Preparation and use of heterocyclic compound

Abstract

Provided are a CDK4 inhibitor compound as represented by formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, and the use thereof in the preparation of a drug for preventing or treating CDK4-mediated diseases.

Description

Preparation and application of heterocyclic compounds

[0001] Cross-reference to related applications

[0002] This application claims the benefits and priorities of the following Chinese invention patent applications, the entire contents of which are incorporated herein by reference:

[0003] Patent application No. 202411200485.9, filed with the State Intellectual Property Office on August 29, 2024;

[0004] Patent application No. 202411306838.3 was filed with the State Intellectual Property Office on September 19, 2024. Technical Field

[0005] This disclosure pertains to the pharmaceutical field and relates to a cyclin-dependent kinase 4 (CDK4) inhibitor compound or its stereoisomer or a pharmaceutically acceptable salt thereof, pharmaceutical compositions containing the thereof, and their use as CDK4 inhibitors in the prevention or treatment of related diseases. Background Technology

[0006] The development of tumors is associated with an imbalance of various oncogenes and tumor suppressor genes. The functional effects of almost all oncogenes and tumor suppressor genes ultimately converge on the cell cycle. Therefore, tumors can be considered a type of cell cycle disease (CCD), and regulating or blocking the cell cycle is one approach to treating 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 regulatory network.

[0007] CDKs are a group of serine / threonine protein kinases. CDKs drive the cell cycle by chemically acting on serine / threonine proteins and work synergistically with cyclins, making them important factors in cell cycle regulation.

[0008] Among the CDK subtypes involved in the cell cycle, CDK4 / 6 plays an irreplaceable role. Cancer-related cell cycle mutations mainly occur during the G1 phase and the G1 / S phase transition. CDK4 / 6 binds to cyclin D to form a kinase-active complex. Through phosphorylation of the tumor suppressor gene Rb product pRb, it releases the bound transcription factor E2F, which initiates the transcription of genes related to the S phase, prompting the cell to pass the checkpoint and transition from the G1 phase to the S phase.

[0009] However, clinical applications have also demonstrated that CDK4 / 6 inhibitors can cause adverse reactions such as gastrointestinal and / or hematological toxicity, and may lead to acquired resistance with prolonged use. New research has also reported that the hematological side effects of CDK4 / 6 inhibitors may be related to CDK6 inhibition, and CDK4 has been identified as a single oncogene in various breast cancers. Therefore, selective CDK4 inhibitors may offer better safety and efficacy compared to CDK4 / 6 inhibitors. This disclosure aims to develop novel selective CDK4 inhibitors. Summary of the Invention

[0010] This disclosure relates to compounds of formula (I) or their stereoisomers or pharmaceutically acceptable salts.

[0011] in:

[0012] Ring A is selected from C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-12 heteroaryl, the C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-12 heteroaryl groups are optionally substituted with one or more R groups. a replace;

[0013] R 1 and R 6 Independently selected from hydrogen, amino, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic groups, C2-C 10 alkenyl and C2-C 10 alkynyl group, the amino group, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic groups, C2-C 10 alkenyl and C2-C 10 The alkynyl group is optionally surrounded by one or more R groups. 1a replace;

[0014] R 2 and R 2’ Independently selected from hydrogen, hydroxyl, amino, mercapto, cyano, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the hydroxyl, amino, mercapto, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally coated with one or more R groups.2a replace;

[0015] Or, R 1 and R 2 The atoms connected to the ring and the ring together form a 4-10 membered heterocycle or a 5-12 membered heteroaromatic ring, wherein the 4-10 membered heterocycle and the 5-12 membered heteroaromatic ring are optionally bounded by one or more R atoms. b replace;

[0016] Or, R 2 and R 2’ Together with the atoms they connect, they form C3-C 12 Saturated carbocyclic, oxo-, or 4-10 membered heterocyclic rings, wherein the C3-C 12 Saturated carbon rings or 4-10 membered heterocycles may be selectively coupled with one or more R atoms. c replace;

[0017] R 3 R 4 R 7 R 8 and R 9 Independently selected from hydrogen, halogen, hydroxyl, amino, mercapto, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy and C1-C 10 Halogenated alkyl groups;

[0018] Or, R 7 and R 6 The atoms connected to it together form a 5-10 membered heterocycle, which is optionally bounded by one or more R atoms. d replace;

[0019] Or, R 6 and R 2’ The atoms connected to it together form a 4-10 membered heterocycle, which is optionally bounded by one or more R atoms. e replace;

[0020] R 5 Selected from hydrogen, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 Alkyl, the C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 Alkyl groups are optionally surrounded by one or more R 5a replace;

[0021] Each R 1a Independently selected from halogen, hydroxyl, cyano, amino and C1-C 10 Alkoxy;

[0022] Each R 2a Independently selected from halogens, hydroxyl groups, cyano groups, amino groups, C1-C8 alkyl groups, C1-C8 alkoxy groups, and C1-C8 haloalkyl groups;

[0023] Each R 5a Independently selected from halogens, hydroxyl groups, cyano groups, and amino groups;

[0024] Each R a Independently selected from halogen, hydroxyl, oxo, amino, cyano, -C(O)-R f -OC(O)-R f -S(O)2-R f C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the hydroxyl, amino, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally coated with one or more R groups. g replace;

[0025] Each R b R c R d and R e Independently selected from halogen, hydroxyl, mercapto, cyano, oxo, amino, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 alkylamine group and C1-C 10 Halogenated alkyl groups;

[0026] Each R g Independently selected from cyano, amino, halogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the amino, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally coated with one or more R groups. h replace;

[0027] Each R f and R h The group is independently selected from halogen, hydroxyl, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy and 4-10 membered heterocyclic groups, wherein the amino, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy and 4-10 membered heterocyclic groups are optionally substituted with amino, halogen, hydroxyl and C1-C4 alkyl.

[0028] One or more hydrogen atoms in the compound of formula (I) may be selected as deuterium atoms.

[0029] In some embodiments, ring A is selected from 4-10-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 4-10-membered heterocyclic group and the 5-10-membered heteroaryl group are optionally surrounded by one or more R groups. a replace.

[0030] In some embodiments, ring A is selected from 4-7 membered heterocyclic groups, which are optionally surrounded by one or more R groups. a replace.

[0031] In some embodiments, ring A is selected from a 6-membered heterocyclic group, which is optionally surrounded by one or more R groups. a replace.

[0032] In some embodiments, the 4-10 membered heterocyclic group, the 4-7 membered heterocyclic group, and the 6 membered heterocyclic group contain one or two heteroatoms selected from O or N.

[0033] In some embodiments, the 4-10 membered heterocyclic group, the 4-7 membered heterocyclic group, and the 6 membered heterocyclic group contain one O heteroatom.

[0034] In some embodiments, ring A is a tetrahydropyranyl group, which is optionally surrounded by one or more R groups. a replace.

[0035] In some implementation schemes, each R a Independently selected from halogen, hydroxyl, amino, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy and C1-C 10 Halogenated alkyl groups.

[0036] In some implementation schemes, each R a It is independently selected from halogen, hydroxyl, amino, cyano and C1-C4 alkyl groups.

[0037] In some implementation schemes, each R a It is independently selected from halogens, hydroxyl groups, and C1-C4 alkyl groups.

[0038] In some implementation schemes, R a It is a hydroxyl group.

[0039] In some implementations, ring A is

[0040] In some implementations, ring A is

[0041] In some implementation schemes, R 1 Selected from hydrogen and C1-C 10 Alkyl, the C1-C 10 Alkyl groups may be optionally replaced by halogens or deuterium.

[0042] In some implementation schemes, R 1 The alkyl group is selected from hydrogen and C1-C4 alkyl groups, wherein the C1-C4 alkyl groups are optionally substituted with halogens or deuterium, and the halogens are preferably fluorine.

[0043] In some implementation schemes, R 1 The halogen is selected from hydrogen, methyl, and ethyl, wherein the methyl and ethyl groups are optionally substituted with halogen or deuterium, and the halogen is preferably fluorine.

[0044] In some implementation schemes, R 1 Selected from hydrogen and C1-C 10 alkyl.

[0045] In some implementation schemes, R 1 It can be hydrogen or methyl.

[0046] In some implementation schemes, R 1 Selected from hydrogen, methyl, CD3 and CH2CHF2.

[0047] In some implementation schemes, R 1 Selected from hydrogen, methyl and CH2CHF2.

[0048] In some implementation schemes, R 2 and R 2’ Independently selected from hydrogen, halogen, hydroxyl, amino, mercapto, cyano, and C1-C 10 Alkyl groups, including hydroxyl, amino, mercapto, and C1-C groups. 10 Alkyl groups are optionally surrounded by one or more R groups. 2a replace.

[0049] In some implementation schemes, R 2 and R 2’ Independently selected from hydrogen and C1-C 10 Alkyl, the C1-C 10 Alkyl groups are optionally surrounded by one or more R groups. 2a replace.

[0050] In some implementation schemes, R 2 and R 2’Independently selected from hydrogen and C1-C4 alkyl groups, wherein the C1-C4 alkyl group is optionally surrounded by one or more R... 2a replace.

[0051] In some implementation schemes, R 2 and R 2’ The radicals are independently selected from hydrogen, methyl, ethyl, and isopropyl, wherein the methyl, ethyl, and isopropyl groups are optionally separated by one or more R groups. 2a replace.

[0052] In some implementation schemes, R 2 and R 2’ The radicals are independently selected from hydrogen, methyl, and isopropyl, wherein the methyl and isopropyl groups are optionally separated by one or more R groups. 2a replace.

[0053] In some implementation schemes, R 2 and R 2’ Independently selected from hydrogen and methyl, wherein the methyl group is optionally separated by one or more R 2a replace.

[0054] In some implementation schemes, R 2 Selected from hydrogen, methyl, and isopropyl, wherein the methyl and isopropyl groups are optionally surrounded by one or more R groups. 2a replace.

[0055] In some implementation schemes, R 2’ Selected from methyl and ethyl, wherein the methyl and ethyl groups are optionally separated by one or more R... 2a replace.

[0056] In some implementation schemes, each R 2a It is independently selected from halogens, hydroxyl groups, C1-C8 alkyl groups, and C1-C8 alkoxy groups.

[0057] In some implementation schemes, each R 2a It is independently selected from hydroxyl and C1-C8 alkoxy groups.

[0058] In some implementation schemes, each R 2a It is independently selected from C1-C8 alkoxy groups.

[0059] In some implementation schemes, each R 2a It is independently selected from hydroxyl and C1-C4 alkoxy groups.

[0060] In some implementation schemes, each R 2a It is independently selected from C1-C4 alkoxy groups, such as methoxy groups.

[0061] In some implementation schemes, each R 2a It is independently selected from hydroxyl and methoxy groups.

[0062] In some implementation schemes, R 2a It is a methoxy group.

[0063] In some implementation schemes, R 2a It is a hydroxyl group.

[0064] In some implementation schemes, R 2 and R 2’ Independently selected from hydrogen, methyl, ethyl, And methoxymethyl.

[0065] In some implementation schemes, R 2 and R 2’ Independently selected from methyl and

[0066] In some implementation schemes, R 1 and R 2 The atoms connected to it together form a 4-10 membered heterocycle, which is optionally bounded by one or more R atoms. b replace.

[0067] In some implementation schemes, R 1 and R 2 The atoms connected to it together form a 4-6 membered heterocycle, which is optionally bounded by one or more R atoms. b replace.

[0068] In some implementation schemes, R 1 and R 2 The atoms connected to it together form a 5-6 membered heterocycle, which is optionally bounded by one or more R atoms. b replace.

[0069] In some implementation schemes, R 1 and R 2 The atoms bonded to the tetrahydropyrrole ring and the azahexacyclic butane together form a tetrahydropyrrole ring and an azahexacyclic butane, which are optionally bonded by one or more R atoms. b replace.

[0070] In some implementation schemes, R 1 and R 2 The atoms connected to it together form a tetrahydropyrrole ring, which is optionally bounded by one or more R atoms. b replace.

[0071] In some implementation schemes, each R b It is independently selected from halogen, hydroxyl, mercapto, cyano, oxo, amino and C1-C4 alkyl groups.

[0072] In some implementation schemes, each R b It is independently selected from halogens, such as fluorine.

[0073] In some implementation schemes, R b It is fluorine.

[0074] In some implementation schemes, R 2 and R 2’ The atoms connected to it together form a C3-C5 saturated carbon ring or a 4-6 membered heterocycle, wherein the C3-C5 saturated carbon ring or the 4-6 membered heterocycle is optionally bounded by one or more R atoms. c replace.

[0075] In some implementation schemes, R 2 and R 2’ The atoms connected to it together form a C3-C5 saturated carbon ring or a 5-6 membered heterocycle, wherein the C3-C5 saturated carbon ring or the 5-6 membered heterocycle is optionally bounded by one or more R atoms. c replace.

[0076] In some implementation schemes, R 2 and R 2’ The atoms bonded to the cyclopropane ring and the tetrahydropyrrole ring together form a cyclopropane, tetrahydrofuran, cyclopentane, oxetane, cyclobutane, or piperidine ring, wherein the cyclopropane, tetrahydropyrrole, tetrahydrofuran, cyclopentane, oxetane, cyclobutane, or piperidine ring is optionally bounded by one or more R atoms. c replace.

[0077] In some implementation schemes, R 2 and R 2’ The atoms bonded to the cyclopropane ring and the tetrahydropyrrole ring together form a cyclopropane, tetrahydrofuran, cyclopentane, or piperidine ring, wherein the cyclopropane, tetrahydropyrrole, tetrahydrofuran, cyclopentane, or piperidine ring is optionally bounded by one or more R atoms. c replace.

[0078] In some implementation schemes, each R c It is independently selected from halogen, hydroxyl, mercapto, cyano, oxo, amino and C1-C4 alkyl groups.

[0079] In some implementation schemes, R 2 and R 2’ Together with the atoms they are connected to, they form cyclopropane, tetrahydropyrrole ring, tetrahydrofuran ring, cyclopentane, oxacyclobutane, cyclobutane, or piperidine ring.

[0080] In some implementation schemes, R 2 and R 2’ Together with the atoms they are connected to, they form cyclopropane, tetrahydropyrrole ring, tetrahydrofuran ring, cyclopentane, or piperidine ring.

[0081] In some implementation schemes, R 3 R 4 R7 R 8 and R 9 It is independently selected from hydrogen, halogen, hydroxyl, cyano and C1-C4 alkyl.

[0082] In some implementation schemes, R 3 R 4 R 7 R 8 and R 9 It is independently selected from hydrogen and halogens.

[0083] In some implementation schemes, R 3 R 4 R 7 R 8 and R 9 It is independently selected from hydrogen, chlorine, and fluorine.

[0084] In some implementation schemes, R 3 and R 8 At least one is selected from halogens, with fluorine and chlorine being preferred halogens.

[0085] In some implementation schemes, R 3 and R 8 All are halogens, with fluorine and chlorine being preferred. In some embodiments, R 3 Selected from halogens.

[0086] In some implementation schemes, R 3 It is chlorine or fluorine.

[0087] In some implementation schemes, R 8 It is either hydrogen or fluorine.

[0088] In some implementation schemes, R 3 Selected from fluorine and chlorine, R 8 Selected from hydrogen and fluorine, and when R 3 When it is chlorine, R 8 It is hydrogen.

[0089] In some implementation schemes, R 7 It is either hydrogen or fluorine.

[0090] In some implementation schemes, R 4 and R 9 It is hydrogen.

[0091] In some implementation schemes, R 4 R 7 and R 9 It is hydrogen.

[0092] In some implementation schemes, R 6 Selected from hydrogen and C1-C 10 alkyl.

[0093] In some implementation schemes, R 6 Selected from C1-C4 alkyl groups.

[0094] In some implementation schemes, R 6 Selected from methyl, CD3 and isopropyl.

[0095] In some implementation schemes, R 6 Selected from methyl and isopropyl.

[0096] In some implementation schemes, R 7 and R 6 The atoms connected to it together form a 5-7 membered heterocycle, which is optionally bounded by one or more R atoms. d replace.

[0097] In some implementation schemes, R 7 and R 6 The atoms connected to it together form a dihydrooxazine ring, which is optionally bounded by one or more R atoms. d replace.

[0098] In some implementation schemes, R 7 and R 6 Together with the atoms they connect, they form The c and b keys represent keys shared with the connected rings, the Optional by one or more R d replace.

[0099] In some implementation schemes, each R d Selected from halogens, cyano groups, and C1-C4 alkyl groups.

[0100] In some implementation schemes, R 7 and R 6 The atoms bonded to it together form a dihydrooxazine ring. In some embodiments, R 7 and R 6 Together with the atoms they connect, they form The c and b keys represent keys shared with the connected rings.

[0101] In some implementation schemes, R 6 and R 2’ The atoms connected to it together form a 5-7 membered heterocycle, which is optionally bounded by one or more R atoms. e replace.

[0102] In some implementation schemes, R 6 and R 2’ Together with the atoms they connect, they form a tetrahydropyrrole ring, a piperazine ring, and a piperidine ring. The tetrahydropyrrole ring, piperazine ring, piperidine ring, Optional by one or more R e Replacement, where the 'a' key represents a key shared with the connected ring.

[0103] In some implementation schemes, each R e Independently selected from halogens, oxometalates, and C1-C 10 alkyl.

[0104] In some implementation schemes, each R e It is independently selected from halogens, oxo- and C1-C4 alkyl groups.

[0105] In some implementation schemes, each R e It is independently selected from fluorine, oxo, and methyl.

[0106] In some implementation schemes, R 5 It is hydrogen.

[0107] In some embodiments, the compound of formula (I) of this application, or its stereoisomer or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (II) or its stereoisomer or a pharmaceutically acceptable salt thereof.

[0108] Among them, R 1 R 2 R 2’ R 3 R 6 R 7 and R 8 As defined above.

[0109] In some embodiments, the compound of formula (I) of this application, or its stereoisomer or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (III) of this application, or its stereoisomer or a pharmaceutically acceptable salt thereof.

[0110] Where n is 1, 2, or 3, t is 0, 1, or 2, and R b R 2’ R 3 R 6 R 7 and R 8 As defined above.

[0111] In some implementations, n is 1 or 2.

[0112] In some implementations, t is 0.

[0113] In some embodiments, the compound of formula (I) of this application, or its stereoisomer or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (IV) or its stereoisomer or a pharmaceutically acceptable salt thereof.

[0114] Where p is selected from 0, 1, and 2, X is selected from -CH2-, -NHCH2-, -CH2CH2-, -CH2NHCH2-, and -NHCH2CH2-, R e R 1 R 2 R 3 R 7 and R 8 As defined above.

[0115] In some implementations, p is 0.

[0116] In some implementations, X is selected from -CH2- and -CH2CH2-.

[0117] In some embodiments, the compound of formula (I) of this application, or its stereoisomer or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (V), or its stereoisomer or a pharmaceutically acceptable salt thereof.

[0118] Among them, R 1 R 2 R 2’ R 3 and R 8 As defined above.

[0119] In some embodiments, the compounds of formula (I) of this disclosure, or their stereoisomers, or their pharmaceutically acceptable salts, are selected from the following compounds or their pharmaceutically acceptable salts:

[0120] On the other hand, this disclosure provides pharmaceutical compositions comprising a compound of formula (I) or (II) or (III) or (IV) or (V) of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0121] On the other hand, this disclosure provides a method for treating an individual (e.g., a mammal) with a CDK4-mediated disease, comprising administering to the individual (e.g., a mammal, preferably a human) a therapeutically effective amount of a compound of formula (I) or (II) or (III) or (IV) or (V) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0122] On the other hand, this disclosure provides the use of compounds of formula (I) or (II) or (III) or (IV) or (V) or their stereoisomers or pharmaceutically acceptable salts or their pharmaceutical compositions in the preparation of medicaments for the prevention or treatment of CDK4-mediated diseases.

[0123] On the other hand, this disclosure provides the use of compounds of formula (I) or (II) or (III) or (IV) or (V) or stereoisomers thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of CDK4-mediated diseases.

[0124] On the other hand, this disclosure provides compounds of formula (I), (II), (III), (IV), or (V) for the prevention or treatment of CDK4-mediated diseases, or stereoisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0125] In some implementations, the CDK4-mediated disease is a tumor.

[0126] Terminology Definitions and Explanations

[0127] Unless otherwise stated, the terms used in this disclosure have the following meanings: the definitions of groups and terms recorded in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, definitions of specific compounds in the examples, etc., can be arbitrarily combined and combined with each other. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient.

[0128] In this article Indicates the connection site.

[0129] The term "stereoisomer" refers to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.

[0130] The diagrammatic representation of racemic or enantiomerically pure compounds in this article is derived from Maehr, J. Chem. Ed. 1985, 62:114-120. Unless otherwise specified, wedge-shaped real and wedge-shaped imaginary bonds are used. The absolute configuration of a solid center is represented by direct real keys and direct virtual keys. It indicates the relative configuration of a stereocenter (such as the cis-trans configuration of alicyclic compounds).

[0131] When a substituent is cross-bonded to two atoms on a ring, it can bond to any atom on that ring. For example, structural units. R represents e Substitution can occur at any position on the ring.

[0132] The compounds disclosed herein may have asymmetric atoms such as carbon, sulfur, nitrogen, and phosphorus atoms, or asymmetric double bonds, and therefore may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E- and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof or other mixtures, such as mixtures enriched with enantiomers or diastereomers. All such isomers and mixtures thereof are within the scope of the definition of the compounds disclosed herein. Alkyl groups or other substituents may contain additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms. All such isomers involved in all substituents, and mixtures thereof, are also included within the scope of the definition of the compounds disclosed herein. The compounds containing asymmetric atoms disclosed herein can be isolated in optically active pure form or in racemic form. The optically active pure form can be separated from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0133] The term "substituted" refers to the substitution of one or more hydrogen atoms on a specific atom by a substituent, provided that the valence state of the specific atom is normal and the resulting compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are substituted; oxo substitution does not occur on aromatic groups.

[0134] The terms “optional” or “optionally” mean that the event or condition described below may or may not occur, including both the occurrence and non-occurrence of said event or condition. For example, “optionally” substituted with one or more halogens means that the ethyl group can 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 and / or cannot be synthesized is introduced.

[0135] When any variable (e.g., R) a R b When a group appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is surrounded by two R... b Replaced, then each R b Each has its own independent options.

[0136] C in this article m -C n It refers to having an integer number of carbon atoms in the range mn. For example, "C1-C 10 "" means that the group can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms.

[0137] The term "alkyl" refers to a compound with the general formula C10. n H 2n+1 The alkyl group can be straight-chain or branched. The term "C1-C" refers to a hydrocarbon group. 10 "Alkyl" can be understood as representing a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3 ... -Dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, etc.; the term "C1-C6 alkyl" can be understood as referring to an alkyl group having 1 to 6 carbon atoms, specific examples including but 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 as referring to a straight-chain or branched saturated alkyl group having 1 to 4 carbon atoms. The term "C1-C3 alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms. The "C1-C6 alkyl" 10 The term "alkyl" can encompass the range of "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 "halogenated alkyl" refers to an alkyl group substituted with one or more halogens such as F, Cl, Br, or I. The term "C1-C4 haloalkyl" refers to a C1-C4 alkyl group substituted with one or more halogens such as F, Cl, Br, or I, including monosubstituted, polysubstituted, or fully substituted alkyl groups.

[0138] The term "alkoxy" refers to a group formed by the loss of a hydrogen atom from a hydroxyl group in straight-chain or branched alcohols; it can be understood as "alkyloxy" or "alkyl-O-". The term "C1-C"... 10 "Alkoxy" can be understood as "C1-C"10 "alkyloxy" or "C1-C" 10 Alkyl-O-"; the term "C1-C6 alkoxy" can be understood as "C1-C6 alkyloxy" or "C1-C6 alkyl-O-". The "C1-C" 10 "Alkoxy" can include the range of "C1-C6 alkoxy" and "C1-C3 alkoxy", and the "C1-C6 alkoxy" can further include "C1-C3 alkoxy".

[0139] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms and having at least one double bond. The term "C2-C"... 10 "Alkenyl" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, "C2-C". 10 "Alkenyl" can include "C2-C6 alkenyl", "C2-C4 alkenyl", C2 or C3 alkenyl. It is understood that when the alkenyl group contains more than one double bond, the double bonds can be separable or conjugated. Specific examples of alkenyl groups 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.

[0140] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one triple bond. The term "C2-C"... 10 "Alkyne" can be understood as representing a straight-chain or branched unsaturated hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. "C2-C" 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH) and propynyl (-C≡CCH). 3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl, or but-3-ynyl. "C2-C 10 "Alynyl" can include "C2-C3 alkynyl", and examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), propynyl-1-alkynyl (-C≡CCH3), and propynyl-2-alkynyl (-CH2C≡CH).

[0141] The term "cycloalkyl" refers to a fully saturated carbocyclic group that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 20-membered ring. The term "C3-C" is also used. 10"Cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms in the ring. The term "C3-C6 cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, or 6 carbon atoms in the ring.

[0142] The term "heterocyclic group" or "heterocycle" refers to a fully saturated or partially saturated (not aromatic as a whole) monocyclic, fused-ring, spirocyclic, or bridged-ring group containing 1-5 (e.g., 1-3 or 1-2) heteroatoms or heteroatom groups (i.e., groups containing heteroatoms). These "heteratoms or heteroatom groups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-. The term "4-10 membered heterocyclic group" refers to a heterocyclic group with 4, 5, 6, 7, 8, 9, or 10 ring atoms, containing 1-5 heteroatoms or heteroatom groups independently selected from those described above. "4-10 membered heterocyclic groups" can include "4-7 membered heterocyclic groups". The term "4-7 membered heterocyclic group" refers to a heterocyclic group with 4, 5, 6 or 7 ring atoms, and whose ring atoms contain 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups independently selected from those described above. Specific examples of 4 membered heterocyclic groups include, but are not limited to, azirrocyclobutane or oxacyclobutane; specific examples of 5 membered heterocyclic groups include, but are not limited to, tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoalkyl, pyrazolyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclic groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazine, trithiaalkyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7 membered heterocyclic groups include, but are not limited to, diazacycloheptane. The heterocyclic group can also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopentano[c]pyrrolo-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group can be a benzofused cyclic group of the above-mentioned 4-7-membered heterocyclic groups, specific examples of which include, but are not limited to, dihydroisoquinolinyl, etc. "4-10 membered heterocyclic group" can include the ranges of "5-10 membered heterocyclic group", "4-7 membered heterocyclic group", "5-6 membered heterocyclic group", "6-8 membered heterocyclic group", "4-10 membered heterocyclic alkyl group", "5-10 membered heterocyclic alkyl group", "4-7 membered heterocyclic alkyl group", "5-6 membered heterocyclic alkyl group", and "6-8 membered heterocyclic alkyl group". "4-7 membered heterocyclic group" can further include the ranges of "4-6 membered heterocyclic group", "5-6 membered heterocyclic group", "4-7 membered heterocyclic alkyl group", "4-6 membered heterocyclic alkyl group", and "5-6 membered heterocyclic alkyl group".Although some bicyclic heterocyclic groups in this disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic groups as a whole are still non-aromatic. The term "4-10 membered monocyclic heterocyclic group" refers to a monocyclic heterocyclic group containing 4-10 ring atoms.

[0143] The term "heterocyclic alkyl" refers to a fully saturated cyclic group existing in the form of a monocyclic, fused, bridged, or spirocyclic ring, wherein the ring atoms contain 1-5 heteroatoms or heteroatom groups (i.e., groups containing heteroatoms). These "heteroatoms or heteroatom groups" include, but are not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O)2-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-. The term "4-10 membered heterocyclic alkyl" refers to a heterocyclic alkyl group with 4, 5, 6, 7, 8, 9, or 10 ring atoms, and its ring atoms contain 1-5 independently selected heteroatoms or heteroatom groups as described above. The term "5-10 membered heterocyclic alkyl" refers to a heterocyclic alkyl group with 5, 6, 7, 8, 9 or 10 ring atoms, and whose ring atoms contain 1 to 5 independent heteroatoms or heterogroups selected from those described above. "4-10-membered heterocyclic alkyl" and "5-10-membered heterocyclic alkyl" include "4-7-membered heterocyclic alkyl", wherein specific examples of 4-membered heterocyclic alkyl include, but are not limited to, acridine, oxadiazolyl, or thiobutylcycloyl; specific examples of 5-membered heterocyclic alkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, imidazolyl, or tetrahydropyrazolyl; specific examples of 6-membered heterocyclic alkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, piperazine, 1,4-thiaoxalyl, 1,4-dioxane, thiomorpholinyl, 1,3-dithiaalkyl, or 1,4-dithiaalkyl; and specific examples of 7-membered heterocyclic alkyl include, but are not limited to, azirheptanyl, oxaheptanyl, or thioheptanyl.

[0144] The term "aryl" refers to an aromatic ring group consisting of an all-carbon monocyclic or fused polycyclic aromatic cyclic group with a conjugated π-electron system. Aryl groups can have 6-20, 6-14, or 6-12 carbon atoms. The term "C6-C"... 10 "Aryl" can be understood as an aryl group having 6 to 10 carbon atoms. Examples include a ring with 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring with 9 carbon atoms ("C9 aryl"), such as indenyl or indenyl; or a ring with 10 carbon atoms ("C9 aryl"). 10 Aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0145] The term "heteroaryl" refers to an aromatic monocyclic or fused polycyclic system containing at least one ring atom selected from N, O, or S, with the remaining ring atoms being C. The term "5-10-membered heteroaryl" can be understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9, or 10 ring atoms, for example, 5, 6, 9, or 10 ring atoms, and containing 1-5, for example 1-3, heteroatoms independently selected from N, O, and S. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl and their benzo[derivatives], such as benzofuranyl, benzothienyl, benzothiazolyl, benzooxazolyl, benzoisooxazolyl, benzoimidazolyl, benzotriazolyl, indazole, indolyl or isindolyl; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl and their benzo[derivatives], such as quinolinyl, quinazolinyl or isoquinolinyl; or acrylinyl, inazinyl, purinyl and their benzo[derivatives]; or cyclolinyl, phthalazinyl, quinazolinyl, quinoxolinyl, naphthidyl, pteridinyl, carbazolyl, acrylinyl, phenazinyl, phenothiazinyl or phenothiazinyl. The term "6-10-membered heteroaryl" can be understood to include monocyclic or bicyclic aromatic ring systems having 6, 7, 8, 9, or 10 ring atoms, for example, 6, 9, or 10 ring atoms, and containing 1 to 5, for example 1 to 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 to 3, for example 1 to 2, heteroatoms independently selected from N, O, and S.

[0146] The term "halogen" or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0147] The term "hydroxyl group" refers to the -OH group.

[0148] The term "cyano" refers to the -CN group.

[0149] The term "amino" refers to the -NH2 group.

[0150] The term "nitro" refers to the -NO2 group.

[0151] The term "thiol" refers to the -SH group.

[0152] The term "treatment" means administering the compound or preparation described in this application to improve or eliminate a disease or one or more symptoms related to said disease, and includes:

[0153] (i) Suppress the disease or disease state, that is, curb its development;

[0154] (ii) Relieve the disease or disease state, even if the disease or disease state subsides.

[0155] The term "therapeutic effective amount" means (i) the amount of the disclosed compound used to treat a particular disease, condition, or disorder, and (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder. The amount of the disclosed compound constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by someone skilled in the art based on their own knowledge and the content of this disclosure.

[0156] The term “prevention” means administering the compound or formulation described in this 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 (e.g., a mammal), particularly when such an individual (e.g., a mammal) is susceptible to the disease state but has not yet been diagnosed with the disease state.

[0157] The term "individual" includes both mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock such as cattle, horses, sheep, goats, and pigs; domesticated animals such as rabbits, dogs, and cats; and laboratory animals, including rodents such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human. The terms "patient" and "individual" are used interchangeably.

[0158] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0159] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of an acid or base, including salts formed by a compound with an inorganic or organic acid, and salts formed by a compound with an inorganic or organic base.

[0160] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or salts thereof with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the disclosed compounds to an organism.

[0161] The term "pharmaceuticalally acceptable excipient" refers to excipients that do not cause significant irritation to 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.

[0162] The word “comprise” or “include” and its English variants such as comprises or comprising can be understood as having an open, non-exclusive meaning, that is, “including but not limited to”.

[0163] This disclosure also includes compounds of this disclosure that are identical to those described herein, but in which one or more atoms are labeled with isotopes whose atomic weights or mass numbers differ from those commonly found in nature. Examples of isotopes that can be incorporated into 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.

[0164] Certain isotope-labeled compounds of this disclosure (e.g., using...) 3 H and 14 C-labeling can be used in the analysis of compound and / or substrate tissue distribution. Tritiumization (i.e., 3 H) and carbon-14 (i.e. 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Positron-emitting isotopes, such as... 15 O、 13 N、 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotopically labeled compounds of this disclosure can typically be prepared by replacing the unlabeled reagent with an isotopically labeled reagent using a procedure similar to those disclosed in the schemes and / or examples below.

[0165] The pharmaceutical compositions disclosed herein can be prepared by combining the compounds disclosed herein with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalers, gels, microspheres and aerosols.

[0166] Typical routes of administration of the disclosed compounds or their pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0167] The pharmaceutical compositions disclosed herein can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, emulsification, freeze drying, etc.

[0168] In some embodiments, the pharmaceutical composition is in an 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 this disclosure to be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquids, gels, pastes, suspensions, etc., for oral administration to patients.

[0169] Solid oral compositions can be prepared using conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, 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 sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, flow aids, or flavoring agents.

[0170] The pharmaceutical composition may also be suitable for parenteral administration, such as in suitable unit dosage forms of sterile solutions, suspensions or lyophilized products.

[0171] The dosage is determined based on factors such as the specific compound, the disease condition and its severity, the identity of the subject or host requiring treatment (e.g., weight, sex), and the specific circumstances of the case, including, for example, the specific formulation administered, the route of administration, the condition being treated, and the subject or host being treated.

[0172] 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 separate doses. The daily dose and unit dose may vary according to many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the route of administration, the individual subject's requirements, the severity of the disease or condition to be treated, and the practitioner's judgment.

[0173] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0174] The chemical reactions in the specific embodiments of this disclosure are carried out in a suitable solvent, which must be suitable for the chemical changes of this disclosure and the reagents and materials required therefor. In order to obtain the compounds of this disclosure, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction flow based on existing embodiments.

[0175] The following abbreviations are used in this disclosure:

[0176] DMF represents N,N-dimethylformamide; THF represents tetrahydrofuran; MeOH represents methanol; EtOH represents ethanol; MeCN represents acetonitrile; TCFH represents N,N,N',N'-tetramethylchloroformamidin hexafluorophosphate; dioxane represents dioxane; Pd(PPh3)4 represents tetrakis(triphenylphosphine)palladium; DIEA / DIPEA represents N,N-diisopropylethylamine; DMSO represents dimethyl sulfoxide; B2pin2 represents pinacol diboronate. Pd(dppf)Cl2 represents 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride; KOAc represents potassium acetate; TEA represents triethylamine; HATU represents 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DCE represents 1,2-dichloroethane; (PPh3)AuCl represents triphenylphosphine chlorogold; AgOTf represents silver trifluoromethanesulfonate; LC-MS represents liquid chromatography-mass spectrometry; MS represents mass spectrometry. 1 1H NMR represents proton nuclear magnetic resonance spectroscopy; ESI represents electrospray ionization; 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 The half-maximal inhibitory concentration (WMC) refers to the concentration at which half of the maximum inhibitory effect is achieved; ELISA stands for enzyme-linked immunosorbent assay. Detailed Implementation

[0177] The compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed herein, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments disclosed herein.

[0178] The present disclosure is described in detail below with reference to embodiments, but this does not imply any adverse limitation thereof. The present disclosure has been described in detail herein, including specific embodiments thereof. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present disclosure without departing from the spirit and scope thereof. All reagents used in this disclosure are commercially available and can be used without further purification.

[0179] Unless otherwise stated, the proportions of mixed solvents are volume-based.

[0180] Unless otherwise stated, % refers to weight percentage (wt%).

[0181] Compounds are processed manually or Software naming conventions are used; commercially available compounds use supplier catalog names.

[0182] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts are measured in units of 10⁻⁶. -6 (ppm). The solvents used for NMR determination were deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard was tetramethylsilane (TMS).

[0183] The eluent or mobile phase may be a mixture of two or more solvents, with the ratio being the volume ratio of each solvent.

[0184] Example 1: 4-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-11a-methyl-1,2,9,10,11,11a-hexahydro-7H-[1,4]oxazin[2,3,4-ij]pyrrolo[2,1-b]quinazolin-7-one

[0185] Step 1: Methyl 8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carboxylate (compounds 1-2)

[0186] Compound 1-1 (440 mg, 1.79 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of 1,2-dibromoethane (504 mg, 2.68 mmol) and potassium carbonate (1.23 g, 8.94 mmol). The reaction mixture was stirred at 80 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was collected, concentrated under reduced pressure, and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to give compound 1-2 (62 mg, yield 13%).

[0187] m / z(ESI): 272[M+H] +

[0188] Step 4: 8-Bromo-3,4-dihydro-2H-benzo[b][1,4]oxazine-5-carboxylic acid (compounds 1-3)

[0189] Compounds 1-2 (60 mg, 220.58 μmol) were dissolved in a tetrahydrofuran / methanol / water solution (3:1:1, 5 mL), followed by the addition of lithium hydroxide (26.41 mg, 1.10 mmol). The reaction mixture was stirred at 50 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature, and the pH of the reaction solution was adjusted to 3 by adding 2 M hydrochloric acid. The solution was then filtered to obtain compounds 1-3 (45 mg, 79% yield).

[0190] m / z(ESI): 258 [M+H] +

[0191] Step 5: (8-bromo-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)(2-(bromomethyl)pyrrolidine-1-yl)methyl ketone (compounds 1-5)

[0192] Compounds 1-3 (45 mg, 174.42 μmol) and 2-(bromomethyl)pyrrolidine (compounds 1-4, 42.91 mg, 261.56 μmol) were dissolved in acetonitrile (5 mL), followed by the addition of N,N,N',N'-tetramethylchloromethamphexane hexafluorophosphate (146.78 mg, 523.12 μmol) and 2,4,6-trimethylpyridine (105.74 mg, 871.86 μmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to give compounds 1-5 (25 mg, yield 35%).

[0193] m / z(ESI): 405[M+H] +

[0194] Step 6: 4-Bromo-11a-methyl-1,2,9,10,11,11a-hexahydro-7H-[1,4]oxazino[2,3,4-ij]pyrrolo[2,1-b]quinazolin-7-one (compounds 1-6)

[0195] Compound 1-5 (20 mg, 49.50 μmol) was dissolved in N,N-dimethylformamide (1 mL) at 0 °C, and sodium hydride (7.13 mg, 296.96 μmol) was added. The mixture was stirred for 10 minutes, and then stirred at room temperature for 2 hours. After the reaction was completed, the mixture was purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to give compound 1-6 (13 mg, yield 81%).

[0196] m / z(ESI): 323[M+H]+

[0197] Step 7: 11a-methyl-4-(trimethyltinyl)-1,2,9,10,11,11a-hexahydro-7H-[1,4]oxazino[2,3,4-ij]pyrrolo[2,1-b]quinazolin-7-one (compounds 1-7)

[0198] Compounds 1-6 (18 mg, 55.73 μmol) were dissolved in dioxane (2 mL) solution under an argon atmosphere. Tetra(triphenylphosphine)palladium (6.72 mg, 5.82 μmol) and hexamethyldistin (28.61 mg, 87.33 μmol) were then added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain crude compound 1-7 (20 mg). This crude compound was used directly in the next reaction without further purification.

[0199] m / z(ESI): 409[M+H] +

[0200] Step 8: 4-(2-chloro-5-fluoropyrimidin-4-yl)-11a-methyl-1,2,9,10,11,11a-hexahydro-7H-[1,4]oxazino[2,3,4-ij]pyrrolo[2,1-b]quinazolin-7-one (compounds 1-8)

[0201] Compounds 1-7 (20 mg, 49.14 μmol) were dissolved in dioxane (2 mL) solution under an argon atmosphere. Tetra(triphenylphosphine)palladium (5.88 mg, 5.09 μmol), cuprous chloride (5.04 mg, 50.88 μmol), and 2,4-dichloro-5-fluoropyrimidine (12.74 mg, 76.32 μmol) were then added. The reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was collected, concentrated under reduced pressure, and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compounds 1-8 (8 mg, two-step yield 38%).

[0202] m / z(ESI): 375[M+H] +

[0203] Step 9: 4-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-11a-methyl-1,2,9,10,11,11a-hexahydro-7H-[1,4]oxazino[2,3,4-ij]pyrrolo[2,1-b]quinazolin-7-one (Compound 1)

[0204] Compounds 1-8 (8 mg, 21.39 mmol) were dissolved in dimethyl sulfoxide (5 mL) solution, followed by the addition of N,N-diisopropylethylamine (82.6 mg, 640.35 μmol) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (50.01 mg, 325.59 μmol). The reaction mixture was stirred at 120 °C for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain target compound 1 (2 mg, 21%).

[0205] m / z(ESI): 456 [M+H] +

[0206] 1 H NMR (400MHz, DMSO-d6) δ8.33(s,1H),7.35(d,J=8.0Hz,1H),7.16(d,J=7.8Hz,1H),6.77(d,J=8.0Hz,1H),4.91(d,J=5.2Hz,1H),4.33(d,J=11.1Hz,1H) ,4.16(s,1H),3.87–3.57(m,6H),3.55–3.43(m,3H),3.02(t,J=10.4Hz,1H) ,2.32–2.14(m,2H),2.07–1.85(m,3H),1.45(d,J=11.9Hz,1H),1.31(s,3H).

[0207] Example 2: 8-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3a-methyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one (Compound 2)

[0208] Step 1: 8-Bromo-3a-methyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one (compound 2-2)

[0209] Compound 2-1 (300 mg, 1.40 mmol) was dissolved in methanol (8 mL), followed by the addition of 4-pentyn-1-ol (117.35 mg, 1.40 mmol) and platinum chloride (46.87 mg, 139.50 μmol), respectively. The reaction mixture was stirred at 80 °C for 48 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was collected, concentrated under reduced pressure, and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 2-2 (180 mg, 46%).

[0210] m / z(ESI): 281[M+H]+

[0211] Step 2: 3a-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborone-2-yl)-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one (compounds 2-3)

[0212] Under an argon atmosphere, compound 2-2 (30 mg, 106.70 μmol) was dissolved in 2 mL of dioxane solution. Then, 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7.71 mg, 10.54 μmol), pinacol diborate (40.49 mg, 159.44 μmol), and potassium acetate (31.37 mg, 319.65 μmol) were added. The reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain crude compound 2-3 (33 mg). This crude product required no purification and was used directly in the next reaction step.

[0213] m / z(ESI): 329[M+H] +

[0214] Step 3: 8-(2,5-dichloropyrimidin-4-yl)-3a-methyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one (compounds 2-4)

[0215] Compound 2-3 (33 mg, 100.54 μmol) was dissolved in dioxane / water (8:1, 1.9 mL) under an argon atmosphere. Then, 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (7.36 mg, 10.06 μmol), 2,4,5-trichloropyrimidine (36.88 mg, 201.07 μmol), and potassium carbonate (41.63 mg, 301.21 μmol) were added, and the reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to give compound 2-4 (17 mg, two-step yield 46%).

[0216] m / z(ESI): 349[M+H] +

[0217] Step 4: 8-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3a-methyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one (Compound 2)

[0218] Compounds 2-4 (15 mg, 42.95 μmol) were dissolved in dimethyl sulfoxide (0.2 mL) solution, followed by the addition of N,N-diisopropylethylamine (110.82 mg, 857.47 μmol) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (compound 2-5, 98.97 mg, 644.29 μmol). The reaction mixture was stirred at 120 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain target compound 2 (9 mg, 49%).

[0219] m / z(ESI): 430[M+H] +

[0220] 1 H NMR (400MHz, DMSO-d6) δ8.41(d,J=14.9Hz,2H),7.75(d,J=7.9Hz,1H),7.46( s,1H),6.99(d,J=8.0Hz,1H),6.87(s,1H),4.92(dd,J=5.4,1.5Hz,1H),3.80 (dd,J=11.3,5.3Hz,3H),3.47(d,J=12.5Hz,3H),3.31–3.26(m,1H),3.03(t, J=10.3Hz,1H),2.13–1.89(m,5H),1.47(dd,J=12.3,4.3Hz,1H),1.28(s,3H).

[0221] Example 3: 6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-8-fluoro-4-isopropyl-3a-methyl-2,3,3a,4-tetrahydropyrrolo[2,1-b]quinazolin-9(1H)-one (Compound 3)

[0222] Step 1: 4-Bromo-2-fluoro-6-(isopropylamino)benzoic acid (compound 3-2)

[0223] Compound 3-1 (1 g, 4.22 mmol) was dissolved in pyridine (4 mL) solution, followed by the addition of isopropylamine (1.25 g, 21.15 mmol) and triethylamine (2.13 g, 21.05 mmol), respectively. The reaction mixture was stirred overnight at 110 °C. After the reaction was complete, the solution was concentrated under reduced pressure, and the pH was adjusted to 2-3 using 1 N hydrochloric acid. The mixture was filtered, and the residue was collected to give compound 3-2 (500 mg, 43%). m / z (ESI): 276 [M+H] +

[0224] Step 2: 4-Bromo-2-fluoro-6-(isopropylamino)-N-(pent-4-yn-1-yl)benzamide (compound 3-3)

[0225] Compound 3-2 (500 mg, 1.81 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of 4-pentyne-1-amine (225.82 mg, 2.72 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.03 g, 2.71 mmol), and N,N-diisopropylethylamine (700.83 mg, 5.42 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, compound 3-3 (385 mg, 62%) was purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 3-3.

[0226] m / z(ESI): 341[M+H] +

[0227] Step 3: 6-Bromo-8-fluoro-4-isopropyl-3a-methyl-2,3,3a,4-tetrahydropyrrolo[2,1-b]quinazolin-9(1H)-one (compounds 3-4)

[0228] Compound 3-3 (150 mg, 439.60 μmol) was dissolved in 1,2-dichloroethane (5 mL), followed by the addition of 4A molecular sieve (800 mg), triphenylphosphine chloride (217.48 mg, 439.61 μmol), and silver trifluoromethanesulfonate (112.60 mg, 438.23 μmol). The reaction mixture was stirred at 110 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was collected, concentrated under reduced pressure, and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 3-4 (30 mg, 20%). m / z (ESI): 341 [M+H] +

[0229] Step 4: 8-Fluoro-4-isopropyl-3a-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborpentan-2-yl)-2,3,3a,4-tetrahydropyrrolo[2,1-b]quinazolin-9(1H)-one (compounds 3-5)

[0230] Under an argon atmosphere, compound 3-4 (30 mg, 87.92 μmol) was dissolved in 2 mL of dioxane solution. Then, 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (6.44 mg, 8.80 μmol), pinacol diborate (33.37 mg, 131.41 μmol), and potassium acetate (25.85 mg, 263.40 μmol) were added. The reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain crude compound 3-5 (30 mg). This crude product required no purification and was used directly in the next reaction step.

[0231] m / z(ESI): 389[M+H] +

[0232] Step 5: 6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4-isopropyl-3a-methyl-2,3,3a,4-tetrahydropyrrolo[2,1-b]quinazolin-9(1H)-one (compounds 3-6)

[0233] Compound 3-5 (30 mg, 77.26 μmol) was dissolved in dioxane / water (8:1, 1.9 mL) under an argon atmosphere. Then, 1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (6.42 mg, 8.77 μmol), 2,4,5-trichloropyrimidine (32.16 mg, 175.34 μmol), and potassium carbonate (36.29 mg, 262.57 μmol) were added, and the reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to give compound 3-6 (21 mg, two-step yield 58%).

[0234] m / z(ESI): 409[M+H] +

[0235] Step 6: 6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-8-fluoro-4-isopropyl-3a-methyl-2,3,3a,4-tetrahydropyrrolo[2,1-b]quinazolin-9(1H)-one (Compound 3)

[0236] Compounds 3-6 (20 mg, 48.87 μmol) were dissolved in dimethyl sulfoxide (0.2 mL) solution, followed by the addition of N,N-diisopropylethylamine (131.87 mg, 1.02 mmol) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (compounds 2-5, 117.77 mg, 766.68 μmol). The reaction mixture was stirred at 120 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain target compound 3 (12 mg, 50%).

[0237] m / z(ESI): 490[M+H] +

[0238] 1 H NMR (400MHz, DMSO-d6) δ8.41(s,1H),7.50(d,J=8.1Hz,1H),7.16(d,J=49.4Hz,1H),6. 89(s,1H),4.93(s,1H),4.04(p,J=7.0Hz,1H),3.81(dd,J=11.4,5.7Hz,3H),3.65–3.46 (m,3H),3.39(td,J=6.7,6.1,2.8Hz,1H),3.00(s,1H),2.41(dd,J=11.4,6.0Hz,1H),2 .25(q,J=11.4Hz,1H),1.96(dq,J=9.7,5.8Hz,3H),1.44(t,J=6.8Hz,7H),1.37(s,3H).

[0239] Example 4: 6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-8-fluoro-3a,4-dimethyl-2,3,3a,4-tetrahydropyrrolo[2,1-b]quinazolin-9(1H)-one (Compound 4)

[0240] Following the synthetic steps of compound 3, replacing isopropylamine in the first step with methylamine hydrochloride yields the title compound 4 (10 mg).

[0241] m / z(ESI): 462[M+H] + .

[0242] 1H NMR (400MHz, DMSO-d6) δ8.42(s,1H),7.54(s,1H),6.91(s,2H),4.92(d,J=5.2Hz,1H),3.80(q,J=5.0Hz,3H),3.63–3.53(m,2H),3.52–3 .36(m,5H),3.08–3.02(m,1H),2.40–2.31(m,1H),2.21(dd,J=12.5,7.8Hz,1H),2.06–1.90(m,3H),1.48(d,J=11.3Hz,1H),1.24(s,3H).

[0243] Example 5: 7-Fluoro-9-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4a-methyl-1,2,3,4,4a,5-hexahydro-6H-pyrido[1,2-a]quinazolin-6-one (Compound 5)

[0244] Step 1: 9-Bromo-7-fluoro-4a-methyl-1,2,3,4,4a,5-hexahydro-6H-pyrido[1,2-a]quinazolin-6-one (compound 5-3)

[0245] Compound 5-1 (100 mg, 0.43 mmol) was dissolved in methanol (2 mL), followed by the addition of compound 5-2 (42 mg, 0.43 mmol) and platinum chloride (14.5 mg, 0.043 mmol). The reaction mixture was stirred at 90 °C for 16 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was collected, concentrated under reduced pressure, and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 5-3 (10 mg, 7%).

[0246] m / z(ESI): 313[M+H] +

[0247] Step 2: 7-Fluoro-4a-methyl-9-(trimethyltinyl)-1,2,3,4,4a,5-hexahydro-6H-pyrido[1,2-a]quinazolin-6-one (compounds 5-4)

[0248] Compound 5-3 (10 mg, 31.93 μmol) was dissolved in dioxane (2 mL) solution under an argon atmosphere. Hexamethyldistin (15.69 mg, 47.89 μmol) and tetraphenylphosphine palladium (3.69 mg, 3.19 μmol) were then added. The reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain crude compound 5-4 (12.7 mg). This crude compound was used directly in the next reaction without further purification.

[0249] m / z(ESI): 399[M+H] +

[0250] Step 3: 9-(2-chloro-5-fluoropyrimidin-4-yl)-7-fluoro-4a-methyl-1,2,3,4,4a,5-hexahydro-6H-pyrido[1,2-a]quinazolin-6-one (compound 5-5)

[0251] Compound 5-4 (12.7 mg, crude) was dissolved in dioxane (1.0 mL) solution under an argon atmosphere. Tetra(triphenylphosphine)palladium (3.69 mg, 3.19 μmol), cuprous chloride (3.16 mg, 31.92 μmol), and 2,4-dichloro-5-fluoropyrimidine (10.66 mg, 63.84 μmol) were then added. The reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the solution was cooled to room temperature and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 5-5 (5 mg).

[0252] m / z(ESI): 365[M+H] +

[0253] Step 4: 7-Fluoro-9-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4a-methyl-1,2,3,4,4a,5-hexahydro-6H-pyrido[1,2-a]quinazolin-6-one (Compound 5)

[0254] Compound 5-5 (5 mg, 13.71 μmol) was dissolved in dimethyl sulfoxide (0.2 mL) solution, followed by the addition of N,N-diisopropylethylamine (35.43 mg, 274.14 μmol) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (compound 2-5, 24.09 mg, 156.83 μmol). The reaction mixture was stirred at 120 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to give compound 5 (2 mg, 33%).

[0255] m / z(ESI): 446[M+H]+

[0256] Example 6: 4-(2,2-difluoroethyl)-8-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3a-methyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one (Compound 6)

[0257] Step 1: 2-Amino-4-bromo-N-(2,2-difluoroethyl)benzamide (compound 6-3)

[0258] Compound 6-1 (1 g, 4.63 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.64 g, 6.94 mmol), N,N-diisopropylethylamine (1.79 g, 13.85 mmol), and 2,2-difluoroethylamine (562.86 mg, 6.94 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to give compound 6-3 (1.0 g, 77%).

[0259] m / z(ESI): 279[M+H] +

[0260] Step 2: 8-Bromo-4-(2,2-difluoroethyl)-3a-methyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one (compound 6-5)

[0261] Compound 6-3 (1.0 g, 3.58 mmol) was dissolved in methanol (20 mL), followed by the addition of 4-pentyn-1-ol (300.99 mg, 3.58 mmol) and platinum chloride (120.71 mg, 358.31 μmol), respectively. The reaction mixture was stirred at 90 °C for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was collected, concentrated under reduced pressure, and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 6-5 (120 mg, 10%).

[0262] m / z(ESI): 345[M+H] +

[0263] Step 3: 4-(2,2-difluoroethyl)-3a-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one (compound 6-6)

[0264] Under an argon atmosphere, compound 6-5 (120 mg, 347.63 μmol) was dissolved in 2 mL of dioxane solution. Then, 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (25.44 mg, 34.77 μmol), pinacol diborate (97.37 mg, 383.44 μmol), and potassium acetate (101.05 mg, 1.03 mmol) were added. The reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain crude compound 6-6 (135 mg). This crude product required no purification and was used directly in the next reaction step.

[0265] m / z(ESI): 393[M+H] +

[0266] Step 4: 8-(2-chloro-5-fluoropyrimidin-4-yl)-4-(2,2-difluoroethyl)-3a-methyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one (compounds 6-7)

[0267] Compound 6-6 (135 mg, crude) was dissolved in dioxane / water (4:1, 2 mL) under an argon atmosphere. Tetra(triphenylphosphine)palladium (39.70 mg, 34.36 μmol), 2,4-dichloro-5-fluoropyrimidine (114.77 mg, 687.37 μmol), and potassium carbonate (109.28 mg, 0.79 mmol) were then added. The reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete and cooled to room temperature, compound 6-7 (66 mg) was purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 6-7.

[0268] m / z(ESI): 397[M+H] +

[0269] Step 5: 4-(2,2-difluoroethyl)-8-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3a-methyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one (Compound 6)

[0270] Compounds 6-7 (65 mg, 163.81 μmol) were dissolved in dimethyl sulfoxide (0.5 mL) solution, followed by the addition of N,N-diisopropylethylamine (423.43 mg, 3.28 mmol) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (compounds 2-5, 287.85 mg, 1.87 mmol). The reaction mixture was stirred at 120 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to give compound 6 (20 mg, 26%).

[0271] m / z(ESI): 478[M+H] +

[0272] 1 H NMR (400MHz, DMSO-d6) δ8.43(d,J=4.0Hz,1H),7.83(d,J=8.0Hz,1H),7.30(d,J=4.0Hz, 1H),7.21(d,J=8.0Hz,1H),7.16(d,J=4.0Hz,1H),6.07-6.37(m,1H),4.91(dd,J=4.0Hz, 1H),3.96-4.08(m,1H),3.79-3.84(m,2H),3.55-3.63(m,1H),3.47-3.53(m,4H),3.03– 3.08(m,1H),3.05(t,J=10.0Hz,1H),1.97–2.31(m,4H),1.46-1.52(m,1H),1.29(s,3H).

[0273] Example 7: 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-2-(2-hydroxypropyl-2-yl)-1-isopropyl-2-methyl-2,3-dihydroquinazoline-4(1H)-one (Compound 7)

[0274] Step 1: 4-Bromo-2-fluoro-6-(isopropylamino)benzamide (compound 7-2)

[0275] Compound 7-1 (300 mg, 1.27 mmol) was dissolved in pyridine (5 mL) solution, followed by the addition of isopropylamine (751.35 mg, 12.71 mmol) and triethylamine (643.12 mg, 6.36 mmol), respectively. The reaction mixture was stirred overnight at 110 °C. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was collected, concentrated under reduced pressure, and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 7-2 (250 mg, 72%).

[0276] m / z(ESI): 275[M+H] +

[0277] Step 2: Methyl 7-bromo-5-fluoro-1-isopropyl-2-methyl-4-oxo-1,2,3,4-tetrahydroquinazoline-2-carboxylate (compound 7-4)

[0278] Compound 7-2 (15 mg, 54.52 μmol) was dissolved in ethanol (1 mL), followed by the addition of methyl pyruvate (5.6 mg, 54.52 μmol) and trifluoroacetic acid (50 μL), and the reaction mixture was refluxed overnight. After the reaction was completed, compound 7-4 (5 mg, 26%) was purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 7-4.

[0279] m / z(ESI): 359[M+H] +

[0280] Step 3: 7-Bromo-5-fluoro-2-(2-hydroxypropyl-2-yl)-1-isopropyl-2-methyl-2,3-dihydroquinazoline-4(1H)-one (compound 7-5)

[0281] Compound 7-4 (260 mg, 723.83 μmol) was dissolved in tetrahydrofuran (5 mL) at 0 °C, followed by the addition of 2 M methylmagnesium bromide tetrahydrofuran solution (505 μL, 1.11 mmol). The reaction mixture was then cooled to room temperature and stirred for 30 minutes. After the reaction was completed, the mixture was quenched with ammonium chloride and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 7-5 (25 mg, 10%).

[0282] m / z(ESI): 359[M+H] +

[0283] Step 4: 5-Fluoro-2-(2-hydroxypropyl-2-yl)-1-isopropyl-2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3-dihydroquinazolin-4(1H)-one (compounds 7-6)

[0284] Compound 7-5 (25 mg, 69.59 μmol) was dissolved in 1 mL of dioxane solution under an argon atmosphere. Then, 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (5.09 mg, 6.96 μmol), pinacol diborate (26.51 mg, 104.39 μmol), and potassium acetate (20.49 mg, 208.78 μmol) were added. The reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain crude compound 7-6 (24 mg). This crude compound was used directly in the next reaction without further purification.

[0285] m / z(ESI): 407[M+H] +

[0286] Step 5: 7-(2,5-dichloropyrimidin-4-yl)-5-fluoro-2-(2-hydroxypropyl-2-yl)-1-isopropyl-2-methyl-2,3-dihydroquinazolin-4(1H)-one (compound 7-7)

[0287] Compound 7-6 (24 mg, crude) was dissolved in dioxane / water (8:1, 1.9 mL) under an argon atmosphere. Then, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (4.32 mg, 5.90 μmol), 2,4,5-trichloropyrimidine (27.09 mg, 147.69 μmol), and potassium carbonate (24.45 mg, 176.90 μmol) were added, and the reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 7-7 (16 mg).

[0288] m / z(ESI): 427[M+H] +

[0289] Step 6: 7-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-5-fluoro-2-(2-hydroxypropyl-2-yl)-1-isopropyl-2-methyl-2,3-dihydroquinazoline-4(1H)-one (Compound 7)

[0290] Compound 7-7 (16 mg, 37.44 μmol) was dissolved in dimethyl sulfoxide (0.2 mL) solution, followed by the addition of N,N-diisopropylethylamine (96.79 mg, 748.92 μmol) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (compound 2-5, 86.28 mg, 561.68 μmol). The reaction mixture was stirred at 120 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to give compound 7 (3 mg, 16%).

[0291] m / z(ESI): 508 [M+H] +

[0292] 1 H NMR (400MHz, DMSO-d6) δ8.40(s,1H),7.98(s,1H),7.47(d,J=7.9Hz,1H),4.84(d,J=65.6Hz,2H),4.33–4.20(m,1H),3.8 1(dd,J=12.2,6.5Hz,4H),3.49(s,4H),3.00(s,1H),1.92(d,J=10.9Hz,1H),1.70–1.37(m,9H),1.08(d,J=25.3Hz,6H).

[0293] Example 8: 8-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3a,4-dimethyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one (Compound 8)

[0294] Step 1: 8-Bromo-3a,4-Dimethyl-2,3,3a,4-Tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one (Compound 8-3)

[0295] Compound 8-1 (500 mg, 2.18 mmol) was dissolved in methanol (8 mL), followed by the addition of 4-pentyn-1-ol (compound 6-4, 183.60 mg, 2.18 mmol) and platinum chloride (73.53 mg, 218.26 μmol), respectively. The reaction mixture was stirred at 80 °C for 48 hours. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was collected, concentrated under reduced pressure, and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 8-3 (240 mg, 37%).

[0296] m / z(ESI): 295[M+H] +

[0297] Step 2: 3a,4-Dimethyl-8-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-2,3,3a,4-Tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one (Compound 8-4)

[0298] Under an argon atmosphere, compound 8-3 (112 mg, 379.43 μmol) was dissolved in 5 mL of dioxane solution. Then, 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (27.76 mg, 37.94 μmol), pinacol diborate (144.53 mg, 569.15 μmol), and potassium acetate (111.71 mg, 1.14 mmol) were added, and the reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain crude compound 8-4 (120 mg). This crude product required no purification and was used directly in the next reaction.

[0299] m / z(ESI): 343[M+H] +

[0300] Step 3: 8-(2-chloro-5-fluoropyrimidin-4-yl)-3a,4-dimethyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one (compound 8-5)

[0301] Compound 8-4 (120 mg, crude) was dissolved in dioxane / water (8:1, 2.5 mL) under an argon atmosphere. Then, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (25.66 mg, 35.07 μmol), 2,4-dichloro-5-fluoropyrimidine (117.09 mg, 701.26 μmol), and potassium carbonate (145.38 mg, 1.05 mmol) were added. The reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 8-5 (100 mg).

[0302] m / z(ESI): 347[M+H] +

[0303] Step 4: 8-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3a,4-dimethyl-2,3,3a,4-tetrahydropyrrolo[1,2-a]quinazolin-5(1H)-one (Compound 8)

[0304] Compound 8-5 (60 mg, 173.02 μmol) was dissolved in dimethyl sulfoxide (0.4 mL) solution, followed by the addition of N,N-diisopropylethylamine (447.22 mg, 3.46 mmol) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (compound 2-5, 398.65 mg, 2.60 mmol). The reaction mixture was stirred at 120 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to give compound 8 (40 mg, 54%).

[0305] m / z(ESI): 428[M+H] +

[0306] 1 H NMR (400MHz, DMSO-d6) δ8.43(d,J=3.6Hz,1H),7.80(d,J=8.1Hz,1H),7.28(dd,J= 8.2,1.7Hz,1H),7.16(dd,J=18.4,5.7Hz,2H),4.91(dd,J=5.3,1.9Hz,1H),3.81(d q,J=8.7,4.9Hz,3H),3.48(ddd,J=14.4,8.8,5.3Hz,3H),3.36(dd,J=11.7,2.3Hz, 1H),3.10–3.02(m,1H),2.95(s,3H),2.25–2.04(m,4H),1.49(s,1H),1.25(s,3H).

[0307] Example 9: 5-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3-isopropyl-2a-methyl-1,2,2a,3-tetrahydro-8H-aza[2,1-b]quinazolin-8-one (Compound 9)

[0308] Step 1: 4-Bromo-2-(isopropylamino)benzoic acid (compound 9-2)

[0309] Compound 9-1 (1 g, 4.57 mmol) was dissolved in pyridine (5 mL) solution, followed by the addition of isopropylamine (2.70 g, 45.68 mmol) and triethylamine (2.31 g, 22.83 mmol), respectively. The reaction mixture was stirred overnight at 110 °C. After the reaction was complete, the solution was concentrated under reduced pressure, and the pH was adjusted to 2-3 using 1 N hydrochloric acid. The mixture was filtered, and the residue was collected to obtain compound 9-2 (240 mg, 20%).

[0310] m / z(ESI): 258 [M+H] +

[0311] Step 2: 4-Bromo-N-(But-3-yn-1-yl)-2-(Isopropylamino)benzamide (Compound 9-4)

[0312] Compound 9-2 (300 mg, 1.16 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of but-3-yn-1-amine (compound 9-3, 184.05 mg, 2.66 mmol), 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (662.91 mg, 1.74 mmol), and N,N-diisopropylethylamine (150.21 mg, 1.16 mmol). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, compound 9-4 (300 mg, 84%) was purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1).

[0313] m / z(ESI): 309[M+H] +

[0314] Step 3: 5-Bromo-3-isopropyl-2a-methyl-1,2,2a,3-tetrahydro-8H-aza[2,1-b]quinazolin-8-one (compound 9-5)

[0315] Compound 9-4 (260 mg, 840.85 μmol) was dissolved in 1,2-dichloroethane (5 mL), followed by the addition of molecular sieve (800 mg), triphenylphosphine chloride (623.99 mg, 1.26 mmol), and silver trifluoromethanesulfonate (324.08 mg, 1.26 mmol). The reaction mixture was stirred at 110 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was collected, concentrated under reduced pressure, and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 9-5 (120 mg, 46%).

[0316] m / z(ESI): 309[M+H] +

[0317] Step 4: 3-Isopropyl-2a-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-1,2,2a,3-tetrahydro-8H-aza[2,1-b]quinazolin-8-one (compounds 9-6)

[0318] Under an argon atmosphere, compound 9-5 (63 mg, 203.75 μmol) was dissolved in 2 mL of dioxane solution. Then, 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (14.91 mg, 20.38 μmol), pinacol diborate (77.61 mg, 305.62 μmol), and potassium acetate (59.99 mg, 611.27 μmol) were added. The reaction mixture was stirred at 100 °C for 1 hour. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain crude compound 9-6 (70 mg). This crude compound was used directly in the next reaction without further purification.

[0319] m / z(ESI): 357[M+H] +

[0320] Step 5: 5-(2-chloro-5-fluoropyrimidin-4-yl)-3-isopropyl-2a-methyl-1,2,2a,3-tetrahydro-8H-aza[2,1-b]quinazolin-8-one (compounds 9-7)

[0321] Compound 9-6 (70 mg, crude) was dissolved in dioxane / water (8:1, 1.9 mL) under an argon atmosphere. Then, 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride (14.38 mg, 19.65 μmol), 2,4-dichloro-5-fluoropyrimidine (65.61 mg, 392.94 μmol), and potassium carbonate (81.47 mg, 589.47 μmol) were added. The reaction mixture was stirred at 100 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 9-7 (25 mg).

[0322] m / z(ESI): 361[M+H] +

[0323] Step 6: 5-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3-isopropyl-2a-methyl-1,2,2a,3-tetrahydro-8H-aza[2,1-b]quinazolin-8-one (Compound 9)

[0324] Compound 9-7 (18 mg, 49.89 μmol) was dissolved in dimethyl sulfoxide (0.2 mL) solution, followed by the addition of N,N-diisopropylethylamine (128.95 mg, 997.76 μmol) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (114.95 mg, 748.32 μmol). The reaction mixture was stirred at 120 °C for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and purified by reversed-phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain target compound 9 (2 mg, 9%).

[0325] m / z(ESI): 442[M+H] +

[0326] Biological testing experiments

[0327] Test Example 1: Detection of CDK4 and CDK6 kinase inhibitory effects

[0328] The experimental method for CDK4 kinase is as follows:

[0329] The in vitro activity of CDK4 was determined by detecting the phosphorylation level of the substrate in the kinase reaction using Perkin Elmer's Lance Ultra TR-FRET kinase assay kit.

[0330] The reaction buffer contains the following components: 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 2 mM DTT, and 0.01% Tween 20.

[0331] Preparation of CDK4 kinase solution: Human recombinant CDK4 / CycD1 protein (ProQinase, 0142-0143-1) was diluted with reaction buffer to prepare a 3 nM kinase solution;

[0332] Preparation of substrate reaction solution: Dilute with reaction buffer to prepare 100 nM ULight-4E-BP1 kinase substrate (PerkinElmer, TRF0128) and 600 μM ATP;

[0333] Preparation of detection buffer: Europium-anti-phospho-4E-BP1 antibody (PerkinElmer, TRF0216) and EDTA were diluted with 1× detection buffer (PerkinElmer, CR97-100) to prepare 2 nM antibody solution and 20 mM EDTA solution, respectively.

[0334] Preparation of compound solutions of different concentrations: Using DMSO as the diluent, the mother liquor of the compound was serially diluted using the dose-response program of the spiking instrument. The initial concentration of the compound to be tested was 200 nM, and it was diluted 4 times to obtain 8 concentration points.

[0335] Using an Echo 650 automated workstation, 100 nmol of compound solutions of varying concentrations were added to a 384-well detection plate (Perkin Elmer, 6007299), followed by 5 μL of CDK4 kinase solution. After thorough mixing, the mixture was incubated at room temperature for 5 minutes. Then, 5 μL of substrate reaction solution was added, and the reaction mixture was incubated at room temperature for 60 minutes. Next, 10 μL of detection buffer, equal in volume to the reaction mixture, was added, thoroughly mixed, and allowed to stand at room temperature for 60 minutes. The reaction progress was monitored 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 degree of substrate phosphorylation, thus detecting CDK4 kinase activity. In this experiment, the group without CDK4 kinase protein was designated as the 100% inhibition group, and the group with CDK4 kinase protein but without the compound was designated as the 0% inhibition group.

[0336] The percentage of CDK4 activity inhibition by a compound can be calculated using the following formula:

[0337] Inhibition percentage = 100 - 100 * (signal value of the compound at a specific concentration - signal value of the 100% inhibition group) / (signal value of the 0% inhibition group - signal value of the 100% inhibition group).

[0338] Compound IC 50 The values ​​were calculated from eight concentration points using XLfit (ID Business Solutions Ltd., UK) software via the following formula:

[0339] Y=Bottom+(Top-Bottom) / (1+10^((logIC 50 -X)×slope factor))

[0340] Where Y is the inhibition percentage, X is the logarithm of the concentration of the analyte, Bottom is the minimum inhibition percentage, Top is the maximum inhibition percentage, and slope factor is the curve slope coefficient.

[0341] The experimental method for CDK6 kinase is as follows:

[0342] The in vitro activity of CDK6 was determined by detecting the phosphorylation level of the substrate in the kinase reaction using Perkin Elmer's Lance Ultra TR-FRET kinase assay kit.

[0343] The reaction buffer contains the following components: 50 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 2 mM DTT, and 0.01% Tween 20.

[0344] Preparation of CDK6 kinase solution: Human recombinant CDK6 / CycD3 (Carna Biosciences, 04-107) protein was diluted with reaction buffer to a 2 nM kinase solution;

[0345] Preparation of substrate reaction solution: Dilute with reaction buffer to prepare 100 nM ULight-4E-BP1 kinase substrate (PerkinElmer, TRF0128) and 200 μM ATP;

[0346] Preparation of detection buffer: Europium-anti-phospho-4E-BP1 antibody (PerkinElmer, TRF0216) and EDTA were diluted with 1× detection buffer (PerkinElmer, CR97-100) to prepare 2 nM antibody solution and 20 mM EDTA solution, respectively.

[0347] Preparation of compound solutions of different concentrations: Using DMSO as the diluent, the mother liquor of the compound was serially diluted using the dose-response program of the spiking instrument. The initial concentration of the compound to be tested was 1 μM, and it was diluted 4 times to obtain 8 concentration points.

[0348] Using an Echo 650 automated workstation, 100 nmol of compound solutions of varying concentrations were added to a 384-well detection plate (Perkin Elmer, 6007299), followed by 5 μL of CDK6 kinase solution. After thorough mixing, the mixture was incubated at room temperature for 5 minutes. Then, 5 μL of substrate reaction solution was added, and the reaction mixture was incubated at room temperature for 60 minutes. Next, 10 μL of detection buffer, equal in volume to the reaction mixture, was added, thoroughly mixed, and allowed to stand at room temperature for 60 minutes. The reaction progress was monitored 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 degree of substrate phosphorylation, thus detecting CDK6 kinase activity. In this experiment, the group without CDK6 kinase protein was designated as the 100% inhibition group, and the group with CDK6 kinase protein but without the compound was designated as the 0% inhibition group.

[0349] The percentage of CDK6 activity inhibition by a compound can be calculated using the following formula:

[0350] Inhibition percentage = 100 - 100 * (signal value of the compound at a specific concentration - signal value of the 100% inhibition group) / (signal value of the 0% inhibition group - signal value of the 100% inhibition group).

[0351] Compound IC 50 The values ​​were calculated from eight concentration points using XLfit (ID Business Solutions Ltd., UK) software via the following formula:

[0352] Y=Bottom+(Top-Bottom) / (1+10^((logIC 50 -X)×slope factor))

[0353] Where Y is the inhibition percentage, X is the logarithm of the concentration of the analyte, Bottom is the minimum inhibition percentage, Top is the maximum inhibition percentage, and slope factor is the curve slope coefficient.

[0354] Experimental results:

[0355] Table 1

[0356] Test Example 2: Antiproliferative Activity Experiment of MCF7 Cells

[0357] Using Sigma-Aldrich's Cell Proliferation ELISA, BrdU (11669915001) chemiluminescent assay, cell proliferation is quantified by measuring BrdU incorporation during DNA synthesis in replicating (circulating) cells. ATCC-derived MCF7 cells were cultured to the logarithmic growth phase according to the recommended medium. After trypsin digestion and centrifugation to obtain cell pellets, cell counts were performed. Cells were seeded at a density of 3000 cells / well in 40 μL of 384-well plates (Corning, 3570) and cultured overnight. Using an Echo 650 automated workstation, 40 nL of compound solutions of different concentrations were added to 384-well assay plates (Perkin Elmer, 6007299). The preparation method was as follows: using DMSO as the diluent, the compound stock solution was serially diluted using the dip-response program of the pipette. The starting concentration of the test compound was 5 μM, 4-fold dilution, 8 concentration points. After 24 hours of treatment, cell proliferation ELISA and BrdU (chemiluminescence) assay kits were used for detection according to their instructions. The Luminescence signal value was detected using an Envision plate reader. The signal value is directly proportional to the amount of DNA synthesized in the cells, and the amount of DNA synthesized is directly proportional to the cell proliferation rate, thus allowing the detection of the proliferative activity of MCF7 cells. In this experiment, the group without cells was considered the 100% inhibition group, while the group with cells but without the compound was considered the 0% inhibition group.

[0358] The percentage of inhibition of MCF7 cell proliferation activity by the compound can be calculated using the following formula:

[0359] Inhibition percentage = 100 - 100 * (signal value of the compound at a specific concentration - signal value of the 100% inhibition group) / (signal value of the 0% inhibition group - signal value of the 100% inhibition group).

[0360] Compound IC 50 The values ​​were calculated from eight concentration points using XLfit (ID Business Solutions Ltd., UK) software via the following formula:

[0361] Y=Bottom+(Top-Bottom) / (1+10^((logIC 50 -X)×slope factor))

[0362] Where Y is the inhibition percentage, X is the logarithm of the concentration of the analyte, Bottom is the minimum inhibition percentage, Top is the maximum inhibition percentage, and slope factor is the curve slope coefficient.

[0363] The compound disclosed herein exhibits antiproliferative activity against MCF7 cells.

[0364] Test Example 3: Antiproliferative Activity Experiment of T47D Cells

[0365] The human breast cancer cells T47D used in this experiment were purchased from Kangyuan Bochuang (catalog number KC-0199) and cultured in RPMI-1640 medium (Shanghai Yuanpei Biotechnology Co., Ltd., L240KJ) supplemented with 10% FBS (Longsa Biotechnology Co., Ltd., S211201T) and 8 μg / mL human insulin (Yisheng Biotechnology Co., Ltd., 40112ES60). Cell proliferation was quantified by detecting BrdU incorporation during DNA synthesis in replicating cells using a Sigma-Aldrich cell proliferation ELISA kit (Sigma, catalog number: 11669915001). T47D cells were digested with trypsin (Shanghai Yuanpei Biotechnology Co., Ltd., S310KJ), centrifuged to obtain cell pellets, and then seeded at a density of 3000 cells / well in 40 μL solutions in 384-well plates (Corning, 3570) and cultured overnight. Using an Echo 650 automated workstation, 40 nL of compound solutions or DMSO of different concentrations were added to 384-well plates. (The method for preparing different concentration compound solutions is as follows: using DMSO as the diluent, the compound is serially diluted using the dip-response program of the pipette. The initial concentration of the test compound is 3 μM, 3-fold dilution, 8 concentration points, and the concentration range of the compound solution is 3 μM to 1.37 nM). The final concentration of DMSO in the system is 0.1%. After incubating the cell plates at 37°C and 5% CO2 for 24 hours, cell proliferation ELISA was performed using a BrdU detection kit according to its instructions. The Luminescence signal value was detected using an Envision microplate reader (PerkinElmer, Envision 2105). The signal value is directly proportional to the amount of DNA synthesized in the cells, and the amount of DNA synthesized is directly proportional to the cell proliferation rate, thus allowing the detection of the proliferative activity of T47D cells.

[0366] In this experiment, the cell group without BrdU labeling reagent was the 100% inhibition group, and the cell group with BrdU labeling reagent but without compound was the 0% inhibition group.

[0367] The percentage of inhibition of T47D cell proliferation activity by the compound can be calculated using the following formula:

[0368] Inhibition percentage = 100 * (0% inhibition group signal value - signal value of the analyte at a specific concentration) / (0% inhibition group signal value - 100% inhibition group signal value).

[0369] The inhibition curve was fitted using XLfit (ID Business Solutions Ltd., UK) software according to the following formula, and the half-maximal inhibitory concentration (IC50) was calculated. 50 ):

[0370] Y=Bottom+(Top-Bottom) / (1+10^((logIC 50 -X)×slope factor))

[0371] Where Y is the inhibition percentage, X is the logarithm of the concentration of the analyte, Bottom is the minimum inhibition percentage, Top is the maximum inhibition percentage, and slope factor is the curve slope coefficient.

[0372] Experimental results:

[0373] Table 2

[0374] The disclosed compound exhibits good anti-proliferative activity in T47D cells.

Claims

1. A compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in: Ring A is selected from C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-12 heteroaryl, the C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-12 heteroaryl groups are optionally substituted with one or more R groups. a replace; R 1 and R 6 Independently selected from hydrogen, amino, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic groups, C2-C 10 alkenyl and C2-C 10 alkynyl group, the amino group, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic groups, C2-C 10 alkenyl and C2-C 10 The alkynyl group is optionally surrounded by one or more R groups. 1a replace; R 2 and R 2’ Independently selected from hydrogen, hydroxyl, amino, mercapto, cyano, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the hydroxyl, amino, mercapto, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally coated with one or more R groups. 2a replace; Or, R 1 and R 2 The atoms connected to the ring and the ring together form a 4-10 membered heterocycle or a 5-12 membered heteroaromatic ring, wherein the 4-10 membered heterocycle and the 5-12 membered heteroaromatic ring are optionally bounded by one or more R atoms. b replace; Or, R 2 and R 2’ Together with the atoms they connect, they form C3-C 12 Saturated carbocyclic, oxo-, or 4-10 membered heterocyclic rings, wherein the C3-C 12 Saturated carbon rings or 4-10 membered heterocycles may be selectively coupled with one or more R atoms. c replace; R 3 R 4 R 7 R 8 and R 9 Independently selected from hydrogen, halogen, hydroxyl, amino, mercapto, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy and C1-C 10 Halogenated alkyl groups; Or, R 7 and R 6 The atoms connected to it together form a 5-10 membered heterocycle, which is optionally bounded by one or more R atoms. d replace; Or, R 6 and R 2’ The atoms connected to it together form a 4-10 membered heterocycle, which is optionally bounded by one or more R atoms. e replace; R 5 Selected from hydrogen, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 Alkyl, the C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 Alkyl groups are optionally surrounded by one or more R 5a replace; Each R 1a Independently selected from halogen, hydroxyl, cyano, amino and C1-C 10 Alkoxy; Each R 2a Independently selected from halogens, hydroxyl groups, cyano groups, amino groups, C1-C8 alkyl groups, C1-C8 alkoxy groups, and C1-C8 haloalkyl groups; Each R 5a Independently selected from halogens, hydroxyl groups, cyano groups, and amino groups; Each R a Independently selected from halogen, hydroxyl, oxo, amino, cyano, -C(O)-R f -OC(O)-R f -S(O)2-R f C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the hydroxyl, amino, C2-C 10 alkenyl, C2-C 10 Alkyne group, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally coated with one or more R groups. g replace; Each R b R c R d and R e Independently selected from halogen, hydroxyl, mercapto, cyano, oxo, amino, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 alkylamine group and C1-C 10 Halogenated alkyl groups; Each R g Independently selected from cyano, amino, halogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the amino, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally coated with one or more R groups. h replace; Each R f and R h The group is independently selected from halogen, hydroxyl, amino, cyano, C1-C4 alkyl, C1-C4 alkoxy and 4-10 membered heterocyclic groups, wherein the amino, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy and 4-10 membered heterocyclic groups are optionally substituted with amino, halogen, hydroxyl and C1-C4 alkyl. One or more hydrogen atoms in the compound of formula (I) may be selected as deuterium atoms.

2. The compound of formula (I) according to claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from 4-10-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 4-10-membered heterocyclic group and the 5-10-membered heteroaryl group are optionally surrounded by one or more R groups. a Replacement; or ring A is selected from 4-7 membered heterocyclic groups, wherein the 4-7 membered heterocyclic group is optionally replaced by one or more R a Replacement; or ring A is selected from a 6-membered heterocyclic group, wherein the 6-membered heterocyclic group is optionally replaced by one or more R a Substitution; or ring A is a tetrahydropyranyl group, wherein the tetrahydropyranyl group is optionally replaced by one or more R groups. a Replacement; or ring A is Or ring A is 3. The compound of formula (I) according to any one of claims 1 or 2, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Each R a Independently selected from halogen, hydroxyl, amino, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy and C1-C 10 Halogenated alkyl groups; or each R a Individually selected from halogens, hydroxyl groups, amino groups, cyano groups, and C1-C4 alkyl groups; or each R a Independently selected from halogens, hydroxyl groups, and C1-C4 alkyl groups; or R a It is a hydroxyl group.

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 1 Selected from hydrogen and C1-C 10 Alkyl, the C1-C 10 Alkyl groups may be optionally substituted with halogens or deuterium; or R 1 Selected from hydrogen and C1-C4 alkyl groups, wherein the C1-C4 alkyl groups are optionally substituted with halogens or deuterium, with halogens preferably being fluorine; or R 1 Selected from hydrogen, methyl, and ethyl, wherein the methyl and ethyl groups are optionally substituted with halogen or deuterium, the halogen being preferably fluorine; or R 1 Selected from hydrogen and C1-C 10 Alkyl; or R 1 It is hydrogen or methyl; or R 1 Selected from hydrogen, methyl, CD3 and CH2CHF2; or R 1 Selected from hydrogen, methyl and CH2CHF2.

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 and R 2’ Independently selected from hydrogen, halogen, hydroxyl, amino, mercapto, cyano, and C1-C 10 Alkyl groups, hydroxyl groups, amino groups, mercapto groups, and C1-C2 groups 10 Alkyl groups are optionally surrounded by one or more R groups. 2a Replace; or R 2 and R 2’ Independently selected from hydrogen and C1-C 10 Alkyl, the C1-C 10 Alkyl groups are optionally surrounded by one or more R groups. 2a Substitution; or R2 and R2' are independently selected from hydrogen and C1-C4 alkyl groups, wherein the C1-C4 alkyl groups are optionally substituted by one or more R2a; or R 2 and R 2’ The radicals are independently selected from hydrogen, methyl, ethyl, and isopropyl, wherein the methyl, ethyl, and isopropyl groups are optionally separated by one or more R groups. 2a Replace; or R 2 and R 2’ The radicals are independently selected from hydrogen, methyl, and isopropyl, wherein the methyl and isopropyl groups are optionally separated by one or more R groups. 2a Replace; or R 2 and R 2’ Independently selected from hydrogen and methyl, wherein the methyl group is optionally separated by one or more R 2a Replace; or R 2 Selected from hydrogen, methyl, and isopropyl, wherein the methyl and isopropyl groups are optionally surrounded by one or more R groups. 2a Replace; or R 2’ Selected from methyl and ethyl, wherein the methyl and ethyl groups are optionally separated by one or more R... 2a Replace; or R 2 and R 2’ Independently selected from hydrogen, methyl, ethyl, and methoxymethyl; or R 2 and R 2’ Independently selected from methyl and Or R 2 and R 2’ The atoms connected to it together form a C3-C5 saturated carbon ring or a 4-6 membered heterocycle, wherein the C3-C5 saturated carbon ring or the 4-6 membered heterocycle is optionally bounded by one or more R atoms. c Replace; or R 2 and R 2’ The atoms connected to it together form a C3-C5 saturated carbon ring or a 5-6 membered heterocycle, wherein the C3-C5 saturated carbon ring or the 5-6 membered heterocycle is optionally bounded by one or more R atoms. c Replace; or R 2 and R 2’ The atoms connected to it together form a cyclopropane, tetrahydropyrrole ring, tetrahydrofuran ring, cyclopentane, oxetane, cyclobutane, or piperidine ring, wherein the cyclopropane, tetrahydropyrrole ring, tetrahydrofuran ring, cyclopentane, oxetane, cyclobutane, or piperidine ring is optionally bounded by one or more R atoms. c Replace; or R 2 and R 2’ The atoms bonded to the cyclopropane ring and the tetrahydropyrrole ring together form a cyclopropane, tetrahydrofuran, cyclopentane, or piperidine ring, wherein the cyclopropane, tetrahydropyrrole, tetrahydrofuran, cyclopentane, or piperidine ring is optionally bounded by one or more R atoms. c Replace; or R 2 and R 2’ The atoms bonded to them together form cyclopropane, tetrahydropyrrole ring, tetrahydrofuran ring, cyclopentane, oxetane, cyclobutane, or piperidine ring; or R 2 and R 2’ Together with the atoms they are connected to, they form cyclopropane, tetrahydropyrrole ring, tetrahydrofuran ring, cyclopentane, or piperidine ring.

6. The compound of formula (I) according to any one of claims 1-5, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Each R 2a Independently selected from halogens, hydroxyl groups, C1-C8 alkyl groups, and C1-C8 alkoxy groups; or each R 2a Independently selected from hydroxyl and C1-C8 alkoxy groups; or each R 2a Independently selected from C1-C8 alkoxy groups; or each R 2a Independently selected from hydroxyl and C1-C4 alkoxy groups; or each R 2a Independently selected from C1-C4 alkoxy groups, such as methoxy groups; or each R 2a Independently selected from hydroxyl and methoxy groups; or R 2a It is a methoxy group; or R 2a It is a hydroxyl group.

7. The compound of formula (I) according to any one of claims 1-6, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 1 and R 2 The atoms connected to it together form a 4-10 membered heterocycle, which is optionally bounded by one or more R atoms. b Replace; or R 1 and R 2 The atoms connected to it together form a 4-6 membered heterocycle, which is optionally bounded by one or more R atoms. b Replace; or R 1 and R 2 The atoms connected to it together form a 5-6 membered heterocycle, which is optionally bounded by one or more R atoms. b Replace; or R 1 and R 2 The atoms bonded to the tetrahydropyrrole ring and the azahexacyclic butane together form a tetrahydropyrrole ring and an azahexacyclic butane, which are optionally bonded by one or more R atoms. b Replace; or R 1 and R 2 The atoms connected to it together form a tetrahydropyrrole ring, which is optionally bounded by one or more R atoms. b Replace; and / or each R b Independently selected from halogen, hydroxyl, mercapto, cyano, oxo, amino, and C1-C4 alkyl; or each R b Independently selected from halogens, such as fluorine; or R b It is fluorine.

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 3 R 4 R 7 R 8 and R 9 Independently selected from hydrogen, halogen, hydroxyl, cyano, and C1-C4 alkyl; or R 3 R 4 R 7 R 8 and R 9 Independently selected from hydrogen and halogens; or R 3 R 4 R 7 R 8 and R 9 Independently selected from hydrogen, chlorine, and fluorine; or R 3 and R 8 At least one is selected from halogens, preferably fluorine and chlorine; or R 3 and R 8 Both are halogens, with fluorine and chlorine being the preferred halogens; or R 3 Selected from halogens; or R 3 It is chlorine or fluorine; or R 8 It is hydrogen or fluorine; or R 3 Selected from fluorine and chlorine, R 8 Selected from hydrogen and fluorine, and when R 3 When it is chlorine, R 8 It is hydrogen; or R 7 It is hydrogen or fluorine; or R 4 and R 9 It is hydrogen; or R 4 R 7 and R 9 It 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 6 Selected from hydrogen and C1-C 10 Alkyl; or R 6 Selected from C1-C4 alkyl groups; or R 6 Selected from methyl, CD3 and isopropyl; or R 6 Selected from methyl and isopropyl.

10. The compound of formula (I) according to any one of claims 1-9, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 7 and R 6 The atoms connected to it together form a 5-7 membered heterocycle, which is optionally bounded by one or more R atoms. d Replace; or R 7 and R 6 The atoms connected to it together form a dihydrooxazine ring, which is optionally bounded by one or more R atoms. d Replace; or R 7 and R 6 Together with the atoms they connect, they form The c and b keys represent keys shared with the connected rings, the Optional by one or more R d Replace; or R 7 and R 6 The atoms connected to it together form a dihydrooxazine ring; or R 7 and R 6 Together with the atoms they connect, they form The c and b keys represent keys shared with the connected rings; and / or each R d Selected from halogens, cyano groups, and C1-C4 alkyl groups.

11. The compound of formula (I) according to any one of claims 1-10, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 6 and R 2’ The atoms connected to it together form a 5-7 membered heterocycle, which is optionally bounded by one or more R atoms. e Replace; or R 6 and R 2’ Together with the atoms they connect, they form a tetrahydropyrrole ring, a piperazine ring, and a piperidine ring. The tetrahydropyrrole ring, piperazine ring, piperidine ring, Optional by one or more R e Replacement, where the 'a' key represents a key shared with the connected ring; and / or each R e Independently selected from halogens, oxometalates, and C1-C 10 Alkyl; or each R e Individually selected from halogens, oxo- and C1-C4 alkyl groups; or each R e It is independently selected from fluorine, oxo, and methyl.

12. The compound of formula (I) according to any one of claims 1-11, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 5 It is hydrogen.

13. The compound of formula (I) as claimed in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the compound of formula (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. in, R 1 R 2 R 2’ R 3 R 6 R 7 and R 8 As defined in any one of claims 1-12.

14. The compound of formula (I) as claimed in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the compound of formula (III) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. in, n is 1, 2, or 3, t is 0, 1, or 2, R b R 2’ R 3 R 6 R 7 and R 8 As defined in any one of claims 1-12.

15. The compound of formula (I) as claimed in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the compound of formula (IV) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. in, p is selected from 0, 1, and 2; X is selected from -CH2-, -NHCH2-, -CH2CH2-, -CH2NHCH2-, and -NHCH2CH2-; R e R 1 R 2 R 3 R 7 and R 8 As defined in any one of claims 1-12.

16. The compound of formula (I) as claimed in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the compound of formula (V) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof. in, R 1 R 2 R 2’ R 3 and R 8 As defined in any one of claims 1-12.

17. The compound of formula (I) as claimed in claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds or pharmaceutically acceptable salts thereof.

18. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1-17, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

19. Use of the compound of formula (I) according to any one of claims 1-17, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18, in the preparation of a medicament for the prevention or treatment of CDK4-mediated diseases.

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