L aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile, 60-90% acetonitrile ratio, elution time: 8 min) to obtain the title compound (14.0 mg).

[0572] MS m / z(ESI):524.2[M+H] + .

[0573] 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),8.73(s,1H),8.33(s,1H),7.47-7.42(m,2H),7.37(s,1H),7. 02-6.98(m,1H),3.59-3.58(m,4H),3.50(s,3H),2.58(s,3H),2.41-2.36(m,2H),1.06-1.02(m,3H).

[0574] Example 41. Synthesis of N-[6-(4-acetylpiperazin-1-yl)thiazolo[4,5-b]pyrazin-2-yl]-4-(5-chloro-2-methoxy-phenyl)-6-methyl-pyridine-3-carboxamide (Compound 41)

[0575] Intermediate Int4 (55.0 mg), starting material 41-1 (22.0 mg), tris(dibenzylideneacetone)dipalladium (21.0 mg), (2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl) (10.0 mg), and cesium carbonate (110.0 mg) were added to 1,4-dioxane (1 mL) and heated at 100°C under nitrogen for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, acetonitrile ratio 75-95%) to obtain the title compound (5.0 mg).

[0576] MS m / z(ESI):538.1[M+H] + .

[0577] 1 H NMR(400MHz,DMSO-d6)δ8.75(s,1H),8.33(s,1H),7.46-7.41(m,2H),7.36(s,1H),7.03-6 .97(m,1H),3.67-3.61(m,2H),3.59-3.58(m,6H),3.50(s,3H),2.58(s,3H),2.05(s,3H).

[0578] Example 42: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-[6-[4-methyl-3-(trifluoromethyl)piperazin-1-yl]thiazolo[4,5-b]pyrazin-2-yl]nicotinamide (Compound 42)

[0579] Step 1: Synthesis of 1-methyl-2-trifluoromethylpiperazine (Intermediate 42-2)

[0580] The starting material 42-1 (680.0 mg) was dissolved in a methanol / acetic acid mixture (10 mL). 10% wet palladium on carbon (200.0 mg) was added and the system was reacted at room temperature under a hydrogen atmosphere for 16 h. After the reaction was completed, the mixture was filtered through a pad of celite and the filter cake was washed with methanol. The filtrate was concentrated to dryness under reduced pressure. Acetonitrile (10 mL) and water (3 mL) were added to the residue, and potassium carbonate (1.0 g) was added. The reaction was stirred for 2 h. The reaction solution was filtered and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (440.0 mg).

[0581] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-[6-[4-methyl-3-trifluoromethyl)piperazin-1-yl]thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 42)

[0582] Intermediate Int4 (49.0 mg), intermediate 42-2 (34.0 mg), 2-bicyclohexylphosphino-2',6'-diisopropoxybiphenyl (5.0 mg), and sodium tert-butoxide (38.4 mg) were dissolved in dioxane (2 mL). Di-tert-butyl-(4-dimethylaminophenyl)phosphine palladium dichloride (7.1 mg) was added. The mixture was heated at 100°C under nitrogen for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (column: YMC C18; mobile phase: 0.1% aqueous ammonium bicarbonate; B%: 20%-90%, B is acetonitrile, 25 mL / min) to obtain the title compound (8.0 mg).

[0583] MS m / z(ESI):578.1[M+H] + .

[0584] 1 H NMR(400MHz, CDCl3)δ9.66(s,1H),8.91(s,1H),8.04(s,1H),7.41-7.35(m,1H),7.14(s,1H),6.89-6.84(m,1H),4.14-4 .05(m,1H),3.82-3.75(m,1H),3.74-3.62(m,4H),3.57-3.49(m,1H),3.09-2.98(m,2H),2.71-2.61(m,4H),2.57(s,3H).

[0585] Example 43. Synthesis of 4-(5-chlorobenzofuran-7-yl)-N-[6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide (Compound 43)

[0586] Step 1: Synthesis of 2-(5-chlorobenzofuran-7-yl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane (Intermediate 43-2)

[0587] Starting material 43-1 (1.0 g), pinacol diboron (1.3 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (156.8 mg), and potassium acetate (1.3 g) were added to 1,4-dioxane (10 mL) and heated at 100°C under nitrogen for 16 h. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was flash purified (ethyl acetate:petroleum ether 0-50%) to afford the title compound (0.9 g).

[0588] MS m / z(ESI):279.5[M+H] + .

[0589] Step 2: Synthesis of 4-(5-chlorobenzofuran-7-yl)-6-methyl-pyridine-3-carboxylic acid methyl ester (Intermediate 43-3)

[0590] Intermediate 43-2 (689.9 mg), methyl 4-chloro-6-methyl-pyridine-3-carboxylate hydrochloride (500.0 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (163.4 mg), and potassium carbonate (933.5 mg) were added to 1,4-dioxane (10 mL) and water (2 mL). The mixture was heated at 90°C under nitrogen for 16 h. After the reaction was complete, the mixture was concentrated to dryness under reduced pressure, and the residue was purified with Flash (ethyl acetate:petroleum ether 0-20%) to obtain the title compound (0.5 g).

[0591] MS m / z(ESI):302.7[M+H] + .

[0592] Step 3: Synthesis of 4-(5-chlorobenzofuran-7-yl)-6-methyl-pyridine-3-carboxylic acid (Intermediate 43-4)

[0593] Intermediate 43-3 (475.0 mg) was added to tetrahydrofuran (10 mL) and water (5 mL), followed by the addition of lithium hydroxide monohydrate (145.5 mg). The mixture was heated to react for 16 h. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure. The residue was adjusted to pH 5-6 with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the title compound (400.0 mg).

[0594] MS m / z(ESI):288.7[M+H] + .

[0595] Step 4: Synthesis of 4-(5-chlorobenzofuran-7-yl)-N-[6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide (Compound 43)

[0596] Intermediate 43-4 (30.0 mg) was dissolved in N,N-dimethylformamide (1 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (59.0 mg) and N,N-diisopropylethylamine (40.4 mg) were added. The mixture was heated for 1 h, and then Intermediate Int5 (26.4 mg) was added. The mixture was heated at 45°C for 16 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove some of the solvent, and the residue was purified by reverse phase chromatography (water:acetonitrile 0%-100%) to obtain the title compound (27.0 mg).

[0597] MS m / z(ESI):523.0[M+H]+ .

[0598] 1 H NMR(400MHz,DMSO-d6)δ13.61(s,1H),9.34(s,1H),8.97(s,1H),8.35-8.39(m,2H),8.00-8.02(m,2H),7.92(d ,J=4.0Hz,1H),7.83(d,J=4.0Hz,1H),7.66(s,1H),7.52(d,J=4.0Hz,1H),6.92(d,J=4.0Hz,1H),2.65(s,3H).

[0599] Example 44. Synthesis of N-[6-(3-azabicyclo[3.1.0]hexane-3-yl)thiazolo[4,5-b]pyrazin-2-yl]-4-(5-chloro-2-methoxy-phenyl)-6-methyl-pyridine-3-carboxamide (Compound 44)

[0600] Intermediate Int4 (100.0 mg) and starting material 44-1 (36.5 mg) were dissolved in dioxane (2 mL). Tris(dibenzylideneacetone)dipalladium (37.3 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (19.0 mg), and cesium carbonate (199.1 mg) were added. Under nitrogen, the mixture was stirred at 100°C for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove some of the solvent. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 75-95% acetonitrile) to obtain the title compound (6.0 mg).

[0601] MS m / z(ESI):493.1[M+H] + .

[0602] 1 H NMR(400MHz,DMSO-d6)δ12.77(s,1H),8.72(s,1H),7.95(s,1H),7.45(s,1H),7.45-7.42(m,1H),7.38(s,1H),7.04-6.95(m,1H) ,3.73(d,J=10.3Hz,2H),3.49(s,3H),3.48-3.44(m,2H),2.58(s,3H),1.79-1.69(m,2H),0.81-0.72(m,1H),0.29-0.15(m,1H).

[0603] Example 45. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylnicotinamide (Compound 45)

[0604] Intermediate Int4 (50.0 mg), starting material 45-1 (14.7 mg), cesium carbonate (116.2 mg), tris(dibenzylideneacetone)dipalladium (9.3 mg), and (2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl) (9.5 mg) were added to 1,4-dioxane (1 mL) and heated at 100°C under nitrogen for 16 h. After the reaction was complete, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, acetonitrile ratio 75-95%) to obtain the title compound (3.0 mg).

[0605] MS m / z(ESI):521.1[M+H] + .

[0606] 1 H NMR(400MHz,DMSO-d6)δ12.76(s,1H),8.73(s,1H),7.90(s,1H),7.42-7.45(m,2H),7.37(s,1H),6.98-7.01(m,1 H),3.60-3.63(m,2H),3.49(s,3H),3.47-3.45(m,2H),2.58(s,3H),1.59-1.58(m,2H),1.07(s,3H),0.83(s,3H).

[0607] Example 46. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(3-hydroxy-1-piperidinyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 46)

[0608] Intermediate Int4 (70.0 mg), starting material 46-1 (72.1 mg), and N,N-diisopropylethylamine (36.8 mg) were dissolved in N-methylpyrrolidone (1 mL) and heated at 130°C for 4 h under nitrogen. After the reaction, the system was diluted with ethyl acetate (30 mL) and washed three times with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TAR column, 7 mmol / L aqueous ammonium bicarbonate solution, 38-68% acetonitrile, elution time 8 min) to obtain the title compound (15.0 mg).

[0609] MS m / z(ESI):511.2[M+H] + .

[0610] 1 H NMR(400MHz,DMSO-d6)δ12.43(s,1H),8.75(s,1H),8.27(s,1H),7.47-7.38(m ,2H),7.35(s,1H),7.04-6.95(m,1H),4.90-4.89(m,1H),4.12-4.08(m,1H),3. 93-3.89(m,1H),3.59-3.55(m,1H),3.51(s,3H),3.19-3.09(m,1H),2.98-2.93 (m,1H),2.58(s,3H),1.91-1.87(m,1H),1.80-1.76(m,1H),1.52-1.38(m,2H).

[0611] Example 47. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(3-cyano-1-piperidinyl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 47)

[0612] Starting material 47-1 (34.0 mg) was dissolved in 1,4-dioxane (2.3 mL), and N,N-diisopropylethylamine (53 μL) was added. The mixture was stirred at room temperature for 0.5 h. Intermediate Int4 (100.0 mg), tris(dibenzylideneacetone)dipalladium (37.0 mg), (2-bicyclohexylphosphino-2',6'-diisopropoxybiphenyl) (19.0 mg), and cesium carbonate (199.0 mg) were then added to the system. The reaction was heated at 100°C under nitrogen for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 75-95% acetonitrile) to obtain the title compound (10.0 mg).

[0613] MS m / z(ESI):520.1[M+H] + .

[0614] 1H NMR (400MHz, DMSO-d6) δ8.77(s,1H),8.36(s,1H),7.44-7.41(m,2H),7.33(s,1H),7.01-6.98(m,1H),3.81-3.77(m,4Hz, 1H),3.69(s,1H),3.56-3.54(m,1H),3.50(s,3H),3.15-3.13(m,1H),2.57(s,3H),1.99-1.88(m,2H),1.79-1.56(m,2H).

[0615] Example 48. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-[4-(hydroxymethyl)-1-piperidinyl]thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 48)

[0616] Intermediate Int4 (70.0 mg), starting material 48-1 (82.1 mg), and N,N-diisopropylethylamine (36.8 mg) were dissolved in N-methylpyrrolidone (1 mL) and heated at 130°C for 4 h under nitrogen. After the reaction, the system was diluted with ethyl acetate (30 mL) and washed three times with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TAR column, 7 mmol / L aqueous ammonium bicarbonate solution, 37-55% acetonitrile, elution time 8 min) to obtain the title compound (10.0 mg).

[0617] MS m / z(ESI):525.1[M+H] + .

[0618] 1 H NMR (400MHz, DMSO-d6) δ8.74(s,1H),8.29(s,1H),7.45-7.42(m,2H),7.35(s,1H),7.00(d,J=9.4Hz,1H),4.50-4.48(m,1H) ,4.35-4.32(m,2H),3.50(s,3H),3.29-3.27(m,2H),2.92-2.85(m,2H),2.58(s,3H),1.77-1.74(m,2H),1.19-1.12(m,3H).

[0619] Example 49. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(6,7-dihydro-4H-isoxazolo[4,3-c]pyridin-5-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 49)

[0620] Starting material 49-1 (12.7 mg), intermediate Int4 (50.0 mg), tris(dibenzylideneacetone)dipalladium (18.7 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (9.5 mg), and cesium carbonate (99.6 mg) were added to dioxane (1 mL) and heated at 100°C under nitrogen for 18 h. After the reaction, ethyl acetate (20 mL) and water (20 mL) were added to the reaction solution, stirred, and the layers separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ ammonium bicarbonate-water & acetonitrile system, 25 mL / min, 30-60% acetonitrile) to obtain the title compound (3.0 mg).

[0621] MS m / z(ESI):534.1[M+H] +

[0622] 1 H NMR (400MHz, DMSO-d6) δ12.85(s,1H),8.76(d,J=4.7Hz,2H),8.43(s,1H),7.43(d,J=7.4Hz,2H),7. 35(s,1H),6.99(d,J=9.3Hz,1H),4.74(s,2H),3.99(m,2H),3.49(s,3H),2.93(m,2H),2.57(s,3H).

[0623] Example 50. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(3-methyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)thiazolo[4,5-b]pyrazin-2-yl]nicotinamide (Compound 50)

[0624] Intermediate Int4 (50.0 mg) and starting material 50-1 (35.4 mg) were dissolved in dioxane (1 mL). Tris(dibenzylideneacetone)dipalladium (23.6 mg), 2-dicyclohexylphosphine-2',6'-diisopropoxy-1,1'-biphenyl (9.5 mg), and cesium carbonate (100.0 mg) were added. Under nitrogen, the mixture was stirred at 100°C for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove some of the solvent. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 75-95% acetonitrile) to obtain the title compound (1.0 mg).

[0625] MS m / z(ESI):547.1[M+H] + .

[0626] 1 H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.40(s,1H),7.47(s,1H),7.46-7.38(m,2H),7.33(s,1H),6.99(d, J=8.6Hz,1H),4.63(s,2H),3.97-3.89(m,2H),3.60(s,3H),3.50(s,3H),2.68-2.61(m,2H),2.57(s,3H).

[0627] Example 51. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(1-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridin-5-yl)thiazolo[4,5-b]pyrazin-2-yl]nicotinamide (Compound 51)

[0628] Intermediate Int4 (70.0 mg), starting material 51-1 (195.6 mg), and N,N-diisopropylethylamine (36.9 mg) were dissolved in N-methylpyrrolidone (1 mL) and heated at 130°C for 16 h under nitrogen. After the reaction, the system was diluted with ethyl acetate (30 mL) and washed three times with saturated brine (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TA column, mobile phase A: 7 mmol / L aqueous ammonium bicarbonate solution, mobile phase B: acetonitrile, acetonitrile ratio: 38-68%, elution time: 8 min) to obtain the title compound (14.0 mg).

[0629] MS m / z(ESI):547.1[M+H] + .

[0630] 1H NMR (400MHz, DMSO-d6) δ8.82(s,1H),8.28(s,1H),7.47(s,1H),7.4-7.38(m,1H),7.35(s,1H),7.26(s,1H),6. 98(d,J=8.9Hz,1H),4.50(s,2H),3.98-3.95(m,2H),3.51(s,3H),3.50(s,3H),2.74-2.71(m,2H),2.55(s,3H).

[0631] Example 52. Synthesis of N-[6-(4-(1H-imidazol-1-yl)piperidin-1-yl)thiazolo[4,5-b]pyrazin-2-yl]-4-(5-chloro-2-methoxyphenyl)-6-methylnicotinamide (Compound 52)

[0632] Intermediate Int4 (49.0 mg), starting material 52-1 (30.2 mg), 2-bicyclohexylphosphino-2',6'-diisopropoxybiphenyl (5.0 mg), and cesium carbonate (130.4 mg) were dissolved in dioxane (2 mL). Tris(dibenzylideneacetone)bispalladium (9.2 mg) was added and the mixture was heated at 100°C under nitrogen for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (column: YMC C18; mobile phase: 0.1% aqueous ammonium bicarbonate; B%: 20%-90%, B is acetonitrile, 25 mL / min) to obtain the title compound (7.0 mg).

[0633] MS m / z(ESI):561.1[M+H] + .

[0634] 1 H NMR(400MHz, CDCl3)δ8.92(s,1H),8.14(s,1H),7.60(s,1H),7.41-7.36(m,1H),7.29-7.27(m,1H),7.15(s,1H),7.08(s,1H),6.98(s,1H),6 .89-6.85(m,1H),4.57-4.49(m,2H),4.28-4.19(m,1H),3.71(s,3H), 3.15-3.05(m,2H),2.67(s,3H),2.29-2.20(m,2H),2.06-1.96(m,2H).

[0635] Example 53. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(3-cyano-8-azabicyclo[3.2.1]oct-8-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 53)

[0636] Intermediate Int4 (100.0 mg) and starting material 53-1 (176.0 mg) were dissolved in N-methylpyrrolidone (3 mL), and N,N-diisopropylethylamine (248 μL) was added to the system. The reaction was heated at 130°C for 8 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was directly purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 45-80% acetonitrile ratio) to obtain the title compound (10.0 mg).

[0637] MS m / z(ESI):546.1[M+H] + .

[0638] 1 H NMR(400MHz,DMSO-d6)δ8.74(s,1H),8.23(s,1H),7.48-7.40(m,2H),7.36(s,1H),7.01-6.99(m,1H), 4.64-4.62(m,2H),3.51(s,3H),3.47-3.38(m,1H),2.58(s,3H),2.02-1.98(m,2H),1.94-1.84(m,6H).

[0639] Example 54. Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-[6-(8-cyano-3-azabicyclo[3.2.1]oct-3-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylnicotinamide (Compound 54)

[0640] Step 1: Synthesis of 3-azabicyclo[3.2.1]octane-8-carbonitrile (Intermediate 54-2)

[0641] Starting material 54-1 (1.0 g) was dissolved in dioxane (5 mL), followed by the addition of 4 M hydrochloric acid in dioxane (5 mL) and the reaction mixture was allowed to react at room temperature for 2 h. Upon completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. Acetonitrile (10 mL) and water (3 mL) were added to the residue, along with potassium carbonate (1.0 g), and the mixture was stirred for 2 h. The reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure to afford the title compound (300.0 mg).

[0642] MS m / z(ESI):137.1[M+H] + .

[0643] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-[6-(8-cyano-3-azabicyclo[3.2.1]octan-3-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide (Compound 54)

[0644] Intermediate Int4 (49.0 mg), intermediate 54-2 (27.2 mg), 2-bicyclohexylphosphino-2',6'-diisopropoxybiphenyl (5.0 mg), and cesium carbonate (130.4 mg) were dissolved in dioxane (2 mL). Tris(dibenzylideneacetone)bispalladium (9.2 mg) was added and the mixture was heated at 100°C under nitrogen for 16 h. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure and purified by preparative chromatography (column: YMC C18; mobile phase: 0.1% aqueous ammonium bicarbonate; B%: 10%-90%, B is acetonitrile, 25 mL / min) to obtain the title compound (10.0 mg).

[0645] MS m / z(ESI):546.1[M+H] + .

[0646] 1 H NMR(400MHz, CDCl3)δ8.91(s,1H),8.02-7.96(m,1H),7.41-7.36(m,1H),7.28-7.26(m,1H),7.14(s,1H),6.89-6.83(m,1H),4.13-4.08(m,1H),4 .06-4.00(m,1H),3.71(s,3H),3.45-3.38(m,1H),3.06-3.01(m,1H),2.8 1-2.75(m,2H),2.74-2.64(m,4H),2.16-2.10(m,1H),1.89-1.75(m,3H).

[0647] Example 55. Synthesis of N-[6-(Benzo[d]oxazol-5-yl)thiazolo[4,5-b]pyrazin-2-yl]-4-(5-chloro-2-methoxyphenyl)-6-methylnicotinamide (Compound 55)

[0648] Intermediate Int4 (30.0 mg), starting material 55-1 (18.0 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (4.4 mg), and potassium carbonate (16.9 mg) were added to 1,4-dioxane (1 mL) and water (0.2 mL). The mixture was heated at 90°C under nitrogen for 16 h. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 75-95% acetonitrile) to obtain the title compound (2.0 mg).

[0649] MS m / z(ESI):529.1[M+H] + .

[0650] 1 H NMR (400MHz, DMSO-d6) δ9.13(s,1H),8.91(s,1H),8.82(s,1H),8.52(s,1H),8.22-8.25(m,1H),7.90(d,J= 8.0Hz,1H),7.40-7.43(m,1H),7.36(s,1H),7.27(s,1H),7.00(d,J=8.0Hz,1H),3.52(s,3H),2.57(s,3H).

[0651] Example 56. Synthesis of N-[6-(Benzo[d]oxazol-6-yl)thiazolo[4,5-b]pyrazin-2-yl]-4-(5-chloro-2-methoxyphenyl)-6-methylpyridine-3-carboxamide (Compound 56)

[0652] Step 1: Synthesis of benzo[d]oxazole-5-boronic acid pinacol ester (Intermediate 56-2)

[0653] Starting material 56-1 (594.2 mg), diboron pinacol ester (1.2 g), and potassium acetate (600.0 mg) were dissolved in dioxane (10 mL). 1,1-Bis(diphenylphosphino)diphenylferric palladium chloride (220.0 mg) was added and the mixture was heated at 100°C under nitrogen for 6 h. After the reaction, the reaction solution was concentrated to dryness under reduced pressure. The residue was added with water (30 mL) and dichloromethane (30 mL), stirred, and the layers separated. The aqueous phase was extracted twice with dichloromethane (30 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the title compound (530.0 mg).

[0654] MS m / z(ESI):164.1[M+H] + .

[0655] Step 2: Synthesis of N-[6-(benzo[d]oxazol-6-yl)thiazolo[4,5-b]pyrazin-2-yl]-4-(5-chloro-2-methoxyphenyl)-6-methylpyridine-3-carboxamide (Compound 56)

[0656] Intermediate 56-2 (45.0 mg), intermediate Int4 (49.0 mg), and potassium carbonate (28.4 mg) were dissolved in a mixture of dioxane and water (2 mL). 1,1-Bis(diphenylphosphino)diphenylferric palladium chloride (7.3 mg) was added and the mixture was heated at 90°C under nitrogen for 16 h. After the reaction, the reaction solution was concentrated to dryness under reduced pressure. The residue was added with water (30 mL) and dichloromethane (30 mL), stirred, and separated. The aqueous phase was extracted once with dichloromethane (30 mL x 1). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (column: YMC C18; mobile phase: 0.1% aqueous ammonium bicarbonate; B%: 10%-90%, B is acetonitrile, 25 mL / min) to obtain the title compound (10.0 mg).

[0657] MS m / z(ESI):529.0[M+H] + .

[0658] 1 H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.89(s,1H),8.83(s,1H),8.52(s,1H),8.26-8.19(m,1H),7.92(d ,J=8.4Hz,1H),7.44-7.36(m,2H),7.32-7.25(m,1H),7.01(d,J=8.4Hz,1H),3.52(s,3H),2.57(s,3H).

[0659] Example 57. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)thiazolo[4,5-b]pyrazin-2-yl]nicotinamide (Compound 57)

[0660] Step 1: Synthesis of 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3H-imidazo[4,5-b]pyridine (Intermediate 57-2)

[0661] The starting material 57-1 (300.0 mg), pinacol diboron (431.1 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (114.7 mg), and potassium acetate (277.7 mg) were added to dioxane (3 mL). The mixture was heated at 100°C under nitrogen for 18 hours. After the reaction was complete, ethyl acetate (20 mL) and water (20 mL) were added to the reaction solution, stirred, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain the title compound (360.0 mg).

[0662] MS m / z(ESI):260.3[M+H] + .

[0663] Step 2: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 57)

[0664] Intermediate 57-2 (45.1 mg), intermediate Int4 (57.0 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (7.5 mg), and potassium carbonate (32.1 mg) were added to dioxane (1 mL) and water (0.2 mL). The mixture was heated at 90°C under nitrogen for 18 h. After the reaction, ethyl acetate (20 mL) and water (20 mL) were added to the reaction solution, stirred, and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The title compound (3.7 mg) was obtained by preparative chromatography (YMC TAR column, 0.5‰ ammonium bicarbonate-water & acetonitrile system, 25 mL / min, 30-60% acetonitrile).

[0665] MS m / z(ESI):543.0[M+H] + .

[0666] 1 H NMR (400MHz, DMSO-d6) δ9.08(d,J=2.0Hz,1H),9.01(s,1H),8.92(s,1H),8.65(d,J=2.0Hz,1H),8.47(s,1H),7 .36(m,1H),7.23(d,J=2.7Hz,1H),7.12(s,1H),6.98(d,J=8.8Hz,1H),3.88(s,3H),3.52(s,3H),2.53(s,3H).

[0667] Example 58. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(3-methyl-3H-imidazo[4,5-c]pyridin-6-yl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 58)

[0668] Step 1: Synthesis of 6-bromo-N-methyl-4-nitropyridin-3-amine (Intermediate 58-2)

[0669] Dissolve N,N-diisopropylethylamine (2.8 g) and methylamine hydrochloride (1.5 g) in ethanol (40 mL) and stir for 5 minutes. Then, add starting material 58-1 (4.0 g) and react at room temperature for 4 hours. After the reaction is complete, filter, wash the filter cake with ethanol, and dry it to obtain the title compound (2.7 g), which is used directly in the next reaction.

[0670] Step 2: Synthesis of 6-bromo-N3-methyl-pyridine-3,4-diamine (Intermediate 58-3)

[0671] Intermediate 58-2 (1.2 g) was dissolved in ethanol (20 mL) and water (4 mL), and ammonium chloride (2.2 g) and iron powder (2.3 g) were added. The system was heated at 80°C for 3 h. After the reaction was completed, the reaction solution was cooled to room temperature and filtered through a pad of celite. The filter cake was washed with methanol, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (ethyl acetate:petroleum ether 0%-50%) to obtain the title compound (0.9 g).

[0672] Step 3: Synthesis of 6-bromo-3-methyl-3H-imidazo[4,5-c]pyridine (Intermediate 58-4)

[0673] Intermediate 58-3 (0.9 g) was dissolved in anhydrous methanol (10 mL), and trimethyl orthoformate (2.1 g) and p-toluenesulfonic acid (136.4 mg) were added. The mixture was heated at 100°C for 3 h. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:petroleum ether 0%-50%) to obtain the title compound (760.0 mg).

[0674] Step 4: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(3-methyl-3H-imidazo[4,5-c]pyridin-6-yl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 58)

[0675] Intermediate Int7 (98.9 mg) and intermediate 58-4 (30.0 mg) were dissolved in dioxane (2 mL) and water (0.4 mL). Potassium carbonate (39.1 mg) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (20.5 mg) were added. Under nitrogen, the mixture was stirred and heated at 90°C for 2 h. The mixture was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 75-95% acetonitrile) to obtain the title compound (5.0 mg).

[0676] MS m / z(ESI):543.1[M+H] + .

[0677] 1 H NMR (400MHz, DMSO-d6) δ13.35(s,1H),9.52(s,1H),9.10(s,1H),8.85(s,1H),8.56(d,J=7.0Hz,1H),8.4 7(s,1H),7.47-7.39(m,2H),7.37(s,1H),7.02(d,J=8.0Hz,1H),4.00(s,3H),3.53(s,3H),2.59(s,3H).

[0678] Example 59. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide (Compound 59)

[0679] Step 1: Synthesis of (1,2-dimethyl-1H-benzo[d]imidazol-5-yl)boronic acid (Intermediate 59-2)

[0680] Starting material 59-1 (0.2 g) was dissolved in dioxane (2 mL), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex (108.0 mg), pinacol diboron (270.8 mg), and potassium acetate (261.6 mg) were added. Under nitrogen, the mixture was stirred at 100°C for 16 h. Upon completion of the reaction, the reaction solution was concentrated under reduced pressure to remove some of the solvent. The residue was purified by reverse phase chromatography (water:acetonitrile 0%-100%) to afford the title compound (100.0 mg).

[0681] MS m / z(ESI):191.1[M+H] + .

[0682] Step 2: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(1,2-dimethyl-1H-benzo[d]imidazol-5-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methylpyridine-3-carboxamide (Compound 59)

[0683] Intermediate 59-2 (37.2 mg) and intermediate Int4 (60.0 mg) were dissolved in dioxane (1 mL) and water (0.2 mL). Potassium carbonate (33.8 mg) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (17.7 mg) were added. Under nitrogen, the mixture was stirred and heated at 90°C for 2 h. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 75-95% acetonitrile) to obtain the title compound (5.0 mg).

[0684] MS m / z(ESI):556.1[M+H] + .

[0685] 1 H NMR (400MHz, DMSO-d6) δ13.26(s,1H),9.23(s,1H),8.82(s,1H),8.31(s,1H),8.07-7.99(m,1H),7.62(d,J=8. 0Hz,1H),7.45(m,2H),7.38(s,1H),7.02(d,J=8.0Hz,1H),3.78(s,3H),3.53(s,3H),2.59(s,3H),2.56(s,3H).

[0686] Example 60. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(1-methyl-1H-indazol-5-yl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 60)

[0687] Intermediate Int4 (100.0 mg), starting material 60-1 (63.0 mg), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (33.0 mg), and potassium phosphate (130.0 mg) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The mixture was heated at 90°C under nitrogen for 16 h. After the reaction, the reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was directly purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 45-80% acetonitrile ratio) to obtain the title compound (10.0 mg).

[0688] MS m / z(ESI):542.1[M+H] + .

[0689] 1 H NMR(400MHz,DMSO-d6)δ9.26(s,1H),8.81(s,1H),8.59(s,1H),8.24-8.22(m,1H),8.18(s,1H),7.80-7 .78(m,1H),7.50-7.42(m,2H),7.39(s,1H),7.03-7.01(m,1H),4.10(s,3H),3.52(s,3H),2.60(s,3H).

[0690] Example 61. Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(1-cyclopropyl-6-oxo-1,6-dihydropyridazin-4-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 61)

[0691] Step 1: Synthesis of 2-cyclopropyl-5-iodopyridazin-3(2H)-one (Intermediate 61-2)

[0692] Starting material 61-1 (1.0 g) was dissolved in 1,2-dichloroethane (20 mL), and cyclopropylboronic acid (773.9 mg), copper acetate (1.6 g), pyridine (1.8 g), and triethylamine (1.8 g) were added. The mixture was heated at 100°C under an oxygen atmosphere for 4 h. After the reaction was completed, the reaction solution was cooled to room temperature and filtered through a pad of celite. The filter cake was rinsed with methanol, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (ethyl acetate:petroleum ether 0-40%) to obtain the title compound (865.0 mg).

[0693] MS m / z(ESI):262.9[M+H] + .

[0694] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(1-cyclopropyl-6-oxo-1,6-dihydropyridazin-4-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 61)

[0695] Intermediate 61-2 (12.2 mg), intermediate Int6 (25.0 mg), potassium carbonate (19.3 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3.4 mg) were added to 1,4-dioxane (1 mL) and water (0.2 mL). The mixture was heated at 100°C under nitrogen for 16 h. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 75-95% acetonitrile) to obtain the title compound (8.0 mg).

[0696] MS m / z(ESI):546.0[M+H] + .

[0697] 1 H NMR (400MHz, DMSO-d6) δ13.49(s,1H),9.35(s,1H),8.81(m,1H),8.64(d,J=4.0Hz,1H),7.66(s,1H),7.44-7.4 8(m,2H),7.41(s,1H),7.01(d,J=8.0Hz,1H),4.08-4.13(m,1H),3.50(s,3H),2.60(s,3H),0.98-1.06(m,4H).

[0698] Example 62: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(3,4-dimethylpiperazin-1-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 62)

[0699] Intermediate Int4 (50.0 mg) and starting material 62-1 (116.0 mg) were dissolved in N-methylpyrrolidone (3 mL), and N,N-diisopropylethylamine (35 μL) was added to the system. The reaction was heated at 130°C for 8 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was directly purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 45-80% acetonitrile ratio) to obtain the title compound (26.0 mg).

[0700] MS m / z(ESI):524.2[M+H] + .

[0701] 1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),8.34(s,1H),7.48-7.41(m,2H),7.37(s,1H),7.08-6.92(m,1H),4.19-4.03(m,2H),3.50(s,3H), 3.10-2.94(m,1H),2.86-2.82(m,1H),2.69-2.63(m,1H),2.58(s,3H),2.22(s,3H),2.21-2.15(m,1H),2.11(s,1H),1.08-1.07(m,3H).

[0702] Example 63. Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-[6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 63)

[0703] Step 1: Synthesis of (3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)boronic acid (Intermediate 63-2)

[0704] Dissolve starting material 63-1 (300.0 mg), diboron pinacol ester (546.0 g), and potassium acetate (300.0 mg) in dioxane (10 mL). Add 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (411.2 mg). Heat at 100°C under nitrogen for 16 hours. After completion of the reaction, concentrate the reaction mixture to dryness under reduced pressure. Add methyl tert-butyl ether (10 mL) to the residue, stir, filter, and dry the filter cake to obtain the title compound (530.0 mg).

[0705] MS m / z(ESI):178.1[M+H] + .

[0706] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-[6-(3-methyl-[1,2,4]triazolo[4,3-a]pyridin-7-yl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 63)

[0707] To a mixture of Intermediate 63-2 (53.1 mg), Intermediate Int4 (49.0 mg), and potassium carbonate (42.6 mg) in dioxane and water (2 mL) was added 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (7.3 mg). The mixture was heated at 90°C under nitrogen for 16 h. After the reaction, the reaction solution was concentrated to dryness under reduced pressure. The residue was added with water (15 mL) and dichloromethane (15 mL), stirred, and separated. The aqueous phase was extracted twice with dichloromethane (10 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (column: YMC C18; mobile phase: 0.1% aqueous ammonium bicarbonate; B%: 10%-90%, B is acetonitrile, 25 mL / min) to obtain the title compound (9.0 mg).

[0708] MS m / z(ESI):5430.0[M+H] + .

[0709] 1 H NMR (400MHz, DMSO-d6) δ9.26(s,1H),8.92(s,1H),8.46(d,J=7.4Hz,2H),7.76(d,J=7.2Hz,1H),7.41(d ,J=8.8Hz,1H),7.36(s,1H),7.26(s,1H),7.00(d,J=8.9Hz,1H),3.52(s,3H),2.73(s,3H),2.56(s,3H).

[0710] Example 64. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(3-methylimidazo[1,5-a]pyridin-7-yl)thiazolyl[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 64)

[0711] Step 1: Synthesis of (3-methylimidazo[1,5-a]pyridin-7-yl)boronic acid (Intermediate 64-2)

[0712] Starting material 64-1 (100.0 mg), bis(pinacolato)diboron (180.0 mg), potassium acetate (140.0 mg), and (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (77.0 mg) were dissolved in 1,4-dioxane (2 mL) and heated at 100°C under nitrogen for 6 h. After the reaction, the reaction solution was cooled to room temperature, filtered, washed with petroleum ether, and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound, which was used directly in the next step.

[0713] MS m / z(ESI):177.1[M+H] + .

[0714] Step 2: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-[6-(3-methylimidazo[1,5-a]pyridin-7-yl)thiazolo[4,5-b]pyrazin-2-yl]pyridine-3-carboxamide (Compound 64)

[0715] Intermediate Int4 (70.0 mg), potassium carbonate (59.0 mg), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (9.0 mg), and intermediate 64-2 (150.0 mg) were added to 1,4-dioxane (2 mL) and ethanol (0.4 mL). The reaction was heated at 90°C under nitrogen for 16 h. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 45-80% acetonitrile ratio) to obtain the title compound (15.0 mg).

[0716] MS m / z(ESI):542.1[M+H] + .

[0717] 1 H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.87(s,1H),8.36(s,1H),8.20-8.18(m,1H),7.4 8-7.36(m,4H),7.30(s,1H),7.01-6.99(m,1H),3.52(s,3H),2.63(s,3H),2.57(s,3H).

[0718] Example 65. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-(6-(imidazo[1,2-a]pyridin-7-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-pyridine-3-carboxamide (Compound 65)

[0719] Step 1: Synthesis of imidazo[1,2-a]pyridin-7-ylboronic acid (Intermediate 65-2)

[0720] Compound 65-1 (100.0 mg), bis(pinacolato)diboron (258.0 mg), potassium acetate (149.0 mg), and (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (83.0 mg) were dissolved in 1,4-dioxane (2 mL) and heated at 100°C under nitrogen for 6 h. After the reaction, the reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. Methyl tert-butyl ether (30 mL) was added to the residue, stirred for 2 h, filtered, and the filter cake dried to obtain the title compound (100.0 mg), which was used directly in the next step.

[0721] MS m / z(ESI):163.1[M+H] + .

[0722] Step 2: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-(6-(imidazo[1,2-a]pyridin-7-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-pyridine-3-carboxamide (Compound 65)

[0723] Intermediate Int4 (50.0 mg), potassium carbonate (42.0 mg), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (7.0 mg), and intermediate 65-2 (99.0 mg) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL). The mixture was heated at 90°C under nitrogen for 16 h. After the reaction, the reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TAR column, 0.5‰ formic acid-water & acetonitrile system, 25 mL / min, 45-80% acetonitrile) to obtain the title compound (10.0 mg).

[0724] MS m / z(ESI):528.0[M+H] + .

[0725] 1 H NMR(400MHz,DMSO-d6)δ9.36(s,1H),8.83(s,1H),8.68-8.67(m,1H),8.43(s,1H),8.04(s,1H),7.74-7.7 2(m,1H),7.69-7.68(m,1H),7.52-7.41(m,2H),7.37(s,1H),7.02-7.00(m,1H),3.52(s,3H),2.59(s,3H).

[0726] Example 66, 4-(5-chloro-2-methoxyphenyl)-N-(6-(1-difluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (Compound 66)

[0727] Step 1: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(6-(2-oxo-1,2-dihydropyridin-4-yl)thiazolo[4,5-b]pyrazin-2-yl)nicotinamide (Intermediate 66-1)

[0728] Intermediate Int4 (2.5 g), 2-hydroxypyridine-4-boronic acid pinacol ester (1.2 g), and potassium carbonate (1.4 g) were dissolved in a mixture of dioxane and water (10:1) (80 mL). 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (366.0 mg) was added under a nitrogen atmosphere, and the mixture was heated at 90°C for 12 h. After the reaction, the solvent was removed under reduced pressure. The residue was added to water (100 mL) and extracted three times with dichloromethane (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-50%) to obtain the title compound (1.8 g).

[0729] MS m / z(ESI):505.0[M+H] + .

[0730] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(1-difluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (Compound 66)

[0731] Intermediate 66-1 (250.8 mg) and potassium carbonate (76.0 mg) were dissolved in anhydrous acetonitrile (15 mL) and reacted at 60°C for 30 min under a nitrogen atmosphere. Difluorobromomethyltrimethylsilane (121.8 mg) was added to the reaction mixture, and the reaction was continued at 60°C for 12 h. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated to dryness, and the residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 20%-90%, elution time 8 min) to obtain the title compound (10.0 mg).

[0732] MS m / z(ESI):555.0[M+H] + .

[0733] 1H NMR (400MHz, DMSO-d6) δ13.48(s,1H),9.32(s,1H),8.87(s,1H),8.40(d,J=5.1Hz,1H),8.02(d,J=5.2Hz,1 H),7.78-7.82(m,1H),7.39-7.47(m,2H),7.30-7.38(m,1H),6.98-7.04(m,1H),3.51(s,3H),2.58(s,3H).

[0734] Example 67, 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(6-(3-methylimidazo[1,2-a]pyridin-7-yl)thiazolo[4,5-b]pyrazin-2-yl)nicotinamide (Compound 67)

[0735] Step 1: Synthesis of 7-bromo-3-methylimidazo[1,2-a]pyridine (Intermediate 67-3)

[0736] Starting material 67-2 (3.8 g) was dissolved in 1,4-dioxane (6.4 mL) and water (1.6 mL). Hydrochloric acid solution (2 mL, 2N) was added and the mixture was heated at 90°C for 1 h. The mixture was cooled to room temperature and the pH was adjusted to approximately 8.0 with saturated sodium bicarbonate solution. Starting material 67-1 (1.8 g) was added to the mixture and microwave-treated at 100°C for 1 h. Upon completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was stirred with water (30 mL), filtered, and the filter cake dried to afford the title compound (700 mg).

[0737] MS m / z(ESI):211.0[M+H] + .

[0738] Step 2: Synthesis of 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine (Intermediate 67-4)

[0739] Intermediate 67-3 (500.0 mg), pinacol diboron (1.2 g), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (171.9 mg), and potassium acetate (697.5 mg) were dissolved in 1,4-dioxane (10 mL) and heated at 80°C under a nitrogen atmosphere for 16 hours. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain the title compound (800.0 mg). The product was used directly in the next step without further purification.

[0740] Step 3: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(6-(3-methylimidazo[1,2-a]pyridin-7-yl)thiazolo[4,5-b]pyrazin-2-yl)nicotinamide (Compound 67)

[0741] Intermediate Int4 (150.0 mg), intermediate 67-4 (160.0 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (19.7 mg) and potassium carbonate (126.7 mg) were added to a reaction flask, and 1,4-dioxane (1 mL) and water (0.2 mL) were added. The reaction was heated at 80°C under a nitrogen atmosphere for 16 h. After the reaction was completed, ethyl acetate (25 mL) and saturated brine (10 mL) were added to the reaction solution, the liquid was separated, and the organic phase was washed twice with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative chromatography on a YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (7 mmol ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 30%-65%, elution 8 min) to give the title compound (15.0 mg).

[0742] MS m / z(ESI):542.0[M+H] + .

[0743] 1 H NMR (400MHz, DMSO-d6) δ9.24 (s, 1H), 9.00 (s, 1H), 8.48-8.32 (m, 2H), 7.81 (d, J = 7.2Hz, 1H), 7.52-7 .46(m,2H),7.40(s,1H),7.31(s,1H),7.07(d,J=8.8Hz,1H),3.59(s,3H),3.40(s,3H),2.63(s,3H).

[0744] Example 68, 4-(5-chloro-2-methoxyphenyl)-N-(6-(6-cyanospiro[3.3]hept-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (Compound 68)

[0745] Step 1: Synthesis of methyl 6-(2-((tert-butoxycarbonyl)amino)thiazolo[4,5-b]pyrazin-6-yl)-6-hydroxyspiro[3.3]heptane-2-carboxylate (Intermediate 68-2)

[0746] Intermediate Int1 (2.0 g) was dissolved in tetrahydrofuran (20 mL); the mixture was cooled to -78°C, and n-butyllithium (5.1 mL, 2.5 M) was slowly added dropwise to the reaction mixture. The mixture was allowed to react at -78°C for 0.5 h. A solution of the starting material, Intermediate 68-1 (1.2 g), in tetrahydrofuran (10 mL) was then slowly added to the reaction mixture, and the reaction was continued at -78°C for 2 h. Upon completion of the reaction, saturated ammonium chloride solution (30 mL) was added to quench the reaction mixture, followed by ethyl acetate (15 mL). The mixture was stirred, separated, and the aqueous phase was extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was directly purified by flash column chromatography (ethyl acetate:petroleum ether 0-50%) to obtain the title compound (727.0 mg).

[0747] MS m / z(ESI):421.2[M+H] + .

[0748] Step 2: Synthesis of methyl 6-(2-((tert-butoxycarbonyl)amino)thiazolo[4,5-b]pyrazin-6-yl)-6-chlorospiro[3.3]heptane-2-carboxylate (Intermediate 68-3)

[0749] Intermediate 68-2 (677.0 mg) was dissolved in dichloromethane (7 mL). Dimethyl sulfoxide (374 μL) was added dropwise to the reaction mixture at 0°C and allowed to react at room temperature for 4 h. Upon completion of the reaction, the reaction mixture was slowly added dropwise to an ice-saturated sodium bicarbonate solution, and the pH was adjusted to 7-8. The mixture was then extracted three times with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (680.0 mg).

[0750] MS m / z(ESI):439.0[M+H] + .

[0751] Step 3: Synthesis of methyl 6-(2-((tert-butoxycarbonyl)amino)thiazolo[4,5-b]pyrazin-6-yl)spiro[3.3]heptane-2-carboxylate (Intermediate 68-4)

[0752] Intermediate 68-3 (146.0 mg) was dissolved in ethyl acetate (5 mL). 10% palladium on carbon (15.0 mg.0 mg) and 10% Pd(OH)2 (15.0 mg) were added to the reaction mixture. The atmosphere was replaced with hydrogen three times and the reaction was allowed to proceed at room temperature for 16 h. After the reaction, the reaction mixture was filtered, and the filter cake was washed with an appropriate amount of ethyl acetate. The filtrate was concentrated under reduced pressure to remove the solvent, and the residue was directly purified on a flash column (ethyl acetate:petroleum ether 0-50%) to obtain the title compound (74 mg).

[0753] MS m / z(ESI):405.1[M+H] + .

[0754] Step 4: Synthesis of tert-butyl (6-(6-carbamoylspiro[3.3]hept-2-yl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 68-5)

[0755] Intermediate 68-4 (74.0 mg) was dissolved in aqueous ammonia (1 mL) and reacted at room temperature for 12 h. After the reaction was complete, the mixture was concentrated to dryness under reduced pressure to obtain the title compound (45.0 mg).

[0756] MS m / z(ESI):390.2[M+H] + .

[0757] Step 5: Synthesis of tert-butyl (6-(6-cyanospiro[3.3]hept-2-yl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 68-6)

[0758] Intermediate 68-5 (35.0 mg) and Burgess reagent (54.0 mg) were dissolved in dichloromethane (1 mL) and reacted at room temperature for 12 h. After the reaction, dilution was added with dichloromethane (15 mL) and the mixture was washed three times with water (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (40.0 mg).

[0759] MS m / z(ESI):372.1[M+H] + .

[0760] Step 6: Synthesis of 6-(2-aminothiazolo[4,5-b]pyrazin-6-yl)spiro[3.3]heptane-2-carbonitrile (Intermediate 68-7)

[0761] Intermediate 68-6 (40.0 mg) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The mixture was reacted at room temperature for 12 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Saturated sodium bicarbonate was added to the residue to adjust the pH to 7-8. The residue was extracted three times with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (10.0 mg).

[0762] MS m / z(ESI):272.1[M+H] + .

[0763] Step 7: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(6-cyanospiro[3.3]hept-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (Compound 68)

[0764] Intermediate Int2 (21.0 mg) was dissolved in dichloromethane (1 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (31.0 mg) and N,N-diisopropylethylamine (40 μL) were added to the mixture and reacted at room temperature for 2 h. After the reaction was completed, dilution was added with dichloromethane (10 mL), and the mixture was washed twice with water (5 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1 mL), and intermediate 68-7 (10.0 mg) and N,N-diisopropylethylamine (19 μL) were then added to the mixture. The mixture was heated at 45°C for 16 h. After the reaction was completed, the reaction solution was directly purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 45%-95%, elution 8 min) to obtain the title compound (2.0 mg).

[0765] MS m / z(ESI):531.1[M+H] + .

[0766] 1 H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.44(s,1H),7.45(s,1H),7.43-7.42(m,1H),7.37(s,1H),7.0 1-6.98(m,1H),3.71-3.62(m,1H),3.49(s,3H),3.28-3.22(m,1H),2.58(s,3H),2.48-2.23(m,8H).

[0767] Example 69, 4-(5-chloro-2-methoxy-phenyl)-N-(6-(6-cyano-2-azaspiro[3.3]hept-2-yl)thiazolo[4,5-b]pyrazin-2-yl]-6-methyl-pyridine-3-carboxamide (Compound 69)

[0768] Step 1: Synthesis of 2-azaspiro[3.3]heptane-6-carbonitrile (Intermediate 69-2)

[0769] Starting material 69-1 (100.0 mg) was dissolved in ethyl acetate (2 mL). A 4 M HCl solution in ethyl acetate (2 mL) was added at 0°C and stirred for 30 minutes. The mixture was then allowed to warm to room temperature for 2 hours. After completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure to obtain the title compound (60 mg).

[0770] MS m / z(ESI):123.1[M+H] +.

[0771] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(6-cyano-2-azaspiro[3.3]hept-2-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 69)

[0772] Intermediate 69-2 (15.0 mg), intermediate Int4 (30.0 mg), cesium carbonate (60.0 mg), 2-bicyclohexylphosphino-2',6'-diisopropoxybiphenyl (5.7 mg), and tris(dibenzylideneacetone)dipalladium (5.6 mg) were added to 1,4-dioxane (1 mL) and heated at 100°C under a nitrogen atmosphere for 16 h. After the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 75%-95%, elution time 8 min) to obtain the title compound (1.1 mg).

[0773] MS m / z(ESI):532.2[M+H] +

[0774] 1 H NMR(400MHz,Chloroform-d)δ9.45(s,1H),8.95(s,1H),7.72(s,1H),7.42-7.39(m,1H),7.30(d,J=4.0Hz ,1H),7.17(s,1H),6.89(d,J=8.0Hz,1H),4.22-4.19(m,4H),3.74(s,3H),2.77-2.70(m,4H),2.68(s,3H).

[0775] Example 70, 4-(5-chloro-2-methoxy-phenyl)-N-(6-(2-cyano-7-azaspiro[3.5]non-7-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-pyridine-3-carboxamide (Compound 70)

[0776] Step 1: Synthesis of 7-azaspiro[3.5]nonane-2-carbonitrile (Intermediate 70-2)

[0777] The starting material 70-1 (600.0 mg) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (5 mL) was added thereto. The mixture was stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure to obtain the title compound (600 mg).

[0778] MS m / z(ESI):151.1[M+H] + .

[0779] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(2-cyano-7-azaspiro[3.5]non-7-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 70)

[0780] Intermediate 70-2 (30.6 mg), intermediate Int4 (50.0 mg), tris(dibenzylideneacetone)dipalladium (18.7 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (9.5 mg), and cesium carbonate (166 mg) were dissolved in 1,4-dioxane (1 mL) and stirred at 80°C for 16 h under a nitrogen atmosphere. After the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 30%-50%, elution time 8 min) to obtain the title compound (4.5 mg).

[0781] MS m / z(ESI):560.1[M+H] + .

[0782] 1 H NMR (400MHz, DMSO-d6) δ12.81(s,1H),8.72(s,1H),8.34(s,1H),7.46-7.43(m,2H),7.38(s,1H),7.01-6.99(m,1H),3. 57-3.51(m,4H),3.50(s,3H),3.41-3.37(m,1H),2.58(s,3H),2.28-2.23(m,2H),2.14-2.08(m,2H),1.69-1.64(m,4H).

[0783] Example 71, 4'-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 71)

[0784] Step 1: Synthesis of methyl 6-chloro-4-(5-chloro-2-methoxyphenyl)nicotinate (Intermediate 71-3)

[0785] Starting material 71-1 (1.5 g), starting material 71-2 (1.1 g), 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (438.0 mg), and potassium carbonate (2.5 g) were dissolved in 1,4-dioxane (15 mL) and water (3 mL). The mixture was reacted at 80°C under a nitrogen atmosphere for 16 h. After the reaction, the reaction solution was concentrated under reduced pressure to remove some of the solvent. The residue was directly purified by flash column chromatography (petroleum ether:ethyl acetate 0-50%) to obtain the title compound (1.5 g).

[0786] MS m / z(ESI):312.0[M+H] + .

[0787] Step 2: Synthesis of methyl 4'-(5-chloro-2-methoxyphenyl)-4-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carboxylate (Intermediate 71-4)

[0788] Intermediate 71-3 (100.0 mg), 4-methyl-1H-pyridin-2-one (69.9 mg), and potassium carbonate (88.6 mg) were dissolved in dimethyl sulfoxide (1 mL) and reacted at 90°C for 18 h. After the reaction, ethyl acetate (10 mL) and water (10 mL) were added, and the layers were separated to obtain the organic phase, which was washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (123.0 mg).

[0789] MS m / z(ESI):385.0[M+H] + .

[0790] Step 3: Synthesis of 4'-(5-chloro-2-methoxyphenyl)-4-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carboxylic acid (Intermediate 71-5)

[0791] Intermediate 71-4 (123.0 mg) was dissolved in tetrahydrofuran (1 mL), and a solution of lithium hydroxide monohydrate (33.5 mg) in water (1 mL) was added. The mixture was allowed to react at room temperature for 2 h. After the reaction was complete, water (5 mL) and ethyl acetate (5 mL) were added to separate the layers. The aqueous phase was adjusted to pH 3 with 2N hydrochloric acid and extracted twice with ethyl acetate (5 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (100.0 mg).

[0792] MS m / z(ESI):371.0[M+H] + .

[0793] Step 4: Synthesis of 4'-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 71)

[0794] Intermediate 71-5 (40.0 mg), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (90.8 mg), and N-methylimidazole (44.3 mg) were added to N,N-dimethylformamide (1 mL) and reacted at room temperature under a nitrogen atmosphere for 2 h. Intermediate Int5 (41.0 mg) was then added and heated at 60°C for 16 h. After the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio: 30%-50%, elution time: 8 min) to obtain the title compound (1.1 mg).

[0795] MS m / z(ESI):606.2[M+H] +

[0796] 1 H NMR(400MHz,DMSO-d6)δ13.65(s,1H),9.00(s,1H),8.36-8.38(m,2H),8.01-7.99(m,2H),7.94-7.96(m,1H),7.51- 7.43(m,2H),7.22-7.18(m,1H),7.11-7.01(m,1H),6.71-6.68(m,1H),6.45-6.31(m,2H),3.55(s,3H),2.23(s,3H).

[0797] Example 72: Synthesis of 5'-chloro-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-methoxy-5-(5-methyl-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-2-carboxamide (Compound 72)

[0798] Step 1: Synthesis of methyl 2-bromo-4-(5-methyl-1,3,4-oxadiazol-2-yl)benzoate (Intermediate 72-2)

[0799] Starting material 72-1 (2.0 g) was added to thionyl chloride (20 mL), and DMF (28.2 mg) was added. The mixture was heated under reflux at 80°C for 3 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was dissolved in dichloromethane (25 mL), pyridine (1.8 g) was added, and the mixture was stirred. Subsequently, a dichloromethane solution (6 mL) of tert-butyl carbazate (1.1 g) was slowly added, and the mixture was stirred at room temperature for 20 min. Trifluoroacetic acid (20 mL) was added, and the mixture was stirred at room temperature for 1 h. Triethyl orthoacetate (2.9 g) was added to the reaction mixture, and the mixture was heated at 50°C for 1 h. After the reaction was completed, the reaction solution was added to water (40 mL) and extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed once with saturated brine (15 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by Flash chromatography (ethyl acetate: petroleum ether 0-65%) to give the title compound (0.7 g).

[0800] MS m / z(ESI):297.1[M+H] + .

[0801] Step 2: Synthesis of 5'-chloro-2'-methoxy-5-(5-methyl-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-2-carboxylic acid methyl ester (Intermediate 72-4)

[0802] Starting material 72-3 (75.3 mg), intermediate 72-2 (100.0 mg), potassium carbonate (93.0 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (24.4 mg) were added to a mixture of 1,4-dioxane (1 mL) and water (0.2 mL). The mixture was heated at 90°C under a nitrogen atmosphere for 2 h. Upon completion of the reaction, the reaction solution was directly concentrated to dryness under reduced pressure. The residue was purified by flash chromatography (ethyl acetate:petroleum ether 20-55%) to obtain the title compound (100.0 mg).

[0803] MS m / z(ESI):359.0[M+H] + .

[0804] Step 3: Synthesis of 5'-chloro-2'-methoxy-5-(5-methyl-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-2-carboxylic acid (Intermediate 72-5)

[0805] Intermediate 72-4 (100.0 mg) was added to a mixed solution of water (1 mL) and tetrahydrofuran (2 mL), and lithium hydroxide monohydrate (25.7 mg) was added. The reaction was heated at 45°C under a nitrogen atmosphere for 16 h. After the reaction was completed, water (10 mL) was added and the mixture was extracted once with methyl tert-butyl ether (10 mL x 1). The aqueous phase was adjusted to pH 5 with 1N dilute hydrochloric acid and filtered. The filter cake was rinsed with water and dried under reduced pressure to obtain the title compound (60.0 mg).

[0806] MS m / z(ESI):345.0[M+H] + .

[0807] Step 4: Synthesis of 5'-chloro-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-methoxy-5-(5-methyl-1,3,4-oxadiazol-2-yl)-[1,1'-biphenyl]-2-carboxamide (Compound 72)

[0808] Intermediate 72-5 (30.0 mg), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (73.2 mg), and N-methylimidazole (35.7 mg) were added to N,N-dimethylformamide (1 mL) and reacted at room temperature under a nitrogen atmosphere for 2 h. Intermediate Int5 (33.0 mg) was then added and stirred at 60°C for 16 h. After the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 30%-50%, elution time 8 min) to obtain the title compound (1.0 mg).

[0809] MS m / z(ESI):580.2[M+H] + .

[0810] 1 H NMR(400MHz,DMSO-d6)δ13.50(s,1H),9.32(s,1H),8.39-8.48(m,2H),8.15-8.22(m,1H),8.01-8.10(m, 3H),7.95(s,1H),7.50-7.55(m,1H),7.40-7.45(m,1H),7.01(d,J=8.0Hz,1H),3.55(s,3H),2.65(s,3H).

[0811] Example 73, 4'-(5-chloro-2-methoxyphenyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)-4-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 73)

[0812] Intermediate 71-5 (40.0 mg), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (90.8 mg), and N-methylimidazole (44.3 mg) were dissolved in N,N-dimethylformamide (1 mL) and stirred at room temperature for 0.5 h. Intermediate 5-2 (20.7 mg) was added and the mixture was allowed to react at 45°C for 18 h. After completion of the reaction, the reaction solution was diluted with ethyl acetate (50 mL), washed twice with water (20 mL x 2) and twice with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio: 30%-50%, elution time: 8 min) to obtain the title compound (3.4 mg).

[0813] MS m / z(ESI):545.1[M+H] + .

[0814] 1 H NMR(400MHz,DMSO-d6)δ8.87(s,1H),8.43(s,1H),7.86(m,1H),7.79(s,1H),7.44-7.31(m,2H),6.9 6(m,1H),6.30(s,1H),6.25-6.23(m,1H),3.45(s,3H),2.20(m,1H),2.15(s,3H),0.99-0.90(m,4H).

[0815] Example 74, 5-(5-chloro-2-methoxy-phenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (Compound 74)

[0816] Step 1: Synthesis of methyl 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (Intermediate 74-2)

[0817] Starting material 74-1 (5.0 g) and cesium carbonate (14.0 g) were dissolved in acetonitrile (100 mL) and stirred at 0°C for 15 min. Iodomethane (4.6 g) was added, the temperature was slowly raised to room temperature, and the mixture was stirred for 16 h. After the reaction was complete, the mixture was filtered, and the filtrate was diluted with ethyl acetate (100 mL) and washed twice with saturated brine (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (methanol:dichloromethane 0-10%) to obtain the title compound (2.2 g).

[0818] MS m / z(ESI):245.9[M+H] + .

[0819] Step 2: Synthesis of methyl 5-(5-chloro-2-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylate (Intermediate 74-3)

[0820] Intermediate 74-2 (500.0 mg), (5-chloro-2-methoxyphenyl)boronic acid (454.5 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (147.5 mg), and potassium carbonate (561.7 mg) were dissolved in a mixture of 1,4-dioxane (5 mL) and water (1 mL). The mixture was heated at 100°C under a nitrogen atmosphere for 16 h. After the reaction, ethyl acetate (30 mL) was added to dilute the mixture and filtered. The organic phase was washed twice with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (methanol:dichloromethane 0-15%) to obtain the title compound (200.0 mg).

[0821] MS m / z(ESI):308.1[M+H] + .

[0822] Step 3: Synthesis of 5-(5-chloro-2-methoxyphenyl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (Intermediate 74-4)

[0823] Intermediate 74-3 (120.0 mg) and lithium hydroxide (23.4 mg) were added to a mixed solvent of water (1 mL) and tetrahydrofuran (1 mL) and stirred at room temperature for 16 h. After the reaction, the pH was adjusted to 5 with 1N dilute hydrochloric acid solution, and ethyl acetate (25 mL) and saturated brine (10 mL) were added to the reaction solution. The layers were separated, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (100.0 mg).

[0824] MS m / z(ESI):294.0[M+H] + .

[0825] Step 4: Synthesis of 5-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (Compound 74)

[0826] Intermediate 74-4 (100.0 mg), intermediate Int5 (129.3 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (97.9 mg) and N-hydroxy-7-azabenzotriazole (69.5 mg) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (132.0 mg) was added thereto, and the reaction was heated at 55°C for 16 h. After the reaction was completed, the mixture was diluted with ethyl acetate (30 mL), and the organic phase was washed twice with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 30%-50%, elution 8 min) to give the title compound (15.0 mg).

[0827] MS m / z(ESI):529.1[M+H] + .

[0828] 1 H NMR (400MHz, DMSO-d6) δ13.54(s,1H),9.32(s,1H),8.36(d,J=8.1Hz,2H),8.00(d,J=8.1Hz,2H),7.88(s ,1H),7.40(s,1H),7.34(d,J=8.6Hz,1H),6.91(d,J=8.7Hz,1H),6.79(s,1H),3.52(s,3H),3.46(s,3H).

[0829] Example 75, 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyridine-3-carboxamide (Compound 75)

[0830] Step 1: Synthesis of 6-chloro-4-(5-chloro-2-methoxyphenyl)pyridine-3-carboxylic acid (Intermediate 75-1)

[0831] Intermediate 71-3 (400.0 mg) was added to a mixture of tetrahydrofuran (4 mL) and water (2 mL), and lithium hydroxide monohydrate (118.3 mg) was added. The mixture was reacted at room temperature for 16 h. After the reaction was completed, water (20 mL) was added and the mixture was extracted once with methyl tert-butyl ether (15 mL). The aqueous phase was adjusted to pH 5 with 1N dilute hydrochloric acid and filtered. The filter cake was rinsed with water and dried under reduced pressure to obtain the title compound (35.0 mg).

[0832] MS m / z(ESI):298.0[M+H] + .

[0833] Step 2: Synthesis of 6-chloro-4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)pyridine-3-carboxamide (Intermediate 75-2)

[0834] Intermediate 75-1 (100.0 mg), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (282.3 mg), and N-methylimidazole (137.5 mg) were added to N,N-dimethylformamide (2 mL) and reacted at room temperature under a nitrogen atmosphere for 2 h. Intermediate Int5 (110.5 mg) was then added and stirred at 60°C for 16 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the residue was purified by flash chromatography (ethyl acetate:petroleum ether 0-50%) to obtain the title compound (76.0 mg).

[0835] MS m / z(ESI):533.1[M+H] + .

[0836] Step 3: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-(1-methyl-1H-pyrazol-3-yl)pyridine-3-carboxamide (Compound 75)

[0837] Intermediate 75-3 (19.5 mg), intermediate 75-2 (50.0 mg), potassium carbonate (38.9 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13.6 mg) were added to a mixture of water (0.2 mL) and 1,4-dioxane (1 mL). The mixture was heated at 90°C under a nitrogen atmosphere for 2 h. After the reaction, the solvent was removed by concentration under reduced pressure. The residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 30%-50%, elution time 8 min) to obtain the title compound (1.1 mg).

[0838] MS m / z(ESI):579.1[M+H] + .

[0839] 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),9.06(s,1H),8.96(s,1H),8.18(d,J=8.4Hz,2H),7.93(s,1H),7.834-7.81 4(m,2H),7.50(s,1H),7.45-7.43(m,1H),7.37(s,1H),7.02(s,1H),6.94-6.91(m,1H),4.02(s,3H),3.77(s,3H).

[0840] Example 76, N-(6-(3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compounds 76-P1 and 76-P2)

[0841] Intermediate Int3 (55.8 mg) and intermediate 22-5-P1 (50.0 mg) were dissolved in anhydrous N,N-dimethylformamide (2 mL), followed by the addition of 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (200.1 mg) and N,N-diisopropylethylamine (0.2 mL). The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the reaction solution was directly purified by preparative liquid chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 45%-95%, elution time 8 min) to obtain the title compound 76-P1 (4.5 mg).

[0842] Intermediate Int3 (96.8 mg) and intermediate 22-5-P2 (92.4 mg) were dissolved in anhydrous N,N-dimethylformamide (3 mL), followed by the addition of 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (419.1 mg) and N,N-diisopropylethylamine (0.3 mL). The mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the reaction solution was directly purified by preparative liquid chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 45%-95%, elution time 8 min) to obtain the title compound 76-P2 (15.0 mg).

[0843] Two isomers were analyzed by chromatography:

[0844] Compound 76-P1:

[0845] Under the above chromatographic conditions, the retention time of compound 76-P1 was 5.558 min.

[0846] MS m / z(ESI):472.0[M+H] + .

[0847] 1 H NMR(400MHz,DMSO-d6)δ13.37(s,1H),8.90(s,1H),8.41(s,1H),8.17(s,1H),7.32(s,1 H),7.25(s,1H),3.80(m,1H),3.58(s,3H),2.72-2.60(m,4H),2.58(s,3H),2.48(s,3H).

[0848] Compound 76-P2:

[0849] Under the above chromatographic conditions, the retention time of compound 76-P2 was 5.608 min.

[0850] MS m / z(ESI):472.0[M+H] + .

[0851] 1 H NMR(400MHz, CDCl3)δ8.93(s,1H),8.32(s,1H),8.21(s,1H),7.18(s,1H),7.07(s,1H),4.02-4.10(m, 1H),3.80(s,3H),3.69-3.75(m,2H),3.36-3.41(m,1H),3.15-3.21(m,2H),2.68(s,3H),2.56(s,3H).

[0852] Example 77, N-(6-(3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2-methoxy-5-(trifluoromethyl)phenyl)-6-methylnicotinamide (Compounds 77-P1 and 77-P2)

[0853] Intermediate 77-1 (93.3 mg) and intermediate 22-5-P1 (69.4 mg) were dissolved in anhydrous N,N-dimethylformamide (2 mL). 1H-Benzotriazol-1-yloxytripyrrolidinoyl hexafluorophosphate (312.2 mg) and N,N-diisopropylethylamine (0.3 mL) were then added and allowed to react at room temperature for 12 h. After completion of the reaction, the reaction solution was directly purified by preparative liquid chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 45%-95%, elution time 8 min) to obtain the title compound 77-P1 (12 mg).

[0854] Intermediate 77-1 (93.3 mg) and intermediate 22-5-P2 (69.4 mg) were dissolved in anhydrous N,N-dimethylformamide (2 mL). 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (312.2 mg) and N,N-diisopropylethylamine (0.3 mL) were then added and allowed to react at room temperature for 12 h. After completion of the reaction, the reaction solution was directly purified by preparative liquid chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 45%-95%, elution time 8 min) to obtain the title compound 77-P2 (14 mg).

[0855] Two isomers were analyzed by chromatography:

[0856] Compound 77-P1:

[0857] Under the above chromatographic conditions, the retention time of compound 77-P1 was 8.085 min.

[0858] MS m / z(ESI):525.1[M+H] + .

[0859] 1 H NMR (400MHz, CDCl3) δ8.94(s,1H),8.31(s,1H),7.68-7.75(m,1H),7.55-7.61(m,1H),7.21(s,1 H),6.94-7.05(d,J=8.7Hz,1H),3.77(s,4H),3.15-3.18(m,1H),2.74-2.91(m,3H),2.70(s,3H).

[0860] Compound 77-P2:

[0861] Under the above chromatographic conditions, the retention time of compound 77-P2 was 9.218 min.

[0862] MS m / z(ESI):525.1[M+H] + .

[0863] 1 H NMR(400MHz, CDCl3)δ8.93(s,1H),8.29(s,1H),7.68-7.75(m,1H),7.54-7.59(m,1H),7.20(s,1H),6 .99-7.04(m,1H),4.02-4.10(m,1H),3.77(s,3H),3.36–3.43(m,1H),2.77-2.86(m,4H),2.69(s,3H).

[0864] Example 78, 4-(5-chloro-2-methoxy-phenyl)-6-methyl-N-(6-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)thiazolo[4,5-b]pyrazin-2-yl)pyridine-3-carboxamide (Compound 78)

[0865] Intermediate Int6 (30.0 mg), starting material 78-1 (13.2 mg), potassium carbonate (23.1 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (4.0 mg) were added to a mixture of water (0.2 mL) and 1,4-dioxane (1 mL). The mixture was heated at 70°C under a nitrogen atmosphere for 4 h. After the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 75%-95%, elution time 8 min) to obtain the title compound (3.0 mg).

[0866] MS m / z(ESI):520.0[M+H] + .

[0867] 1 H NMR(400MHz,DMSO-d6)δ13.50(s,1H),9.29(s,1H),8.86(s,1H),8.65(s,1H),7.64(s,1H),7 .45-7.45(m,2H),7.35(s,1H),7.00(d,J=8.0Hz,1H),3.71(s,3H),3.50(s,3H),2.58(s,3H).

[0868] Example 79, 4-(5-chloro-2-methoxy-phenyl)-N-(6-imidazo[1,2-b]pyridazin-7-ylthiazolo[4,5-b]pyrazin-2-yl)-6-methyl-pyridine-3-carboxamide (Compound 79)

[0869] Intermediate Int7 (50.0 mg), starting material 79-1 (18.6 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (14.6 mg), and potassium phosphate (59.2 mg) were dissolved in dioxane (1 mL) and water (0.2 mL) and reacted at 100°C for 18 h under a nitrogen atmosphere. After the reaction, the mixture was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 30%-50%, elution time 8 min) to obtain the title compound (7.0 mg).

[0870] MS m / z(ESI):529.0[M+H] + .

[0871] 1 H NMR(400MHz,DMSO-d6)δ9.30(m,2H),8.90-8.83(m,2H),8.39(s,1H),7.88(s,1H) ,7.46-7.36(m,2H),7.29(s,1H),7.00(d,J=8.8Hz,1H),3.51(s,3H),2.57(s,3H)

[0872] Example 80, N-(6-(2-oxa-6-azaspiro[3.4]octan-6-yl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-chloro-2-methoxyphenyl)-6-methylpyridine-3-carboxamide (Compound 80)

[0873] Starting material 80-1 (13.8 mg), intermediate Int4 (50.0 mg), cesium carbonate (99.6 mg), 2-bicyclohexylphosphino-2',6'-diisopropoxybiphenyl (9.5 mg), and tris(dibenzylideneacetone)dipalladium (9.3 mg) were added to 1,4-dioxane (1 mL) and heated at 100°C under a nitrogen atmosphere for 4 h. After the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 75%-95%, elution time 8 min) to obtain the title compound (10.0 mg).

[0874] MS m / z(ESI):523.1[M+H] +

[0875] 1 H NMR (400MHz, DMSO-d6) δ12.79(s,1H),8.74(s,1H),7.95(s,1H),7.46-7.43(m,2H),7.37(s,1H),7.02-6.99( m,1H),4.63-4.60(m,2H),4.53-4.50(m,2H),3.75(s,2H),3.52-3.48(m,5H),2.58(s,3H),2.30-2.27(m,2H).

[0876] Example 81, N-(6-(1-oxa-6-azaspiro[3.4]octan-6-yl)thiazolo[4,5-b]pyrazin-2-yl)-4-(5-chloro-2-methoxyphenyl)-6-methylpyridine-3-carboxamide (Compound 81)

[0877] Intermediate Int4 (50.0 mg) and starting material 81-1 (23.1 mg) were dissolved in dioxane (1 mL). Tris(dibenzylideneacetone)dipalladium (23.6 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (9.5 mg), and cesium carbonate (100.0 mg) were added, and the mixture was heated at 100°C under a nitrogen atmosphere for 12 h. After the reaction, the reaction solution was concentrated under reduced pressure to remove some of the solvent, and the residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 30%-70%, elution time 8 min) to obtain the title compound (12.0 mg).

[0878] MS m / z(ESI):523.0[M+H]+ .

[0879] 1 H NMR (400MHz, DMSO-d6) δ12.74(s,1H),8.73(s,1H),7.96(s,1H),7.48-7. 40(m,2H),7.37(s,1H),7.07-6.97(m,1H),4.50-4.34(m,2H),3.93-3.81( m,1H),3.67-3.56(m,2H),3.50(s,3H),3.49-3.40(m,1H),2.84-2.73(m,1 H),2.72-2.63(m,1H),2.58(s,3H),2.41-2.29(m,1H),2.22-2.09(m,1H).

[0880] Example 82. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-[6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl]-6-(3-oxymorpholin-4-yl)pyridine-3-carboxamide (Compound 82)

[0881] Step 1: Synthesis of 6-chloro-4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)pyridine-3-carboxamide (Intermediate 82-1)

[0882] Intermediate 75-1 (100.0 mg), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (282.4 mg), and N-methylimidazole (137.7 mg) were dissolved in anhydrous N,N-dimethylformamide (2 mL) and stirred at room temperature for 0.5 h. Intermediate Int5 (85.0 mg) was then added and the mixture was allowed to react at 45°C for 18 h. After the reaction, ethyl acetate and water were added to the reaction solution, and the organic phase was washed once with saturated sodium chloride and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-20%) to obtain the title compound (30.0 mg).

[0883] MS m / z(ESI):530.9[MH] - .

[0884] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-(3-oxomorpholinyl)pyridine-3-carboxamide (Compound 82)

[0885] Intermediate 82-1 (17.0 mg), intermediate 82-2 (3.9 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (3.4 mg), tris(dibenzylideneacetone)dipalladium (2.9 mg), and potassium phosphate (13.5 mg) were dissolved in anhydrous tert-butanol (1 mL) and stirred at 100°C under a nitrogen atmosphere for 18 h. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 10%-90%, elution time 8 min) to obtain the title compound (15.0 mg).

[0886] MS m / z(ESI):596.0[MH] - .

[0887] 1 H NMR (400MHz, DMSO-d6) δ13.46(s,1H),9.30(s,1H),8.86(s,1H),8.36(d,J=8.3Hz,2H),8.13(m,1H),8.04-7.9 7(m,2H),7.49-7.46(m,1H),7.39(m,1H),7.04(d,J=8.9Hz,1H),4.32(s,2H),4.11-4.00(m,4H),3.54(s,3H).

[0888] Example 83, 4-(5-chloro-2-methoxy-phenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methoxypyridine-3-carboxamide (Compound 83)

[0889] Step 1: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methoxypyridine-3-carboxylic acid (Intermediate 83-1)

[0890] Intermediate 71-3 (100.0 mg) was dissolved in methanol (0.3 mL), and sodium methoxide methanol solution (5.4 M, 1.2 mL) was added. The mixture was heated at 60°C for 4 h. After the reaction, the pH of the reaction solution was adjusted to 5 with dilute hydrochloric acid and extracted three times with ethyl acetate (5 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (130.0 mg).

[0891] MS m / z(ESI):294.1[M+H] + .

[0892] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methoxypyridine-3-carboxamide (Compound 83)

[0893] Intermediate 83-1 (30.0 mg) was dissolved in dichloromethane (0.6 mL), followed by the addition of N,N'-dicyclohexylcarbodiimide (25.3 mg) and N-hydroxysuccinimide (14.1 mg). The mixture was allowed to react at room temperature for 1 h. After the reaction, the reaction mixture was filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was dissolved in N,N-dimethylformamide (0.5 mL). N,N-diisopropylethylamine (49.6 mg) and Intermediate Int5 (38.9 mg) were then added, and the mixture was heated at 100°C for 8 h. After the reaction, the reaction mixture was purified by preparative chromatography (YMC TAR-C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio: 40%-65%, elution time: 8 min) to obtain the title compound (2.0 mg).

[0894] MS m / z(ESI):529.0[M+H] +

[0895] 1 H NMR (400MHz, DMSO-d6) δ13.41 (s, 1H), δ9.22 (s, 1H), 8.66 (s, 1H), 8.34 (d, J = 8.3Hz, 2H), 7.98 (d ,J=8.2Hz,2H),7.48-7.33(m,2H),7.00(d,J=8.7Hz,1H),6.84(s,1H),3.97(s,3H),3.52(s,3H).

[0896] Example 84. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)-6-(3-oxomorpholino)pyridine-3-carboxamide (Compound 84)

[0897] Step 1: Synthesis of 6-chloro-4-(5-chloro-2-methoxyphenyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)pyridine-3-carboxamide (Intermediate 84-1)

[0898] Intermediate 75-1 (100.0 mg), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (282.4 mg), and N-methylimidazole (137.7 mg) were dissolved in anhydrous N,N-dimethylformamide (2 mL) and stirred at room temperature for 0.5 h. Intermediate 5-2 (85.0 mg) was then added and the mixture was allowed to react at 45°C for 18 h. After the reaction was complete, ethyl acetate and water were added to the reaction solution, and the organic phase was washed once with saturated sodium chloride and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-20%) to obtain the title compound (30.0 mg).

[0899] MS m / z(ESI):472[M+H] + .

[0900] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-(3-oxomorpholino)pyridine-3-carboxamide (Compound 84)

[0901] Intermediate 84-1 (46.0 mg), 3-morpholinone (14.8 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (10.5 mg), tris(dibenzylideneacetone)dipalladium (8.9 mg), and potassium phosphate (41.3 mg) were dissolved in anhydrous tert-butanol (2 mL) and stirred at 100°C under a nitrogen atmosphere for 18 h. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 10%-90%, elution time 8 min) to obtain the title compound (17.0 mg).

[0902] MS m / z(ESI):537.0[M+H] + .

[0903] 1 H NMR(400MHz,DMSO-d6)δ13.17(s,1H),8.81(s,1H),8.55(s,1H),8.10(s,1H),7.48-7.45(m,1H),7.37(s,1H ),7.02(d,J=8.9Hz,1H),4.31(s,2H),4.08-4.02(m,4H),3.51(s,3H),2.32-2.28(m,1H),1.11-0.94(m,4H).

[0904] Example 85. Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)-6-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)nicotinamide (Compound 85)

[0905] Step 1: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-(2-methoxy-2-oxoethyl)nicotinic acid (Intermediate 85-1)

[0906] The intermediate Int2 (2.8 g) was dissolved in anhydrous tetrahydrofuran (50 mL), cooled to -78 ° C, and then lithium diisopropylamide (2.5 M, 12.5 mL) was added dropwise. The reaction was kept at -78 ° C for 1 hour, followed by the addition of dimethyl carbonate (2 mL), and the reaction was continued at -78 ° C for 2 hours. After the reaction was completed, the reaction solution was quenched with 3N aqueous hydrochloric acid and the pH was adjusted to 3. Water (100 mL) was added, and then extracted three times with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (3.2 g).

[0907] MS m / z(ESI):336.0[M+H] + .

[0908] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-(2-hydrazino-2-oxoethyl)nicotinic acid (Intermediate 85-2)

[0909] Intermediate 85-1 (3.2 g) was dissolved in ethanol (50 mL), and hydrazine hydrate (1.1 g, 80% in water) was added. The mixture was stirred at 80°C for 3 h. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure to obtain the title compound (3.2 g).

[0910] MS m / z(ESI):336.0[M+H] + .

[0911] Step 3: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)nicotinic acid (Intermediate 85-3)

[0912] Intermediate 85-2 (3.2 g) was dissolved in triethyl orthoacetate (20 mL) and heated at 100°C for 4 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-100%) to obtain the title compound (300.0 mg).

[0913] MS m / z(ESI):360.1[M+H] + .

[0914] Step 4: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)-6-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)nicotinamide (Compound 85)

[0915] Intermediate 85-3 (100.0 mg) and intermediate 5-2 (62.8 mg) were dissolved in anhydrous N,N-dimethylformamide (3 mL). 1H-Benzotriazol-1-yloxytripyrrolidino hexafluorophosphate (289.6 mg) and N,N-diisopropylethylamine (0.3 mL) were then added and allowed to react at room temperature for 12 h. After completion of the reaction, the reaction solution was directly purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 10%-90%, elution time 8 min) to obtain the title compound (8.0 mg).

[0916] MS m / z(ESI):534.1[M+H] + .

[0917] 1 H NMR(400MHz,DMSO-d6)δ13.21(s,1H),8.82(s,1H),8.57(s,1H),7.59(s,1H),7.43-7.53(m,2H), 6.99-7.08(m,1H),4.53(s,2H),3.50(s,3H),2.48(s,3H),2.27-2.35(m,1H),1.07-0.98(m,4H).

[0918] Example 86, 4'-(5-chloro-2-methoxyphenyl)-4-methyl-2-oxo-N-(thiazolo[4,5-b]pyrazin-2-yl)-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 86)

[0919] Intermediate 2-2 (25 mg) was dissolved in acetonitrile (2 mL), and N-methylimidazole (0.5 mL) was added. The mixture was stirred at room temperature for 15 min. Intermediate 71-5 (80 mg) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (93.1 mg) were added to the above reaction mixture, along with additional N-methylimidazole (1 mL). The mixture was heated and stirred at 40°C for 16 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure, and the residue was directly purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 30%-60%, elution time 8 min) to obtain the title compound (1.2 mg).

[0920] MS m / z(ESI):504.9[M+H] + .

[0921] 1 H NMR (400MHz, DMSO-d6) δ9.03(s,1H),8.27(s,1H),8.23(s,1H),8.10(s,1H),7.94(d,J=7.2Hz,1H),7.71(s,1H),7.41(dd,J=8. 8,2.7Hz,1H),7.30(d,J=2.7Hz,1H),7.01(d,J=8.8Hz,1H),6.35(s,1H),6.29(dd,J=7.3,1.8Hz,1H),3.52(s,3H),2.21(s,3H).

[0922] Example 87, 4'-(5-chloro-2-methoxyphenyl)-4-methyl-N-(6-methylthiazolo[4,5-b]pyrazin-2-yl)-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 87)

[0923] Step 1: Synthesis of tert-butyl (6-methylthiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 87-2)

[0924] Intermediate Int1 (300.0 mg), starting material 87-1 (776 μL, 3.5 M), 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (131.0 mg), and potassium carbonate (376.0 mg) were dissolved in ethylene glycol dimethyl ether (3 mL) and reacted at 110°C under a nitrogen atmosphere for 16 hours. Upon completion of the reaction, the reaction solution was concentrated under reduced pressure to remove some of the solvent, and the residue was directly purified by flash column chromatography (ethyl acetate:petroleum ether 0-50%) to obtain the title compound (174.0 mg).

[0925] MS m / z(ESI):267.1[M+H] + .

[0926] Step 2: Synthesis of 6-methylthiazolo[4,5-b]pyrazine-2-amine (Intermediate 87-3)

[0927] Intermediate 87-2 (58.0 mg) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL) was added. The mixture was reacted at room temperature for 3 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure. Saturated aqueous sodium bicarbonate solution was added to the residue to adjust the pH to 7-8. The residue was then extracted three times with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (30.0 mg).

[0928] MS m / z(ESI):167.1[M+H] + .

[0929] Step 3: Synthesis of 4'-(5-chloro-2-methoxyphenyl)-4-methyl-N-(6-methylthiazolo[4,5-b]pyrazin-2-yl)-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 87)

[0930] Intermediate 71-5 (60.0 mg) was dissolved in dichloromethane (2 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (67.0 mg) and N,N-diisopropylethylamine (85 μL) were added to the reaction mixture. The mixture was allowed to react at room temperature for 2 h. After the reaction was completed, the mixture was diluted with dichloromethane (10 mL), washed three times with water (3 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was dissolved in N,N-dimethylformamide (1 mL), and Intermediate 87-3 (30.0 mg) and N,N-diisopropylethylamine (84 μL) were added to the mixture. The mixture was heated at 45°C for 16 h. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 45%-95%, elution time 8 min) to obtain the title compound (5.0 mg).

[0931] MS m / z(ESI):519.0[M+H] + .

[0932] 1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.47(s,1H),7.94-7.93(m,1H),7.90(s,1H),7.49-7.45(m,2H ),7.05-7.03(m,1H),6.37-6.36(m,1H),6.32-6.30(m,1H),3.53(s,3H),2.58(s,3H),2.22(m,3H).

[0933] Example 88, 4'-(5-chloro-2-methoxyphenyl)-N-(6-methoxythiazolo[4,5-b]pyrazin-2-yl)-4-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 88)

[0934] Step 1: Synthesis of tert-butyl (6-methoxythiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 88-1)

[0935] Intermediate Int1 (100.0 mg) and sodium methoxide (50.0 mg) were dissolved in methanol (2 mL) and heated at 60°C for 16 h. After the reaction was complete, the mixture was diluted with ethyl acetate (30 mL), and the organic phase was washed twice with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-30%) to obtain the title compound (30.0 mg).

[0936] MS m / z(ESI):283.0[M+H] + .

[0937] Step 2: Synthesis of 6-methoxythiazolo[4,5-b]pyrazin-2-amine (Intermediate 88-2)

[0938] Intermediate 88-1 (30.0 mg) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (2 mL) was added and reacted at room temperature for 3 h. After the reaction was completed, the reaction solution was directly concentrated to dryness under reduced pressure to obtain the title compound (40.0 mg).

[0939] MS m / z(ESI):183.0[M+H] + .

[0940] Step 3: Synthesis of 4'-(5-chloro-2-methoxyphenyl)-N-(6-methoxythiazolo[4,5-b]pyrazin-2-yl)-4-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 88)

[0941] Intermediate 71-5 (80.0 mg) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (93.1 mg) were dissolved in acetonitrile (1.5 mL). N-methylimidazole (54.5 mg) was added, and the mixture was stirred at room temperature for 0.5 h. Intermediate 88-2 (40.0 mg) was then added, and the mixture was heated at 40°C for 16 h. After the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio: 60%-90%, elution time: 8 min) to obtain the title compound (2.5 mg).

[0942] MS m / z(ESI):535.0[M+H] + .

[0943] 1 H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.91(s,1H),8.27(s,1H),7.96-7.90(m,2H),7.52-7.45(m,2H), 7.04(d,J=8.6Hz,1H),6.37(s,1H),6.31(dd,J=7.3,1.8Hz,1H),3.98(s,3H),3.53(s,3H),2.22(s,3H).

[0944] Example 89, 4-(5-chloro-2-methoxy-phenyl)-N-(6-(1-cyclopropyl-6-oxo-1,6-dihydropyrimidin-4-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (Compound 89)

[0945] Step 1: Synthesis of 6-bromo-3-cyclopropylpyrimidin-4(3H)-one (Intermediate 89-2)

[0946] The starting material 89-1 (2.0 g), cyclopropylboronic acid (1.9 g), acetic acid ketone (249.1 mg), 4,4-di-tert-butylbipyridyl (368.1 mg), and potassium carbonate (3.2 g) were added to toluene (50 mL) and reacted at 70°C for 16 h under oxygen protection. After the reaction was completed, ethyl acetate (50 mL) was added to dilute the mixture and filtered. The filtrate was washed twice with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (methanol:dichloromethane 0-5%) to obtain the title compound (620.0 mg).

[0947] MS m / z(ESI):215.0[M+H] +.

[0948] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(1-cyclopropyl-6-oxo-1,6-dihydropyrimidin-4-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (Compound 89)

[0949] Intermediate Int6 (25.0 mg), intermediate 89-2 (19.9 mg), and potassium carbonate (19.3 mg) were dissolved in 1,4-dioxane (1 mL) and water (0.2 mL). Under a nitrogen atmosphere, [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (3.0 mg) was added, and the mixture was heated at 90°C for 16 h. After the reaction, ethyl acetate (25 mL) and saturated brine (10 mL) were added to the reaction solution. The layers were separated, and the organic phase was washed twice with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (7 mmol ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio: 35%-55%, elution time: 8 min) to obtain the title compound (10.0 mg).

[0950] MS m / z(ESI):546.0[M+H] + .

[0951] 1 H NMR(400MHz,DMSO-d6)δ13.51(s,1H),9.34(s,1H),8.82(s,1H),8.55(s,1H),7.45(m,2H),7.39(s, 1H),7.18(s,1H),7.01(d,J=8.9Hz,1H),3.51(s,3H),3.27(m,1H),2.59(s,3H),1.07-0.97(m,4H).

[0952] Example 90. Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyano-2-oxopiperidin-1-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (Compound 90)

[0953] Step 1: Synthesis of methyl 1-(2-((tert-Butyloxycarbonyl)amino)thiazolo[4,5-b]pyrazin-6-yl)-2-oxopiperidine-4-carboxylate (Intermediate 90-1)

[0954] Intermediate Int1 (6.6 g), methyl 2-oxopiperidine-4-carboxylate (2.0 g), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (1.1 g), and tripotassium phosphate (8.5 g) were dissolved in anhydrous dioxane (100 mL). Tris(dibenzylideneacetone)dipalladium (912.2 mg) was added under a nitrogen atmosphere, and the mixture was heated at 100°C for 12 h. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent. Water (150 mL) was added to the residue, and the mixture was extracted three times with dichloromethane (150 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-80%) to obtain the title compound (810.2 mg).

[0955] MS m / z(ESI):408.1[M+H] + .

[0956] Step 2: Synthesis of tert-butyl (6-(4-carbamoyl-2-oxopiperidin-1-yl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 90-2)

[0957] Intermediate 90-1 (810.2 mg) was dissolved in ammonia methanol solution (7 M, 20.0 mL) and stirred at 45°C for 16 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure to obtain the title compound (850.1 mg).

[0958] MS m / z(ESI):393.1[M+H] + .

[0959] Step 3: Synthesis of tert-butyl (6-(4-cyano-2-oxopiperidin-1-yl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 90-3)

[0960] Intermediate 90-2 (850.1 mg) was dissolved in anhydrous tetrahydrofuran (40 mL), followed by the addition of Burgess reagent (2.1 g). The reaction was stirred at room temperature for 4 h. Upon completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-100%) to afford the title compound (430.3 mg).

[0961] MS m / z(ESI):375.1[M+H] + .

[0962] Step 4: Synthesis of 1-(2-aminothiazolo[4,5-b]pyrazin-6-yl)-2-oxopiperidine-4-carbonitrile (Intermediate 90-4)

[0963] Intermediate 90-3 (430.3 mg) was dissolved in trifluoroacetic acid (30 mL) and heated at 60°C for 4 h. After the reaction was complete, the reaction solution was concentrated under reduced pressure to remove the solvent. Saturated aqueous sodium bicarbonate solution (20 mL) was added to the residue, stirred, filtered, and the filter cake was collected and dried to obtain the title compound (190 mg).

[0964] MS m / z(ESI):275.0[M+H] + .

[0965] Step 5: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyano-2-oxopiperidin-1-yl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylnicotinamide (Compound 90)

[0966] Intermediate Int2 (100.0 mg), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (164.4 mg), and N,N-diisopropylethylamine (0.3 mL) were dissolved in N,N-dimethylformamide (3 mL) and stirred at room temperature for 1 h. Intermediate 90-4 (148.3 mg) was then added and the reaction continued at room temperature for 12 h. After completion of the reaction, the reaction solution was purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio 30%-60%, elution time 8 min) to obtain the title compound (15.0 mg).

[0967] MS m / z(ESI):534.1[M+H] + .

[0968] 1 H NMR (400MHz, CDCl3) δ10.40(s,1H),9.01(s,1H),8.91(s,1H),7.36-7.44(m,1H),7.21-7.25(m,1H),7.16(s,1H),6.8 4-6.93(m,1H),4.08–4.21(m,2H),3.70(s,3H),3.21-3.30(m,1H),2.89-3.03(m,2H),2.68(s,3H),2.30-2.45(m,2H).

[0969] Example 91, 4-(5-chloro-2-methoxy-phenyl)-N-(6-(3-(methoxymethyl)cyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methyl-pyridine-3-carboxamide (Compounds 91-P1 and 91-P2)

[0970] Step 1: Synthesis of tert-butyl (6-(1-hydroxy-3-(methoxymethyl)cyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 91-2)

[0971] Intermediate Int1 (1.0 g) was dissolved in anhydrous tetrahydrofuran (20 mL). Under a nitrogen atmosphere, the temperature was lowered to -78°C. n-Butyllithium (0.65 mL, 2.5 M in n-hexane) was slowly added dropwise to the reaction mixture until complete, and the mixture was allowed to react at -78°C for 1 h. A solution of 3-(methoxymethyl)cyclobutanone (517.0 mg) in tetrahydrofuran (10 mL) was then added dropwise until complete, stirred at -78°C for 1 h, and then slowly warmed to room temperature for 16 h. Upon completion of the reaction, the reaction mixture was poured into saturated ammonium chloride solution (100 mL), then extracted three times with methyl tert-butyl ether (50 mL x 3). The resulting organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-55%) to yield the title compound (450.0 mg).

[0972] MS m / z(ESI):367.1[M+H] + .

[0973] Step 2: Synthesis of tert-butyl (6-(1-chloro-3-(methoxymethyl)cyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 91-3)

[0974] Intermediate 91-2 (200.0 mg) was dissolved in dichloromethane (2 mL). Thionyl chloride (162.3 mg) was added dropwise at 0°C and stirred for 30 min. The temperature was then gradually raised to room temperature for 2 h. Upon completion of the reaction, the reaction solution was quenched by adding saturated aqueous sodium bicarbonate solution (25 mL). The solution was then extracted three times with ethyl acetate (15 mL x 3). The resulting organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to afford the title compound (200.0 mg).

[0975] MS m / z(ESI):385.0[M+H] + .

[0976] Step 3: Synthesis of tert-butyl (6-(1-isopropoxy-3-(methoxymethyl)cyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 91-4)

[0977] Intermediate 91-3 (120.0 mg) was dissolved in ethyl acetate (2 mL) and isopropanol (2 mL), and triethylamine (0.5 mL) was added. The mixture was stirred at room temperature for 16 h. After the reaction was completed, the solvent was removed by concentration under reduced pressure. The residue was dissolved in dichloromethane (20 mL), washed twice with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the title compound (120.0 mg).

[0978] MS m / z(ESI):409.2[M+H] + .

[0979] Step 4: Synthesis of 6-(3-(methoxymethyl)cyclobutyl)thiazolo[4,5-b]pyrazin-2-amine (Intermediate 91-5)

[0980] Intermediate 91-4 (120.0 mg) was dissolved in dichloromethane (2 mL), and triethylsilane (1 mL) and boron trifluoride-diethyl ether (1 mL) were added, followed by stirring at 40°C for 4 h. After completion of the reaction, the reaction solution was dropwise added to a saturated aqueous sodium bicarbonate solution (10 mL) to quench the reaction, and extracted four times with ethyl acetate (5 mL x 4). The resulting organic phase was washed twice with saturated brine (5 mL x 2), dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the title compound (70.0 mg).

[0981] MS m / z(ESI):251.1[M+H] + .

[0982] Step 5: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(3-(methoxymethyl)cyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Compound 91)

[0983] Intermediate Int2 (100.0 mg), O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (209.0 mg) and N,N-diisopropylethylamine (179.0 mg) were dissolved in N,N-dimethylformamide (2 mL), stirred at room temperature for 1 h, and then intermediate 91-5 (70.0 mg) was added thereto, and the mixture was heated at 55°C for 16 h. After the reaction was completed, the mixture was diluted with ethyl acetate (30 mL). The organic phase was washed twice with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 45%-75%, elution time 8 min) to obtain the title compound 91-P1 (4.5 mg) and 91-P2 (3.5 mg) as two isomers. The two isomers were analyzed by chromatographic methods:

[0984] Compound 91-P1

[0985] Under the above chromatographic conditions, the retention time of compound 91-P1 was 9.446 min.

[0986] MS m / z(ESI):510.0[M+H] + .

[0987] 1 H NMR (400MHz, DMSO-d6) δ8.78(s,1H),8.48(s,1H),7.46-7.42(m,2H),7.38(s,1H),7.00(d,J=8.6Hz,1H),3.70-3. 66(m,1H),3.45-3.41(m,1H),3.31-3.27(m,2H),3.50(s,3H),3.25(s,3H),2.59(s,3H),2.39(m,2H),2.06(m,2H).

[0988] Compound 91-P2

[0989] Under the above chromatographic conditions, the retention time of compound 91-P2 was 9.558 min.

[0990] MS m / z(ESI):510.0[M+H] + .

[0991] 1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.45(s,1H),7.44(m,2H),7.37(m,1H),7.00(m,1H),3.91-3.81(m,1H ),3.53-3.51(m,1H),3.50(s,3H),3.42-3.46(m,2H),3.30(s,3H),2.59(s,3H),2.41(m,2H),2.15(m,2H).

[0992] Example 92. Synthesis of N-(6-(1-cyclopropyl-6-oxo-1,6-dihydropyridazin-4-yl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 92)

[0993] Step 1: Synthesis of tert-butyl (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 92-1)

[0994] Intermediate Int1 (500.0 mg) was dissolved in 1,4-dioxane (5 mL), and potassium acetate (177.5 mg), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (109.5 mg), and diboronic acid pinacol ester (460.0 mg) were added. The reaction was heated at 100°C under a nitrogen atmosphere for 16 hours. Upon completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified on a flash column (ethyl acetate:petroleum ether 0-50%) to obtain the title compound (200.0 mg).

[0995] MS m / z(ESI):379.2[M+H] + .

[0996] Step 2: Synthesis of tert-butyl (6-(1-cyclopropyl-6-oxo-1,6-dihydropyridazin-4-yl)thiazolo[4,5-b]pyrazin-2-yl)carbamate (Intermediate 92-3)

[0997] Intermediate 92-1 (60.0 mg) was dissolved in 1,4-dioxane (1 mL) and water (0.2 mL). Starting material 92-2 (53.1 mg) was added, followed by [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (14.7 mg) and potassium carbonate (84.0 mg). The mixture was heated at 70°C under a nitrogen atmosphere for 2 h. Upon completion of the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified on a flash column (ethyl acetate:petroleum ether 0-45%) to obtain the title compound (50.0 mg).

[0998] MS m / z(ESI):387.4[M+H] + .

[0999] Step 3: Synthesis of 5-(2-aminothiazolo[4,5-b]pyrazin-6-yl)-2-cyclopropylpyridazin-3(2H)-one (Intermediate 92-4)

[1000] Intermediate 92-3 (50.0 mg) was dissolved in ethyl acetate (0.5 mL), and then ethyl acetate hydrochloride (2 M, 1 mL) was added. The mixture was stirred at room temperature for 4 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure to obtain the title compound (50.0 mg).

[1001] MS m / z(ESI):287.2[M+H] + .

[1002] Step 4: Synthesis of N-(6-(1-cyclopropyl-6-oxo-1,6-dihydropyridazin-4-yl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 92)

[1003] Intermediate Int3 (30.0 mg), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (95.8 mg), and N-methylimidazole (47.7 mg) were added to N,N-dimethylformamide (1 mL) and reacted at room temperature under a nitrogen atmosphere for 2 h. Intermediate 92-4 (33.0 mg) was then added and heated at 60°C for 16 h. After the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative chromatography (YMC TA-C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 10%-90%, elution time 8 min) to obtain the title compound (1.0 mg).

[1004] MS m / z(ESI):527.1[M+H] + .

[1005] 1 H NMR (400MHz, DMSO-d6) δ9.06 (s, 1H), 8.99 (s, 1H), 8.59 (d, J = 2.0Hz, 1H), 8.14 (s, 1H), 7.46 (s, 1H), 7.13-7. 11(m,2H),4.11-4.00(m,1H),3.58(s,3H),2.54(s,3H),2.45(s,3H),1.07-1.02(m,2H),1.00-0.97(m,2H).

[1006] Example 93, N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2,5-dimethylmorpholino)-6-methylnicotinamide (Compound 93)

[1007] Step 1: Synthesis of 4-bromo-6-methylpyridine-3-carboxylic acid (Intermediate 93-2)

[1008] Starting material 1 (8.0 g) was dissolved in tetrahydrofuran (50 mL), and an aqueous solution of lithium hydroxide monohydrate (2.9 g) (50 mL) was added, followed by reaction at room temperature for 2 h. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and the residue was diluted with water (30 mL). The pH was adjusted to 3 with 2N dilute hydrochloric acid, and the mixture was extracted three times with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the title compound (4.0 g).

[1009] Step 2: Synthesis of 4-bromo-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-6-methylpyridine-3-carboxamide (Intermediate 93-3)

[1010] Intermediate 93-2 (221.7 mg) was dissolved in N,N-dimethylformamide (5 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (387.3 mg) and N,N-diisopropylethylamine (306.2 mg) were added. The mixture was stirred at room temperature for 30 min, followed by the addition of Intermediate Int5 (0.2 g). The mixture was allowed to react at room temperature for 2 h. After the reaction, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR column, mobile phase: 0.5‰ formic acid-water & acetonitrile, 25 mL / min, 75-95% acetonitrile) to obtain the title compound (150.0 mg).

[1011] MS m / z(ESI):451.0[M+H] + .

[1012] Step 3: Synthesis of N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-4-(2,5-dimethylmorpholino)-6-methylnicotinamide (Compound 93)

[1013] Intermediate 93-3 (30.0 mg), starting material 93-4 (9.6 mg), cesium carbonate (65.0 mg), 2-bicyclohexylphosphino-2',6'-diisopropoxybiphenyl (9.3 mg), and tris(dibenzylideneacetone)dipalladium (9.1 mg) were added to 1,4-dioxane (1 mL) and heated at 100°C under a nitrogen atmosphere for 16 h. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 75%-95%, elution time 8 min) to obtain the title compound (0.7 mg).

[1014] MS m / z(ESI):486.2[M+H] +

[1015] 1 H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.42(s,1H),8.38-8.36(m,2H),8.01-7.99(m,2H),6.85(s,1H),3.7 1-3.63(m,2H),3.59-3.56(m,1H),3.31-3.21(m,2H),3.14-2.98(m,1H),2.44(s,3H),1.12-1.07(m,6H).

[1016] Example 94, 4'-(5-chloro-2-methoxyphenyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 94)

[1017] Step 1: Synthesis of 4'-(5-chloro-2-methoxyphenyl)-2-oxo-2H-[1,2'-bipyridine]-5'-carboxylic acid (Intermediate 94-1)

[1018] Intermediate 71-3 (311.0 mg) and 2-pyridone (190.1 mg) were dissolved in N,N-dimethylformamide (5 mL), followed by the addition of potassium carbonate (276.2 mg) and the reaction mixture was heated at 100°C for 12 h. After the reaction was complete, the mixture was cooled to room temperature, and water (20 mL) and sodium hydroxide (200.3 mg) were added to the reaction mixture, followed by the reaction mixture at room temperature for 3 h. After the reaction was complete, the pH was adjusted to 3 with 2N hydrochloric acid solution, and the mixture was filtered. The filter cake was collected and dried to obtain the title compound (280.0 mg).

[1019] MS m / z(ESI):357.0[M+H] + .

[1020] Step 2: Synthesis of 4'-(5-chloro-2-methoxyphenyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 94)

[1021] Intermediate 94-1 (178.4 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (228.0 mg), and N,N-diisopropylethylamine (0.2 mL) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 1 h. Intermediate 5-2 (143.2 mg) was then added, and the mixture was allowed to react at room temperature for 12 h. After completion of the reaction, the reaction solution was purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 10%-90%, elution time 8 min) to obtain the title compound (20.0 mg).

[1022] MS m / z(ESI):531.0[M+H] + .

[1023] 1 H NMR(400MHz, CDCl3)δ8.92(s,1H),8.41(s,1H),8.07(s,1H),7.98-8.04(m,1H),7.40-7.47(m,1H),7.34-7.39(m, 2H),6.79-6.84(m,1H),6.64-6.70(m,1H),6.31-6.40(m,1H),3.65(s,3H),2.12-2.18(m,1H),1.08-1.14(m,4H).

[1024] Example 95, 4-(5-chloro-2-methoxyphenyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)-6-(4-methyl-2-oxopiperazin-1-yl)nicotinamide (Compound 95)

[1025] Intermediate 84-1 (20.0 mg) was dissolved in tert-butanol (1 mL), and starting material 95-1 (7.3 mg), potassium phosphate (18.0 mg), tris(dibenzylideneacetone)dipalladium (3.9 mg), and 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (4.5 mg) were added. The mixture was heated at 100°C under a nitrogen atmosphere for 16 h. After the reaction, the reaction solution was directly concentrated to dryness, and the residue was purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 10%-90%, elution time 8 min) to obtain the title compound (3.0 mg).

[1026] MS m / z(ESI):550.1[M+H] + .

[1027] 1 H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.44(s,1H),7.91(s,1H),7.44-7.42(m,1H),7.32(s,1H),7.02-6.99(m,1H),3.99-3.9 6(m,2H),3.50(s,3H),3.23(s,2H),2.76-2.79(m,2H),2.30(s,3H),2.26-2.22(m,1H),1.03-1.01(m,2H),0.97-0.93(m,2H).

[1028] Example 96, 5'-chloro-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5-(2-(dimethylamino)-2-oxoethyl)-2'-methoxy-[1,1'-biphenyl]-2-carboxamide (Compound 96)

[1029] Step 1: Synthesis of methyl 2-(5'-chloro-6-((6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)carbamoyl)-2'-methoxy-[1,1'-biphenyl]-3-yl)acetate (Intermediate 96-1)

[1030] Intermediate 85-1 (100.0 mg), intermediate Int5 (113.0 mg), 48 mg of 1-hydroxybenzotriazole, and N,N-diisopropylethylamine (156 μL) were dissolved in N,N-dimethylformamide (1.5 mL). The mixture was stirred at room temperature for 10 min, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (63.0 mg) was added. The mixture was heated at 45°C for 12 h. After the reaction was completed, ethyl acetate (20 mL) was added to dilute the reaction solution, and the mixture was washed three times with water (7 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (200.0 mg).

[1031] MS m / z(ESI):570.1[M+H] + .

[1032] Step 2: Synthesis of 2-(5'-chloro-6-((6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)carbamoyl)-2'-methoxy-[1,1'-biphenyl]-3-yl)acetic acid (Intermediate 96-2)

[1033] Intermediate 96-1 (100.0 mg) and lithium hydroxide (11.0 mg) were dissolved in a mixed solvent of tetrahydrofuran (1 mL), water (1 mL), and methanol (0.4 mL) and reacted at room temperature for 8 h. After the reaction, dilute hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 3. Water (15 mL) was added to the reaction solution, and the solution was extracted three times with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (90.0 mg).

[1034] MS m / z(ESI):556.1[M+H] + .

[1035] Step 3: Synthesis of 5'-chloro-N-(6-(4-cyanophenyl)thiazolo[4,5-b]pyrazin-2-yl)-5-(2-(dimethylamino)-2-oxoethyl)-2'-methoxy-[1,1'-biphenyl]-2-carboxamide (Compound 96)

[1036] Intermediate 96-2 (90.0 mg), dimethylamine hydrochloride (132.0 mg), 1-hydroxybenzotriazole (26.0 mg), and N,N-diisopropylethylamine (367 μL) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 10 min. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (34.0 mg) was then added and the reaction continued at room temperature for 20 h. After completion of the reaction, the reaction solution was directly purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 20%-80%, elution time 8 min) to obtain the title compound (2.0 mg).

[1037] MS m / z(ESI):583.1[M+H] + .

[1038] 1 H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.33-8.23(m,3H),7.96-7.83(m,3H),7.35-7.24(m,2H),7.20 -7.14(m,1H),7.11(s,1H),6.97-6.88(m,1H),3.77(s,2H),3.48(s,3H),3.04(s,3H),2.85(s,3H).

[1039] Example 97, 4-(5-chloro-2-methoxyphenyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)-6-(4-methyl-6-oxopyridazin-1(6H)-yl)nicotinamide (Compound 97)

[1040] Intermediate 84-1 (20.0 mg) was dissolved in tert-butanol (1 mL), and starting material 97-1 (7.0 mg), potassium phosphate (18.0 mg), tris(dibenzylideneacetone)dipalladium (3.9 mg), and 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (4.5 mg) were added. The mixture was heated at 100°C under a nitrogen atmosphere for 16 h. After the reaction, the reaction solution was directly concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 10%-90%, elution time 8 min) to obtain the title compound (0.4 mg).

[1041] MS m / z(ESI):546.1[M+H] +.

[1042] 1 H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.16(s,1H),8.00(s,1H),7.45-7.42(m,2H),7.39-7.37(m,1H),7.22(d, J=8.0Hz,1H),6.91(s,1H),3.52(s,3H),2.34-2.32(m,1H),2.27(s,3H),1.03-1.00(m,2H),0.97-0.93(m,2H).

[1043] Example 98. Synthesis of 4-(5-chloro-2-methoxy-phenyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)-6-(4,4-dimethyl-2-oxo-1-piperidinyl)pyridine-3-carboxamide (Compound 98)

[1044] Intermediate 84-1 (25.0 mg), starting material 98-1 (10.1 mg), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (5.7 mg), tris(dibenzylideneacetone)dipalladium (4.9 mg), and potassium phosphate (22.5 mg) were dissolved in anhydrous tert-butanol (2 mL) and stirred at 100°C under a nitrogen atmosphere for 18 h. After the reaction, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 10%-90%, elution time 8 min) to obtain the title compound (15.0 mg).

[1045] MS m / z(ESI):563.1[M+H] + .

[1046] 1 H NMR(400MHz,DMSO-d6)δ13.11(s,1H),8.70(s,1H),8.51(s,1H),7.77(s,1H),7.43-7.35(m,1H),7.33-7.30(m,1H),6.94(d ,J=8.9Hz,1H),3.94-3.89(m,2H),3.43(s,3H),2.32-2.18(m,3H),1.75-1.71(m,2H),1.10-0.99(m,8H),0.95-0.89(m,2H).

[1047] Example 99. Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)-6-(4-methyl-2-oxopiperidin-1-yl)nicotinamide (Compound 99)

[1048] Intermediate 84-1 (50.0 mg), 4-methylpiperidin-2-one (24.0 mg), tris(dibenzylideneacetone)dipalladium (10.0 mg), 2-(dicyclohexylphosphine)-3,6-dimethoxy-2'-4'-6'-tri-1-propyl-11'-biphenyl (11.0 mg), and potassium phosphate (67.0 mg) were dissolved in tert-butanol (1 mL) and reacted at 100°C for 16 h under a nitrogen atmosphere. After the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 30%-90%, elution time 8 min) to obtain the title compound (2.0 mg).

[1049] MS m / z(ESI):549.1[M+H] + .

[1050] 1 H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.51(s,1H),8.15(s,1H),7.79(s,1H),7. 52-7.39(m,1H),7.38-7.28(m,1H),7.08-6.90(m,1H),4.13-3.99(m,1H),3.94 -3.80(m,3H),2.61-2.54(m,1H),2.34-2.25(m,1H),2.25-2.16(m,1H),2.14-2.05( m,1H),2.04-1.97(m,1H),1.62-1.50(m,1H),1.08-1.01(m,5H),1.00-0.95(m,2H).

[1051] Example 100. Synthesis of 5'-chloro-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)-5-(2-(dimethylamino)-2-oxoethyl)-2'-methoxy-[1,1'-biphenyl]-2-carboxamide (Compound 100)

[1052] Step 1: Synthesis of methyl 2-(6-((6-bromothiazolo[4,5-b]pyrazin-2-yl)carbamoyl)-5'-chloro-2'-methoxy-[1,1'-biphenyl]-3-yl)acetate (Intermediate 100-2)

[1053] Intermediate 85-1 (200.0 mg), Intermediate 100-1 (207.0 mg), 1-hydroxybenzotriazole (97.0 mg), and N,N-diisopropylethylamine (312 μL) were dissolved in N,N-dimethylformamide (3 mL). The mixture was stirred at room temperature for 10 min, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (126.0 mg) was added. The mixture was heated at 45°C for 12 h. After the reaction was completed, ethyl acetate (10 mL) was added to dilute the mixture, and the mixture was washed three times with water (3 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 (ethyl acetate:petroleum ether 0-80%) to obtain the title compound (120.0 mg).

[1054] MS m / z(ESI):547.0[M+H] + .

[1055] Step 2: Synthesis of methyl 2-(5'-chloro-6-((6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)carbamoyl)-2'-methoxy-[1,1'-biphenyl]-3-yl)acetate (Intermediate 100-3)

[1056] Intermediate 100-2 (110.0 mg) and iron triacetylacetonate (14.0 mg) were dissolved in ultra-dry tetrahydrofuran (2 mL). Under a nitrogen atmosphere, cyclopropylmagnesium bromide (2.1 mL, 0.5 M) was slowly added dropwise at -20°C. The reaction was maintained at -20°C for 0.5 h, then warmed to room temperature and continued for 2 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent. Saturated ammonium chloride solution (20 mL) was added to the residue, and the mixture was extracted three times with ethyl acetate (10 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-80%) to obtain the title compound (43.0 mg).

[1057] MS m / z(ESI):509.1[M+H] + .

[1058] Step 3: Synthesis of 2-(5'-chloro-6-((6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)carbamoyl)-2'-methoxy-[1,1'-biphenyl]-3-yl)acetic acid (Intermediate 100-4)

[1059] Intermediate 100-3 (43.0 mg) and lithium hydroxide (9.0 mg) were dissolved in a mixed solvent of tetrahydrofuran (0.5 mL), water (0.5 mL), and methanol (0.1 mL) and reacted at room temperature for 8 h. After the reaction, dilute hydrochloric acid was added dropwise to the reaction solution to adjust the pH to 3. Water (10 mL) was added to the reaction solution, and the solution was extracted three times with ethyl acetate (5 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (32.0 mg).

[1060] MS m / z(ESI):495.1[M+H] + .

[1061] Step 4: Synthesis of 5'-chloro-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)-5-(2-(dimethylamino)-2-oxoethyl)-2'-methoxy-[1,1'-biphenyl]-2-carboxamide (Compound 100)

[1062] Intermediate 100-4 (32.0 mg), dimethylamine hydrochloride (82.0 mg), 1-hydroxybenzotriazole (10.0 mg), and N,N-diisopropylethylamine (146 μL) were dissolved in N,N-dimethylformamide (3 mL) and stirred at room temperature for 10 min. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14.0 mg) was then added and the reaction continued at room temperature for 20 h. After completion of the reaction, the reaction solution was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 20%-80%, elution time 8 min) to obtain the title compound (4.3 mg).

[1063] MS m / z(ESI):522.0[M+H] + .

[1064] 1 H NMR(400MHz,DMSO-d6)δ8.57(s,1H),7.70-7.64(m,1H),7.39-7.36(m,1H),7.37-7.34(m,1H),7.33-7.31(m,1H),7.30-7.27(m,1H ),6.97-6.91(m,1H),3.83(s,2H),3.47(s,3H),3.06(s,3H),2.85(s,3H),2.35-2.25(m,1H),1.10-1.03(m,2H),1.02-0.96(m,2H).

[1065] Example 101, 4-(5-chloro-2-methoxy-phenyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)-6-(1-methylpyrazol-3-yl)pyridine-3-carboxamide (Compound 101)

[1066] Intermediate 84-1 (30.0 mg), starting material 101-1 (13.2 mg), potassium carbonate (26.3 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (4.6 mg) were added to 1,4-dioxane (1 mL) and water (0.2 mL). The mixture was heated at 100°C under a nitrogen atmosphere for 4 h. After the reaction, the solvent was removed by concentration under reduced pressure. The residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 75%-95%, elution time 8 min) to obtain the title compound (1.0 mg).

[1067] MS m / z(ESI):518.0[M+H] +

[1068] 1 H NMR (400MHz, DMSO-d6) δ13.21(s,1H),8.90(s,1H),8.58(s,1H),7.87(s,1H),7.85(d,J=4.0Hz,1H),7.51(d,J=4.0Hz,1H),7.48-7.46( m,1H),7.03(d,J=8.0Hz,1H),6.95(d,J=4.0Hz,1H),3.95(s,3H),3.52(s,3H),2.34-2.27(m,1H),1.10-1.04(m,2H),1.02-0.98(m,2H).

[1069] Example 102. Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-(cyanomethyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)nicotinamide (Compound 102)

[1070] Step 1: Synthesis of methyl 4-(5-chloro-2-methoxyphenyl)-6-(dibromomethyl)nicotinate (Intermediate 102-1)

[1071] Intermediate Int2-4 (2.0 g), azobisisobutyronitrile (112.6 mg), and N-bromosuccinimide (1.8 g) were dissolved in anhydrous acetonitrile (20 mL) and stirred at 75°C for 18 h. Upon completion of the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-20%) to obtain the title compound (780.0 mg).

[1072] MS m / z(ESI):447.8[M+H] + .

[1073] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-(dibromomethyl)nicotinic acid (Intermediate 102-2)

[1074] Intermediate 102-1 (300.0 mg) was dissolved in tetrahydrofuran (2 mL), followed by the addition of an aqueous solution (2 mL) of lithium hydroxide monohydrate (70.0 mg) and the mixture was stirred at room temperature for 2 h. After the reaction was complete, ethyl acetate (10 mL) and water (15 mL) were added to the reaction solution, and the layers were separated by stirring. The aqueous phase was adjusted to pH 3 with 2N hydrochloric acid and extracted twice with ethyl acetate (15 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (240.0 mg).

[1075] MS m / z(ESI):433.8[M+H] + .

[1076] Step 3: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)-6-(dibromomethyl)nicotinamide (Intermediate 102-3)

[1077] Intermediate 102-2 (200.0 mg), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (386.6 mg), and N-methylimidazole (188.5 mg) were dissolved in anhydrous N,N-dimethylformamide (3 mL) and stirred at room temperature for 0.5 h. Intermediate Int5-2 (88.3 mg) was then added and reacted at 45°C for 18 h. After the reaction was complete, ethyl acetate (20 mL) and water (10 mL) were added to the reaction solution, and the layers were separated. The organic phase was washed once with saturated sodium chloride (10 mL x 1) and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-30%) to obtain the title compound (80.0 mg).

[1078] MS m / z(ESI):607.9[M+H] + .

[1079] Step 4: Synthesis of 6-(bromomethyl)-4-(5-chloro-2-methoxyphenyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)nicotinamide (Intermediate 102-4)

[1080] Intermediate 102-3 (75.0 mg) was dissolved in tetrahydrofuran (2 mL), followed by the addition of diethyl phosphite (25.3 mg) and N,N-diisopropylethylamine (79.5 mg), and the mixture was stirred at room temperature for 4 h. After the reaction, ethyl acetate (10 mL) and water (5 mL) were added to the reaction solution. The layers were separated, and the organic phase was washed once with saturated sodium chloride solution (5 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (65.0 mg).

[1081] MS m / z(ESI):529.9[M+H] + .

[1082] Step 5: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-(cyanomethyl)-N-(6-cyclopropylthiazolo[4,5-b]pyrazin-2-yl)nicotinamide (Compound 102)

[1083] Intermediate 102-4 (60.0 mg) was dissolved in tetrahydrofuran (0.5 mL) and acetonitrile (0.5 mL), followed by the addition of anhydrous potassium carbonate (31.2 mg) and trimethylsilyl cyanide (16.8 mg), and stirred at room temperature for 4 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 10%-90%, elution time 8 min) to obtain the title compound (1.5 mg).

[1084] MS m / z(ESI):477.1[M+H] + .

[1085] 1 H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.37(s,1H),7.46-7.38(m,3H),7.01(d,J=8.9Hz, 1H),4.29(s,2H),3.50(s,3H),2.25-2.20(m,1H),1.02-0.93(m,2H),0.92-0.85(m,2H).

[1086] Example 103. Synthesis of N-(6-(3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 103)

[1087] Step 1: Synthesis of 4-bromo-2-(difluoromethyl)-5-methoxypyridine (Intermediate 103-2)

[1088] The starting material 103-1 (3.0 g) was dissolved in dichloromethane (30 mL), and diethylaminosulfur trifluoride (5.7 mL) was added to the mixture at 0°C. The mixture was stirred at 0°C for 3 h. After the reaction was completed, a saturated aqueous sodium bicarbonate solution (30 mL) was added to the mixture to quench the reaction. The mixture was stirred, separated, and the aqueous phase was extracted three times with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the solvent, and the residue was directly purified by flash column chromatography (ethyl acetate:petroleum ether 0-25%) to obtain the title compound (2.8 g).

[1089] MS m / z(ESI):238.0[M+H] + .

[1090] Step 2: Synthesis of (2-(difluoromethyl)-5-methoxypyridin-4-yl)boronic acid (Intermediate 103-3)

[1091] Intermediate 103-2 (200.0 mg), bis(pinacolato)diboron (256.0 mg), potassium acetate (247.0 mg), and (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (137.0 mg) were dissolved in 1,4-dioxane (4 mL) and heated at 100°C under a nitrogen atmosphere for 6 h. After the reaction, the reaction solution was cooled to room temperature, filtered, and washed with an appropriate amount of ethyl acetate. The filtrate was concentrated under reduced pressure to dryness to obtain the title compound (500.0 mg).

[1092] MS m / z(ESI):204.1[M+H] + .

[1093] Step 3: Synthesis of methyl 2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (Intermediate 103-5)

[1094] Intermediate 103-3 (115.0 mg), starting material 103-4 (100.0 mg), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (70 mg), and potassium carbonate (223.0 mg) were dissolved in a mixture of 1,4-dioxane (1 mL) and water (0.2 mL). The mixture was heated at 100°C under a nitrogen atmosphere for 10 h. After the reaction was complete, the reaction solution was cooled to room temperature and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-80%) to obtain the title compound (70.0 mg).

[1095] MS m / z(ESI):309.1[M+H] + .

[1096] Step 4: Synthesis of N-(6-(3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-(difluoromethyl)-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 103)

[1097] Intermediate 103-5 (50.0 mg), intermediate 22-5-P2 (45.0 mg), and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (113 mg) were dissolved in tetrahydrofuran (2 mL) and reacted at 70°C for 4 h. After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative chromatography (YMC TAR-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 20%-80%, elution time 8 min) to obtain the title compound (9.0 mg).

[1098] MS m / z(ESI):508.0[M+H] + .

[1099] 1 H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.44(s,1H),8.38(s,1H),8.15(s,0H),7.65(s,1H),7.34(s,1H),6. 98(t,J=55.1Hz,1H),4.10-3.99(m,1H),3.69(s,3H),3.53-3.42(m,1H),2.76-2.62(m,4H),2.59(s,3H).

[1100] Example 104, N-(6-(3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 104)

[1101] Step 1: Synthesis of methyl 2'-cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylate (Intermediate 104-2)

[1102] Intermediate Int3-3 (1.0 g), cyclopropylboronic acid (880.3 mg), dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (242.6 mg), and potassium phosphate (2.2 g) were dissolved in 1,4-dioxane (15 mL) and water (3 mL). The mixture was stirred under a nitrogen atmosphere at 100°C for 8 h. After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:petroleum ether 0-50%) to obtain the title compound (650.0 mg).

[1103] MS m / z(ESI):299.1[M+H] + .

[1104] Step 2: Synthesis of N-(6-(3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide

[1105] Intermediate 104-1 (100.0 mg), intermediate 22-5-P2 (30.2 mg), and 1,5,7-triazabicyclo[4.4.0]de-5-ene (140.0 mg) were dissolved in tetrahydrofuran (1 mL) and stirred at 70°C for 18 h. After the reaction, ethyl acetate (20 mL) and water (8 mL) were added, stirred, and the layers separated. The organic phase was washed once with saturated sodium chloride solution (8 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 10%-90%, elution time 8 min) to obtain the title compound (3.3 mg).

[1106] MS m / z(ESI):498.1[M+H] +

[1107] 1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.28(s,1H),8.12(s,1H),7.28-7.10(m,2H),4.05-3.98(m,1H), 3.56(s,3H),3.50-3.43(m,1H),2.74-2.63(m,4H),2.56(s,3H),2.15-2.08(m,1H),0.92-0.88(m,4H).

[1108] Example 105, N-(6-(3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-3'-fluoro-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 105)

[1109] Intermediate 105-1 (37.0 mg, synthesized according to the method reported in patent WO2022118210), intermediate 22-5-P2 (29.5 mg), and 1,5,7-triazabicyclo[4.4.0]de-5-ene (88.7 mg) were dissolved in tetrahydrofuran (0.5 mL) and stirred at 70°C for 18 h. After the reaction, ethyl acetate (15 mL) and water (10 mL) were added. The layers were separated, and the organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio: 40%-80%, elution time: 10 min) to obtain the title compound (2.3 mg).

[1110] LC-MS: m / z(ESI):490.0[M+H] + .

[1111] 1 H NMR(400MHz,DMSO-d6)δ13.47(s,1H),9.01(s,1H),8.52(s,1H),8.17(s,1H),7.41(s,1H),4. 14-4.06(m,1H),3.67(s,3H),3.51-3.44(m,1H),2.76-2.64(m,4H),2.60(s,3H),2.44(s,3H).

[1112] Example 106, N-(6-(3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-(difluoromethoxy)-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 106)

[1113] Intermediate 106-1 (50.0 mg, synthesized according to the method reported in patent WO2022259204), intermediate 22-5-P2 (30.0 mg), and 1,5,7-triazabicyclo[4.4.0]de-5-ene (112.9 mg) were dissolved in tetrahydrofuran (0.5 mL) and the system was heated and stirred at 70°C for 18 h. After the reaction, ethyl acetate (15 mL) and water (10 mL) were added. The layers were separated, and the organic phase was washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by preparative chromatography (column: YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 30 mL / min; acetonitrile ratio: 30%-70%, elution time: 9.0 min) to obtain the title compound (4.2 mg).

[1114] LC-MS: m / z(ESI):508.1[M+H] + .

[1115] 1 H NMR(400MHz,DMSO-d6)δ13.50(s,1H),9.01(s,1H),8.50(s,1H),8.32(s,1H),7.43-7.37(m,2H),7. 25-6.88(m,1H),4.13-4.05(m,1H),3.51-3.44(m,1H),2.76-2.64(m,4H),2.61(s,3H),2.54(s,3H).

[1116] Example 107, N-(6-(3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-2'-(trifluoromethoxy)-[4,4'-bipyridine]-3-carboxamide (Compound 107)

[1117] Step 1: Synthesis of methyl 5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxylate (Intermediate 107-3)

[1118] Intermediate 107-1 (255.0 mg, synthesized according to patent WO2023002409) was dissolved in a 1,4-dioxane / water mixture (10 mL / 2 mL). Potassium carbonate (420.0 mg), intermediate 107-2 (300.0 mg), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (50.0 mg) were then added. The atmosphere was purged with nitrogen three times, and the system was heated at 85°C for 12 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by chromatography (ethyl acetate:petroleum ether 0-100%) to obtain the title compound (230.0 mg).

[1119] LC-MS: m / z(ESI):327.0[M+H] + .

[1120] Step 2: Synthesis of 5'-methoxy-6-methyl-2'-(trifluoromethyl)-[4,4'-bipyridine]-3-carboxylic acid (Intermediate 107-4)

[1121] Intermediate 107-3 (220.0 mg) was dissolved in a mixture of tetrahydrofuran and water (5 mL / 1 mL), and sodium hydroxide (100.0 mg) was added. The mixture was stirred at room temperature for 2 h. After the reaction, the pH was adjusted to approximately 2-3 with 2N hydrochloric acid. The system was concentrated under reduced pressure to remove tetrahydrofuran. Dichloromethane (20 mL) and water (10 mL) were added to the residue, stirred, and the layers separated. The aqueous phase was extracted once with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (195.0 mg).

[1122] LC-MS: m / z(ESI):313.0[M+H] + .

[1123] Step 3: Synthesis of N-(6-(3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-5'-methoxy-6-methyl-2'-(trifluoromethoxy)-[4,4'-bipyridine]-3-carboxamide (Compound 107)

[1124] Intermediate 107-4 (100.0 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (136.2 mg), and N,N-diisopropylethylamine (0.2 mL) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 1 h. Intermediate 22-5-P2 (91.6 mg) was then added and allowed to react at room temperature for 12 h. After completion of the reaction, the reaction solution was purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 10%-90%, elution 10 min) to obtain the title compound (15.0 mg).

[1125] LC-MS: m / z(ESI):526.0[M+H] + .

[1126] 1 H NMR(400MHz,DMSO-d6)δ13.45(s,1H),8.92(s,1H),8.52(s,1H),7.97(s,1H),7.52(s,1 H),4.09-4.14(m,1H),3.73(s,3H),3.47-3.53(m,1H),2.68-2.74(m,4H),2.62(s,3H).

[1127] Example 108, N-(6-(3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-cyclopropyl-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 108)

[1128] Step 1: Synthesis of 2'-cyclopropyl-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid methyl ester (Intermediate 108-2)

[1129] Intermediate 108-1 (0.3 g, synthesized according to the method reported in patent WO2022118210) was dissolved in ethylene glycol dimethyl ether (20 mL). Potassium carbonate (0.5 g), cyclopropylboronic acid (0.2 g), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15.0 mg) were then added. The atmosphere was purged with nitrogen three times. The system was heated at 85°C for 12 h. Upon completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by chromatography (ethyl acetate:petroleum ether 0-100%) to yield the title compound (212.0 mg).

[1130] LC-MS: m / z(ESI):317.1[M+H] + .

[1131] Step 2: Synthesis of 2'-cyclopropyl-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxylic acid (Intermediate 108-3)

[1132] Intermediate 108-2 (210.0 mg) was dissolved in a mixed solvent of tetrahydrofuran and water (5 mL / 1 mL). After the reaction was completed, the pH was adjusted to about 2-3 with 2N hydrochloric acid. The system was concentrated under reduced pressure to remove tetrahydrofuran. Dichloromethane (20 mL) and water (10 mL) were added to the residue, stirred, and the layers were separated. The aqueous phase was extracted once with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (200.0 mg).

[1133] LC-MS: m / z(ESI):303.0[M+H] + .

[1134] Step 3: Synthesis of N-(6-(3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-cyclopropyl-3'-fluoro-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 108)

[1135] Intermediate 108-3 (90.1 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (136.2 mg), and N,N-diisopropylethylamine (0.2 mL) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 1 h. Intermediate 22-5-P2 (138.6 mg) was then added and allowed to react at room temperature for 12 h. After completion of the reaction, the reaction solution was purified by preparative chromatography (YMC TA-C18 column, 30*150 mm, 5 μm; mobile phase A: water (0.05% formic acid), mobile phase B: acetonitrile; flow rate: 25 mL / min; acetonitrile ratio 30%-50%, elution time 10 min) to obtain the title compound (20.0 mg).

[1136] LC-MS: m / z(ESI):516.1[M+H] + .

[1137] 1H NMR(400MHz, CDCl3)δ8.97(s,1H),8.24(s,1H),8.05(s,1H),7.23(s,1H),3.99-4.10(m,1H),3.80(s,3H),3 .34-3.46(m,1H),2.75-2.90(m,4H),2.68(s,3H),2.17-2.26(m,1H),1.07-1.13(m,1H),0.95-1.02(m,3H).

[1138] Example 109, 3'-chloro-N-(6-(3-cyanocyclobutyl)thiazolo[4,5-b]pyrazin-2-yl)-2'-cyclopropyl-5'-methoxy-6-methyl-[4,4'-bipyridine]-3-carboxamide (Compound 109)

[1139] Step 1: Synthesis of 2-bromo-3-chloro-5-methoxypyridine (Intermediate 109-2)

[1140] Intermediate 109-1 (4.2 g), iodomethane (7.7 g), and potassium carbonate (9.4 g) were dissolved in anhydrous acetonitrile (40 mL) and allowed to react at 25°C for 18 h. The reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (ethyl acetate:petroleum ether 0-50%) to obtain the title compound (3.6 g).

[1141] LC-MS: m / z(ESI):222.0[M+H] + .

[1142] Step 2: Synthesis of 3-chloro-2-cyclopropyl-5-methoxypyridine (Intermediate 109-3)

[1143] Intermediate 109-2 (2.3 g) was dissolved in ethylene glycol dimethyl ether (100 mL), followed by th...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, in, Ring A is selected from 5-10 membered heteroaryl, C6-C 14 aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally replaced by R 1a replace; Every R 1a are independently selected from hydroxy, amino, cyano, halogen, oxo or optionally replaced by R 1b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, -(CH2) q -5-10 membered heteroaryl or -(CH2) z -C(O)NH2, -NHC(O)C1-C6 alkyl, C1-C 10 Alkoxy acyl, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl, C2-C 10 Alkenyl or -(CH2) q -4-12 membered heterocyclic group; q and z are each independently selected from 0, 1, 2 or 3; R 1 Selected from 5-10 membered heteroaryl, C6-C 14 aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 The aryl or 4-12 membered heterocyclic group is optionally replaced by R 2a replace; Every R 2a independently selected from halogen, cyano, hydroxyl, amino or optionally replaced by R 2b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl or 4-12 membered heterocyclic group; R 2S is selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, C4-C 10 Cycloalkenyl or 4-12 membered heterocyclic group; Every R 3a are independently selected from cyano, hydroxy, halogen, oxo or optionally replaced by R 3b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C(O)NH2, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl or 5-10 membered heteroaryl; Every R 1b , R 2b , R 3b independently selected from hydroxy, cyano, halogen, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 4-12 membered heterocyclyl, C1-C6 haloalkyl, C(O)NH2, C(O)NH(C1-C6 alkyl) or C(O)N(C1-C6 alkyl)2; The condition is that R 2S Not selected from phenyl, pyridyl, The phenyl group is substituted by one or two substituents selected from cyano, halogen, methoxy, cyclopropyl, -OCHF2, methyl or OCF3, and the pyridyl group is substituted by one substituent selected from cyano, methoxy, cyclopropyl, CF3, chlorine, -C(CH3)2CN or -C(CH3)2OH.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 2S is selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted with the following groups: C1-C6 alkyl, C1-C6 alkoxy, C4-C8 cycloalkenyl, C6-C 10 Aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl or 4-12 membered heterocyclyl; The condition is that R 2S Not selected from phenyl, pyridyl, The phenyl group is substituted by one or two substituents selected from cyano, halogen, methoxy, cyclopropyl, -OCHF2, methyl or OCF3, and the pyridyl group is substituted by one substituent selected from cyano, methoxy, cyclopropyl, CF3, chlorine, -C(CH3)2CN or -C(CH3)2OH; or, Among them, R 2S is selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted from the following groups: C1-C3 alkyl, C1-C3 alkoxy, C6 cycloalkenyl, phenyl, 5-10 membered heteroaryl, C3-C7 cycloalkyl or 4-10 membered heterocyclyl; The condition is that R 2S Not selected from phenyl, pyridyl, The phenyl group is substituted by one or two substituents selected from cyano, halogen, methoxy, cyclopropyl, -OCHF2, methyl or OCF3, and the pyridyl group is substituted by one substituent selected from cyano, methoxy, cyclopropyl, CF3, chlorine, -C(CH3)2CN or -C(CH3)2OH; or, Among them, R 2S is selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted from the following groups: C1-C3 alkyl, C1-C3 alkoxy, C6 cycloalkenyl, 7-10 membered heteroaryl, C3-C7 cycloalkyl or 4-10 membered heterocyclyl; The condition is that R 2S Not selected from or, Among them, R 2S is selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted from the following groups: C1-C3 alkyl, C1-C3 alkoxy, C6 cycloalkenyl or C3-C7 cycloalkyl; or, Among them, R 2S is selected from hydrogen, pyridyl optionally substituted by isopropyl, phenyl optionally substituted by C(O)CH3 or C(CH3)2OH or optionally substituted by R 3a Substituted from the following groups: methyl, methoxy, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentyl, cyclohexenyl, piperidinyl, dihydropyranyl, piperazinyl, azetidinyl, furanyl, or, Among them, R 2S Selected from hydrogen, methyl, methoxy, 3. A compound of formula (II) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, in, Ring A is selected from 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group; n is selected from 1, 2, 3 or 4; Every R 1Sa are independently selected from hydroxy, amino, cyano, halogen, oxo or optionally replaced by R 1b Substituted with the following groups: C1-C 10 Alkoxy, -(CH2) q -5-10 membered heteroaryl or -(CH2) z -C(O)NH2, -NHC(O)C1-C6 alkyl, C1-C 10 Alkoxy acyl, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl, C2-C 10 Alkenyl or -(CH2) q -4-12 membered heterocyclic group; q and z are each independently selected from 0, 1, 2 or 3; R 1 Selected from 5-10 membered heteroaryl, C6-C 14 aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic ring The group is optionally replaced by R 2a replace; Every R 2a independently selected from halogen, cyano, hydroxyl, amino or optionally replaced by R 2b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl or 4-12 membered heterocyclic group; R 2 is selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, C4-C 10 Cycloalkenyl or 4-12 membered heterocyclic group; Every R 3a are independently selected from cyano, hydroxy, halogen, oxo or optionally replaced by R 3b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C(O)NH2, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl or 5-10 membered heteroaryl; Every R 1b , R 2b , R 3b independently selected from hydroxy, cyano, halogen, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 4-12 membered heterocyclyl, C1-C6 haloalkyl, C(O)NH2, C(O)NH(C1-C6 alkyl) or C(O)N(C1-C6 alkyl)2.

4. The compound of formula (II) according to claim 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: n is selected from 1.

5. The compound of formula (II) according to any one of claims 3 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Every R 1Sa independently selected from oxo or optionally replaced by R 1b Substituted with the following groups: C1-C6 alkoxy, -(CH2) q -5-10 membered heteroaryl or -(CH2) z -C(O)NH2, -NHC(O)C1-C6 alkyl or -(CH2) q -4-10 membered heterocyclic group; or Among them, each R 1Sa independently selected from oxo or optionally replaced by R 1b Substituted with the following groups: C1-C3 alkoxy, -(CH2) q -5-membered heteroaryl or -(CH2) z -C(O)NH2, -NHC(O)C1-C3 alkyl or 6-membered heterocyclic group; or Among them, each R 1Sa independently selected from oxo or optionally replaced by R 1b Substituted with the following groups: methoxy, -NHC(O)CH3, -CH2C(O)NH2, 1-oxa-3,4-oxadiazole, pyrazolyl, morpholinyl, Piperazinyl, piperidinyl or Or, where each R 1Sa Independently selected from oxo, methoxy, 6. The compound of formula (II) according to any one of claims 3 to 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound of formula (II) or its pharmaceutically acceptable salt or its stereoisomer is selected from the compound of formula (IIa) or its pharmaceutically acceptable salt or its stereoisomer, wherein ring B is selected from 1b Substituted with the following groups: 5-10 membered heteroaryl or 4-12 membered heterocyclic group; Ring A, q, R 1b , R 1 or R 2 As defined in any one of claims 3 to 5, a compound of formula (II).

7. The compound of formula (II) according to claim 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Ring B is selected from 1b Substituted with the following groups: 5-10 membered heteroaryl or 4-10 membered heterocyclic group; or wherein ring B is selected from 1b Substituted with the following groups: 5-membered heteroaryl or 6-membered heterocyclic group; or wherein ring B is selected from 1b Substituted with the following groups: 1-oxa-3,4-oxadiazole, pyrazolyl, morpholinyl, piperazinyl or piperidinyl; or, Wherein, ring B is selected from 8. A compound of formula (III) or a pharmaceutically acceptable salt or a stereoisomer thereof, in, Ring A S Selected from R 1a Substituted with the following groups: * indicates the same as R 1 connect; Every R 1a are independently selected from hydroxy, amino, cyano, halogen, oxo or optionally replaced by R 1b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, -(CH2) q -5-10 membered heteroaryl or -(CH2) z -C(O)NH2, -NHC(O)C1-C6 alkyl, C1-C 10 Alkoxy acyl, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl, C2-C 10 Alkenyl or -(CH2) q -4-12 membered heterocyclic group; q and z are each independently selected from 0, 1, 2 or 3; R 1 Selected from 5-10 membered heteroaryl, C6-C 14 aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 The aryl or 4-12 membered heterocyclic group is optionally replaced by R 2a replace; Every R 2a independently selected from halogen, cyano, hydroxyl, amino or optionally replaced by R 2b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl or 4-12 membered heterocyclic group; R 2 is selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, C4-C 10 Cycloalkenyl or 4-12 membered heterocyclic group; Every R 3a are independently selected from cyano, hydroxy, halogen, oxo or optionally replaced by R 3b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C(O)NH2, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl or 5-10 membered heteroaryl; Every R 1b , R 2b , R 3b independently selected from hydroxy, cyano, halogen, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 4-12 membered heterocyclyl, C1-C6 haloalkyl, C(O)NH2, C(O)NH(C1-C6 alkyl) or C(O)N(C1-C6 alkyl)2.

9. The compound of formula (III) according to claim 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Ring A S Selected from * indicates the same as R 1 connect.

10. A compound of formula (IV) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, in, Ring A is selected from 5-10 membered heteroaryl, C6-C 14 aryl or 4-12 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 14 Aryl or 4-12 membered heterocyclic group is optionally replaced by R 1a replace; Every R 1a are independently selected from hydroxy, amino, cyano, halogen, oxo or optionally replaced by R 1b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, -(CH2) q -5-10 membered heteroaryl or -(CH2) z -C(O)NH2, -NHC(O)C1-C6 alkyl, C1-C 10 Alkoxy acyl, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl, C2-C 10 Alkenyl or -(CH2) q -4-12 membered heterocyclic group; q and z are each independently selected from 0, 1, 2 or 3; R 1S Selected from R 2a Substituted with the following groups: C 10 -C 14 Aryl, 5-10 membered heteroaryl or 4-12 membered heterocyclyl; Every R 2a independently selected from halogen, cyano, hydroxyl, amino or optionally replaced by R 2b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C3-C 10 Cycloalkyl, C2-C 10 Alkynyl or 4-12 membered heterocyclic group; The conditions are: R 1S Not selected from phenyl, pyridyl or The phenyl or pyridyl group is replaced by 1 or 2 selected from halogen, cyano, OCHF2, methyl, ethynyl, cyclopropyl, methoxy, CF3, OCF3, OCD3 or substituted by a substituent; R 2 is selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C6-C 14 Aryl, 5-10 membered heteroaryl, C3-C 10 Cycloalkyl, C4-C 10 Cycloalkenyl or 4-12 membered heterocyclic group; Every R 3a are independently selected from cyano, hydroxy, halogen, oxo or optionally replaced by R 3b Substituted with the following groups: C1-C 10 Alkyl, C1-C 10 Alkoxy, C(O)NH2, C1-C 10 Alkyl acyl, C3-C 10 Cycloalkyl or 5-10 membered heteroaryl; Every R 1b , R 2b , R 3b independently selected from hydroxy, cyano, halogen, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, 4-12 membered heterocyclyl, C1-C6 haloalkyl, C(O)NH2, C(O)NH(C1-C6 alkyl) or C(O)N(C1-C6 alkyl)2.

11. The compound of formula (IV) according to claim 10, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 1S is selected from 7-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the 7-10 membered heteroaryl is optionally substituted by R 2a The 4-10 membered heterocyclic group is replaced by R 2a replace; or, Among them, R 1S is selected from 9-membered heteroaryl or morpholinyl, wherein the 9-membered heteroaryl is optionally replaced by R 2a The morpholinyl group is replaced by R 2a replace; or, Among them, R 1S Selected from morpholinyl, Said Optional R 2a The morpholinyl group is replaced by R 2a replace; or, Among them, R 1S Selected from Selected from 12. The compound according to any one of claims 1 to 7, 10 to 11, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Ring A is selected from 5-10 membered heteroaryl, C6-C 10 Aryl or 4-10 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 10 The aryl or 4-10 membered heterocyclic group is optionally replaced by R 1a replace.

13. The compound according to any one of claims 1 to 2, 8 to 12, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 1a Selected from oxo or optionally R 1b Substituted with the following groups: C1-C6 alkyl, C1-C6 alkoxy, -(CH2) q -5-10 membered heteroaryl or -(CH2) z -C(O)NH2, -NHC(O)C1-C6 alkyl or -(CH2) q -4- to 10-membered heterocyclic group.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 1b Selected from cyano, C1-C6 alkyl or oxo.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: q is selected from 0 or 1.

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: z is selected from 1.

17. The compound according to any one of claims 1 to 9, 12 to 16, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 1 Selected from 5-10 membered heteroaryl, C6-C 10 Aryl or 5-10 membered heterocyclic group, the 5-10 membered heteroaryl, C6-C 10 The aryl or 5-10 membered heterocyclic group is optionally replaced by R 2a replace.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 2a is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl is optionally replaced by R 2b replace.

19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 2b Selected from halogen.

20. The compound according to any one of claims 3 to 19, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 2 is selected from hydrogen, fluorine, chlorine, iodine or optionally R 3a Substituted with the following groups: C1-C6 alkyl, C1-C6 alkoxy, C4-C8 cycloalkenyl, C6-C 10 aryl, 5-10 membered heteroaryl, C3-C8 cycloalkyl or 4-12 membered heterocyclyl.

21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 3a is selected from cyano, hydroxy, halogen, oxo, C1-C6 alkyl, C1-C6 alkoxy, C(O)NH2, C1-C6 alkylacyl, C3-C8 cycloalkyl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C1-C6 alkoxy, C(O)NH2, C1-C6 alkylacyl, C3-C8 cycloalkyl or 5-10 membered heteroaryl is optionally replaced by R 3b replace.

22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 3b Selected from hydroxy, cyano, halogen, oxo or C1-C3 alkoxy.

23. A compound or a pharmaceutically acceptable salt or a stereoisomer thereof:

24. A pharmaceutical composition comprising the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt or a stereoisomer thereof and a pharmaceutically acceptable excipient.

25. Use of the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or the pharmaceutical composition according to claim 24 in the preparation of a medicament for preventing or treating a disease mediated by DNA polymerase θ.

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