Thiazole ring compound and application thereof

Abstract

The invention provides a thiazole fused ring compound shown in a formula (I) or pharmaceutically acceptable salts or stereoisomers thereof, a pharmaceutical composition containing the thiazole fused ring compound or the pharmaceutically acceptable salts or the stereoisomers thereof, and application of the thiazole fused ring compound or the pharmaceutically acceptable salts or the stereoisomers thereof in preparation of drugs for preventing or treating DNA polymerase theta mediated diseases. # imgabs0 #

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This disclosure claims the priority and benefits of the following Chinese patent applications filed with the State Intellectual Property Office of China: Chinese Patent Application No. 202310971358.8 filed on August 2, 2023; Chinese Patent Application No. 202410676984.9 filed on May 29, 2024. The entire text of the above patent application is incorporated herein by reference in its entirety. Technical Field

[0003] The present disclosure relates to thiazolinyl compounds or pharmaceutically acceptable salts or stereoisomers thereof, pharmaceutical compositions containing the same, and uses thereof as DNA polymerase θ inhibitors in preventing or treating related diseases. Background Art

[0004] DNA double-strand break repair is essential for maintaining genome stability and cell survival. There are three main repair pathways for DNA double-strand breaks: homologous recombination (HR), non-homologous end joining (NHEJ), and non-conventional non-homologous end joining (alt-NHEJ). Microhomology-mediated end joining (MMEJ) is the most common non-conventional non-homologous end joining. Homologous recombination is a high-fidelity, accurate repair mechanism that maintains genome stability and avoids inducing cancer. 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 usually 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 will be more dependent on microhomology-mediated end joining repair. Multiple evidences 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 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. The two domains work together to play a role 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 tumor cells with homologous recombination defects (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 and poorly prognostic ovarian, uterine, and breast cancers (Higgins et al. Oncotarget (2010), 1, 175-184, Lemee et al. PNAS (2010), 107 (30), 13390-13395, Ceccaldi et al. (2015), supra). More importantly, compared with tumor tissues, the expression of POLQ in normal tissues is suppressed (Kawamura et al. International Journal of Cancer (2004), 109 (1), 9-16).

[0008] In summary, POLQ is essential for cells with homologous recombination defects, and there is currently an unmet market demand for the treatment of homologous recombination defective tumors. Inhibiting the function of POLQ can inhibit microhomology-mediated end joining repair in cells, and the development of POLQ function inhibitors can provide a new strategy for targeted treatment of homologous recombination defective tumors. Summary of the invention

[0009] The present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof,

[0010]

[0011] in, Indicates a single bond or a double bond. When it is a single bond, X 1 It is N, X 2 is CO; or, when When it is a double bond, X 1 It is C, X 2is N or CH;

[0012] Selected from:

[0013] n is selected from 0, 1, 2, 3 or 4;

[0014] R B is selected from oxo, halogen, hydroxyl, cyano, carboxyl, amino, -C(=O)NH2, C2-C8 alkynyl, C2-C8 alkenyl, C1-C8 alkyl, C1-C8 alkoxy, C3-C6 cycloalkyl, phenyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl, wherein the amino, -C(=O)NH2, C2-C8 alkynyl, C2-C8 alkenyl, C1-C8 alkyl, C1-C8 alkoxy, C3-C6 cycloalkyl, phenyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally replaced by R Ba replace;

[0015] R Ba Selected from halogen, hydroxy, cyano, amino, C1-C6 alkyl or C1-C6 alkoxy;

[0016] R 1 Selected from C6-C 14 Aryl, 5-10 membered heteroaryl, 6-12 membered heterocyclic group or C4-C 10 Cycloalkenyl, the C6-C 14 Aryl, 5-10 membered heteroaryl, 6-12 membered heterocyclic group or C4-C 10 The cycloalkenyl group is optionally substituted by R 1a replace;

[0017] R 1a is selected from halogen, hydroxy, cyano, carboxyl, oxo, amino, -C(=O)NH2, C1-C 10 Alkyl, C1-C 10 Alkoxy, -C(=O)-C1-C 10 Alkyl, C3-C 10 Cycloalkyl, -O-C3-C 10 Cycloalkyl, SO2C1-C 10 Alkyl, C2-C 10 Alkynyl, C2-C 10 alkenyl, 4-12 membered heterocyclic group or -O-4-8 membered heterocyclic group, the amino, -C(=O)NH2, C1-C 10 Alkyl, C1-C 10 Alkoxy, -C(=O)-C1-C 10 Alkyl, C3-C 10 Cycloalkyl, -O-C3-C 10 Cycloalkyl, SO2C1-C10 Alkyl, C2-C 10 Alkynyl, C2-C 10 an alkenyl group, a 4-12 membered heterocyclic group or an -O-4-8 membered heterocyclic group is optionally replaced by R 1b replace;

[0018] Every R 1b Independently selected from halogen, carboxyl, hydroxyl, oxo, cyano, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, sulfonyl, C1-C6 alkyl or C1-C6 alkoxy;

[0019] T is selected from a bond, CH2, NR T NR T CO, -O-(CH2) z -、-CO-(CH2) x - or cyclopropylene;

[0020] z, x are independently selected from 0 or 1;

[0021] R T is selected from hydrogen, C1-C6 alkyl or C1-C6 deuterated alkyl;

[0022] R 3 Selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C(=O)NR 3 'R 3 "、amino、C1-C 10 Alkyl, C1-C 10 Alkoxy, C2-C 10 Alkynyl, -C(=O)-C1-C 10 Alkyl, SO2C1-C 10 Alkyl, SOC1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl, the amino, C1-C 10 Alkyl, C1-C 10 Alkoxy, C2-C 10 Alkynyl, -C(=O)-C1-C 10 Alkyl, SO2C1-C 10 Alkyl, SOC1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally replaced by R 3a Substitution; when T is selected from a bond, R 3 It is not hydrogen;

[0023] R 3aSelected from oxo, halogen, cyano, hydroxyl, -C(=O)NR 3a 'R 3a ", amino, NH (C1-C6 alkyl), N (C1-C6 alkyl) 2, NHCOC1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, COOC1-C6 alkyl, -C (= O) -C1-C6 alkyl, SO2C1-C 10 alkyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl, the amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, COOC1-C6 alkyl, -C(=O)-C1-C6 alkyl, SO2C1-C 10 Alkyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl group are optionally replaced by R 3b replace;

[0024] R 3 '、R 3 " are each independently selected from hydrogen or C1-C6 alkyl, or R 3 '、R 3 " and the N atom to which it is connected together form a 4-12 membered heterocyclic group, wherein the 4-12 membered heterocyclic group is optionally replaced by R N1 replace;

[0025] R 3a '、R 3a " are each independently selected from hydrogen or C1-C6 alkyl, or R 3 '、R 3 " and the N atom to which it is connected together form a 4-12 membered heterocyclic group, wherein the 4-12 membered heterocyclic group is optionally replaced by R N2 replace;

[0026] R 3b , R N1 , R N2 Each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, SO2C1-C 10 Alkyl, C3-C6 cycloalkyl, carboxyl or hydroxyl.

[0027] In some embodiments, is a double bond, X 1 It is C, X 2 It is N.

[0028] In some embodiments, n is selected from 0, 1 or 2.

[0029] In some embodiments, n is selected from 0 or 1.

[0030] In some embodiments, n is selected from 0.

[0031] In some embodiments, n is selected from 1.

[0032] In some embodiments, n is selected from 2.

[0033] In some embodiments, Selected from:

[0034] In some embodiments, Selected from:

[0035] In some embodiments, R B is selected from oxo, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, phenyl or 5-10 membered heteroaryl is optionally replaced by R Ba replace.

[0036] In some embodiments, R B is selected from oxo, C1-C3 alkyl, C3-C4 cycloalkyl, phenyl or 5-10 membered heteroaryl, wherein the C1-C3 alkyl, C3-C4 cycloalkyl, phenyl or 5-10 membered heteroaryl is optionally replaced by R Ba replace.

[0037] In some embodiments, R B Selected from oxo, methyl, cyclopropyl, phenyl or The methyl, cyclopropyl, phenyl or Optional R Ba replace.

[0038] In some embodiments, R Ba Selected from cyano or C1-C6 alkyl.

[0039] In some embodiments, R Ba Selected from cyano or C1-C3 alkyl.

[0040] In some embodiments, R Ba Selected from cyano or methyl.

[0041] In some embodiments, R B Selected from oxo, methyl, cyclopropyl,

[0042] In some embodiments, R B is selected from oxo, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R Ba replace.

[0043] In some embodiments, R B is selected from oxo, C1-C3 alkyl or C3-C4 cycloalkyl, wherein the C1-C3 alkyl or C3-C4 cycloalkyl is optionally replaced by R Ba replace.

[0044] In some embodiments, R 1 Selected from C6-C 10 Aryl or 5-10 membered heteroaryl, the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 1a replace.

[0045] In some embodiments, R 1 is selected from phenyl or 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is optionally replaced by R 1a replace.

[0046] In some embodiments, R 1 is selected from phenyl or pyridyl, wherein the phenyl or pyridyl is optionally replaced by R 1a replace.

[0047] In some embodiments, R 1a 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 1b replace.

[0048] In some embodiments, R 1a Selected from halogen, C1-C3 alkyl or C1-C3 alkoxy.

[0049] In some embodiments, R 1a Selected from chlorine, methyl or methoxy.

[0050] In some embodiments, R 1 Selected from

[0051] In some embodiments, T is selected from a bond.

[0052] In some embodiments, R 3 is selected from C1-C6 alkyl or 4-12 membered heterocyclic group, wherein the C1-C6 alkyl or 4-12 membered heterocyclic group is optionally replaced by R 3a replace.

[0053] In some embodiments, R 3 is selected from C1-C3 alkyl or 5-6 membered heterocyclic group, wherein the C1-C3 alkyl or 5-6 membered heterocyclic group is optionally replaced by R 3a replace.

[0054] In some embodiments, R 3is selected from C1-C3 alkyl or 6-membered heterocyclic group, wherein the C1-C3 alkyl or 6-membered heterocyclic group is optionally replaced by R 3a replace.

[0055] In some embodiments, R 3 Selected from methyl or The methyl or Optional R 3a replace.

[0056] In some embodiments, R 3a Selected from oxo or C1-C3 alkyl.

[0057] In some embodiments, R 3a Selected from oxo or methyl.

[0058] In some embodiments, R 3 Selected from methyl or

[0059] In some embodiments, R 3 is selected from 4-12 membered heterocyclic groups or 5-10 membered heteroaryl groups, wherein the 4-12 membered heterocyclic groups or 5-10 membered heteroaryl groups are optionally replaced by R 3a replace.

[0060] In some embodiments, R 3 is selected from 4-12 membered heterocyclic groups, wherein the 4-12 membered heterocyclic groups are optionally substituted by R 3a In some embodiments, R 3 is selected from 4-7 membered heterocyclic groups, wherein the 4-7 membered heterocyclic groups are optionally substituted by R 3a replace.

[0061] In some embodiments, R 3 is selected from a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted by R 3a replace.

[0062] In some embodiments, R 3 is selected from a 6-membered heterocyclic group, wherein the 6-membered heterocyclic group is optionally substituted by R 3a replace.

[0063] In some embodiments, R 3 Selected from Said Optional R 3a replace.

[0064] In some embodiments, R 3 Selected from Said Optional R 3a replace.

[0065] In some embodiments, R 3 Selected from

[0066] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the compound of formula (II) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

[0067]

[0068] Wherein, ring C is selected from 4-12 membered heterocyclic groups, wherein the 4-12 membered heterocyclic groups are optionally replaced by R 3a replace;

[0069] T.X 1 , X 2 , R 1 , Ring B, R B or n is as defined in the compound of formula (I).

[0070] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

[0071]

[0072] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) of the present disclosure or a pharmaceutically acceptable salt or a stereoisomer thereof and a pharmaceutically acceptable excipient.

[0073] In another aspect, the present disclosure 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.

[0074] In another aspect, the present disclosure 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 medicament for preventing or treating a disease mediated by DNA polymerase θ.

[0075] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, in preventing or treating a disease mediated by DNA polymerase θ.

[0076] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, for preventing or treating a disease mediated by DNA polymerase θ.

[0077] In some embodiments, the DNA polymerase theta-mediated disease is a disease in which DNA polymerase theta is overexpressed.

[0078] In some embodiments, the DNA polymerase theta-mediated disease is cancer.

[0079] In some embodiments, the cancer is a homologous recombination (HR)-deficient cancer.

[0080] In some embodiments, the cancer is a cancer with reduced or absent BRCA gene expression, a lack of BRCA genes, or reduced BRCA protein function.

[0081] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating cancer.

[0082] Definitions and explanations of terms

[0083] Unless otherwise specified, the terms used in this disclosure have the following meanings, and the groups and term definitions recorded in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be arbitrarily combined and combined with each other. A specific term should not be considered as uncertain or unclear in the absence of special definition, but should be understood according to the common meaning in the art. When a trade name appears in this article, it is intended to refer to its corresponding commodity or its active ingredient.

[0084] In this article Indicates the connection site.

[0085] The notation for racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the wedge and dashed 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).

[0086] The term "tautomer" refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule. The compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist in 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; while in phenols, the enol form predominates. The present disclosure includes all tautomeric forms of the compounds.

[0087] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0088] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present invention 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 mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and their mixtures. 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 their mixtures involved in all substituents are also included within the definition of the compounds of the present invention. The compounds of the present disclosure 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.

[0089] The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is oxo (ie, =O), it means that two hydrogen atoms are replaced.

[0090] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, ethyl is "optionally" substituted by halogen, meaning that ethyl can 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 substitution or substitution pattern that may not exist and / or cannot be synthesized in space will not be introduced.

[0091] When any variable (such as R a , R b ) occurs 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 2 R bis replaced, then each R b All have independent options.

[0092] In this article, C m -C n It means having an integer number of carbon atoms in the range of 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.

[0093] 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 or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl , 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C1-C6 alkyl" can be understood to mean an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, and specific examples 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" can be understood to mean a straight or branched saturated alkyl group having 1, 2 or 3 carbon atoms. The "C1-C 10 "Alkyl" may include "C1-C6 alkyl" or "C1-C3 alkyl" and the like, and the "C1-C6 alkyl" may further include "C1-C3 alkyl".

[0094] The term "deuterated alkyl" means an "alkyl" group substituted with deuterium and may be monosubstituted (eg, CH2CH2D), polysubstituted (eg, CH2CHD2, CHDCH2D) or fully substituted (eg, CD2CD3).

[0095] 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, which can be understood as "alkyloxy" or "alkyl-O-". 10 "Alkoxy" can be understood as "C1-C10 Alkyloxy" or "C1-C 10 The term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". 10 The term "alkoxy" may include "C1-C6 alkoxy" and "C1-C3 alkoxy" and the like, and the "C1-C6 alkoxy" may further include "C1-C3 alkoxy".

[0096] The term "alkenyl" refers to a straight 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 group 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 or conjugated with each other. 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.

[0097] 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 straight-chain 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.

[0098] 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 usually a 3- to 10-membered ring. The term "C3-C 10The term "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.

[0099] 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 generally a 4 to 10-membered ring having 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl, etc.

[0100] The term "heterocyclic group" 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), wherein 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 the ring atoms thereof contain 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above. 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 the ring atoms thereof contain 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above. 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 examples of the ring atoms, 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 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazine-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 4-7 membered heterocyclic group, and specific examples include but are not limited to dihydroisoquinolyl, 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", "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered heterocycloalkyl", etc., 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", etc.

[0101] 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 The term "aryl" is understood to mean 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 or a ring having 14 carbon atoms ("C 14 The term "C6-C 10 "Aryl" is understood to mean 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.

[0102] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system with aromaticity, 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: it has 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 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, furanyl, 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 azinyl, 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.

[0103] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0104] The term "hydroxy" refers to an -OH group.

[0105] The term "cyano" refers to a -CN group.

[0106] The term "amino" refers to a -NH2 group.

[0107] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of a compound of the present disclosure 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 one skilled in the art based on their own knowledge and the present disclosure.

[0108] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0109] 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 an organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0110] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0111] The term "pharmaceutically acceptable excipients" refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0112] The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be construed in an open and non-exclusive sense, ie, "including but not limited to".

[0113] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where 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 may be incorporated into compounds of the present disclosure 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.

[0114] Certain isotopically labeled compounds of the present disclosure (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 disclosure 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.

[0115] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they 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.

[0116] Typical routes of administration of the disclosed compounds or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0117] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0118] 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 disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0119] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.

[0120] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0121] In all the methods of administration of the compounds of general formula (I) described herein, the daily dosage is 0.1 mg / kg to 1000 mg / kg body weight, in the form of single or divided doses.

[0122] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art, and preferred embodiments include but are not limited to the embodiments disclosed herein.

[0123] The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments. Specific embodiments

[0124] The invention is described in detail below by way of examples, but this does not mean any adverse limitation to the present disclosure. The present disclosure has been described in detail herein, and specific embodiments thereof are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0125] 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.

[0126] Compounds are manually or The software names were used, and commercially available compounds were named using the supplier's catalog names.

[0127] 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 determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 ” refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.

[0128] In the following purification by high performance liquid chromatography, unless otherwise specified, the amount of acid or base 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 phase A and mobile phase B during gradient elution, and "B%: 50%-70%" means that during gradient elution, the ratio of the volume of mobile phase B to the total volume of mobile phase A and mobile phase B varies from 50% to 70%.

[0129] Example 1. Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)-7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl)-6-methylnicotinamide (Compound 1)

[0130]

[0131] Step 1: Synthesis of 2-chloro-N-(4-cyanophenyl)acetamide (Intermediate 1-2)

[0132] The starting material 1-1 (4.8 g) was dissolved in acetone (100 mL), and then potassium carbonate (11.2 g) and chloroacetyl chloride (5.0 g) were added, and the mixture was heated at 50° C. for 5 h. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (7.1 g).

[0133] LC-MS: m / z(ESI):195.0[M+H] + .

[0134] Step 2: Synthesis of 4-amino-N-(4-cyanophenyl)-2-methylthiothiazole-5-carboxamide (Intermediate 1-3)

[0135] The intermediate 1-2 (4.9 g) was dissolved in acetone (80 mL), and an aqueous solution (30 mL) of dipotassium cyanamide dithiocarbamate (5.9 g) was added, followed by an aqueous solution of sodium hydroxide (2M, 12.5 mL). The mixture was stirred at 25°C for 2 h, and then the temperature was raised to 80°C for 0.5 h. The temperature was lowered to 25°C, and iodomethane (7.2 g) was added thereto. The mixture was stirred at room temperature for 2 h, filtered, and the filter cake was washed with water and dried to obtain the title compound (6.8 g).

[0136] LC-MS: m / z(ESI):291.0[M+H] + .

[0137] Step 3: Synthesis of 4-(2-methylthio)-7-oxothiazolo[4,5-d]pyrimidin-6(7H)-yl)benzonitrile (Intermediate 1-4)

[0138] Intermediate 1-3 (6.7 g) was dissolved in formic acid (50 mL), and heated at 100°C for 4 h under nitrogen protection. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure to obtain the title compound (6.9 g).

[0139] LC-MS: m / z(ESI):301.0[M+H] + .

[0140] Step 4: Synthesis of 4-(2-methylsulfonyl)-7-oxothiazolo[4,5-d]pyrimidin-6(7H)-yl)benzonitrile (Intermediate 1-5)

[0141] Intermediate 1-4 (6.9 g) was dissolved in anhydrous dichloromethane (100 mL), and then m-chloroperbenzoic acid (7.0 g) was added, and the mixture was stirred at 25°C for 18 h under nitrogen protection. After the reaction was completed, dichloromethane and saturated sodium bicarbonate aqueous solution were added, and the organic phase after stratification was washed twice with saturated sodium bicarbonate aqueous solution and saturated sodium chloride, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (6.3 g).

[0142] LC-MS: m / z(ESI):333.0[M+H] + .

[0143] Step 5: Synthesis of 4-(2-((2,4-dimethylbenzyl)amino)-7-oxothiazolo[4,5-d]pyrimidin-6(7H)-yl)benzonitrile (Intermediate 1-6)

[0144] Intermediate 1-5 (5.7 g) was dissolved in 1,4-dioxane (80 mL), and then 2,4-dimethoxybenzylamine (2.7 g) was added and reacted at 100°C for 2 h. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure, water (100 mL) was added to the residue, and then extracted three times with dichloromethane (100 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 (6.7 g).

[0145] LC-MS: m / z(ESI):420.1[M+H] + .

[0146] Step 6: Synthesis of 4-(2-amino-7-oxothiazolo[4,5-d]pyrimidin-6(7H)-yl)benzonitrile (Intermediate 1-7)

[0147] Intermediate 1-6 (6.7 g) was dissolved in trifluoroacetic acid (50 mL) and reacted at 50°C for 4 h. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure, water (50 mL) was added to the residue, and then the pH was adjusted to 7-8 with saturated sodium bicarbonate, filtered, and the filter cake was collected and dried to obtain the title compound (4.1 g).

[0148] LC-MS: m / z(ESI):270.0[M+H] + .

[0149] Step 7: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)-7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl)-6-methylnicotinamide (Compound 1)

[0150] The intermediate Int1 (100.0 mg) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (164.0 mg) were dissolved in N,N-dimethylformamide (2.5 mL), and then N,N-diisopropylethylamine (0.5 mL) was added, stirred at room temperature for 0.5 h, and the intermediate 1-7 (160.7 mg) was added, and the reaction was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was purified by preparative chromatography (chromatographic column: YMC C18; mobile phase A: water (0.5‰ formic acid), A%: 10%-90%, B is acetonitrile, 25 mL / min) to obtain the title compound (10.0 mg).

[0151] LC-MS: m / z(ESI):529.0[M+H] + .

[0152] 1 H NMR(400MHz,DMSO-d6)δ13.34(s,1H),8.78(s,1H),8.52(s,1H),8.04-8.12(m,2H),7.78- 7.84(m,2H),7.42-7.50(m,2H),7.39(s,1H),6.97-7.04(m,1H),3.47(s,3H),2.59(s,3H).

[0153] Example 2. Synthesis of N-(5-(4-cyanophenyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 2)

[0154]

[0155] Step 1: Synthesis of tert-butyl 2-(5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (Intermediate 2-2)

[0156] The intermediate Int2 (505.7 mg) was dissolved in N, N-dimethylformamide (2 mL), and 2-(7-azabenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (105.8 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (150.2 mg) and N, N-diisopropylethylamine (253.1 mg) were added, and the mixture was heated at 45°C for 2 h. Then, the starting material 2-1 (100.0 mg) was added, and the mixture was heated at 45°C for 16 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography (ethyl acetate: petroleum ether 0-80%) to obtain the title compound (100.0 mg).

[0157] LC-MS: m / z(ESI):496.1[M+H] + .

[0158] Step 2: Synthesis of 5'-methoxy-2',6-dimethyl-N-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-[4,4'-bipyridine]-3-carboxamide (Intermediate 2-3)

[0159] Intermediate 2-2 (90.0 mg) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1 mL) was added, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was directly concentrated to dryness under reduced pressure to obtain the title compound (70.0 mg).

[0160] LC-MS: m / z(ESI):396.5[M+H] + .

[0161] Step 3: Synthesis of N-(5-(4-cyanophenyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-5'-methoxy-2',6-dimethyl-[4,4'-bipyridine]-3-carboxamide (Compound 2)

[0162] Intermediate 2-3 (60.0 mg), starting material 2-4 (27.6 mg), sodium tert-butoxide (36.5 mg), (2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl) (14.2 mg) and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (10.8 mg) were added to 1,4-dioxane (1 mL), and heated at 100°C for 16 h under nitrogen protection. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR column, mobile phase A: water (0.5‰ formic acid), mobile phase B: acetonitrile, 25 mL / min, B%: 75-95%) to obtain the title compound (3.0 mg).

[0163] LC-MS: m / z(ESI):497.1[M+H] + .

[0164] 1 H NMR (400MHz, DMSO-d6) δ8.72(s,1H),8.17(s,1H),7.60(d,J=8.0Hz,2H),7.33(m,1H),7.23(s,1H),7.1 2(d,J=8.0Hz,2H),4.56(s,2H),3.82-3.80(m,2H),3.55(s,3H),2.75(m,2H),2.57(s,3H),2.47(s,3H).

[0165] Example 3. Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(5-(4-cyanophenyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-6-methylnicotinamide (Compound 3)

[0166]

[0167] Step 1: Synthesis of tert-butyl 2-(4-(5-chloro-2-methoxyphenyl)-6-methylnicotinylamino)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (Intermediate 3-2)

[0168] The intermediate Int1 (326.3 mg) was dissolved in N,N-dimethylformamide (2 mL), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (158.8 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (225.2 mg) and N,N-diisopropylethylamine (303.7 mg) were added, and the mixture was heated at 45°C for 2 h. Then, the starting material 3-1 (200.0 mg) was added, and the mixture was heated at 45°C for 16 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography (ethyl acetate: petroleum ether 0-80%) to obtain the title compound (300.0 mg).

[0169] LC-MS: m / z(ESI):515.1[M+H] + .

[0170] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)pyridine-3-carboxamide (Intermediate 3-3)

[0171] Intermediate 3-2 (300.0 mg) was added to 4M hydrochloric acid / ethyl acetate solution (5 mL) and reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was directly concentrated to dryness under reduced pressure to obtain the title compound (200.0 mg).

[0172] LC-MS: m / z(ESI):415.1[M+H] + .

[0173] Step 3: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(5-(4-cyanophenyl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-6-methylnicotinamide (Compound 3)

[0174] Intermediate 3-3 (120.0 mg), intermediate 3-4 (63.2 mg), sodium tert-butoxide (97.3 mg), 2-bicyclohexylphosphino-2',6'-diisopropoxybiphenyl (27.0 mg) and dichlorodi-tert-butyl-(4-dimethylaminophenyl)phosphine palladium (II) (20.5 mg) were added to 1,4-dioxane (1 mL), and heated at 100°C for 16 h under nitrogen protection. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR column, mobile phase A: water (0.5‰ formic acid), mobile phase B: acetonitrile, 25 mL / min, B%: 75-95%) to obtain the title compound (20.0 mg).

[0175] LC-MS: m / z(ESI):516.1[M+H] + .

[0176] 1 H NMR (400MHz, DMSO-d6) δ12.43(s,1H),8.65(s,1H),7.59-7.62(m,2H),7.41-7.38(m,2H),7.34(m,1H),7.11-7. 13(m,2H),7.00(d,J=8.0Hz,1H),4.57(s,2H),3.83-3.80(m,2H),3.48(s,3H),2.76-2.74(m,2H),2.56(s,3H).

[0177] Example 4. Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(5-(4-cyanophenyl)-4-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-6-methylnicotinamide (Compound 4)

[0178]

[0179] Step 1: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(4-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)nicotinamide (Intermediate 4-2)

[0180] The starting material intermediate Int1 (164.1 mg) (synthesis see WO2022118210) was dissolved in N, N-dimethylformamide (2 mL), 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (334.5 mg) and N, N-diisopropylethylamine (229.1 mg) were added, and the reaction was heated at 45 ° C for 2 h, and then the starting material 4-1 (100.0 mg) was added, and the reaction was heated at 45 ° C for 16 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and purified by silica gel column chromatography (ethyl acetate: petroleum ether 0-80%) to obtain the title compound (80.0 mg).

[0181] LC-MS: m / z(ESI):429.1[M+H] + .

[0182] Step 2: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(5-(4-cyanophenyl)-4-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-6-methylnicotinamide (Compound 4) Intermediate 4-2 (60.0 mg), intermediate 4-3 (30.6 mg), cesium carbonate (159.5 mg), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (13.1 mg) and tris(dibenzylideneacetone)dipalladium (12.8 mg) were added to 1,4-dioxane (1 mL) and heated at 100°C for 16 h under nitrogen protection. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the residue was purified by preparative chromatography (YMC TAR column, mobile phase A: water (0.5‰ formic acid), mobile phase B: acetonitrile, 25 mL / min, B%: 75-95%) to obtain the title compound (8.0 mg).

[0183] LC-MS: m / z(ESI):530.0[M+H] + .

[0184] 1H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.75 (s, 1H), 7.84-7.87 (m, 2H), 7.57-7.60 (m, 2H), 7.40-7.45 (m, 2H), 7.34 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.13-4.10 (m, 2H), 3.48 (s, 3H), 3.10-3.07 (m, 2H), 2.57 (s, 3H). Example 5. Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(5-(4-cyanophenyl)-4-oxo-4,5-dihydrothiazolidine [5,4-c] pyridin-2-yl)-6-methylnicotinamide (Compound 5)

[0185]

[0186] Step 1: Synthesis of ethyl 4-bromo-2-((tert-butoxycarbonyl)amino)thiazole-5-carboxylate (Intermediate 5-2)

[0187] Lithium diisopropylamide (2M, 29.5mL) was dissolved in tetrahydrofuran (15.0mL), and added dropwise to a solution of the starting material 5-1 (5.0g) dissolved in tetrahydrofuran (15.0mL) at 0°C under nitrogen protection, and then reacted at 0°C for 15min, and then ethyl ethoxycarbonyl carbonate (9.6g) was added dropwise at 0°C, and the reaction was completed, and the temperature was restored to room temperature for 3h. After the reaction was completed, the reaction solution was quenched with a saturated ammonium chloride solution, and then extracted with ethyl acetate, the organic phase was dried and concentrated to dryness, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether 0-20%) to obtain the title compound (1.3g).

[0188] LC-MS: m / z(ESI):351.0[M+H] + .

[0189] Step 2: Synthesis of ethyl 2-((tert-butoxycarbonyl)amino)-4-(2-trimethylsilylethynyl)thiazole-5-carboxylate (Intermediate 5-3)

[0190] The intermediate 5-2 (1.0 g) was dissolved in triethylamine (24.0 mL), and trimethylethynylsilane (1.4 g), tetrakis(triphenylphosphine)palladium (658.0 mg) and cuprous iodide (54.2 mg) were added thereto, and then reacted at 75° C. for 3 h. After the reaction was completed, the reaction solution was directly concentrated to dryness, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether 0-50%) to obtain the title compound (700.0 mg).

[0191] LC-MS: m / z(ESI):369.1[M+H] +

[0192] Step 3: Synthesis of 2-((tert-butoxycarbonyl)amino)-4-ethynylthiazole-5-carboxylic acid (Intermediate 5-4)

[0193] Intermediate 5-3 (650.0 mg) was dissolved in tetrahydrofuran (2.0 mL), water (2.0 mL) and methanol (1.0 mL), and lithium hydroxide monohydrate (370.0 mg) was added to react at room temperature for 3 h. After the reaction was completed, the reaction solution was adjusted to pH 5-6 with dilute hydrochloric acid, then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol 0-10%) to obtain the title compound (360.0 mg).

[0194] LC-MS: m / z(ESI):269.1[M+H] +

[0195] Step 4: Synthesis of tert-butyl N-(5-carbamoyl-4-ethynylthiazol-2-yl)carbamate (Intermediate 5-5)

[0196] Intermediate 5-4 (280.0 mg) was dissolved in dichloromethane (2.0 mL), and N,N'-dicyclohexylcarbodiimide (258.4 mg) and N-hydroxysuccinimide (144.0 mg) were added, and then reacted at room temperature for 2 h. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with dichloromethane, the filtrate was concentrated to dryness under reduced pressure, and the residue was added with ammonia in dioxane solution (2.0 mL) and reacted at 50°C for 1 h. After the reaction was completed, the reaction solution was directly concentrated to dryness, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 0-10%) to obtain the title compound (200.0 mg).

[0197] LC-MS: m / z(ESI):268.1[M+H] +

[0198] Step 5: Synthesis of tert-butyl (4-oxo-4,5-dihydrothiazolo[5,4-c]pyridin-2-yl)carbamate (Intermediate 5-6)

[0199] Intermediate 5-5 (200.0 mg) was dissolved in tetrahydrofuran (8.0 mL), and potassium tert-butoxide (222.9 mg) was added and then reacted at 70° C. for 2 h. After the reaction was completed, the reaction solution was diluted with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol 0-10%) to obtain the title compound (64.0 mg).

[0200] LC-MS: m / z(ESI):268.1[M+H]+

[0201] Step 6: Synthesis of tert-butyl (5-(4-cyanophenyl)-4-oxo-4,5-dihydrothiazolo[5,4-c]pyridin-2-yl]carbamate (Intermediate 5-7)

[0202] Intermediate 5-6 (65.0 mg) was dissolved in tetrahydrofuran (3.2 mL), and pyridine (153.8 mg), triethylamine (123.0 mg), cuprous iodide (88.3 mg) and (4-cyanophenyl)boric acid (107.2 mg) were added, and then reacted at 70° C. for 10 h under an oxygen atmosphere. After the reaction was completed, the reaction solution was directly concentrated to dryness, and the residue was purified by silica gel column chromatography (dichloromethane: methanol 0-10%) to obtain the title compound (20.0 mg).

[0203] LC-MS: m / z(ESI):369.1[M+H] +

[0204] Step 7: Synthesis of 4-(2-amino-4-oxothiazolo[5,4]pyridin-5(4H)-yl)benzonitrile (Intermediate 5-8)

[0205] Intermediate 5-7 (20.0 mg) was dissolved in a mixed solution of dichloromethane (0.3 mL) and trifluoroacetic acid (0.1 mL), and then reacted at room temperature for 1 h. After the reaction was completed, the reaction solution was directly concentrated to dryness under reduced pressure, and the residue was purified by reverse phase chromatography (water: acetonitrile 5-40%) to obtain the title compound (11.0 mg).

[0206] LC-MS: m / z(ESI):269.1[M+H] +

[0207] Step 8: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(5-(4-cyanophenyl)-4-oxo-4,5-dihydrothiazolidine[5,4-c]pyridin-2-yl)-6-methylnicotinamide (Compound 5)

[0208] The intermediate Int2 (8.3 mg) was dissolved in acetonitrile (0.2 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (16.7 mg) and N-methylimidazole (6.1 mg) were added, and then reacted at room temperature for 20 min, and then the intermediate 5-8 (8.0 mg) was added, and then reacted at 70°C for 2 h. After the reaction was completed, the reaction solution was directly concentrated to dryness under reduced pressure, and the residue was purified by preparative chromatography (chromatographic column: YMC C18; mobile phase A: water (0.5‰ formic acid), A%: 10%-90%, B is acetonitrile, 25 mL / min) to obtain the title compound (0.4 mg).

[0209] LC-MS: m / z(ESI):528.1[M+H] +

[0210] 1 H NMR(400MHz,DMSO-d6)δ13.20(s,1H),δ8.77(s,1H),8.04-8.02(m,2H),7.75-7.47(m,3 H),7.45-7.42(m,3H),7.02-7.00(m,1H),6.89-6.88(m,1H),3.47(s,3H),2.60(s,3H).

[0211] Example 6. Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(5-(4-cyanophenyl)-6,7-dihydro-5H-pyrano[3,2-d]thiazol-2-yl)-6-methylnicotinamide (Compound 6)

[0212]

[0213] Step 1: Synthesis of 5-oxo-5,6-dihydro-2H-pyran-2-acetate (Intermediate 6-2)

[0214] The starting material 6-1 (7.9 g) was dissolved in anhydrous dichloromethane (100 mL), and then acetic anhydride (7.2 mL) and pyridine (6.2 mL) were added, and the reaction was allowed to react at room temperature for 12 h. After the reaction was completed, water (100 mL) was added to the reaction solution, and then the pH was adjusted to about 3 with 2N hydrochloric acid, followed by dichloromethane (100 mL x 3) extraction three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and 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 (6.3 g).

[0215] LC-MS: m / z(ESI):157.1[M+H] + .

[0216] Step 2: Synthesis of 6-(4-bromophenyl)-2H-pyran-3(6H)-one (Intermediate 6-3)

[0217] The intermediate 6-2 (4.7 g) was dissolved in anhydrous tetrahydrofuran (100 mL), and potassium carbonate (8.3 g), p-bromophenylboronic acid (12.0 g) and tris(dibenzylideneacetone)dipalladium (2.7 g) were added, and the nitrogen was replaced 3 times, and the reaction was stirred at room temperature for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether 0-50%) to obtain the title compound (5.4 g).

[0218] LC-MS: m / z(ESI):253.0[M+H] + .

[0219] Step 3: Synthesis of 6-(4-bromophenyl)dihydropyran-2H-3(4H)-one (Intermediate 6-4)

[0220] Intermediate 6-3 (5.0 g) was dissolved in ethyl acetate (100 mL), and then palladium chloride (1.8 g) was added and stirred at room temperature for 5 h. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (4.9 g).

[0221] LC-MS: m / z(ESI):255.1[M+H] + .

[0222] Step 4: Synthesis of 5-(4-bromophenyl)-6,7-dihydro-5H-pyrano[3,2-d]thiazol-2-amine (Intermediate 6-5)

[0223] Dissolve intermediate 6-4 (5.1 g), piperidine (1.7 g) and p-toluenesulfonic acid (334.0 mg) in cyclohexane (100 mL) and heat under reflux for 12 h. After the reaction is completed, the reaction solution is concentrated under reduced pressure, methanol (100 mL), triethylamine (4.1 g), aminonitrile (840.1 mg) and sulfur (640.0 mg) are added to the residue, and the reaction is heated at 50°C for 6 h. The reaction solution is filtered, the filtrate is concentrated to dryness under reduced pressure, and the residue is purified by reverse phase chromatography (acetonitrile: water 0-90%) to obtain the title compound (150.0 mg).

[0224] LC-MS: m / z(ESI):311.2[M+H] + .

[0225] Step 5: Synthesis of N-(5-(4-bromophenyl)-6,7-dihydro-5H-pyrano[3,2-d]thiazol-2-yl)-4-(5-chloro-2-methoxyphenyl)-6-methylnicotinamide (Intermediate 6-6)

[0226] Intermediate 6-5 (257.0 mg) was dissolved in anhydrous N, N-dimethylformamide (10 mL), and then intermediate Int2 (277.7 mg), N-methylimidazole (410.5 mg) and N, N, N', N'-tetramethylchloroformamidine hexafluorophosphate (841.7 mg) were added, and the reaction was heated at 45°C for 12 h. After the reaction was completed, water (30 mL) was added to the reaction solution, and then extracted three times with ethyl acetate (30 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 (523.8 mg).

[0227] LC-MS: m / z(ESI):570.1[M+H] + .

[0228] Step 6: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(5-(4-cyanophenyl)-6,7-dihydro-5H-pyrano[3,2-d]thiazol-2-yl)-6-methylnicotinamide (Compound 6)

[0229] Intermediate 6-6 (285.4 mg), zinc cyanide (117.4 mg) and tetrakis(triphenylphosphine)palladium (57.7 mg) were dissolved in N,N-dimethylformamide (5 mL), and heated at 100°C for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was filtered and the filtrate was purified by preparative chromatography (chromatographic column: YMC C18; mobile phase A: water (0.5‰ formic acid), A%: 10%-90%, B is acetonitrile, 25 mL / min) to obtain the title compound (25.0 mg). The sample was subjected to supercritical fluid chromatography (Column: DAICEL CHIRALPAK AD (250mm*30mm, 10um), fluidity A: CO2, B: ethanol (containing 0.1% ammonia water), flow rate: 80mL / min, maintaining a mixture of polarity B (60%-60%) as eluent) to obtain compound 6-P1 (1.5mg, first peak, retention time 1.005 minutes) and compound 6-P2 (3.4mg, second peak, retention time 1.337 minutes).

[0230] Compound 6-P1:

[0231] LC-MS: m / z(ESI):517.0[M+H] + .

[0232] 1 H NMR(400MHz,DMSO-d6)δ8.64(s,1H),7.85-7.93(m,2H),7.59-7.68(m,2H),7.43-7.49(m,1H),7.35-7.41(m,1H),7.28-7 .33(m,1H),6.96-7.02(m,1H),5.26-5.35(m,1H),3.52(s,3H),2.78-2.85(m,1H),2.54-2.61(m,4H),2.05-2.32(m,2H).

[0233] Compound 6-P2:

[0234] LC-MS: m / z(ESI):517.2[M+H] + .

[0235] 1H NMR(400MHz,DMSO-d6)δ8.64(s,1H),7.95-8.01(m,2H),7.72-7.76(m,2H),7.51-7.55(m,1H),7.35-7.40(m,1H),7.28-7 .33(m,1H),7.08-7.11(m,1H),5.28-5.35(m,1H),3.52(s,3H),2.78-2.85(m,1H),2.54-2.61(m,4H),2.05-2.32(m,2H).

[0236] Example 7. Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(6-(1-methyl-1H-benzo[d]imidazol-5-yl)-7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl)nicotinamide (Compound 7)

[0237]

[0238] Step 1: Synthesis of 2-chloro-N-(1-methyl-1H-benzo[d]imidazol-5-yl)acetamide (Intermediate 7-2)

[0239] The starting material 7-1 (4.4 g) was dissolved in acetone (100 mL), and then potassium carbonate (8.3 g) and chloroacetyl chloride (3.4 g) were added, and the mixture was heated at 50° C. for 5 h. After the reaction was completed, the mixture was filtered and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (6.3 g).

[0240] LC-MS: m / z(ESI):224.0[M+H] + .

[0241] Step 2: Synthesis of 4-amino-2-ethylthio-N-(1-methyl-1H-benzo[d]imidazol-5-yl)thiazole-5-carboxamide (Intermediate 7-3)

[0242] The intermediate 7-2 (5.6 g) was dissolved in acetone (80 mL), added to an aqueous solution (30 mL) of dipotassium cyanamide dithiocarbamate (5.9 g), and then added to an aqueous solution of sodium hydroxide (2M, 12.5 mL). The mixture was stirred at 25 °C for 2 h, then heated to 80 °C for 0.5 h, then cooled to 25 °C, iodoethane (7.8 g) was added, stirred at room temperature for 2 h, filtered, the filter cake was washed with water, and dried to obtain the title compound (7.2 g).

[0243] LC-MS: m / z(ESI):334.1[M+H] + .

[0244] Step 3: Synthesis of 2-ethylthio-6-(1-methyl-1H-benzo[d]imidazol-5-yl)thiazolo[4,5-d]pyrimidin-7(6H)one (Intermediate 7-4)

[0245] The intermediate 7-3 (6.7 g) was dissolved in formic acid (50 mL) and reacted at 100°C for 4 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure to obtain the title compound (6.9 g).

[0246] LC-MS: m / z(ESI):344.1[M+H] + .

[0247] Step 4: Synthesis of 2-ethylsulfonyl-6-(1-methyl-1H-benzo[d]imidazol-5-yl)thiazolo[4,5-d]pyrimidin-7(6H)one (Intermediate 7-5)

[0248] Dissolve the intermediate 7-4 (6.9 g) in anhydrous dichloromethane (100 mL), then add m-chloroperbenzoic acid (6.0 g), and react at 25°C for 18 h under nitrogen protection. After the reaction is completed, add dichloromethane and saturated sodium bicarbonate aqueous solution, and wash the organic phase after separation with saturated sodium bicarbonate aqueous solution and saturated sodium chloride twice, respectively, dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure to obtain the title compound (6.3 g).

[0249] LC-MS: m / z(ESI):376.0[M+H] + .

[0250] Step 5: Synthesis of 2-(2,4-dimethoxybenzyl)amino)-6-(1-methyl-1H-benzo[d]imidazol-5-yl)thiazolo[4,5-d]pyrimidin-7(6H)one (Intermediate 7-6)

[0251] Dissolve the intermediate 7-5 (5.7 g) in 1,4-dioxane (80 mL), then add 2,4-dimethoxybenzylamine (2.7 g), and react at 100°C for 2 h. After the reaction is completed, concentrate to dryness under reduced pressure, add water (100 mL) to the residue, extract three times with dichloromethane (100 mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate to dryness under reduced pressure to obtain the title compound (6.7 g).

[0252] LC-MS: m / z(ESI):449.1[M+H]+.

[0253] Step 6: Synthesis of 2-amino-6-(1-methyl-1H-benzo[d]imidazol-5-yl)thiazolo[4,5-d]pyrimidin-7(6H)-one (Intermediate 7-7)

[0254] Intermediate 7-6 (6.7 g) was dissolved in trifluoroacetic acid (50 mL) and reacted at 50°C for 4 h. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure, water (50 mL) was added to the residue, and then the pH was adjusted to 7-8 with saturated sodium bicarbonate, filtered, the filter cake was collected, and dried to obtain the title compound (4.1 g).

[0255] LC-MS: m / z(ESI):299.0[M+H]+.

[0256] Step 6: Synthesis of 4-(5-chloro-2-methoxyphenyl)-6-methyl-N-(6-(1-methyl-1H-benzo[d]imidazol-5-yl)-7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl)nicotinamide (Compound 7)

[0257] The intermediate Int2 (100.0 mg) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (164.0 mg) were dissolved in N,N-dimethylformamide (2.5 mL), and then N,N-diisopropylethylamine (0.5 mL) was added, stirred at room temperature for 0.5 h, and the intermediate 7-7 (160.7 mg) was added, and the reaction was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was purified by preparative chromatography (chromatographic column: YMC C18; mobile phase A: water (0.5‰ formic acid), A%: 10%-90%, B is acetonitrile, 25 mL / min) to obtain the title compound (10.0 mg).

[0258] LC-MS: m / z(ESI):558.0[M+H]+.

[0259] 1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.35(s,1H),8.32(s,1H),8.27(s,1H),7.75-7.80(m,1H),7.68-7.72(m,1H), 7.37-7.41(m,1H),7.32-7.35(m,1H),7.22-7.26(m,1H),6.97-7.01(m,1H),3.90(s,3H),3.49(s,3H),2.55(s,3H).

[0260] Example 8. Synthesis of 4'-(5-chloro-2-methoxyphenyl)-N-(5-cyclopropyl-4-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-4-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 8)

[0261]

[0262]

[0263] Step 1: Synthesis of tert-butyl(tert-butyloxycarbonyl)(4-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbamate (Intermediate 8-2)

[0264] The starting material 8-1 (1.1 g), di-tert-butyl dicarbonate (2.8 g), 4-dimethylaminopyridine (80.0 mg) and triethylamine (2.0 g) were added to dichloromethane (20 mL) and reacted at room temperature for 12 h. After the reaction was completed, the filtrate was filtered and concentrated to dryness under reduced pressure. The residue was purified by column chromatography (ethyl acetate: petroleum ether 0-80%) to obtain the title compound (331.2 mg).

[0265] LC-MS: m / z(ESI):370.1[M+H] + .

[0266] Step 2: Synthesis of tert-butyl(tert-butyloxycarbonyl)(5-cyclopropyl-4-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbamate (Intermediate 8-3)

[0267] The intermediate 8-2 (200.0 mg) was dissolved in 1,2-dichloroethane (5 mL), and cyclopropylboronic acid (186.0 mg), copper acetate (19.7 mg), triethylamine (136.9 mg) and 2,2'-bipyridine (25.4 mg) were added, and the mixture was stirred at 60°C for 18 h under an oxygen atmosphere. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (ethyl acetate: petroleum ether 0-60%) to obtain the title compound (120.0 mg).

[0268] LC-MS: m / z(ESI):410.1[M+H] + .

[0269] Step 3: Synthesis of 2-amino-5-cyclopropyl-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)one (Intermediate 8-4)

[0270] Intermediate 8-3 (120.0 mg) was dissolved in 10 M hydrochloric acid ethanol (5 mL) and 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 (60.9 mg).

[0271] LC-MS: m / z(ESI):210.0[M+H] + .

[0272] Step 4: Synthesis of 4'-(5-chloro-2-methoxyphenyl)-N-(5-cyclopropyl-4-oxo-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-4-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 8)

[0273] Intermediate 8-5 (100.0 mg) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl) urea hexafluorophosphate (164.0 mg) were dissolved in N,N-dimethylformamide (2.5 mL), and then N,N-diisopropylethylamine (0.5 mL) was added, stirred at room temperature for 0.5 h, and intermediate 8-4 (60.9 mg) was added, and stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was purified by preparative chromatography (chromatographic column: YMC C18; mobile phase A: water (0.5‰ formic acid), A%: 10%-90%, B is acetonitrile, 25 mL / min) to obtain the title compound (8.9 mg).

[0274] LC-MS: m / z(ESI):562.1[M+H] + .

[0275] 1 H NMR(400MHz,DMSO-d6)δ8.86(s,1H),7.89-7.94(m,1H),7.85(s,1H),7.44-7.49(m,1H),7.39-7.43(m,1H),6.98-7.07(m,1H),6.3 6(s,1H),6.27-6.32(m,1H),3.54-3.58(m,2H),3.49(s,3H),2.83-2.90(m,2H),2.62-2.66(m,1H),2.21(s,3H),0.58-0.78(m,4H).

[0276] Synthesis of intermediate 8-5:

[0277] Step 1: Synthesis of 6-chloro-4-(5-chloro-2-methoxyphenyl)nicotinate (Intermediate 8-8)

[0278] The starting material 8-6 ​​(1.5 g), the starting material 8-7 (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), and reacted at 80° C. for 16 h under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove part of the solvent, and the residue was directly purified by Flash column (petroleum ether: ethyl acetate 0-50%) to obtain the title compound (1.5 g).

[0279] LC-MS: m / z(ESI):312.0[M+H] + .

[0280] Step 2: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-(4-methyl-2-oxo-1-pyridinyl)pyridine-3-carboxylic acid methyl ester (Intermediate 8-10)

[0281] Intermediate 8-8 (100.0 mg), starting material 8-9 (69.9 mg) and potassium carbonate (88.6 mg) were dissolved in dimethyl sulfoxide (1.0 mL) and stirred at 90° C. for 18 h. After the reaction was completed, ethyl acetate (10 mL) and water (10 mL) were added, and the organic phase was separated and 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).

[0282] LC-MS: m / z(ESI):385.0[M+H] + .

[0283] Step 3: Synthesis of 4-(5-chloro-2-methoxy-phenyl)-6-(4-methyl-2-oxo-1-pyridinyl)pyridine-3-carboxylic acid (Intermediate 8-5)

[0284] Intermediate 8-10 (123.0 mg) was dissolved in tetrahydrofuran (1.0 mL), and a solution of lithium hydroxide monohydrate (33.5 mg) in water (1.0 mL) was added, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, water (5.0 mL) and ethyl acetate (5.0 mL) were added to separate the layers, and the pH of the aqueous phase was adjusted to 3-4 with 2N hydrochloric acid aqueous solution, and the mixture was extracted twice with ethyl acetate (5.0 mL x 2), and 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).

[0285] LC-MS: m / z(ESI):371.0[M+H] + .

[0286] Example 9. Synthesis of 4'-(5-chloro-2-methoxyphenyl)-N-(6-cyclopropyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl)-4-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 9)

[0287]

[0288] Step 1: Synthesis of 2-chloro-N-cyclopropylacetamide (Intermediate 9-2):

[0289] Under nitrogen protection at 0°C, the starting material 9-1 (2.0 g) was dissolved in anhydrous dichloromethane (30 mL), and then cyclopropylamine (2.0 g) was added dropwise and reacted at 0°C for 1 h. After the reaction was completed, the mixture was filtered, the filter cake was rinsed with dichloromethane, and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (2.3 g).

[0290] 1 H NMR (400MHz, Chloroform-d) δ6.66 (s, 1H), 4.03 (d, J = 1.2Hz, 2H), 2.74-2.78 (m, 1H), 0.93-0.76 (m, 2H), 0.70-0.54 (m, 2H).

[0291] Step 2: Synthesis of 4-amino-N-cyclopropyl-2-(methylthio)thiazole-5-carboxamide (Intermediate 9-4):

[0292] The intermediate 9-2 (2.0 g) was dissolved in acetone (20 mL), and an aqueous solution (20 mL) of dipotassium cyanamide dithiocarbamate (2.9 g) was added, followed by an aqueous solution of sodium hydroxide (2M, 7.5 mL). The mixture was stirred at 25°C for 2 h, and then the temperature was raised to 80°C for 0.5 h. The temperature was lowered to 25°C, and iodomethane (2.1 g) was added thereto. The mixture was stirred at room temperature for 2 h, filtered, and the filter cake was washed with water and dried to obtain the title compound (2.7 g).

[0293] 1 H NMR(400MHz,Chloroform-d)δ6.06(s,2H),5.36-5.30(m,1H),2.74-2.78(m,1H),2.63(s,3H),0.89-0.75(m,2H),0.66-0.53(m,2H).

[0294] Step 3: Synthesis of 6-cyclopropyl-2-(methylthio)thiazolo[4,5-d]pyrimidin-7(6H)-one (Intermediate 9-5):

[0295] Intermediate 9-4 (2.0 g) was dissolved in anhydrous formic acid (20 mL) and reacted at 100°C for 18 h under nitrogen protection. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure to obtain the title compound (2.1 g).

[0296] LC-MS: m / z(ESI):240.0[M+H] + .

[0297] Step 4: Synthesis of 6-cyclopropyl-2-(methylsulfonyl)thiazolo[4,5-d]pyrimidin-7(6H)-one (Intermediate 9-6):

[0298] The intermediate 9-5 (2.1 g) was dissolved in anhydrous dichloromethane (20 mL), and then m-chloroperbenzoic acid (4.4 g) was added, and the reaction was carried out at 25°C under nitrogen protection for 18 h. After the reaction was completed, dichloromethane and saturated sodium bicarbonate aqueous solution were added, and after stirring and layering, the organic phase was washed twice with saturated sodium bicarbonate aqueous solution and saturated sodium chloride, respectively, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (2.3 g).

[0299] LC-MS: m / z(ESI):272.0[M+H] + .

[0300] Step 5: Synthesis of 2-amino-6-cyclopropylthiazolo[4,5-d]pyrimidin-7(6H)-one (Intermediate 9-7)

[0301] Intermediate 9-6 (0.5 g) was dissolved in ammonia solution in 1,4-dioxane (0.4 M, 20 mL) and reacted at 25° C. for 3 h. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure and purified on a reverse phase C18 column (water / acetonitrile 5-95%) to obtain the title compound (50.0 mg).

[0302] LC-MS: m / z(ESI):209.0[M+H] + .

[0303] Step 6: Synthesis of 4'-(5-chloro-2-methoxyphenyl)-N-(6-cyclopropyl-7-oxo-6,7-dihydrothiazolo[4,5-d]pyrimidin-2-yl)-4-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 9)

[0304] Intermediate 8-5 (50.0 mg), N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (113.5 mg) and N-methylimidazole (55.4 mg) were dissolved in N,N-dimethylformamide (1 mL), stirred at room temperature for 0.5 h, and intermediate 9-7 (28.1 mg) was added, and the reaction was stirred at 45°C for 16 h under nitrogen protection. After the reaction was completed, ethyl acetate and water were added to dilute, and the organic phase obtained by stratification was washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by preparative chromatography (chromatographic column: YMC C18; mobile phase A: water (0.5‰ formic acid), A%: 10%-90%, B is acetonitrile, 25 mL / min) to obtain the title compound (10.0 mg).

[0305] LC-MS: m / z(ESI):561.1[M+H] + .

[0306] 1H NMR (400MHz, DMSO-d6) δ8.94(s,1H),8.28(s,1H),7.93(d,J=7.2Hz,1H),7.81(s,1H),7.44(m,1H),7.38(d,J=2.6Hz,1H),7.02(d, J=8.9Hz,1H),6.38-6.32(m,1H),6.29(d,J=7.3,1H),3.48(s,3H),3.21(m,1H),2.21(m,3H),1.08-0.96(m,2H),0.99-0.90(m,2H).

[0307] Example 10. Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)-6,7-dihydro-4H-pyrano[3,4-d]thiazol-2-yl)-6-methylnicotinamide (Compound 10)

[0308]

[0309] Step 1: Synthesis of 5-oxo-5,6-dihydro-2H-pyran-2-acetate (Intermediate 10-2)

[0310] The starting material 10-1 (7.9 g) was dissolved in anhydrous dichloromethane (100 mL), and then acetic anhydride (7.2 mL) and pyridine (6.2 mL) were added, and the reaction was stirred at room temperature for 12 h. After the reaction was completed, dichloromethane (100 mL) was added to the reaction system for dilution, and then washed twice with water (50 mL x2), washed twice with 2N hydrochloric acid solution (50 mL x2), and washed once with saturated brine (50 mL x1), the organic phase was dried over anhydrous sodium sulfate, filtered, and 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 (6.3 g).

[0311] LC-MS: m / z(ESI):157.1[M+H] + .

[0312] Step 2: Synthesis of 6-(4-bromophenyl)-2H-pyran-3(6H)-one (Intermediate 10-3)

[0313] The intermediate 10-2 (4.7 g) was dissolved in anhydrous tetrahydrofuran (100 mL), and potassium carbonate (8.3 g), p-bromophenylboronic acid (12.0 g) and tris(dibenzylideneacetone)dipalladium (2.7 g) were then added, and the nitrogen atmosphere was replaced three times. The system was stirred at room temperature for 12 h. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether 0-50%) to obtain the title compound (5.4 g).

[0314] LC-MS: m / z(ESI):253.0[M+H] + .

[0315] Step 3: Synthesis of 6-(4-bromophenyl)dihydro-2H-pyran-3(4H)-one (Intermediate 10-4)

[0316] Intermediate 10-3 (5.0 g) was dissolved in ethyl acetate (100 mL), and then palladium chloride (1.8 g) was added and stirred at room temperature for 5 h. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (4.9 g).

[0317] LC-MS: m / z(ESI):255.1[M+H] + .

[0318] Step 4: Synthesis of 6-(4-bromophenyl)-6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-amine (Intermediate 10-5)

[0319] Intermediate 10-4 (5.1 g), piperidine (1.7 g) and p-toluenesulfonic acid (334.0 mg) were dissolved in cyclohexane (100 mL), and the system was heated under reflux for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove part of the solvent, and methanol (100 mL), triethylamine (4.1 g), aminonitrile (840.1 mg) and sulfur (640.0 mg) were added to the residue, and the reaction was heated at 50°C for 6 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile: water 0-90%) to obtain the title compound (150.0 mg).

[0320] LC-MS: m / z(ESI):311.2[M+H] + .

[0321] Step 5: Synthesis of 4-(2-amino-6,7-dihydro-4H-pyrano[4,3-d]thiazol-6-yl)benzonitrile (Intermediate 10-6)

[0322] Intermediate 10-5 (311.2 mg), zinc cyanide (450.4 mg) and tetrakis(triphenylphosphine)palladium (115.6 mg) were added to N,N-dimethylformamide (8 mL), and the system was heated at 100°C for 16 h. After the reaction was completed, the reaction solution was diluted with ethyl acetate (80 mL), then washed twice with water (20 mL x 2), and washed twice with saturated brine (20 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the title compound (523.8 mg).

[0323] LC-MS: m / z(ESI):258.1[M+H]+ .

[0324] Step 6: Synthesis of 4-(5-chloro-2-methoxyphenyl)-N-(6-(4-cyanophenyl)-6,7-dihydro-4H-pyrano[3,4-d]thiazol-2-yl)-6-methylnicotinamide (Compound 10)

[0325] The intermediate 10-6 (50.1 mg) was dissolved in anhydrous N, N-dimethylformamide (10 mL), and then the intermediate 10-7 (55.5 mg), N-methylimidazole (82.5 mg) and N, N, N', N'-tetramethylchloroformamidine hexafluorophosphate (168.3 mg) were added, and the system was heated at 45°C for 12 h. After the reaction was completed, 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 30%-50%, elution 8 min) to obtain the title compound (15.0 mg).

[0326] LC-MS: m / z(ESI):517.0[M+H] + .

[0327] 1 H NMR (400MHz, CDCl3) δ10.31(s,1H),8.77(s,1H),7.64-7.72(m,2H),7.49-7.56(m,2H),7.35-7.40(m,1H),7.19-7.22(m,1H),7.16 (s,1H),6.83-6.89(m,1H),4.66-4.72(m,1H),4.31-4.54(m,1H),3.65(s,3H),2.98-3.05(m,1H),2.84-2.92(m,1H),2.67(s,3H).

[0328] Example 11. Synthesis of 4'-(5-chloro-2-methoxyphenyl)-N-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-4-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 11)

[0329]

[0330] Step 1: Synthesis of 6-chloro-4-(5-chloro-2-methoxyphenyl)nicotinate (Intermediate 11-3)

[0331] The starting material 11-1 (1.5 g), the starting material 11-2 (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), and reacted at 80° C. for 16 h under a nitrogen atmosphere. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove part of the solvent, and the residue was directly purified by a Flash column (petroleum ether: ethyl acetate 0-50%) to obtain the title compound (1.5 g).

[0332] MS m / z(ESI):312.0[M+H] + .

[0333] Step 2: Synthesis of methyl 4'-(5-chloro-2-methoxyphenyl)-4-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carboxylate (Intermediate 11-4)

[0334] Intermediate 11-3 (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 was completed, ethyl acetate (10 mL) and water (10 mL) were added, and the organic phase was separated and washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain the title compound (123.0 mg).

[0335] MS m / z(ESI):385.0[M+H] + .

[0336] Step 3: Synthesis of 4'-(5-chloro-2-methoxyphenyl)-4-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carboxylic acid (Intermediate 11-5)

[0337] The intermediate 11-4 (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, and the mixture was reacted at room temperature for 2 h. After the reaction was completed, water (5 mL) and ethyl acetate (5 mL) were added to separate the layers, and the pH of the aqueous phase was adjusted to 3 with 2N hydrochloric acid aqueous solution, and the mixture was extracted twice with ethyl acetate (5 mL x 2), and 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).

[0338] MS m / z(ESI):371.0[M+H] + .

[0339] Step 4: Synthesis of 4'-(5-chloro-2-methoxyphenyl)-N-(6,7-dihydro-4H-pyrano[4,3-d]thiazol-2-yl)-4-methyl-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 11)

[0340] The intermediate 11-5 (100.1 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (123.2 mg) and N,N-diisopropylethylamine (0.2 mL) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 1 h; then the starting material intermediate 11-6 (63.2 mg) was added to the system and reacted at room temperature for 12 h. After the reaction was completed, 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 10%-90%, elution 8 min) to obtain the title compound (30.0 mg).

[0341] LC-MS: m / z(ESI):509.1[M+H] + .

[0342] 1 H NMR(400MHz, CDCl3)δ10.98(s,1H),8.74(s,1H),8.06(s,1H),7.87-7.93(m,1H),7.32-7.40(m,1H),7.27-7.29(m,1H),6 .80-6.87(m,1H),6.46(s,1H),6.16-6.24(m,1H),4.70-4.77(m,2H),3.82-3.89(m,2H),3.61(s,3H),2.09-2.32(m,5H).

[0343] Example 12: Synthesis of 4'-(5-chloro-2-methoxyphenyl)-4-methyl-2-oxo-N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 12)

[0344]

[0345] The intermediate 11-5 (100.1 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (123.2 mg) and N,N-diisopropylethylamine (0.2 mL) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 1 h; then the starting material intermediate 12-1 (63.2 mg) was added to the system and reacted at room temperature for 12 h. After the reaction was completed, 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 10%-90%, elution 8 min) to obtain the title compound (22.0 mg).

[0346] LC-MS: m / z(ESI):507.0[M+H] + .

[0347] 1 H NMR(400MHz, CDCl3)δ8.71(s,1H),8.06(s,1H),7.87-7.95(m,1H),7.30-7.37(m,1H),7.25(s,1H),6.77-6.87(m,1H) ,6.45(s,1H),6.14-6.26(m,1H),3.63(s,3H),2.62-2.72(m,2H),2.25(s,3H),2.00-2.20(m,2H),1.67-1.78(m,4H).

[0348] Example 13. Synthesis of 4'-(5-chloro-2-methoxyphenyl)-4-methyl-N-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2-oxo-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 13)

[0349]

[0350] The intermediate 11-5 (100.1 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (123.2 mg) and N,N-diisopropylethylamine (0.2 mL) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 1 h; then the starting material intermediate 13-1 (63.2 mg) was added to the system and reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, 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 8 min) to obtain the title compound (26.0 mg).

[0351] LC-MS: m / z(ESI):522.1[M+H] + .

[0352] 1 H NMR(400MHz,DMSO-d6)δ12.54(s,1H),8.80(s,1H),7.86-7.96(m,2H),7.44-7.50(m,1H),7.40-7.44(m,1H),7.02-7.0 8(m,1H),6.34-6.41(m,1H),6.27-6.34(m,1H),3.51(s,3H),3.48(s,2H),2.64-2.72(m,4H),2.37(s,3H),2.22(s,3H).

[0353] Example 14. Synthesis of 4'-(5-chloro-2-methoxyphenyl)-4-methyl-2-oxo-N-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 14)

[0354]

[0355] The intermediate 11-5 (100.1 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (123.2 mg) and N,N-diisopropylethylamine (0.2 mL) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 1 h; then the starting material intermediate 14-1 (62.8 mg) was added to the system and reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, 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 8 min) to obtain the title compound (18.0 mg).

[0356] LC-MS: m / z(ESI):508.0[M+H] + .

[0357] 1 H NMR(400MHz,DMSO-d6)δ8.79(s,1H),7.89-7.94(m,1H),7.87(s,1H),7.44-7.49(m,1H),7.40-7.43(m,1H),7.02-7.06 (m,1H),6.36(s,1H),6.28-6.32(m,1H),3.79(s,2H),3.51(s,3H),2.91-3.00(m,2H),2.52-2.58(m,2H),2.22(s,3H).

[0358] Example 15. Synthesis of 4'-(5-chloro-2-methoxyphenyl)-4-methyl-2-oxo-N-(thiazo[5,4-b]pyridin-2-yl)-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 15)

[0359]

[0360] The intermediate 11-5 (100.1 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (123.2 mg) and N,N-diisopropylethylamine (0.2 mL) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 1 h; then the starting material intermediate 15-1 (61.2 mg) was added to the system and reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, 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 8 min) to obtain the title compound (36.0 mg).

[0361] LC-MS: m / z(ESI):504.0[M+H] + .

[0362] 1 H NMR (400MHz, CDCl3) δ11.17(s,1H),8.80(s,1H),8.42-8.48(m,1H),8.11(s,1H),7.82-7.89(m,1H),7.44-7.50(m,1H),7.36-7.41 (m,1H),7.29-7.32(m,1H),7.22-7.26(m,1H),6.80-6.85(m,1H),6.45-6.51(m,1H),6.14-6.23(m,1H),3.62(s,3H),2.22(s,3H).

[0363] Example 16. Synthesis of 4-(5-chloro-2-methoxyphenyl)-4-methyl-2-oxo-N-thiazolo[5,4-d]pyrimidin-2-yl)-2H-[1,2'-bipyridine]-5'-carboxamide (Compound 16)

[0364]

[0365] Intermediate 11-5 (100.1 mg), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (123.2 mg) and N,N-diisopropylethylamine (0.2 mL) were dissolved in N,N-dimethylformamide (2 mL) and stirred at room temperature for 1 h. Then, the starting material intermediate 16-1 (61.6 mg) was added to the system and reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, 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 8 min) to obtain the title compound (23.0 mg).

[0366] LC-MS: m / z(ESI):505.0[M+H] + .

[0367] 1 H NMR(400MHz,DMSO-d6)δ13.40(s,1H),9.15(s,1H),9.00(s,1H),8.93(s,1H),7.87-7.99(m,2H),7. 40-7.55(m,2H),7.01-7.08(m,1H),6.35-6.42(m,1H),6.28-6.34(m,1H),3.52(s,3H),2.22(s,3H).

[0368] Biological activity and related properties test examples

[0369] The compounds in the following test examples were all prepared according to the methods of the above embodiments of the present disclosure.

[0370] Test Example 1: POLQ enzyme activity inhibition experiment

[0371] Brief introduction to experimental principle: After the N-terminal active peptide segment (M1-N899) of POLQ with ATPase activity is incubated with the compound, it reacts with the substrate dT50 under the action of ATP to generate ADP, participates in the subsequent NADH oxidation-coupled enzymatic reaction, and catalyzes the reaction of NADH to generate NAD + The decrease in NADH OD at 340 nm was measured using Perkin Elmer's Envision microplate reader to reflect enzyme activity.

[0372] Experimental instruments: Echo 650 pipetting system from Labcyte; Envision microplate reader from Perkin Elmer; 5810R centrifuge from Eppendorf, BSD-YX3400 constant temperature shaker from Boxun.

[0373] Experimental Materials:

[0374] Reagents brand POLQ(M1-N899) Synthesized by Pharmaron ATP Sigma dT50 Synthesized by GenScript NADH Roche PEP Sigma Lactate dehydrogenase Sigma Pyruvate kinase Sigma 384-well plate Greiner Bio-One

[0375] Experimental method: POLQ enzyme was diluted to 100 nM in reaction buffer (20 mM Tris HCl (pH 7.80), 80 mM KCl, 10 mM MgCl2, 1 mM DTT (dithiothreitol), 0.01% w / v bovine serum albumin, 0.01% v / v Tween-20, 5% v / v glycerol). The test compound was diluted to different concentrations in dimethyl sulfoxide (DMSO) using the Echo 650 pipetting system, transferred to a 384-well plate, and 20 μL / well of 100 nM POLQ enzyme was added and incubated at room temperature for 15 minutes. The reaction mixture solution was prepared, and the concentrations of each component in the reaction mixture solution were: 100 μM ATP, 300 nM dT50, 300 μM NADH, 6 mM PEP, 10 U / mL lactate dehydrogenase and 20 U / mL pyruvate kinase. 20 μL / well of the reaction mixture solution was added to start the enzyme reaction. The final concentration of the compound in the reaction system started from 10 μM, and was diluted 3 times in a gradient, ranging from 10 μM to 0.0005 μM, and the final concentration of DMSO in the system was 0.2% v / v. After the 384-well plate was placed at room temperature for 20 minutes, the OD value at 340 nm was read using an Envision microplate reader.

[0376] Data Analysis:

[0377] The inhibition rate was calculated and the IC of the compound was obtained using XLfit software. 50 .

[0378] The experiment set up a blank group and a DMSO group. The reaction system of the blank group was 0.2% v / v DMSO and reaction mixture solution, and the inhibition rate was considered to be 100% at this time; the reaction system of the DMSO group was 0.2% v / v DMSO, POLQ(N) (100 nM) and reaction mixture solution, and the inhibition rate was considered to be 0 at this time.

[0379] Inhibition rate (%) = (100-100*(OD max -OD 化合物 ) / (OD max -OD min ))%

[0380] Among them, OD max Refers to the OD value of the well containing the reaction mixture and 0.2% v / v DMSO. 化合物 Refers to the OD value of the well containing the compound, enzyme and reactant mixture. minRefers to the OD value of the well containing enzyme, reactant mixture and 0.2% v / v DMSO.

[0381] The biological activity of the disclosed compounds was determined by the above test, and the IC 50 The values ​​are shown in Table 1 below.

[0382] Table 1 IC of the Example compounds on the inhibition of POLQ enzyme activity 50

[0383]

[0384]

[0385] In the above table, the symbols used to indicate inhibitory activity mean the following:

[0386] “++++” indicates the IC value of the enzyme inhibitory activity of the tested compound 50 Range: IC 50 <100nM.

[0387] “+++” indicates the inhibitory activity of the tested compound on the enzyme IC 50 Range: 100nM≤IC 50 <500nM.

[0388] “++” indicates the inhibitory activity of the tested compound on the enzyme IC 50 Range: 500nM≤IC 50 <1000nM.

[0389] “+” indicates the inhibitory activity of the tested compound on the enzyme IC 50 Range: 1000nM≤IC 50 <5000nM.

[0390] Test Example 2: Experiment on the inhibition of tumor cell proliferation by compounds

[0391] Brief introduction to experimental principle: After the compound is co-incubated with tumor cells for 7 days, the ATP in the living cells is quantified using the CTG kit of Promega, thereby reflecting the effect of the compound on the proliferation of tumor cells.

[0392] Experimental instruments: Envision microplate reader from Perkin Elmer; 5810R centrifuge from Eppendorf, automatic cell counter from Countstar.

[0393] Experimental Materials:

[0394] Reagents brand Part Number DLD-1 parental cells Horizon HD PAR-008 DLD-1BRCA2(- / -) cell line Horizon HD 105-007 RPMI 1640 medium Gibco A10491-01 FBS Gibco 10099-141C 0.25%Trypsin-EDTA Gibco 25200-172 PBS HyClone SH30256.01 96-well plate Corning 3610 CelltiterGlo assay kit (CTG) Promega G7573

[0395] Experimental method: DLD-1 parental cells or DLD-1BRCA2 (- / -) cells were diluted with RPMI1640 medium containing 10% FBS and added to a 96-well plate (90 μL / well). The number of cells was 600 / well or 1200 / well, respectively, and cultured in a 37°C, 5% CO2 incubator overnight. The test compound was diluted to different concentrations in dimethyl sulfoxide (DMSO) and added to a 96-well plate. The final concentration of the compound in the reaction system started from 25 μM, and the compound concentration ranged from 25 μM to 0.0004 μM in a 4-fold gradient dilution. The final concentration of DMSO was 0.25% v / v. After incubation for 7 days, 50 μL / well of CTG was added and incubated at room temperature for 10 minutes. The light signal value (Lum) was read using an Envision microplate reader, and the inhibition rate and half inhibitory concentration (IC) were calculated. 50 ).

[0396] Data Analysis:

[0397] The inhibition rate was calculated and the IC of the compound was obtained using XLfit software. 50 .

[0398] The experiment set up blank wells and DMSO wells. The blank wells were 100 μL of RPMI Medium 1640 culture medium containing 10% FBS, and the inhibition rate of the compound on tumor cell growth was considered to be 100% at this time; the DMSO wells were cell wells with 0.25% v / v DMSO added, and the inhibition rate of the compound on tumor cell growth was considered to be 0 at this time.

[0399] Inhibition rate = 100*(Lum max -Lum 化合物 ) / (Lum max -Lum min )%

[0400] Among them, Lum max Refers to the light signal value of the well containing cells and 0.25% v / v DMSO, Lum 化合物 Refers to the light signal value of the wells containing compounds and cells. min Refers to the light signal values ​​of wells containing culture medium and 0.25% v / v DMSO.

[0401] The inhibitory effect of the compounds of the present application on the growth of tumor cells was determined by the above test, and the IC 50 value.

[0402] The test showed that the compounds of the embodiments of the present invention had a good inhibitory effect on BRCA2 mutated tumor cells and had good selectivity.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof: in, Indicates a single bond or a double bond. When it is a single bond, X 1 It is N, X 2 is CO; or, when When it is a double bond, X 1 It is C, X 2 is N or CH; Selected from: n is selected from 0, 1, 2, 3 or 4; R B is selected from oxo, halogen, hydroxyl, cyano, carboxyl, amino, -C(=O)NH2, C2-C8 alkynyl, C2-C8 alkenyl, C1-C8 alkyl, C1-C8 alkoxy, C3-C6 cycloalkyl, phenyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl, wherein the amino, -C(=O)NH2, C2-C8 alkynyl, C2-C8 alkenyl, C1-C8 alkyl, C1-C8 alkoxy, C3-C6 cycloalkyl, phenyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally replaced by R Ba replace; R Ba Selected from halogen, hydroxy, cyano, amino, C1-C6 alkyl or C1-C6 alkoxy; R 1 Selected from C6-C 14 Aryl, 5-10 membered heteroaryl, 6-12 membered heterocyclic group or C4-C 10 Cycloalkenyl, the C6-C 14 Aryl, 5-10 membered heteroaryl, 6-12 membered heterocyclic group or C4-C 10 The cycloalkenyl group is optionally substituted by R 1a replace; R 1a is selected from halogen, hydroxy, cyano, carboxyl, oxo, amino, -C(=O)NH2, C1-C 10 Alkyl, C1-C 10 Alkoxy, -C(=O)-C1-C 10 Alkyl, C3-C 10 Cycloalkyl, -O-C3-C 10 Cycloalkyl, SO2C1-C 10 Alkyl, C2-C 10 Alkynyl, C2-C 10 alkenyl, 4-12 membered heterocyclic group or -O-4-8 membered heterocyclic group, the amino, -C(=O)NH2, C1-C 10 Alkyl, C1-C 10 Alkoxy, -C(=O)-C1-C 10 Alkyl, C3-C 10 Cycloalkyl, -O-C3-C 10 Cycloalkyl, SO2C1-C 10 Alkyl, C2-C 10 Alkynyl, C2-C 10 an alkenyl group, a 4-12 membered heterocyclic group or an -O-4-8 membered heterocyclic group is optionally replaced by R 1b replace; Every R 1b Independently selected from halogen, carboxyl, hydroxyl, oxo, cyano, amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, -C(=O)NH2, -C(=O)NH(C1-C6 alkyl), -C(=O)N(C1-C6 alkyl)2, sulfonyl, C1-C6 alkyl or C1-C6 alkoxy; T is selected from a bond, CH2, NR T NR T CO, -O-(CH2) z -、-CO-(CH2) x - or cyclopropylene; z, x are independently selected from 0 or 1; R T is selected from hydrogen, C1-C6 alkyl or C1-C6 deuterated alkyl; R 3 Selected from hydrogen, halogen, cyano, hydroxyl, carboxyl, -C(=O)NR 3 'R 3 "、amino、C1-C 10 Alkyl, C1-C 10 Alkoxy, C2-C 10 Alkynyl, -C(=O)-C1-C 10 Alkyl, SO2C1-C 10 Alkyl, SOC1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl, the amino, C1-C 10 Alkyl, C1-C 10 Alkoxy, C2-C 10 Alkynyl, -C(=O)-C1-C 10 Alkyl, SO2C1-C 10 Alkyl, SOC1-C 10 Alkyl, C3-C 10 Cycloalkyl, 4-12 membered heterocyclyl or 5-10 membered heteroaryl is optionally replaced by R 3a Substitution; when T is selected from a bond, R 3 It is not hydrogen; R 3a Selected from oxo, halogen, cyano, hydroxyl, -C(=O)NR 3a 'R 3a ", amino, NH (C1-C6 alkyl), N (C1-C6 alkyl) 2, NHCOC1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, COOC1-C6 alkyl, -C (= O) -C1-C6 alkyl, SO2C1-C 10 alkyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl, the amino, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, COOC1-C6 alkyl, -C(=O)-C1-C6 alkyl, SO2C1-C 10 Alkyl, 4-12 membered heterocyclic group or 5-10 membered heteroaryl group are optionally replaced by R 3b replace; R 3 '、R 3 " are each independently selected from hydrogen or C1-C6 alkyl, or R 3 '、R 3 " and the N atom to which it is connected together form a 4-12 membered heterocyclic group, wherein the 4-12 membered heterocyclic group is optionally replaced by R N1 replace; R 3a '、R 3a " are each independently selected from hydrogen or C1-C6 alkyl, or R 3 '、R 3 " and the N atom to which it is connected together form a 4-12 membered heterocyclic group, wherein the 4-12 membered heterocyclic group is optionally replaced by R N2 replace; R 3b , R N1 , R N2 Each independently selected from halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, SO2C1-C 10 Alkyl, C3-C6 cycloalkyl, carboxyl or hydroxyl.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: is a double bond, X 1 It is C, X 2 It is N.

3. The compound of formula (I) according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: n is selected from 0, 1 or 2; Or, wherein n is selected from 0 or 1; or, wherein n is selected from 0; or, wherein n is selected from 1; or, wherein n is selected from 2.

4. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: Selected from: or, in, Selected from:

5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R B is selected from oxo, C1-C6 alkyl, C3-C6 cycloalkyl, phenyl or 5-10 membered heteroaryl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, phenyl or 5-10 membered heteroaryl is optionally replaced by R Ba replace; or, Among them, R B is selected from oxo, C1-C3 alkyl, C3-C4 cycloalkyl, phenyl or 5-10 membered heteroaryl, wherein the C1-C3 alkyl, C3-C4 cycloalkyl, phenyl or 5-10 membered heteroaryl is optionally replaced by R Ba replace; or, Among them, R B Selected from oxo, methyl, cyclopropyl, phenyl or The methyl, cyclopropyl, phenyl or Optional R Ba replace; or, Among them, R B is selected from oxo, C1-C6 alkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl or C3-C6 cycloalkyl is optionally replaced by R Ba replace; or, Among them, R B is selected from oxo, C1-C3 alkyl or C3-C4 cycloalkyl, wherein the C1-C3 alkyl or C3-C4 cycloalkyl is optionally replaced by R Ba replace.

6. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 1 Selected from C6-C 10 Aryl or 5-10 membered heteroaryl, the C6-C 10 Aryl or 5-10 membered heteroaryl is optionally replaced by R 1a replace.

7. A compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: T is selected from a bond.

8. The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: R 3 is selected from C1-C6 alkyl or 4-12 membered heterocyclic group, wherein the C1-C6 alkyl or 4-12 membered heterocyclic group is optionally replaced by R 3a replace; or, Among them, R 3 is selected from C1-C3 alkyl or 5-6 membered heterocyclic group, wherein the C1-C3 alkyl or 5-6 membered heterocyclic group is optionally replaced by R 3a replace; or, Among them, R 3 is selected from C1-C3 alkyl or 6-membered heterocyclic group, wherein the C1-C3 alkyl or 6-membered heterocyclic group is optionally replaced by R 3a replace; or, Among them, R 3 Selected from methyl or The methyl or Optional R 3a replace; or, Among them, R 3 is selected from 4-12 membered heterocyclic groups or 5-10 membered heteroaryl groups, wherein the 4-12 membered heterocyclic groups or 5-10 membered heteroaryl groups are optionally replaced by R 3a replace; or, Among them, R 3 is selected from 4-12 membered heterocyclic groups, wherein the 4-12 membered heterocyclic groups are optionally substituted by R 3a replace; or, Among them, R 3 is selected from 4-7 membered heterocyclic groups, wherein the 4-7 membered heterocyclic groups are optionally substituted by R 3a replace; or, Among them, R 3 is selected from a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted by R 3a replace; or, Among them, R 3 is selected from a 6-membered heterocyclic group, wherein the 6-membered heterocyclic group is optionally substituted by R 3a replace; or, Among them, R 3 Selected from Said Optional R 3a replace; or, Among them, R 3 Selected from Said Optional R 3a replace; or, Among them, R 3 Selected from 9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the compound of formula (II) or a pharmaceutically acceptable salt thereof: Wherein, ring C is selected from 4-12 membered heterocyclic groups, wherein the 4-12 membered heterocyclic groups are optionally replaced by R 3a replace; T.X 1 , X 2 , R 1 , Ring B, R B Or n is defined as in any one of claims 1-8.

10. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein: The compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt or a stereoisomer thereof and a pharmaceutically acceptable excipient.

12. Use of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or the pharmaceutical composition according to claim 11, in the preparation of a medicament for preventing or treating a disease mediated by DNA polymerase θ.

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