Membrane-associated tyrosine and threonine kinase inhibitor compound and use thereof

Abstract

The present disclosure relates to a PKMYT1 inhibitor compound represented by formula (II') or a stereoisomer or pharmaceutically acceptable salt thereof, a preparation method therefor, a pharmaceutical composition containing the compound or a stereoisomer or pharmaceutically acceptable salt thereof, and the use of same in the prevention or treatment of PKMYT1-related diseases.

Description

Membrane-associated tyrosine and threonine kinase inhibitor compounds and their applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to the following Chinese invention patent application, the entire contents of which are hereby incorporated by reference herein:

[0003] Patent application No. 202410336501.0 submitted to the State Intellectual Property Office of China on March 22, 2024. Technical Field

[0004] The present application belongs to the field of medicine and relates to a cyclic compound or its stereoisomer or pharmaceutically acceptable salt as a PKMYT1 inhibitor, a preparation method thereof, a pharmaceutical composition containing the compound or its stereoisomer or pharmaceutically acceptable salt thereof, and its use in preventing or treating diseases related to PKMYT1. Background Art

[0005] Continuous exposure of cellular genomic DNA to a variety of harmful factors from both inside and outside the body may cause DNA damage. Therefore, cells have evolved a series of complex DNA damage response mechanisms to cope with these harmful factors, thereby maintaining the integrity of the genome and avoiding the occurrence of diseases including tumors due to genomic instability. Activation of the cell cycle checkpoint pathway is one of the important mechanisms. Cell cycle checkpoints include checkpoints in the G1, S, G2, and M phases. Unlike normal cells, the survival of tumor cells often depends on the misregulation of DNA damage repair. Many tumor cells lose the G1 checkpoint due to the presence of p53 gene mutations, and are therefore more dependent on the G2 checkpoint to repair DNA damage, thereby maintaining the survival of tumor cells.

[0006] The membrane-associated tyrosine and threonine kinase (Myt1 kinase, also known as PKMYT1) is encoded by the PKMYT1 gene. PKMYT1 inhibits CDC2 activity by phosphorylating CDC2 at Thr-14 and Tyr-15, thereby regulating the cell cycle and arresting cells in the G2-M phase, allowing them to repair DNA damage. Studies have shown that inhibiting PKMYT1 leads to CDC2 activation, forcing cells to enter mitosis prematurely and unable to repair DNA damage, thereby killing rapidly proliferating tumor cells.

[0007] Therefore, PKMYT1 inhibitors have the potential to inhibit tumor proliferation, and the development of PKMYT1 inhibitors can provide a new strategy for tumor targeted therapy. Summary of the Invention

[0008] In one aspect, the present application relates to a compound of formula (II') or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0009] in,

[0010] n is selected from 0 and 1;

[0011] R 1 、R 3 independently selected from hydrogen, hydroxy, amino, nitro, halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C9 cycloalkyl-O-, 4-9 membered heterocyclyl-O-, C1-C6 alkyl-C(O)O-, C3-C9 cycloalkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O- and NH2C(O)O-, said C1-C6 alkyl, C1-C6 alkoxy, C3-C9 cycloalkyl-O-, 4-9 membered heterocyclyl-O-, C1-C6 alkyl-C(O)O-, C3-C9 cycloalkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O- and NH2C(O)O-, said C1-C6 alkyl, C1-C6 alkoxy, C3-C9 cycloalkyl-O-, 4-9 membered heterocyclyl-O-, C1-C6 alkyl-C(O)O-, C3-C9 cycloalkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O- or NH2C(O)O- being optionally substituted by one or more R 11 replace;

[0012] R 2 Selected from hydrogen, cyano, halogen, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl, 5-9 membered heteroaryl, C(=O)H, C2-C6 alkenyl and C2-C6 alkynyl, the C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 Aryl, 5-9 membered heteroaryl, C(=O)H, C2-C6 alkenyl or C2-C6 alkynyl are optionally substituted by one or more R a replace;

[0013] R 4 Selected from amino, hydroxyl, mercapto, halogen, cyano, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl and -C(=O)NH2, the amino, hydroxyl, thiol, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 Aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or -C(=O)NH2 is optionally substituted by one or more R a replace;

[0014] R 5 and R 5' and the atoms connected thereto together form a benzene ring, a pyridine ring, a pyrimidine ring, a thiazole ring, an isothiazole ring, an oxazole ring or an isoxazole ring, wherein the benzene ring, the pyridine ring or the pyrimidine ring is further surrounded by one or more R a1 The thiazole ring, isothiazole ring, oxazole ring or isoxazole ring is optionally replaced by R a1 replace;

[0015] R 7 、R 8 independently selected from hydrogen, halogen, and C1-C6 alkyl, said C1-C6 alkyl being optionally substituted with deuterium;

[0016] R 11 Selected from C1-C 10 Alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C1-C6 alkoxy, C3-C9 cycloalkyl-O-, 4-9 membered heterocyclyl-O-, C1-C6 alkyl-C(O)O-, C3-C9 cycloalkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O, NH2C(O)O- and C1-C6 alkyl-OC(O)O-;

[0017] R a 、R a1 Each independently selected from deuterium, halogen, CN, methyl and C2-C4 alkenyl, said methyl and C2-C4 alkenyl being optionally substituted by one or more R b replace;

[0018] R b independently selected from deuterium, halogen, NH2, NHCH3 and N(CH3)2;

[0019] Provided that the compound of formula (II') or its stereoisomer or pharmaceutically acceptable salt thereof does not include the following compounds:

[0020] In some embodiments, n is 1.

[0021] In some embodiments, n is 0.

[0022] In some embodiments, R 1 、R 3 independently selected from hydrogen, halogen, hydroxy, C1-C6 alkoxy, C1-C6 alkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O- and NH2C(O)O-, wherein the C1-C6 alkoxy, C1-C6 alkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O- and NH2C(O)O- are optionally substituted by one or more R 11 replace.

[0023] In some embodiments, R 1 、R 3 independently selected from hydrogen, halogen, hydroxy, P(O)(OH)2O- and C1-C6 alkoxy, the C1-C6 alkoxy being optionally substituted by one or more R 11 replace.

[0024] In some embodiments, R 1 、R 3 are independently selected from hydrogen, halogen and hydroxy.

[0025] In some embodiments, R 1 、R 3 are independently selected from hydrogen and hydroxy.

[0026] In some embodiments, R 1 is selected from hydroxy, P(O)(OH)2O- and C1-C6 alkoxy, wherein the C1-C6 alkoxy is optionally substituted by one or more R 11 Replacement, R 3 is hydrogen or halogen.

[0027] In some embodiments, R 1 Selected from P(O)(OH)2O- and R 11 Substituted methoxy, R 3 For hydrogen.

[0028] In some embodiments, R 1 is hydroxyl group, R 3 is hydrogen or halogen.

[0029] In some embodiments, R 1 is hydroxyl group, R 3 For hydrogen.

[0030] In some embodiments, R 1 is hydroxyl group, R 3 It is a halogen.

[0031] In some embodiments, R 2 For hydrogen.

[0032] In some embodiments, R 1 It is a hydroxyl group.

[0033] In some embodiments, R 2 is hydrogen, R 3 is hydrogen or halogen.

[0034] In some embodiments, R 2 and R 3 All are hydrogen.

[0035] In some embodiments, R 1is hydroxyl group, R 2 H, R 3 is hydrogen or halogen such as F.

[0036] In some embodiments, R 1 is hydroxyl group, R 2 and R 3 All are hydrogen.

[0037] In some embodiments, R 11 Selected from C1-C 10 Alkyl, 4-9 membered heterocyclyl, C1-C6 alkyl-C(O)O-, 4-9 membered heterocyclyl-C(O)O-, P(O)(OH)2O and C1-C6 alkyl-OC(O)O-.

[0038] In some embodiments, R 11 Selected from C1-C6 alkyl-C(O)O-, 5-6 membered heterocyclyl-C(O)O-, P(O)(OH)2O- and C1-C6 alkyl-OC(O)O-.

[0039] In some embodiments, R 11 Selected from and P(O)(OH)2O-.

[0040] In some embodiments, R 1 Selected from -OH,

[0041] In some embodiments, R 1 Selected from -OH, P(O)(OH)2O-,

[0042] In some embodiments, R 4 Selected from amino, hydroxy, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl and 5-9 membered heteroaryl, the amino, hydroxyl, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclic, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R a replace.

[0043] In some embodiments, R 4 is selected from amino, hydroxy, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl, wherein the amino, hydroxy, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted by one or more R a replace.

[0044] In some embodiments, R 4 Selected from -CH3, -CH(CH3)2, -OCH3, -N(CH3)2, -CF3, -CHF2, -CH2F,

[0045] In some embodiments, R 4 Selected from optionally one or more R a Substituted C1-C3 alkyl.

[0046] In some embodiments, R 4 is selected from methyl optionally substituted by one or more halogen (eg F).

[0047] In some embodiments, R 4 Selected from methyl and -CHF2.

[0048] In some embodiments, R 5 and R 5 ' and the atoms connected thereto together form a benzene ring, a pyridine ring, a thiazole ring or an isothiazole ring, wherein the benzene ring and the pyridine ring are further separated by one or more R a1 Substituted, the thiazole ring or isothiazole ring is optionally replaced by R a1 replace.

[0049] In some embodiments, R 5 and R 5 ' and the atoms connected thereto together form a benzene ring, a pyridine ring or a pyrimidine ring, and the benzene ring, the pyridine ring or the pyrimidine ring is further surrounded by one or more R a1 In some embodiments, R 5 and R 5 ' and the atoms connected thereto together form a benzene ring or a pyridine ring, said benzene ring or pyridine ring being further surrounded by one or more R a1 replace.

[0050] In some embodiments, R 5 and R 5 ' and the atoms to which they are connected together form a thiazole ring, an isothiazole ring, an oxazole ring or an isoxazole ring, wherein the thiazole ring, the isothiazole ring, the oxazole ring or the isoxazole ring is optionally replaced by R a1 In some embodiments, R 5 and R 5 ' and the atoms to which they are connected together form a thiazole ring or an isothiazole ring, wherein the thiazole ring or the isothiazole ring is optionally replaced by R a1 replace.

[0051] In some embodiments, R 7 、R 8 Independently selected from halogen and C1-C6 alkyl.

[0052] In some embodiments, R 7 、R 8 Independently selected from C1-C3 alkyl.

[0053] In some embodiments, R 7 and R 8 All are methyl.

[0054] In some embodiments, R a 、R a1 independently selected from halogen, CN, methyl and C2-C4 alkenyl, said methyl and C2-C4 alkenyl being optionally substituted by one or more R b replace.

[0055] In some embodiments, R b Independently selected from halogen, NH2, NHCH3 and N(CH3)2.

[0056] In some embodiments, R b Independently selected from halogen (eg, F) ​​and N(CH3)2.

[0057] In some embodiments, R a are independently selected from halogen, such as fluorine.

[0058] In some embodiments, R a1 Independently selected from CN, methyl, CF2H, CF3, CH2N(CH3)2 and propenyl.

[0059] In some embodiments, the compound of formula (II') of the present application or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (II-1) or its stereoisomer or its pharmaceutically acceptable salt,

[0060] Among them, X 1 is selected from CH and N, m is selected from 1, 2 and 3, n, R 1 、R 2 、R 3 、R 4 、R 7 、R 8 and R a1 As defined above.

[0061] In some embodiments, the compound of formula (II') of the present application or its stereoisomer or its pharmaceutically acceptable salt is selected from the compound of formula (II-2) or its stereoisomer or its pharmaceutically acceptable salt,

[0062] Among them, X 2 、X 3One is N, the other is CH, k is selected from 0 and 1, n, R 1 、R 2 、R 3 、R 4 、R 7 、R 8 and R a1 As defined above.

[0063] In some embodiments, the compound of the present application or its stereoisomer or its pharmaceutically acceptable salt is selected from the following compounds or their stereoisomers or their pharmaceutically acceptable salts,

[0064] On the other hand, the present application provides a pharmaceutical composition comprising a compound of formula (II'), formula (II-1), formula (II-2) or the above-mentioned specific compound or a stereoisomer or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0065] On the other hand, the present application provides a method for treating a PKMYT1-mediated disease in a mammal, comprising administering a therapeutically effective amount of a compound of formula (II'), formula (II-1), formula (II-2) or the above-mentioned specific compounds or their stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof to a mammal, preferably a human, in need of such treatment.

[0066] On the other hand, the present application provides the use of compounds of formula (II'), formula (II-1), formula (II-2) or the above-mentioned specific compounds or their stereoisomers or pharmaceutically acceptable salts, or their pharmaceutical compositions in the preparation of drugs for preventing or treating PKMYT1-mediated diseases.

[0067] On the other hand, the present application provides the use of compounds of formula (II'), formula (II-1), formula (II-2) or the above-mentioned specific compounds or their stereoisomers or pharmaceutically acceptable salts, or their pharmaceutical compositions in preventing or treating PKMYT1-mediated diseases.

[0068] On the other hand, the present application provides compounds of formula (II'), formula (II-1), formula (II-2) or the above-mentioned specific compounds or their stereoisomers or pharmaceutically acceptable salts, or pharmaceutical compositions thereof for preventing or treating PKMYT1-mediated diseases.

[0069] In some embodiments, the PKMYT1-mediated disease is a tumor. In some embodiments, the PKMYT1-mediated disease is breast cancer.

[0070] Definitions and Explanations of Terms

[0071] Unless otherwise indicated, the terms used in this disclosure have the following meanings. The definitions of groups and terms described in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the examples, may be combined and coupled with each other in any manner. A particular term should not be considered as undefined or unclear unless specifically defined, but should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0072] In this article Indicates the attachment site.

[0073] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom in a molecule between two positions. The compounds of the present disclosure may exhibit tautomerism. Tautomeric compounds may exist as two or more interconvertible species. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties 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 encompasses all tautomeric forms of the compounds.

[0074] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0075] Certain compounds of the present invention may exist as atropisomers, which are conformational isomers that occur when rotation about a single bond in a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule. The compounds disclosed herein include all atropisomers, either pure individual atropisomers, or enriched in one of the atropisomers, or nonspecific mixtures of each. If the rotational potential about the single bond is high enough and the interconversion between conformations is slow enough, this may allow separation of the isomers. For example, For a pair of atropisomers, in which the phenyl Indicates that the side is facing outward. Indicates that the side is facing inwards, and Represents relative configuration, referring to the above The asterisk indicates the position of the chiral axis.

[0076] 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 that 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 and Z 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 mixtures thereof. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of which are within the definition of the compounds of the present invention and mixtures thereof. 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 reagents.

[0077] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0078] The term "optional" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, an ethyl group is "optionally" substituted with halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.), or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any sterically impossible and / or incomposable replacement or substitution pattern will not be introduced.

[0079] When any variable (such as n, R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options.

[0080] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a bond.

[0081] When one of the variables is selected from a chemical bond or does not exist, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0082] In this article, C m -C n It means having an integer number of carbon atoms in the range mn. For example, "C1-C 10 ” means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0083] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10 The term "alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of the alkyl radical include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2- dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C1-C6 alkyl" can be understood to mean an alkyl group having 1 to 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-chain or branched saturated alkyl group having 1 to 3 carbon atoms. The "C1-C 10 The term "alkyl" may include "C1-C6 alkyl" or "C1-C3 alkyl", and the "C1-C6 alkyl" may further include "C1-C3 alkyl". The term "C1-C3 haloalkyl" refers to a C1-C3 alkyl substituted by one or more halogens such as F, Cl, Br or I, including mono-, poly- or fully substituted.

[0084] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane group by removing two hydrogen atoms, and is an alkylene group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, preferably an alkylene group containing 1, 2, 3, 4, 5, or 6 carbon atoms (i.e., C1-C6 alkylene group), more preferably an alkylene group containing 1, 2, or 3 carbon atoms (i.e., C1-C3 alkylene group). Non-limiting examples of alkylene groups include, but are not limited to, methylene, -CH(CH3)-, -CH2CH2-, -CH(CH2CH3)-, -CH2CH(CH3)-, -CH2CH2CH2-, and the like.

[0085] 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-". The term "C1-C 10 "Alkoxy" can be understood as "C1-C 10 Alkyloxy" or "C1-C 10 The term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". The "C1-C 10 "Alkoxy" may include "C1-C6 alkoxy" and "C1-C3 alkoxy" and the like, and the "C1-C6 alkoxy" may further include "C1-C3 alkoxy". The term "C1-C3 haloalkoxy" refers to C1-C3 haloalkyl-O-.

[0086] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. 10 "Alkenyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C2-C 10 "Alkenyl" is preferably "C2-C6 alkenyl", further preferably "C2-C4 alkenyl", and further preferably C2 or C3 alkenyl. It will be understood that when the alkenyl contains more than one double bond, the double bonds may be separated from each other or conjugated. Specific examples of the alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.

[0087] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. 10 "Alkynyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C2-C 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH 3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl or but-3-ynyl. "C2-C 10 The term "alkynyl" may include "C2-C3 alkynyl". Examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), and prop-2-ynyl (-CH2C≡CH).

[0088] The term "cycloalkyl" refers to a 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 10 "Cycloalkyl" is understood to mean a saturated monocyclic, bicyclic, spirocyclic or bridged ring having 3 to 10 (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 to 6 carbon atoms. Specific examples include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0089] The term "cycloalkyloxy" may be understood as "cycloalkyl-O-".

[0090] The term "heterocyclyl" or "heterocycle" refers to a saturated or partially saturated (heteroaromatic as a whole that is not aromatic) monocyclic, fused, spiro or bridged ring group, which contains 1 to 5 heteroatoms or heteroatomic groups (i.e., heteroatom-containing groups) in its ring atoms, wherein the "heteroatoms or heteroatomic 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-. The term "4-9 membered heterocyclyl" refers to a heterocyclyl group having 4, 5, 6, 7, 8 or 9 ring atoms, and containing 1, 2, 1-3 or 1-5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms or heteroatomic groups in its ring atoms. “4-7 membered heterocyclyl” and “4-9 membered heterocyclyl” may respectively contain 1-3 (1, 2 or 3) heteroatoms independently selected from N, O and S. “4-9 membered heterocyclyl” includes “4-7 membered heterocyclyl”, wherein specific examples of 4 membered heterocyclyl include but are not limited to azetidinyl or oxetanyl; specific examples of 5 membered heterocyclyl 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 heterocyclyl 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 heterocyclyl include but are not limited to diazepanyl. 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]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7-membered heterocyclic groups, specific examples of which include but are not limited to dihydroisoquinolinyl and the like. "4-9 membered heterocyclyl" may include "5-9 membered heterocyclyl", "4-7 membered heterocyclyl", "5-6 membered heterocyclyl", "6-8 membered heterocyclyl", "4-9 membered heterocycloalkyl", "5-9 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered heterocycloalkyl", etc., and "4-7 membered heterocyclyl" may further include "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", etc. Although some bicyclic heterocyclyl groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclyl group as a whole is still non-aromatic.

[0091] The term "heterocycloalkyl" refers to a saturated cyclic group in the form of a monocyclic, fused, bridged or spirocyclic ring, wherein the ring atoms of the ring contain 1, 2, 1-3 or 1-5 heteroatoms or heteroatomic groups (i.e., heteroatomic groups containing heteroatoms), wherein the "heteroatoms or heteroatomic 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)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-. The term "4-9 membered heterocycloalkyl" refers to a heterocycloalkyl group having 4, 5, 6, 7, 8 or 9 ring atoms, wherein the ring atoms contain 1-5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms or heteroatomic groups. “4-7 membered heterocycloalkyl” and “4-9 membered heterocycloalkyl” may respectively contain 1-3 (1, 2 or 3) heteroatoms independently selected from N, O and S. “4-9 membered heterocycloalkyl” includes “4-7 membered heterocycloalkyl”, wherein specific examples of 4 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl or thietanyl; specific examples of 5 membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl or tetrahydropyrazolyl; specific examples of 6 membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl or 1,4-dithianyl; specific examples of 7 membered heterocycloalkyl include, but are not limited to, azepanyl, oxetanyl or thiepanyl.

[0092] 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, 6-12 or 6-10 carbon atoms. The term "C6-C 20 "Aryl" is understood to be an aromatic radical having 6 to 20 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 or a ring having 13 carbon atoms ("C 13 aryl) such as fluorenyl; or a ring having 14 carbon atoms ("C 14 The term "C6-C 10"Aryl" is understood to be an aromatic radical having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C 10 "aryl"), for example tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0093] The term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or fused polycyclic ring system with aromatic character, which contains at least one (1, 2 or 3) ring atom selected from N, O, S, and the remaining ring atoms are C. The term "5-9 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems: which have 5, 6, 7, 8 or 9 ring atoms, in particular 5 or 6 or 9 ring atoms, and which contain 1 to 5, preferably 1 to 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or acinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl, and the like. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms and containing 1-3, preferably 1-2, heteroatoms independently selected from N, O and S.

[0094] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0095] The term "hydroxymethyl" refers to -CH2OH.

[0096] The term "hydroxy" refers to an -OH group.

[0097] The term "cyano" refers to a -CN group.

[0098] The term "mercapto" refers to a -SH group.

[0099] The term "amino" refers to a -NH2 group.

[0100] The term "nitro" refers to a -NO2 group.

[0101] 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 as 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 knowledge and this disclosure.

[0102] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0103] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0104] 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.

[0105] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0106] The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0107] 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 can be incorporated into the 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.

[0108] 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.

[0109] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0110] 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, and intravenous administration.

[0111] 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.

[0112] 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, and the like for oral administration to a patient.

[0113] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0114] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0115] In all administration methods of the compounds of formula (II'), formula (II-1), formula (II-2) or the above-mentioned specific compounds or their stereoisomers or pharmaceutically acceptable salts described herein, the daily dosage is 0.01 mg / kg to 200 mg / kg body weight, preferably 0.05 mg / kg to 50 mg / kg body weight, more preferably 0.1 mg / kg to 30 mg / kg body weight, in the form of single or divided doses.

[0116] 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 the same with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0117] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations 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 synthetic steps or reaction schemes based on existing embodiments.

[0118] The present disclosure uses the following abbreviations: DCM: dichloromethane; DMF: N,N-dimethylformamide; TsOH·H2O: p-toluenesulfonic acid monohydrate; B(OMe)3: trimethyl borate; NMP: N-methylpyrrolidone; DME: ethylene glycol dimethyl ether; KOAc: potassium acetate; AcOH: acetic acid; tBuOH: tert-butyl alcohol; dppf: 1,1'-bis(diphenylphosphino)ferrocene; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride; Pd2(dba)3: tris(dibenzylideneacetone)dipalladium; Pd(dba)2: di(dibenzylideneacetone)palladium; rt: room temperature; min: minute; h: hour; Me: methyl; MeOH: methanol; Boc: tert-butyloxycarbonyl; BocNH2: tert-butyl carbamate; THF: tetrahydrofuran; TEA / Et3N: triethylamine; Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl; Xphos Pd G2: chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II); Pd(PPh3)4: tetrakis(triphenylphosphine)palladium; meCgPPh: 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane; 1,4-dioxane: 1,4-dioxane; Raney-Ni: Raney nickel; DPPA: diphenylphosphoryl azide; Et3SiH: triethylsilane; PhNTf2: N-phenylbis(trifluoromethanesulfonyl)imide; DPPF: 1,1'-bis(diphenylphosphino)ferrocene; ACN: acetonitrile; NBS: N-bromosuccinimide; AcCl: acetyl chloride; t BuONO: tert-butyl nitrite; cataCXium A Pd G3: [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate; TMSI: trimethylsilyl iodide; DIEA / DIPEA: N,N-diisopropylethylamine; TFA: trifluoroacetic acid; BF3·Et2O: boron trifluoride etherate; TMP: 2,2,6,6-tetramethylpiperidine; SFC: supercritical fluid chromatography; MeB(OH)2: methylboric acid; LDA: lithium diisopropylamide; DIBAL-H: diisobutylaluminum hydride; PMBN H2: 4-methoxybenzylamine; PMB: 4-methoxybenzyl; Sn2Me6: hexamethyldistannoyl; xylene: xylene; TfOH: trifluoromethanesulfonic acid; NMe2CH2BF3K: potassium (dimethylamino)methyl)trifluoroborate; reflux / ref: reflux; NaOMe: sodium methoxide; overnight: overnight reaction; EtOH: ethanol; ATP: adenosine triphosphate; CDK1: cyclin-dependent kinase 1; ADP: adenosine diphosphate; FBS: fetal bovine serum.

[0119] The invention is described in detail below by way of examples, but this is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific embodiments thereof, various modifications thereof will be readily apparent to those skilled in the art without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure were commercially available and used without further purification.

[0120] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios.

[0121] Unless otherwise stated, % refers to wt%.

[0122] Compounds are manually or Software naming, commercially available compounds use supplier catalog names.

[0123] 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-maximal inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.

[0124] The eluent mentioned below can be a mixed eluent formed by two or more solvents, and the ratio thereof is the volume ratio of each solvent.

[0125] Example 1: Preparation of Compound 1

[0126] Step 1: tert-Butyl (2-bromo-6-hydroxybenzyl)carbamate (1b)

[0127] Compound 1a (2 g, 10 mmol) and tert-butyl carbamate (3.5 g, 30 mmol) were dissolved in anhydrous dichloromethane (20 mL) and anhydrous acetonitrile (60 mL). Triethylsilane (3.5 g, 30 mmol) was added, and trifluoroacetic acid (3.4 g, 30 mmol) was slowly added dropwise in an ice bath. After completion of the addition, the mixture was allowed to react at room temperature for 48 hours. Water (20 mL) was added to the reaction system to quench the reaction. The mixture was then extracted three times with dichloromethane (50 mL x 3). The organic phases were combined and washed sequentially with saturated aqueous sodium carbonate (100 mL) and saturated aqueous sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting solid was purified by normal phase silica gel column chromatography (PE:EA = 10:1) to afford product 1b (2.2 g, 73% yield). m / z (ESI): 246.0 [Mt-Bu+H] + .

[0128] Step 2: tert-Butyl (2-hydroxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (1c)

[0129] Compound 1b (2.0 g, 6.6 mmol) and pinacol diboron (2.5 g, 10 mol) were dissolved in anhydrous 1,4-dioxane (20 mL). [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (0.48 g, 0.66 mmol) and potassium acetate (2.0 g, 20 mmol) were added sequentially. The atmosphere was purged with nitrogen, and the mixture was reacted at 90°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed three times with ethyl acetate (20 mL x 3). The organic phases were combined and washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting solid was purified by normal phase silica gel column chromatography (PE:EA = 10:1) to obtain product 1c (1.3 g, 56% yield). m / z (ESI): 348.3 [MH] - .

[0130] Step 3: 6-Chloro-5-iodo-N-(3-methoxy-2,6-dimethylphenyl)-2-methylpyrimidin-4-amine (1f)

[0131] Compound 1d (10 g, 35 mmol) and compound 1e (6.3 g, 42 mmol) were dissolved in anhydrous 1,4-dioxane (50 mL). Boron trifluoride etherate (49 g, 0.35 mol) was added and the mixture was reacted at 100°C for 72 hours. After cooling to room temperature, the reaction solution was poured into ice water (50 mL) and extracted three times with ethyl acetate (100 x 3 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by normal phase silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:2) to obtain compound 1f (5.9 g, 42% yield). m / z (ESI): 404.1 [M+H] + .

[0132] Step 4: 6-amino-4-chloro-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (1 g)

[0133] Methyl cyanoacetate (4.8 g, 48 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (30 mL). Cesium carbonate (23 g, 72 mmol) was added portionwise. The mixture was stirred at room temperature for 30 minutes, followed by the addition of compound 1f (4.8 g, 12 mmol) and [1,1'-bis(diphenylphosphino)ferrocene] (0.44 g, 0.60 mmol). The atmosphere was purged with nitrogen, and the mixture was reacted at 85°C for 2 hours under nitrogen. The reaction mixture was cooled to room temperature, filtered to remove insoluble matter, and the filter cake was washed three times with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by normal phase silica gel column chromatography (petroleum ether:ethyl acetate = 10:1 to 1:2) to obtain product 1g (3.0 g, 67% yield). m / z (ESI): 375.2 [M+H] + .

[0134] Compound 1g (3.0 g, 8.0 mmol) was subjected to preparative SFC chiral separation (column: DAICEL CHIRLPAK IC-3 (250*25 mm, 10 μm); conditions: mobile phase A:CO2, B:IPA; mobile phase A:B = 30:70, wavelength: 214 nm; flow rate: 2.5 mL / min, column temperature: 25°C, back pressure: 100 bar) to afford compounds 1g-1 (1.35 g, 2.46 min) and 1g-2 (1.29 g, 2.76 min).

[0135] 1g-1:m / z(ESI):375.2[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.28(d,J=8.0Hz,1H),7.20(s,2H),7.13(d,J=8.0Hz,1H),3.86(s,3H),3.79(s,3H),2.40(s,3H),1.80(s,3H),1.71(s,3H).

[0136] 1g-2:m / z(ESI):375.2[M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ7.28(d,J=8.0Hz,1H),7.20(s,2H),7.13(d,J=8.0Hz,1H),3.86(s,3H),3.79(s,3H),2.40(s,3H),1.80(s,3H),1.71(s,3H).

[0137] Step 5: Synthesis of Intermediate 1h

[0138] Compound 1c (0.52 g, 1.5 mmol), compound 1g-2 (0.37 g, 1.0 mmol), tris(dibenzylideneacetone)dipalladium (92 mg, 0.10 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (0.12 g, 0.40 mmol), and potassium carbonate (0.41 g, 3.0 mmol) were dissolved in 1,4-dioxane / water (4 mL / 0.8 mL). The atmosphere was replaced with nitrogen three times. The reaction mixture was then moved to 85°C for 2 hours. After cooling to room temperature, the insoluble material was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to afford compound 1h (0.42 g, 75% yield). m / z(ESI):562.2[M+H] + .

[0139] Step 6: Synthesis of Intermediate 1i

[0140] At room temperature, compound 1h (0.42 g, 0.75 mmol) was dissolved in anhydrous methanol (10 mL), and acetyl chloride (10 mL) was added dropwise. The reaction was continued under these conditions for 2 hours. The reaction solution was concentrated, and the resulting crude product 1i was used directly in the next reaction without purification. m / z (ESI): 462.2 [M+H] + .

[0141] Step 7: Synthesis of Intermediate 1j

[0142] Compound 1i (0.35 g, 0.75 mmol) was dissolved in methanol / tetrahydrofuran / water (10 ml / 10 mL / 10 mL), and lithium hydroxide monohydrate (0.32 g, 7.6 mmol) was added. The reaction mixture was heated to 50°C and reacted for 1 hour. The reaction solution was concentrated, and the resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 1j (0.29 g, 91% yield). m / z (ESI): 430.2 [M+H] + .

[0143] Step 8: Synthesis of Intermediate 1k

[0144] Compound 1j (0.29 g, 0.67 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). N-phenylbis(trifluoromethanesulfonyl)imide (0.26 g, 0.74 mmol) and cesium carbonate (0.24 g, 0.74 mmol) were added sequentially. The mixture was allowed to react at room temperature for 1 hour. The reaction solution was directly purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 1k (0.33 g, 88% yield). m / z (ESI): 562.1 [M+H] + .

[0145] Step 9: Synthesis of Intermediate 11

[0146] Compound 1k (10 mg, 18 μmol), methylboronic acid (5.3 mg, 89 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.3 mg, 1.8 μmol), and potassium carbonate (7.4 mg, 54 μmol) were dissolved in 1,4-dioxane / water (2 mL / 0.2 mL). The atmosphere was replaced with nitrogen three times. The reaction mixture was then moved to 80°C for 30 minutes. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 1l (6.8 mg, 89% yield). m / z (ESI): 428.2 [M+H] + .

[0147] Step 10: Synthesis of Compound 1

[0148] Compound 11 (6.8 mg, 16 μmol) was dissolved in anhydrous dichloromethane (5 mL), and a dichloromethane solution of boron tribromide (1 mol / L, 2 mL) was added. The mixture was allowed to react at room temperature for 30 minutes. The reaction solution was quenched with methanol (5 mL), and the pH was adjusted to 14 with aqueous ammonia. The reaction solution was then concentrated, and the resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 1 (4.8 mg, 72% yield).

[0149] m / z(ESI):414.4[M+H] + .

[0150] 1H NMR (400MHz, DMSO-d6) δ9.67-9.63(m,1H),8.25-8.11(m,1H),7.54(d,J=8.0Hz,1H),7.45-7.35(m,2H),7.14-7.09(m,1H),6 .98(d,J=8.4Hz,1H),5.01-4.93(m,1H),4.28-4.20(m,1H),2.54(s,3H),2.50(s,3H),1.92-1.83(m,3H),1.71-1.62(m,3H).

[0151] Example 2: Preparation of (E)-2-amino-1-(3-hydroxy-2,6-dimethylphenyl)-11-methyl-6-(prop-1-en-1-yl)-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 2)

[0152] Step 1: Synthesis of intermediate 2b

[0153] Compound 1g-2 (0.75 g, 2.0 mmol), compound 2a (0.53 g, 3.0 mmol), tris(dibenzylideneacetone)dipalladium (0.18 g, 0.20 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (0.24 g, 0.80 mmol), and potassium carbonate (0.83 g, 6.0 mmol) were dissolved in 1,4-dioxane / water (4 mL / 0.8 mL) at room temperature. The atmosphere was replaced with nitrogen three times. The reaction mixture was then moved to 80°C for 2 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration. The filter cake was washed with ethyl acetate (50 mL). The organic phases were combined and the filtrate was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 2b (0.79 g, yield 84%). m / z (ESI): 473.2 [M+H] + .

[0154] Step 2: Synthesis of intermediate 2c

[0155] At room temperature, compound 2b (0.79 g, 1.7 mmol) was dissolved in anhydrous methanol (10 mL), and Raney nickel (50 mg) was added. The air was purged with hydrogen, and the reaction was continued at 40 psi for 4 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated. The crude product 2c was used directly in the next reaction without purification. m / z (ESI): 477.2 [M+H] + .

[0156] Step 3: Synthesis of intermediate 2d

[0157] Compound 2c (0.79 g, 1.7 mmol) was dissolved in methanol / tetrahydrofuran / water (10 ml / 10 mL / 10 mL), and lithium hydroxide monohydrate (0.71 g, 17 mmol) was added. The mixture was heated to 50°C and reacted for 2 hours. The reaction solution was concentrated, and the resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 2d (0.64 g, yield 84%). m / z (ESI): 445.2 [M+H] + .

[0158] Step 4: Synthesis of intermediate 2e

[0159] Compound 2d (80 mg, 0.18 mmol) was dissolved in anhydrous acetonitrile (2 mL), and trimethylsilyl iodide (63 mg, 0.31 mmol) was slowly added. The reaction was allowed to react at 50°C for 1 hour. After cooling to room temperature, saturated aqueous sodium thiosulfate (2 mL) was slowly added to the reaction mixture to quench the reaction. The mixture was then extracted three times with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated aqueous sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 2e (75 mg, 97% yield). m / z (ESI): 431.2 [M+H] + .

[0160] Step 5: Synthesis of intermediate 2f

[0161] Compound 2e (75 mg, 0.17 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL). N-phenylbis(trifluoromethanesulfonyl)imide (68 mg, 0.19 mmol) and cesium carbonate (62 mg, 0.19 mmol) were added sequentially. The mixture was allowed to react at room temperature for 1 hour. The reaction solution was directly purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 2f (81 mg, 83% yield). m / z (ESI): 563.1 [M+H] + .

[0162] Step 6: Synthesis of Intermediate 2g

[0163] Compound 2f (8.0 mg, 14 μmol), trans-1-propen-1-ylboronic acid (6.1 mg, 71 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.0 mg, 1.4 μmol), and potassium carbonate (5.9 mg, 43 μmol) were dissolved in 1,4-dioxane / water (2 mL / 0.2 mL). The atmosphere was replaced with nitrogen three times. The reaction mixture was then moved to 80°C for 1 hour. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 2g (5.4 mg, 84% yield). m / z (ESI): 455.2 [M+H] + .

[0164] Step 7: Synthesis of Compound 2

[0165] Compound 2g (5.4 mg, 12 μmol) was dissolved in anhydrous dichloromethane (5 mL), and a dichloromethane solution of boron tribromide (1 mol / L, 2 mL) was slowly added. The mixture was allowed to react at room temperature for 30 minutes. The reaction solution was quenched with methanol (5 mL), and the pH was adjusted to 14 with aqueous ammonia. The reaction solution was then concentrated, and the resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 2 (4.2 mg, 80% yield).

[0166] m / z(ESI):441.2[M+H] + .

[0167] 1 H NMR (400MHz, DMSO-d6) δ9.61(d,J=10.0Hz,1H),8.57(d,J=4.2Hz,1H),8.11-8.07(m,1H),7.51(t,J=4.2Hz,1H),7.21-7.08(m,4H), 7.00-6.95(m,2H),5.08-4.99(m,1H),4.37-4.31(m,1H),2.50(s,3H),1.99(d,J=6.8Hz,3H),1.90-1.81(m,3H),1.69-1.60(m,3H).

[0168] Example 3: Preparation of Compound 3

[0169] Step 1: Synthesis of intermediate 3b

[0170] A solution of lithium diisopropylamide in tetrahydrofuran (1.7 mL, 2M, 3.5 mmol) and 2,2,6,6-tetramethylpiperidine (0.72 g, 5.1 mmol) were dissolved in anhydrous tetrahydrofuran (10 mL). The air was purged with nitrogen. Compound 3a (0.29 g, 1.7 mmol) in tetrahydrofuran (10 mL) was then slowly added at -78°C. After 30 minutes, trimethyl borate (0.52 g, 5.2 mmol) was added and the temperature was slowly raised to 0°C for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride (20 mL) under an ice bath. The mixture was then extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The crude product 3b was used directly in the next step without purification. m / z (ESI): 217.0 [M+H] + .

[0171] Step 2: Synthesis of intermediate 3c

[0172] At room temperature, compound 3b (0.35 g, 1.6 mmol), compound 1g-2 (0.20 g, 0.53 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (39 mg, 53 μmol), and cesium carbonate (0.52 g, 1.6 mmol) were dissolved in 1,4-dioxane / water (10 mL / 2 mL). The atmosphere was replaced with nitrogen, and the reaction mixture was moved to 100°C for 2 hours. After cooling to room temperature, the insoluble material was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 3c (0.20 g, 74% yield). m / z (ESI): 511.2 [M+H] + .

[0173] Step 3: Synthesis of intermediate 3d

[0174] Compound 3c (0.14 g, 0.27 mmol) was dissolved in anhydrous methanol (5 mL), and Raney nickel (80 mg, 1.4 mmol) was added. The air was then purged with hydrogen and the reaction was allowed to proceed at room temperature for 4 hours. The insoluble matter was removed by filtration, and the crude product 3d was used directly in the next step without purification. m / z (ESI): 515.2 [M+H] + .

[0175] Step 4: Synthesis of intermediate 3e

[0176] Compound 3d (80 mg, 0.16 mmol) was dissolved in methanol / tetrahydrofuran / water (2 ml / 2 mL / 2 mL), and lithium hydroxide monohydrate (65 mg, 1.5 mmol) was added. The reaction mixture was then placed in a 50°C oil bath for 1 hour. The reaction solution was concentrated, and the resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 3e (60 mg, yield 79%). m / z (ESI): 483.2 [M+H] + .

[0177] Step 5: Synthesis of compound 3

[0178] Compound 3e (60 mg, 0.12 mmol) was dissolved in anhydrous dichloromethane (10 mL). Boron tribromide in dichloromethane (1 mol / L, 1 mL) was added under ice-cooling conditions, and the mixture was allowed to warm to room temperature for 30 minutes. Methanol (5 mL) was added to the reaction system to quench the reaction. The reaction solution was concentrated, and the resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 3 (35 mg, 61% yield).

[0179] m / z(ESI):469.2[M+H] + .

[0180] 1 H NMR (400MHz, DMSO-d6) δ9.30(s,1H),8.79(d,J=5.2Hz,1H),8.00(d,J=5.2Hz,1H),7.68(t,J=7.2Hz,1H),7.31(s,2H),7.14- 7.09(m,1H),6.98(d,J=8.0Hz,1H),5.31-5.26(m,1H),4.44-4.38(m,1H),2.50(s,3H),1.91-1.82(m,3H),1.71-1.62(m,3H).

[0181] Example 4: Preparation of Compound 4

[0182] Step 1: 5-bromothiazole-4-carboxaldehyde (4b)

[0183] Compound 4a (0.52 g, 2.2 mmol) was placed in a 250 mL three-necked flask. The air was purged with nitrogen, and anhydrous tetrahydrofuran (30 mL) was added. Then, a solution of diisobutylaluminum hydride in tetrahydrofuran (4.9 mL, 1 M, 4.9 mmol) was slowly added at -78°C. After completion of the addition, the mixture was allowed to react at room temperature for 30 minutes. Saturated aqueous potassium sodium tartrate (20 mL) was slowly added to quench the reaction in an ice bath. The mixture was then extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting crude product 4b was used directly in the next step without further purification. m / z (ESI): 191.9 [M+H] + .

[0184] Step 2: 1-(5-bromothiazol-4-yl)-N-(4-methoxybenzyl)methanamine (4c)

[0185] Compound 4b (0.42 g, 2.2 mmol) and 4-methoxybenzylamine (0.60 g, 4.4 mmol) were dissolved in anhydrous methanol (10 mL) and reacted at room temperature for 30 minutes. Sodium borohydride (0.25 g, 6.6 mmol) was then added at 0°C and the mixture was allowed to react at room temperature for 1 hour. The reaction was quenched with water under ice-cooling and stirred for 30 minutes. The insoluble material was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 4c (0.53 g, 76% yield). m / z (ESI): 313.2 [M+H] + .

[0186] Step 3: N-(4-methoxybenzyl)-1-(5-(trimethylstannyl)thiazol-4-yl)methanamine (4d)

[0187] Compound 4c (50 mg, 0.16 mmol) was dissolved in anhydrous xylene (5 mL), and tetrakis(triphenylphosphine)palladium (18 mg, 16 μmol) and hexamethyldistanane (79 mg, 0.24 mmol) were added. The mixture was then reacted at 150°C under a nitrogen atmosphere for 1 hour. After the reaction mixture was cooled to room temperature, the insoluble material was filtered out, and the filtrate was concentrated. The crude product 4d was used directly in the next step without purification. m / z (ESI): 399.1 [M+H] + .

[0188] Step 4: Synthesis of intermediate 4e

[0189] At room temperature, compound 4d (64 mg, 0.16 mmol), 1g-2 (30 mg, 80 μmol), and tetrakis(triphenylphosphine)palladium (9 mg, 8 μmol) were dissolved in anhydrous N,N-dimethylformamide (3 mL). The air was replaced with nitrogen three times, and the temperature was raised to 135°C for 1 hour. After the reaction was cooled to room temperature, the insoluble material was removed by filtration. The filter cake was washed with ethyl acetate (20 mL), and the filtrate was concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 4e (15 mg, 32% yield). m / z (ESI): 573.2 [M+H] + .

[0190] Step 5: Synthesis of intermediate 4f

[0191] Compound 4e (5.0 mg, 8.7 μmol) was dissolved in trifluoroacetic acid (5 mL) and trifluoromethanesulfonic acid (1 mL) at room temperature and reacted at 80°C for 3 hours. The reaction solution was diluted with dichloromethane (20 mL) and concentrated. The resulting product 4f was used directly in the next step without purification. m / z (ESI): 453.2 [M+H] + .

[0192] Step 6: Synthesis of Intermediate 4g

[0193] Compound 4f (4.0 mg, 8.8 μmol) was dissolved in methanol / tetrahydrofuran / water (2 ml / 2 mL / 2 mL), and lithium hydroxide monohydrate (3.7 mg, 88 μmol) was added. The temperature was then raised to 50°C and the reaction mixture was allowed to react for 1 hour. The reaction solution was concentrated, and the resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 4g (2.8 mg, yield 76%). m / z (ESI): 421.2 [M+H] + .

[0194] Step 7: Synthesis of compound 4

[0195] Compound 4g (2.8 mg, 6.7 μmol) was dissolved in anhydrous dichloromethane (3 mL). Boron tribromide in dichloromethane (1 mol / L, 1 mL) was added dropwise in an ice bath. The mixture was then allowed to warm to room temperature for 30 minutes. The reaction was quenched with methanol (5 mL), and the pH was adjusted to 14 with aqueous ammonia. The residue was concentrated and purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 4 (2.1 mg, 78% yield).

[0196] m / z(ESI):407.3[M+H] + .

[0197] 1 H NMR (400MHz, DMSO-d6) δ9.64(s,1H),9.13(s,1H),8.08(t,J=6.8Hz,1H),7.12(s,1H),7.10( d,J=8.9Hz,2H),6.95(d,J=8.2Hz,1H),4.90(s,1H),4.29(s,1H),2.43(s,3H),1.75(m,6H).

[0198] Example 5: Preparation of Compound 5

[0199] Step 1: Synthesis of intermediate 5a

[0200] Compound 1k (50 mg, 89 μmol), potassium ((dimethylamino)methyl)trifluoroborate (73 mg, 0.45 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (7.0 mg, 8.9 μmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (4.2 mg, 8.9 μmol), and potassium carbonate (37 mg, 0.27 mmol) were dissolved in 1,4-dioxane / water (2 mL / 0.2 mL). The air was replaced with nitrogen three times. The reaction was then incubated at 80°C under a nitrogen atmosphere for 2 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 5a (19 mg, yield 45%). m / z (ESI): 471.2 [M+H] + .

[0201] Step 2: Synthesis of compound 5

[0202] Compound 5a (19 mg, 40 μmol) was dissolved in anhydrous dichloromethane (10 mL). Boron tribromide (1 mol / L, 2 mL) in dichloromethane was added dropwise under an ice bath, and the mixture was allowed to warm to room temperature for 30 minutes. The reaction was quenched with methanol (5 mL), and the pH was adjusted to 14 with aqueous ammonia. The residue was concentrated, and purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 5 (15 mg, 82% yield).

[0203] m / z(ESI):457.2[M+H] + .

[0204] 1H NMR (400MHz, DMSO-d6) δ9.64-9.61(m,1H),7.68-7.60(m,2H),7.44-7.30(m,2H),7.13-7.10(m,1H),6.97(s,2H),6.96(d,J=8.0Hz,1H),4. 93-4.83(m,1H),4.62-4.54(m,1H),3.79-3.69(m,1H),3.48-4.42(m, 1H),2.46(s,3H),2.21(s,6H),1.92-1.83(m,3H),1.68-1.60(m,3H).

[0205] Example 6: Preparation of Compound 6

[0206] Step 1: tert-Butyl (2-bromo-4-hydroxybenzyl)carbamate (6b)

[0207] 2-Bromo-4-hydroxybenzaldehyde 6a (1.0 g, 5.0 mmol) and tert-butyl carbamate (1.8 g, 15 mmol) were dissolved in anhydrous dichloromethane (10 mL) and anhydrous acetonitrile (30 mL). Triethylsilane (1.7 g, 15 mmol) was added dropwise, followed by trifluoroacetic acid (1.7 g, 15 mmol) in an ice bath. After completion of the addition, the mixture was allowed to react at room temperature for 24 hours. Ice water (20 mL) was added to the reaction system to quench the reaction. The mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined and washed sequentially with saturated aqueous sodium carbonate (100 mL) and saturated aqueous sodium chloride (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting residue was purified by normal phase silica gel column chromatography (PE:EA = 10:1) to afford compound 6b (1.1 g, 73% yield). m / z (ESI): 246.0 [Mt-Bu+H] + .

[0208] Step 2: tert-Butyl (2-hydroxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (6c)

[0209] Compound 6b (0.30 g, 1.0 mmol) and pinacol diboron (0.30 g, 1.2 mol) were dissolved in anhydrous 1,4-dioxane (5 mL). [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (36 mg, 50 μmol) and potassium acetate (0.19 g, 2.0 mmol) were added sequentially. The atmosphere was purged with nitrogen, and the mixture was reacted at 90°C under nitrogen for 2 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with ethyl acetate (30 mL). The organic phases were combined and washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting solid was purified by normal phase silica gel column chromatography (PE:EA = 10:1-3:1) to obtain compound 6c (0.25 g, 71% yield). m / z (ESI): 350.3 [M+H] + .

[0210] Step 3: Synthesis of intermediate 6d

[0211] Compound 1g-2 (40 mg, 0.11 mmol), compound 6c (56 mg, 0.16 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.8 mg, 11 μmol), and potassium carbonate (44 mg, 0.32 mmol) were dissolved in 1,4-dioxane / water (5 mL / 1 mL). The atmosphere was replaced with nitrogen, and the temperature was raised to 85°C for 2 hours. The reaction mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 6d (48 mg, 78% yield). m / z (ESI): 562.2 [M+H] + .

[0212] Step 4: Synthesis of intermediate 6e

[0213] Compound 6d (48 mg, 85 μmol) was dissolved in anhydrous methanol (10 mL). Acetyl chloride (2 mL) was slowly added under an ice bath, and the mixture was allowed to warm to room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated. The resulting crude product, compound 6e, was used directly in the next step without purification. m / z (ESI): 462.2 [M+H] + .

[0214] Step 5: Synthesis of intermediate 6f

[0215] Compound 6e (39 mg, 85 μmol) was dissolved in methanol / tetrahydrofuran / water (10 ml / 10 mL / 10 mL), and lithium hydroxide monohydrate (36 mg, 0.85 mmol) was added. The mixture was allowed to react at room temperature for 4 hours. The reaction solution was concentrated, and the resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 6f (35 mg, yield 96%). m / z (ESI): 430.2 [M+H] + .

[0216] Step 6: Synthesis of Intermediate 6g

[0217] Compound 6f (35 mg, 82 μmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). N-phenylbis(trifluoromethanesulfonyl)imide (35 mg, 98 μmol) and cesium carbonate (32 mg, 98 μmol) were added sequentially and allowed to react at room temperature for 10 minutes. The reaction solution was directly purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 6g (42 mg, 92% yield). m / z (ESI): 562.1 [M+H] + .

[0218] Step 7: Synthesis of Intermediate 6h

[0219] Compound 6g (42 mg, 75 μmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). Zinc (2.5 mg, 37 μmol), zinc cyanide (8.8 mg, 75 μmol), tris(dibenzylideneacetone)dipalladium (6.9 mg, 7.5 μmol), and 1,1'-bis(diphenylphosphino)ferrocene (4.2 mg, 7.5 μmol) were added sequentially. The atmosphere was replaced with nitrogen three times, and the reaction mixture was moved to 90°C for 30 minutes. After cooling to room temperature, the reaction mixture was directly purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 6h (28 mg, 85% yield). m / z (ESI): 439.3 [M+H] +

[0220] Step 8: Synthesis of Compound 6

[0221] Compound 6h (25 mg, 57 μmol) was dissolved in anhydrous dichloromethane (5 mL). Boron tribromide (1 mol / L, 2 mL) in dichloromethane was added dropwise under an ice bath, and the mixture was allowed to warm to room temperature for 30 minutes. The reaction was quenched with methanol (5 mL), and the pH was adjusted to 14 with aqueous ammonia. The residue was concentrated, and purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 6 (21 mg, 86% yield).

[0222] m / z(ESI):425.3[M+H] + .

[0223] 1 H NMR (400MHz, DMSO-d6) δ9.64-9.62(m,1H),8.14(t,J=1.2Hz,1H),7.96-7.93(m,2H),7.51(d,J=8.0Hz,1H),7.13-7.08(m,1H) ,6.97(s,2H),6.96(d,J=8.4Hz,1H),5.09-5.02(m,1H),4.17-4.11(m,1H),2.54(s,3H),1.90-1.81(m,3H),1.70-1.60(m,3H).

[0224] Example 7: Preparation of Compound 7

[0225] Step 1: Synthesis of intermediate 7a

[0226] Compound 6g (30 mg, 53 μmol), methylboronic acid (13 mg, 0.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (3.9 mg, 5.3 μmol), and potassium carbonate (14 mg, 0.1 mmol) were dissolved in 1,4-dioxane / water (3 mL / 0.3 mL). The atmosphere was replaced with nitrogen three times. The reaction mixture was then moved to 80°C for 30 minutes. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 7a (22 mg, 97% yield). m / z (ESI): 428.2 [M+H] + .

[0227] Step 2: Synthesis of compound 7

[0228] Compound 7a (22 mg, 51 μmol) was dissolved in anhydrous dichloromethane (5 mL), and a dichloromethane solution of boron tribromide (1 mol / L, 2 mL) was added. The reaction was allowed to react at room temperature for 30 minutes. The reaction was quenched with methanol (5 mL), and the pH was adjusted to 14 with aqueous ammonia. The reaction solution was concentrated, and the resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 7 (16 mg, 76% yield).

[0229] m / z(ESI):414.4[M+H] + .

[0230] 1 H NMR (400MHz, DMSO-d6) δ9.60-9.58(m,1H),7.84(t,J=7.2Hz,1H),7.56(s,1H),7.27(d,J=8.0Hz,1H),7.19(d,J=7.7Hz,1H),7.12-7.07(m,1H ),6.95(d,J=8.4Hz,1H),6.92(s,2H),4.92-4.86(m,1H),4.00-3.94(m ,1H),2.51(s,3H),2.37(s,3H),1.90-1.81(m,3H),1.68-1.59(m,3H).

[0231] Example 8: Preparation of Compound 8

[0232] Compound 8 was prepared by replacing compound 6a with compound 8a and adopting a method similar to Example 6.

[0233] m / z(ESI):425.3[M+H] + .

[0234] 1 H NMR(400MHz, DMSO-d6)δ9.60(d,J=8.8Hz,1H),7.95-7.89(m,2H),7.83(t,J=7.2Hz,1H),7.72(d,J=1.6Hz,1H),7.12-7.07(m,1H ),7.04(s,2H),6.95(d,J=8.4Hz,1H),5.07-5.00(m,1H),4.16-4.10(m,1H),2.51(s,3H),1.90-1.81(m,3H),1.69-1.60(m,3H).

[0235] Example 9: Preparation of Compound 9

[0236] Step 1: 4-Bromo-3-methylisothiazol-5-amine (9b)

[0237] 5-Amino-3-methylisothiazole hydrochloride 9a (1.0 g, 6.6 mmol) was dissolved in anhydrous acetonitrile (5 mL). N,N-diisopropylethylamine (1.7 g, 13 mmol) and N-bromosuccinimide (1.3 g, 7.3 mmol) were added sequentially under ice-cooling conditions. The mixture was then warmed to room temperature for 1 hour and concentrated under reduced pressure. The resulting residue was purified by normal phase chromatography (petroleum ether:ethyl acetate = 100:1-2:1) to obtain compound 9b (1.0 g, yield 78%). m / z (ESI): 193.1 [M+H]+ .

[0238] Step 2: tert-Butyl ((5-amino-3-methylisothiazol-4-yl)methyl)carbamate (9c)

[0239] Compound 9b (0.30 g, 1.6 mmol) and potassium [(tert-butoxycarbonylamino)methyl]trifluoroborate (1.1 g, 4.7 mmol) were dissolved in a mixture of 1,4-dioxane (5 mL) and water (0.5 mL). [n-Butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (0.11 g, 0.16 mmol) and cesium carbonate (1.5 g, 4.7 mmol) were added. The mixture was reacted at 100°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was purified by reverse phase chromatography (C18, 0.05% ammonia water:acetonitrile = 20:1 to 1:20) to obtain compound 9c (0.21 g, 55% yield). m / z (ESI): 244.2 [M+H] + .

[0240] Step 3: tert-Butyl ((5-bromo-3-methylisothiazol-4-yl)methyl)carbamate (9d)

[0241] Dissolve tert-butyl nitrite (0.16 g, 1.6 mmol) and copper bromide (0.17 g, 0.78 mmol) in anhydrous acetonitrile (3 mL). Stir for 30 minutes, then slowly add a solution of 9c (0.19 g, 0.78 mmol) in acetonitrile (2 mL). Warm the mixture to room temperature and continue the reaction for 2 hours. Concentrate under reduced pressure, and the resulting residue is purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 9d (90 mg, 38% yield). m / z (ESI): 307.2 [M+H] + .

[0242] Step 4: tert-Butyl ((3-methyl-5-(trimethyltinyl)isothiazol-4-yl)methyl)carbamate (9e)

[0243] Compound 9d (90 mg, 0.29 mmol) and hexamethyltin (0.14 g, 0.44 mmol) were dissolved in xylene (5 mL). Tetrakis(triphenylphosphine)palladium (34 mg, 29 μmol) was added. The mixture was reacted at 145°C under nitrogen for 30 minutes. The crude product 9e was concentrated under reduced pressure and used directly in the next step without purification. m / z (ESI): 393.1 [M+H] + .

[0244] Then, compound 9 was prepared by replacing compound 4d with compound 9e in a similar manner to Example 4.

[0245] m / z(ESI):421.2[M+H] + .

[0246] 1 H NMR(400MHz, DMSO-d6)δ9.63(s,1H),8.10(t,J=6.9Hz,1H),7.18(s,2H),7.10(d,J=8.3Hz,1H),6.96 (d,J=8.3Hz,1H),4.94-4.76(m,1H),4.25-4.08(m,1H),2.49(s,3H),2.44(s,3H),1.90-1.61(m,6H).

[0247] Example 10: Preparation of Compound 10

[0248] Step 1: tert-Butyl (3-methylisothiazol-4-yl)carbamate (10b)

[0249] Compound 10a (0.50 g, 3.5 mmol) was dissolved in tert-butanol (10 mL). Triethylamine (0.5 mL, 3.5 mmol) and diphenylphosphoryl azide (0.96 g, 3.5 mmol) were added sequentially, and the mixture was allowed to react under reflux for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by normal phase silica gel column chromatography (petroleum ether:ethyl acetate = 100:1-1:1) to obtain compound 10b (0.69 g, 92% yield). m / z (ESI): 215.1 [M+H] + .

[0250] Step 2: tert-Butyl (5-bromo-3-methylisothiazol-4-yl)carbamate (10c)

[0251] Compound 10b (0.20 g, 0.93 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL), followed by the addition of N-bromosuccinimide (0.25 g, 1.4 mmol) and the reaction was allowed to react at room temperature for 16 hours. Saturated aqueous sodium thiosulfate was added to the reaction system to quench the reaction, which was then concentrated under reduced pressure. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 10c (0.22 g, 80% yield). m / z (ESI): 293.2 [M+H] + .

[0252] Step 3: tert-Butyl (3-methyl-5-(trimethyltinyl)isothiazol-4-yl)carbamate (10d)

[0253] Compound 10c (0.20 g, 0.68 mmol), hexamethyltin (0.34 g, 1.0 mmol), and tetrakis(triphenylphosphine)palladium (79 mg, 68 μmol) were dissolved in xylene (5 mL). The mixture was reacted at 145°C under nitrogen for 30 minutes. The crude product 10d was concentrated under reduced pressure and used directly in the next step without purification. m / z (ESI): 379.1 [M+H] + .

[0254] Compound 10 was prepared by replacing compound 4d with compound 10d in a similar manner to Example 4.

[0255] m / z(ESI):407.0[M+H] + .

[0256] 1 H NMR (400MHz, DMSO-d6) δ9.63 (s, 1H), 8.44 (s, 1H), 7.09 (d, J = 8.3Hz, 1H), 7.02 (s ,2H),6.95(d,J=8.3Hz,1H),2.41(s,3H),2.37(s,3H),1.80(s,3H),1.71(s,3H).

[0257] Example 11: Preparation of 2-amino-11-(difluoromethyl)-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 11)

[0258] Step 1: 6-Chloro-2-(difluoromethyl)-5-iodo-N-(3-methoxy-2,6-dimethylphenyl)pyrimidin-4-amine (11b)

[0259] Compound 11a (0.62 g, 1.9 mmol) and 3-methoxy-2,6-dimethylaniline (0.58 g, 3.8 mmol) were dissolved in N-methylpyrrolidone (5 mL). p-Toluenesulfonic acid monohydrate (38 mg, 0.2 mmol) was added and the reaction temperature was raised to 110°C for 3 hours. After cooling to room temperature, the reaction solution was directly purified by reverse phase chromatography (C18, 0.05% ammonia water:acetonitrile = 20:1 to 1:20) to obtain compound 11b (0.66 g, 78% yield). m / z (ESI): 440.6 [M+H] + .

[0260] Step 2: 6-amino-4-chloro-2-(difluoromethyl)-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (11c)

[0261] Methyl cyanoacetate (0.27 g, 2.7 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (20 mL), and cesium carbonate (1.3 g, 4.1 mmol) was added. After reacting at room temperature for 30 minutes, compound 11b (0.30 g, 0.68 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (50 mg, 68 μmol) were added. The mixture was then reacted at 70°C under nitrogen for 1 hour. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 11c (0.16 g, 57% yield). m / z (ESI): 411.8 [M+H] + .

[0262] Step 3: 6-amino-4-(3-cyano-2-methylpyridin-4-yl)-2-(difluoromethyl)-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (11e)

[0263] Compound 11c (40 mg, 97 μmol), compound 11d (47 mg, 0.29 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (14 mg, 19 μmol), and cesium carbonate (95 mg, 0.29 mmol) were dissolved in 1,4-dioxane / water (4 mL / 0.5 mL) and reacted at 100°C under nitrogen for 2 hours. The reaction mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia water:acetonitrile = 20:1 to 1:20) to obtain compound 11e (35 mg, 72% yield). m / z (ESI): 493.5 [M+H] + .

[0264] Step 4: 6-amino-4-(3-(aminomethyl)-2-methylpyridin-4-yl)-2-(difluoromethyl)-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (11f)

[0265] Compound 11e (20 mg, 40 μmol) was dissolved in glacial acetic acid (5 mL) and Raney nickel (0.20 g) was added. The reaction was then allowed to react at room temperature for 30 minutes under a hydrogen atmosphere. The insoluble matter was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 11f (11 mg, 54% yield). m / z (ESI): 497.5 [M+H] + .

[0266] Step 5: 2-amino-11-(difluoromethyl)-1-(3-methoxy-2,6-dimethylphenyl)-6-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (11 g)

[0267] Compound 11f (11 mg, 22 μmol) was dissolved in tetrahydrofuran / methanol / water (3 mL / 3 mL / 3 mL), and lithium hydroxide monohydrate (9.2 mg, 0.22 mmol) was added. The mixture was allowed to react at room temperature for 8 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 11g (10 mg, 97% yield). m / z (ESI): 465.5 [M+H] + .

[0268] Step 6: 2-amino-11-(difluoromethyl)-1-(3-hydroxy-2,6-dimethylphenyl)-6-methyl-4,5-dihydro-1,4,7,10,12-pentaazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]inden-3(1H)-one (Compound 11)

[0269] Compound 11g (10 mg, 21 μmol) was dissolved in anhydrous dichloromethane (5 mL). Boron tribromide (1 mol / L, 0.5 mL) in dichloromethane was slowly added under ice-cooling conditions, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was quenched with methanol (5 mL), the pH adjusted to 14 with aqueous ammonia, and then concentrated. The resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 11 (4 mg, 41% yield).

[0270] m / z(ESI):451.4[M+H] + .

[0271] 1H NMR(400MHz,DMSO-d6)δ9.70-9.68(m,1H),8.52(d,J=5.2Hz,1H),8.39-8.35(m,1H),7 .50(d,J=5.2Hz,1H),7.42(s,2H),7.15-7.10(m,1H),6.98(d,J=8.0Hz,1H),6.85(t,J H-F =54.4Hz,1H),5.13-5.07(m,1H),4.31-4.25(m,1H),2.69(s,3H),1.95-1.78(m,3H),1.74-1.56(m,3H).

[0272] Example 12: Preparation of 2-amino-11-(difluoromethyl)-1-(3-hydroxy-2,6-dimethylphenyl)-3-carbonyl-1,3,4,5-tetrahydro-1,4,10,12-tetraazabenzo[4,5]cyclooctatetraeno[1,2,3-cd]indene-6-carbonitrile (Compound 12)

[0273] Step 1: 6-amino-4-(2-(((tert-butoxycarbonyl)amino)methyl)-3-hydroxyphenyl)-2-(difluoromethyl)-7-(3-methoxy-2,6-dimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (12a)

[0274] Compound 11c (80 mg, 0.19 mmol), compound 1c (0.14 g, 0.40 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 19 μmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (23 mg, 78 μmol), and cesium carbonate (0.19 g, 0.58 mmol) were dissolved in dioxane / water (4 mL / 0.5 mL). The atmosphere was replaced with nitrogen and the temperature was raised to 90°C for 2 hours. The reaction mixture was cooled to room temperature, filtered to remove insoluble matter, and the filtrate was concentrated. The resulting residue was purified by reverse phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 12a (42 mg, 30% yield). m / z (ESI): 598.3 [M+H] + .

[0275] Compound 12a was substituted for compound 6d, and a method similar to Example 6 was used to prepare compound 12.

[0276] m / z(ESI):461.3[M+H] + .

[0277] 1H NMR (400MHz, DMSO-d6) δ9.69-9.67(m,1H),8.35-8.31(m,1H),8.07(d,J=8.0Hz,1H),8.01(d,J=7 .2Hz,1H),7.71(t,J=8.0Hz,1H),7.39(s,2H),7.15-7.10(m,1H),6.98(d,J=8.0Hz,1H),6.85(t,J H-F =54.4Hz,1H),5.25-5.18(m,1H),4.41-4.35(m,1H),1.91-1.83(m,3H),1.70-1.61(m,3H).

[0278] Example 13: Preparation of Compound 13

[0279] Step 1: tert-Butyl (5-bromothiazol-4-yl)carbamate (13b)

[0280] Compound 13a (0.20 g, 0.96 mmol) was dissolved in tert-butanol (10 mL), and triethylamine (0.13 g, 1.3 mmol) and diphenylphosphoryl azide (0.36 g, 1.3 mmol) were added sequentially. The mixture was then reacted at 90°C for 6 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by normal phase silica gel column chromatography (petroleum ether:ethyl acetate = 100:1-1:1) to obtain compound 13b (0.20 g, yield 74%). m / z (ESI): 279.1 [M+H] + .

[0281] Compound 13b was used instead of compound 9d, and compound 13 was prepared by a method similar to Example 9.

[0282] m / z(ESI):393.1[M+H] + .

[0283] 1 H NMR (400MHz, DMSO-d6) δ8.97(s,1H),7.53(s,1H),7.09(d,J=8.3Hz,1H),6.95(d,J=8.3Hz,1H),6.88(s,2H),2.34(s,3H),1.80(s,3H),1.71(s,3H).

[0284] Example 14: Preparation of Compound 14

[0285] Step 1: Synthesis of intermediate 14a

[0286] Compound 1k (5.6 g, 10 mmol) was dissolved in anhydrous N,N-dimethylformamide (20 mL). Zinc (0.33 g, 5.0 mmol), zinc cyanide (1.2 g, 10 μmol), tris(dibenzylideneacetone)dipalladium (0.46 g, 0.5 mmol), and 1,1'-bis(diphenylphosphino)ferrocene (0.55 g, 1.0 mmol) were added sequentially. The atmosphere was replaced with nitrogen three times, and the reaction mixture was moved to 90°C for 1 hour. After cooling to room temperature, the reaction mixture was directly purified by reverse-phase chromatography (C18, 0.05% ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 14a (3.9 g, 89% yield). m / z (ESI): 439.3 [M+H] +

[0287] Step 2: Synthesis of compound 14

[0288] Compound 14a (3.9 g, 8.9 mmol) was dissolved in anhydrous dichloromethane (500 mL), and a dichloromethane solution of boron tribromide (1 mol / L, 50 mL) was added. The mixture was allowed to react at room temperature for 30 minutes. The reaction solution was quenched with methanol (20 mL), and the pH was adjusted to 14 with aqueous ammonia. The reaction solution was then concentrated, and the resulting residue was purified by reverse-phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to afford compound 14 (3.2 g, 85% yield).

[0289] m / z(ESI):425.3[M+H] + .

[0290] 1 H NMR (400MHz, DMSO-d6) δ9.62(d,J=9.2Hz,1H),8.12(t,J=6.8Hz,1H)8.07(d,J=8.0Hz,1H),7.97(d,J=8.0Hz,1H),7.66(t,J=8. 0Hz,1H),7.13-7.07(m,3H),6.96(d,J=8.0Hz,1H),5.11-5.06(m,1H),4.39-4.33(m,1H),1.90-1.81(m,3H),1.70-1.61(m,3H).

[0291] Example 15: Preparation of Compound 15

[0292] Compound 14 (85 mg, 0.20 mmol) was dissolved in anhydrous N,N-dimethylformamide (10 mL), and then 15b (40 mg, 0.22 mmol) and cesium carbonate (98 mg, 0.30 mmol) were added sequentially. The reaction was carried out at room temperature for 3 hours. The reaction solution was directly purified by reverse phase chromatography (C18, 0.05% ammonia water:acetonitrile = 20:1 to 1:20) to obtain compound 15 (82 mg, yield 72%).

[0293] m / z(ESI):568.2[M+H] + .

[0294] 1 H NMR (400MHz, DMSO-d6) δ8.16-8.12(m,1H),8.08(d,J=8.0Hz,1H),7.98(d,J=8.0Hz,1H),7.67(t,J=8.0Hz,1H),7.34-7.29(m,2H),7.18(s ,2H),5.85(d,J=7.6Hz,2H),5.18-5.12(m,1H),4.40-4.34(m,1H),3.61-3.53(m,8H),2.51(s,3H),1.98-1.86(m,3H),1.77-1.66(m,3H).

[0295] Example 16: Preparation of Compound 16

[0296] Compound 14 (3.3 g, 7.8 mmol) was dissolved in anhydrous dichloromethane (10 mL), and then phosphorus oxychloride (3.6 g, 23 mmol) and N,N-diisopropylethylamine (4.0 mL, 23 mmol) were added sequentially at -78°C. The reaction mixture was then heated to room temperature for 16 hours. The reaction was quenched by adding water and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (C18, 0.05% formic acid-water:acetonitrile = 20:1 to 1:20) to obtain compound 16 (3.5 g, yield 89%).

[0297] m / z(ESI):505.3[M+H] + .

[0298] 1H NMR (400MHz, DMSO-d6) δ8.19-8.15(m,1H),8.09-8.06(m,1H),7.99-7.97(m,1H),7.67(t,J=8.0Hz,1H),7.44(d,J=8.4Hz,1H ),7.33-7.28(m,1H),7.19(s,2H),5.19-5.12(m,1H),4.39-4.34(m,1H),2.50(s,3H),1.99-1.93(m,3H),1.78-1.72(m,3H).

[0299] Example 17: Synthesis of Compound 17

[0300] Compound 16 (2.5 g, 5.0 mmol) was dissolved in anhydrous methanol (10 mL), and then an aqueous solution of sodium hydroxide (0.20 g, 5.0 mmol) was added under an ice bath. The reaction was continued under the same conditions for 2 hours. The solvent was removed by concentration under reduced pressure, and the residue was directly lyophilized to obtain compound 17 (2.7 g, yield 100%).

[0301] m / z(ESI):505.3[M+H] + .

[0302] 1 H NMR(400MHz,CD3OD-d4)δ8.08-8.05(m,1H),7.89-7.87(m,1H),7.76-7.72(m,1H),7.68-7.64(m,1H),7.1 9-7.13(m,1H),5.36-5.31(m,1H),4.61-4.57(m,1H),2.58(s,3H),2.07-1.99(m,3H),1.89-1.79(m,3H).

[0303] Example 18: Synthesis of Compound 18

[0304] Step 1: Synthesis of Intermediate 18b

[0305] Compound 14 (0.21 g, 0.50 mmol) and 18a (0.26 g, 1.0 mmol) were dissolved in N,N-dimethylformamide (2 mL), and cesium carbonate (0.33 g, 1.0 mmol) was added. The mixture was reacted at 50°C for 12 hours. The insoluble matter was removed by filtration, and the filtrate was purified by reverse phase chromatography (C18, 0.05% aqueous ammonia:acetonitrile = 20:1 to 1:20) to obtain compound 18b (0.24 g, yield 75%). m / z (ESI): 647.2 [M+H] + .

[0306] Step 2: Synthesis of Intermediate 18c

[0307] Compound 18b (0.24 g, 0.37 mmol) was dissolved in anhydrous dichloromethane (20 mL), followed by the addition of trifluoroacetic acid (3 mL). The mixture was reacted at room temperature for 1 hour, concentrated under reduced pressure, and the resulting residue was purified by reverse phase chromatography (C18, 0.05% formic acid-water:acetonitrile = 20:1 to 1:20) to afford compound 18c (0.14 g, 71% yield). m / z (ESI): 535.3 [M+H] + .

[0308] Step 3: Synthesis of compound 18

[0309] Compound 18c (0.14 g, 0.26 mmol) was dissolved in methanol (2 mL) under ice-bath conditions, and then a solution of sodium hydroxide (21 mg, 0.52 mmol) in water (2 mL) was added. The mixture was reacted at room temperature for 30 minutes, concentrated under reduced pressure, and the residue was directly lyophilized to obtain compound 18 (0.16 g, yield 100%).

[0310] m / z(ESI):535.3[M+H] + .

[0311] 1 H NMR (400MHz, DMSO-d6) δ8.11-8.06(m,2H),7.96(d,J=7.6Hz,1H),7.66(t,J=7.6Hz,1H),7.39(d,J=8.4Hz,1H),7.26-7. 18(m,3H),5.51-5.43(m,2H),5.17-5.13(m,1H),4.39-4.33(m,1H),2.48(s,3H),1.95-1.87(m,3H),1.74-1.67(m,3H).

[0312] Example 19: Synthesis of Compound 19

[0313] Step 1: 1,5-Difluoro-2,4-dimethyl-3-nitrobenzene (19b)

[0314] Compound 19a (5.5 g, 17.36 mmol), methylboronic acid (6.23 g, 104.14 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (1.26 g, 1.74 mmol), and cesium carbonate (16.97 g, 52.07 mmol) were dissolved in dioxane / water (100 mL / 10 mL). The atmosphere was replaced with argon and the temperature was raised to 80°C for 12 hours. After the reaction mixture was cooled to room temperature, the insoluble material was filtered off and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride aqueous solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting crude product 19b was used directly in the next reaction without purification.

[0315] Step 2: 1-Fluoro-5-methoxy-2,4-dimethyl-3-nitrobenzene (19c)

[0316] Compound 19b (3.2 g, 17.10 mmol) was dissolved in anhydrous methanol, and sodium methoxide (5.0 M, 6.84 mL, 34.20 mmol) was added. The temperature was then raised to 85°C for 2 hours, followed by an additional addition of sodium methoxide (5.0 M, 6.84 mL, 34.20 mmol) and the reaction continued at 85°C overnight. The reaction solution was concentrated, and the crude product was poured into ice water and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The resulting crude product 19c was used directly in the next reaction without purification.

[0317] Step 3: 3-Fluoro-5-methoxy-2,6-dimethylaniline (19d)

[0318] Compound 19c (3.4 g, 17.07 mmol) and ammonium chloride (4.39 g, 85.35 mmol) were dissolved in ethanol / water (20 mL / 20 mL). Acetic acid (102.5 mg, 1.71 mmol) was added and the mixture was allowed to react at 50°C for 30 minutes. Iron powder (9.53 g, 170.7 mmol) was then added and the temperature was raised to 90°C for another 30 minutes. The mixture was filtered while hot and the filtrate was concentrated. The crude product was purified by normal phase chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1) to afford compound 19d (1.67 g, yield: 58%). m / z (ESI): 170.2 [M+H] + .

[0319] Step 4: 6-Chloro-N-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-5-iodo-2-methylpyrimidin-4-amine (19e)

[0320] Compound 1d (500 mg, 1.73 mmol) and compound 19d (439 mg, 2.60 mmol) were dissolved in anhydrous 1,4-dioxane (20 mL). Boron trifluoride etherate (58% BF3) solution (1.50 mL, 5.8 mmol) was added, and the reaction temperature was raised to 100°C for 36 hours. After cooling to room temperature, ice water (10 mL) was slowly added to the reaction system to quench the reaction. The mixture was then extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by normal phase silica gel column chromatography (petroleum ether:ethyl acetate = 15:1 to 10:1) to obtain compound 19e (160 mg, yield: 22%). m / z (ESI): 422.0 [M+H] + .

[0321] Step 5: 6-amino-4-chloro-7-(3-fluoro-5-methoxy-2,6-dimethylphenyl)-2-methyl-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid methyl ester (19f)

[0322] Methyl cyanoacetate (150 mg, 1.52 mmol) was dissolved in anhydrous ethylene glycol dimethyl ether (5.0 mL), and cesium carbonate (741.8 mg, 2.28 mmol) was added. After reacting at room temperature for 30 minutes, compound 19e (160 mg, 379 μmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (27.7 mg, 37.9 μmol) were added. The mixture was then reacted at 85°C under argon for 2 hours. After cooling to room temperature, the reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by normal phase chromatography (petroleum ether:ethyl acetate = 10:1 to 1:2) to obtain compound 19f (85 mg, 57% yield). m / z (ESI): 393.8 [M+H] + .

[0323] Compound 19f (85 mg, 216 μmol) was subjected to SFC chiral separation (column: Cellulose-2 (100*4.6 mm, 5 μm); mobile phases: A: CO2, B: EtOH; mobile phase B gradient from 5% to 40% over 4 minutes, maintained at 40% for 0.5 minutes, then from 40% back to 5% over 1.5 minutes. Detection wavelength: 214 nm; flow rate: 2.8 mL / min; column temperature: 35°C; back pressure: 1500 psi) to afford compounds 19f-1 (32.4 mg, 2.94 min) and 19f-2 (33.8 mg, 3.86 min).

[0324] Compound 19 was prepared by replacing compound 1g-2 with compound 19f-1 using a method similar to Example 3.

[0325] m / z(ESI):487.3[M+H] + .

[0326] 1 H NMR (400MHz, DMSO-d6) δ8.80(d,J=5.2Hz,1H),8.02(t,J=5.2Hz,1H),7.67(t,J=7.2Hz,1H),7.40(s,2H),7.67(t,J=8.0H z,1H),6.85(d,J=10.4Hz,1H),5.31-5.25(m,1H),4.44-4.38(m,1H),2.53(s,3H),1.82-1.78(m,3H),1.62-1.57(m,3H).

[0327] Example 20: Synthesis of Compound 20

[0328] Compound 20 was prepared by replacing compound 11c with compound 19f-1 and adopting a method similar to Example 12.

[0329] m / z(ESI):443.3[M+H] + .

[0330] 1 H NMR (400MHz, DMSO-d6) δ10.13(d,J=10.4Hz,1H),8.16(t,J=6.8Hz,1H),8.07(t,J=8.0Hz,1H),7.98(d,J=8.0,1H),7.67(t,J=8.0Hz ,1H),7.24(s,2H),6.85(d,J=10.4Hz,1H),5.17-5.12(m,1H),4.39-4.33(m,1H),2.50(s,3H),1.81-1.78(m,3H),1.62-1.57(m,3H).

[0331] Biological activity and related properties test examples

[0332] Test Example 1: Compound inhibition experiment on tumor cell proliferation

[0333] Brief introduction to experimental principle: After incubating the compound with tumor cells for 7 days, the ATP in the living cells is quantified using Promega's CTG kit to reflect the effect of the compound on tumor cell proliferation.

[0334] Experimental instruments: Envision microplate reader from Perkin Elmer; 5810R centrifuge from Eppendorf; automatic cell counter from Countstar.

[0335] Experimental Materials:

[0336] Experimental method: The cultured cells were resuspended (adherent cells were rinsed with PBS and digested with 0.25% Trypsin-EDTA) and then counted to obtain cell density and viability information. 3000 HCC1569 cells / well were diluted with RPMI Medium 1640 containing 10% FBS and added to a 96-well plate (90 μL / well), and cultured in a 37°C, 5% CO2 incubator for 24 hours. 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 was diluted 4-fold to a final DMSO concentration of 0.25%. After the compound and cells were incubated for 7 days in a 37°C, 5% CO2 incubator, 50 μL / well CTG was added to measure the compound's inhibition on tumor cell growth, and the inhibition rate and half-maximal inhibitory concentration (IC50) were calculated. 50 ).

[0337] Data Analysis:

[0338] Calculate the % compound inhibition and use XLfit software to fit the compound IC 50 .

[0339] The experiment set up blank wells and DMSO wells. The blank wells contained 100 μL of RPMI Medium 1640 culture medium containing 10% FBS, and the inhibition rate of the compound on tumor cell growth at this time was considered to be 100%; the DMSO wells were cell wells with 0.25% DMSO added, and the inhibition rate of the compound on tumor cell growth at this time was considered to be 0.

[0340] Compound inhibition percentage = (100*(DMSO well - experimental well) / (DMSO well - blank well))%

[0341] The inhibition of tumor cell growth by the compounds of the present application was determined by the above test, and the measured IC 50 The values ​​are shown in Table 1 below.

[0342] Table 1 IC of compounds against HCC1569 cell growth inhibition 50

[0343] Test Example 2: Pharmacokinetic Properties in Rats

[0344] 1. Test Materials

[0345] 6- to 8-week-old SD male rats (purchased from Weitonglihua)

[0346] 2. Test methods

[0347] Male Sprague-Dawley rats were fasted for at least 12 hours prior to dosing and resumed feeding 4 hours after dosing. Water was freely available throughout the experiment. On the day of the experiment, a 0.5 mg / mL solution of compound 15 and a 10 mg / mL solution of compounds 16, 17, and 18 were prepared using 20% ​​HP-β-CD (purchased from Bidex Pharmaceuticals). The animals were administered a single dose of the compound shown in the table below by gavage. Animals were weighed before dosing, and the dosing volume was calculated based on their weight. Samples were collected at 0 (pre-dose), 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours. Approximately 100 μL of whole blood was collected from the jugular vein at each time point into a centrifuge tube containing anticoagulant. Plasma was separated by centrifugation at 12,000 rpm at 4°C for 5 minutes and stored at -80°C. All animals were euthanized by CO2 anesthesia after the final plasma sample was collected.

[0348] Plasma samples were thawed at room temperature and vortexed for 1 minute. 20 μL was quantitatively transferred to a 1.5 mL centrifuge tube. 300 μL of internal standard solution (10 ng / mL verapamil (purchased from Sigma) in acetonitrile) was added and shaken (1000 rpm for 3 minutes). The tube was centrifuged (14,000 rpm for 5 minutes). 60 μL of the supernatant was transferred to a 350 μL 96-well plate. 60 μL of diluent (water) was added and the plate was shaken (1000 rpm for 3 minutes). The plate was then centrifuged (1500 rpm for 5 minutes). Quantitative analysis was performed using an AB Sciex Triple Quad 6500+ system. Plasma concentrations and corresponding pharmacokinetic parameters were calculated using a non-compartmental model using Phoenix WinNonlin (version 8.3.4) pharmacokinetic software.

[0349] 3. Test results

[0350] The results of the pharmacokinetic study in rats are shown in Table 2.

[0351] Table 2 Pharmacokinetic parameters of the compounds after single oral administration in rats

Claims

1. A compound of formula (II') or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in, n is selected from 0 and 1; R 1 Selected from -OH, R 2 is hydrogen, R 3 is hydrogen or halogen; R 4 Selected from amino, hydroxyl, mercapto, halogen, cyano, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl and --C(=O)NH2, the amino, hydroxyl, thiol, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclyl, C6-C 10 Aryl, 5-9 membered heteroaryl, C2-C6 alkenyl, C2-C6 alkynyl or -C(=O)NH2 is optionally substituted by one or more R a replace; R 5 and R 5 ' and the atoms connected thereto together form a benzene ring, a pyridine ring, a pyrimidine ring, a thiazole ring, an isothiazole ring, an oxazole ring or an isoxazole ring, wherein the benzene ring, the pyridine ring or the pyrimidine ring is further surrounded by one or more R a1 The thiazole ring, isothiazole ring, oxazole ring or isoxazole ring is optionally replaced by R a1 replace; R 7 、R 8 independently selected from hydrogen, halogen, and C1-C6 alkyl, said C1-C6 alkyl being optionally substituted with deuterium; R a 、R a1 Each independently selected from deuterium, halogen, CN, methyl and C2-C4 alkenyl, said methyl and C2-C4 alkenyl being optionally substituted by one or more R b replace; R b independently selected from deuterium, halogen, NH2, NHCH3 and N(CH3)2; Provided that the compound of formula (II') or its stereoisomer or pharmaceutically acceptable salt thereof does not include the following compounds:

2. The compound of formula (II') or its stereoisomer compound or its pharmaceutically acceptable salt according to claim 1, wherein: n is 1.

3. The compound of formula (II') according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: n is 0.

4. The compound of formula (II') according to any one of claims 1 to 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 4 Selected from amino, hydroxy, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclic group, C6-C 10 Aryl and 5-9 membered heteroaryl, the amino, hydroxyl, C1-C6 alkyl, C3-C9 cycloalkyl, 4-9 membered heterocyclic, C6-C 10 Aryl or 5-9 membered heteroaryl is optionally substituted with one or more R a Replace; or R 4 is selected from amino, hydroxy, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl and 5-6 membered heteroaryl, wherein the amino, hydroxy, C1-C3 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl is optionally substituted by one or more R a Replace; or R 4 Selected from -CH3, -CH(CH3)2, -OCH3, -N(CH3)2, -CF3, -CHF2, -CH2F, or R 4 is selected from methyl optionally substituted by one or more halogen (eg F).

5. The compound of formula (II') according to any one of claims 1 to 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 5 and R 5 ' and the atoms connected thereto together form a benzene ring, a pyridine ring, a thiazole ring or an isothiazole ring, wherein the benzene ring and the pyridine ring are further separated by one or more R a1 Substituted, the thiazole ring or isothiazole ring is optionally replaced by R a1 replace.

6. The compound of formula (II') according to claim 5, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein: R 5 and R 5 ' and the atoms connected thereto together form a benzene ring, a pyridine ring or a pyrimidine ring, wherein the benzene ring, the pyridine ring and the pyrimidine ring are further separated by one or more R a1 Replace; or, R 5 and R 5 ' and the atoms connected thereto together form a benzene ring or a pyridine ring, wherein the benzene ring and the pyridine ring are further separated by one or more R a1 replace.

7. The compound of formula (II') according to claim 6, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein: R 5 and R 5 ' and the atoms to which they are connected together form a thiazole ring, an isothiazole ring, an oxazole ring or an isoxazole ring, wherein the thiazole ring, the isothiazole ring, the oxazole ring or the isoxazole ring is optionally replaced by R a1 Replace; or, R 5 and R 5 ' and the atoms to which they are connected together form a thiazole ring or an isothiazole ring, wherein the thiazole ring or the isothiazole ring is optionally replaced by R a1 replace.

8. The compound of formula (II') according to any one of claims 1 to 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 7 、R 8 are independently selected from halogen and C1-C6 alkyl; or, R 7 、R 8 are independently selected from C1-C3 alkyl; or R 7 and R 8 All are methyl.

9. The compound of formula (II') according to any one of claims 1 to 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R a 、R a1 independently selected from halogen, CN, methyl and C2-C4 alkenyl, said methyl and C2-C4 alkenyl being optionally substituted by one or more R b replace.

10. The compound of formula (II') according to any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R b are independently selected from halogen, NH2, NHCH3 and N(CH3)2; or, R b Independently selected from halogen (eg, F) ​​and N(CH3)2.

11. The compound of formula (II') according to any one of claims 1 to 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R a1 Independently selected from CN, methyl, CF2H, CF3, CH2N(CH3)2 and propenyl.

12. The compound of formula (II') according to any one of claims 1 to 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the compound of formula (II-1) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, X 1 is selected from CH and N, m is selected from 1, 2 and 3, n, R 1 、R 2 、R 3 、R 4 、R 7 、R 8 and R a1 As defined in any one of claims 1 to 11.

13. The compound of formula (II') according to any one of claims 1 to 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the compound of formula (II-2) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, in, X 2 、X 3 One is N, the other is CH, k is selected from 0 and 1, n, R 1 、R 2 、R 3 、R 4 、R 7 、R 8 and R a1 As defined in any one of claims 1 to 11.

14. A compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

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

16. A method for treating a disease mediated by PKMYT1 in a mammal, comprising administering a therapeutically effective amount of the compound according to any one of claims 1 to 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 15 to a mammal, preferably a human, in need of such treatment.

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