Cyclin dependent kinase inhibitor compound and application thereof

Abstract

The invention relates to a CDK inhibitor compound shown in a formula (I) or pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the CDK inhibitor compound or the pharmaceutically acceptable salt, and application of the CDK inhibitor compound or the pharmaceutically acceptable salt in preparation of drugs for preventing or treating CDK-mediated diseases. # imgabs0 #

Description

[0001] Cross - reference to related applications

[0002] This application claims the rights and priorities of the following Chinese patent applications, the entire contents of which are hereby incorporated herein by reference in their entirety:

[0003] Patent Application No. 202410053664.8, filed with the National Intellectual Property Administration on January 12, 2024. Technical field

[0004] This disclosure belongs to the field of medicine and relates to a cyclin - dependent kinase (CDK) inhibitor compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing them, and their use as a CDK inhibitor in the prevention or treatment of related diseases. Background art

[0005] The occurrence of tumors is related to the imbalance of multiple oncogenes and tumor suppressor genes. The functional effects of almost all oncogenes and tumor suppressor genes will ultimately converge on the cell cycle. Therefore, it can be said that tumors are a type of cell cycle disease (Cell Cycle Disease, CCD), and regulating or blocking the cell cycle is one of the ways to treat tumors. Currently, many molecules related to cell cycle regulation have been discovered, among which cyclin - dependent kinases (CDKs) are the core molecules of the cell cycle regulation network.

[0006] CDKs are a group of serine / threonine protein kinases. CDKs drive the cell cycle through the chemical action on serine / threonine proteins and act in synergy with cyclins, which are important factors in cell cycle regulation.

[0007] Among the CDK subtypes involved in the cell cycle, CDK4 / 6 plays an irreplaceable role. The cell cycle mutations related to cancer mainly occur in the G1 phase and the G1 / S phase transition. CDK4 / 6 binds to cyclin D (CvclinD) to form a kinase - active complex, phosphorylates the product pRb of the tumor suppressor gene Rb, releases the bound transcription factor E2F, initiates the transcription of genes related to the S phase, promotes the cell to pass through the checkpoint, and transfers from the G1 phase to the S phase.

[0008] However, clinical applications have also demonstrated that CDK4 / 6 inhibitors can cause adverse reactions such as gastrointestinal and / or hematological toxicity, and acquired drug resistance may occur with the accumulation of usage time. Moreover, new research reports have shown that the hematological side effects caused by CDK4 / 6 inhibitors may be related to the inhibition of CDK6, and CDK4 has been identified as a single oncogenic factor in various breast cancers. Therefore, selective CDK4 inhibitors may offer better safety and efficacy compared to CDK4 / 6 inhibitors. The present invention is dedicated to the development of novel selective CDK4 inhibitors. SUMMARY OF THE INVENTION

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

[0010]

[0011] wherein:

[0012] X 1 and X 2 each independently selected from N and CR 6 ;

[0013] R 1 is selected from hydrogen, halogen, amino, mercapto, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl, -OR 1a , -C(O)R 1a , -C(O)OR 1a , -C(O)NR 1a R 1b , -NR 1a R 1b , -NR 1a C(O)R 1b , -NR 1a C(O)OR 1b and -NR 1a C(O)NR 1b R 1c , and the amino, mercapto, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted by one or more R 1A ;

[0014] R 2 is selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 alkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-C 10 alkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more R 2A substituents;

[0015] Each R 2A is independently selected from halogen, cyano, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 12 cycloalkyl, 4- to 12-membered heterocyclic, C6-C 10 aryl, 5- to 10-membered heteroaryl, oxo, -OR 2a 、-S(O)2R 2a 、-S(O)2NR 2a R 2b 、-C(O)R 2a 、-C(O)OR 2a 、-C(O)NR 2a R 2b 、-NR 2a R 2b 、-NR 2a C(O)R 2b 、-NR 2a C(O)OR 2b 、-NR 2a C(O)NR 2b R 2c and -NR 2a S(O)2R 2b ,wherein the C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 12 cycloalkyl, 4- to 12-membered heterocyclic, C6-C 10 aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more R 2d substituents;

[0016] R 3 、R 4 、R 6 are independently selected from hydrogen, halogen, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic, C6-C10 aryl, 5- to 10-membered heteroaryl, -OR 3a , -C(O)R 3a , -C(O)OR 3a , -C(O)NR 3a R 3b , -NR 3a R 3b , -NR 3a C(O)R 3b , -NR 3a C(O)OR 3b and -NR 3a C(O)NR 3b R 3c , said C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 3A substituents;

[0017] Each R 1a , R 1b , R 1c , R 3a , R 3b , R 3c is independently selected from hydrogen, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl and 5- to 10-membered heteroaryl, said C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 1f substituents;

[0018] R 5 is selected from hydrogen, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 alkyl, said C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 alkyl are optionally substituted by one or more R 5A substituents;

[0019] Ring A is selected from 4- to 10-membered heterocycles and 5- to 10-membered heteroaryl rings, and the 4- to 10-membered heterocycles and 5- to 10-membered heteroaryl rings are optionally substituted with one or more R a substituents;

[0020] Ring B is selected from C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl, and 5- to 12-membered heteroaryl, and the C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl, and 5- to 12-membered heteroaryl are optionally substituted with one or more R b substituents;

[0021] Each R a , R b is independently selected from halogen, cyano, oxo, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl, 5- to 10-membered heteroaryl, -OR 4a , -C(O)R 4a , -C(O)OR 4a , -C(O)NR 4a R 4b , -NR 4a R 4b , -NR 4a C(O)R 4b , -NR 4a C(O)OR 4b , -NR 4a C(O)NR 4b R 4c , S(O)2R 4a and S(O)2NR 4a R 4b , and the C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more R 4A substituents;

[0022] Each R 2a , R 2b , R 2c , R 4a , R 4b, R 4c each independently selected from hydrogen, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10-membered heterocyclic group, C6-C 10 aryl and 5-10-membered heteroaryl, said C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10-membered heterocyclic group, C6-C 10 aryl, 5-10-membered heteroaryl optionally substituted by one or more R 2f substituents;

[0023] Each R 2d , R 2f each independently selected from hydrogen, hydroxy, halogen, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10-membered heterocyclic group, C6-C 10 aryl, 5-10-membered heteroaryl, oxo, C(O)R g and -S(O)2R g , said hydroxy, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10-membered heterocyclic group, C6-C 10 aryl, 5-10-membered heteroaryl optionally substituted by at least one substituent selected from the following: halogen, hydroxy, oxo, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 cycloalkyl, C3-C 12 halocycloalkyl, 4-10-membered heterocyclic group, 4-10-membered halocyclic group, C6-C 10 aryl, C6-C 10 haloaryl, 5-10-membered heteroaryl and 5-10-membered hal heteroaryl;

[0024] Each R 1A , R 1f , R 3A , R 4A , R 5A , R gIndependently selected from hydrogen, amino, halogen, hydroxyl, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl and 5-10 membered heteroaryl, the amino, hydroxyl, C 1-8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted with at least one substituent selected from: halogen, hydroxyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 cycloalkyl, C3-C 12 halocycloalkyl, 4-10 membered heterocyclic group, 4-10 membered halocyclic group, C6-C 10 aryl, C6-C 10 haloaryl, 5-10 membered heteroaryl and 5-10 membered hal heteroaryl;

[0025] One or more hydrogen atoms of the compound are optionally deuterium atoms.

[0026] In some embodiments, X 1 and X 2 At least one is CR 6 .

[0027] In some embodiments, X 1 and X 2 Are both CR 6 , preferably CH.

[0028] In some embodiments, R 1 Is selected from hydrogen, halogen, amino, mercapto, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 alkyl, the amino, mercapto, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 alkyl are optionally substituted with one or more R 1A .

[0029] In some embodiments, R 1 Is selected from hydrogen and C1-C 10 alkyl, the C1-C 10 alkyl is optionally substituted with one or more R 1A .

[0030] In some embodiments, R 1 is selected from hydrogen and methyl, and the methyl is optionally substituted with one or more R 1A .

[0031] In some embodiments, R 1A is independently selected from halogen and hydroxy.

[0032] In some embodiments, R 1 is selected from hydrogen and methyl.

[0033] In some embodiments, R 2 is selected from C1-C 10 alkyl and 5-10-membered heteroaryl, and the C1-C 10 alkyl and 5-10-membered heteroaryl are optionally substituted with one or more R 2A .

[0034] In some embodiments, R 2 is selected from C1-C4 alkyl and 5-6-membered heteroaryl, and the C1-C4 alkyl and 5-6-membered heteroaryl are optionally substituted with one or more R 2A .

[0035] In some embodiments, R 2 is selected from methyl, isopropyl and thiazolyl, and the methyl, isopropyl and thiazolyl are optionally substituted with one or more R 2A .

[0036] In some embodiments, R 2 is selected from methyl, isopropyl and the methyl, isopropyl and are optionally substituted with one or more R 2A .

[0037] In some embodiments, R 2A is independently selected from halogen, cyano, C3-C 12 cycloalkyl, 4-12-membered heterocyclic group, C6-C 10 aryl, 5-10-membered heteroaryl, -OR 2a and -NR 2a R 2b , and the C3-C 12 cycloalkyl, 4-12-membered heterocyclic group, C6-C 10 aryl and 5-10-membered heteroaryl are optionally substituted with one or more R 2d .

[0038] In some embodiments, R 2A is independently selected from 4-10-membered heterocyclic group, -OR 2a and -NR 2a R2b and the 4- to 10-membered heterocyclic group is optionally substituted with one or more R 2d .

[0039] In some embodiments, R 2A is independently selected from a 4- to 7-membered heterocyclic group, -OR 2a and -NR 2a R 2b , and the 4- to 7-membered heterocyclic group is optionally substituted with one or more R 2d .

[0040] In some embodiments, R 2A is independently selected from morpholinyl, -OR 2a and -NR 2a R 2b , and the morpholinyl is optionally substituted with one or more R 2d .

[0041] In some embodiments, R 2a is independently selected from hydrogen, C2-C 10 alkenyl, C2-C 10 alkynyl, and C1-C 10 alkyl.

[0042] In some embodiments, R 2a is hydrogen.

[0043] In some embodiments, R 2b is independently selected from hydrogen, C2-C 10 alkenyl, C2-C 10 alkynyl, and C1-C 10 alkyl.

[0044] In some embodiments, R 2b is hydrogen.

[0045] In some embodiments, R 2A is independently selected from amino and hydroxy, and the amino and hydroxy are optionally substituted with one or more R 2d .

[0046] In some embodiments, R 2A is independently selected from amino and hydroxy, and the is optionally substituted with one or more R 2d .

[0047] In some embodiments, R 2d is independently selected from halogen, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl, and C1-C10 Alkyl group.

[0048] In some embodiments, R 2d is independently selected from C1-C 10 alkyl group.

[0049] In some embodiments, R 2d is independently selected from C1-C4 alkyl groups.

[0050] In some embodiments, R 2d is methyl.

[0051] In some embodiments, R 2 is selected from methyl, aminomethyl,

[0052] In some embodiments, R 2 is selected from and aminomethyl.

[0053] In some embodiments, R 2 is

[0054] In some embodiments, R 3 is selected from hydrogen, halogen, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 alkyl group.

[0055] In some embodiments, R 3 is selected from hydrogen and halogen.

[0056] In some embodiments, R 3 is fluorine or chlorine.

[0057] In some embodiments, R 3 is fluorine.

[0058] In some embodiments, R 4 is selected from hydrogen, halogen, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 alkyl group.

[0059] In some embodiments, R 4 is selected from hydrogen and halogen.

[0060] In some embodiments, R 4 is hydrogen.

[0061] In some embodiments, R 5 is selected from hydrogen and C1-C 10 alkyl group.

[0062] In some embodiments, R 5 is hydrogen.

[0063] In some embodiments, R 6 is selected from hydrogen, halogen, cyano, and C1-C 10 alkyl.

[0064] In some embodiments, R 6 is selected from hydrogen and halogen.

[0065] In some embodiments, R 6 is hydrogen or fluorine.

[0066] In some embodiments, R 6 is hydrogen.

[0067] In some embodiments, ring A is selected from 5- to 6-membered heterocycles, the 5- to 6-membered heterocycles being optionally substituted with one or more R a substituents.

[0068] In some embodiments, ring A is selected from dioxazine rings, thiazine rings, tetrahydropyridine rings, pyrrole rings, and pyrrolidine rings, the dioxazine rings, thiazine rings, tetrahydropyridine rings, pyrrole rings, and pyrrolidine rings being optionally substituted with one or more R a substituents.

[0069] In some embodiments, R a is independently selected from halogen, cyano, and C1-C 10 alkyl, the C1-C 10 alkyl being optionally substituted with one or more R 4A substituents.

[0070] In some embodiments, R a is independently selected from C1-C4 alkyl, the C1-C4 alkyl being optionally substituted with one or more R 4A substituents.

[0071] In some embodiments, R a is independently selected from methyl and ethyl, the methyl and ethyl being optionally substituted with one or more halogens.

[0072] In some embodiments, R a is independently selected from methyl, trifluoromethyl, and ethyl.

[0073] In some embodiments, is selected from wherein n is selected from 0 and 1.

[0074] In some embodiments, is selected from where n is selected from 0 and 1.

[0075] In some embodiments, selected from where n is selected from 0 and 1.

[0076] In some embodiments, ring B is selected from 4- to 10-membered heterocyclic groups and 5- to 12-membered heteroaryl groups, and the 4- to 10-membered heterocyclic groups and 5- to 12-membered heteroaryl groups are optionally substituted with one or more R b substituents.

[0077] In some embodiments, ring B is selected from 4- to 10-membered heterocyclic groups and 5- to 6-membered heteroaryl groups, and the 4- to 10-membered heterocyclic groups and 5- to 6-membered heteroaryl groups are optionally substituted with one or more R b substituents.

[0078] In some embodiments, ring B is selected from tetrahydropyranyl, piperidinyl, tetrahydronaphthyridinyl, and pyridinyl, and the tetrahydropyranyl, piperidinyl, tetrahydronaphthyridinyl, and pyridinyl are optionally substituted with one or more R b substituents.

[0079] In some embodiments, ring B is selected from the optionally substituted with one or more R b substituents.

[0080] In some embodiments, ring B is selected from the optionally substituted with one or more R b substituents.

[0081] In some embodiments, R b is independently selected from halogen, cyano, C1-C 10 alkyl, 4- to 10-membered heterocyclic groups, -OR 4a and S(O)2R 4a wherein the C1-C 10 alkyl and 4- to 10-membered heterocyclic groups are optionally substituted with one or more R 4A substituents.

[0082] In some embodiments, R b is independently selected from C1-C4 alkyl, 4- to 7-membered heterocycles, -OR 4a and S(O)2R 4a wherein the C1-C4 alkyl and 4- to 7-membered heterocycles are optionally substituted with one or more R 4A substituents.

[0083] In some embodiments, R bIndependently selected from methyl, hydroxy, piperidinyl, and S(O)2CH3, wherein the methyl, hydroxy, piperidinyl, and S(O)2CH3 are optionally substituted with one or more R 4A substituents.

[0084] In some embodiments, R 4A is selected from methyl and methylpiperazinyl.

[0085] In some embodiments, R b is independently selected from hydroxy, methyl, and S(O)2CH3.

[0086] In some embodiments, ring B is selected from

[0087] In some embodiments, ring B is

[0088] In some embodiments, the compound of formula (I) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the compound of formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0089]

[0090] wherein R 1 , R 2 , R 3 and ring A are as defined above.

[0091] In some embodiments, the compound of formula (I) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from the following compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0092]

[0093]

[0094] On the other hand, the present disclosure provides a pharmaceutical composition comprising the compound of formula (I) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0095] On the other hand, the present disclosure provides a method for treating a CDK-mediated disease in an individual (such as a mammal), comprising administering to an individual (such as a mammal, preferably a human) in need of such treatment a therapeutically effective amount of the compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0096] On the other hand, the present disclosure provides the use of the compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a drug for preventing or treating a CDK-mediated disease.

[0097] On the other hand, the present disclosure provides the use of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of CDK-mediated diseases.

[0098] On the other hand, the present disclosure provides a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the prevention or treatment of CDK-mediated diseases.

[0099] In some embodiments, the CDK-mediated disease is a tumor.

[0100] In some embodiments, the CDK-mediated disease is selected from CDK4-mediated diseases.

[0101] Term Definitions and Explanations

[0102] Unless otherwise specified, the terms used in the present disclosure have the following meanings. The definitions of the groups and terms described in the present disclosure, including their exemplary definitions, illustrative definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in examples, etc., can be combined and combined with each other arbitrarily. A particular term should not be considered indeterminate or unclear without a specific definition, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears in this text, it is intended to refer to the corresponding product or its active ingredient.

[0103] In this text represents a connecting site.

[0104] The representations of racemates or enantiomerically pure compounds in this text are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise specified, the solid wedge and dashed wedge represent the absolute configuration of a stereocenter, and the solid straight and dashed straight represent the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0105] When the bond of a substituent cross-links to two atoms on a ring, such a substituent can be bonded to any atom on this ring. For example, the structural unit represents that R a can be substituted at any position on the ring.

[0106] The compounds of the present disclosure may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, and thus the compounds of the present disclosure 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, diastereoisomers, (D)-isomers, (L)-isomers, and their racemic mixtures or other mixtures, such as enantiomer- or diastereomer-enriched mixtures. All of the above isomers and their mixtures are within the scope of the definition of the compounds of the present disclosure. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and these isomers and their mixtures involved in all substituents are also included within the scope of the definition of the compounds of the present disclosure. The compounds of the present disclosure containing asymmetric atoms may be isolated in optically pure form or in racemic form. The optically pure form may be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.

[0107] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, provided that the valence of the particular atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and oxo does not occur on an aromatic group.

[0108] The term "optionally" or "optionally" means that the subsequent described event or situation may or may not occur, and the description includes the occurrence and non-occurrence of the described event or situation. For example, ethyl "optionally" substituted by one or more halogens means that ethyl may be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl, etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2, etc.) or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3, etc.). Those skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern that is spatially impossible to exist and / or cannot be synthesized will be introduced.

[0109] When any variable (e.g., R a 、R b ) appears more than once in the composition or structure of a compound, its definition in each case is independent. For example, if a group is substituted by two R b , then each R b has an independent option.

[0110] C m -C nrefers to a hydrocarbon group having an integer number of carbon atoms in the range of m - n. For example, "C1 - C 10 " means that the group may 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.

[0111] The term "alkyl" refers to a hydrocarbon group with the general formula C n H 2n+1 , and the alkyl group can be straight-chain or branched-chain. The term "C1 - C 10 alkyl" can be understood to represent a straight-chain or branched-chain saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc.; the term "C1 - C8 alkyl" can be understood to represent an alkyl group having 1 to 8 carbon atoms; the term "C1 - C6 alkyl" can be understood to represent 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 - C4 alkyl" can be understood to represent a straight-chain or branched-chain saturated alkyl group having 1 to 4 carbon atoms. The term "C1 - C3 alkyl" can be understood to represent a straight-chain or branched-chain saturated alkyl group having 1 to 3 carbon atoms. The "C1 - C 10 alkyl" can include ranges such as "C1 - C6 alkyl", "C1 - C4 alkyl", or "C1 - C3 alkyl", and the "C1 - C6 alkyl" can further include "C1 - C4 alkyl" or "C1 - C3 alkyl". The term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C1 - C8 haloalkyl" means a C1 - C8 alkyl group as defined above that is substituted by one or more halogen atoms, including but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl, etc.

[0112] The term "alkoxy" refers to a group formed by removing the hydrogen atom on the hydroxyl group of a straight-chain or branched-chain alcohol, and can be understood as "alkyloxy" or "alkyl - O - ". The term "C1 - C 10 alkoxy" can be understood as "C1 - C10 "alkyloxy" or "C1-C 10 "alkyl-O-"; the term "C1-C8 alkyloxy" can be understood as "C1-C8 alkyloxy" or "C1-C8 alkyl-O-"; the term "C1-C6 alkyloxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". The said "C1-C 10 alkyloxy" can include ranges such as "C1-C6 alkyloxy" and "C1-C3 alkyloxy", and the said "C1-C6 alkyloxy" can further include "C1-C3 alkyloxy". The term "haloalkyloxy" is intended to include monohaloalkyl and polyhaloalkyloxy. For example, the term "C1-C8 haloalkyloxy" means a C1-C8 alkyloxy as defined above that is substituted by one or more halogen atoms.

[0113] The term "alkenyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one double bond. The term "C2-C 10 alkenyl" can be understood to represent a straight-chain or branched-chain unsaturated hydrocarbon group that contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms; the term "C2-C8 alkenyl" can be understood to represent a straight-chain or branched-chain unsaturated hydrocarbon group that contains one or more double bonds and has 2, 3, 4, 5, 6, 7, or 8 carbon atoms; "C2-C 10 alkenyl" can include "C2-C6 alkenyl", "C2-C4 alkenyl", C2 or C3 alkenyl. It is understood that in the case where the alkenyl contains more than one double bond, the double bonds can be separated or conjugated with each other. Specific examples of the alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, or (Z)-1-methylprop-1-enyl, etc.

[0114] The term "alkynyl" refers to a straight-chain or branched-chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms and having at least one triple bond. The term "C2-C 10 alkynyl" can be understood to represent a straight-chain or branched-chain unsaturated hydrocarbon group that contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The term "C2-C8 alkynyl" can be understood to represent a straight-chain or branched-chain unsaturated hydrocarbon group that contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Examples of "C2-C 10 alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl or but-3-ynyl. "C2-C 10 alkynyl" may include "C2-C3 alkynyl", and examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), prop-2-ynyl (-CH2C≡CH).

[0115] The term "cycloalkyl" refers to a carbocyclic group that is completely saturated and exists in the form of a monocyclic, fused-ring, bridged-ring or spiro-ring, etc. Unless otherwise indicated, the carbocyclic ring is usually a 3- to 20-membered ring. The term "C3-C 12 cycloalkyl" refers to a cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring carbon atoms. The term "C3-C 10 cycloalkyl" refers to a cycloalkyl having 3, 4, 5, 6, 7, 8, 9 or 10 ring carbon atoms. The term "C3-C6 cycloalkyl" refers to a cycloalkyl having 3, 4, 5 or 6 ring carbon atoms.

[0116] The term "heterocyclic group" or "heterocycle" refers to a monocyclic, fused-ring, spiro or bridged-ring group that is fully saturated or partially saturated (not aromatic heterocyclic as a whole), and contains 1-5 (e.g., 1-3 or 1-2) heteroatoms or heteroatomic groups (i.e., atomic groups containing heteroatoms) among its ring atoms. The "heteroatom or heteroatomic group" includes, but is not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-, etc. The term "4-12 membered heterocyclic group" refers to a heterocyclic group having 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, and containing 1-5 heteroatoms or heteroatomic groups independently selected from the above-mentioned ones among its ring atoms. The term "4-10 membered heterocyclic group" refers to a heterocyclic group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1-5 heteroatoms or heteroatomic groups independently selected from the above-mentioned ones among its ring atoms. The "4-10 membered heterocyclic group" may include the "4-7 membered heterocyclic group". The term "4-7 membered heterocyclic group" refers to a heterocyclic group having 4, 5, 6 or 7 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned ones among its ring atoms. Among them, specific examples of the 4-membered heterocyclic group include, but are not limited to, azetidinyl or oxetanyl; specific examples of the 5-membered heterocyclic group include, but are not limited to, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrroline, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of the 6-membered heterocyclic group include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridyl or 4H-[1,3,4]thiadiazinyl; specific examples of the 7-membered heterocyclic group include, but are not limited to, diazepanyl. The heterocyclic group may also be a bicyclic group. Among them, specific examples of the 5,5 bicyclic group include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of the 5,6 bicyclic group include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7 membered heterocyclic group, and specific examples include, but are not limited to, dihydroisoquinolinyl, etc."4- to 10-membered heterocyclic group" may include "5- to 10-membered heterocyclic group", "4- to 7-membered heterocyclic group", "5- to 6-membered heterocyclic group", "6- to 8-membered heterocyclic group", "4- to 10-membered heterocycloalkyl group", "5- to 10-membered heterocycloalkyl group", "4- to 7-membered heterocycloalkyl group", "5- to 6-membered heterocycloalkyl group", "6- to 8-membered heterocycloalkyl group", etc. "4- to 7-membered heterocyclic group" may further include "4- to 6-membered heterocyclic group", "5- to 6-membered heterocyclic group", "4- to 7-membered heterocycloalkyl group", "4- to 6-membered heterocycloalkyl group", "5- to 6-membered heterocycloalkyl group", etc. Although some bicyclic heterocyclic groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is still non-aromatic.

[0117] The term "heterocycloalkyl group" refers to a completely saturated cyclic group in the form of a monocyclic, fused ring, bridged ring, or spiro ring, etc., and the ring atoms of the ring contain 1 to 5 heteroatoms or heteroatomic groups (i.e., atomic groups containing heteroatoms). The "heteroatom or heteroatomic group" includes but is 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-, etc. The term "4- to 10-membered heterocycloalkyl group" means a heterocycloalkyl group with 4, 5, 6, 7, 8, 9, or 10 ring atoms, and its ring atoms contain 1 to 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned ones. The term "5- to 10-membered heterocycloalkyl group" means a heterocycloalkyl group with 5, 6, 7, 8, 9, or 10 ring atoms, and its ring atoms contain 1 to 5 heteroatoms or heteroatomic groups independently selected from the above-mentioned ones. "4- to 10-membered heterocycloalkyl group" and "5- to 10-membered heterocycloalkyl group" include "4- to 7-membered heterocycloalkyl group". Among them, specific examples of 4-membered heterocycloalkyl group include but are not limited to azetidinyl, oxetanyl, or thietanyl; specific examples of 5-membered heterocycloalkyl group include but are not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, or tetrahydropyrazolyl; specific examples of 6-membered heterocycloalkyl group 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 group include but are not limited to azepanyl, oxepanyl, or thiepanyl.

[0118] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. The aryl may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. The term "C6-C 10"Aryl" can be understood as an aryl group having 6 to 10 carbon atoms. For example, a ring having 6 carbon atoms ("C6 aryl"), such as a phenyl group; or a ring having 9 carbon atoms ("C9 aryl"), such as an indanyl group or an indenyl group; or a ring having 10 carbon atoms ("C 10 aryl"), such as a tetrahydronaphthyl group, a dihydronaphthyl group or a naphthyl group.

[0119] The term "heteroaryl" refers to a monocyclic or fused polycyclic system having aromaticity, wherein the ring atoms contain at least one ring atom selected from N, O, S, and the remaining ring atoms are aromatic ring groups of C. The term "5-10 membered heteroaryl" can be understood to include such monocyclic or bicyclic aromatic ring systems: having 5, 6, 7, 8, 9 or 10 ring atoms, such as 5 or 6 or 9 or 10 ring atoms, and containing 1-5, such as 1-3 heteroatoms independently selected from N, O and S. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl etc. and their benzo derivatives, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl etc. and their benzo derivatives, such as quinolinyl, quinazolinyl or isoquinolinyl etc.; or azocinyl, indolizinyl, purinyl etc. and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl or phenoxazinyl etc. The term "6-10 membered heteroaryl" can be understood to include such monocyclic or bicyclic aromatic ring systems: having 6, 7, 8, 9 or 10 ring atoms, such as 6 or 9 or 10 ring atoms, and containing 1-5, such as 1-3 heteroatoms independently selected from N, O and S. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and containing 1-3, such as 1-2 heteroatoms independently selected from N, O and S.

[0120] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0121] The term "hydroxy" refers to the -OH group.

[0122] The term "cyano" refers to the -CN group.

[0123] The term "amino" refers to the -NH2 group.

[0124] The term "nitro" refers to the -NO2 group.

[0125] The term "treatment" means administering the compounds or preparations described in the present application to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0126] (i) Suppress a disease or disease state, that is, contain its development;

[0127] (ii) Alleviate a disease or disease state, that is, make the disease or disease state subside.

[0128] The term "therapeutically effective amount" means the amount of a compound of the present disclosure that (i) treats a particular disease, condition or disorder, and (ii) alleviates, ameliorates or eliminates one or more symptoms of a particular disease, condition or disorder. The amount of the 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 those skilled in the art based on their own knowledge and the present disclosure.

[0129] The term "prevent" means administering the compounds or formulations described in the present application to prevent a disease or one or more symptoms associated with the disease, and includes preventing the occurrence of a disease or disease state in an individual (such as a mammal), especially when such an individual (such as a mammal) is susceptible to the disease state but has not been diagnosed as having the disease state.

[0130] The term "individual" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (such as chimpanzees and other apes and monkeys); domestic animals, such as cows, horses, sheep, goats, pigs; domesticated animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc. Examples of non-human mammals include, but are not limited to, birds and fish, etc. In one embodiment of the methods and compositions provided herein, the mammal is a human. The terms "patient" and "individual" can be used interchangeably.

[0131] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0132] The term "pharmaceutically acceptable salt" refers to salts of pharmaceutically acceptable acids or bases, including salts formed by the compound with inorganic acids or organic acids, and salts formed by the compound with inorganic bases or organic bases.

[0133] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof and pharmaceutically acceptable excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compounds of the present disclosure to an organism.

[0134] The term "pharmaceutically acceptable excipient" refers to those excipients that have no significant irritating effect on the organism and do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.

[0135] The term "comprise" or "comprising" and its English variants such as "comprises" or "comprising" can be understood in an open, non-exclusive sense, i.e., "including but not limited to".

[0136] This disclosure also includes isotopically labeled compounds of this disclosure that are the same as those described herein, but in which one or more atoms are replaced by atoms having an atomic weight or mass number different from the atomic weight or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds of this 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, etc.

[0137] Certain isotopically labeled compounds of this disclosure (e.g., labeled with 3 H and 14 C) can be used in compound and / or substrate tissue distribution analysis. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because of 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 this disclosure can generally be prepared by substituting an isotopically labeled reagent for an unlabeled reagent by procedures similar to those described in the protocols and / or examples disclosed below.

[0138] 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, etc.

[0139] Typical routes of administration of the compounds of the present disclosure or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0140] The pharmaceutical compositions 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, lyophilization methods, etc.

[0141] 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, syrups, suspensions, etc. for oral administration to a patient.

[0142] Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or dragee. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.

[0143] The pharmaceutical composition is also suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

[0144] The dosage administered depends on factors such as the specific compound, the disease condition and its severity, the identity of the subject or host to be treated (e.g., weight, gender), and is determined by the specific circumstances of the case, including, for example, the specific formulation administered, the route of administration, the disorder being treated, and the subject or host being treated.

[0145] In all methods of administration of the compounds of general formula (I) described herein, in the case of oral administration, the daily dose is from 0.001 mg / kg to 5000 mg / kg body weight, preferably from 0.01 mg / kg to 100 mg / kg body weight, in the form of single or divided doses. The daily dose and unit dose are varied according to a number of variables, including but not limited to the activity of the compound used, the disease or disorder to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or disorder being treated, and the judgment of the practitioner.

[0146] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present disclosure.

[0147] The chemical reactions of the specific embodiments of the present disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of the present disclosure and the reagents and materials required therefor. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes on the basis of the existing embodiments.

[0148] The present disclosure uses the following abbreviations:

[0149] DCM represents dichloromethane; MeOH represents methanol; TFA represents trifluoroacetic acid; DCE represents dichloroethane; TfOH represents trifluoromethanesulfonic acid; Tf2O represents trifluoromethanesulfonic anhydride; B2Pin2 represents bis(pinacolato)diboron; KOAc represents potassium acetate; Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; Pd(PPh3)4 represents tetrakis(triphenylphosphine)palladium; MeCN represents acetonitrile; DMSO represents dimethyl sulfoxide; MeSO3H-P2O5 represents Eaton's reagent; TEA represents triethylamine; Ms2O represents methanesulfonic anhydride; TBSCl represents tert-butyldimethylchlorosilane; Pd-PEPPSI-IPent catalyst represents [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II); TBAF represents tetrabutylammonium fluoride; DIPEA represents N,N-diisopropylethylamine; LC-MS represents liquid chromatography-mass spectrometry; MS represents mass spectrometry; 11H NMR represents nuclear magnetic resonance hydrogen spectrum; ESI represents electrospray ionization; rt represents room temperature; SFC represents supercritical fluid chromatography; NADPH represents reduced coenzyme II; iPrOH represents isopropanol; HEPES represents N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffer; EGTA represents ethylene glycol-bis(2-aminoethyl ether) tetraacetic acid; DTT represents dithiothreitol; ATP represents adenosine triphosphate; EDTA represents ethylenediaminetetraacetic acid; IC 50 represents the half inhibitory concentration, which refers to the concentration when reaching half of the maximum inhibitory effect. ELISA represents enzyme-linked immunosorbent assay. Specific embodiments

[0150] The compounds of the present disclosure can be prepared by a variety of synthetic methods well-known to those skilled in the art, including the specific embodiments listed herein, the embodiments formed by the combination of it with other chemical synthesis methods, and the equivalent replacement methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0151] The present disclosure will be described in detail below by way of examples, but this does not mean any adverse limitation to the present disclosure. The present disclosure has been described in detail herein, and its specific embodiments have also been disclosed. It will be obvious to those skilled in the art to make various changes and improvements to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0152] Unless otherwise stated, the ratio represented by the mixed solvent is the volume mixing ratio.

[0153] Unless otherwise stated, % refers to weight percentage wt%.

[0154] The compounds are named manually or by software. Commercially available compounds use the supplier catalog names.

[0155] The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS);

[0156] The eluent or mobile phase can be a mixed eluent or mobile phase composed of two or more solvents, and the ratio is the volume ratio of each solvent. Example 1: 5-(((3S,5S)-3,5-dimethylmorpholinyl)methyl)-10-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3-methyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 1)

[0157]

[0158] Step 1: 8-bromo-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (Compound 1-2)

[0159] At 0 °C, potassium carbonate (1.62 g, 11.70 mmol, 992.05 μL) and bromoacetone (1.60 g, 11.70 mmol) were added to a solution of 2-amino-6-bromophenol in acetone (15 mL of acetone, 2 g of 2-amino-6-bromophenol, 10.64 mmol), and then the reaction was carried out at room temperature for 2 hours. Then, trifluoroacetic acid (1.6 g, 14 mmol) and sodium cyanoborohydride (668 mg, 10.6 mmol) were added, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate, the organic phase was collected, concentrated, and purified by column chromatography (the eluent was water:acetonitrile = 1:9) to obtain Compound 1-2 (1.2 g, yield 49.5%).

[0160] LC-MS: m / z (ESI): 228 [M+H] + .

[0161] Step 2: Methyl 10-bromo-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-5-carboxylate (Compound 1-3)

[0162] Compound 1-2 (50 mg, 0.22 mmol) was dissolved in dichloroethane (2 mL), then dimethyl acetylenedicarboxylate (37 mg, 0.26 mmol), copper(I) iodide (2 mg, 0.01 mmol), trifluoromethanesulfonic acid (33 mg, 0.22 mmol) and trifluoromethanesulfonic anhydride (62 mg, 0.22 mmol) were added, and the reaction was heated at 120 °C for 24 hours until the reaction was completed. The reaction solution was directly concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (the eluent was water:acetonitrile = 1:9) to obtain Compound 1-3 (5 mg, yield 6.7%).

[0163] LC-MS: m / z (ESI): 338 [M+H] + .

[0164] Step 3: 10-Bromo-5-(hydroxymethyl)-3-methyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 1-4)

[0165] Dissolve Compound 1-3 (50 mg, 0.15 mmol) in methanol (2 mL). After cooling the system to 0 °C, add sodium borohydride (6 mg, 0.15 mmol). React at room temperature for 2 hours. After the reaction is completed, quench the reaction with water, and then concentrate under reduced pressure to dryness. The residue is purified by column chromatography (eluent: water:acetonitrile = 1:9) to obtain Compound 1-4 (40 mg, yield 87%).

[0166] LC-MS: m / z (ESI): 310 [M+H] + .

[0167] Step 4: 10-(2-Chloro-5-fluoropyrimidin-4-yl)-5-(hydroxymethyl)-3-methyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 1-5)

[0168] Dissolve Compound 1-4 (30 mg, 0.096 mmol) and bis(pinacolato)diboron (49 mg, 0.19 mmol) in 1,4-dioxane (2 mL). Then add potassium acetate (19 mg, 0.19 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (3 mg, 0.004 mmol). React at 100 °C for 5 hours under a nitrogen atmosphere until the reaction is completed. Filter the reaction solution directly, and then add 2,4-dichloro-5-fluoropyrimidine (16 mg, 0.096 mmol), sodium carbonate (30 mg, 0.29 mmol), tetrakis(triphenylphosphine)palladium (11 mg, 0.009 mmol) and water (0.2 mL) to the filtrate. React at 100 °C for 16 hours. After the reaction is completed, purify by column chromatography (eluent: water:acetonitrile = 1:9) to obtain Compound 1-5 (15 mg, yield 43%).

[0169] LC-MS: m / z (ESI): 362 [M+H] + .

[0170] Step 5: 10-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-5-(hydroxymethyl)-3-methyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 1-6)

[0171] Compounds 1-5 (15 mg, 0.041 mmol) and (3S,4R)-4-amino-3-hydroxytetrahydropyran (5 mg, 0.041 mmol) were dissolved in 1,4-dioxane (2 mL). Under nitrogen, (SP-4-1)-[1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichlorido(3-chloropyridine-κN)palladium (4 mg, 0.004 mmol) and cesium carbonate (40 mg, 0.124 mmol) were added. The reaction was carried out at 100 °C for 16 hours. After the reaction, it was purified by column chromatography (eluent: water:acetonitrile = 1:9) to obtain compound 1-6 (15 mg, yield 82%).

[0172] LC-MS: m / z (ESI): 443 [M+H] + .

[0173] Step 6: 5-(((3S,5S)-3,5-Dimethylmorpholinyl)methyl)-10-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3-methyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 1)

[0174] Compound 1-6 (30 mg, 0.067 mmol) was dissolved in dichloromethane (4 mL). Under a nitrogen protection environment, the system was cooled to 0 °C, and then thionyl chloride (12 mg, 0.1 mmol) was slowly added. The reaction was carried out at room temperature for 2 hours. After the reaction, it was concentrated under reduced pressure. The resulting mixture was directly dissolved in acetonitrile (2 mL), and then potassium carbonate (28 mg, 0.2 mmol), potassium iodide (22 mg, 0.135 mmol) and (3S,5S)-3,5-dimethylmorpholine (8 mg, 0.068 mmol) were added. The reaction was carried out at 50 °C for 16 hours. After the reaction, it was purified by column chromatography (eluent: water:acetonitrile = 1:9) to obtain compound 1 (4 mg, yield 10%).

[0175] LC-MS: m / z (ESI): 540 [M+H] + .

[0176] The NMR is that of a mixture of two isomers.

[0177] 11H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 2H), 8.40 (d, J = 1.8 Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.3 Hz, 2H), 6.44 (s, 1H), 6.35 (s, 1H), 4.93 (s, 2H), 4.53–4.40 (m, 2H), 4.32–4.18 (m, 2H), 4.05 (d, J = 15.3 Hz, 2H), 3.87–3.72 (m, 6H), 3.72–3.48 (m, 8H), 3.03 (t, J = 10.8 Hz, 4H), 2.93–2.83 (m, 3H), 2.80–2.71 (m, 3H), 2.71–2.62 (m, 2H), 2.40–2.29 (m, 2H), 2.03–1.92 (m, 4H), 1.38 (t, J = 7.5 Hz, 6H), 1.03 (d, J = 6.3 Hz, 12H).

[0178] Example 2: 4-(((3S,5S)-3,5-Dimethylmorpholin-4-yl)methyl)-9-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinolin-6-one (Compound 2)

[0179]

[0180] Step 1: Dimethyl 2-(4-bromo-1H-indol-1-yl)malonate (Compound 2-2)

[0181] Dissolve 4-bromoindole (Compound 2-1, 1.10 g, 5.55 mmol) in methanol (4 mL) solution, then add dimethyl acetylenedicarboxylate (0.94 g, 6.61 mmol), and stir the reaction mixture at room temperature for 3 hours. After the reaction is completed, filter, wash, collect the solid and dry it to obtain the crude product of Compound 2-2 (1.80 g), which can be directly used in the next step without purification.

[0182] m / z (ESI): 340 [M+H] +

[0183] Step 2: Methyl 9-bromo-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-4-carboxylate (Compound 2-3)

[0184] Under an argon atmosphere, compound 2-2 (1.0 g, 2.94 mmol) was dissolved in a solution of Eaton's reagent (6 mL), and the reaction mixture was stirred at 100 °C for 5 h. After the reaction was completed, the mixture was cooled to room temperature and purified by reverse-phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain compound 2-3 (0.34 g, two-step yield 20%).

[0185] m / z (ESI): 308 [M+H] +

[0186] Step 3: 9-Bromo-4-(hydroxymethyl)-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinolin-6-one (Compound 2-4)

[0187] Compound 2-3 (140.0 mg, 0.45 mmol) was dissolved in a solution of tetrahydrofuran (2 mL) and methanol (2 mL). Sodium borohydride (34.2 mg, 0.90 mmol) was slowly added to the reaction mixture, and the reaction mixture was stirred at room temperature for 5 h. After the reaction was completed, the mixture was purified by reverse-phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain compound 2-4 (90.0 mg, yield 71%).

[0188] m / z (ESI): 280 [M+H] +

[0189] Step 4: 9-Bromo-4-(((3S,5S)-3,5-dimethylmorpholino)methyl)-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinolin-6-one (Compound 2-5)

[0190] Under an argon atmosphere, compound 2-4 (90.0 mg, 0.32 mmol) was dissolved in a solution of dichloromethane (2 mL). The reaction mixture was stirred in an ice bath, and a solution of triethylamine (97.0 mg, 0.96 mmol) and methanesulfonic anhydride (97.0 mg, 0.56 mmol) in dichloromethane (1.0 mL) was slowly added to the reaction mixture. The reaction mixture was stirred in the ice bath for an additional 2 h. After the reaction was completed, the reaction mixture was concentrated. Under an argon atmosphere, N,N-dimethylformamide (2 mL) was added to dissolve the residue. Then, (3S,5S)-3,5-dimethylmorpholine (73.6 mg, 0.64 mmol) and triethylamine (97.0 mg, 0.96 mmol) were added to the reaction mixture, and the reaction mixture was stirred at 85 °C for 5 h. After the reaction was completed, the mixture was purified by reverse-phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain compound 2-5 (40.0 mg, yield 33%).

[0191] m / z (ESI): 377 [M+H] +

[0192] Step 5: 4-(((3S,5S)-3,5-Dimethylmorpholinyl)methyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinolin-6-one (Compound 2-6)

[0193] Compound 2-5 (20.0 mg, 0.053 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.9 mg, 5.3 μmol), bis(pinacolato)diboron (20.2 mg, 0.079 mmol) and potassium acetate (15.7 mg, 0.16 mmol) were placed in a reaction tube. The air in the reaction tube was replaced with argon, 1,4-dioxane (3 mL) was added, and the reaction solution was stirred in an oil bath at 100 °C for 10 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the crude product of Compound 2-6 in the dioxane filtrate was directly used for the next reaction step.

[0194] m / z(ESI): 425 [M+H] +

[0195] Step 6: (3S,4R)-4-((4-(4-(((3S,5S)-3,5-Dimethylmorpholinyl)methyl)-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinolin-9-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-yl acetate (Compound 2-7)

[0196] The above crude Compound 2-6 solution, Compound 2-8 (15.4 mg, 0.053 mmol), sodium carbonate (17.0 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium (6.1 mg, 5.3 μmol) and water (0.1 mL) were placed in a reaction tube. The air in the reaction tube was replaced with argon, and the reaction solution was stirred in an oil bath at 100 °C for 4 - 8 hours. After the reaction was completed, the reaction solution was concentrated and purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain Compound 2-7 (2.5 mg, overall yield in two steps 9%).

[0197] m / z(ESI): 552 [M+H] +

[0198] Step 7: 4-(((3S,5S)-3,5-Dimethylmorpholinyl)methyl)-9-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinolin-6-one (Compound 2)

[0199] Compound 2-7 (2.5 mg, 4.5 μmol) and ethanol (1 mL) were placed in a reaction tube. The air in the reaction tube was displaced with argon, and hydrazine hydrate (0.5 mL) was added to the reaction tube. The reaction tube was placed in an oil bath at 60 °C and stirred for 3 hours. After the reaction was completed, the reaction solution was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:9) to obtain Compound 2 (1.9 mg, yield 82%).

[0200] m / z (ESI): 510 [M+H] +

[0201] Example 3: 5-(Aminomethyl)-10-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3,6-dimethyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 3)

[0202]

[0203] Step 1: 10-Bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 3-1)

[0204] Compound 1-4 (229 mg, 0.74 mmol) and tert-butyldimethylchlorosilane (73 mg, 0.48 mmol) were dissolved in dichloromethane (7.5 mL), and then imidazole (60 mg, 0.89 mmol) was added and stirred at room temperature for 15 hours. After the reaction was completed, it was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to dryness, and the residue was purified by normal-phase column chromatography (petroleum ether:ethyl acetate = 50:50) to obtain the title compound 3-1 (247 mg, yield 79%).

[0205] m / z (ESI): 424 [M+H] + .

[0206] Step 2: 5-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 3-2)

[0207] Compound 3-1 (247 mg, 0.57 mmol), bis(pinacolato)diboron (289 mg, 1.14 mmol), dichlorobis(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) (42 mg, 0.057 mmol), and potassium acetate (112 mg, 1.14 mmol) were dissolved in dioxane (6.0 mL). The reaction was carried out at 90 °C for 12 h under a nitrogen atmosphere. After completion of the reaction, the reaction mixture was filtered to obtain a dioxane solution of compound 3-2, which was directly used for the next step.

[0208] m / z(ESI): 472 [M+H] + .

[0209] Step 4: 5-(((tert-Butyldimethylsilyl)oxy)methyl)-10-(2-chloro-5-fluoropyrimidin-4-yl)-3-methyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 3-3)

[0210] To a solution of compound 3-2 (273 mg, crude) in dioxane (5.0 mL) were added tetrakis(triphenylphosphine)palladium(0) (67 mg, 0.058 mmol), sodium carbonate (92 mg, 0.87 mmol), 2,4-dichloro-5-fluoropyrimidine (145 mg, 0.87 mmol), and water (1.0 mL). The reaction was carried out at 95 °C for 18 h under a nitrogen atmosphere. After completion of the reaction, the organic phase was concentrated to dryness under reduced pressure and purified by reverse-phase column chromatography (eluent: water:acetonitrile = 1:9) to obtain the title compound 3-3 (50 mg, 18% yield over two steps).

[0211] m / z(ESI): 476 [M+H] + .

[0212] Step 5: 5-(((tert-Butyldimethylsilyl)oxy)methyl)-10-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3-methyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 3-4)

[0213] Compound 3-3 (50 mg, 0.11 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (32.3 mg, 0.21 mmol), cesium carbonate (71.7 mg, 0.22 mmol), [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride (8.7 mg, 0.011 mmol) were reacted at 100 °C for 24 hours under a nitrogen atmosphere until the reaction was completed. The organic phase was concentrated to dryness under reduced pressure and purified by reverse-phase column chromatography (eluent: water:acetonitrile = 3:7) to obtain the title compound 3-4 (28 mg, yield 46%).

[0214] m / z(ESI): 557 [M+H] + .

[0215] Step 6: 5-(((tert-Butyldimethylsilyl)oxy)methyl)-10-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-6-iodo-3-methyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 3-5)

[0216] Compound 3-4 (28 mg, 0.05 mmol) and iodine (13 mg, 0.05 mmol) were dissolved in acetonitrile (1.0 mL), ammonium cerium(IV) nitrate (26 mg, 0.05 mmol) was added, and the reaction was stirred at 50 °C for 20 minutes. The reaction was quenched with sodium thiosulfate, and the organic phase was extracted with ethyl acetate and concentrated under reduced pressure to obtain the crude product of Compound 3-5, which was directly used in the next step of the reaction.

[0217] m / z(ESI): 683 [M+H] + .

[0218] Step 7: 5-(((tert-Butyldimethylsilyl)oxy)methyl)-10-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3,6-dimethyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 3-6)

[0219] Compound 3-5 (34 mg, crude) was dissolved in N,N-dimethylformamide (0.25 mL), then tetrakis(triphenylphosphine)palladium (5.8 mg, 0.005 mmol) and trimethylaluminum (1 M, 0.5 mL) were added, and the reaction was carried out at 80 °C for 10 minutes under a nitrogen atmosphere. After the reaction was completed, the reaction was quenched with saturated potassium sodium tartrate aqueous solution, and the organic phase was extracted with ethyl acetate. The organic phase was concentrated under reduced pressure to dryness, and the residue was purified by normal-phase column chromatography (methylene chloride:methanol = 96:04) to obtain the title compound 3-6 (28.7 mg, two-step yield 100%).

[0220] m / z(ESI):571[M+H] + .

[0221] Step 8: 10-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-5-(hydroxymethyl)-3,6-dimethyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 3-7)

[0222] Compound 3-6 (28.7 mg, 0.05 mmol) was dissolved in tetrahydrofuran (0.5 mL), then tetrabutylammonium fluoride tetrahydrofuran solution (1.0 M, 0.05 mL) was added, and the reaction was carried out at room temperature for 1 minute. After the reaction was completed, the reaction was quenched with water, the organic phase was extracted with ethyl acetate, and concentrated under reduced pressure to obtain the crude product of compound 3-7, which was directly used for the next step of the reaction.

[0223] m / z(ESI):457[M+H] + .

[0224] Step 9: 5-(Aminomethyl)-10-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3,6-dimethyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 3)

[0225] Compound 3-7 (23.0 mg, crude) was dissolved in dichloromethane (0.5 mL), then thionyl chloride (0.05 mL) was added, and the reaction was carried out at room temperature for 1 minute. After the reaction was completed, the reaction was quenched with water, the organic phase was extracted with ethyl acetate, and concentrated under reduced pressure to obtain the residue, which was directly used for the next step.

[0226] The residue was dissolved in acetonitrile (0.5 mL), and then N,N-diisopropylethylamine (0.1 mL), ammonia water (0.1 mL), and potassium iodide (8.0 mg, 0.05 mmol) were added. The reaction system was stirred at 55 °C for 15 hours. Ethyl acetate was added to extract the organic phase, which was then concentrated. The obtained residue was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 3:7) to give compound 3 (9.3 mg, 41% yield over two steps).

[0227] m / z(ESI): 456[M+H] + .

[0228] Compound 3 was separated and purified by SFC (prep.HPLC (DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase A: CO2, mobile phase B: iPrOH (0.1% NH3H2O); B%: 50%, 80 mL / min)) to obtain compound 3A and compound 3B.

[0229] Compound 3A:

[0230] Analyzed by SFC (column: Chiralpak AD-3 50 * 4.6 mm I.D., 3 μm; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol (containing 0.05% diethylamine), isocratic elution with B% (40%), flow rate 4 mL / min), the retention time was 0.626 minutes.

[0231] 1 1H NMR (400 MHz, DMSO-d6) δ 8.39 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 6.8 Hz, 1H), 5.07 (d, J = 7.4 Hz, 1H), 4.92 (d, J = 5.3 Hz, 1H), 4.49 (d, J = 11.3 Hz, 1H), 4.25 (d, J = 11.2 Hz, 1H), 4.03 (d, J = 14.1 Hz, 1H), 3.84–3.76 (m, 4H), 3.03 (t, J = 10.5 Hz, 1H), 2.68–2.65 (m, 1H), 2.34–2.31 (m, 1H), 2.16 (s, 3H), 2.02–1.91 (m, 1H), 1.52–1.42 (m, 1H), 1.37 (d, J = 6.5 Hz, 3H), 0.85 (s, 1H). Compound 3B:

[0232] Analyzed by SFC (column: Chiralpak AD-3 50*4.6mm I.D., 3μm; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol (containing 0.05% diethylamine), isocratic elution with B% (40%), flow rate 4 mL / min), the retention time was 0.944 minutes.

[0233] 1 H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 2.0 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 7.8 Hz, 1H), 5.08 (d, J = 7.0 Hz, 1H), 4.91 (d, J = 5.3 Hz, 1H), 4.49 (d, J = 11.2 Hz, 1H), 4.25 (d, J = 11.2 Hz, 1H), 4.03 (d, J = 14.2 Hz, 1H), 3.88–3.69 (m, 4H), 3.52–3.45 (m, 1H), 3.03 (t, J = 10.3 Hz, 1H), 2.68–2.65 (m, 1H), 2.34–2.31 (m, 1H), 2.16 (s, 3H), 2.01–1.95 (m, 1H), 1.49–1.44 (m, 1H), 1.37 (d, J = 6.5 Hz, 3H), 1.24 (s, 1H).

[0234] Example 4: 5-(((3S,5S)-3,5-Dimethylmorpholino)methyl)-10-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3,6-dimethyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 4)

[0235]

[0236] Procedure: 5-(((3S,5S)-3,5-Dimethylmorpholino)methyl)-10-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3,6-dimethyl-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinolin-7-one (Compound 4)

[0237] Dissolve Compound 3-7 (13.0 mg, 0.029 mmol) in dichloromethane (0.5 mL), then add thionyl chloride (0.05 mL). The reaction system was stirred at room temperature for 1.0 hour to complete the reaction. Quench the reaction with water, extract the organic phase with ethyl acetate, and concentrate under reduced pressure to obtain the residue directly for the next step.

[0238] The residue was dissolved in acetonitrile (0.5 mL), followed by the addition of N,N-diisopropylethylamine (0.05 mL), (3S,5S)-3,5-dimethylmorpholine (100 mg, 0.87 mmol), and potassium iodide (4.8 mg, 0.03 mmol). The reaction system was stirred at 55 °C for 15 h. Ethyl acetate was added to extract the organic phase, which was then concentrated. The obtained residue was purified by reverse-phase column chromatography (eluent: water:acetonitrile = 3:7) to give the title compound 4 (2.0 mg, yield 12%). m / z (ESI): 554 [M+H] + .

[0239] 1 1H NMR (400 MHz, DMSO-d6) δ 8.30 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.34–7.31 (m, 1H), 7.26–7.22 (m, 1H), 4.92 (d, J = 5.4 Hz, 1H), 4.53 (d, J = 11.1 Hz, 1H), 4.32–4.26 (m, 1H), 4.21–4.12 (m, 1H), 3.84–3.77 (m, 4H), 3.60–3.54 (m, 4H), 2.68–2.65 (m, 3H), 2.34–2.32 (m, 2H), 2.22 (d, J = 2.8 Hz, 3H), 2.17–2.14 (m, 1H), 1.35–1.32 (m, 2H), 1.23 (s, 3H), 1.04 (d, J = 6.3 Hz, 3H), 0.98 (d, J = 6.2 Hz, 3H).

[0240] Comparative Example

[0241] Synthesize the patented compound A according to Patent WO2023208172.

[0242]

[0243] Biological Test Experiment

[0244] Test Example 1: Detection of the inhibitory effects on CDK4 and CDK6 kinases

[0245] The experimental method for CDK4 kinase is as follows:

[0246] The Lance Ultra TR-FRET kinase detection reagent from Perkin Elmer was used to determine the in vitro activity of CDK4 by detecting the phosphorylation level of the substrate in the kinase reaction.

[0247] The reaction buffer contains the following components: 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 2 mM DTT, 0.01% Tween 20; Preparation of the CDK4 kinase solution: The human recombinant CDK4 / CycD1 protein (ProQinase, 0142-0143-1) is diluted with the reaction buffer to a 3 nM kinase solution; Preparation of the substrate reaction solution: The ULight-4E-BP1 kinase substrate (PerkinElmer, TRF0128) is diluted with the reaction buffer to 100 nM and 600 μM ATP; Preparation of the detection buffer: The Europium-anti-phospho-4E-BP1 antibody (PerkinElmer, TRF0216) and EDTA are respectively diluted with 1× detection buffer (PerkinElmer, CR97-100) to a 2 nM antibody solution and a 20 mM EDTA solution. Preparation of compound solutions at different concentrations: Using DMSO as the dilution solution, the compound stock solution is gradient-diluted through the dose-response program of the pipettor. The starting concentration of the compound to be tested is 200 nM, with a 4-fold dilution and 8 concentration points.

[0248] Using an Echo650 automated workstation, 100 nL of compound solutions at different concentrations are added to a 384-well detection plate (Perkin Elmer, 6007299), and then 5 μL of the CDK4 kinase solution is added. After mixing evenly, it is incubated at room temperature for 5 minutes. Subsequently, 5 μL of the substrate reaction solution is added, and the reaction mixture is incubated at room temperature for 60 minutes. Then, 10 μL of the detection buffer equal in volume to the reaction is added, mixed evenly, and left to stand at room temperature for 60 minutes. The reaction process is detected using an Envision plate reader (Perkin Elmer) at wavelengths of 615 nm and 665 nm. The signal value (absorbance at 665 nm / absorbance at 615 nm) is positively correlated with the phosphorylation degree of the substrate, thereby detecting the activity of the CDK4 kinase. In this experiment, the group without the CDK4 kinase protein is used as the 100% inhibition group, and the group with the CDK4 kinase protein but without the compound is used as the 0% inhibition group.

[0249] The percentage inhibition of the compound on CDK4 activity can be calculated using the following formula:

[0250] Inhibition percentage = 100 - 100 * (signal value at a specific concentration of the compound to be tested - signal value of the 100% inhibition group) / (signal value of the 0% inhibition group - signal value of the 100% inhibition group).

[0251] The IC50 value of the compound is calculated using XLfit (ID Business Solutions Ltd., UK) software from 8 concentration points through the following formula:

[0252] Y = Bottom + (Top - Bottom) / (1 + 10^((logIC50 - X) × slope factor))

[0253] Where Y is the percentage of inhibition, X is the logarithm of the concentration of the compound to be tested, Bottom is the minimum percentage of inhibition, Top is the maximum percentage of inhibition, and slope factor is the curve slope coefficient.

[0254] The experimental method of CDK6 kinase is as follows:

[0255] The in vitro activity of CDK6 was determined by using the Lance Ultra TR-FRET kinase detection reagent of Perkin Elmer and detecting the phosphorylation level of the substrate in the kinase reaction.

[0256] The reaction buffer contains the following components: 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 2 mM DTT, 0.01% Tween 20; Preparation of the CDK6 kinase solution: The human recombinant CDK6 / CycD3 (Carna Biosciences, 04-107) protein was diluted with the reaction buffer to a 2 nM kinase solution; Preparation of the substrate reaction solution: The ULight-4E-BP1 kinase substrate (Perkin Elmer, TRF0128) and 200 μM ATP were diluted with the reaction buffer to 100 nM; Preparation of the detection buffer: The Europium-anti-phospho-4E-BP1 antibody (Perkin Elmer, TRF0216) and EDTA were diluted with 1× detection buffer (Perkin Elmer, CR97-100) to a 2 nM antibody solution and a 20 mM EDTA solution respectively. Preparation of compound solutions with different concentrations: Using DMSO as the dilution solution, the compound stock solution was gradient-diluted through the dose-response program of the pipettor. The starting concentration of the compound to be tested was 1 μM, with a 4-fold dilution and 8 concentration points.

[0257] Using an Echo 650 automated workstation, 100 nL of compound solutions with different concentrations were added to a 384-well assay plate (Perkin Elmer, 6007299). Then, 5 μL of CDK6 kinase solution was added. After mixing evenly, the mixture was incubated at room temperature for 5 minutes. Subsequently, 5 μL of substrate reaction solution was added, and the reaction mixture was incubated at room temperature for 60 minutes. Then, 10 μL of detection buffer with the same volume as the reaction was added, mixed evenly, and left to stand at room temperature for 60 minutes. The reaction process was detected using an Envision plate reader (Perkin Elmer) at wavelengths of 615 nm and 665 nm. The signal value (absorbance at 665 nm / absorbance at 615 nm) was positively correlated with the phosphorylation degree of the substrate, thereby detecting the activity of CDK6 kinase. In this experiment, the group without adding CDK6 kinase protein was used as the 100% inhibition group, and the group with added CDK6 kinase protein but without added compound was used as the 0% inhibition group.

[0258] The percentage of inhibition of compound on CDK6 activity can be calculated using the following formula:

[0259] Percentage of inhibition = 100 - 100 * (signal value at a specific concentration of the test compound - signal value of the 100% inhibition group) / (signal value of the 0% inhibition group - signal value of the 100% inhibition group).

[0260] Compound IC 50 The value was calculated from 8 concentration points using XLfit (ID Business Solutions Ltd., UK) software through the following formula:

[0261] Y = Bottom + (Top - Bottom) / (1 + 10^((logIC 50 -X) × slope factor))

[0262] Where Y is the percentage of inhibition, X is the logarithm of the concentration of the test compound, Bottom is the minimum percentage of inhibition, Top is the maximum percentage of inhibition, and slope factor is the curve slope coefficient.

[0263] Experimental results:

[0264] Compound <![CDATA[CDK4 IC 50 (nM)]]> <![CDATA[CDK6 IC 50 (nM) <!-- 22 -->]]> Compound 1 18 716 Compound 2 21 762 Compound 4 9 159

[0265] Test Example 2: Anti-proliferative activity experiment of MCF7 cells

[0266] Cell proliferation was quantified by measuring BrdU incorporation during DNA synthesis in replicating (cycling) cells using the Cell Proliferation ELISA, BrdU (11669915001) chemiluminescent detection reagent from Sigma-Aldrich. MCF7 cells from ATCC were cultured in their recommended medium until the logarithmic growth phase. After trypsin digestion and centrifugation to obtain cell pellets, cell counting was performed. The cells were seeded at a density of 3000 cells / well in a 40 μL system in 384-well plates (Corning, 3570) and cultured overnight. Using an Echo 650 automated workstation, 40 nL of compound solutions at different concentrations (preparation method: using DMSO as the dilution solution, the stock solution of the compound was serially diluted by the dose-response program of the pipettor, the starting concentration of the test compound was 5 μM, 4-fold dilution, 8 concentration points) were added to the 384-well detection plates (Perkin Elmer, 6007299). After 24 hours of treatment, the Cell Proliferation ELISA, BrdU (chemiluminescent) detection kit was used for detection according to its operation manual. The Luminescence signal value was measured using an Envision plate reader. The signal value is proportional to the amount of DNA synthesis in the cells, and the amount of DNA synthesis is proportional to the cell proliferation rate, thus the proliferation activity of MCF7 cells can be detected. In this experiment, the group without cells was used as the 100% inhibition group, and the group with cells but without compounds was used as the 0% inhibition group.

[0267] The percentage inhibition of the compound on the proliferation activity of MCF7 cells can be calculated using the following formula:

[0268] Percentage inhibition = 100 - 100 * (signal value at a specific concentration of the test compound - signal value of the 100% inhibition group) / (signal value of the 0% inhibition group - signal value of the 100% inhibition group).

[0269] Compound IC 50 values were calculated from the 8 concentration points using XLfit (ID Business Solutions Ltd., UK) software using the following formula:

[0270] Y = Bottom + (Top - Bottom) / (1 + 10^((logIC50 - X) × slope factor))

[0271] where Y is the percentage inhibition, X is the logarithm of the concentration of the test compound, Bottom is the minimum percentage inhibition, Top is the maximum percentage inhibition, and slope factor is the curve slope coefficient.

[0272] Test Example 3: Determination of the metabolic stability of the compounds of the present invention in liver microsomes

[0273] I. Test materials and test equipment

[0274] 1. Reagent

[0275] Reagent Supplier Article Number NADPH Roche 10107824001 Verapamil Sigma MKBV4993V Propranolol Sigma BCBZ3154 Glipizide Sigma LRAA8855 Disodium Hydrogen Phosphate Sinopharm Chemical 20040618 Potassium Dihydrogen Phosphate Sinopharm Chemical 10017628

[0276] 2. Liver microsomes

[0277] Species Article Number Gender and Strain Supplier Rat 452501 Pooled, Male SD Corning

[0278] 3. Test equipment

[0279] Project Supplier Instrument Model Ultra-Pure Water Instrument Millipore Integral 10 Ultra-Low Temperature Incubator (-80°C) Thermo Fisher Scientific FDE60086FV Vortex Oscillator Dragon Lab MX-S Constant Temperature Incubator Shaker Shanghai Zhicheng Analytical Instrument Manufacturing Co., Ltd. 2WY-100H Centrifuge Eppendorf AG 5804R -25°C Low Temperature Refrigerator Zhongke Meiling Cryogenic Technology Co., Ltd. DW-YL270 Ultra Performance Liquid Chromatography Waters Waters ACQUITY UPLC Mass Spectrometer AB Sciex Triple Quad 6500Plus

[0280] II. Test procedures

[0281] 1. Preparation of stock solutions

[0282] Prepare 10 mM DMSO stock solutions of the positive compound verapamil and the test compound respectively, and dilute them to 100 μM with acetonitrile.

[0283] 2. Preparation of 100 mM phosphate buffer (PBS, pH 7.4)

[0284] First, weigh 7.098 g of disodium hydrogen phosphate, add 500 mL of pure water and dissolve it by ultrasonic treatment as solution A. Weigh 3.400 g of potassium dihydrogen phosphate, add 250 mL of pure water and dissolve it by ultrasonic treatment as solution B. Slowly add solution B to solution A on a stirrer until the pH value reaches 7.4. Store the phosphate buffer at 4 °C for later use.

[0285] 3. Preparation of 10 mM NADPH

[0286] Weigh an appropriate amount of NADPH before the test and prepare a working solution with a concentration of 10 mM using phosphate buffer. The final concentration of NADPH in the test system is 1 mM.

[0287] 4. Preparation of incubation system

[0288] The preparation of the incubation system is shown in the following table and preheat it in a 37 °C incubator for 10 minutes before use.

[0289] Component Stock Solution Concentration Volume Final Concentration of the System Analyte or Verapamil 100 μM 2 μL 1 μM Liver Microsomes 20 mg / mL 5 μL 0.5 mg / mL PBS 100 mM 173 μL 99 mM

[0290] 5. Test method

[0291] The entire incubation process was carried out in a 96-well plate. First, 178 μL of the incubation system was added to the 96-well plate, and then 2 μL of the stock solution of the compound of the present invention at 100 μM or the stock solution of the positive control compound verapamil was added. Before initiating the reaction with 20 μL of 10 mM NADPH solution or PBS solution, the incubation system was preheated at 37 °C for 10 minutes. After adding 20 μL of 10 mM NADPH or PBS to initiate the reaction, 25 μL of the incubation sample was taken out at 0, 5, 15, 30, and 60 min, and 200 μL of ice-cold acetonitrile (containing internal standards: 10 ng / mL glipizide, 10 ng / mL propranolol) was added to terminate the reaction. After vortexing and mixing, the deep-well plate was centrifuged at 4000 g at 4 °C for 10 minutes. 100 μL of the supernatant was transferred to a new 96-well plate, and 100 μL of pure water was added and mixed for LC-MS / MS analysis.

[0292] III. Data Analysis

[0293] All data were calculated using Microsoft Excel software. The peak area was detected by extracting the ion chromatogram. The slope value k was determined by the linear regression of the natural logarithm of the remaining percentage of the parent drug versus the incubation time curve, and the in vitro half-life (t 1 / 2 ) of the parent drug was calculated.

[0294] in vitro t 1 / 2 = 0.693 / k

[0295] The in vitro intrinsic clearance rate (CL int ) was calculated by the following formula:

[0296] in vitro CL int = (0.693 / t 1 / 2 ) * (volume of incubation / amount of proteins)

[0297] (Note: volume of incubation, incubation volume (μL); amount of protein, protein amount (mg))

[0298] The intrinsic clearance rate values calculated by the above formula are shown in Table 1.

[0299] Table 1 Intrinsic clearance rate values of the compounds of the present invention in liver microsome stability

[0300]

Claims

1. A compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: X 1 and X 2 each independently selected from N and CR 6 ; R 1 Selected from hydrogen, halogen, amino, mercapto, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl, 5- to 10-membered heteroaryl, -OR 1a 、-C(O)R 1a 、-C(O)OR 1a 、-C(O)NR 1a R 1b 、-NR 1a R 1b 、-NR 1a C(O)R 1b 、-NR 1a C(O)OR 1b and -NR 1a C(O)NR 1b R 1c , wherein the amino, mercapto, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 1A substituents; R 2 Selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 alkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl, wherein the C1-C 10 alkyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl are optionally substituted by one or more R 2A substituents; Each R 2A is independently selected from halogen, cyano, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 12 cycloalkyl, 4- to 12-membered heterocycloalkyl, C6-C 10 aryl, 5- to 10-membered heteroaryl, oxo, -OR 2a , -S(O)2R 2a , -S(O)2NR 2a R 2b , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2a R 2b , -NR 2a R 2b , -NR 2a C(O)R 2b , -NR 2a C(O)OR 2b , -NR 2a C(O)NR 2b R 2c and -NR 2a S(O)2R 2b , wherein the C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 12 cycloalkyl, 4- to 12-membered heterocycloalkyl, C6-C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted with one or more R 2d ; R 3 、R 4 、R 6 are independently selected from hydrogen, halogen, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl, 5- to 10-membered heteroaryl, -OR 3a 、-C(O)R 3a 、-C(O)OR 3a 、-C(O)NR 3a R 3b 、-NR 3a R 3b 、-NR 3a C(O)R 3b 、-NR 3a C(O)OR 3b and -NR 3a C(O)NR 3b R 3c , wherein the C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 3A ; Each R 1a 、R 1b 、R 1c 、R 3a 、R 3b 、R 3c is independently selected from hydrogen, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl and 5- to 10-membered heteroaryl, wherein the C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 1f substituents; R 5 selected from hydrogen, C2-C 10 alkenyl, C2-C 10 alkynyl, and C1-C 10 alkyl, wherein the C2-C 10 alkenyl, C2-C 10 alkynyl, and C1-C 10 alkyl is optionally substituted with one or more R 5A substituents; Ring A is selected from 4- to 10-membered heterocycles and 5- to 10-membered heteroaryl rings, and the 4- to 10-membered heterocycles and 5- to 10-membered heteroaryl rings are optionally substituted with one or more R a substituents; Ring B is selected from C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl, and 5- to 12-membered heteroaryl, wherein the C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl, and 5- to 12-membered heteroaryl are optionally substituted by one or more R b substituents; Each R a 、R b is independently selected from halogen, cyano, oxo, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10-membered heterocyclic group, C6-C 10 aryl, 5-10-membered heteroaryl, -OR 4a 、-C(O)R 4a 、-C(O)OR 4a 、-C(O)NR 4a R 4b 、-NR 4a R 4b 、-NR 4a C(O)R 4b 、-NR 4a C(O)OR 4b 、-NR 4a C(O)NR 4b R 4c 、S(O)2R 4a and S(O)2NR 4a R 4b ; wherein the C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10-membered heterocyclic group, C6-C 10 aryl and 5-10-membered heteroaryl are optionally substituted with one or more R 4A ; Each R 2a 、R 2b 、R 2c 、R 4a 、R 4b 、R 4c is independently selected from hydrogen, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl and 5-10 membered heteroaryl, wherein the C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, 5-10 membered heteroaryl is optionally substituted with one or more R 2f substituents; Each R 2d and R 2f are each independently selected from hydrogen, hydroxy, halogen, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl, 5- to 10-membered heteroaryl, oxo, C(O)R g and -S(O)2R g , where the hydroxy, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4- to 10-membered heterocyclic group, C6-C 10 aryl, 5- to 10-membered heteroaryl are optionally substituted by at least one substituent selected from: halogen, hydroxy, oxo, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 cycloalkyl, C3-C 12 halocycloalkyl, 4- to 10-membered heterocyclic group, 4- to 10-membered halocyclic group, C6-C 10 aryl, C6-C 10 haloaryl, 5- to 10-membered heteroaryl and 5- to 10-membered haloheteroaryl; Each R 1A 、R 1f 、R 3A 、R 4A 、R 5A 、R g is independently selected from hydrogen, amino, halogen, hydroxy, C1-C8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl and 5-10 membered heteroaryl, and the amino, hydroxy, C 1-8 alkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted with at least one substituent selected from halogen, hydroxy, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 cycloalkyl, C3-C 12 halocycloalkyl, 4-10 membered heterocyclic group, 4-10 membered halocyclic group, C6-C 10 aryl, C6-C 10 haloaryl, 5-10 membered heteroaryl and 5-10 membered hal heteroaryl; one or more hydrogen atoms of the compound are optionally deuterium atoms.

2. The compound of formula (I) according to claim 1, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, X 1 and X 2 at least one is CR 6 ; or X 1 and X 2 are both CR 6 , preferably CH.

3. The compound of formula (I) according to any one of claims 1-2, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, R 1 selected from hydrogen, halogen, amino, mercapto, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 alkyl, wherein the amino, mercapto, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 alkyl are optionally substituted by one or more R 1A ; or R 1 is selected from hydrogen and C1-C 10 alkyl, wherein the C1-C 10 alkyl are optionally substituted by one or more R 1A ; or R 1 is selected from hydrogen and methyl, wherein the methyl is optionally substituted by one or more R 1A ; or R 1 is selected from hydrogen and methyl.

4. The compound of formula (I) according to any one of claims 1-3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 1A Independently selected from halogen and hydroxyl group.

5. The compound of formula (I) according to any one of claims 1-4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2 selected from C1-C 10 alkyl and 5- to 10-membered heteroaryl, the C1-C 10 alkyl and 5- to 10-membered heteroaryl being optionally substituted by one or more R 2A ; or R 2 is selected from C1-C4 alkyl and 5- to 6-membered heteroaryl, the C1-C4 alkyl and 5- to 6-membered heteroaryl being optionally substituted by one or more R 2A ; or R 2 is selected from methyl, isopropyl and thiazolyl, the methyl, isopropyl and thiazolyl being optionally substituted by one or more R 2A ; or R 2 is selected from methyl, isopropyl and the methyl, isopropyl and being optionally substituted by one or more R 2A ; or R 2 is selected from methyl, aminomethyl, or R 2 is selected from and aminomethyl; or R 2 is 6. A compound of formula (I) according to any one of claims 1-5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2A Independently selected from halogen, cyano, C3-C 12 cycloalkyl, 4- to 12-membered heterocyclic group, C6-C 10 aryl, 5- to 10-membered heteroaryl, -OR 2a and -NR 2a R 2b , where the C3-C 12 cycloalkyl, 4- to 12-membered heterocyclic group, C6-C 10 aryl and 5- to 10-membered heteroaryl are optionally substituted by one or more R 2d ; or R 2A is independently selected from 4- to 10-membered heterocyclic group, -OR 2a and -NR 2a R 2b , where the 4- to 10-membered heterocyclic group is optionally substituted by one or more R 2d ; or R 2A is independently selected from 4- to 7-membered heterocyclic group, -OR 2a and -NR 2a R 2b , where the 4- to 7-membered heterocyclic group is optionally substituted by one or more R 2d ; or R 2A is independently selected from morpholinyl, -OR 2a and -NR 2a R 2b , where the morpholinyl is optionally substituted by one or more R 2d ; or R 2A is independently selected from amino and hydroxy, where the amino and hydroxy are optionally substituted by one or more R 2d ; or R 2A is independently selected from amino and hydroxy, where the is optionally substituted by one or more R 2d substituted.

7. The compound of formula (I) according to any one of claims 1-6, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R 2a independently selected from hydrogen, C2-C 10 alkenyl, C2-C 10 alkynyl, and C1-C 10 alkyl; or R 2a is hydrogen.

8. The compound of formula (I) according to any one of claims 1-7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2b independently selected from hydrogen, C2-C 10 alkenyl, C2-C 10 alkynyl, and C1-C 10 alkyl; or R 2b is hydrogen.

9. The compound of formula (I) according to any one of claims 1-8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2d independently selected from halogen, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 alkyl; or R 2d independently selected from C1-C 10 alkyl; or R 2d independently selected from C1-C4 alkyl; or R 2d is methyl.

10. The compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein, R 3 selected from hydrogen, halogen, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 alkyl; or R 3 selected from hydrogen and halogen; or R 3 is fluorine or chlorine; or R 3 is fluorine.

11. The compound of formula (I) according to any one of claims 1-10, or its stereoisomer or its pharmaceutically acceptable salt, wherein, R 4 selected from hydrogen, halogen, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 alkyl; or R 4 is selected from hydrogen and halogen; or R 4 is hydrogen.

12. The compound of formula (I) according to any one of claims 1-11, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R 5 selected from hydrogen and C1-C 10 alkyl; or R 5 is hydrogen.

13. A compound of formula (I) according to any one of claims 1-12, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R 6 selected from hydrogen, halogen, cyano and C1-C 10 alkyl; or R 6 selected from hydrogen and halogen; or R 6 is hydrogen or fluorine; or R 6 is hydrogen.

14. The compound of formula (I) according to any one of claims 1-13, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, Ring A is selected from 5- to 6-membered heterocycles, and the 5- to 6-membered heterocycles are optionally substituted with one or more R a ; or Ring A is selected from dihydrooxazine rings, dihydrothiazine rings, tetrahydropyridine rings, pyrrole rings, and dihydropyrrole rings, and the dihydrooxazine rings, dihydrothiazine rings, tetrahydropyridine rings, pyrrole rings, and dihydropyrrole rings are optionally substituted with one or more R a substituents.

15. The compound of formula (I) according to any one of claims 1-14, or its stereoisomer or its pharmaceutically acceptable salt, wherein, R a independently selected from halogen, cyano and C1-C 10 alkyl, wherein the C1-C 10 alkyl is optionally substituted by one or more R 4A ; or R a is independently selected from C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted by one or more R 4A ; or R a is independently selected from methyl and ethyl, wherein the methyl and ethyl are optionally substituted by one or more halogens; or R a is independently selected from methyl, trifluoromethyl and ethyl.

16. The compound of formula (I) according to any one of claims 1-15, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Selected from where n is selected from 0 and 1; or Selected from where n is selected from 0 and 1; or Selected from where n is selected from 0 and 1.

17. The compound of formula (I) according to any one of claims 1-16, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring B is selected from 4- to 10-membered heterocyclic groups and 5- to 12-membered heteroaryl groups, and the 4- to 10-membered heterocyclic groups and 5- to 12-membered heteroaryl groups are optionally substituted with one or more Rs b or Ring B is selected from 4- to 10-membered heterocyclic groups and 5- to 6-membered heteroaryl groups, and the 4- to 10-membered heterocyclic groups and 5- to 6-membered heteroaryl groups are optionally substituted by one or more Rs b ; or Ring B is selected from tetrahydropyranyl, piperidinyl, tetrahydronaphthyridinyl, and pyridinyl, and the tetrahydropyranyl, piperidinyl, tetrahydronaphthyridinyl, and pyridinyl are optionally substituted by one or more Rs b ; or Ring B is selected from the is optionally substituted by one or more Rs b ; or Ring B is selected from the is optionally substituted by one or more Rs b ; or Ring B is selected from Or Ring B is 18. The compound of formula (I) according to any one of claims 1-17, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R b independently selected from halogen, cyano, C1-C 10 alkyl, 4-10-membered heterocyclic group, -OR 4a and S(O)2R 4a , wherein the C1-C 10 alkyl and 4-10-membered heterocyclic group are optionally substituted by one or more R 4A ; or R b is independently selected from C1-C4 alkyl, 4-7-membered heterocycle, -OR 4a and S(O)2R 4a , wherein the C1-C4 alkyl and 4-7-membered heterocycle are optionally substituted by one or more R 4A ; or R b is independently selected from methyl, hydroxy, piperidinyl and S(O)2CH3, and the methyl, hydroxy, piperidinyl and S(O)2CH3 are optionally substituted by one or more R 4A ; or R b is independently selected from hydroxy, methyl and S(O)2CH3.

19. The compound of formula (I) according to any one of claims 1-18, or its stereoisomer, or its pharmaceutically acceptable salt, wherein, R 4A Selected from methyl and methylpiperazinyl.

20. The compound of formula (I) according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (II) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof Among them, Said R 1 , R 2 , R 3 and ring A are as defined in any one of claims 1-19.

21. The compound of formula (I) according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof 22. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1-21, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. Use of the compound of formula (I) according to any one of claims 1-21, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22, in the manufacture of a medicament for preventing or treating a CDK-mediated disease.

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