Heterocyclic compound as CDK inhibitor and use thereof

Abstract

The present disclosure relates to a CDK4 inhibitor compound represented by formula (Z) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising same, and use thereof in the preparation of a medicament for preventing or treating a CDK4-mediated disease.

Description

Heterocyclic compounds as cdk inhibitors and uses thereof

[0001] Cross-reference to related applications

[0002] The present disclosure claims priority to and the benefit of Chinese Patent Application No. 202410690167.9, filed May 30, 2024, Chinese Patent Application No. 202410923712.4, filed July 10, 2024, and Chinese Patent Application No. 202411380899.4, filed September 30, 2024, the contents of all of the above-mentioned patent applications are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0003] The present disclosure belongs to the field of medicine, and relates to a cyclin-dependent kinase (CDK) inhibitor compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing the same, and use thereof as a CDK inhibitor in the prevention or treatment of related diseases. BACKGROUND

[0004] The occurrence of tumors is related to the imbalance of a variety of oncogenes and tumor suppressor genes. The functional effects of almost all oncogenes and tumor suppressor genes ultimately converge on the cell cycle. Therefore, it can be said that tumors are a kind of cell cycle disease (CCD), and regulating or blocking the cell cycle is one of the ways to treat tumors. At present, many molecules related to cell cycle regulation have been found, among which cyclin-dependent kinases (CDKs) are core molecules in the cell cycle regulation network.

[0005] CDKs are a group of serine / threonine protein kinases, and CDKs drive the cell cycle through chemical action on serine / threonine proteins, and cooperate with cyclins to be important factors in cell cycle regulation.

[0006] Among the CDK subtypes involved in the cell cycle, CDK4 / 6 plays an irreplaceable role, and cancer-related cell cycle mutations mainly exist in the G1 phase and G1 / S phase transition process. CDK4 / 6 combines with cyclin D (CvclinD) to form a kinase-active complex, phosphorylates the tumor suppressor Rb product pRb, releases the bound transcription factor E2F, initiates the transcription of genes related to the S phase, and promotes the cell to pass through the checkpoint and transfer from the G1 phase to the S phase.

[0007] However, clinical application also proves that CDK4 / 6 inhibitors can bring adverse reactions such as gastrointestinal and / or hematological toxicity, and can bring acquired drug resistance with the accumulation of use time. New research reports that the hematological side effects brought by CDK4 / 6 inhibitors may be related to the inhibition of CDK6, and CDK4 is identified as a single oncogenic factor for various breast cancers. Therefore, selective CDK4 inhibitors can bring better safety and efficacy than CDK4 / 6 inhibitors. The present application is committed to developing new selective CDK4 inhibitors. DETAILED DESCRIPTION

[0008] The present disclosure relates to a compound of Formula (Z), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0009] wherein:

[0010] are independently selected from a double bond or a single bond, and and are not both double bonds;

[0011] Q 1 is selected from CO, SO2, O and NR 8 ;

[0012] Q 2 is selected from NR 9 , CHR 10 , CO and O;

[0013] X is selected from N, NR 4 and O;

[0014] n is selected from 0, 1, 2 and 3;

[0015] Ring A is selected from C3-C 12 cycloalkyl, 4-10 membered monocyclic heterocyclyl, C6-C 10 aryl and 5-12 membered heteroaryl, said C3-C 12 cycloalkyl, 4-10 membered monocyclic heterocyclyl, C6-C 10 aryl and 5-12 membered heteroaryl are optionally substituted with 1 or more R a , X is not O when Ring A is cyclopropyl;

[0016] each R 1 , R 5 and R 6 is independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 alkyl, C3-C6cycloalkyl, C2-C 10 alkenyl and C2-C 10 alkynyl, said hydroxyl, C1-C 10alkyl, C3-C6cycloalkyl, C2-C6alkenyl, and C2-C6alkynyl are optionally substituted with 1 or more R 10 alkyl, C3-C6cycloalkyl, C2-C6alkenyl, and C2-C6alkynyl are optionally substituted with 1 or more R 10 alkyl, C3-C6cycloalkyl, C2-C6alkenyl, and C2-C6alkynyl are optionally substituted with 1 or more R 1a substituents;

[0017] R 2’ and R 3’ are independently selected from the group consisting of null, hydrogen, halogen, and C1-C 10 alkyl;

[0018] R 2 and R 10 are independently selected from the group consisting of hydrogen, halogen, oxo, hydroxyl, amino, thiol, cyano, C1-C 10 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, said hydroxyl, amino, thiol, C1-C 10 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R 2a substituents;

[0019] R 3 is selected from the group consisting of hydrogen, halogen, oxo, hydroxyl, amino, thiol, cyano, C1-C 10 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, said hydroxyl, amino, thiol, C1-C 10 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R 3a substituents;

[0020] R 2 and R 3 and the atom to which they are attached together form a C5-C 12 saturated carbocyclic ring, 4-10 membered heterocyclic ring, C6-C 10 aromatic ring, and 5-10 membered heteroaromatic ring, said C5-C 12 saturated carbocyclic ring, 4-10 membered heterocyclic ring, C6-C 10 aromatic ring, and 5-10 membered heteroaromatic ring are optionally substituted with 1 or more R 1b substituents;

[0021] R3 and the atom to which they are attached together form a C3-C6saturated carbocyclic ring, which is optionally substituted with 1 or more R 3’ and the atom to which they are attached together form a C3-C6saturated carbocyclic ring, which is optionally substituted with 1 or more R 4b ;

[0022] R 4 , R 7 , R 8 and R 9 are independently selected from the group consisting of hydrogen, amino, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, and 4-10 membered heterocyclyl, which amino, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, and 4-10 membered heterocyclyl is optionally substituted with 1 or more R 4a ;

[0023] or, R 3 and R 4 , together with the atom to which they are attached, form a 4-10 membered heterocyclic ring and a 5-10 membered heteroaromatic ring, which is optionally substituted with 1 or more R 2b ;

[0024] or / and, R 2 and R 9 , together with the atom to which they are attached, form a 4-10 membered heterocyclic ring and a 5-10 membered heteroaromatic ring, which is optionally substituted with 1 or more R 3b ;

[0025] each R a is independently selected from the group consisting of halogen, hydroxyl, amino, cyano, -C(O)-NR e R e , -C(O)-R e , -SO2R e , -NR e C(O)NR e , C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-5 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, which hydroxyl, amino, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10Alkyl, C3-C 12 cycloalkyl, 4-5 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally coated with one or more R groups. d replace;

[0026] Each R 1a Independently selected from halogen, hydroxyl, cyano, amino and C1-C 10 alkyl;

[0027] Each R 2a R 3a and R 4a Independently selected from halogen, hydroxyl, cyano, amino, C1-C8 alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the hydroxyl, amino, C1-C8 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. c replace;

[0028] Each R 1b R 2b R 3b R 4b R c R d and R e Independently selected from halogen, hydroxyl, cyano, amino, C1-C 10 Alkyl, C3-C 12 Cycloalkyl and 4-10 membered heterocyclic groups, wherein the hydroxyl, amino, C1-C 10 Alkyl, C3-C 12 Cycloalkyl and 4-10 membered heterocyclic groups are optionally surrounded by one or more amino, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C 12 Cycloalkyl and 4-10 membered heterocyclic groups are substituted;

[0029] One or more hydrogen atoms in the compound may be selected as deuterium atoms.

[0030] In some implementation schemes, It is a single bond. In some implementations, It is a single key. It is a double bond.

[0031] In some implementation schemes, It is a double bond. It is a single key.

[0032] In some embodiments, and are single bonds. In some embodiments, Q 1 is CO.

[0033] In some embodiments, Q 1 is SO2.

[0034] In some embodiments, Q 1 is O.

[0035] In some embodiments, Q 1 is selected from NR 8 .

[0036] In some embodiments, Q 1 is selected from CO, SO2, O, and NCH3.

[0037] In some embodiments, Q 2 is selected from NR 9 and O.

[0038] In some embodiments, Q 2 is selected from NR 9 .

[0039] In some embodiments, Q 2 is selected from CHR 10 .

[0040] In some embodiments, Q 2 is CO.

[0041] In some embodiments, Q 2 is O.

[0042] In some embodiments, Q 1 is CO, and Q 2 is selected from NR 9 .

[0043] In some embodiments, Q 1 is CO, and Q 2 is O.

[0044] In some embodiments, Q 1 is SO2, and Q 2 is selected from CHR 10 .

[0045] In some embodiments, Q 1 is SO2, and Q 2 is selected from NR 9 .

[0046] In some embodiments, Q 1is O, and Q 2 is CO.

[0047] In some embodiments, Q 1 is selected from NR 8 , and Q 2 is CO.

[0048] In some embodiments, Q 1 is O, and Q 2 is selected from CHR 10 .

[0049] In some embodiments, X is NR 4 and O.

[0050] In some embodiments, X is NR 4 .

[0051] In some embodiments, X is N.

[0052] In some embodiments, X is O.

[0053] In some embodiments, n is 0 or 1.

[0054] In some embodiments, n is 1.

[0055] In some embodiments, n is 0.

[0056] In some embodiments, ring A is selected from 4-10 membered mono heterocyclyl and 5-10 membered heteroaryl, optionally substituted with 1 or more R a substituents.

[0057] In some embodiments, ring A is selected from 4-10 membered mono heterocyclyl, optionally substituted with 1 or more R a substituents.

[0058] In some embodiments, ring A is selected from 4-7 membered mono heterocyclyl, optionally substituted with 1 or more R a substituents.

[0059] In some embodiments, ring A is selected from 4-7 membered mono heterocyclyl having one N atom or one O atom, optionally substituted with 1 or more R a substituents. In some embodiments, ring A is selected from tetrahydropyranyl and piperidinyl, optionally substituted with 1 or more R a substituents.

[0060] In some embodiments, ring A is selected from tetrahydropyranyl, optionally substituted with 1 or more R asubstituted.

[0061] In some embodiments, ring A is selected from piperidinyl, which is optionally substituted with 1 or more R a substituted.

[0062] In some embodiments, each R a is independently selected from halogen, hydroxyl, amino, cyano, -SO2CH3, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, said hydroxyl, amino, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl is optionally substituted with 1 or more R d substituted.

[0063] In some embodiments, each R a is independently selected from halogen, hydroxyl, amino, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, said hydroxyl, amino, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl is optionally substituted with 1 or more R d substituted.

[0064] In some embodiments, each R a is independently selected from halogen, hydroxyl, amino, cyano, and -SO2CH3, said hydroxyl and amino is optionally substituted with 1 or more R d substituted.

[0065] In some embodiments, each R a is independently selected from halogen, hydroxyl, amino, cyano, said hydroxyl and amino is optionally substituted with 1 or more R d substituted. In some embodiments, each R d is independently selected from halogen, hydroxyl, cyano, amino, C1-C 10 alkyl, C3-C 12 cycloalkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, C1-C 10 alkyl, C3-C 12 cycloalkyl, and 4-10 membered heterocyclyl is optionally substituted with 1 or more amino, halogen, cyano, C3-C 12 cycloalkyl, and 4-10 membered heterocyclyl.

[0066] In some embodiments, each R d is independently selected from C1-C4 alkyl.

[0067] In some implementation schemes, R a Selected from hydroxyl and -SO2CH3.

[0068] In some implementation schemes, R a It is a hydroxyl group.

[0069] In some embodiments, ring A is selected from tetrahydropyranyl groups optionally substituted with hydroxyl groups.

[0070] In some implementations, ring A is

[0071] In some implementation schemes, R 1 Selected from halogens.

[0072] In some implementation schemes, R 1 It is fluorine.

[0073] In some implementation schemes, R 2 Selected from hydrogen, halogen, oxo, 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.

[0074] In some implementation schemes, R 2 Selected from hydrogen, C1-C 10 Alkyl groups and 4-10 membered heterocyclic groups, the C1-C 10 Alkyl groups and 4-10 membered heterocyclic groups are optionally surrounded by one or more R groups. 2a replace.

[0075] In some implementation schemes, R 2 Selected from hydrogen, oxo, C1-C4 alkyl, and 4-6 membered heterocyclic groups, wherein the C1-C4 alkyl and 4-6 membered heterocyclic groups are optionally surrounded by one or more R groups. 2a replace.

[0076] In some implementation schemes, R 2 Selected from hydrogen, oxo, and C1-C4 alkyl groups, wherein the C1-C4 alkyl group is optionally surrounded by one or more R groups. 2a replace.

[0077] In some implementation schemes, R 2 Selected from hydrogen, oxo, methyl, isopropyl, and oxetyl, wherein the methyl, isopropyl, and oxetyl groups are optionally surrounded by one or more R groups. 2a replace.

[0078] In some implementation schemes, R 2selected from hydrogen, methyl, isopropyl and oxetanyl, said methyl and isopropyl being optionally substituted with 1 or more R 2a substituted.

[0079] In some embodiments, R 2 is selected from hydrogen and C1-C4 alkyl, said C1-C4 alkyl being optionally substituted with 1 or more R 2a substituted.

[0080] In some embodiments, R 2 is selected from hydrogen, methyl and isopropyl, said methyl and isopropyl being optionally substituted with 1 or more R 2a substituted.

[0081] In some embodiments, R 2 is selected from hydrogen and isopropyl, said isopropyl being optionally substituted with 1 or more R 2a substituted.

[0082] In some embodiments, each R 2a is independently selected from halogen, hydroxyl, cyano, C1-C8 alkoxy and amino.

[0083] In some embodiments, each R 2a is independently selected from halogen, hydroxyl, cyano, methoxy and amino.

[0084] In some embodiments, each R 2a is independently selected from fluorine, methoxy and hydroxyl.

[0085] In some embodiments, each R 2a is independently selected from halogen, hydroxyl, cyano and amino.

[0086] In some embodiments, R 2a is hydroxyl.

[0087] In some embodiments, R 2 is selected from hydrogen, methyl, oxetanyl, fluoromethyl, trifluoromethyl, methoxymethyl and oxo.

[0088] In some embodiments, R 2 is selected from hydrogen, oxo and C1-C4 alkyl.

[0089] In some embodiments, R 2 is selected from hydrogen, methyl and oxo.

[0090] In some embodiments, R 2’ is selected from absent, hydrogen and C1-C4 alkyl.

[0091] In some embodiments, R 2’is selected from the group consisting of hydrogen, halogen, oxo, hydroxyl, amino, thiol, cyano, C1-C4alkyl, C3-C5cycloalkyl, and 4-7 membered heterocyclyl, optionally substituted with 1 or more R

[0092] In some embodiments, R 3 is selected from the group consisting of hydrogen, halogen, oxo, hydroxyl, amino, thiol, cyano, C1-C4alkyl, C3-C5cycloalkyl, and 4-7 membered heterocyclyl, optionally substituted with 1 or more R 10 In some embodiments, R 12 is selected from the group consisting of hydrogen, halogen, oxo, hydroxyl, amino, thiol, cyano, C1-C4alkyl, C3-C5cycloalkyl, and 4-7 membered heterocyclyl, optionally substituted with 1 or more R 10 In some embodiments, R 12 is selected from the group consisting of hydrogen, halogen, oxo, hydroxyl, amino, thiol, cyano, C1-C4alkyl, C3-C5cycloalkyl, and 4-7 membered heterocyclyl, optionally substituted with 1 or more R 3a In some embodiments, R

[0093] In some embodiments, R 3 is selected from the group consisting of hydrogen, halogen, oxo, hydroxyl, amino, thiol, cyano, C1-C4alkyl, C3-C5cycloalkyl, and 4-7 membered heterocyclyl, optionally substituted with 1 or more R 10 In some embodiments, R 10 is selected from the group consisting of hydrogen, halogen, oxo, hydroxyl, amino, thiol, cyano, C1-C4alkyl, C3-C5cycloalkyl, and 4-7 membered heterocyclyl, optionally substituted with 1 or more R 3a In some embodiments, R

[0094] In some embodiments, R 3 is selected from the group consisting of hydrogen, oxo, C1-C4alkyl, C3-C5cycloalkyl, and 4-7 membered heterocyclyl, optionally substituted with 1 or more R 10 In some embodiments, R 10 is selected from the group consisting of hydrogen, oxo, C1-C4alkyl, C3-C5cycloalkyl, and 4-7 membered heterocyclyl, optionally substituted with 1 or more R 3a In some embodiments, R

[0095] In some embodiments, R 3 is selected from the group consisting of hydrogen, oxo, C1-C4alkyl, C3-C5cycloalkyl, and 4-7 membered heterocyclyl, optionally substituted with 1 or more R 3a In some embodiments, R

[0096] In some embodiments, R 3 is selected from the group consisting of hydrogen, oxo, and C1-C4alkyl, optionally substituted with 1 or more R 3a In some embodiments, R

[0097] In some embodiments, R 3 is selected from the group consisting of hydrogen, oxo, C1-C4alkyl, and 4-7 membered heterocyclyl, optionally substituted with 1 or more R 3a In some embodiments, R 3 is selected from the group consisting of hydrogen, oxo, isopropyl, methyl, ethyl, cyclopropyl, tetrahydropyrrolyl, and piperidinyl, optionally substituted with 1 or more R 3a In some embodiments, R

[0098] In some embodiments, R3 selected from hydrogen, oxo, isopropyl, methyl, tetrahydropyrrolyl, and piperidinyl, said isopropyl, methyl, tetrahydropyrrolyl, and piperidinyl being optionally substituted with 1 or more R 3a substituents.

[0099] In some embodiments, R 3 selected from hydrogen, oxo, isopropyl, methyl, and tetrahydropyrrolyl, said isopropyl, methyl, and tetrahydropyrrolyl being optionally substituted with 1 or more R 3a substituents.

[0100] In some embodiments, R 3 selected from hydrogen, oxo, methyl, and ethyl, said methyl and ethyl being optionally substituted with 1 or more R 3a substituents.

[0101] In some embodiments, R 3 selected from piperidinyl, said piperidinyl being optionally substituted with 1 or more R 3a substituents.

[0102] In some embodiments, each R 3a is independently selected from halogen, hydroxyl, cyano, amino, C1-C8 alkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, C1-C8 alkyl, and 4-10 membered heterocyclyl being optionally substituted with 1 or more R c substituents.

[0103] In some embodiments, each R 3a is independently selected from hydroxyl and 4-10 membered heterocyclyl, said hydroxyl and 4-10 membered heterocyclyl being optionally substituted with 1 or more R c substituents.

[0104] In some embodiments, each R 3a is independently selected from hydroxyl and 4-7 membered heterocyclyl, said hydroxyl and 4-7 membered heterocyclyl being optionally substituted with 1 or more R c substituents.

[0105] In some embodiments, each R 3a is independently selected from halogen, hydroxyl, and morpholinyl, said hydroxyl and morpholinyl being optionally substituted with 1 or more R c substituents.

[0106] In some embodiments, each R 3a is independently selected from fluorine, hydroxyl, and morpholinyl, said hydroxyl and morpholinyl being optionally substituted with 1 or more R c substituents.

[0107] In some embodiments, each R 3a is independently selected from hydroxyl and morpholinyl, said hydroxyl and morpholinyl being optionally substituted with 1 or more R creplace.

[0108] In some implementation schemes, each R 3a It is independently selected from fluorine, hydroxyl and morpholino groups.

[0109] In some implementation schemes, each R 3a It is independently selected from hydroxyl and morpholino groups.

[0110] In some implementation schemes, R 3 Selected from hydrogen, oxo, Methyl, ethyl, CH3CF3, tetrahydropyrrolyl, cyclopropyl, and piperidinyl.

[0111] In some implementation schemes, R 3 Selected from hydrogen and C1-C4 alkyl groups.

[0112] In some implementation schemes, R 3 Selected from hydrogen, methyl, and ethyl.

[0113] In some implementation schemes, R 3’ Selected from non-existent, hydrogen, and C1-C4 alkyl groups.

[0114] In some implementation schemes, R 3’ Selected from non-existent, hydrogen, and methyl.

[0115] In some implementation schemes, R 2 and R 3 Together with the atoms they connect, they form C5-C7 saturated carbon rings, 4-7 membered heterocycles, and C6-C... 10 Aromatic rings and 5-7 membered heteroaromatic rings, wherein the C5-C7 saturated carbon rings, 4-7 membered heterocycles, C6-C 10 Aromatic rings and 5-7 quinone heterocyclic aromatic rings are optionally bounded by one or more R... 1b replace.

[0116] In some implementation schemes, R 2 and R 3 The atoms connected to the rings together form a C5-C7 saturated carbon ring and a 4-7 membered heterocycle, wherein the C5-C7 saturated carbon ring and the 4-7 membered heterocycle are optionally bounded by one or more R atoms. 1b replace.

[0117] In some implementation schemes, R 2 and R 3 The atoms connected to it together form a C5-C7 saturated carbon ring and a 4-7 membered heterocycle having one O atom and / or one N atom, wherein the C5-C7 saturated carbon ring and the 4-7 membered heterocycle are optionally separated by one or more R atoms. 1b replace.

[0118] In some implementation schemes, R 2 and R3 and the atoms to which they are attached collectively form a benzene ring, a pyridine ring, a cyclopentane, a cyclohexane, a tetrahydrofuran ring, a tetrahydropyran ring, and a tetrahydropyrrole ring, which is optionally substituted with 1 or more R 1b substituents.

[0119] In some embodiments, R 2 and R 3 and the atoms to which they are attached collectively form a benzene ring, a pyridine ring, a cyclopentane, a cyclohexane, and a tetrahydropyrrole ring, which is optionally substituted with 1 or more R 1b substituents.

[0120] In some embodiments, R 2 and R 3 and the atoms to which they are attached collectively form a benzene ring, a pyridine ring, a cyclopentane, and a tetrahydropyrrole ring, which is optionally substituted with 1 or more R 1b substituents.

[0121] In some embodiments, R 2 and R 3 and the atoms to which they are attached collectively form a cyclohexane, a tetrahydrofuran ring, and a tetrahydropyran ring, which is optionally substituted with 1 or more R 1b substituents.

[0122] In some embodiments, each R 1b is independently selected from the group consisting of halogen, hydroxyl, cyano, amino, and C1-C4alkyl.

[0123] In some embodiments, R 3 and R 3’ and the atoms to which they are attached collectively form a C3-C4saturated carbocyclic ring, which is optionally substituted with 1 or more R 4b substituents.

[0124] In some embodiments, R 3 and R 3’ and the atoms to which they are attached collectively form a cyclopropane, which is optionally substituted with 1 or more R 4b substituents.

[0125] In some embodiments, each R 4b is independently selected from the group consisting of halogen, hydroxyl, cyano, amino, and C1-C4alkyl.

[0126] In some embodiments, R 5 is selected from halogen.

[0127] In some embodiments, R5 selected from fluoro and chloro.

[0128] In some embodiments, R 6 is selected from hydrogen and halo.

[0129] In some embodiments, R 6 is hydrogen.

[0130] In some embodiments, R 10 is selected from hydrogen and halo.

[0131] In some embodiments, R 10 is hydrogen.

[0132] In some embodiments, R 4 , R 7 , R 8 , and R 9 are independently selected from hydrogen and Ci-C 10 alkyl, said Ci-C 10 alkyl is optionally substituted with 1 or more R 4a .

[0133] In some embodiments, R 4 , R 7 , R 8 , and R 9 are independently selected from hydrogen, methyl, ethyl, and isopropyl, said methyl and isopropyl is optionally substituted with 1 or more R 4a .

[0134] In some embodiments, R 4 , R 7 , R 8 , and R 9 are independently selected from hydrogen, methyl, and isopropyl, said methyl and isopropyl is optionally substituted with 1 or more R 4a .

[0135] In some embodiments, each R 4a is independently selected from halo, hydroxy, cyano, and amino.

[0136] In some embodiments, R 4 is selected from methyl, ethyl, trifluoroethyl, and isopropyl.

[0137] In some embodiments, R 4 is selected from methyl and isopropyl.

[0138] In some embodiments, R 4 is methyl.

[0139] In some embodiments, R 7 is hydrogen.

[0140] In some embodiments, R 8 is methyl.

[0141] In some embodiments, R 9 is hydrogen or methyl.

[0142] In some embodiments, R 9 is methyl.

[0143] In some embodiments, R 3 and R 4 and the atoms to which they are attached collectively form a 4-7 membered heterocyclic ring and a 5-7 membered heteroaromatic ring, which is optionally substituted with 1 or more R 2b .

[0144] In some embodiments, R 3 and R 4 and the atoms to which they are attached collectively form a 4-7 membered heterocyclic ring and a 5-7 membered heteroaromatic ring, which is optionally substituted with 1 or more R 2b , and which has 1 or 2 heteroatoms selected from N, O.

[0145] In some embodiments, R 3 and R 4 and the atoms to which they are attached collectively form a 4-6 membered heterocyclic ring, which is optionally substituted with 1 or more R 2b .

[0146] In some embodiments, R 3 and R 4 and the atoms to which they are attached collectively form a 4-6 membered heterocyclic ring having 1 N atom, which is optionally substituted with 1 or more R 2b .

[0147] In some embodiments, R 3 and R 4 and the atoms to which they are attached collectively form an azetidine, a piperazine ring, a morpholine ring, a tetrahydropyrrole ring, and an imidazole ring, which is optionally substituted with 1 or more R 2b .

[0148] In some embodiments, R 3 and R 4 and the atoms to which they are attached collectively form a piperazine ring, a morpholine ring, a tetrahydropyrrole ring, and an imidazole ring, which is optionally substituted with 1 or more R 2b .

[0149] In some embodiments, R 3 and R 4 and the atoms to which they are attached together form a piperazine ring, morpholine ring, and imidazole ring, which is optionally substituted with 1 or more R 2b .

[0150] In some embodiments, R 3 and R 4 and the atoms to which they are attached together form a tetrahydropyrrole ring, which is optionally substituted with 1 or more R 2b .

[0151] In some embodiments, R 3 and R 4 and the atoms to which they are attached together form an azetidine and tetrahydropyrrole ring, which is optionally substituted with 1 or more R 2b . In some embodiments, each R 2b is independently selected from halogen, hydroxyl, cyano, amino, and C1-C4 alkyl.

[0152] In some embodiments, each R 2b is independently selected from halogen, hydroxyl, cyano, amino, and C1-C4 alkyl.

[0153] In some embodiments, each R 2b is independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy.

[0154] In some embodiments, each R 2b is independently selected from halogen and C1-C4 alkyl.

[0155] In some embodiments, each R 2b is independently selected from C1-C4 alkyl.

[0156] In some embodiments, each R 2b is selected from fluoro, methyl, methoxy, and trifluoromethoxy.

[0157] In some embodiments, each R 2b is selected from fluoro and methoxy.

[0158] In some embodiments, R 2b is methyl.

[0159] In some embodiments, R 2 and R 9and the atom to which they are attached together form a 4-10 membered heterocyclic ring, which is optionally substituted with 1 or more R 3b substituted.

[0160] In some embodiments, R 2 and R 9 and the atom to which they are attached together form a 4-6 membered heterocyclic ring, which is optionally substituted with 1 or more R 3b substituted.

[0161] In some embodiments, R 2 and R 9 and the atom to which they are attached together form a 4-6 membered heterocyclic ring having 1 or 2 heteroatoms selected from O, N, which is optionally substituted with 1 or more R 3b substituted.

[0162] In some embodiments, R 2 and R 9 and the atom to which they are attached together form an azetidine, oxazolidine, morpholino ring, and tetrahydropyrrole ring, which is optionally substituted with 1 or more R 3b substituted.

[0163] In some embodiments, R 2 and R 9 and the atom to which they are attached together form an oxazolidine, morpholino ring, and tetrahydropyrrole ring, which is optionally substituted with 1 or more R 3b substituted.

[0164] In some embodiments, R 2 and R 9 and the atom to which they are attached together form a tetrahydropyrrole ring, which is optionally substituted with 1 or more R 3b substituted.

[0165] In some embodiments, each R 3b is independently selected from halogen, hydroxyl, cyano, amino, and C1-C4 alkyl.

[0166] In some embodiments, R 2 and R 9 and the atom to which they are attached together form a 4-10 membered heterocyclic ring, which is optionally substituted with 1 or more R 3b substituted, and R 3 and R 4 and the atom to which they are attached together form a 4-7 membered heterocyclic ring, which is optionally substituted with 1 or more R 2b substituted.

[0167] In some embodiments, R2 and R 9 The atoms bonded to the oxazolane together form an oxazolane, which is optionally bonded by one or more R atoms. 3b Replace, and R 3 and R 4 The atoms connected to it together form a tetrahydropyrrole ring, which is optionally bounded by one or more R atoms. 2b replace.

[0168] In some implementation schemes, R 2 and R 9 The atoms connected to it together form oxazolidine, and R 3 and R 4 Together with the atoms they are connected to, they form a tetrahydropyrrole ring.

[0169] In some implementation schemes, R 3 and R 3’ The atoms connected to it together form a C3-C4 saturated carbon ring, which is optionally bounded by one or more R atoms. 4b Replace, and R 2 and R 9 The atoms connected to it together form a 4-10 membered heterocycle, which is optionally bounded by one or more R atoms. 3b replace.

[0170] In some implementation schemes, R 3 and R 3’ The atoms bonded to it together form cyclopropane, which is optionally bonded by one or more R atoms. 4b Replace, R 2 and R 9 The atoms bonded to the oxazolane together form an oxazolane, which is optionally bonded by one or more R atoms. 3b replace.

[0171] In some implementation schemes, R 3 and R 3’ The atoms connected to it together form cyclopropane, and R 2 and R 9 Together with the atoms they are connected to, they form oxazolidine.

[0172] In some implementation schemes, each R 1b R 2b R 3b R c R d and R e Independently selected from halogen, hydroxyl, cyano, amino, C1-C 10 Alkyl, C3-C 12 Cycloalkyl and 4-10 membered heterocyclic groups, wherein the hydroxyl, amino, C1-C10 Alkyl, C3-C 12 Cycloalkyl and 4-10 membered heterocyclic groups are optionally surrounded by one or more amino, halogen, cyano, C1-C4 alkyl, C3-C 12 Cycloalkyl and 4-10 membered heterocyclic groups are substituted.

[0173] In some embodiments, the compound of formula (Z) of this disclosure, or its stereoisomer or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (I), or its stereoisomer or a pharmaceutically acceptable salt thereof.

[0174] in:

[0175] Selected from double bonds or single bonds;

[0176] Q 1 Selected from CO, SO2, O and NR 8 ;

[0177] Q 2 Selected from NR 9 CHR 10 , CO and O;

[0178] n is selected from 0, 1, 2, and 3;

[0179] Ring A is selected from C3-C 12 Cycloalkyl, 4-10 membered monoheterocyclic group, C6-C 10 Aryl and 5-12 heteroaryl, the C3-C 12 Cycloalkyl, 4-10 membered monoheterocyclic group, C6-C 10 Aryl and 5-12 heteroaryl groups are optionally substituted with one or more R groups. a replace;

[0180] Each R 1 R 5 and R 6 Independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 Alkyl, C3-C6 cycloalkyl, C2-C 10 alkenyl and C2-C 10 alkynyl group, the hydroxyl group, C1-C 10 Alkyl, C3-C6 cycloalkyl, C2-C 10 alkenyl and C2-C 10 The alkynyl group is optionally surrounded by one or more R groups. 1a replace;

[0181] R 2 and R 10 Independently selected from hydrogen, halogen, oxo, hydroxyl, amino, mercapto, cyano, C1-C 10alkyl, C2-C6alkenyl, C2-C6alkynyl, said hydroxy, amino, mercapto, C1-C 10 alkyl, C2-C6alkenyl, C2-C6alkynyl, said hydroxy, amino, mercapto, C1-C 2a substituted;

[0182] R 3 is selected from the group consisting of hydrogen, halogen, oxo, hydroxy, amino, mercapto, cyano, C1-C 10 alkyl, C2-C6alkenyl, C2-C6alkynyl, said hydroxy, amino, mercapto, C1-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said hydroxy, amino, mercapto, C1-C 10 alkyl, C2-C6alkenyl, C2-C6alkynyl, said hydroxy, amino, mercapto, C1-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said hydroxy, amino, mercapto, C1-C 3a substituted;

[0183] or, R 2 and R 3 together with the atom to which they are attached form a C5-C 12 saturated carbocyclic ring, 4-10 membered heterocyclic ring, C6-C 10 aromatic ring and 5-10 membered heteroaromatic ring, said C5-C 12 saturated carbocyclic ring, 4-10 membered heterocyclic ring, C6-C 10 aromatic ring and 5-10 membered heteroaromatic ring, said hydroxy, amino, mercapto, C1-C 1b substituted;

[0184] R 4 , R 7 , R 8 and R 9 are independently selected from the group consisting of hydrogen, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 alkyl, said C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 alkyl, said C2-C 4a substituted;

[0185] or, R 3 and R 4 together with the atom to which they are attached form a 4-10 membered heterocyclic ring and 5-10 membered heteroaromatic ring, said 4-10 membered heterocyclic ring and 5-10 membered heteroaromatic ring being optionally substituted with 1 or more R 2b substituted;

[0186] each R ahalo, hydroxyl, cyano, amino, C1-C8alkyl, C3-C8cycloalkyl, 4-10 membered 10 heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl, said halo, hydroxyl, cyano, amino, C1-C8alkyl, C3-C8cycloalkyl, 4-10 membered 10 heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R 10 halo, hydroxyl, cyano, amino, C1-C8alkyl, C3-C8cycloalkyl, 4-10 membered 12 heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl, said halo, hydroxyl, cyano, amino, C1-C8alkyl, C3-C8cycloalkyl, 4-10 membered 10 heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R 10 halo, hydroxyl, cyano, amino, C1-C8alkyl, C3-C8cycloalkyl, 4-10 membered 10 heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl, said halo, hydroxyl, cyano, amino, C1-C8alkyl, C3-C8cycloalkyl, 4-10 membered 10 heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R 12 halo, hydroxyl, cyano, amino, C1-C8alkyl, C3-C8cycloalkyl, 4-10 membered 10 heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl, said halo, hydroxyl, cyano, amino, C1-C8alkyl, C3-C8cycloalkyl, 4-10 membered d heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R

[0187] each R 1a is independently selected from the group consisting of halo, hydroxyl, cyano, amino, C1-C8alkyl, C3-C8cycloalkyl, 4-10 membered 10 heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl, said halo, hydroxyl, cyano, amino, C1-C8alkyl, C3-C8cycloalkyl, 4-10 membered

[0188] each R 2a , R 3a , and R 4a are independently selected from the group consisting of halo, hydroxyl, cyano, amino, C1-C8alkyl, C3-C8cycloalkyl, 4-10 membered 12 heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl, said halo, hydroxyl, cyano, amino, C1-C8alkyl, C3-C8cycloalkyl, 4-10 membered 10 heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R 12 halo, hydroxyl, cyano, amino, C1-C8alkyl, C3-C8cycloalkyl, 4-10 membered 10 heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl, said halo, hydroxyl, cyano, amino, C1-C8alkyl, C3-C8cycloalkyl, 4-10 membered c heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R

[0189] each R 1b , R 2b , R c , and R d are independently selected from the group consisting of halo, hydroxyl, cyano, amino, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy;

[0190] one or more hydrogen atoms of the compound are optionally deuterium atoms.

[0191] In some embodiments, the compound of Formula (Z) or Formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, of the present disclosure is selected from a compound of Formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0192] wherein, is a single or double bond; n, Q 1 , Q 2 , R 1R 2 R 3 R 4 R 5 and R 6 As defined above.

[0193] In some embodiments, the compound of formula (Z) of this application, or its stereoisomer or a pharmaceutically acceptable salt thereof, is selected from the compound of formula (III), or its stereoisomer or a pharmaceutically acceptable salt thereof.

[0194] Where, n, Q 2 R 1 R 2 R 2’ R 3 R 3’ R 4 R 5 and R 6 As defined above.

[0195] In some embodiments, the compounds of formula (Z) of this disclosure, or their stereoisomers or pharmaceutically acceptable salts, are selected from the following compounds, or their stereoisomers or pharmaceutically acceptable salts:

[0196] On the other hand, this disclosure provides pharmaceutical compositions comprising a compound of formula (Z) or formula (I) or formula (II) or formula (III) of this disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0197] 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 (Z) or formula (I) or formula (II) or formula (III) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0198] On the other hand, this disclosure provides the use of compounds of formula (Z) or formula (I) or formula (II) or formula (III) 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.

[0199] On the other hand, this disclosure provides the use of compounds of formula (Z) or formula (I) or formula (II) or formula (III) or stereoisomers thereof or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the prevention or treatment of CDK4-mediated diseases.

[0200] In another aspect, the present disclosure provides a compound of Formula (Z) or Formula (I) or Formula (II) or Formula (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in preventing or treating a CDK4-mediated disease.

[0201] In some embodiments, the CDK4-mediated disease is a tumor.

[0202] The compound of Formula (Z) or Formula (I) or Formula (II) or Formula (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, of the present disclosure can achieve at least one of the following advantages: (1) good, even excellent, inhibitory effect on CDK4-mediated tumor cell proliferation; (2) good, even excellent, CDK4 kinase inhibitory selectivity; and (3) good, even excellent, membrane permeability and transport properties.

[0203] Definitions and explanations of terms

[0204] Unless otherwise indicated, the terms used in the present disclosure have the following meanings. The definitions of groups and terms recited in the present disclosure, including the definitions thereof as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in examples, etc., can be combined and incorporated with each other arbitrarily. A specific term should not be considered indefinite or unclear without a specific definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to the corresponding product or active ingredient thereof.

[0205] Herein represents a point of attachment.

[0206] Herein, a bond depicted by a solid line and a dashed line represents a single or double bond.

[0207] The term "stereoisomer" refers to isomers that have the same molecular formula but different structures resulting from the different spatial arrangement of atoms. It includes enantiomers, diastereomers, and geometric isomers.

[0208] The graphical representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, a wedge solid bond and a wedge dashed bond represents the absolute configuration of a stereocenter, with a straight solid bond and a straight dashed bond represents the relative configuration of a stereocenter (e.g., the cis-trans configuration of an alicyclic compound).

[0209] The compounds of the present disclosure can have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and thus the compounds of the present disclosure can exist in particular geometric or stereoisomeric forms. The particular geometric or stereoisomeric forms can be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)- isomers, (L)-isomers, as well as racemic mixtures or other mixtures thereof, such as those that contain one enantiomeric or diastereomeric excess, all of which are within the scope of the compounds of the present disclosure. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms can be present in a substituent group, and all such isomers and mixtures thereof are included within the definition of the compounds of the present disclosure. The compounds of the present disclosure containing an asymmetric atom can be isolated in optically active form or as racemic mixtures, and the optically active forms can be obtained by separation from the racemic mixtures or by using chiral starting materials or chiral reagents in the synthetic sequence.

[0210] The term "substituted" means that any one or more hydrogen atoms on the particular atom is replaced with a substituent group, provided that the valency of the particular atom is not exceeded and that the substituted compound is stable. When the substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced, and oxo cannot be on an aromatic group.

[0211] The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances where the event or circumstance occurs and instances where it does not. For example, an ethyl group "optionally" substituted with one or more halogens means that the ethyl group can be unsubstituted (CH2CH3), mono-substituted (CH2CH2F, CH2CH2C1, etc.), poly-substituted (CHFCH2F, CH2CHF2, CHFCH2C1, CH2CHC12, etc.), or fully substituted (CF2CF3, CF2CC13, CC12CC13, etc.). One skilled in the art will appreciate that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is not possible under normal synthetic procedures.

[0212] When a bond to a substituent interdigitates with a bond to a ring atom, the substituent can be bonded to either atom of the ring. For example, the structural element represents R 1 Substitution can occur at any position on the phenyl ring.

[0213] When a compound has a chiral center marked "or 1", it represents a racemic compound with an enantiomeric ratio of 1 : 1. For example, represents The mixture, and The molar ratio is 1:1.

[0214] 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.

[0215] 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.

[0216] 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-C8 alkyl" can be understood as referring to an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms; the term "C1-C6 alkyl" can be understood as referring to an alkyl group having 1, 2, 3, 4, 5, or 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, 2, 3, or 4 carbon atoms. The term "C1-C3 alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 1, 2, or 3 carbon atoms. The "C1-C6" refers to... 10The 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 "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.

[0217] 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".

[0218] 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.

[0219] 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" 10Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH3), prop-1 -ynyl (-CH2C≡CH), but-1 -ynyl, but-2-ynyl, or but-3-ynyl. "C2-C3alkynyl" can include "C2-C3alkynyl" examples include ethynyl (-C≡CH), prop-1 -ynyl (-C≡CCH3), prop-2-ynyl (-CH2C≡CH). 3、 -CH2C≡CH), but-1 -ynyl, but-2-ynyl, or but-3-ynyl. "C2-C 10 "alkynyl" can include "C2-C3alkynyl", "C2-C3alkynyl" examples include ethynyl (-C≡CH), prop-1 -ynyl (-C≡CCH3), prop-2-ynyl (-CH2C≡CH).

[0220] The term "cycloalkyl" refers to a carbocyclic radical that is completely saturated and exists in a single ring, fused rings, bridged rings, or spiro rings, etc. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 20-membered ring. The term "C3-C10cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 ring carbon atoms. 10 "Cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 ring carbon atoms. The term "C3-C6cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, or 6 ring carbon atoms.

[0221] The term "heterocyclyl" or "heterocycle" refers to a monocyclic, fused ring, spiro, or bridged ring radical which is completely saturated or partially saturated (i.e., not an aromatic heteroaromatic radical overall) having from 1 to 5 (e.g., 1 to 3 or 1 to 2) heteroatoms or heteroatom groups (i.e., groups of atoms containing heteroatoms) in the ring members, including, but not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=0)2-, -S(=0)-, -P(=0)2-, -P(=0)-, -NH-, -S(=0)(=NH)-, -C(=0)NH-, or -NHC(=0)NH-, etc. The term "4-10 membered heterocyclyl" refers to a heterocyclyl radical having a ring atom number of 4, 5, 6, 7, 8, 9, or 10, and having from 1 to 5 ring members independently selected from the heteroatoms or heteroatom groups described above. A "4-10 membered heterocyclyl" can include a "4-7 membered heterocyclyl." The term "4-7 membered heterocyclyl" refers to a heterocyclyl radical having a ring atom number of 4, 5, 6, or 7, and having from 1, 2, 3, 4, or 5 ring members independently selected from the heteroatoms or heteroatom groups described above. The term "4-5 membered heterocyclyl" refers to a heterocyclyl radical having a ring atom number of 4 or 5, and having from 1, 2, 3, or 4 ring members independently selected from the heteroatoms or heteroatom groups described above. Specific examples of 4-membered heterocyclyls include, but are not limited to, azetidinyl or oxetanyl; specific examples of 5-membered heterocyclyls include, but are not limited to, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl, or 2,5-dihydro-lH-pyrrolyl; specific examples of 6-membered heterocyclyls include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H-[l,3,4]thiadiazinyl; and specific examples of 7-membered heterocyclyls include, but are not limited to, diazepanyl. The heterocyclyl can also be a bicyclic radical, with specific examples of 5,5 membered bicyclic radicals including, but not limited to, hexahydrocyclopenta[c]pyrrol-2(lH)-yl; specific examples of 5,6 membered bicyclic radicals including, but not limited to, hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[l,5-a]pyrazinyl. Optionally, the heterocyclyl can be a benzo-fused ring of the aforementioned 4-7 membered heterocyclyls, with specific examples including, but not limited to, dihydroisoquinolinyl, etc."4-10 membered heterocyclyl" can include the range of "5-10 membered heterocyclyl", "4-7 membered heterocyclyl", "5-6 membered heterocyclyl", "6-8 membered heterocyclyl", "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered heterocycloalkyl", etc. "4-7 membered heterocyclyl" can further include the range of "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", etc. Although some bicyclic heterocyclyl groups in the present disclosure contain a benzene ring or a heteroaromatic ring partially, the heterocyclyl group as a whole is still non-aromatic. The term "4-10 membered monocyclic heterocyclyl" refers to a monocyclic heterocyclyl group having 4-10 ring atoms in the 4-10 membered heterocyclyl group.

[0222] The term "heterocycloalkyl" refers to a fully saturated cyclic group existing in the form of a monocyclic, fused ring, bridged ring, or spirocyclic ring, having 1-5 heteroatoms or heteroatom groups (i.e., an atom group containing a heteroatom) in the ring atoms of the ring, which "heteroatoms or heteroatom groups" include, but are not limited to, a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S), a phosphorus atom (P), a boron atom (B), -S(=O)2-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-, etc. The term "4-10 membered heterocycloalkyl" refers to a heterocycloalkyl group having 4, 5, 6, 7, 8, 9, or 10 ring atoms, and having 1-5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms or heteroatom groups in the ring atoms. The term "5-10 membered heterocycloalkyl" refers to a heterocycloalkyl group having 5, 6, 7, 8, 9, or 10 ring atoms, and having 1-5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms or heteroatom groups in the ring atoms. "4-10 membered heterocycloalkyl" and "5-10 membered heterocycloalkyl" include "4-7 membered heterocycloalkyl", wherein specific examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, or thietanyl; specific examples of 5-membered heterocycloalkyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, or tetrahydropyrazolyl; specific examples of 6-membered heterocycloalkyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxinanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, or 1,4-dithianyl; and specific examples of 7-membered heterocycloalkyl groups include, but are not limited to, azepanyl, oxepanyl, or thiepanyl.

[0223] The term "aryl" refers to a fully carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. The aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 10Aryl" is understood to mean an aromatic radical having 6 to 10 carbon atoms. For example, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. 10 Aryl" is understood to mean an aromatic radical having 6 to 10 carbon atoms. For example, a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.

[0224] The term "heteroaryl" means a monocyclic or fused polycyclic ring system having aromaticity, wherein at least one ring atom is selected from N, O, S, the remaining ring atoms being C. The term "5-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, for example 5 or 6 or 9 or 10 ring atoms, and which contain 1-5, for example 1-3, heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl and the like and their benzo derivatives, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzoisoxazolyl, benzoimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or pyrazinyl and the like and their benzo derivatives, such as quinolinyl, quinazolinyl or isoquinolinyl and the like; or azocinyl, indolizinyl, purinyl and the like and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl or phenoxazinyl and the like. The term "6-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 6, 7, 8, 9 or 10 ring atoms, for example 6 or 9 or 10 ring atoms, and which contain 1-5, for example 1-3, heteroatoms independently selected from N, O and S. The term "5-6 membered heteroaryl" means an aromatic ring system having 5 or 6 ring atoms, and which contains 1-3, for example 1-2, heteroatoms independently selected from N, O and S.

[0225] The term "halo" or "halogen" means fluorine, chlorine, bromine or iodine.

[0226] The term "hydroxy" means an -OH group.

[0227] The term "cyano" means a -CN group.

[0228] The term "amino" means an -NH2 group.

[0229] The term "nitro" means an -NO2 group.

[0230] The term "mercapto" means an -SH group.

[0231] The term "treatment" means the administration of a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0232] (i) inhibiting the disease or condition, i.e., arresting its development;

[0233] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0234] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) reduces, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by the skilled practitioner as a matter of routine application of his knowledge and the present disclosure.

[0235] The term "prevention" means the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing the disease or condition from occurring in an individual (e.g., a mammal), particularly when such individual (e.g., a mammal) is predisposed to having the disease or condition but has not yet been diagnosed as having it.

[0236] The term "individual" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds and fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human. The terms "patient" and "individual" are used interchangeably.

[0237] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0238] The term "pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of acids or bases that are included in the art, including salts of compounds with inorganic or organic acids, and salts of compounds with inorganic or organic bases.

[0239] The term "pharmaceutical composition" means a mixture of one or more compounds of the disclosure or salts thereof with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the disclosure to an organism.

[0240] The term "pharmaceutically acceptable excipient" means an excipient that is not

[0241] The words "comprise" or "comprising" and variations thereof such as "comprises" or "comprising" are to be interpreted as encompassing the meanings of "includes" or "including" and variations thereof such as "includes" or "including" without

[0242] The present disclosure also includes isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, 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, and the like.

[0243] Certain isotopically-labeled compounds of the disclosure (for example, those 3 H and 14 C) are useful in compound and / or substrate tissue distribution analysis. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Positron emission isotopes such as 15 O, 13 N, 11 C, and 18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present disclosure can generally be prepared by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent in a

[0244] The pharmaceutical compositions of the present disclosure can be prepared by combining a compound of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.

[0245] Typical routes of administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, include, but are not limited to, oral, rectal, topical, inhalant, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0246] The pharmaceutical compositions of the present disclosure can be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, emulsifying, re- freezing drying, or lyophilizing processes.

[0247] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by combining the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated as tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like, for oral administration to a patient.

[0248] Solid oral compositions can be prepared by conventional mixing or compaction methods. For example, the active compounds can be mixed with a solid excipient, optionally ground, and then filled into a capsule, if desired with addition of another appropriate excipient. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0249] The pharmaceutical compositions can also be adapted for parenteral administration, such as sterile solutions, suspensions, or lyophilized products in appropriate unit dosage forms.

[0250] The dosage administered will depend on such factors as the particular compound, the disease condition and its severity, the identity of the subject or host to be treated (e.g., body weight, sex), and the particular formulation to be used, the route of administration, the condition being treated, and the subject or host being treated.

[0251] In all methods of administration of the compounds of general formula (I) described herein, the daily dose is from 0.001 mg / kg to 5000 mg / kg of body weight, preferably from 0.01 mg / kg to 100 mg / kg of body weight, in single or divided doses, in the case of oral administration. The daily dose and unit dose vary depending on a number of variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0252] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of other chemical synthetic methods, and equivalents thereof well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.

[0253] The chemical reactions of the present disclosure are performed in solvents appropriate to the reaction step and the reagents and materials used therein. In order to carry out the synthesis of the compounds of the present disclosure, it is sometimes necessary to modify or select the synthetic steps or reaction sequences based on the skill of the art on the basis of the embodiments already described.

[0254] The present disclosure employs the following abbreviations:

[0255] DMF stands for N,N-dimethylformamide; DCM stands for dichloromethane; TFA stands for trifluoroacetic acid; THF stands for tetrahydrofuran; MeOH stands for methanol; Mel stands for methyl iodide; DIEA / DIPEA stands for N,N-diisopropylethylamine; NMP stands for N-methylpyrrolidone; HATU stands for O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate); dioxane stands for 1,4-dioxane; Pd2(dba)3 stands for tris(dibenzylideneacetone)dipalladium; Xantphos stands for 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Pd(PPh3)4 stands for tetrakis(triphenylphosphine)palladium; DMSO stands for dimethylsulfoxide; Pd(dtBPF)Cl2 stands for [l,l'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium; LiHMDS stands for lithium bis(trimethylsilyl)amide; TBS stands for tert-butyldimethylsilyl; IBX stands for 2-iodoxybenzoic acid; TBDPSCl stands for tert-butyldiphenylsilyl chloride; PddppfCl2 stands for [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium; B2Pin2 stands for pinacolatoboronate; TEA stands for triethylamine; DABCO stands for triethylenediamine; TsOH stands for p-toluenesulfonic acid; Pd-PEPPSI-IPent stands for dichloro[l,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II); TsOH stands for p-toluenesulfonic acid; MeCN stands for acetonitrile; imidazole stands for imidazole; DMSO stands for dimethylsulfoxide; DMP stands for Dess-Martin periodinane; DAST stands for diethylaminosulfur trifluoride; Py stands for pyridine; DMAP stands for 4-dimethylaminopyridine; Ms20 stands for methanesulfonic anhydride; LC-MS stands for liquid chromatography-mass spectrometry; MS stands for mass spectrometry; 1 HNMR stands for proton nuclear magnetic resonance; ESI stands for electrospray ionization; HEPES stands for N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffer; Trypsin / EDTA stands for trypsin-ethylenediaminetetraacetic acid; EGTA stands for ethylene glycol-bis(2-aminoethylether)tetraacetic acid; DTT stands for dithiothreitol; ATP stands for adenosine triphosphate; EDTA stands for ethylenediaminetetraacetic acid; IC 50 IC50 stands for half maximal inhibitory concentration, the concentration of a substance which induces a response halfway between the baseline and the maximal response; ELISA stands for enzyme-linked immunosorbent assay.

[0256] DETAILED DESCRIPTION

[0257] The compounds of the present disclosure can be prepared by a variety of synthetic methods well-known to those skilled in the art, including the specific embodiments listed herein, the embodiments formed by their combination with other chemical synthesis methods, and equivalent substitution methods well-known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present disclosure.

[0258] The present disclosure will be described in detail below by way of examples, which does not mean any adverse limitation to the present disclosure. The present disclosure has been described in detail herein, and specific embodiments thereof have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0259] Unless otherwise stated, the ratio represented by the mixed solvent is the volume mixing ratio.

[0260] Unless otherwise stated, % refers to weight percentage wt%.

[0261] The compounds are named manually or by software, and commercially available compounds use the supplier catalog names.

[0262] The structure of the compounds is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS);

[0263] The eluent or mobile phase can be a mixed eluent or mobile phase composed of two or more solvents, and the ratio thereof is the volume ratio of each solvent. Example 1: 8-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1,4-dimethyl-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin-5-one

[0264] Step 1: Methyl 4-bromo-2-((2-((tert-butoxycarbonyl)(methyl)amino)ethyl)amino)benzoate (Compound 1-2)

[0265] Compound 1-1 (1 g, 4.29 mmol) was dissolved in N,N-dimethylformamide (5 mL) solution, followed by the addition of tert-butyl (2-aminoethyl)(methyl)carbamate (1.5 g, 8.58 mmol) and potassium carbonate (1.78 g, 12.87 mmol), and the reaction was stirred at 100°C for 2 hours. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by normal phase column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to obtain compound 1-2 (1.07 g, 64%).

[0266] m / z (ESI): 387 [M+H] +

[0267] Step 2: methyl 4-bromo-2-((2-(methylamino)ethyl)amino)benzoate (compound 1-3)

[0268] Compound 1-2 (1.07 g, 2.76 mmol) was dissolved in dichloromethane (5 mL) solution, followed by the addition of trifluoroacetic acid (2 mL), and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, it was directly concentrated to dryness under reduced pressure to obtain compound 1-3 crude (790 mg), which was used in the next reaction without purification.

[0269] m / z (ESI): 287 [M+H] +

[0270] Step 3: 4-bromo-2-((2-(methylamino)ethyl)amino)benzoic acid (compound 1-4)

[0271] Compound 1-3 (790 mg, 2.76 mmol) was dissolved in tetrahydrofuran / methanol / water (3:1:1, 25 mL) solution, followed by the addition of lithium hydroxide (198 mg, 8.28 mmol), and the reaction was stirred at 50°C for 2 hours. After the reaction was completed, it was cooled to room temperature, the pH of the reaction was adjusted to 3 by the addition of 2M hydrochloric acid, and the solid was collected by filtration to obtain compound 1-4 (710 mg, 94%).

[0272] m / z (ESI): 273 [M+H] +

[0273] Step 4: 4-bromo-2-((2-(methylamino)ethyl)amino)benzoic acid (compound 1-5)

[0274] Compound 1-4 (710 mg, 2.61 mmol) was dissolved in N,N-dimethylformamide (5 mL), followed by the addition of 2-(7-azabenzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate (1.40 mg, 3.90 mmol) and N,N- diisopropylethylamine (671 mg, 5.20 mmol), and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, purification was performed by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 1-5 (650 mg, 98%).

[0275] m / z (ESI): 255 [M+H] +

[0276] Step 5: 8-Bromo-1,4-dimethyl-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin-5-one (Compound 1-6)

[0277] Compound 1-5 (650 mg, 2.55 mmol) was dissolved in N,N-dimethylformamide (5 mL) at 0°C, sodium hydride (122 mg, 5.10 mmol) was added, stirred for 10 minutes, followed by the addition of iodomethane (723 mg, 5.10 mmol), and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, extraction was performed with ethyl acetate, dried over anhydrous sodium sulfate, and purification was performed by normal phase column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to obtain compound 1-6 (450 mg, 65%).

[0278] m / z (ESI): 269 [M+H] +

[0279] Step 6: 1,4-Dimethyl-8-(trimethylstannyl)-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin-5-one (Compound 1-7)

[0280] Compound 1-6 (50 mg, 186.57 µmol) was dissolved in dioxane (2 mL) under an argon atmosphere, followed by the addition of tetrakis(triphenylphosphine)palladium (22 mg, 19.60 µmol), hexamethylditin (96 mg, 293.99 µmol), and the reaction solution was stirred at 100°C for 1 hour. After the reaction was completed, it was allowed to decrease to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain crude compound 1-7 (66 mg), which was used directly in the next reaction without purification.

[0281] m / z (ESI): 355 [M+H] +

[0282] Step 7: 8-(2-chloro-5-fluoropyrimidin-4-yl)-1,4-dimethyl-1,2,3,4- tetrahydro-5H-benzo[e][1,4]diazepin-5-one (Compound 1-8)

[0283] Compound 1-7 (66 mg, 186.94 μmol) was dissolved in dioxane (2 mL) under argon atmosphere, followed by the addition of tetrakis(triphenylphosphine)palladium (22 mg, 19.60 μmol), copper(I) chloride (18 mg, 181.81 μmol) and 2,4-dichloro-5-fluoropyrimidine (47 mg, 280 μmol) respectively. The reaction was stirred at 100 °C for 1 h. After the reaction was completed, it was allowed to cool down to room temperature, filtered, the filtrate was evaporated to dryness and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1 : 1) to give Compound 1-8 (35 mg, 58%).

[0284] m / z (ESI): 321 [M+H] +

[0285] Step 8: 8-(5-fluoro-2-((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 1,4-dimethyl-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin-5-one (Compound 1)

[0286] Compound 1-8 (20 mg, 62.48 μmol) was dissolved in dioxane (2 mL) under argon atmosphere, followed by the addition of (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (10 mg, 65.36 μmol), tris(dibenzylideneacetone)dipalladium (5 mg, 5.51 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6 mg, 10.37 μmol) and cesium carbonate (360 mg, 110 μmol) respectively. The reaction was stirred at 110 °C for 4 h. After the reaction was completed, it was allowed to cool down to room temperature, filtered, the filtrate was concentrated to dryness under reduced pressure and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1 : 1) to give Compound 1 (4 mg, 16%).

[0287] m / z (ESI): 402 [M+H] +

[0288] 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 3.7 Hz, 1H), 7.54 (q, J = 8.3 Hz, 3H), 7.19 (d, J = 7.6 Hz, 1H), 4.93 (d, J = 5.3 Hz, 1H), 3.82 (dd, J = 11.8, 5.8 Hz, 3H), 3.48 (dt, J = 28.1, 5.4 Hz, 2H), 3.30 (s, 3H), 3.08 (s, 3H), 3.03 (d, J = 10.4 Hz, 1H), 2.83 (s, 3H), 2.00 (d, J = 11.3 Hz, 1H), 1.55 - 1.45 (m, 1H), 1.24 (s, 1H).

[0289] Example 2: 8-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-10-methyl-1,2,3,10,11,11a-hexahydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5-one (Compound 2)

[0290] According to the synthetic procedure of Example 1, the first step, tert-butyl (2- aminoethyl)(methyl)carbamate was replaced by tert-butyl (2-(aminomethyl)pyrrolidine-1- carboxylate) to give the title compound 2 (16 mg). (2-(Aminomethyl)pyrrolidine-1-carboxylate) to give the title compound 2 (16 mg).

[0291] m / z (ESI): 428 [M+H] + .

[0292] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 3.7 Hz, 1H), 7.54 (q, J = 8.3 Hz, 3H), 7.19 (d, J = 7.6 Hz, 1H), 4.93 (d, J = 5.3 Hz, 1H), 3.82 (dd, J = 11.8, 5.8 Hz, 3H), 3.48 (dt, J = 28.1, 5.4 Hz, 2H), 3.30 (s, 3H), 3.08 (s, 3H), 3.03 (d, J = 10.4 Hz, 1H), 2.83 (s, 3H), 2.00 (d, J = 11.3 Hz, 1H), 1.55 - 1.45 (m, 1H), 1.24 (s, 1H).

[0293] Example 3: Trans-3-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-5,10-dimethyl-5,5a,6,7,8,9,9a,10-octahydro-11H-dibenzo[b,e][1,4]diazepin-11-one (Compound 3)

[0294] Step 1: Trans- (4-bromo-2-fluoro-N-methyl-N- [2- (methylamino) cyclohexyl] benzamide (Compound 3-2)

[0295] Trans-N 1 ,N 2 -dimethylcyclohexane-1, 2-diamine (1S, 2S)-N 1 ,N 2 -dimethylcyclohexane-1, 2-diamine / (1R, 2R)-N 1 ,N 2 -dimethylcyclohexane-1, 2-diamine = 1: 1, 548.81 mg, 3.86 mmol) and 4-bromo-2-fluoro-benzoic acid (650 mg, 2.97 mmol) was dissolved in N, N- dimethylformamide (10 mL), to the mixture was added 2-(7-azabenzotriazol-1- yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (1.68 g, 4.45 mmol) and N, N- diisopropylethylamine (1.15 g, 8.90 mmol) at 0 °C. The mixture was stirred at room temperature for 1 hour. Water (50 mL) was added, ethyl acetate was extracted (50 mL*3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, the crude product was purified by reverse phase column chromatography (column: Fast silica gel column; mobile phase: acetonitrile / water = 80:20) to give the title compound 3-2 (330 mg, yield 32%).

[0296] MS m / z (ESI): 343 [M+H]+.

[0297] Step 2: Trans-3-bromo-5, 10-dimethyl-5, 5a, 6, 7, 8, 9, 9a, 10- octahydro-11H-dibenzo[b, e] [1, 4] diazepin-11-one (Compound 3-3)

[0298] Compound 3-2 (330.00 mg, 962.10 μmol) was dissolved in N-methyl pyrrolidine (1 mL), then N, N-diisopropyl ethylamine (372.78 mg, 2.88 mmol) was added, heated to 180 °C under microwave for 1 hour. Cooled to room temperature, purified by reverse phase column chromatography (column: Fast silica gel column; mobile phase: acetonitrile / water = 80:20) to give compound 3-3 (230 mg, yield 74%).

[0299] MS m / z (ESI): 323 [M+H]+.

[0300] Step 3: Trans-5,10-dimethyl-3-(trimethylstannyl)-5,5a,6,7,8,9,9a,10- octahydro-11H-dibenzo[b,e][1,4]diazepin-11-one (Compound 3-4)

[0301] A mixture of hexamethylditin (15.20 mg, 46.39 μmol), Compound 3-3 (10.00 mg, 30.96 μmol), and [1,1'-bis(ditert-butylphosphine)ferrocene]palladium dichloride (2.00 mg, 3.09 μmol) was vacuumed and purged with argon, then 1,4-dioxane (1 mL) was added by syringe. Heat to 100 °C for 1 h. Filter and concentrate to get crude Compound 3-4 (12.6 mg, yield 100%).

[0302] MS m / z (ESI): 409 [M+H]+.

[0303] Step 4: Trans-(3S,4R)-4-((4-(5,10-dimethyl-11-oxo-5a,6,7,8,9,9a,10,11- octahydro-5H-dibenzo[b,e][1,4]diazepin-3-yl)-5-fluoropyrimidin-2-yl)amino)tetrahydro- 2H-pyran-3-yl acetate (Compound 3-5)

[0304] A mixture of Compound 3A (8.90 mg, 30.72 μmol), Compound 3-4 (12.60 mg, 30.88 μmol), copper(I)chloride (3.06 mg, 30.91 μmol), and bis(tri-tert-butylphosphine)palladium(0) (1.59 mg, 3.10 μmol) was vacuumed and purged with argon, then 1,4-dioxane (1 mL) was added, heat to 100 °C for 1 h. Cool to room temperature, then purify by reverse phase column (column: Fast silica gel column; mobile phase: acetonitrile / water = 5%-95% in 10 min) to get Compound 3-5 (13 mg, yield 85%).

[0305] MS m / z (ESI): 498 [M+H]+.

[0306] Step 5: Trans-3-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin- 4-yl)-5,10-dimethyl-5,5a,6,7,8,9,9a,10-octahydro-11H-dibenzo[b,e][1,4]diazepin-11-one (Compound 3)

[0307] Compound 3-5 (13 mg, 26.16 μmol) and potassium carbonate (11 mg, 79.59 μmol) were dissolved in water (0.5 mL) and methanol (0.5 mL), heated to 50 °C, and reacted for 1 hour. After cooling to room temperature, compound 3 (9 mg, yield 76%) was obtained by reverse phase column chromatography (chromatography column: XBridge Prep OBD C18 OBD, 19 x 200 mm, 5-μm packing; mobile phase: acetonitrile / water = 5%-95%, 10 minutes). Fast silica gel column; mobile phase: acetonitrile / water = 5%-95%, 10 minutes) to obtain compound 3 (9 mg, yield 76%).

[0308] MS m / z (ESI): 456 [M+H]+.

[0309] 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 3.7 Hz, 1H), 7.62 - 7.43 (m, 3H), 7.21 (d, J = 7.6 Hz, 1H), 3.82 (dd, J = 10.7, 5.0 Hz, 3H), 3.52 (d, J = 4.7 Hz, 2H), 3.05 (d, J = 9.7 Hz, 1H), 2.99 (s, 3H), 2.81 (s, 3H), 2.13 (s, 1H), 1.98 (d, J = 12.0 Hz, 2H), 1.67 (d, J = 14.2 Hz, 3H), 1.48 (d, J = 11.0 Hz, 2H), 1.29 - 1.05 (m, 3H), 0.84 (s, 2H).

[0310] Example 4: 9-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-5-methyl-1,2,3,3a,4,5-hexahydro-6H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-6-one (Compound 4)

[0311] According to the synthesis procedure of Example 1, the tert-butyl (2-aminoethyl)(methyl)carbamate of the first step was replaced by tert-butyl (methyl(pyrrolidin-2-ylmethyl)carbamate) to obtain compound 4 (15 mg). (methyl(pyrrolidin-2-ylmethyl)carbamate) to obtain compound 4 (15 mg).

[0312] m / z (ESI): 428 [M+H] + .

[0313] 1H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 3.8 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.40 - 7.12 (m, 3H), 4.93 (s, 1H), 3.78 (ddd, J = 34.0, 10.9, 4.9 Hz, 4H), 3.50 (d, J = 14.9 Hz, 2H), 3.41 (dd, J = 13.5, 6.1 Hz, 4H), 3.05 (s, 4H), 2.16 (dd, J = 11.7, 5.8 Hz, 1H), 2.02 (s, 2H), 1.89 (s, 1H), 1.67 - 1.45 (m, 2H).

[0314] Example 5: (R)-8-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 2,2a,3,4-tetrahydroazepino[l,2-a]benzo[f][l,4]diazepin-5(lH)-one (Compound 5)

[0315] According to the synthesis procedure of Example 1, the first step, tert-butyl (2- aminoethyl)(methyl)carbamate was replaced by tert-butyl ((R)-(azetidin-2- ylmethyl)carbamate hydrochloride) to give Compound 5 (8 mg). ((R)-(azetidin-2-ylmethyl)carbamate hydrochloride) to give Compound 5 (8 mg).

[0316] m / z (ESI): 400 [M+H] + .

[0317] 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 3.6 Hz, 1H), 8.31 - 8.20 (m, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.21 (dd, J = 20.6, 8.0 Hz, 2H), 7.01 (s, 1H), 4.93 (d, J = 5.3 Hz, 1H), 4.46 (d, J = 7.1 Hz, 1H), 4.26 - 4.12 (m, 1H), 3.91 (dt, J = 10.0, 7.4 Hz, 1H), 3.81 (dd, J = 11.1, 5.0 Hz, 3H), 3.48 (ddd, J = 14.1, 9.6, 4.7 Hz, 3H), 3.30 - 3.17 (m, 2H), 3.04 (dd, J = 11.1, 9.7 Hz, 1H), 2.14 (tt, J = 10.7, 5.3 Hz, 1H), 1.99 (d, J = 12.9 Hz, 1H), 1.48 (qd, J = 11.9, 4.5 Hz, 1H).

[0318] Example 6: (3aR,10aS)-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-4,10-dimethyl-3a,4,10,10a-tetrahydro-lH-benzo[e]furo[3,4- b] [l,4]diazepin-9(3H)-one (Compound 6)

[0319] According to the synthetic procedure of Example 1, substituting tert-butyl (2- aminoethyl)(methyl)carbamate in the first step with tert-butyl (((3S,4R)-4- aminotetrahydrofuran-3-yl)carbamate) gave Compound 6 (5 mg). (((3S,4R)-4-aminotetrahydrofuran-3-yl)carbamate) gave Compound 6 (5 mg).

[0320] m / z (ESI): 444 [M+H] + .

[0321] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 3.7 Hz, 1H), 7.74 - 7.57 (m, 3H), 7.21 (d, J = 7.7 Hz, 1H), 4.93 (s, 1H), 4.15 (s, 2H), 3.96 - 3.79 (m, 8H), 3.15 (s, 3H), 3.05 (t, J = 10.3 Hz, 2H), 2.76 (s, 3H), 1.98 (s, 1H), 1.49 (d, J = 10.8 Hz, 1H).

[0322] Example 7: (3aS,10aR)-6-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-4,10-dimethyl-3a,4,10,10a-tetrahydro-lH-benzo[e]furo[3,4- b] [l,4]diazepin-9(3H)-one (Compound 7)

[0323] According to the synthetic procedure of Example 1, substituting tert-butyl (2- aminoethyl)(methyl)carbamate in the first step with tert-butyl (((3S,4R)-4- aminotetrahydrofuran-3-yl)carbamate) gave Compound 6 (5 mg). (((3S,4R)-4-aminotetrahydrofuran-3-yl)carbamate) gave Compound 6 (5 mg).

[0324] m / z (ESI): 444 [M+H] + .

[0325] 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 3.6 Hz, 1H), 7.67 - 7.51 (m, 3H), 7.21 (d, J = 7.7 Hz, 1H), 4.93 (dd, J = 5.4, 1.6 Hz, 1H), 4.15 (d, J = 5.3 Hz, 1H), 3.96 - 3.76 (m, 8H), 3.67 - 3.56 (m, 2H), 3.15 (s, 3H), 3.05 (t, J = 10.3 Hz, 1H), 2.76 (s, 3H), 2.00 (s, 1H), 1.49 (d, J = 12.1 Hz, 1H).

[0326] Example 8: 2-ethyl-8-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-1,4-dimethyl-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin- 5-one (Compound 8)

[0327] According to the synthetic procedure of Example 1, the first step, tert-butyl (2- aminoethyl)(methyl)carbamate was replaced by tert-butyl ((2-aminobutyl)carbamate) to give Compound 8 (8 mg). ((2-aminobutyl)carbamate) to give Compound 8 (8 mg).

[0328] m / z (ESI): 430 [M+H] + .

[0329] 1 H NMR (400 MHz, DMSO-d6) δ 8.42 (d, J = 3.7 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.48 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 3.81 (dt, J = 11.3, 5.6 Hz, 3H), 3.57 - 3.37 (m, 5H), 3.09 (s, 3H), 3.07 - 3.02 (m, 1H), 2.88 (s, 3H), 2.00 (d, J = 13.0 Hz, 1H), 1.84 - 1.60 (m, 1H), 1.55 - 1.33 (m, 2H), 0.81 (td, J = 7.5, 3.1 Hz, 3H).

[0330] Example 9: (R)-9-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-1,2,3,3a,4,5-hexahydro-6H-benzo[f]pyrrolo[1,2-a][1,4]diazepin- 6-one (Compound 9)

[0331] According to the synthetic procedure of Example 1, substituting methyl 2-fluoro-4- bromobenzoate for methyl 2-fluoro-4-iodobenzoate in the first step, ((R)-(pyrrolidin-2-ylmethyl)carbamic acid tert-butyl ester) to give compound 9 (14 mg).

[0332] m / z (ESI): 414 [M+H] + .

[0333] 1 H NMR (400 MHz, DMSO-d6) δ 8.41 (d, J = 3.7 Hz, 1H), 8.15 (dd, J = 7.4, 4.3 Hz, 1H), 7.93 (d, J = 8.3 Hz, 1H), 7.31 (s, 1H), 7.18 (dd, J = 14.3, 7.9 Hz, 2H), 4.93 (d, J = 5.3 Hz, 1H), 3.85 - 3.65 (m, 4H), 3.57 - 3.34 (m, 5H), 3.21 - 2.98 (m, 2H), 2.22 - 1.80 (m, 4H), 1.56 (dtd, J = 65.0, 11.6, 7.3 Hz, 2H).

[0334] Example 10: (R)-7-fluoro-9-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-5-methyl-1,2,3,3a,4,5-hexahydro-6H-benzo[f]pyrrolo[1,2- a][1,4]diazepin-6-one (Compound 10)

[0335] According to the synthetic procedure of Example 1, substituting methyl 2-fluoro-4- bromobenzoate for methyl 2-fluoro-4-iodobenzoate in the first step, (4-bromo-2,6-difluorobenzoic acid methyl ester) and substituting (2-aminoethyl)(methyl)carbamic acid tert-butyl ester for (R)-methyl(pyrrolidin-2-ylmethyl)carbamic acid tert-butyl ester in the last step to give compound 10 (14 mg).

[0336] m / z (ESI): 414 [M+H] + .

[0337] 1 ​H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 3.6 Hz, 1H), 7.25 - 7.12 (m, 2H), 7.01 (d, J = 11.6 Hz, 1H), 4.93 (d, J = 5.1 Hz, 1H), 3.87 - 3.47 (m, 7H), 3.46 - 3.37 (m, 3H), 3.05 (t, J = 10.4 Hz, 1H), 2.99 (s, 3H), 2.18 - 1.81 (m, 4H), 1.52 (ddt, J = 17.2, 12.4, 6.6 Hz, 2H).

[0338] Example 11: 8-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 2,2,4-trimethyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (Compound 11)

[0339] Step 1: 8-bromo-2,2-dimethyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (Compound 11-2)

[0340] Compound 11-1 (50 mg, 196.0 μmol) was dissolved in dichloromethane (2 mL), then potassium azide (23.85 mg, 294.01 μmol) and methanesulfonic acid (28.26 mg, 294.04 μmol) were added respectively, and the reaction was stirred at 0 °C for 2 hours. After the reaction was completed, sodium bicarbonate was quenched, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to give Compound 11-2 (45 mg, 85%).

[0341] m / z (ESI): 270 [M+H] +

[0342] Step 2: 8-bromo-2,2,4-trimethyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (Compound 11-3)

[0343] Compound 11-2 (45 mg, 166.59 μmol) was dissolved in tetrahydrofuran (5 mL) at 0 °C, and lithium bis(trimethylsilyl)amide (55.8 mg, 333.47 μmol) was added, stirred for 10 minutes, then methyl trifluoromethanesulfonate (82 mg, 499.70 μmol) was added, and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, Compound 11-3 (30 mg, 63%) was obtained by purification by reverse phase column chromatography (eluent: water: acetonitrile = 1:1).

[0344] m / z (ESI): 284 [M+H] +

[0345] Step 3: 2,2,4-Trimethyl-8-(trimethylstannyl)-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)- one (Compound 11-4)

[0346] Compound 11-3 (30 mg, 105.58 μmol) was dissolved in dioxane (2 mL) under argon atmosphere, then tetra(triphenylphosphine)palladium (12.19 mg, 10.55 μmol), hexamethylditin (51.89 mg, 158.38 μmol) were added respectively, the reaction was stirred at 100 °C for 1 h. After the reaction was completed, it was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure to give compound 11-4 (35 mg) as a crude product, which was used directly in the next step without purification.

[0347] m / z (ESI): 368 [M+H] +

[0348] Step 4: (3S,4R)-4-[(5-Fluoro-4-(2,2,4-trimethyl-5-oxo-2,3,4,5-tetrahydrobenzo[f][l,4]oxazepin-8- yl)pyrimidin-2-yl]amino]tetrahydro-2H-pyran-3-yl acetate (Compound 11-5)

[0349] Compound 11-4 (35 mg, 95.09 μmol) was dissolved in dioxane (2 mL) under argon atmosphere, then tetra(triphenylphosphine)palladium (10.98 mg, 9.50 μmol), cuprous chloride (9.41 mg, 95.05 μmol) and 3A (41.32 mg, 142.64 μmol) were added respectively, the reaction was stirred at 100 °C for 1 h. After the reaction was completed, it was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to give compound 11-5 (25 mg, 57%).

[0350] m / z (ESI): 459 [M+H] +

[0351] Step 5: 8-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 2,2,4-trimethyl-3,4-dihydrobenzo[f][l,4]oxazepin-5(2H)-one (Compound 11)

[0352] Compound 11-5 (10 mg, 21.81 µmol) was dissolved in methanol / water (3:1, 2 mL) solution, then potassium carbonate (9.03 mg, 65.34 µmol) was added, and the reaction was stirred at 50 °C for 0.5 h. Purification by reverse phase column chromatography (eluent: water:acetonitrile = 2:1) gave compound 11 (7 mg, 77%).

[0353] m / z (ESI): 417 [M+H] +

[0354] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 3.6 Hz, 1H), 7.80 (dt, J = 8.1, 1.5 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 1.4 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 4.92 (d, J = 5.1 Hz, 1H), 3.82 (dd, J = 11.8, 5.8 Hz, 3H), 3.50 (dt, J = 9.3, 4.7 Hz, 1H), 3.34 (s, 3H), 3.15 (s, 3H), 3.05 (dd, J = 11.1, 9.6 Hz, 1H), 1.97 (d, J = 12.5 Hz, 1H), 1.54 – 1.41 (m, 1H), 1.34 (d, J = 1.4 Hz, 6H).

[0355] Example 12: (R)-9-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 1,2,3,3a-tetrahydro-4H-benzopyrrolo[1,2-a][1,4]diazepine-4,6(5H)-dione (Compound 12)

[0356] Step 1: (R)-4-bromo-2-(2-(hydroxymethyl)pyrrolidin-1-yl)benzamide (Compound 12-2)

[0357] Compound 12-1 (1 g, 4.59 mmol) was dissolved in N,N-dimethylformamide (30 mL) solution, then (R)-2-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine (1.49 g, 6.92 mmol) and potassium carbonate (3.18 g, 23.01 mmol) were added, respectively, and the reaction was stirred at 100 °C overnight. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and purified by normal phase column chromatography (eluent: dichloromethane:methanol = 20:1) to give compound 12-2 (1.01 g, 74%).

[0358] m / z (ESI): 299 [M+H]+

[0359] Step 2: (R)-9-bromo-1,2,3,3a-tetrahydro-4H-benzo[f]pyrrolo[l,2-a][l,4]diazepine-4,6(5H)- dione (Compound 12-3)

[0360] Compound 12-2 (1.01 g, 3.38 mmol) was dissolved in dimethyl sulfoxide (5 mL) solution, then 2-iodoxybenzoic acid (1.40 g, 5.00 mmol) was added, the reaction was stirred at room temperature for 1 hour. After the reaction was completed, ethyl acetate was extracted, dried over anhydrous sodium sulfate, and purified by normal phase column chromatography (eluent: dichloromethane:methanol = 20:1) to obtain compound 12-3 (250 mg, 25%).

[0361] m / z (ESI): 295 [M+H] +

[0362] Step 3: (R)-9-(trimethylstannyl)-l,2,3,3a-tetrahydro-4H-benzo[f]pyrrolo[l,2-a][l,4]diazepine-4,6(5H)- dione (Compound 12-4)

[0363] Compound 12-3 (30 mg, 101.65 μmol) was dissolved in dioxane (2 mL) solution under argon atmosphere, then tetrakis(triphenylphosphine)palladium (11.78 mg, 10.19 μmol), hexamethylditin (50.14 mg, 153.04 μmol) were added, respectively, the reaction was stirred at 100°C for 1 hour. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 12-4 (37 mg) as a crude product, which was used directly in the next reaction without purification.

[0364] m / z (ESI): 379 [M+H] +

[0365] Step 4: (R)-9-(2-chloro-5-fluoropyrimidin-4-yl)-l,2,3,3a-tetrahydro-4H-benzo[f]pyrrolo[l,2-a][l,4]diazepine- 4,6(5H)-dione (Compound 12-5)

[0366] Compound 12-4 (37 mg, 97.61 pmol) was dissolved in dioxane (2 mL) under argon atmosphere, then tetra(triphenylphosphine)palladium (10.8 mg, 9.35 pmol), copper(I) chloride (9.6 mg, 96.97 pmol) and 2,4-dichloro-5-fluoropyrimidine (24 mg, 143.74 pmol) were added respectively, and the reaction was stirred at 100 °C for 1 h. After the reaction was completed, it was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to give compound 12-5 (25 mg, 71% yield for two steps).

[0367] m / z (ESI): 347 [M+H] +

[0368] Step 5: (R)-9-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 1,2,3,3a-tetrahydro-4H-benzo[f]pyrrolo[1,2-a][1,4]diazepine-4,6(5H)-dione (Compound 12)

[0369] Compound 12-5 (10 mg, 28.84 pmol) was dissolved in dimethyl sulfoxide (1 mL), then N,N-diisopropylethylamine (74.56 mg, 576.91 pmol) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (50.7 mg, 330.06 pmol) were added, and the reaction was stirred at 120 °C for 4 h. After the reaction was completed, it was cooled to room temperature, purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to give the target compound 12 (3 mg, 24%).

[0370] m / z (ESI): 428 [M+H] +

[0371] 1 H NMR (400 MHz, DMSO-d6) d 8.47 (d, J = 3.6 Hz, 1H), 8.24 (s, 1H), 7.60 - 7.38 (m, 2H), 7.25 (d, J = 7.7 Hz, 1H), 4.93 (d, J = 5.3 Hz, 1H), 3.94 - 3.76 (m, 6H), 2.00 (s, 4H), 1.50 (s, 2H), 1.23 (s, 4H).

[0372] Example 13: (3R,3aS)-9-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-3-methoxy-2,3,3a,4-tetrahydro-lH,6H-benzo[e]pyrrolo[2,l- c][l,4]oxazepin-6-one (Compound 13)

[0373] Step 1: (2S,3R)-3-hydroxy-2-(hydroxymethyl)pyrrolidine-l-carboxylate (Compound 13-2)

[0374] Compound 13-1 (660 mg, 2.85 mmol) was dissolved in tetrahydrofuran (5 mL), borane dimethyl sulfide complex (7 ml, 2M in THF) was added under ice bath, slowly recovered to room temperature and stirred overnight. After the reaction was completed, methanol was slowly added under ice bath, and concentrated to dryness under reduced pressure to obtain crude compound 13-2 (600 mg).

[0375] LC-MS: m / z (ESI): 218 [M+H] + .

[0376] Step 2: (2S,3R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-hydroxypyrrolidine-l- carboxylate (Compound 13-3)

[0377] Compound 13-2 (600.0 mg) was dissolved in N,N-dimethylformamide (5 mL), imidazole (408 mg, 5.99 mmol) was added, and tert-butyldiphenylsilyl chloride (1.41 g, 5.13 mmol) was added under ice bath, slowly recovered to room temperature and reacted for 8 hours. After the reaction was completed, it was quenched with an aqueous ammonium chloride solution, and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1-1:19) to obtain compound 13-3 (700 mg, 54% yield for two steps).

[0378] LC-MS: m / z (ESI): 456 [M+H] + .

[0379] Step 3: (2S,3R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-methoxypyrrolidine-l- carboxylate (Compound 13-4)

[0380] Compound 13-3 (280.0 mg, 0.61 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydride (36.7 mg, 0.92 mmol) was added at 0 °C and stirred for 10 minutes, iodomethane (142 mg, 1.00 mmol) was added and slowly returned to room temperature and reacted for 1 hour. The reaction was quenched with aqueous ammonium chloride solution and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1-1:19) to obtain compound 13-4 (140 mg, 49%).

[0381] LC-MS: m / z (ESI): 470 [M+H] + .

[0382] Step 4: (2S,3R)-2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-methoxypyrrolidine (Compound 13-5)

[0383] Compound 13-4 (140.0 mg, 0.30 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.5 mL) was added and reacted at 20 °C for 1 hour. The reaction was quenched and concentrated to dryness under reduced pressure and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1-1:19) to obtain compound 13-5 (60 mg, 54%).

[0384] LC-MS: m / z (ESI): 370 [M+H] + .

[0385] Step 5: (3R,3aS)-9-bromo-3-methoxy-2,3,3a,4-tetrahydro-1H,6H-benzo[e]pyrrolo[2,1-c][1,4]oxazepin-6-one (Compound 13-6)

[0386] Compound 13-5 (150 mg, 0.41 mmol), methyl 2-fluoro-4-bromobenzoate (95 mg, 0.41 mmol) were dissolved in dimethyl sulfoxide (2 mL), N,N-diisopropylethylamine (157 mg, 1.21 mmol) was added and reacted at 80 °C for 12 hours. The reaction was quenched and purified by reverse phase column chromatography (eluent: water: acetonitrile = 2:3) to obtain compound 13-6 (20 mg, yield 16%).

[0387] LC-MS: m / z (ESI): 312 [M+H] + .

[0388] Step 6: (3R,3aS)-3-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,3a,4-tetrahydro-1H,6H-benzo[e]pyrrolo[2,1-c][1,4]oxazepin-6-one (Compound 13-7)

[0389] Compound 13-6 (20 mg, 0.064 mmol) was dissolved in 1,4-dioxane (2 mL), then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (5.8 mg, 0.008 mmol), bis(pinacolato)diboron (30.5 mg, 0.12 mmol) and potassium acetate (23 mg, 0.23 mmol) were added, and the reaction was heated at 80 °C under nitrogen for 2 hours. The reaction was filtered directly, and the filtrate was concentrated to dryness under reduced pressure to obtain crude compound 13-7 (23 mg).

[0390] LC-MS: m / z (ESI): 360 [M+H] + .

[0391] Step 7: (3R,3aS)-9-(2-chloro-5-fluoropyrimidin-4-yl)-3-methoxy-2,3,3a,4- tetrahydro-1H,6H-benzo[e]pyrrolo[2,1-c][1,4]oxazepin-6-one (Compound 13-8)

[0392] Compound 13-7 (23 mg, 0.064 mmol) was dissolved in a mixture of 1,4-dioxane (2 mL) and water (0.3 mL), then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (5.8 mg, 0.008 mmol), 2,4-dichloro-5-fluoropyrimidine (26 mg, 0.16 mmol) and potassium carbonate (33 mg, 0.24 mmol) were added, and the reaction was heated at 80 °C under nitrogen for 12 hours. The reaction was concentrated to dryness under reduced pressure, and purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 13-8 (18 mg, 77% yield over two steps).

[0393] LC-MS: m / z (ESI): 364 [M+H] + .

[0394] Step 8: (3R,3aS)-9-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3-methoxy-2,3,3a,4-tetrahydro-1H,6H-benzo[e]pyrrolo[2,1-c][1,4]oxazepin-6-one (Compound 13)

[0395] Compound 13-8 (17.0 mg, 0.047 mmol) was dissolved in dimethyl sulfoxide (0.4 mL), then (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (71.5 mg, 0.47 mmol), N,N-diisopropylethylamine (90 mg, 0.70 mmol) were added, and the reaction was heated at 80 °C for 12 h. The reaction was completed. The reaction solution was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain compound 13 (10.0 mg, yield 48%).

[0396] LC-MS: m / z (ESI): 445 [M+H] + .

[0397] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 3.6 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 7.28 - 7.20 (m, 2H), 4.94 (s, 1H), 4.54 - 4.35 (m, 2H), 3.87 - 3.68 (m, 4H), 3.59 - 3.49 (m, 2H), 3.49 - 3.39 (m, 2H), 3.38 (s, 3H), 3.33 - 3.25 (m, 1H), 3.10 - 2.99 (m, 1H), 2.47 - 2.42 (m, 1H), 2.11 - 1.94 (m, 1H), 1.89 - 1.74 (m, 1H), 1.55 - 1.42 (m, 1H).

[0398] Example 14: (3R,3aS)-9-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-3-methoxy-1,2,3,3a,4,5-hexahydro-6H-benzo[f]pyrrolo[1,2- a][1,4]diazepin-6-one (Compound 14)

[0399] Step 1: Methyl 4-bromo-2-((2S,3R)-2-(hydroxymethyl)-3-methoxypyrrolidin-1-yl)benzoate (Compound 14-1)

[0400] Compound 13-5 (150 mg, 0.41 mmol), methyl 2-fluoro-4-bromobenzoate (95 mg, 0.41 mmol) were dissolved in dimethyl sulfoxide (2 mL), N,N-diisopropylethylamine (157 mg, 1.21 mmol) was added, and the reaction was heated at 80 °C for 12 h. The reaction was completed. Purification by reverse phase column chromatography (eluent: water: acetonitrile = 2:3) to obtain compound 14-1 (50 mg, yield 35%).

[0401] LC-MS: m / z (ESI): 344 [M+H] + .

[0402] Step 6: (3R,3aS)-9-bromo-3-methoxy-1,2,3,3a,4,5-hexahydro-6H- benzo[f]pyrrolo[1,2-a][1,4]diazepin-6-one (Compound 14-2)

[0403] Compound 14-1 (50 mg, 0.15 mmol) was dissolved in dichloromethane (1 mL), then triethylamine (44 mg, 0.43 mmol), methanesulfonic anhydride (50 mg, 0.29 mmol) were added, and the reaction was stirred at 20 °C for 2 h. Ammonia methanol solution (2 ml, 7M in MeOH) was added, and the reaction was stirred at 50 °C for 2 h. The reaction was completed, and the reaction solution was concentrated to dryness under reduced pressure. Purification was performed by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain Compound 14-2 (25 mg, yield 54%).

[0404] LC-MS: m / z (ESI): 311 [M+H] + .

[0405] Step 7: (3R,3aS)-3-methoxy-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,2,3,3a,4,5-hexahydro-6H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-6-one (Compound 14-3)

[0406] Compound 14-2 (25 mg, 0.080 mmol) was dissolved in 1,4-dioxane (2 mL), then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (5.8 mg, 0.008 mmol), pinacol diboronic acid (30.5 mg, 0.12 mmol), and potassium acetate (23 mg, 0.23 mmol) were added, and the reaction was heated at 80 °C for 2 h under nitrogen. The reaction was completed, and the reaction solution was directly filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain crude Compound 14-3 (28 mg).

[0407] LC-MS: m / z (ESI): 359 [M+H] + .

[0408] Step 8: 8-(2,5-dichloropyrimidin-4-yl)-1,2,4-trimethyl-1,2,3,4-tetrahydro-5H- benzo[e][1,4]diazepin-5-one (Compound 14-4)

[0409] Compound 14-3 (28 mg, 0.078 mmol) was dissolved in a mixture of 1,4-dioxane (2 mL) and water (0.3 mL), then [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (5.8 mg, 0.008 mmol), 2,4-dichloro-5-fluoropyrimidine (26 mg, 0.16 mmol) and potassium carbonate (33 mg, 0.24 mmol) were added, and the reaction was heated at 80 °C for 12 h under nitrogen. The reaction was concentrated to dryness under reduced pressure and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to give compound 14-4 (14 mg, 48% yield over two steps).

[0410] LC-MS: m / z (ESI): 363 [M+H] + .

[0411] Step 9: (3R,3aS)-9-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3-methoxy-1,2,3,3a,4,5-hexahydro-6H-benzo[f]pyrrolo[1,2-a][1,4]diazepin-6-one (Compound 14)

[0412] Compound 14-4 (12.0 mg, 0.033 mmol) was dissolved in dimethyl sulfoxide (0.4 mL), then (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (50.5 mg, 0.33 mmol) and N,N-diisopropylethylamine (65 mg, 0.50 mmol) were added, and the reaction was heated at 100 °C for 12 h. The reaction was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to give compound 14 (8.0 mg, 55% yield).

[0413] LC-MS: m / z (ESI): 444 [M+H] + .

[0414] 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.55 - 7.50 (m, 1H), 7.48 - 7.41 (m, 1H), 7.35 - 7.21 (m, 2H), 4.91 (d, J = 5.4 Hz, 1H), 3.87 - 3.75 (m, 3H), 3.68 (s, 1H), 3.50 (s, 1H), 3.47 - 3.40 (m, 2H), 3.23 - 3.12 (m, 1H), 3.10 (s, 3H), 3.07 - 3.00 (m, 1H), 2.80 (s, 3H), 2.01 - 1.87 (m, 1H), 1.57 - 1.41 (m, 1H), 1.02 - 0.93 (m, 3H).

[0415] Example 15: 8-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-1,2,4-trimethyl-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin- 5-one (Compound 15)

[0416] According to the synthetic procedure of Example 1, substituting tert-butyl (2- aminoethyl)(methyl)carbamate for the first step tert-butyl (2-aminopropylcarbamate) and 2,4-dichloro-5-fluoropyrimidine for the 7th step (2,4,5-trichloropyrimidine) to give Compound 15 (20 mg).

[0417] LC-MS: m / z (ESI): 432 [M+H] + .

[0418] 1 H NMR (400 MHz, DMSO-d6) d 8.40 (s, 1H), 7.55 - 7.50 (m, 1H), 7.48 - 7.41 (m, 1H), 7.35 - 7.21 (m, 2H), 4.91 (d, J = 5.4 Hz, 1H), 3.87 - 3.75 (m, 3H), 3.68 (s, 1H), 3.50 (s, 1H), 3.47 - 3.40 (m, 2H), 3.23 - 3.12 (m, 1H), 3.10 (s, 3H), 3.07 - 3.00 (m, 1H), 2.80 (s, 3H), 2.01 - 1.87 (m, 1H), 1.57 - 1.41 (m, 1H), 1.02 - 0.93 (m, 3H).

[0419] Example 16: 8-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-1,3,4-trimethyl-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin- 5-one (Compound 16)

[0420] Step 1 : tert-butyl (2-(4-bromo-2-fluorobenzamide)propyl)carbamate (Compound 16-2)

[0421] Compound 3-1 (380 mg, 1.78 mmol), tert-butyl 2-aminopropylcarbamate (362 mg, 2.08 mmol) were dissolved in N,N-dimethylformamide (5 mL), N,N- diisopropylethylamine (672 mg, 5.20 mmol) was added, 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (857 mg, 2.25 mmol) was added under ice bath, and the reaction was stirred at 25 °C for 1 hour. The reaction was completed. Saturated aqueous ammonium chloride solution was added, and the reaction was extracted with ethyl acetate three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Purification by normal phase column chromatography (methanol / dichloromethane = 3%) gave compound 16-2 (600 mg, yield 90%).

[0422] LC-MS: m / z (ESI): 375 [M+H] + .

[0423] Step 2: N-(1-aminopropan-2-yl)-4-bromo-2-fluorobenzamide (compound 16-3)

[0424] Compound 16-2 (400.0 mg, 1.07 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (0.5 ml) was added, and the reaction was stirred at 20 °C for 1 hour. The reaction was completed, concentrated to dryness under reduced pressure, and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to give compound 16-3 (220 mg, yield 75%).

[0425] LC-MS: m / z (ESI): 275 [M+H] + .

[0426] Step 3: 8-bromo-3-methyl-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin-5-one (compound 16-4)

[0427] The crude compound 16-3 (200.0 mg, 0.73 mmol) was dissolved in N-methylpyrrolidone (3 mL), N,N-diisopropylethylamine (1 ml) was added, and the reaction was subjected to microwave irradiation at 180 °C for 2 hours. The reaction was completed, and purification by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) gave compound 16-4 (90 mg, yield 48%).

[0428] LC-MS: m / z (ESI): 255 [M+H] + .

[0429] Step 4: 8-bromo-1,3,4-trimethyl-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin-5-one (compound 16-5)

[0430] Compound 16-4 (90.0 mg, 0.35 mmol) was dissolved in N,N-dimethylformamide (2 mL), sodium hydride (42 mg, 1.05 mmol) was added at 0 °C and stirred for 20 min, iodomethane (300 mg, 2.11 mmol) was added and slowly recovered to room temperature for 1 h. The reaction was quenched with aqueous ammonium chloride solution and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to give compound 16-5 (40 mg, 40% yield).

[0431] LC-MS: m / z (ESI): 283 [M+H] + .

[0432] Step 5: 1,3,4-Trimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4- tetrahydro-5H-benzo[e][1,4]diazepin-5-one (Compound 16-6)

[0433] Compound 16-5 (40 mg, 0.14 mmol) was dissolved in 1,4-dioxane (2 mL), then [1,1'- bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, 0.014 mmol), bis(pinacolato)diboron (54 mg, 0.21 mmol) and potassium acetate (42 mg, 0.43 mmol) were added, and the reaction was heated at 80 °C for 3 h under nitrogen. The reaction solution was directly filtered, and the filtrate was concentrated to dryness under reduced pressure to give crude compound 16-6 (45 mg).

[0434] LC-MS: m / z (ESI): 283 [M+H] + .

[0435] Step 6: 8-(2,5-Dichloropyrimidin-4-yl)-1,3,4-trimethyl-1,2,3,4-tetrahydro-5H- benzo[e][1,4]diazepin-5-one (Compound 16-7)

[0436] Compound 16-6 (45 mg, 0.14 mmol) was dissolved in a mixture of 1,4-dioxane (2 mL) and water (0.2 mL), then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, 0.014 mmol), 2,4,5-trichloropyrimidine (50 mg, 0.27 mmol) and potassium carbonate (112 mg, 0.81 mmol) were added, and the reaction was heated at 80 °C for 12 h under nitrogen. The reaction solution was concentrated to dryness under reduced pressure and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to give compound 16-7 (27 mg, 55% yield over two steps).

[0437] LC-MS: m / z (ESI): 283 [M+H] + .

[0435] Step 6: 8-(2,5-Dichloropyrimidin-4-yl)-1,3,4-trimethyl-1,2,3,4-tetrahydro-5H- benzo[e][1,4]diazepin-5-one (Compound 16-7)

[0436] Compound 16-6 (45 mg, 0.14 mmol) was dissolved in a mixture of 1,4-dioxane (2 mL) and water (0.2 mL), then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, 0.014 mmol), 2,4,5-trichloropyrimidine (50 mg, 0.27 mmol) and potassium carbonate (112 mg, 0.81 mmol) were added, and the reaction was heated at 80 °C for 12 h under nitrogen. The reaction solution was concentrated to dryness under reduced pressure and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to give compound 16-7 (27 mg, 55% yield over two steps).

[0437] LC-MS: m / z (ESI): 283 [M+H] + .

[0435] Step 6: 8-(2,5-Dichloropyrimidin-4-yl)-1,3,4-trimethyl-1,2,3,4-tetrahydro-5H- benzo[e][1,4]diazepin-5-one (Compound 16-7)

[0436] Compound 16-6 (45 mg, 0.14 mmol) was dissolved in a mixture of 1,4-dioxane (2 mL) and water (0.2 mL), then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, 0.014 mmol), 2,4,5-trichloropyrimidine (50 mg, 0.27 mmol) and potassium carbonate (112 mg, 0.81 mmol) were added, and the reaction was heated at 80 °C for 12 h under nitrogen. The reaction solution was concentrated to dryness under reduced pressure and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to give compound 16-7 (27 mg, 55% yield over two steps).

[0437] LC-MS: m / z (ESI): 283 [M+H] + .

[0435] Step 6: 8-(2,5-Dichloropyrimidin-4-yl)-1,3,4-trimethyl-1,2,3,4-tetrahydro-5H- benzo[e][1,4]diazepin-5-one (Compound 16-7)

[0436] Compound 16-6 (45 mg, 0.14 mmol) was dissolved in a mixture of 1,4-dioxane (2 mL) and water (0.2 mL), then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, 0.014 mmol), 2,4,5-trichloropyrimidine (50 mg, 0.27 mmol) and potassium carbonate (112 mg, 0.81 mmol) were added, and the reaction was heated at 80 °C for 12 h under nitrogen. The reaction solution was concentrated to dryness under reduced pressure and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to give compound 16-7 (27 mg, 55% yield over two steps).

[0437] LC-MS: m / z (ESI): 283 [M+H] + .

[0435] Step 6: 8-(2,5-Dichloropyrimidin-4-yl)-1,3,4-trimethyl-1,2,3,4-tetrahydro-5H- benzo[e][1,4]diazepin-5-one (Compound 16-7)

[0436] Compound 16-6 (45 mg, 0.14 mmol) was dissolved in a mixture of 1,4-dioxane (2 mL) and water (0.2 mL), then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, 0.014 mmol), 2,4,5-trichloropyrimidine (50 mg, 0.27 mmol) and potassium carbonate (112 mg, 0.81 mmol) were added, and the reaction was heated at 80 °C for 12 h under nitrogen. The reaction solution was concentrated to dryness under reduced pressure and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to give compound 16-7 (27 mg, 55% yield over two steps).

[0437] LC-MS: m / z (ESI): 283 [M+H] + .

[0435] Step 6: 8-(2,5-Dichloropyrimidin-4-yl)-1,3,4-trimethyl-1,2,3+ .

[0438] Step 7: 8-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 1,3,4-trimethyl-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin-5-one (Compound 16)

[0439] Compound 16-7 (20.0 mg, 0.057 mmol) was dissolved in dimethyl sulfoxide (1 mL), then (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (87.5 mg, 0.57 mmol), N,N-diisopropylethylamine (110.0 mg, 0.85 mmol) were added, and the reaction was heated at 80 °C for 6 hours. The reaction was completed. The reaction solution was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain Compound 16 (20.0 mg, yield 81%).

[0440] LC-MS: m / z (ESI): 432 [M+H] + .

[0441] 1 H NMR (400 MHz, DMSO-d6) d 8.40 (s, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.34 - 7.17 (m, 2H), 4.97 - 4.85 (m, 1H), 3.89 - 3.71 (m, 4H), 3.55 - 3.48 (m, 1H), 3.48 - 3.40 (m, 1H), 3.34 (s, 1H), 3.07 - 3.02 (m, 1H), 2.99 (s, 3H), 2.96 - 2.89 (m, 1H), 2.81 (s, 3H), 2.01 - 1.85 (m, 1H), 1.56 - 1.42 (m, 1H), 1.23 (d, J = 6.8 Hz, 3H).

[0442] Example 17: 8-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 10-methyl-2,3,11,11a-tetrahydrobenzo[e]oxazolo[3,2-a][1,4]diazepin-5(10H)-one (Compound 17)

[0443] Step 1: 4-bromo-2-((2,2-dimethoxyethyl)(methyl)amino)benzoic acid (Compound 17-3)

[0444] Compound 3-1 (2.0 g, 9.13 mmol), compound 17-2 (1.63 g, 13.7 mmol) and triethylenediamine (4.1 g, 36.5 mmol) were taken in a reaction tube, the reaction tube was purged with argon gas, dimethyl sulfoxide (5 mL) was added to the reaction tube and the reaction mixture was stirred at 135 °C for 8 h. After completion of the reaction, the reaction mixture was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:9) to obtain compound 17-3 (1.2 g, yield 41%).

[0445] m / z (ESI): 318 [M+H]+.

[0446] Step 2: 4-Bromo-2-((2,2-dimethoxyethyl)(methyl)amino)-N-(2- hydroxyethyl)benzamide (compound 17-5)

[0447] Compound 17-3 (500.0 mg, 1.57 mmol) and ethanolamine (144.0 mg, 2.36 mmol) were taken in a reaction tube, the reaction tube was purged with argon gas, anhydrous N,N-dimethylformamide (1.5 mL) and triethylamine (0.5 mL) were added to the reaction tube, the reaction tube was stirred at room temperature, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (897.0 mg, 2.36 mmol) was dissolved in anhydrous N,N-dimethylformamide (1.0 mL) and added dropwise to the reaction mixture, after the addition was completed, the reaction mixture was stirred at room temperature for 5 h. After completion of the reaction, the reaction mixture was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:9) to obtain compound 17-5 (220.0 mg, yield 39%).

[0448] m / z (ESI): 361 [M+H]+.

[0449] Step 3: 8-Bromo-10-methyl-2,3,11,11a-tetrahydrobenzo[e]oxazolo[3,2- a][1,4]diazepin-5(10H)-one (compound 17-6)

[0450] Compound 17-5 (220.0 mg, 0.61 mmol) and p-toluenesulfonic acid (157.0 mg, 0.91 mml) were taken in a reaction tube, the reaction tube was purged with argon gas, anhydrous toluene (1.5 mL) was added to the reaction tube, the reaction mixture was stirred at 120 °C for 8 h. After completion of the reaction, the reaction mixture was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:9) to obtain compound 17-6 (175 mg, yield 97%).

[0451] m / z (ESI): 297 [M+H]+.

[0452] Step 4: 10-Methyl-8-(4, 4, 5, 5-tetramethyl-l, 3, 2-dioxaborolan-2-yl)-2, 3, 11, 11a- tetrahydrobenzo [e] oxazolo [3, 2-a] [ 1, 4] diazepin-5(10H)-one (Compound 17-7)

[0453] A reaction tube was charged with compound 17-6 (175.0 mg, 0.59 mmol), [l,l'- bis(diphenylphosphino)ferrocene]dichloropalladium (21.5 mg, 0.029 mmol), bis(pinacolato)diboron (225.0 mg, 0.88 mmol), potassium acetate (173.0 mg, 1.77 mmol), and the reaction tube was purged with argon. The reaction tube was charged with 1,4-dioxane (2 mL) and the reaction was stirred at 100 °C for 10 h. Upon completion, the reaction was cooled to room temperature and filtered to give a solution of crude compound 17-7, which was used directly in the next step.

[0454] m / z (ESI): 345 [M+H]+.

[0455] Step 5: 8-(2-Chloro-5-fluoropyrimidin-4-yl)-10-methyl-2,3,11,11a-tetrahydrobenzo[e]oxazolo[3,2-a][l,4]diazepin-5(10H)-one (Compound 17-8)

[0456] A reaction tube was charged with the above solution of crude compound 17-7, 2,4- dichloro-5-fluoropyrimidine (147.5 mg, 0.88 mmol), sodium carbonate (187.0 mg, 1.77 mmol), tetrakis(triphenylphosphine)palladium (34.0 mg, 0.029 mmol), and water (0.1 mL) and the reaction tube was purged with argon. The reaction was stirred at 100 °C for 8 h. Upon completion, the reaction was concentrated and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:9) to give compound 17-8 (150.0 mg, 73% over two steps).

[0457] m / z (ESI): 349 [M+H]+.

[0458] Step 6: 8-(5-Fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 10-methyl-2,3,11,11a-tetrahydrobenzo[e]oxazolo[3,2-a][l,4]diazepin-5(10H)-one (Compound 17)

[0459] Compound 17-8 (75.0 mg, 0.22 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (201.5 mg, 1.31 mmol) and N,N-diisopropylethylamine (416.0 mg, 3.22 mmol) were placed in a reaction tube, the tube was purged with argon, dimethyl sulfoxide (2 mL) was added to the tube, and the reaction was stirred in a 120 °C oil bath for 8 hours. After the reaction was completed, the reaction was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:9) to obtain compound 17 (54.0 mg, yield 57%).

[0460] m / z (ESI): 430 [M+H]+.

[0461] 1 H NMR (400 MHz, DMSO-d6) d 8.45 (d, J = 3.7 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.57 (s, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 5.07 (dt, J = 8.5, 2.2 Hz, 1H), 4.95 (dd, J = 5.3, 1.8 Hz, 1H), 4.23 - 4.13 (m, 1H), 3.96 (q, J = 7.7 Hz, 1H), 3.87 - 3.74 (m, 4H), 3.69 - 3.59 (m, 2H), 3.56 - 3.47 (m, 1H), 3.36 - 3.27 (m, 2H), 3.07 - 3.01 (m, 4H), 2.08 - 1.99 (d, J = 31.0 Hz, 1H), 1.54 - 1.44 (m, 1H).

[0462] Example 18: (4aR,11aR)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-5,11-dimethyl-3,4,4a,5,11,11a-hexahydrobenzo[e]pyrano[3,4- b] [1,4]diazepin-10(1H)-one (Compound 18)

[0463] Step 1: 4-bromo-2-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4- yl)amino)benzoic acid (Compound 18-3)

[0464] Compound 3-1 (800 mg, 3.65 mmol), compound 18-2 (948.03 mg, 4.38 mmol) and triethylenediamine (1.64 g, 14.61 mmol) were taken in a reaction tube, the reaction tube was purged with argon, dimethyl sulfoxide (3 mL) was added to the reaction tube, and the reaction mixture was stirred in an oil bath at 130 °C for 8 h. After the reaction was completed, the reaction mixture was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:9) to obtain compound 18-3 (230 mg, yield 15%).

[0465] m / z (ESI): 415 [M+H]+.

[0466] Step 2: (4aR,11aR)-7-bromo-3,4,4a,5,11,11a-hexahydrobenzo[e]pyrano[3,4- b][1,4]diazepin-10(1 H)-one (compound 18-4)

[0467] Compound 18-3 (230 mg, 0.55 mmol) and ethyl acetate hydrogen chloride solution (4 M) (1 mL) were taken in a reaction tube, the reaction mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction mixture was concentrated to dryness and taken in a reaction tube, the reaction tube was purged with argon, anhydrous N,N-dimethylformamide (1.5 mL) and triethylamine (0.5 mL) were added to the reaction tube, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (336.9 mg, 0.55 mmol) was dissolved in anhydrous N,N-dimethylformamide (1.0 mL) and added slowly dropwise to the reaction mixture, after the addition was completed, the reaction mixture was stirred at room temperature for 5 h. After the reaction was completed, the reaction mixture was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:9) to obtain compound 18-4 (50 mg, yield 31%).

[0468] m / z (ESI): 297 [M+H]+.

[0469] Step 3: (4aR,11aR)-7-bromo-5,11-dimethyl-3,4,4a,5,11,11a-hexahydrobenzo[e]pyrano[3,4- b][1,4]diazepin-10(1 H)-one (compound 18-5)

[0470] Compound 18-4 (50 mg, 0.17 mmol) and sodium hydride (24.23 mg, 1.0 mml) were placed in a reaction tube, the air in the reaction tube was replaced by argon, anhydrous N,N-dimethylformamide (1.5 mL) was added into the reaction tube, the reaction solution was stirred at room temperature for half an hour, and methyl iodide (95.5 mg, 0.67 mmol) was slowly added dropwise into the reaction solution. After the dropwise addition was completed, the reaction solution was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:9) to obtain compound 18-5 (45 mg, yield 81%).

[0471] m / z (ESI): 325 [M+H]+.

[0472] Step 4: (4aR,11aR)-5,11-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)- 3,4,4a,5,11,11a-hexahydrobenzo[e]pyrano[3,4-b][1,4]diazepin-10(1H)-one (Compound 18-6)

[0473] Compound 18-5 (45.0 mg, 0.14 mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (11.3 mg, 0.014 mmol), bis(pinacolato)diboron (63.7 mg, 0.25 mmol) and potassium acetate (40.7 mg, 0.42 mmol) were placed in a reaction tube, the air in the reaction tube was replaced by argon, 1,4-dioxane (2 mL) was added, and the reaction solution was stirred in a 100°C oil bath for 10 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and the crude compound 18-6 solution was obtained for use.

[0474] m / z (ESI): 373 [M+H]+.

[0475] Step 5: (4aR,11aR)-7-(2-chloro-5-fluoropyrimidin-4-yl)-5,11-dimethyl-3,4,4a,5,11,11a- hexahydrobenzo[e]pyrano[3,4-b][1,4]diazepin-10(1H)-one (Compound 18-7)

[0476] A solution of the above crude compound 18-6, 2,4-dichloro-5-fluoropyrimidine (35.0 mg, 0.21 mmol), sodium carbonate (44.0 mg, 0.42 mmol), tetrakis(triphenylphosphine)palladium (16.0 mg, 0.014 mmol), a mixed solution of dioxane and water (0.1 mL, 8:2) in a reaction tube was purged with argon to replace the air in the reaction tube. The reaction was stirred in an oil bath at 100 °C for 8 hours. After the reaction was completed, the reaction was concentrated and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:9) to give compound 18-7 (25.0 mg, 47% yield over two steps).

[0477] m / z (ESI): 377 [M+H]+.

[0478] Step 6: (4aR,11aR)-7-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-5,11-dimethyl-3,4,4a,5,11,11a-hexahydrobenzo[e]pyrano[3,4- b] [1,4]diazepin-10(1H)-one (Compound 18)

[0479] A solution of compound 18-7 (10.0 mg, 0.027 mmol), dichloro[1,3-bis(2,6-di-3- pentylphenyl)imidazol-2-ylidene](3-chloropyridinyl)palladium(II) (2.1 mg, 0.0027 mmol), cesium carbonate (26.0 mg, 0.08 mmol), and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (201.5 mg, 1.31 mmol) in a reaction tube was purged with argon to replace the air in the reaction tube. 1,4-Dioxane (2.0 mL) was added to the reaction tube. The reaction was stirred in an oil bath at 100 °C for 12 hours. After the reaction was completed, the reaction was concentrated and purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:9) to give compound 18 (1.5 mg, 12% yield).

[0480] m / z (ESI): 458 [M+H]+.

[0481] 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 3.7 Hz, 1H), 7.69 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 4.93 (s, 1H), 4.16 (d, J = 13.2 Hz, 1H), 4.02 (d, J = 11.2 Hz, 1H), 3.82 (dd, J = 11.0, 4.9 Hz, 2H), 3.65 - 3.53 (m, 1H), 3.49 - 3.37 (m, 1H), 3.27 (s, 3H), 3.04 (t, J = 10.3 Hz, 2H), 2.79 (s, 3H), 2.14 (d, J = 13.3 Hz, 2H), 2.00 (d, J = 10.9 Hz, 2H), 1.73 - 1.61 (m, 2H), 1.57 - 1.41 (m, 2H).

[0482] Example 19: (cis)-3-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-5,10-dimethyl-5,5a,6,7,8,9,9a,10-octahydro-11H- dibenzo[b,e][1,4]diazepin-11-one (Compound 19)

[0483] According to the synthetic procedure of Example 3, trans-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine in the first step was replaced with cis-N 1 ,N 2 -dimethylcyclohexane-1,2-diamine), Compound 19 (11.5 mg) was obtained.

[0484] m / z (ESI): 456 [M+H]+.

[0485] Example 20: (4aS,11aS)-9-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-5,11-dimethyl-3,4,4a,5,11,11a-hexahydrobenzo[e]pyrano[4,3- b][1,4]diazepin-6(1H)-one (Compound 20)

[0486] According to the synthetic procedure of Example 18, Compound 18-2 in the first step was replaced with tert-butyl ((3S,4S)-3-aminotetrahydro-2H-pyran-4-yl)carbamate), Compound 20 (2 mg) was obtained.

[0487] m / z (ESI): 458 [M+H]+.

[0488] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 3.7 Hz, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 4.94 (d, J = 5.0 Hz, 1H), 4.21 (d, J = 12.8 Hz, 1H), 3.95 - 3.64 (m, 7H), 3.56 - 3.46 (m, 1H), 3.22 (s, 1H), 3.17 (s, 3H), 3.05 (t, J = 10.3 Hz, 1H), 2.96 (s, 3H), 2.06 - 1.91 (m, 1H), 1.74 - 1.40 (m, 4H).

[0489] Example 21 : 8-[5-Fluoro-2-[[(3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl]amino]pyrimidin-4-yl]- 1,2,2,4-tetramethyl-1,2,3,4-tetrahydro-5H-benzo[e][1,4]diazepin-5-one (Compound 21)

[0490] According to the synthesis procedure of Example 1, the first step, tert-butyl (2- aminoethyl)(methyl)carbamate was replaced by tert-butyl ((2-amino-2-methylpropyl)carbamate) to give Compound 21 (12 mg). ((2-amino-2 methylpropyl)carbamate) to give Compound 21 (12 mg).

[0491] LC-MS: m / z (ESI): 430.2 [M+H] + .

[0492] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 3.7 Hz, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 8.3 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 4.94 (d, J = 5.0 Hz, 1H), 4.21 (d, J = 12.8 Hz, 1H), 3.95 - 3.64 (m, 7H), 3.56 - 3.46 (m, 1H), 3.22 (s, 1H), 3.17 (s, 3H), 3.05 (t, J = 10.3 Hz, 1H), 2.96 (s, 3H), 2.06 - 1.91 (m, 1H), 1.74 - 1.40 (m, 4H).

[0493] Example 22: 9-(5-fluoro-2-(((3R,4S)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-11-methyl-1,3,4,11,12,12a-hexahydro-6H- benzo[e][1,4]oxazepino[4,3-a][1,4]diazepin-6-one (Compound 22)

[0494] According to the synthetic procedure of Example 16, replacing tert-butyl 2- aminopropylcarbamate in the first step with tert-butyl ((morpholin-3- ylmethyl)carbamate), 2,4,5-trichloropyrimidine in the sixth step with 2,4- dichloro-5-fluoropyrimidine gave Compound 22 (8 mg). ((morpholin-3-ylmethyl)carbamate), 2,4,5-trichloropyrimidine in the sixth step with 2,4-dichloro-5-fluoropyrimidine gave Compound 22 (8 mg). (2,4-dichloro-5-fluoropyrimidine) gave Compound 22 (8 mg).

[0495] LC-MS: m / z (ESI): 444.2 [M+H] + .

[0496] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 3.7 Hz, 1H), 7.57 (d, J = 7.2 Hz, 3H), 7.21 (d, J = 7.6 Hz, 1H), 3.95 (td, J = 10.6, 3.4 Hz, 2H), 3.87 - 3.61 (m, 8H), 3.56 - 3.48 (m, 2H), 3.36 (s, 2H), 3.05 (t, J = 10.3 Hz, 1H), 2.89 (dt, J = 9.2, 2.0 Hz, 1H), 2.83 (s, 3H), 2.05 - 1.96 (m, 1H), 1.55 - 1.43 (m, 1H).

[0497] Example 23: (R)-2,2-difluoro-9-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H- pyran-4-yl)amino)pyrimidin-4-yl)-5-methyl-1,2,3,3a,4,5-hexahydro-6H- benzo[f]pyrrolo[1,2-a][1,4]diazepin-6-one (Compound 23)

[0498] According to the synthetic procedure of Example 16, replacing tert-butyl 2- aminopropylcarbamate in the first step with tert-butyl ((R)-4,4-difluoro-2- ((methylamino)methyl)pyrrolidine-1-carboxylate), 2,4,5-trichloropyrimidine in the sixth step with 2,4-dichloro-5-fluoropyrimidine gave Compound 23 (6 mg). ((R)-4,4-difluoro-2-((methylamino)methyl)pyrrolidine-1-carboxylate), 2,4,5- trichloropyrimidine in the sixth step with 2,4-dichloro-5-fluoropyrimidine gave Compound 23 (6 mg). (2,4-dichloro-5-fluoropyrimidine) gave Compound 23 (6 mg).

[0499] LC-MS: m / z (ESI): 464.2 [M+H]+ .

[0500] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 3.7 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 4.92 (d, J = 5.4 Hz, 1H), 4.12 (dq, J = 12.1, 4.2 Hz, 1H), 4.01 (dd, J = 14.1, 11.2 Hz, 2H), 3.81 (s, 3H), 3.52 (s, 1H), 3.24 (dd, J = 11.3, 3.5 Hz, 2H), 3.10 - 3.01 (m, 2H), 2.90 (s, 3H), 2.80 - 2.73 (m, 1H), 2.40 - 2.31 (m, 1H), 2.01 (d, J = 14.6 Hz, 1H), 1.53 - 1.46 (m, 1H).

[0501] Example 24: (3aR)-9-fluoro-11-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-2,3,3a,3b,5,6-hexahydro-1H,8H-benzo[e]oxazolo[3,2- a]pyrrolo[2,1-c][1,4]diazepin-8-one (Compound 24)

[0502] Step 1: (R)-2-(dimethoxymethyl)pyrrolidine hydrochloride (Compound 24-2)

[0503] Compound 24-1 (10.0 g, 50.2 mmol) and methanol (80 mL) were stirred in a flask at room temperature, acetyl chloride (7.9 g, 100.6 mmol) was added slowly, after reaction for 1 hour, formic acid trimethyl ester (47.9 g, 451.4 mmol) was added slowly, after reaction at room temperature for 48 hours, concentrated to dryness, dissolved in ethyl acetate (100 mL) and stirred for 2 hours, filtered to obtain compound 24-2 (8.7 g, yield 95%).

[0504] m / z (ESI): 146 [M+H] + .

[0505] Step 2: (R)-4-bromo-2-(2-(dimethoxymethyl)pyrrolidin-1-yl)-6-fluorobenzoic acid (Compound 24-3)

[0506] Compound 24-2 (0.87 g, 4.8 mmol), 4-bromo-2,6-difluorobenzoic acid (1.2 g, 5.1 mmol), pyridine (5 mL) and N,N-diisopropylethylamine (1.86 g, 14.4 mmol) were placed in a reaction tube, the air in the reaction tube was replaced by argon, and the reaction solution was stirred in an oil bath at 110 °C for 12 h. After the reaction was completed, the reaction solution was concentrated to dryness, and the crude product was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:9) to give compound 24-3 (0.67 g, yield 39%).

[0507] m / z (ESI): 362 [M+H] + .

[0508] Step 3: (R)-4-bromo-2-(2-(dimethoxymethyl)pyrrolidin-1-yl)-6-fluoro-N-(2- hydroxyethyl)benzamide (compound 24-4)

[0509] Compound 24-3 (670.0 mg, 1.85 mmol), 2-(7-azobenzotriazole)-N,N,N',N'- tetramethyluronium hexafluorophosphate (1.1 g, 2.89 mmol) and N,N- dimethylformamide (3.0 mL) were placed in a reaction tube, the reaction tube was stirred at room temperature, triethylamine (467.0 mg, 4.62 mmol) was added dropwise to the reaction solution, and the reaction was stirred at room temperature for 10 min. After the reaction was completed, ethanolamine (282.0 mg, 4.62 mmol) was added to the reaction solution, and the reaction was stirred at room temperature for 30 min. After the reaction was completed, the reaction solution was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:9) to give compound 24-4 (200.0 mg, yield 27%).

[0510] m / z (ESI): 405 [M+H] + .

[0511] Step 4: (3aR)-11-bromo-9-fluoro-2,3,3a,3b,5,6-hexahydro-1H,8H- benzo[e]oxazolo[3,2-a]pyrrolo[2,1-c][1,4]diazepin-8-one (compound 24-5)

[0512] Compound 24-4 (200 mg, 0.49 mmol), p-toluenesulfonic acid monohydrate (233.0 mg, 1.22 mmol) and acetonitrile (1.0 mL) were placed in a reaction tube, and the reaction solution was stirred in an oil bath at 80 °C for 2 h. After the reaction was completed, the reaction solution was concentrated to dryness, and the crude product was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:9) to give compound 24-5 (151.0 mg, yield 90%).

[0513] m / z (ESI): 341 [M+H] + .

[0514] Step 5: (3aR)-9-fluoro-11-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2,3,3a,3b,5,6-hexahydro-1H,8H-benzo[e]oxazolo[3,2-a]pyrrolo[2,1-c][1,4] diazepin-8-one (Compound 24-6)

[0515] The compound 24-5 (151.0 mg, 0.44 mmol), [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium (32.2 mg, 0.044 mmol), bis(pinacolato)diboron (167.6 mg, 0.66 mmol) and potassium acetate (129.4 mg, 1.32 mmol) were placed in a reaction tube, the reaction tube was replaced with argon, 1,4-dioxane (2 mL) was added, and the reaction was stirred in a 100 °C oil bath for 10 hours. After the reaction was completed, the reaction was cooled to room temperature, and the crude compound 24-6 in 1,4-dioxane was obtained by filtration.

[0516] m / z (ESI): 389 [M+H] + .

[0517] Step 6: (3aR)-11-(2-chloro-5-fluoropyrimidin-4-yl)-9-fluoro-2,3,3a,3b,5,6- hexahydro-1H,8H-benzo[e]oxazolo[3,2-a]pyrrolo[2,1-c][1,4]diazepin-8-one (Compound 24-7)

[0518] The above crude compound 24-6 in 1,4-dioxane, 2,4-dichloro-5-fluoropyrimidine (110.0 mg, 0.66 mmol), sodium carbonate (140.0 mg, 1.32 mmol), tetrakis(triphenylphosphine)palladium (50.0 mg, 0.043 mmol) and water (0.1 mL) were placed in a reaction tube, the reaction tube was replaced with argon, and the reaction was stirred in a 100 °C oil bath for 8 hours. After the reaction was completed, the reaction was concentrated to dryness, and compound 24-7 (150.0 mg) was purified by reverse phase column chromatography (eluent: water:acetonitrile = 1:9).

[0519] m / z (ESI): 393 [M+H] + .

[0520] Step 7: (3aR)-9-fluoro-11-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-2,3,3a,3b,5,6-hexahydro-lH,8H-benzo[e]oxazolo[3,2- a]pyrrolo[2,l-c][l,4]diazepin-8-one (Compound 24)

[0521] Compound 24-7 (70.0 mg, 0.18 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (167.0 mg, 1.09 mmol) and N,N-diisopropylethylamine (345.5 mg, 2.67 mmol) were taken in a reaction tube, the reaction tube was purged with argon to remove air from the reaction tube, dimethyl sulfoxide (2 mL) was added to the reaction tube and the reaction was stirred at 120 °C oil bath for 10 h. After completion of the reaction, the reaction was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:9) to obtain Compound 24 (48.0 mg, 56% yield).

[0522] m / z (ESI): 474 [M+H]+.

[0523] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 3.7 Hz, 1H), 7.25 - 7.16 (m, 2H), 7.00 (d, J = 12.2 Hz, 1H), 5.10 - 4.90 (m, 1H), 4.15 (ddd, J = 8.3, 6.5, 3.9 Hz, 1H), 3.92 (td, J = 8.4, 6.3 Hz, 1H), 3.85 - 3.72 (m, 3H), 3.69 - 3.59 (m, 3H), 3.56 - 3.42 (m, 4H), 3.05 (dd, J = 11.1, 9.6 Hz, 1H), 2.15 - 2.12 (m, 1H), 2.05 - 1.99 (m, 2H), 1.88 - 1.76 (m, 2H), 1.62 - 1.42 (m, 1H), 0.94 (t, J = 7.3 Hz, 1H).

[0524] Example 25: 8-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin- 4-yl)-10,11a-dimethyl-2,3,11,11a-tetrahydrobenzo[e]oxazolo[3,2-a][l,4]diazepin-5(10H)- one (Compound 25)

[0525] Step 1: Methyl 4-bromo-2-(((2-methyl-l,3-dioxolan-2-yl)methyl)amino)benzoate (Compound 25-3)

[0526] Methyl 4-bromo-2-fluorobenzoate (400 mg, 1.72 mmol), (2-methyl-1,3-dioxolan-2- yl)methanamine (301.62 mg, 2.57 mmol) were dissolved in dimethyl sulfoxide (4 mL), diisopropylethylamine (665.52 mg, 5.15 mmol) was added and the reaction was stirred at 80 °C for 12 h. Upon completion of the reaction, the crude product was purified by reverse phase column chromatography (eluent: water: acetonitrile = 2:3) to afford compound 25-3 (410 mg, yield 72%).

[0527] LC-MS: m / z (ESI): 330 [M+H] + .

[0528] Step 2: 4-Bromo-N-(2-hydroxyethyl)-2-(((2-methyl-1,3-dioxolan-2- yl)methyl)amino)benzamide (compound 25-5)

[0529] Compound 25-3 (210 mg, 0.64 mmol), ethanolamine (388.50 mg, 6.36 mmol) were taken in methanol (2 mL), sodium methoxide (343.61 mg, 6.36 mmol) was added and the reaction was stirred at 60 °C for 2 h. Upon completion of the reaction, water was added to quench the reaction and the crude product was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to afford compound 25-5 (180 mg, yield 78%).

[0530] LC-MS: m / z (ESI): 359 [M+H] + .

[0531] Step 3: 8-Bromo-11a-methyl-2,3,11,11a-tetrahydrobenzo[e]oxazolo[3,2- a][1,4]diazepin-5(10H)-one (compound 25-6)

[0532] Compound 25-5 (200 mg, 0.56 mmol), p-toluenesulfonic acid monohydrate (105.91 mg, 0.56 mmol) were taken in acetonitrile (2 mL) and the reaction was stirred at 80 °C for 2 h. Upon completion of the reaction, water was added to quench the reaction and the crude product was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to afford title compound 25-6 (50 mg, yield 30%).

[0533] LC-MS: m / z (ESI): 297 [M+H] + .

[0534] Step 4: 8-Bromo-10,11a-dimethyl-2,3,11,11a-tetrahydrobenzo[e]oxazolo[3,2- a][1,4]diazepin-5(10H)-one (compound 25-7)

[0535] Compound 25-6 (40 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (2 mL), sodium hydride (10.77 mg, purity 60%, 0.27 mmol) was added at 0 °C, and iodomethane (57.32 mg, 0.40 mmol) was added. The reaction was carried out at 10 °C for 2 hours. After the reaction was completed, water was added for quenching, and purification was performed by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 25-7 (35 mg, yield 87%).

[0536] LC-MS: m / z (ESI): 311 [M+H] + .

[0537] Step 5: 10,11a-Dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,11,11a- tetrahydrobenzo[e]oxazolo[3,2-a][1,4]diazepin-5(10H)-one (Compound 25-8)

[0538] Compound 25-7 (35 mg, 112.48 µmol) was dissolved in 1,4-dioxane (2 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6.51 mg, 8.90 µmol), pinacol diboronic acid (33.75 mg, 132.91 µmol), and potassium acetate (26.18 mg, 0.27 mmol) were added. The reaction was carried out at 80 °C for 2 hours under nitrogen. After the reaction was completed, the reaction solution was directly filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain crude compound 25-8 (40 mg).

[0539] LC-MS: m / z (ESI): 359 [M+H] + .

[0540] Step 6: 8-(2-Chloro-5-fluoropyrimidin-4-yl)-10,11a-dimethyl-2,3,11,11a-tetrahydrobenzo[e]oxazolo[3,2-a][1,4]diazepin-5(10H)-one (Compound 25-9)

[0541] Crude compound 25-8 (40 mg) was dissolved in a mixed solution of 1,4-dioxane (2 mL) and water (0.3 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6.47 mg, 8.84 µmol), 2,4-dichloro-5-fluoropyrimidine (29.51 mg, 176.74 µmol), and potassium carbonate (36.63 mg, 0.27 mmol) were added. The reaction was carried out at 80 °C for 12 hours under nitrogen. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure, and purification was performed by reverse phase column chromatography (eluent: water:acetonitrile = 1:1) to obtain compound 25-9 (30 mg).

[0542] LC-MS: m / z (ESI): 363 [M+H] + .

[0543] Step 7: 8-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 10,11a-dimethyl-2,3,11,11a-tetrahydrobenzo[e]oxazolo[3,2-a][1,4]diazepin-5(10H)-one (Compound 25)

[0544] Compound 25-9 (5.0 mg, 0.014 mmol) was dissolved in dimethyl sulfoxide (0.4 mL), then (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (63.5 mg, 0.41 mmol), diisopropylethylamine (106.85 mg, 0.83 mmol) were added, and the reaction was heated at 80 °C for 12 h. The reaction was completed. The reaction solution was purified by reverse phase column chromatography (eluent: water: acetonitrile = 1:1) to obtain Compound 25 (2 mg, yield 32%).

[0545] LC-MS: m / z (ESI): 444 [M+H] + .

[0546] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 3.7 Hz, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.52 (s, 1H), 7.37 - 7.31 (m, 1H), 7.25 - 7.19 (m, 1H), 4.94 (d, J = 5.6 Hz, 1H), 4.11 - 4.00 (m, 2H), 3.96 - 3.89 (m, 1H), 3.84 - 3.72 (m, 4H), 3.60 - 3.50 (m, 2H), 3.27 (d, J = 3.5 Hz, 3H), 3.05 (t, J = 10.3 Hz, 1H), 2.00 (s, 2H), 1.49 (d, J = 11.6 Hz, 2H), 1.26 (s, 3H).

[0547] Example 26: 3,3,7-trifluoro-9-(5-fluoro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4- yl)amino)pyrimidin-4-yl)-1,2,3,3a,4,5-hexahydro-6H-benzo[f]pyrrolo[1,2-a][1,4]diazepin- 6-one (Compound 26)

[0548] Step 1: 2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (compound 26-2)

[0549] 1.0 g (4.6 mmol) of 3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester was added to N,N-dimethylformamide (10 mL), followed by the addition of imidazole (0.78 g, 11.46 mmol) and tert-butyldiphenylchlorosilane (2.1 g, 7.64 mmol) at 0 °C. The mixture was then slowly restored to room temperature and reacted for 16 hours. The solution was concentrated to dryness, and the crude product was subjected to reverse-phase column chromatography (water:acetonitrile = 10:1-1:10) to give compound 26-2 (1.0 g, yield 48%).

[0550] m / z(ESI): 456 [M+H] +

[0551] Step 2: 2-(((tert-butyldiphenylsilyl)oxy)methyl)pyrrolidine-3-ol (compound 26-3)

[0552] Compound 26-2 (1.0 g, 2.19 mmol) was added to dichloromethane (5 mL), followed by the slow addition of trifluoroacetic acid (2.5 mL). The reaction was carried out at room temperature for 2 hours until the reaction was complete. The mixture was then purified by reversed-phase column chromatography (water:acetonitrile = 10:1-1:10) to give compound 26-3 (400 mg, yield 51%).

[0553] m / z(ESI): 356 [M+H] +

[0554] Step 3: Methyl 4-bromo-2-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-hydroxypyrrolidine-1-yl)-6-fluorobenzoate (compound 26-4)

[0555] Compound 26-3 (400 mg, 1.13 mmol) was added to dimethyl sulfoxide (5 mL), followed by the slow addition of N,N-diisopropylethylamine (291 mg, 2.25 mmol) and methyl 4-bromo-2,6-difluorobenzoate (424 mg, 1.69 mmol). The mixture was heated at 65 °C for 2 hours until the reaction was complete. The mixture was purified by reverse-phase column chromatography (water:acetonitrile = 10:1-1:10) to give compound 26-4 (300 mg, yield 45%).

[0556] m / z(ESI): 588[M+H] +

[0557] Step 4: Methyl 4-bromo-2-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-3-oxopyrrolidone-1-yl)-6-fluorobenzoate (compound 26-5) was prepared by adding compound 26-4 (300 mg, 0.51 mmol) to dichloromethane (2 mL), followed by the slow addition of Dysmartin oxidant (650.78 mg, 1.53 mmol). The reaction was carried out at room temperature for 2 hours until completion. The mixture was purified by reversed-phase column chromatography (water:acetonitrile = 10:1-1:10) to give compound 26-5 (160 mg, yield 54%).

[0558] m / z(ESI): 584 [M+H] +

[0559] Step 5: Methyl 4-bromo-2-(2-(((tert-butyldiphenylsilyl)oxy)methyl)-3,3-difluoropyrrolidone-1-yl)-6-fluorobenzoate (compound 26-6) Compound 26-5 (160 mg, 0.27 mmol) was added to diethylaminosulfur trifluoride (2.44 g, 15.14 mmol) and reacted at room temperature for 24 hours until the reaction was complete. The reaction solution was slowly added dropwise to ice-cold saturated sodium bicarbonate aqueous solution (100 mL) and stirred for 0.5 hours. The mixture was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by reversed-phase column chromatography (water:acetonitrile = 10:1-1:10) to give compound 26-6 (100 mg, yield 61%).

[0560] m / z(ESI): 606 [M+H] +

[0561] Step 6: Methyl 4-bromo-2-(3,3-difluoro-2-(hydroxymethyl)pyrrolidone-1-yl)-6-fluorobenzoate (compounds 26-7)

[0562] Compound 26-6 (100 mg, 0.16 mmol) was added to hydrofluoric acid-pyridine (2 mL) and reacted at room temperature for 24 hours until the reaction was complete. The reaction solution was then slowly added dropwise to ice-cold saturated sodium bicarbonate aqueous solution (20 mL), stirred for 0.5 hours, extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated to dryness, and purified by reversed-phase column chromatography (water:acetonitrile = 10:1-1:10) to give compound 26-7 (50 mg, yield 85%).

[0563] m / z(ESI): 368[M+H] +

[0564] Step 7: 9-Bromo-3,3,7-trifluoro-1,2,3,3a,4,5-hexahydro-6H-benzo[f]pyrrolo[1,2-a][1,4]diazepine-6-one (compounds 26-8)

[0565] Compound 26-7 (60 mg, 0.16 mmol) was added to dichloromethane (1 mL), followed by triethylamine (82.46 mg, 0.81 mmol) and methanesulfonic anhydride (137.95 mg, 0.79 mmol). The mixture was reacted at room temperature for two hours until complete. Ammonia-methanol solution (7 M, 1 mL) was added directly, and the mixture was sealed at 100 °C and heated overnight until complete. The mixture was concentrated to dryness and purified by reverse-phase column chromatography (water:acetonitrile = 10:1-1:10) to give compound 26-8 (30 mg, yield 56%).

[0566] m / z(ESI): 335[M+H] +

[0567] Step 9: 3,3,7-trifluoro-9-(trimethyltinyl)-1,2,3,3a,4,5-hexahydro-6H-benzo[f]pyrrolo[1,2-a][1,4]diazepine-6-one (compound 26-9) Compound 26-8 (15 mg, 44.76 μmol), hexamethylditin (22.00 mg, 67.15 μmol), and tetra(triphenylphosphine)palladium (5.17 mg, 4.47 μmol) were added to 1,4-dioxane (1 mL). The mixture was heated at 100 °C for 1 hour under argon protection until the reaction was complete. The crude compound 26-9 was obtained by direct filtration and used directly in the next step of the reaction.

[0568] m / z(ESI): 421[M+H] +

[0569] Step 10: 9-(2-chloro-5-fluoropyrimidin-4-yl)-3,3,7-trifluoro-1,2,3,3a,4,5-hexahydro-6H-benzo[f]pyrrolo[1,2-a][1,4]diazepine-6-one (compounds 26-10)

[0570] The crude compound 26-9 (18.76 mg), 2,4-dichloro-5-fluoropyrimidine (14.95 mg, 89.54 μmol), cuprous chloride (4.43 mg, 44.75 μmol), and tetra(triphenylphosphine)palladium (5.17 mg, 4.47 μmol) were added to 1,4-dioxane (1 mL). The mixture was heated at 100 °C under argon atmosphere until the reaction was complete. The solution was concentrated to dryness and purified by reverse-phase column chromatography (water:acetonitrile = 10:1-1:10) to give compound 26-10 (5 mg).

[0571] m / z(ESI): 387[M+H] +

[0572] Step 11: 9-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-3,3,7-trifluoro-1,2,3,3a,4,5-hexahydro-6H-benzo[f]pyrrolo[1,2-a][1,4]diazepine-6-one (compound 26)

[0573] (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (22.72 mg, 147.91 μmol), compound 26-10 (5 mg, 12.93 μmol), and N,N-diisopropylethylamine (33.42 mg, 258.59 μmol) were added to dimethyl sulfoxide (0.2 mL). The mixture was heated at 120 °C under argon atmosphere for 2 hours until the reaction was complete. The solution was concentrated to dryness and purified by reverse-phase column chromatography (water:acetonitrile = 10:1-1:10) to give compound 26 (1 mg, yield 17%).

[0574] m / z(ESI): 468[M+H] +

[0575] Biological testing experiments

[0576] Test Example 1: Detection of CDK4 and CDK6 kinase inhibitory effects

[0577] The experimental method for CDK4 kinase is as follows:

[0578] 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.

[0579] 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.

[0580] 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;

[0581] Preparation of substrate reaction solution: Dilute with reaction buffer to prepare 100 nM ULight-4E-BP1 kinase substrate (PerkinElmer, TRF0128) and 600 μM ATP;

[0582] 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.

[0583] 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.

[0584] 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.

[0585] The percentage of CDK4 activity inhibition by a compound can be calculated using the following formula:

[0586] 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).

[0587] Compound IC 50 The values ​​were calculated from eight concentration points using XLfit (ID Business Solutions Ltd., UK) software via the following formula:

[0588] Y=Bottom+(Top-Bottom) / (1+10^((logIC 50 -X)×slope factor))

[0589] 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.

[0590] The experimental method for CDK6 kinase is as follows:

[0591] 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.

[0592] 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.

[0593] 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;

[0594] Preparation of substrate reaction solution: Dilute with reaction buffer to prepare 100 nM ULight-4E-BP1 kinase substrate (PerkinElmer, TRF0128) and 200 μM ATP;

[0595] 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.

[0596] 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.

[0597] 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.

[0598] The percentage of CDK6 activity inhibition by a compound can be calculated using the following formula:

[0599] 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).

[0600] Compound IC 50 The values ​​were calculated from eight concentration points using XLfit (ID Business Solutions Ltd., UK) software via the following formula:

[0601] Y=Bottom+(Top-Bottom) / (1+10^((logIC 50 -X)×slope factor))

[0602] 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.

[0603] Experimental results:

[0604] Test Example 2: Antiproliferative Activity Experiment of MCF7 Cells

[0605] 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.

[0606] The percentage of inhibition of MCF7 cell proliferation activity by the compound can be calculated using the following formula:

[0607] 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).

[0608] Compound IC 50 The values ​​were calculated from eight concentration points using XLfit (ID Business Solutions Ltd., UK) software via the following formula:

[0609] Y=Bottom+(Top-Bottom) / (1+10^((logIC 50 -X)×slope factor))

[0610] 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.

[0611] Test Example 3: Determination of Membrane Permeability and Transport Characteristics of Compounds

[0612] The membrane permeability and transport properties of the compounds disclosed herein were determined using the following experimental methods.

[0613] I. Experimental Materials and Instruments

[0614] 1. Caco-2 cells (ATCC)

[0615] 2. HEPES (Solarbio, 24230821003), penicillin / streptomycin (Solarbio, 240006006) and PBS (Solarbio, 20200620)

[0616] 3. Fetal bovine serum (FBS) (AUS FBS00622-1), Fluorescein (Sigma SHBN3650), and NaHCO3 (Sigma SLBZ4647)

[0617] 4. Hank's balanced salt solution (HBSS) (Gibco, 2857293), non-essential amino acids (NEAA) (Gibco, 2670616), and cell culture medium dissociation medium Trypsin / EDTA (Solarbio, 240012022).

[0618] 5. High-glucose DMEM cell culture medium (Hyclone, AK30797121)

[0619] 6.HTS Transwell-96Well Permeable(Corning,3391)

[0620] 7. Resistance meter (Millipore, ERS-2)

[0621] 8. Vision (Nexcelom Bioscience)

[0622] 9. Infinite 200PRO microplate reader (Tecan, Infinite M200PRO)

[0623] 10. Comparison compounds metoprolol (Sinopharm, 100084-202204) and digoxin (MedChemExpres, 265997)

[0624] 11. ABIQTrap 5500 Liquid Chromatography-Mass Spectrometry (LC-MS) System

[0625] II. Experimental Procedure

[0626] 1. Caco-2 cell culture

[0627] 1) Preparation of transport buffer (HBSS containing 25mM HEPES, pH 7.4): Accurately weigh 5.958g HEPES and 0.35g NaHCO3, add 900mL of pure water to dissolve them, then add 100mL of 10×HBSS and stir well. Adjust the pH to 7.4 and filter.

[0628] 2) Preparation of Caco-2 cell culture medium: FBS, penicillin / streptomycin and NEAA were added to high glucose DMEM (containing L-glutamine) medium to prepare cell culture medium containing 10% FBS, 100 units of penicillin / 0.1 mg / mL streptomycin and 1×NEAA.

[0629] 3) Culture Caco-2 cells in T-75 culture flasks at 37℃ and 5% CO2. When the cells reach 80-90% confluence, discard the culture medium. Wash the cells with 5mL PBS, add 1.5mL Trypsin / EDTA dissociation solution, and then incubate at 37℃ for 5-10 minutes until the cells detach in a quicksand-like manner. Finally, neutralize the Trypsin / EDTA with FBS-containing medium.

[0630] 4) Centrifuge the cell suspension at 150 rpm for 10 minutes and discard the supernatant.

[0631] 5) Resuspend the cells in cell culture medium and adjust the density to 6.86 × 10⁻⁶. 5 Cell suspension with cells / mL.

[0632] 2. Caco-2 cell seeding

[0633] 1) Add 50 μL of Caco-2 cell culture medium to each well of the Transwell chamber, add 25 mL of culture medium to the bottom layer, and preheat in a 37°C, 5% CO2 incubator for 1 hour.

[0634] 2) Add 50 μL of cell suspension to each well of the preheated Transwell chamber, resulting in a final seeding density of 2.4 × 10⁻⁶ cells / well. 5 cells / cm 3 (cells / mL)

[0635] 3) Incubate for 14-18 days, changing the culture medium every other day, and changing the culture medium within 48 hours after the initial inoculation. The culture medium must be changed the day before the experiment.

[0636] 3. Assess the integrity of the monolayer cell membrane

[0637] 1) After 14 days of cell culture, the cells fused and differentiated, ready for transport experiments.

[0638] 2) Measure the resistance of the single-layer film using a resistance meter and record the resistance of each hole.

[0639] 3) After the measurement is completed, the Transwell culture plate is incubated again.

[0640] 4) Calculate the transmembrane resistance TEER value:

[0641] TEER value = TEER measurement (Ω) × membrane area (cm²) 2 )

[0642] The electrical resistance of a single cell membrane is <230 Ω·cm 2 This indicates that the single-layer cell membrane has poor density and cannot be used for experiments.

[0643] 4. Transport experiment

[0644] 1) Dilute 10 mM of the stock solution of the disclosed compound or positive control compound with DMSO to obtain a 2 mM stock solution, and then dilute the 2 mM stock solution with transfer buffer to obtain a 10 μM working solution of the disclosed compound or positive control compound.

[0645] 2) Remove the Caco-2 cell plate from the incubator, then wash the Transwell culture plate twice with preheated transport buffer, and then incubate it in a 37°C incubator for 30 minutes.

[0646] 3) To determine the transport rate of the compound from the top to the base (A→B), 108 μL of the compound's working solution was added to the Transwell chamber (top). Simultaneously, 8 μL of sample was immediately removed from the top and transferred to 72 μL of transport buffer. 240 μL of stop solution containing an internal standard was added to terminate the transport and serve as the initial top sample. At the same time, 300 μL of transport buffer was added to the receiving end (base). The experiment used a two-sample setup.

[0647] 4) To determine the transport rate of the compound from the base end to the top end (B→A), add 308 μL of the compound's working solution to the base end, and immediately remove 8 μL of the sample from the base end into 72 μL of transport buffer. Add 240 μL of stop solution containing internal standard to terminate the transport and use it as the initial base end sample. Simultaneously, add 100 μL of transport buffer to the Transwell chamber (top end). The experiment uses a two-sample setup.

[0648] 5) Incubate the cell culture plate in a 37°C CO2 incubator for 2 hours.

[0649] 6) After the transport experiment, take 8 μL of sample from the delivery end (i.e., the top end in the A→B direction and the base end in the B→A direction) and add it to 72 μL of transport buffer. Then, add 240 μL of stop solution containing internal standard to terminate the transport. Take 80 μL of sample from the receiving end (i.e., the base end in the A→B direction and the top end in the B→A direction) and add it to 240 μL of stop solution containing internal standard. Vortex at 1000 rpm for 10 minutes and centrifuge at 4000 rpm for 30 minutes. Take 100 μL of supernatant into the sample plate, add 100 μL of ultrapure water and mix well. Use for LC-MS / MS analysis.

[0650] 7) After the transport experiment, measure the fluorescence value. Prepare a 10mM fluorescein stock solution with water, then dilute it to 100μM with transport buffer. Add 100μL of fluorescein solution to the top of the Transwell chamber and 300μL of transport buffer to the bottom. Incubate at 37℃ in a CO2 incubator for 30 minutes. Transfer 80μL of the solution from the top and bottom to a 96-well plate and measure the cell fluorescence value using a microplate reader at an excitation wavelength of 485nm and an emission wavelength of 530nm (to check membrane integrity).

[0651] Calculate the leakage rate (Percentage leakage (%) or LY (%)) using the following formula: Percentage Leakage = {I acceptor ×0.3 / (I acceptor ×0.3+I donor ×0.1)}×100%

[0652] I acceptor (I 接收端 (I) refers to the fluorescence density on the receiving side (0.3 mL). donor (I 供体 The fluorescence density is measured on the administration side (0.1 mL). LY > 1.0% indicates poor compactness of the monolayer cell membrane, and the corresponding result will be excluded from the evaluation.

[0653] The peak areas of the compound on the administration and receptive sides were determined, and the apparent permeability coefficient (P0) of the compound was calculated. app (Unit: cm / s) and Efflux ratio: P app ={V A ×[drug] acceptor / (Area×incubation time×[drug] initial donor}

[0654] V AThe volume of the receiving solution is 0.3 mL for A→B and 0.1 mL for B→A. The area (membrane surface area) is the transwell-96-well plate membrane area (0.143 cm²). 2 ); incubation time is the incubation period (unit: seconds); [drug] acceptor ([drug] 接收端 () represents the drug concentration at the receiving end; [drug] initial donor ([drug] 初始，供体 () represents the initial concentration of the drug on the administration side.

[0655] P app(B-A) P represents the apparent permeability from the basal end to the apex. app(A-B) The apparent permeability coefficient is measured from the top to the base.

[0656] Tests have shown that the disclosed compound exhibits good membrane permeability and transport properties.

[0657] Experimental results:

[0658] Tests have shown that the disclosed compound exhibits good membrane permeability and transport properties.

Claims

1. A compound of formula (Z) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: is independently selected from a double bond or a single bond, and are not simultaneously double bonds; Q 1 selected from CO, SO2, O and NR 8 ; Q 2 selected from NR 9 , CHR 10 , CO and O; X is selected from N, NR 4 and O; n is selected from 0, 1, 2 and 3; Cycloalkyl, 4-10 membered monocyclic heterocyclyl, C6-C 12 Cycloalkyl, 4-10 membered monocyclic heterocyclyl, C6-C 10 Cycloalkyl, 4-10 membered monocyclic heterocyclyl, C6-C 12 Cycloalkyl, 4-10 membered monocyclic heterocyclyl, C6-C 10 Cycloalkyl, 4-10 membered monocyclic heterocyclyl, C6-C a Cycloalkyl, 4-10 membered monocyclic heterocyclyl, C6-C Each R 1 R 5 and R 6 Independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 Alkyl, C3-C6 cycloalkyl, C2-C 10 alkenyl and C2-C 10 alkynyl group, the hydroxyl group, C1-C 10 Alkyl, C3-C6 cycloalkyl, 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 3’ are independently selected from the group consisting of absent, hydrogen, halogen, and C1-C 10 alkyl; R 2 and R 10 are independently selected from hydrogen, halogen, oxo, hydroxyl, amino, thiol, cyano, C1-C 10 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, said hydroxyl, amino, thiol, C1-C 10 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R 2a ; R 3 selected from hydrogen, halogen, oxo, hydroxy, amino, mercapto, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl, wherein the hydroxy, amino, mercapto, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R 10 12 10 10 12 10 3a substituents;​​​​​​ or R 2 and the atom to which they are attached together form a C5-C 3 saturated carbocyclic ring, 4-10 membered heterocyclic ring, C6-C 12 aromatic ring, and 5-10 membered heteroaromatic ring, said C5-C 10 saturated carbocyclic ring, 4-10 membered heterocyclic ring, C6-C 12 aromatic ring, and 5-10 membered heteroaromatic ring are optionally substituted with 1 or more R 10 1b substituents;​ or R 3 and the atom to which they are attached together form a C3-C6saturated carbocyclic ring, which is optionally substituted with 1 or more R 3’ and the atom to which they are attached together form a C3-C6saturated carbocyclic ring, which is optionally substituted with 1 or more R 4b substituents; R 4 , R 7 , R 8 and R 9 are independently selected from hydrogen, amino, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl and 4-10 membered heterocyclyl, which amino, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl and 4-10 membered heterocyclyl are optionally substituted with 1 or more R 4a ; or R 3 and the atom to which they are attached collectively form a 4-10 membered heterocyclic ring and a 5-10 membered heteroaryl ring, which are optionally substituted with 1 or more R 4 and the atom to which they are attached collectively form a 4-10 membered heterocyclic ring and a 5-10 membered heteroaryl ring, which are optionally substituted with 1 or more R 2b substituents; or / and, R 2 and R 9 and the atoms to which they are attached collectively form a 4-10 membered heterocyclic ring and a 5-10 membered heteroaromatic ring, which are optionally substituted with 1 or more R 3b substituents; Each R a Independently selected from halogen, hydroxyl, amino, cyano, -C(O)-NR e R e -C(O)-R e -SO2R e -NR e C(O)NR e C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl, C3-C 12 cycloalkyl, 4-5 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, 4-5 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally coated with one or more R groups. d replace; each R is independently selected from the group consisting of halogen, hydroxyl, cyano, amino, and Ci-C6alkyl; 1a 10 alkyl;​ Each R 2a R 3a and R 4a Independently selected from halogen, hydroxyl, cyano, amino, C1-C8 alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the hydroxyl, amino, C1-C8 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. c replace; Each R 1b R 2b R 3b R 4b R c R d and R e Independently selected from halogen, hydroxyl, cyano, amino, C1-C 10 Alkyl, C3-C 12 Cycloalkyl and 4-10 membered heterocyclic groups, wherein the hydroxyl, amino, C1-C 10 Alkyl, C3-C 12 Cycloalkyl and 4-10 membered heterocyclic groups are optionally surrounded by one or more amino, halogen, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C3-C 12 Cycloalkyl and 4-10 membered heterocyclic groups are substituted; one or more hydrogen atoms of said compound are optionally deuterium atoms.

2. The compound of claim 1 of formula (Z) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, is a single bond; or is a single bond, is a double bond; or is a double bond, is a single bond; or are both single bonds.

3. The compound of formula (Z) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 or 2, wherein, Q 1 is CO; or Q 1 is SO2; or Q 1 is O; or Q 1 is selected from NR 8 ; or Q 1 is selected from CO, SO2, O and NCH3; and / or, Q 2 is selected from NR 9 ; or Q 2 is selected from CHR 10 ; or Q 2 is CO; or Q 2 is O.

4. The compound of formula (Z) as defined in any one of claims 1 to 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Q 1 is CO, and Q 2 is selected from NR 9 ; or Q 1 is CO, and Q 2 is O; or Q 1 is SO2, and Q 2 is selected from CHR 10 ; or Q 1 is SO2, and Q 2 is selected from NR 9 ; or Q 1 is O, and Q 2 is CO; or Q 1 is selected from NR 8 , and Q 2 is CO; or Q 1 is O, and Q 2 is selected from CHR 10 .

5. The compound of any one of claims 1-4 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, X is NR 4 ; or X is N; or X is O.

6. The compound of any one of claims 1-5 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, n is 0 or 1; or n is 1; or n is 0.

7. The compound of any one of claims 1-6 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from 4-10 membered mono-heterocyclyl and 5-10 membered heteroaryl, optionally substituted with 1 or more R a substituents; or Ring A is selected from 4-10 membered mono-heterocyclyl, optionally substituted with 1 or more R a substituents; or Ring A is selected from 4-7 membered mono-heterocyclyl, optionally substituted with 1 or more R a substituents; or Ring A is selected from tetrahydropyranyl and piperidinyl, optionally substituted with 1 or more R a substituents; or Ring A is selected from tetrahydropyranyl, optionally substituted with 1 or more R a substituents; or Ring A is selected from tetrahydropyranyl, optionally substituted with 1 or more R 8. The compound of Formula (Z) as described in any one of claims 1-7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R a Independently selected from halogen, hydroxyl, amino, cyano, -SO2CH3, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl, hydroxyl, amino, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl groups are optionally surrounded by one or more R groups. d Replace; or each R a The group is independently selected from halogen, hydroxyl, amino, and cyano groups, wherein the hydroxyl and amino groups are optionally surrounded by one or more R groups. d Replace; or R a Selected from hydroxyl and -SO2CH3; or R a It is a hydroxyl group.

9. The compound of any one of claims 1-8 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R d It is independently selected from C1-C4 alkyl groups.

10. The compound of Formula (Z) as described in any one of claims 1-9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 1 selected from halogen; or R 1 is fluorine.

11. The compound of any one of claims 1-10 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2 selected from hydrogen, halogen, oxo, hydroxyl, amino, thiol, cyano, and C1-C4alkyl, said hydroxyl, amino, thiol, and C1-C4alkyl optionally substituted with 1 or more R 10 10 2a substituted with 1 or more R 2 selected from hydrogen, C1-C4alkyl, and 4-10 membered heterocyclyl, said C1-C4alkyl and 4-10 membered heterocyclyl optionally substituted with 1 or more R 10 10 2a substituted with 1 or more R 2 selected from hydrogen, oxo, C1-C4alkyl, and 4-6 membered heterocyclyl, said C1-C4alkyl and 4-6 membered heterocyclyl optionally substituted with 1 or more R 2a 2 2a 2 2a 2 2a 2 2a 2 2a 2 2a 2 selected from hydrogen, methyl, oxetanyl, fluoromethyl, trifluoromethyl, methoxymethyl, and oxo; or R 2 selected from hydrogen, oxo, and C1-C4alkyl; or R 2 selected from hydrogen, methyl, and oxo.​​​​​​​​​​​​​​​​​ 12. The compound of Formula (Z) as described in any one of claims 1-11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, each R is independently selected from the group consisting of halogen, hydroxyl, cyano, C1-C8alkoxy, and amino; or each R 2a is independently selected from the group consisting of halogen, hydroxyl, cyano, methoxy, and amino; or each R 2a is independently selected from the group consisting of halogen, hydroxyl, cyano, methoxy, and amino; or each R 2a is independently selected from the group consisting of fluorine, methoxy, and hydroxyl; each R 2a is independently selected from the group consisting of halogen, hydroxyl, cyano, and amino; or R 2a is hydroxyl.

13. The compound of Formula (Z) as described in any one of claims 1-12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2’ is selected from the group consisting of nothing, hydrogen and C1-C4alkyl; or R 2’ is selected from the group consisting of nothing, hydrogen and methyl.

14. The compound of Formula (Z) as described in any one of claims 1-13, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 3 selected from hydrogen, halogen, oxo, hydroxyl, amino, thiol, cyano, C1-C 10 alkyl, C3-C 12 cycloalkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, thiol, C1-C 10 alkyl, C3-C 12 cycloalkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, thiol, C1-C 3a alkyl, C3-C 3 cycloalkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, thiol, C1-C 10 alkyl, C3-C 10 cycloalkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, thiol, C1-C 3a alkyl, C3-C 3 cycloalkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, thiol, C1-C 10 alkyl, C3-C 10 cycloalkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, thiol, C1-C 3a alkyl, C3-C 3 cycloalkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, thiol, C1-C 3a alkyl, C3-C 3 cycloalkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, thiol, C1-C 3a alkyl, C3-C 3 cycloalkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, thiol, C1-C 3a alkyl, C3-C 3 cycloalkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, thiol, C1-C 3a alkyl, C3-C 3 cycloalkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, thiol, C1-C 3a alkyl, C3-C 3 cycloalkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, thiol, C1-C 3a alkyl, C3-C 3 cycloalkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, thiol, C1-C 3a alkyl, C3-C 3 cycloalkyl, and 4-10 membered heterocyclyl, said hydroxyl, amino, thiol, C1-C 3a substituted; or R 3 selected from hydrogen, oxo, methyl, ethyl, CH3CF3, tetrahydropyrrolyl, cyclopropyl, and piperidinyl; or R 3 selected from hydrogen and C1-C4 alkyl; or R 3 selected from hydrogen, methyl, and ethyl.

15. The compound of any one of claims 1-14 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R 3a The radical is independently selected from halogen, hydroxyl, cyano, amino, C1-C8 alkyl, and 4-10 membered heterocyclic groups, wherein the hydroxyl, amino, C1-C8 alkyl, and 4-10 membered heterocyclic groups are optionally surrounded by one or more R groups. c Replace; or each R 3a Independently selected from hydroxyl groups and 4-10 membered heterocyclic groups, wherein the hydroxyl groups and 4-10 membered heterocyclic groups are optionally surrounded by one or more R... c Replace; or each R 3a Independently selected from hydroxyl and 4-7 membered heterocyclic groups, wherein the hydroxyl and 4-7 membered heterocyclic groups are optionally surrounded by one or more R... c Replace; or each R 3a The radicals are independently selected from halogens, hydroxyl groups, and morpholino groups, wherein the hydroxyl and morpholino groups are optionally surrounded by one or more R groups. c Replace; or each R 3a The groups are independently selected from fluorine, hydroxyl, and morpholino, wherein the hydroxyl and morpholino groups are optionally surrounded by one or more R groups. c Replace; or each R 3a Independently selected from hydroxyl and morpholino groups, said hydroxyl and morpholino groups optionally being surrounded by one or more R... c Replace; or each R 3a Individually selected from fluorine, hydroxyl, and morpholino groups; or each R 3a It is independently selected from hydroxyl and morpholino groups.

16. The compound of any one of claims 1-15 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 3’ is selected from the group consisting of nothing, hydrogen and C1-C4alkyl; or R 3’ is selected from the group consisting of nothing, hydrogen and methyl.

17. The compound of any one of claims 1-16 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2 and R 3 Together with the atoms they connect, they form C5-C7 saturated carbon rings, 4-7 membered heterocycles, and C6-C... 10 Aromatic rings and 5-7 membered heteroaromatic rings, wherein the C5-C7 saturated carbon rings, 4-7 membered heterocycles, C6-C 10 Aromatic rings and 5-7 quinone heterocyclic aromatic rings are optionally bounded by one or more R... 1b Replace; or R 2 and R 3 The atoms connected to the rings together form a C5-C7 saturated carbon ring and a 4-7 membered heterocycle, wherein the C5-C7 saturated carbon ring and the 4-7 membered heterocycle are optionally bounded by one or more R atoms. 1b Replace; or R 2 and R 3 The atoms connected to the ring and the ring together form a benzene ring, a pyridine ring, a cyclopentane ring, a cyclohexane ring, a tetrahydrofuran ring, a tetrahydropyran ring, and a tetrahydropyrrole ring, wherein the benzene ring, pyridine ring, cyclopentane ring, cyclohexane ring, tetrahydrofuran ring, tetrahydropyran ring, and tetrahydropyrrole ring are optionally separated by one or more R atoms. 1b Replace; or R 2 and R 3 The atoms bonded to the rings together form a benzene ring, a pyridine ring, a cyclopentane ring, a cyclohexane ring, and a tetrahydropyrrole ring, wherein the benzene ring, pyridine ring, cyclopentane ring, cyclohexane ring, and tetrahydropyrrole ring are optionally bounded by one or more R atoms. 1b Replace; or R 2 and R 3 The atoms bonded to the rings together form a benzene ring, a pyridine ring, a cyclopentane ring, and a tetrahydropyrrole ring, wherein the benzene ring, pyridine ring, cyclopentane ring, and tetrahydropyrrole ring are optionally bounded by one or more R atoms. 1b Replace; or R 2 and R 3 The atoms bonded to the cyclohexane ring and the tetrahydrofuran ring together form a cyclohexane ring, a tetrahydrofuran ring, and a tetrahydropyran ring, wherein the cyclohexane ring, the tetrahydrofuran ring, and the tetrahydropyran ring are optionally bounded by one or more R atoms. 1b replace.

18. The compound of any one of claims 1-17 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R 1b It is independently selected from halogen, hydroxyl, cyano, amino and C1-C4 alkyl groups.

19. The compound of any one of claims 1-18 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 3 and R 3’ The atoms connected to it together form a C3-C4 saturated carbon ring, which is optionally bounded by one or more R atoms. 4b Replace; or R 3 and R 3’ The atoms bonded to it together form cyclopropane, which is optionally bonded by one or more R atoms. 4b replace.

20. The compound of any one of claims 1-19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R 4b It is independently selected from halogen, hydroxyl, cyano, amino and C1-C4 alkyl groups.

21. The compound of any one of claims 1-20 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 5 selected from halogen; or R 5 is selected from fluorine and chlorine.

22. The compound of any one of claims 1-21 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 6 selected from hydrogen and halogen; or R 6 is hydrogen.

23. The compound of any one of claims 1-22 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 10 selected from hydrogen and halogen; or R 10 is hydrogen.

24. The compound of any one of claims 1-23 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 4 is selected from the group consisting of methyl, ethyl, trifluoroethyl and isopropyl; or R 4 is selected from the group consisting of methyl and isopropyl; or R 4 is methyl.

25. The compound of any one of claims 1-24 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 7 is hydrogen.

26. The compound of any one of claims 1-25 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 8 is methyl.

27. The compound of any one of claims 1-26 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 9 is hydrogen or methyl; or R 9 is methyl.

28. The compound of any one of claims 1-27 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 3 and R 4 The atoms connected to the rings together form 4-7 membered heterocycles and 5-7 membered heteroaromatic rings, wherein the 4-7 membered heterocycles and 5-7 membered heteroaromatic rings are optionally bounded by one or more R atoms. 2b Replace; or R 3 and R 4 The atoms bonded to the azacyclic butane, piperazine ring, morpholine ring, tetrahydropyrrole ring, and imidazole ring together form an azacyclic butane, a piperazine ring, a morpholine ring, a tetrahydropyrrole ring, and an imidazole ring, wherein the azacyclic butane, piperazine ring, morpholine ring, tetrahydropyrrole ring, and imidazole ring are optionally bounded by one or more R atoms. 2b Replace; or R 3 and R 4 The piperazine ring, morpholine ring, tetrahydropyrrole ring, and imidazole ring together form a piperazine ring, a morpholine ring, a tetrahydropyrrole ring, and an imidazole ring, wherein the piperazine ring, morpholine ring, tetrahydropyrrole ring, and imidazole ring are optionally bounded by one or more R atoms. 2b Replace; or R 3 and R 4 The piperazine ring, morpholine ring, and imidazole ring are formed by the atoms connected to them, and the piperazine ring, morpholine ring, and imidazole ring are optionally bounded by one or more R atoms. 2b Replace; or R 3 and R 4 The atoms connected to it together form a tetrahydropyrrole ring, which is optionally bounded by one or more R atoms. 2b Replace; or R 3 and R 4 The atoms bonded to the atom together form an aziridine and a tetrahydropyrrole ring, wherein the aziridine and the tetrahydropyrrole ring are optionally bounded by one or more R atoms. 2b replace.

29. The compound of any one of claims 1-28 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R 2b Independently selected from halogens, hydroxyl groups, cyano groups, amino groups, and C1-C4 alkyl groups, wherein the hydroxyl, amino, and C1-C4 alkyl groups are optionally substituted with one or more amino, halogen, cyano, C1-C4 alkyl, and C1-C4 haloalkyl groups; or each R 2b Individually selected from halogens, hydroxyl groups, cyano groups, amino groups, and C1-C4 alkyl groups; or each R 2b Independently selected from halogens, C1-C4 alkyl groups, C1-C4 alkoxy groups, and C1-C4 haloalkoxy groups; or each R 2b Individually selected from C1-C4 alkyl groups; or each R 2b Independently selected from halogens and C1-C4 alkyl groups; or each R 2b Selected from fluorine, methyl, methoxy, and trifluoromethoxy; or R 2b For methyl; or each R 2b Selected from fluorine and methoxy groups.

30. The compound of any one of claims 1-29 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2 and R 9 The atoms connected to it together form a 4-10 membered heterocycle, which is optionally bounded by one or more R atoms. 3b Replace; or R 2 and R 9 The atoms connected to it together form a 4-6 membered heterocycle, which is optionally bounded by one or more R atoms. 3b Replace; or R 2 and R 9 The atoms bonded to the azacyclic butane, oxazolidine, morpholine ring, and tetrahydropyrrole ring together form an azacyclic butane, oxazolidine, morpholine ring, and tetrahydropyrrole ring, wherein the azacyclic butane, oxazolidine, morpholine ring, and tetrahydropyrrole ring are optionally bounded by one or more R atoms. 3b Replace; or R 2 and R 9 The atoms connected to the oxazolidine ring and the tetrahydropyrrole ring together form an oxazolidine ring, a morpholine ring, and a tetrahydropyrrole ring, wherein the oxazolidine ring, the morpholine ring, and the tetrahydropyrrole ring are optionally bounded by one or more R atoms. 3b Replace; or R 2 and R 9 The atoms connected to it together form a tetrahydropyrrole ring, which is optionally bounded by one or more R atoms. 3b replace.

31. The compound of any one of claims 1-30 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Each R 3b It is independently selected from halogen, hydroxyl, cyano, amino and C1-C4 alkyl groups.

32. The compound of any one of claims 1-31 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 2 and R 9 The atoms connected to it together form a 4-10 membered heterocycle, which is optionally bounded by one or more R atoms. 3b Replace, and R 3 and R 4 The atoms connected to it together form a 4-7 membered heterocycle, which is optionally bounded by one or more R atoms. 2b Replace; or R 2 and R 9 The atoms bonded to the oxazolane together form an oxazolane, which is optionally bonded by one or more R atoms. 3b Replace, and R 3 and R 4 The atoms connected to it together form a tetrahydropyrrole ring, which is optionally bounded by one or more R atoms. 2b Replace; or R 2 and R 9 The atoms connected to it together form oxazolidine, and R 3 and R 4 Together with the atoms they are connected to, they form a tetrahydropyrrole ring.

33. The compound of any one of claims 1-32 of Formula (Z): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R 3 and R 3’ The atoms connected to it together form a C3-C4 saturated carbon ring, which is optionally bounded by one or more R atoms. 4b Replace, and R 2 and R 9 The atoms connected to it together form a 4-10 membered heterocycle, which is optionally bounded by one or more R atoms. 3b Replace; or R 3 and R 3’ The atoms bonded to it together form cyclopropane, which is optionally bonded by one or more R atoms. 4b Replace, R 2 and R 9 The atoms bonded to the oxazolane together form an oxazolane, which is optionally bonded by one or more R atoms. 3b Replace; or R 3 and R 3’ The atoms connected to it together form cyclopropane, and R 2 and R 9 Together with the atoms they are connected to, they form oxazolidine.

34. The compound of claim 1 of formula (Z) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: is selected from a double bond or a single bond; Q 1 selected from CO, SO2, O and NR 8 ; Q 2 NR 9 , CHR 10 , CO and O; n is selected from 0, 1, 2 and 3; Ring A is selected from C3-C 12 Cycloalkyl, 4-10 membered monoheterocyclic group, C6-C 10 Aryl and 5-12 heteroaryl, the C3-C 12 Cycloalkyl, 4-10 membered monoheterocyclic group, C6-C 10 Aryl and 5-12 heteroaryl groups are optionally substituted with one or more R groups. a replace; Each R 1 R 5 and R 6 Independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 Alkyl, C3-C6 cycloalkyl, C2-C 10 alkenyl and C2-C 10 alkynyl group, the hydroxyl group, C1-C 10 Alkyl, C3-C6 cycloalkyl, 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 10 are independently selected from hydrogen, halogen, oxo, hydroxy, amino, mercapto, cyano, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, which hydroxy, amino, mercapto, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl is optionally substituted with 1 or more R 10 ; and 10 ; and 2a ; and R 3 selected from hydrogen, halogen, oxo, hydroxy, amino, mercapto, cyano, Ci-C 10 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, said hydroxy, amino, mercapto, Ci-C 10 alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, said hydroxy, amino, mercapto, Ci-C 3a substituted with 1 or more R Or, R 2 and R 3 Together with the atoms they connect, they form C5-C 12 Saturated carbon rings, 4-10 membered heterocycles, C6-C 10 Aromatic rings and 5-10 quinone heteroaryl rings, the C5-C 12 Saturated carbon rings, 4-10 membered heterocycles, C6-C 10 Aromatic rings and 5-10 heterocyclic aromatic rings are optionally bounded by one or more R... 1b replace; R 4 , R 7 , R 8 and R 9 are independently selected from hydrogen, C2-C 10 alkenyl, C2-C 10 alkynyl and CrC 10 alkyl, said C2-C 10 alkenyl, C2-C 10 alkynyl and CrC 10 alkyl being optionally substituted with 1 or more R 4a ; or R 3 and the atom to which they are attached together form a 4-10 membered heterocyclic ring and a 5-10 membered heteroaryl ring, which are optionally substituted with 1 or more R 4 and the atom to which they are attached together form a 4-10 membered heterocyclic ring and a 5-10 membered heteroaryl ring, which are optionally substituted with 1 or more R 2b substituents; Each R a Independently selected from halogen, hydroxyl, amino, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl group, C1-C 10 Alkyl, C3-C 12 cycloalkyl, 4-5 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, 4-5 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally coated with one or more R groups. d replace; each R is independently selected from the group consisting of halogen, hydroxyl, cyano, amino, and Ci-C6alkyl; 1a each R is independently selected from the group consisting of halogen, hydroxyl, cyano, amino, and Ci-C6alkyl; 10 alkyl; Each R 2a R 3a and R 4a Independently selected from halogen, hydroxyl, cyano, amino, C1-C8 alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the hydroxyl, amino, C1-C8 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. c replace; Each R 1b R 2b R c and R d Independently selected from halogen, hydroxyl, cyano, amino, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy; one or more hydrogen atoms of said compound are optionally deuterium atoms.

35. The compound of claim 1 of formula (Z) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of formula (II) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, selected from a single or double bond; n, Q 1 , Q 2 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 as defined in claims 1-34.

36. The compound of claim 1 of formula (Z) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of formula (III) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, n, Q 2 , R 1 , R 2 , R 2’ , R 3 , R 3’ , R 4 , R 5 and R 6 as defined in claims 1-34.

37. The compound of claim 1 of formula (Z) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the following compounds or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, 38. A pharmaceutical composition comprising a compound of Formula (Z) as described in any one of claims 1-37, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

39. Use of a compound of Formula (Z) as described in any one of claims 1-37, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 38, for the manufacture of a medicament for the prevention or treatment of a CDK4-mediated disease.

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