PIPERIDINOPYRIMIDINE DERIVATIVES CONTAINING THIAZOLYL, THEIR PREPARATION METHODS, AND THEIR ANTIBODY-PHARMACOLOGICAL CONJUGATE

Abstract

The invention relates to a thiazolyl-containing piperidinopyrimidine derivative, and a method for preparing it, and specifically relates to the compound represented by formula (I') or its pharmaceutical salt, in which each group in formula (I') is as defined in the description.

Description

A piperidopyrimidine derivative containing a thiazolyl group, its preparation method and its medical application Technical Field

[0001] The present invention belongs to the field of medicine and relates to a piperidopyrimidine derivative containing a thiazole group, a preparation method thereof and medical application thereof. Background Art

[0002] Cyclin kinases (CDKs) are an important class of kinases and play a crucial role in the division and proliferation of cancer cells and the transcriptional regulation of oncogenes. Currently, there are more than 20 subtypes of cyclin kinases (CDKs) discovered. Due to the sequence and structural similarities of the kinase domains of CDK family members, selective and precise regulation of each subtype is a major challenge.

[0003] Cyclin-dependent kinase 7 (CDK7) is a specialized member of the CDK family, with dual functions in regulating both cell division and transcription. CDK7 binds to cyclin H and MAT1 to form a trimeric cyclin-activated kinase (CAK). This kinase regulates the cell cycle by phosphorylating CDKs involved in cell cycle control (including CDK1, CDK2, CDK4, and CDK6), thereby activating the activity of the corresponding CDK kinases. CDK7 also participates in the co-regulation of transcription as a component of the common transcription factor II H (TFIIH). It is involved in transcription initiation by phosphorylating the Rbp1 subunit of RNA polymerase II (RNAPII), and then regulates transcription elongation by phosphorylating the CDK9 complex.

[0004] Key hallmarks of cancer are uncontrolled cell proliferation and dysregulated transcription. Therefore, CDK7 inhibitors that simultaneously inhibit both transcription and cell cycle progression are theoretically promising targets for cancer treatment. Currently, no drugs are available that selectively regulate this target. The inventors envision developing a highly selective CDK7 inhibitor to treat diseases associated with CDK7 activity.

[0005] Published patent applications for CDK7 inhibitors include WO2016058544, WO2018013867, WO2019143719, WO2019143730, WO2019099298, WO2020093006, WO2020093011, WO2022064009A, etc.

[0006] Summary of the Invention

[0007] The present disclosure provides a compound represented by formula (I') or a pharmaceutically acceptable salt thereof,

[0008] in,

[0009] R 1 Selected from deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, -C 1-6 alkylene-3 to 6-membered heterocycloalkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 to 6-membered heteroaryl, -NH(C=O)-OC 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl and -(C=O)NH2, the C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, -C 1-6 alkylene-3 to 6-membered heterocycloalkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 to 6-membered heteroaryl, -NH(C=O)-OC 1-6 Alkyl and -(C=O)NH-C 1-6 The alkyl groups are each independently optionally substituted with one or more R A Substituted, the R A Selected from deuterium, halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkynyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 each alkynyl group is independently optionally substituted with one or more deuterium or halogen;

[0010] m is selected from 0, 1, 2, 3 and 4;

[0011] L1 is selected from the connecting bond and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R B Substituted, the R B Selected from deuterium, halogen, hydroxyl, oxo, C 1-6 alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1-6 Alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl are each independently optionally substituted with one or more R 1B Substituted, the R 1B Selected from deuterium, hydroxyl, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C1- 6-alkyl;

[0012] R 2 、R 3 、R 4 、R 5 and R 6 are each independently selected from hydrogen and deuterium;

[0013] R 7 C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more deuterium groups;

[0014] L2 is selected from NH, O and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R C Substituted, the R C Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0015] Ring A is selected from phenyl and 5- to 6-membered heteroaryl;

[0016] R 8 Selected from deuterium, halogen, hydroxyl, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2- 6-alkynyl, 3- to 6-membered cycloalkyl, -SC 1-6 Alkyl and -NHR'R", wherein R' and R" are each independently selected from hydrogen and C 1-6 Alkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl and 3 to 6 membered cycloalkyl are each independently optionally substituted with one or more R D Substituted, the R D Selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycloalkyl are each independently optionally substituted with one or more deuterium or halogen;

[0017] n is selected from 0, 1, 2, 3 and 4;

[0018] R 9 is hydrogen or deuterium;

[0019] L3 is C 1-3Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R E Substituted, the R E for deuterium;

[0020] R 10 and R 11 Each independently is C 1-3 Alkyl, the C 1-3 The alkyl group is optionally replaced by one or more R F Substituted, the R F For deuterium.

[0021] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0022] in,

[0023] R 1 Selected from deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, -C 1-6 alkylene-3 to 6-membered heterocycloalkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 to 6-membered heteroaryl, -NH(C=O)-OC 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl and -(C=O)NH2, the C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, -C 1-6 alkylene-3 to 6-membered heterocycloalkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 to 6-membered heteroaryl, -NH(C=O)-OC 1-6 Alkyl and -(C=O)NH-C 1-6 The alkyl groups are each independently optionally substituted with one or more R A Substituted, the R A Selected from deuterium, halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkynyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 each alkynyl group is independently optionally substituted with one or more deuterium or halogen;

[0024] m is selected from 0, 1, 2, 3 and 4;

[0025] L1 is selected from the connecting bond and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R B Substituted, the R B Selected from deuterium, halogen, hydroxyl, oxo, C 1-6 alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1-6 Alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl are each independently optionally further substituted with one or more R 1B Substituted, the R 1B Selected from deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C 1- 6-alkyl;

[0026] R 2 、R 3 、R 4 、R 5 and R 6 are each independently selected from hydrogen and deuterium;

[0027] R 7 C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more deuterium groups;

[0028] L2 is selected from NH, O and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R C Substituted, the R C Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0029] Ring A is selected from phenyl and 5- to 6-membered heteroaryl;

[0030] R 8 Selected from deuterium, halogen, hydroxyl, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2- 6-alkynyl, 3- to 6-membered cycloalkyl, -SC 1-6 Alkyl and -NHR'R", wherein R' and R" are each independently selected from hydrogen and C 1-6 Alkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl and 3 to 6 membered cycloalkyl are each independently optionally substituted with one or more RD Substituted, the R D Selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycloalkyl are each independently optionally substituted with one or more deuterium or halogen;

[0031] n is selected from 0, 1, 2, 3 and 4;

[0032] R 9 is hydrogen or deuterium;

[0033] L3 is C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R E Substituted, the R E for deuterium;

[0034] R 10 and R 11 Each independently is C 1-3 Alkyl, the C 1-3 The alkyl group is optionally replaced by one or more R F Substituted, the R F For deuterium.

[0035] The present disclosure provides a compound represented by formula (I'-A) or a pharmaceutically acceptable salt thereof,

[0036] in,

[0037] R 1 Selected from deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, -C 1-6 alkylene-3 to 6-membered heterocycloalkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 to 6-membered heteroaryl, -NH(C=O)-OC 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl and -(C=O)NH2, the C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, -C 1-6alkylene-3 to 6-membered heterocycloalkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 to 6-membered heteroaryl, -NH(C=O)-OC 1-6 Alkyl and -(C=O)NH-C 1-6 The alkyl groups are each independently optionally substituted with one or more R A Substituted, the R A Selected from deuterium, halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkynyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 each alkynyl group is independently optionally substituted with one or more deuterium or halogen;

[0038] m is selected from 0, 1, 2, 3 and 4;

[0039] L1 is C 1-3 Alkylene, the C 1-3 The alkylene group is replaced by one or more R B Substituted, the R B C 1-6 Alkyl, the C 1-6 The alkyl group is replaced by one or more R 1B Substituted, the R 1B is hydroxyl group;

[0040] R 2 、R 3 、R 4 、R 5 and R 6 are each independently selected from hydrogen and deuterium;

[0041] R 7 C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more deuterium groups;

[0042] L2 is selected from NH, O and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R C Substituted, the R C Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl and halogenated C 1-6 alkyl;

[0043] Ring A is selected from phenyl and 5- to 6-membered heteroaryl;

[0044] R 8 Selected from deuterium, halogen, hydroxyl, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C2-6 Alkenyl, C 2- 6-alkynyl, 3- to 6-membered cycloalkyl, -SC 1-6 Alkyl -NHR'R", wherein R' and R" are each independently selected from hydrogen and C 1-6 Alkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl and 3 to 6 membered cycloalkyl are each independently optionally substituted with one or more R D Substituted, the R D Selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycloalkyl are each independently optionally substituted with one or more deuterium or halogen;

[0045] n is selected from 0, 1, 2, 3 and 4;

[0046] R 9 is hydrogen or deuterium;

[0047] L3 is C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R E Substituted, the R E for deuterium;

[0048] R 10 and R 11 Each independently is C 1-3 Alkyl, the C 1-3 The alkyl group is optionally replaced by one or more R F Substituted, the R F For deuterium.

[0049] In some embodiments, the present disclosure provides compounds of Formula (I'), Formula (I), Formula (I'-A), or pharmaceutically acceptable salts thereof, wherein L2 is NH.

[0050] In some embodiments, the present disclosure provides compounds of formula (I'), formula (I), formula (I'-A), or pharmaceutically acceptable salts thereof, wherein L2 is O.

[0051] In some embodiments, the present disclosure provides compounds represented by formula (I'), formula (I), formula (I'-A), or pharmaceutically acceptable salts thereof, wherein L2 is C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R C Substituted, the RC Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0052] In some embodiments, the present disclosure provides compounds of formula (I'), formula (I), formula (I'-A), or pharmaceutically acceptable salts thereof, wherein L2 is a methylene group, and the methylene group is optionally replaced by one or more R C Substituted, the R C Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl and halogenated C 1-6 alkyl.

[0053] In some embodiments, the present disclosure provides compounds represented by formula (I'), formula (I), formula (I'-A), or pharmaceutically acceptable salts thereof, wherein L2 is a methylene group.

[0054] In some embodiments, the compounds of formula (I'), formula (I), formula (I'-A) or pharmaceutically acceptable salts thereof provided herein are compounds of formula (II) or pharmaceutically acceptable salts thereof,

[0055] Among them, R 1 ,m,L1,R 2 、R 3 、R 4 、R 5 、R 6 , Ring A, R 8 ,n,L3,R 10 and R 11 They are defined as the compounds represented by formula (I'), formula (I), formula (I'-A) or pharmaceutically acceptable salts thereof.

[0056] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein L3 is selected from methylene and ethylene, and the methylene and ethylene are each independently optionally replaced by one or more R E Substituted, the R E For deuterium.

[0057] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein L3 is a methylene group, and the methylene group is optionally replaced by one or more R E Substituted, the R E For deuterium.

[0058] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein L3 is a methylene group, and the methylene group is replaced by one or more R E Substituted, the R E For deuterium.

[0059] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein R 10 Selected from C 1-3 Alkyl (such as methyl, ethyl, n-propyl, isopropyl), the C 1- 3 alkyl is optionally replaced by one or more R F Substituted, the R F For deuterium.

[0060] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein R 10 Selected from methyl and ethyl, said methyl and ethyl are each independently optionally replaced by one or more R F Substituted, the R F For deuterium.

[0061] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein R 10 It is a methyl group.

[0062] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein R 10 It is -CD3.

[0063] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein R 11 Selected from C 1-3 Alkyl (such as methyl, ethyl, n-propyl, isopropyl), the C 1- 3 alkyl is optionally replaced by one or more R F Substituted, the R F For deuterium.

[0064] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein R 11 Selected from methyl and ethyl, said methyl and ethyl are each independently optionally replaced by one or more R F Substituted, the R F For deuterium.

[0065] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein R 11 It is a methyl group.

[0066] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein R 11 It is -CD3.

[0067] In some embodiments, the present disclosure provides compounds represented by formula (I'), (I), (I'-A), (II), or pharmaceutically acceptable salts thereof, wherein ring A is phenyl.

[0068] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein ring A is a 5- to 6-membered heteroaryl group.

[0069] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein ring A is pyridine.

[0070] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein ring A is pyrazole.

[0071] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein ring A is imidazole.

[0072] In some embodiments, the present disclosure provides compounds represented by formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein ring A is thiazole.

[0073] In some embodiments, the present disclosure provides compounds represented by formula (I'), (I), (II) or pharmaceutically acceptable salts thereof, wherein L1 is a connecting bond.

[0074] In some embodiments, the present disclosure provides compounds represented by formula (I'), (I), (II) or pharmaceutically acceptable salts thereof, wherein L1 is C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R B Substituted, the R B Selected from deuterium, halogen, hydroxyl, oxo, C 1-6 alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1-6 Alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl are each independently optionally substituted with one or more R1B Substituted, the R 1B Selected from deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C 1-6 alkyl.

[0075] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (II) or pharmaceutically acceptable salts thereof, wherein L1 is a methylene group, and the methylene group is replaced by one or more R B Substituted, the R B Selected from deuterium, halogen, C 1-6 alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1-6 Alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl are each independently optionally substituted with one or more R 1B Substituted, the R 1B Selected from deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C 1-6 alkyl.

[0076] In some embodiments, the present disclosure provides compounds (I'), (I), (II) or pharmaceutically acceptable salts thereof, wherein L1 is a methylene group, and the methylene group is replaced by one or more R B Substituted, the R B Selected from deuterium, halogen, C 1-3 alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1-3 Alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl are each independently optionally substituted with one or more R 1B Substituted, the R 1B Selected from deuterium and halogen.

[0077] In some embodiments, the present disclosure provides compounds (I'), (I), (II) or pharmaceutically acceptable salts thereof, wherein L1 is a methylene group, and the methylene group is replaced by one or more R B Substituted, the R B Selected from C 1-3 alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1-3 Alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl are each independently optionally substituted with one or more R 1B Substituted, the R 1B Selected from deuterium and halogen.

[0078] In some embodiments, the present disclosure provides compounds represented by formula (I'), (I), (II) or pharmaceutically acceptable salts thereof, wherein L1 is selected from methylene.

[0079] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl;

[0080] R 2 、R 3 、R 4 、R 5 and R 6 are each independently hydrogen;

[0081] R 10 selected from the group consisting of methyl and -CD3;

[0082] R 11 selected from the group consisting of methyl and -CD3;

[0083] L1 is a methylene group, and the methylene group is replaced by one or more R B Substituted, the R B is selected from deuterium, halogen, methyl, ethyl, cyclopropyl and cyclobutyl, wherein the methyl, ethyl, cyclopropyl and cyclobutyl are each independently optionally substituted by one or more R 1B Substituted, the R 1B Selected from deuterium and halogen.

[0084] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein R 8 Selected from deuterium, halogen, hydroxyl, cyano, carboxyl, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 Each alkoxy group is independently optionally substituted with one or more R D Substituted, the R D Selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, and 3- to 6-membered heterocycloalkyl are each independently optionally substituted with one or more deuterium or halogen;

[0085] n is selected from 0, 1, 2 and 3.

[0086] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein R 8is selected from deuterium, halogen, hydroxy, cyano, carboxyl, methyl, ethyl, isopropyl, n-propyl, n-butyl, methoxy, ethoxy, isopropoxy and n-butoxy, wherein the methyl, ethyl, isopropyl, n-propyl, n-butyl, methoxy, ethoxy, isopropoxy and n-butoxy are each independently optionally replaced by one or more R D Substituted, the R D is selected from deuterium, halogen, hydroxy, methyl, ethyl, ethoxy and methoxy, wherein each of the methyl, ethyl, ethoxy and methoxy groups is independently optionally substituted with one or more deuterium or halogen;

[0087] n is selected from 0, 1, 2 and 3.

[0088] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein R 8 is selected from deuterium, halogen, methyl, ethyl, methoxy and ethoxy, wherein the methyl, ethyl, methoxy and ethoxy are each independently optionally replaced by one or more R D Substituted, the R D selected from deuterium, halogen and hydroxyl;

[0089] The n is selected from 0, 1, 2 and 3.

[0090] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein R 1 Selected from deuterium, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl are each independently optionally substituted with one or more R A Substituted, the R A Selected from deuterium, halogen, hydroxy, amino, oxo, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 each alkoxy group is independently optionally substituted with one or more deuterium or halogen;

[0091] m is selected from 0, 1, 2 and 3.

[0092] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein R 1 Selected from C 1-6 Alkyl and 3 to 6 membered cycloalkyl, the C 1-6The alkyl group and the 3 to 6 membered cycloalkyl group are each independently optionally substituted with one or more R A Substituted, the R A is selected from the group consisting of deuterium, halogen, hydroxy, amino, oxo, methyl, ethyl, methoxy, and ethoxy;

[0093] m is selected from 0, 1, 2 and 3.

[0094] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (I'-A), (II) or pharmaceutically acceptable salts thereof, wherein R 1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl and cyclopentyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl and cyclopentyl are each independently optionally substituted by one or more R A Substituted, the R A selected from deuterium, halogen and hydroxyl;

[0095] The m is selected from 0, 1, 2 and 3.

[0096] In some embodiments, the present disclosure provides compounds of formula (I'), (I), (II) or pharmaceutically acceptable salts thereof, wherein L1 is a methylene group, and the methylene group is replaced by one or more R B Substituted, the R B Deuterium or C 1-6 alkyl.

[0097] In some embodiments, the present disclosure provides compounds represented by formula (I'), (I), (II) or pharmaceutically acceptable salts thereof, wherein: for

[0098] In some embodiments, the present disclosure provides compounds represented by formula (I'), (I), (II) or pharmaceutically acceptable salts thereof, wherein: for

[0099] In some embodiments, the present disclosure provides compounds represented by formula (I'), (I), (II) or pharmaceutically acceptable salts thereof, wherein: for

[0100] In some embodiments, the present disclosure provides compounds represented by formula (I'), (I), (II) or pharmaceutically acceptable salts thereof, wherein: for

[0101] In some embodiments, the present disclosure provides compounds represented by formula (I'), (I), (II) or pharmaceutically acceptable salts thereof, wherein: for

[0102] In some embodiments, the present disclosure provides compounds represented by formula (I'), (I), (II) or pharmaceutically acceptable salts thereof, wherein: for

[0103] In some embodiments, the present disclosure provides compounds represented by formula (I'), (I), (II) or pharmaceutically acceptable salts thereof, wherein: for

[0104] In some embodiments, the present disclosure provides compounds represented by formula (I'), (I), (II) or pharmaceutically acceptable salts thereof, wherein: for

[0105] In some embodiments, the compounds of formula (I'), (I), (II) or pharmaceutically acceptable salts thereof provided by the present disclosure are compounds of formula (III-1) or pharmaceutically acceptable salts thereof,

[0106] Among them, R 8 、n、R 1 and m is as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof;

[0107] R B is selected from hydrogen, deuterium, methyl, ethyl, cyclopropyl and cyclobutyl, said methyl, ethyl, cyclopropyl and cyclobutyl being each independently optionally substituted by one or more R 1B Substituted, the R 1B Selected from deuterium and halogen.

[0108] In some embodiments, the compounds of formula (I'), (I), (II) or pharmaceutically acceptable salts thereof provided by the present disclosure are compounds of formula (III-2) or pharmaceutically acceptable salts thereof,

[0109] Among them, R 8 、n、R 1 and m is as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof;

[0110] R B is selected from hydrogen, deuterium, methyl, ethyl, cyclopropyl and cyclobutyl, said methyl, ethyl, cyclopropyl and cyclobutyl being each independently optionally substituted by one or more R 1B Substituted, the R 1B Selected from deuterium and halogen.

[0111] In some embodiments, the compounds of formula (I'), (I), (II) or pharmaceutically acceptable salts thereof provided by the present disclosure are compounds of formula (III-3) or pharmaceutically acceptable salts thereof,

[0112] Among them, R 8 、n、R 1 and m is as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof;

[0113] R B is selected from hydrogen, deuterium, methyl, ethyl, cyclopropyl and cyclobutyl, said methyl, ethyl, cyclopropyl and cyclobutyl being each independently optionally substituted by one or more R 1B Substituted, the R 1B Selected from deuterium and halogen.

[0114] In some embodiments, the compounds of formula (I'), (I), (II) or pharmaceutically acceptable salts thereof provided by the present disclosure are compounds of formula (III-4) or pharmaceutically acceptable salts thereof,

[0115] Among them, R 8 、n、R 1 and m is as defined in the compound represented by formula (I) or a pharmaceutically acceptable salt thereof;

[0116] R B is selected from hydrogen, deuterium, methyl, ethyl, cyclopropyl and cyclobutyl, said methyl, ethyl, cyclopropyl and cyclobutyl being each independently optionally substituted by one or more R 1B Substituted, the R 1B Selected from deuterium and halogen.

[0117] In an optional embodiment, the present disclosure provides compounds represented by formula (III-1), (III-2), (III-3), (III-4) or pharmaceutically acceptable salts thereof, wherein R 8 is selected from deuterium, halogen, methyl, ethyl, methoxy and ethoxy, wherein the methyl, ethyl, methoxy and ethoxy are each independently optionally replaced by one or more R D Substituted, the R D selected from deuterium, halogen and hydroxyl;

[0118] R 1 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl and cyclopentyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl and cyclopentyl are each independently optionally substituted by one or more R A Substituted, the R A selected from deuterium and halogen;

[0119] m and n are each independently selected from 0, 1, 2 and 3.

[0120] In an optional embodiment, the present disclosure provides compounds represented by formula (III-1), (III-2), (III-3), (III-4) or pharmaceutically acceptable salts thereof, wherein R B is selected from methyl and cyclopropyl, said methyl and cyclopropyl being each independently optionally substituted by one or more R 1B Substituted, the R 1B for deuterium;

[0121] R 1 is selected from methyl and cyclopropyl, said methyl and cyclopropyl being each independently optionally substituted by one or more R A Substituted, the R A selected from deuterium and halogen;

[0122] m is selected from 0, 1, 2 and 3;

[0123] n is 0.

[0124] The compounds provided herein, represented by formula (I'), (I), (I'-A), (II), (III-1), (III-2), (III-3), (III-4), or pharmaceutically acceptable salts thereof, are compounds or pharmaceutically acceptable salts thereof shown in Table a.

[0125] Table a

[0126] Another aspect of the present disclosure provides a compound represented by Formula (I'), (I), (I'-A), (II), (III-1), (III-2), (III-3), (III-4) or a pharmaceutically acceptable salt thereof, and an isotopic substitution of the compound of Table A. In an optional embodiment, the isotopic substitution is a deuterated compound.

[0127] The present disclosure also provides a pharmaceutical composition comprising at least one compound represented by Formula (I'), (I), (I'-A), (II), (III-1), (III-2), (III-3), (III-4) or a pharmaceutically acceptable salt thereof and a compound of Table A, an isotope substitute, and a pharmaceutically acceptable excipient.

[0128] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0129] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or a pharmaceutically acceptable salt thereof.

[0130] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0131] Another aspect of the present disclosure provides the use of the compounds represented by the aforementioned formulas (I'), (I), (I'-A), (II), (III-1), (III-2), (III-3), (III-4) or pharmaceutically acceptable salts thereof and the compounds of Table A, isotopic substitutions, and the aforementioned pharmaceutical compositions in the preparation of medicaments for treating or preventing diseases or conditions associated with abnormal activity of serine / threonine kinases.

[0132] Another aspect of the present disclosure provides the use of the compounds represented by the aforementioned formulas (I'), (I), (I'-A), (II), (III-1), (III-2), (III-3), (III-4) or pharmaceutically acceptable salts thereof and the compounds of Table a, isotopic substitutions, and the aforementioned pharmaceutical compositions in the preparation of drugs for treating and / or preventing diseases or conditions associated with abnormal activity of CDK7.

[0133] In an alternative embodiment, the disease or disorder associated with abnormal activity of CDK7 is selected from the group consisting of a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, and an infectious disease.

[0134] On the other hand, the present disclosure provides the compounds represented by the aforementioned formulas (I'), (I), (I'-A), (II), (III-1), (III-2), (III-3), (III-4) or pharmaceutically acceptable salts thereof and the compounds of Table a, isotopic substitutions, and the use of the aforementioned pharmaceutical compositions in the preparation of drugs for treating and / or preventing diseases or conditions selected from proliferative diseases, inflammatory diseases, autoinflammatory diseases, autoimmune diseases and infectious diseases.

[0135] In alternative embodiments, the disease or disorder is a proliferative disease.

[0136] In alternative embodiments, the proliferative disease is cancer.

[0137] In alternative embodiments, the cancer is selected from the group consisting of hematological tumors and solid tumors.

[0138] In an optional embodiment, the blood tumor is selected from leukemia, specifically including: chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), T-cell acute lymphocytic leukemia (T-ALL), chronic myeloid leukemia (CML), acute myeloid leukemia (AML), etc.).

[0139] In an alternative embodiment, the solid tumor is selected from breast cancer, intestinal cancer, lung cancer, pancreatic cancer, prostate cancer, Ewing's sarcoma, osteoma, neuroblastoma, cervical cancer, ovarian cancer, gastric cancer and liver cancer.

[0140] In an alternative embodiment, the breast cancer is triple-negative breast cancer.

[0141] In an alternative embodiment, the breast cancer is ER / PR+HER2- breast cancer.

[0142] In an alternative embodiment, the breast cancer is ER / PR+HER2- breast cancer that is resistant to CDK4 / 6 inhibitors.

[0143] In an alternative embodiment, the CDK4 / 6 inhibitor is Palbociclib.

[0144] In an alternative embodiment, the lung cancer is non-small cell lung cancer.

[0145] In an alternative embodiment, the lung cancer is small cell lung cancer.

[0146] In an alternative embodiment, the intestinal cancer is colon cancer.

[0147] In an alternative embodiment, the intestinal cancer is rectal cancer.

[0148] Another aspect of the present disclosure provides a method for treating and / or preventing a disease or condition associated with abnormal activity of serine / threonine kinase in a patient, comprising administering to the patient a therapeutically effective amount of a compound represented by Formula (I'), (I), (I'-A), (II), (III-1), (III-2), (III-3), (III-4) or a pharmaceutically acceptable salt thereof, and a compound of Table A, isotopic substitutions, and the aforementioned pharmaceutical compositions.

[0149] Another aspect of the present disclosure provides a method for treating and / or preventing a disease or condition associated with abnormal CDK7 activity in a patient, comprising administering to the patient a therapeutically effective amount of a compound represented by Formula (I'), (I), (I'-A), (II), (III-1), (III-2), (III-3), (III-4) or a pharmaceutically acceptable salt thereof, and a compound of Table a, isotopic substitutions, and the aforementioned pharmaceutical compositions.

[0150] In an alternative embodiment, the disease or disorder associated with abnormal activity of CDK7 is selected from the group consisting of a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, and an infectious disease.

[0151] Another aspect of the present disclosure provides a method for treating and / or preventing a disease or condition in a patient, comprising administering to the patient a therapeutically effective amount of a compound represented by Formula (I'), (I), (I'-A), (II), (III-1), (III-2), (III-3), (III-4) or a pharmaceutically acceptable salt thereof, and a compound of Table a, an isotopic substitute, and the aforementioned pharmaceutical composition, wherein the disease or condition is selected from a proliferative disease, an inflammatory disease, an autoinflammatory disease, an autoimmune disease, and an infectious disease; in an optional embodiment, the disease or condition is a proliferative disease.

[0152] In alternative embodiments, the proliferative disease is cancer.

[0153] In alternative embodiments, the cancer is selected from the group consisting of hematological tumors and solid tumors.

[0154] In an optional embodiment, the blood tumor is selected from leukemia, specifically including: chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), T-cell acute lymphocytic leukemia (T-ALL), chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), etc.).

[0155] In an alternative embodiment, the solid tumor is selected from breast cancer, intestinal cancer, lung cancer, pancreatic cancer, prostate cancer, Ewing's sarcoma, osteoma, neuroblastoma, cervical cancer, ovarian cancer, gastric cancer and liver cancer.

[0156] In an alternative embodiment, the breast cancer is triple-negative breast cancer.

[0157] In an alternative embodiment, the breast cancer is ER / PR+HER2- breast cancer.

[0158] In an alternative embodiment, the breast cancer is ER / PR+HER2- breast cancer that is resistant to CDK4 / 6 inhibitors.

[0159] In an alternative embodiment, the CDK4 / 6 inhibitor is Palbociclib.

[0160] In an alternative embodiment, the lung cancer is non-small cell lung cancer.

[0161] In an alternative embodiment, the lung cancer is small cell lung cancer.

[0162] In an alternative embodiment, the intestinal cancer is colon cancer.

[0163] In an alternative embodiment, the intestinal cancer is rectal cancer.

[0164] Another aspect of the present disclosure provides a compound represented by Formula (I'), (I), (I'-A), (II), (III-1), (III-2), (III-3), (III-4) or a pharmaceutically acceptable salt thereof and a compound of Table A, and isotope substitutions thereof, for use as a medicine.

[0165] Another aspect of the present disclosure provides a compound represented by Formula (I'), (I), (I'-A), (II), (III-1), (III-2), (III-3), (III-4) or a pharmaceutically acceptable salt thereof and a compound of Table A, and use of isotope-substituted compounds in the preparation of antibody-drug conjugates or protein-targeted degradation chimeras.

[0166] Another aspect of the present disclosure provides an antibody-drug conjugate comprising a compound represented by Formula (I'), (I), (I'-A), (II), (III-1), (III-2), (III-3), (III-4) or a pharmaceutically acceptable salt thereof, and a compound of Table A, and isotopic substitutions.

[0167] On the other hand, the present disclosure provides a protein-targeted degradation chimera, which comprises a compound represented by Formula (I'), (I), (I'-A), (II), (III-1), (III-2), (III-3), (III-4) or a pharmaceutically acceptable salt thereof and a compound of Table a, and an isotope-substituted product.

[0168] The present disclosure further provides a method for preparing the compound represented by the aforementioned formula (I'), (I), (I'-A) or a pharmaceutically acceptable salt thereof,

[0169] The method comprises the steps of reacting a compound represented by formula (IA) or a pharmaceutically acceptable salt thereof with a compound represented by formula (IB) or a pharmaceutically acceptable salt thereof in an alkaline environment, catalyzed by a catalyst selected from carbonyldiimidazole, phosgene and triphosgene;

[0170] Among them, L2 is NH;

[0171] R 1 ,m,L1,R 2 、R 3 、R 4 、R 5 、R 6 、R 7 , Ring A, R 8 、n、R 9 , L3, R 10 and R 11 As defined in the compound represented by formula (I'), (I), (I'-A) or a pharmaceutically acceptable salt thereof.

[0172] In an optional embodiment, the condensation reaction occurs in an alkaline environment, which is provided by an inorganic base (sodium hydroxide) or an organic base (such as triethylamine, pyridine, piperidine or N,N-diisopropylethylamine), and the solvent in which the reaction occurs is a common solvent (such as DMF, DCM or DMSO).

[0173] The present disclosure further provides a compound represented by formula (IA) or a pharmaceutically acceptable salt thereof,

[0174] Among them, R 1 ,m,L1,R 2 、R 3 、R 4 、R 5 、R 6 、R 7 They are defined as the compounds represented by formula (I'), (I), (I'-A) or their pharmaceutically acceptable salts.

[0175] The pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts. The compounds described in the present disclosure can react with acidic or basic substances to form corresponding salts.

[0176] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0177] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0178] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations.

[0179] Compounds and intermediates of the present disclosure can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. The lactam-lactim equilibrium example is between A and B as shown below.

[0180] All compounds in this disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of this disclosure. The naming of the compounds does not exclude any tautomers.

[0181] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0182] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times the abundance of deuterium greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has a natural abundance greater than deuterium that can be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more abundant deuterium. The disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0183] Explanation of terms:

[0184] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0185] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or domestic animals.

[0186] As used herein, an "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0187] The prefix "C u-v " indicates that the following group has from u to v carbon atoms. For example, "C 1-6 The term "alkyl" refers to an alkyl group having 1 to 6 carbon atoms, and specifically may be an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0188] The term "alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1- 6 alkyl), or 1 to 4 carbon atoms (i.e., C 1-4 Alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by chemical name or determined by molecular formula, all isomers having that number of carbon atoms are included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0189] The term "alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond, having from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), 2 to 6 carbon atoms (i.e., C 2-6 alkenyl), or 2 to 4 carbon atoms (ie, C 2-4 Examples of the alkenyl group include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0190] The term "alkynyl" refers to an alkyl group having at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2-20 Alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 Alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 Alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 Examples of “alkynyl” include ethynyl, propynyl (e.g., 1-propynyl, 2-propynyl), 3-butynyl, pentynyl, hexynyl, and 1-methylpent-2-ynyl.

[0191] The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated cyclic alkyl group having a monocyclic or polycyclic ring (including fused, bridged, and spirocyclic ring systems). The term "cycloalkyl" includes cycloalkenyl groups (i.e., the cyclic group has at least one double bond). As used herein, a cycloalkyl group has 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 7 ring carbon atoms (i.e., C 3-7 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 Cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, cyclohexenyl, and cyclohexadienyl. The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.

[0192] The term "heterocyclyl" or "heterocycloalkyl" refers to a saturated or unsaturated cycloalkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, sulfur and phosphorus. The term "heterocycloalkyl" includes heterocycloalkenyl (i.e., a heterocyclyl group having at least one double bond), bridged-heterocyclyl, fused heterocyclyl and spiro-heterocyclyl. A heterocyclyl group can be monocyclic or polycyclic, wherein the polycyclic rings can be fused, bridged or spirocyclic. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl group, regardless of connection (i.e., it can be bound by carbon atoms or heteroatoms). In addition, the term heterocyclyl is intended to include any non-aromatic ring containing at least one heteroatom, which ring can be fused to an aryl or heteroaryl ring, regardless of connection to the rest of the molecule. As used herein, the heterocyclyl group has 3 to 20 ring atoms (i.e., 3- to 20-membered heterocyclyl), 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclyl), 3 to 10 ring atoms (i.e., 3- to 10-membered heterocyclyl), 3 to 8 ring atoms (i.e., 3- to 8-membered heterocyclyl), 3 to 7 ring atoms (i.e., 3- to 7-membered heterocyclyl), 3 to 6 ring atoms (i.e., 3- to 6-membered heterocyclyl); 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, the ring heteroatoms being independently selected from nitrogen, sulfur, phosphorus, or oxygen. Examples of heterocyclic groups include pyrrolidinyl, imidazolidinyl, oxetanyl, dioxolanyl, azetidinyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.

[0193] Non-limiting examples of "heterocyclyl" include: wait.

[0194] The heterocyclyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0195] wait.

[0196] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0197] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, etc.

[0198] The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0199] The term "alkoxy" refers to the group "alkyl-O-," wherein alkyl is as defined above. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0200] The term "haloalkyl" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms are replaced by a halogen. For example, when a residue is substituted with more than one halogen, it may be referred to using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two or three halogen groups, which may be, but not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0201] The term "haloalkoxy" refers to an alkoxy group as defined above wherein one or more hydrogen atoms are replaced by a halogen.

[0202] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0203] The term "hydroxy" refers to an -OH group.

[0204] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0205] The term "cyano" refers to -CN.

[0206] The term "nitro" refers to -NO2.

[0207] The term "oxo" refers to a =0 substituent.

[0208] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort.

[0209] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1- The term "alkyl" means that halogen or cyano may but need not be present, and the description includes the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano. DETAILED DESCRIPTION

[0210] The present disclosure is further described below with reference to the following embodiments, but these embodiments are not intended to limit the scope of the present disclosure.

[0211] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer or a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6) or deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0212] MS was measured using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS liquid chromatography-mass spectrometer (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a Waters ACQuity UPLC-QD / SQD (manufacturer: Waters, MS model: Waters ACQuity Qda Detector / Waters SQ Detector), and a THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0213] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high performance liquid chromatographs.

[0214] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0215] High performance liquid chromatography (HPLC) was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson GX-281 preparative chromatographs.

[0216] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0217] The CombiFlash rapid preparation instrument used was Combiflash Rf200 (TELEDYNE ISCO).

[0218] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0219] Silica gel column chromatography generally uses Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0220] Average kinase inhibition rate and IC 50 The values ​​were determined using a NovoStar microplate reader (BMG, Germany).

[0221] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, J&K, Accela ChemBio Inc, Shanghai Bid Pharmaceutical, Darui Chemicals, and other companies.

[0222] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0223] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0224] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0225] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0226] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0227] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0228] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the column chromatography eluent system used for purifying the compound, and the developing solvent system for thin layer chromatography included: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, and D: petroleum ether / ethyl acetate / methanol. The volume ratio of the solvent was adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0229] The abbreviations used in the following experiments have the following meanings:

[0230] TFA: trifluoroacetic acid; DCM: dichloromethane; m-CPBA: m-chloroperbenzoic acid; EtONa: sodium ethoxide; Boc: tert-butyloxycarbonyl; MeOH: methanol; HBTU: benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate; TsOH: p-toluenesulfonic acid; EtOAc: ethyl acetate; t-BuOH: tert-butyl alcohol; PdCl2(TPP) 2: Dichlorobis(triphenylphosphine)palladium; XantPhos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene; Pd2dba3: trisdibenzylideneacetone dipalladium; PdCl2(TPP) 2: Dichlorobis(triphenylphosphine)palladium; XantPhos: 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene; Pd2dba3: trisdibenzylideneacetone dipalladium; DMF: N,N-dimethylformamide; CDI: N,N-carbonyldiimidazole; ACN: acetonitrile; DMP: 1,1,1-triacetoxy)-1,1-dihydro-1,2-benzidoxyl-3(1H)-one (Dess-Martin periodinane); DMAP: 4-dimethylaminopyridine.

[0231] Example 1

[0232] (R)-N-((S)-2-(Dimethylamino)-1-phenylethyl)-6-methyl-2-(((4-methylthiazol-2-yl)methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0233] first step

[0234] Ethyl 4-(((R)-1-phenylethyl)amino)pentanoate (1c)

[0235] At room temperature, compound 1a (50.0 g, 412.6 mmol) and compound 1b (67.3 mL, 474.5 mmol) were dissolved in DCM (500 mL). NaBH(OAc)₃ (174 g, 825 mmol) was slowly added portionwise and stirred overnight at room temperature. The reaction mixture was extracted with DCM / MeOH (9:1, 500 × 2 mL) and washed with saturated brine. The organic phase was dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to afford crude compound 1c (80 g, 249 mmol).

[0236] MS m / z(ESI):250.3[M+H] + .

[0237] Step 2

[0238] Ethyl 4-((2-ethoxy-2-oxoethyl)((R)-1-phenylethyl)amino)pentanoate (1e)

[0239] Compound 1c (80.0 g, 249 mmol) and compound 1d (31.7 mL, 320.8 mmol) were dissolved in DCM (1 L) at room temperature. NaBH(OAc)₃ (203 g, 962 mmol) was slowly added portionwise and stirred at room temperature for 2 days. The reaction solution was extracted with DCM / MeOH (9:1, 500 mL x 2) and washed with saturated brine. The organic phase was dried over Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography on silica gel with 1-10% ethyl acetate in petroleum ether as the eluent to obtain compound 1e (40 g, 249 mmol).

[0240] MS m / z(ESI):336.3[M+H] + .

[0241] Step 3

[0242] 5-Hydroxy-2-methyl-1-((R)-1-phenylethyl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid ethyl ester (1f)

[0243] Compound 1e (crude product, 130.0 g) was dissolved in toluene (1.2 L), and potassium tert-butoxide (87.0 g, 776.8 mmol) was added portionwise. The reaction mixture was allowed to react at room temperature for 1.5 h. The reaction mixture was poured into saturated ammonium chloride solution, and the pH was adjusted to approximately 8. The layers were separated, and the aqueous phase was extracted with dichloromethane (500 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 30:1) to obtain compound 1f (33.0 g, 119.9 mmol).

[0244] Step 4

[0245] (R)-6-Methyl-7-((R)-1-phenylethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diol (1 g)

[0246] Compound 1f (108.0 g, 392.7 mmol) was dissolved in methanol (1 L), and urea (89.7 g, 1492.8 mmol) and a 30% methanolic sodium methoxide solution (201.6 g, 1119.6 mmol) were added. The mixture was heated to 70°C and allowed to react for 18 h. The reaction was stopped and concentrated to dryness under reduced pressure. The pH of the reaction mixture was adjusted to approximately 8.0 with 3M hydrochloric acid. The mixture was extracted with DCM (1 L x 3). A large amount of white solid precipitated from the organic phase. The filter cake was filtered to obtain compound 1g. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (DCM:MeOH = 10:1) to obtain compound 1g. The resulting product was combined to yield 77.0 g of compound 1g, with a yield of 72.3%.

[0247] Step 5

[0248] (R)-6-Methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diol (1h)

[0249] Dissolve compound 1g (60.0g, 210.4mmol) in methanol (900mL) and add palladium / carbon (12.0g). Replace the atmosphere with hydrogen three times. Allow to react at room temperature overnight. Filter and concentrate under reduced pressure to obtain compound 1h (crude, 43.0g).

[0250] Step 6

[0251] (R)-2,4-Dichloro-6-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (1i)

[0252] Compound 1h (crude product, 43.0 g) was suspended in phosphorus oxychloride (43 mL), heated to 100°C, and reacted overnight. The mixture was concentrated under reduced pressure, and the resulting crude product was dissolved in ice water (300 mL). The mixture was extracted with DCM (50 mL), and the aqueous phase was retained and directly used in the next step.

[0253] Step 7

[0254] (R)-tert-Butyl 2,4-dichloro-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1j)

[0255] The pH of the aqueous phase containing compound 1i from step 6 was adjusted to 8-9 with NEt3, and di-tert-butyl carbonate (77.7 g, 444.8 mmol) was added. The mixture was allowed to react at room temperature for 2 h. Extraction was performed with DCM (500 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on a neutral alumina column (PE:EA = 10:1) to obtain compound 1j (38.0 g, 119.6 mmol).

[0256] Step 8

[0257] (R)-tert-Butyl 2-chloro-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1k)

[0258] Compound 1j (10.0 g, 31.5 mmol) was dissolved in ethanol (100 mL), and zinc powder (20.6 g) and glacial acetic acid (18.9 g, 314.7 mmol) were added. The mixture was heated to 80°C and allowed to react for 1.5 h. The mixture was filtered, and the filtrate was adjusted to pH 8-9 with NEt3 and concentrated under reduced pressure. The resulting residue was added with water (50 mL), extracted with DCM (100 mL x 3), and concentrated under reduced pressure to afford the crude product. The crude product was purified by reverse-phase column chromatography (CH3CN / H2O) to afford compound 1k (4.5 g, 15.9 mmol, 50.4% yield).

[0259] Step 9

[0260] (R)-tert-Butyl 6-methyl-2-(((4-methylthiazol-2-yl)methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (1m)

[0261] Compound 1l (50 mg, 0.39 mmol) was dissolved in 1,4-dioxane (5 mL), followed by the addition of compound 1k (115 mg, 0.4 mmol), CsCO (390 mg, 1.2 mmol), and dichloro[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) (31 mg, 0.04 mmol). The mixture was stirred at 110°C for 16 h. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (PE:EA = 5:1) to afford compound 1m (80 mg, 0.21 mmol, 53% yield).

[0262] MS m / z(ESI):376.5.

[0263] Step 10

[0264] (R)-6-Methyl-N-((4-methylthiazol-2-yl)methyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-amine (1n)

[0265] Compound 1m (80 mg, 0.21 mmol) was added to a 50 mL flask, followed by 4 mL of a mixed solvent (DCM:TFA = 2:1). After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product 1n (80 mg, crude product).

[0266] MS m / z(ESI):276.4.

[0267] Step 11 (R)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-2-(((4-methylthiazol-2-yl)methyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide (1)

[0268] Compound 1o (54 mg, 0.32 mmol) was dissolved in DMF (2.0 mL), followed by the addition of CDI (104 mg, 0.64 mmol) and NEt3 (63 mg, 0.63 mmol), and the mixture was stirred at room temperature for 0.1 h. In (80 mg, crude) was then added, and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate (10 mL x 3), and the organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to yield the crude product, which was then purified by HPLC to afford compound 1 (6.6 mg, 15% yield).

[0269] MS m / z(ESI):466.8.

[0270] 1 H NMR (400MHz, CD3OD) δ8.13(s,1H),7.42–7.29(m,5H),6.97(d,J=1.2Hz,1H),5.36–5.31(m,1H),4.86–4.73(m,4H),4.16(d,J=1 8.4Hz,1H),3.49–3.40(m,1H),3.27–3.20(m,1H),2.92–2.80(m,7H),2.55(d,J=15.6,1H),2.38(s,3H),1.05(d,J=6.8Hz,3H).

[0271] Example 2

[0272] (R)-N-((S)-2-(Dimethylamino)-1-phenylethyl)-6-methyl-2-(((S)-1-(4-methylthiazol-2-yl)ethyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0273] (R)-N-((S)-2-(Dimethylamino)-1-phenylethyl)-6-methyl-2-(((R)-1-(4-methylthiazol-2-yl)ethyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0274] Referring to the preparation method of compound 1, compound 2 (85 mg, 0.19 mmol) was obtained from compound 2a (125 mg, 0.88 mmol) through three steps.

[0275] MS m / z(ESI):480.2.

[0276] Compound 2 was separated by chiral column (chromatographic column: ChiralPak IG-3 100×4.6 mm ID, 3 μm; mobile phase: A: 50% supercritical CO2 fluid, B: 50% ethanol (0.05% DEA) to obtain compounds 2-1 and 2-2.

[0277] Compound 2-1 (retention time 3.364 minutes)

[0278] MS m / z(ESI):480.2.

[0279] 1 H NMR (400MHz, CD3OD) δ8.10(s,1H),7.39–7.17(m,5H),6.92(d,J=1.3Hz,1H),5.40(q,J=7.0Hz,1H),5.04(dd,J=10.8,4.3Hz,1H),4.83–4.59(m,2H), 4.13(d,J=18.4Hz,1H),2.95–2.78(m,2H),2.58–2.41(m,2H),2.38(d,J=1.0Hz,3H),2.34(s,6H),1.63(d,J=7.0Hz,3H),1.03(d,J=6.7Hz,3H).

[0280] Compound 2-2 (retention time 5.417 minutes)

[0281] MS m / z(ESI):480.2.

[0282] 1H NMR(400MHz,CD3OD)δ8.09(s,1H),7.44–7.18(m,5H),6.93(d,J=1.2Hz,1H),5.39(q,J =7.0Hz,1H),5.12(dd,J=11.0,4.2Hz,1H),4.81–4.67(m,2H),4.10(d,J=18.3Hz,1H),3 .04(dd,J=12.9,11.0Hz,1H),2.88(dd,J=15.6,5.7Hz,1H),2.67(dd,J=13.0,4.3Hz,1H ), 2.54 (s, 1H), 2.48 (s, 6H), 2.39 (s, 3H), 1.63 (d, J = 7.0Hz, 3H), 1.02 (d, J = 6.8Hz, 3H).

[0283] Example 3

[0284] (R)-N-((S)-2-(bis(methyl-d3)amino)-1-phenylethyl)-6-methyl-2-(((S)-1-(4-methylthiazol-2-yl)ethyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0285] (R)-N-((S)-2-(bis(methyl-d3)amino)-1-phenylethyl)-6-methyl-2-(((R)-1-(4-methylthiazol-2-yl)ethyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0286] first step

[0287] (S)-(2-(Bis(methyl-d3)amino)-2-oxo-1-phenylethylcarboxylic acid benzyl ester (3c)

[0288] Compound 3a (500 mg, 1.753 mmol) and HBTU (1329 mg, 3.5 mmol) were dissolved in DCM (7 mL) at room temperature and stirred for 5 minutes. KCO (726 mg, 5.26 mmol) and compound 3b (134.4 mg, 2.63 mmol) were then added. The reaction was stirred at room temperature for 12 hours. The reaction solution was extracted, concentrated, and dried to obtain a crude product. The crude product was purified by column chromatography to obtain compound 3c (900 mg, 2.83 mmol).

[0289] MS m / z(ESI):319.2[M+H] + .

[0290] Step 2

[0291] (S)-2-Amino-N,N-bis(methyl-d3)-2-phenylacetamide (3d)

[0292] Under a hydrogen atmosphere, 10% palladium (Pd / C) was added to a solution of compound 3c (900 mg, 2.83 mmol) in ethyl acetate (15 mL). The mixture was stirred at room temperature for 2 hours. The reaction solution was filtered and concentrated to give the crude product 3d (260 mg). This crude product was used directly in the next reaction (260 mg).

[0293] MS m / z(ESI):185.1[M+H] + .

[0294] Step 3

[0295] (S)-N1,N1-Bis(methyl-d3)-2-phenylethyl-1,2-diamine (3e)

[0296] Under a nitrogen atmosphere, LiAlH4 (82.0 mg, 2.17 mmol) was added to anhydrous THF (5.0 mL). After cooling to -78°C, a THF solution of compound 3d was added dropwise and stirred for 30 minutes. The reaction solution was then warmed to 50°C and allowed to react for 2 hours before being quenched by the addition of ammonium chloride solution. The crude product was extracted, concentrated, and dried to afford the crude product. This crude product was purified by preparative HPLC to afford compound 3e (40.0 mg, 21% yield).

[0297] MS m / z(ESI):171.1[M+H] + .

[0298] Step 4

[0299] (R)-N-((S)-2-(bis(methyl-d3)amino)-1-phenylethyl)-6-methyl-2-((1-(4-methylthiazol-2-yl)ethyl)amino)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide (3)

[0300] Compound 3 (52 mg, 0.11 mmol) was synthesized by replacing compound 1a with compound 3e according to the preparation method of compound 1.

[0301] MS m / z(ESI):486.3.

[0302] Step 5

[0303] Preparation of compounds 3-1 and 3-2

[0304] Compound 3 was separated by chiral column (chromatographic column: ChiralPak IG-3 100×4.6 mm ID, 3 μm; mobile phase: A: 50% supercritical CO2 fluid, B: 50% ethanol (0.05% DEA) to give compounds 3-1 and 3-2.

[0305] Compound 3-1 (retention time 3.288 minutes)

[0306] MS m / z(ESI):486.2.

[0307] 1 H NMR (400MHz, CD3OD) δ8.10(s,1H),7.47–7.11(m,5H),6.92(d,J=1.1Hz,1H),5.40(q,J=7.0Hz,1H),5.04(dd,J=10.8,4.3Hz,1H),4.82 –4.63(m,2H),4.13(d,J=18.4Hz,1H),2.99–2.80(m,2H),2.62–2.45(m,2H),2.38(s,3H),1.63(d,J=7.0Hz,3H),1.03(d,J=6.7Hz,3H).

[0308] Compound 3-2 (retention time 5.344 minutes)

[0309] MS m / z(ESI):486.2.

[0310] 1 H NMR(400MHz,CD3OD)δ8.09(s,1H),7.46–7.20(m,5H),6.93(d,J=1.1Hz,1H),5.45–5.33(m,1H),5.06(dd,J=10.8,4.3Hz,1H),4.82–4 .70(m,2H),4.09(d,J=18.4Hz,1H),2.98–2.84(m,2H),2.60–2.46(m,2H),2.39(s,3H),1.63(d,J=7.0Hz,3H),1.02(d,J=6.7Hz,3H).

[0311] Example 4

[0312] (R)-2-(((S)-1-(4-cyclopropylthiazol-2-yl)ethyl)amino)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0313] first step

[0314] (S,E)-N-((4-bromothiazol-2-yl)methylene)-2-methylpropane-2-sulfenamide (4c)

[0315] Compound 4a (3.0 g, 15.6 mmol) was dissolved in DCM (30 mL), and compound 4b (1.89 g, 15.6 mmol) and CuSO₄ (4.99 g, 31.2 mmol) were added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to afford crude compound 4c (4.5 g), which was used directly in the next reaction.

[0316] MS m / z(ESI):295.0[M+H] + .

[0317] Step 2

[0318] (S)-N-((S)-1-(4-Bromothiazol-2-yl)ethyl)-2-methylpropane-2-xanthinamide (4d)

[0319] To a solution of compound 4c (4.5 g, crude) in DCM (50 mL) under a nitrogen atmosphere at -50°C was added a 3.0 M solution of methylmagnesium bromide in THF (15.2 mL, 45.7 mmol). The mixture was stirred at -50°C for 4 h, then warmed to room temperature and stirred for 18 h. The reaction mixture was quenched with 20 mL of saturated NH4Cl solution, added with water (300 mL), and extracted with DCM (100 mL x 3). The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography on silica gel using 0-60% ethyl acetate in petroleum ether as the eluent to afford compound 4d (2.5 g, 8.0 mmol, 52.7% yield).

[0320] MS m / z(ESI):311.0[M+H] + .

[0321] Step 3

[0322] (S)-N-((S)-1-(4-cyclopropylthiazol-2-yl)ethyl)-2-methylpropane-2-xanthinamide (4f)

[0323] To a mixed solution of compound 4d (500 mg, 1.6 mmol) in toluene (5.0 mL) and water (0.5 mL) were added compound 4e (475.3 mg, 3.2 mmol), Pd(OAc)2 (36.1 mg, 0.16 mmol), CataCXium A (86.39 mg, 0.241 mmol), and Cs2CO3 (1570.1 mg, 4.82 mmol). Under a nitrogen atmosphere, the reaction solution was heated to 100°C and stirred for 16 h. Water (300 mL) and EtOAc (100 mL x 3) were added to the reaction solution, and the organic phase was dried over Na2SO4, filtered, and the filtrate concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography on silica gel with 0-60% MeOH in DCM as the eluent to afford compound 4f (330 mg, 1.21 mmol, 75.4% yield).

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

[0325] 1 H NMR (400MHz, DMSO-d6) δ7.14 (s, 1H), 6.14 (d, J = 7.1Hz, 1H), 4.63-4.54 (m, 1H), 2.05-1 .99(m,1H),1.50(d,J=6.8Hz,3H),1.13(s,9H),0.90-0.83(m,2H),0.85-0.74(m,2H).

[0326] Step 4

[0327] (S)-1-(4-Cyclopropylthiazol-2-yl)ethan-1-amine (4 g)

[0328] To a solution of compound 4f (330 mg, 1.21 mmol) in methanol was added HCl (4.0 M solution in dioxane, 3.028 mL, 12.113 mmol) at room temperature. The mixture was stirred for 1 h and then concentrated under reduced pressure. The residue was added with acetonitrile (10 mL) and water (10 mL), concentrated under reduced pressure to remove the acetonitrile, and lyophilized to afford compound 4g (280 mg, 1.16 mmol, 95.8% yield).

[0329] MS m / z(ESI):169.1[M+H] + .

[0330] 1H NMR(400MHz,DMSO-d6)δ8.77(s,3H),7.33(s,1H),4.74-4.68(m,1H),2.11 -2.07(m,1H),1.58(d,J=6.8Hz,3H),0.93-0.88(m,2H),0.84-0.80(m,2H).

[0331] The synthesis of compound 4 (7.7 mg, 0.015 mmol) was prepared by three steps from compound 4g, referring to the synthesis method of compound 1.

[0332] MS m / z(ESI):506.9.

[0333] 1 H NMR(400MHz,CD3OD)δ8.10(s,1H),7.52–7.14(m,5H),6.84(s,1H),5.39–5.34(m,1H) ),5.21(dd,J=11.2,4.1Hz,1H),4.84–4.64(m,2H),4.14(d,J=18.3Hz,1H),3.26–3.0 6(m,1H),2.92–2.83(m,2H),2.62(s,6H),2.52(d,J=15.6Hz,1H),2.06–1.99(m,1H) ,1.61(d,J=7.0Hz,3H),1.03(d,J=6.8Hz,3H),0.96–0.89(m,2H),0.87–0.72(m,2H).

[0334] Example 5

[0335] (R)-2-(((R)-1-(4-cyclopropylthiazol-2-yl)ethyl)amino)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0336] Referring to the synthesis method of compound 4, compound 5 (11.6 mg, 0.023 mmol) was prepared from starting material 5a (2 g, 10.4 mmol) through 7 steps.

[0337] MS m / z(ESI):506.5.

[0338] 1H NMR(400MHz,CD3OD)δ8.10(d,J=2.0Hz,1H),7.52–7.25(m,5H),6.85(d,J=1.3Hz,1H),5. 45–5.26(m,2H),4.85–4.71(m,2H),4.11(d,J=18.1Hz,1H),3.77–3.50(m,1H),3.39–3.35 (m,1H),2.94(s,6H),2.88(dd,J=16.3,5.4Hz,1H),2.53(d,J=15.5Hz,1H),2.10–1.95(m ,1H),1.61(d,J=7.0Hz,3H),1.04(d,J=6.6Hz,3H),0.93–0.89(m,2H),0.86–0.74(m,2H).

[0339] Example 6

[0340] (R)-2-(((4-cyclopropylthiazol-2-yl)methyl)amino)-N-((S)-2-(dimethylamino)-1-phenylethyl)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0341] Compound 6 (1.1 mg, 0.002 mmol) was synthesized according to the preparation method of compound 1.

[0342] MS m / z(ESI):492.5.

[0343] 1 H NMR (400MHz, CD3OD) δ8.13(s,1H),7.48–7.20(m,5H),6.89(s,1H),5.31(dd,J=11.4,4.2Hz,1H),4.82–4.66(m,4H),4. 16(d,J=18.3Hz,1H),3.43–3.37(m,1H),3.18(dd,J=13.1,4.1Hz,1H),2.89(dd,J=15.7,5.6Hz,1H),2.81(s,6H),2.55 (d,J=15.6Hz,1H),2.06–2.00(m,1H),1.05(d,J=6.8Hz,3H),0.96–0.86(m,2H),0.86–0.72(m,2H).

[0344] Example 7

[0345] (R)-2-(((4-cyclopropylthiazol-2-yl)methyl)amino)-N-((S)-2-(hexadeuteratedimethylamino)-1-phenylethyl)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0346] Compound 1a was replaced by compound 3e, and compound 7 (5.7 mg, 0.012 mmol) was synthesized by referring to the preparation method of compound 1.

[0347] MS m / z(ESI):472.9.

[0348] 1 H NMR (400MHz, CD3OD) δ8.12(d,J=4.7Hz,1H),7.45–7.26(m,5H),6.97–6.89(m,1H),5.36(dd,J=11.7,4.1Hz,1H),4.84–4.72(m,4H),4.15(dd,J=1 8.5,4.2Hz,1H),3.54–3.42(m,1H),3.36–3.17(m,2H),2.96–2.73(m,1H) ,2.53(dt,J=15.7,3.1Hz,1H),2.38(s,3H),1.04(dd,J=7.1,2.9Hz,3H).

[0349] Example 8

[0350] (R)-2-(((4-cyclopropylthiazol-2-yl)methyl)amino)-N-((S)-2-(hexadeuteratedimethylamino)-1-phenylethyl)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0351] Compound 8 (2.3 mg, 0.005 mmol) was synthesized by replacing compound 1a with compound 3e and referring to the preparation method of compound 1.

[0352] MS m / z(ESI):498.5.

[0353] 1H NMR(400MHz,CD3OD)δ8.13(s,1H),7.49–7.19(m,5H),6.90(s,1H),5.33–5. 26(m,1H),4.82–4.73(m,4H),4.16(d,J=18.3Hz,1H),3.84–3.31(m,1H),3. 20–3.07(m,1H),2.89(dd,J=15.6,5.6Hz,1H),2.55(d,J=15.6Hz,1H),2.07 –1.99(m,1H),1.05(d,J=6.8Hz,3H),0.96–0.88(m,2H),0.84–0.77(m,2H).

[0354] Example 9

[0355] (R)-2-(((S)-1-(4-cyclopropylthiazol-2-yl)ethyl)amino)-N-((S)-2-(hexadeuteratedimethylamino)-1-phenylethyl)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0356] Compound 9 (11.3 mg, 0.022 mmol) was synthesized by replacing compound 1a with compound 3e and referring to the preparation method of compound 4.

[0357] MS m / z(ESI):512.5.

[0358] 1 H NMR(400MHz,CD3OD)δ8.11(s,1H),7.43–7.24(m,5H),6.84(s,1H),5.39–5.35(m,1H),5. 28(dd,J=11.5,4.1Hz,1H),4.82–4.64(m,2H),4.15(d,J=18.2Hz,1H),3.38–3.33(m,1H) ,3.13–3.09(m,1H),2.88(dd,J=15.6,5.6Hz,1H),2.55(d,J=15.6Hz,1H),2.06–1.99(m, 1H), 1.61 (d, J = 7.0Hz, 3H), 1.04 (d, J = 6.8Hz, 3H), 0.95–0.89 (m, 2H), 0.84–0.77 (m, 2H).

[0359] Example 10

[0360] (R)-2-(((R)-1-(4-cyclopropylthiazol-2-yl)ethyl)amino)-N-((S)-2-(hexadeuteratedimethylamino)-1-phenylethyl)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0361] Compound 10 (1.4 mg, 0.003 mmol) was synthesized by replacing compound 1a with compound 3e and referring to the preparation method of compound 4.

[0362] MS m / z(ESI):512.9.

[0363] 1 H NMR(400MHz,CD3OD)δ8.10(s,1H),7.52–7.21(m,5H),6.85(s,1H),5.46–5.21(m,2H) ,4.81–4.66(m,2H),4.11(d,J=18.2Hz,1H),3.45–3.37(m,1H),3.23–3.17(dd,J=13. 0,4.2Hz,1H),2.88(dd,J=15.6,5.6Hz,1H),2.53(d,J=15.6Hz,1H),2.08–1.99(m,1H ), 1.61 (d, J = 7.0Hz, 3H), 1.03 (d, J = 6.8Hz, 3H), 0.96–0.85 (m, 2H), 0.85–0.76 (m, 2H).

[0364] Example 11

[0365] (R)-N-((S)-2-(Dimethylamino)-1-phenylethyl)-2-(((S)-1-(4-(hydroxymethyl)thiazol-2-yl)ethyl)amino)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0366] (R)-N-((S)-2-(Dimethylamino)-1-phenylethyl)-2-(((R)-1-(4-(hydroxymethyl)thiazol-2-yl)ethyl)amino)-6-methyl-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide

[0367] Compound 11 (19 mg, 0.038 mmol) was synthesized by referring to the preparation method of compound 2.

[0368] Compound 11 was separated by chiral column (chromatographic column: ChiralPak IG 250×30mm ID, 5μm; mobile phase: A: 55% supercritical CO2 fluid, B: 45% methanol [0.1% NH3 (7M)]) to give compounds 11-1 and 11-2.

[0369] Compound 11-1 (retention time 4.848 minutes)

[0370] MS m / z(ESI):496.2.

[0371] 1 H NMR (400MHz, DMSO-d6) δ8.12(s,1H),7.74(d,J=7.9Hz,1H),7.35–7.26(m,4H),7.19(s,2H),6.78(d,J=7. 6Hz,1H),5.34–5.29(m,1H),5.25(t,J=5.8Hz,1H),4.87(q,J=7.8Hz,1H),4.69–4.59(m,2H),4.51(dd,J=5 .7,1.1Hz,2H),3.93(d,J=18.7Hz,1H),2.77(dd,J=15.6,5.6Hz,1H),2.62(dd,J=12.3,9.4Hz,1H),2.43( d,J=15.3Hz,1H),2.34(dd,J=12.4,5.8Hz,1H),2.17(s,6H),1.55(d,J=7.0Hz,3H),0.94(d,J=6.6Hz,3H).

[0372] Compound 2-2 (retention time 5.503 minutes)

[0373] MS m / z(ESI):496.2.

[0374] 1H NMR(400MHz, DMSO-d6)δ8.13(s,1H),7.74(d,J=7.9Hz,1H),7.35–7.25(m,4H),7.22–7.16(m,2H ),6.79(d,J=7.7Hz,1H),5.34–5.29(m,1H),5.25(t,J=5.7Hz,1H),4.86(q,J=7.7Hz,1H),4.68– 4.49(m,4H),3.96(d,J=18.6Hz,1H),2.77(dd,J=15.6,5.6Hz,1H),2.65–2.58(m,1H),2.36–2.3 0(m,1H),2.15(s,6H),2.00(q,J=7.0,6.5Hz,1H),1.55(d,J=7.0Hz,3H),0.94(d,J=6.7Hz,3H).

[0375] Biological evaluation

[0376] The present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0377] Test Example 1

[0378] Test Example 1. Test of the inhibitory activity of the disclosed compounds on ovarian cancer cells (OVCAR3)

[0379] 1.1 Experimental materials and instruments (see Table 1)

[0380] Table 1 Experimental materials and instruments

[0381] 1.2 Experimental steps

[0382] Ovarian cancer cells OVCAR3 (source: Nanjing Kebai Biotechnology Co., Ltd.) were cultured in a cell culture incubator at 37% and 5% CO2 using RPMI 1640 medium containing 10% FBS. On the first day, cells were plated in 96-well plates at a cell density of 2500 cells / well and cultured overnight in an incubator. Compound treatment was performed on the second day. The highest concentration of compound treatment was 10 μM, 3-fold dilution, 9 concentrations, and the final concentration of DMSO was 0.1%. After the cells were cultured in the incubator for 5 days, the cell viability was tested using the Celltiter Glo detection kit (Promega). The test method was consistent with the operating method provided by the kit. GraphPad Prism 8 was used to process the data and calculate the IC 50 .

[0383] Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)).

[0384] X: logarithmic value of compound concentration; Y: % inhibition; Bottom: bottom; Top: top; HillSlope: Hill slope.

[0385] Table 2. IC values ​​of the compounds disclosed herein against OVCAR3 50 (nM)

[0386] The inhibitory activity of the compounds of Examples 2-1, 3-1, 4, 9, and 11-1 of the present disclosure on OVCAR3 tumor cells is significantly better than that of the disclosed compound Janssen-01.

[0387] Janssen-01 Prepared according to the method provided in WO2022064009A.

[0388] Test Example 2

[0389] Test Example 2. Inhibitory activity test of the disclosed compounds on CDK kinases

[0390] 2.1 Experimental steps

[0391] The ADP-Glo ​​kinase assay is used to test CDK kinase activity. Compounds were diluted in a 384-well plate using Echo, starting at a 10 μM concentration, with 3-fold serial dilutions, 10 concentration points, and duplicate wells for each concentration. The final DMSO concentration in the assay system was 1%. 2.5 μL of CDK kinase solution prepared in assay buffer (final concentrations of 16.5 nM CDK1 / CyclinB, 1 nM CDK2 / CyclinE1, 16.3 nM CDK4 / CyclinD1, 15.7 nM CDK6 / CyclinD3, 80 nM CDK7 / Cyclin H / MAT1, 15.3 nM CDK9 / Cyclin T1) was added, and the enzyme and compound were pre-incubated at room temperature for 10 minutes. 2.5 μL of ATP (concentration of K) prepared in assay buffer was added. m) & substrate solution (20 μM ATP & 0.1 mg / mL histone H1 for CDK1 / CyclinB, 15 μM ATP & 0.1 mg / mL histone H1 for CDK2 / CyclinE1, 200 μM ATP & 0.2 mg / mL DYRKtide for CDK4 / CyclinD1, 200 μM ATP & 0.1 mg / mL histone H1 for CDK6 / CyclinD3, 70 μM ATP & 0.2 mg / mL MBP for CDK7 / Cyclin H / MAT1, 60 μM ATP & 0.2 mg / mL PDKtide for CDK9 / Cyclin T1), mixed well and incubated at room temperature for 120 min for CDK1 / 4 / 9 and 60 min for CDK2 / 6 / 7. Add 4 μL ADP-Glo ​​reagent was incubated at room temperature for 40 minutes. 8 μL of kinase assay reagent was added and incubated at room temperature for 40 minutes. The plate was read using the Envision multi-function microplate reader. The data were processed and the IC was calculated using GraphPad Prism 8. 50 .

[0392] Calculation formula: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC50 - X) * HillSlope)).

[0393] X: logarithmic value of compound concentration; Y: % inhibition; Bottom: bottom; Top: top; HillSlope: Hill slope.

[0394] Table 3. Inhibitory activity of the compounds of the present disclosure on CDK kinases (IC 50 , nM)

Claims

1. A compound represented by formula (I') or a pharmaceutically acceptable salt thereof, in, R 1 Selected from deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, -C 1-6 alkylene-3 to 6-membered heterocycloalkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 to 6-membered heteroaryl, -NH(C=O)-OC 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl and -(C=O)NH2, the C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, -C 1-6 alkylene-3 to 6-membered heterocycloalkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 to 6-membered heteroaryl, -NH(C=O)-OC 1-6 Alkyl and -(C=O)NH-C 1-6 The alkyl groups are each independently optionally substituted with one or more R A Substitution, the R A Selected from deuterium, halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkynyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 The alkynyl groups are each independently optionally substituted with one or more deuterium or halogen; m is selected from 0, 1, 2, 3 and 4; L1 is selected from the connecting bond and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R B Substitution, the R B Selected from deuterium, halogen, hydroxyl, oxo, C 1-6 alkyl, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocycloalkyl, the C 1-6 The alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl groups are each independently optionally substituted with one or more R 1B Substitution, the R 1B Selected from deuterium, hydroxyl, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C 1- 6 alkyl; R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen and deuterium; R 7 C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more deuterium; L2 is selected from NH, O and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R C Substitution, the R C Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl and halogenated C 1-6 alkyl; Ring A is selected from phenyl and 5- to 6-membered heteroaryl; R 8 Selected from deuterium, halogen, hydroxyl, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2- 6-alkynyl, 3- to 6-membered cycloalkyl, -SC 1-6 alkyl and -NHR'R", wherein R' and R" are each independently selected from hydrogen and C 1-6 Alkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 The alkynyl group and the 3- to 6-membered cycloalkyl group are each independently optionally substituted with one or more R D Substitution, the R D Selected from deuterium, halogen, hydroxyl, C 1-6 alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl are each independently optionally substituted with one or more deuterium or halogen; n is selected from 0, 1, 2, 3 and 4; R 9 is hydrogen or deuterium; L3 is C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R E Substitution, the R E for deuterium; R 10 and R 11 Each independently is C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more R F Substitution, the R F For deuterium.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, R 1 Selected from deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, -C 1-6 alkylene-3 to 6-membered heterocycloalkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 to 6-membered heteroaryl, -NH(C=O)-OC 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl and -(C=O)NH2, the C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, -C 1-6 alkylene-3 to 6-membered heterocycloalkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 to 6-membered heteroaryl, -NH(C=O)-OC 1-6 Alkyl and -(C=O)NH-C 1-6 The alkyl groups are each independently optionally substituted with one or more R A Substitution, the R A Selected from deuterium, halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkynyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 The alkynyl groups are each independently optionally substituted with one or more deuterium or halogen; m is selected from 0, 1, 2, 3 and 4; L1 is selected from the connecting bond and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R B Substitution, the R B Selected from deuterium, halogen, hydroxyl, oxo, C 1-6 alkyl, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocycloalkyl, the C 1-6 The alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl groups are each independently optionally substituted with one or more R 1B Substitution, the R 1B Selected from deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C 1-6 alkyl; R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen and deuterium; R 7 C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more deuterium; L2 is selected from NH, O and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R C Substitution, the R C Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl and halogenated C 1-6 alkyl; Ring A is selected from phenyl and 5- to 6-membered heteroaryl; R 8 Selected from deuterium, halogen, hydroxyl, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2- 6-alkynyl, 3- to 6-membered cycloalkyl, -SC 1-6 alkyl and -NHR'R", wherein R' and R" are each independently selected from hydrogen and C 1-6 Alkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 The alkynyl group and the 3- to 6-membered cycloalkyl group are each independently optionally substituted with one or more R D Substitution, the R D Selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl are each independently optionally substituted with one or more deuterium or halogen; n is selected from 0, 1, 2, 3 and 4; R 9 is hydrogen or deuterium; L3 is C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R E Substitution, the R E for deuterium; R 10 and R 11 Each independently is C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more R F Substitution, the R F For deuterium.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (I'-A) or a pharmaceutically acceptable salt thereof, in, R 1 Selected from deuterium, cyano, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, -C 1-6 alkylene-3 to 6-membered heterocycloalkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 to 6-membered heteroaryl, -NH(C=O)-OC 1-6 Alkyl, -(C=O)NH-C 1-6 Alkyl and -(C=O)NH2, the C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 1-6 Alkylene-3 to 6-membered cycloalkyl, -C 1-6 alkylene-3 to 6-membered heterocycloalkyl, 3 to 6-membered cycloalkyl, 3 to 6-membered heterocycloalkyl, phenyl, 5 to 6-membered heteroaryl, -NH(C=O)-OC 1-6 Alkyl and -(C=O)NH-C 1-6 The alkyl groups are each independently optionally substituted with one or more R A Substitution, the R A Selected from deuterium, halogen, hydroxy, amino, oxo, C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkynyl, the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 The alkynyl groups are each independently optionally substituted with one or more deuterium or halogen; m is selected from 0, 1, 2, 3 and 4; L1 is C 1-3 Alkylene, the C 1-3 The alkylene group is replaced by one or more R B Substitution, the R B C 1-6 Alkyl, the C 1-6 The alkyl group is replaced by one or more R 1B Substitution, the R 1B is hydroxyl group; R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen and deuterium; R 7 C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more deuterium; L2 is selected from NH, O and C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R C Substitution, the R C Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl and halogenated C 1-6 alkyl; Ring A is selected from phenyl and 5- to 6-membered heteroaryl; R 8 Selected from deuterium, halogen, hydroxyl, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2- 6-alkynyl, 3- to 6-membered cycloalkyl, -SC 1-6 alkyl and -NHR'R", wherein R' and R" are each independently selected from hydrogen and C 1-6 Alkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 The alkynyl group and the 3- to 6-membered cycloalkyl group are each independently optionally substituted with one or more R D Substitution, the R D Selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl are each independently optionally substituted with one or more deuterium or halogen; n is selected from 0, 1, 2, 3 and 4; R 9 is hydrogen or deuterium; L3 is C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R E Substitution, the R E for deuterium; R 10 and R 11 Each independently is C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more R F Substitution, the R F For deuterium.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: L2 is NH.

5. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: L2 is O.

6. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein: L2 is C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R C Substitution, the R C Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl and halogenated C 1-6 Preferably, L2 is a methylene group, the methylene group is optionally replaced by one or more R C Substitution, the R C Selected from deuterium, halogen, hydroxyl, cyano, C 1-6 Alkyl and halogenated C 1-6 More preferably, L2 is a methylene group.

7. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, in, R 1 ,m,L1,R 2 , R 3 , R 4 , R 5 , R 6 , Ring A, R 8 ,n,L3,R 10 and R 11 As defined in claim 1 or 2.

8. The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein L3 is selected from methylene and ethylene, and the methylene and ethylene are each independently optionally substituted by one or more R E Substitution, the R E for deuterium; Preferably, L3 is a methylene group, which is optionally replaced by one or more R E Substitution, the R E For deuterium.

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R 10 C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with one or more R F Substitution, the R F is deuterium; preferably, the R 10 is selected from methyl and ethyl, the methyl and ethyl groups are each independently optionally substituted by one or more R F Substitution, the R F is deuterium; more preferably, said R 10 Selected from methyl and -CD3.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R 11 C 1- 3 alkyl, the C 1-3 The alkyl group is optionally substituted with one or more R F Substitution, the R F is deuterium; preferably, the R 11 is selected from methyl and ethyl, the methyl and ethyl groups are each independently optionally substituted by one or more R F Substitution, the R F is deuterium; more preferably, said R 11 Selected from methyl and -CD3.

11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl.

12. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5- to 6-membered heteroaryl group, preferably pyridine, pyrazole, imidazole or thiazole.

13. The compound according to any one of claims 1, 2 and 4 to 12, or a pharmaceutically acceptable salt thereof, wherein L1 is a connecting key.

14. The compound according to any one of claims 1, 2 and 4 to 12, or a pharmaceutically acceptable salt thereof, wherein L1 is C 1-3 Alkylene, the C 1-3 The alkylene group is optionally substituted with one or more R B Substitution, the R B Selected from deuterium, halogen, hydroxyl, oxo, C 1-6 alkyl, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocycloalkyl, the C 1-6 The alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl groups are each independently optionally substituted with one or more R 1B Substitution, the R 1B Selected from deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C 1-6 alkyl; Preferably, L1 is a methylene group, the methylene group is replaced by one or more R B Substitution, the R B Selected from deuterium, halogen, C 1-6 alkyl, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocycloalkyl, the C 1-6 The alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl groups are each independently optionally substituted with one or more R 1B Substitution, the R 1B Selected from deuterium, halogen, C 1-6 Alkyl, halogenated C 1-6 Alkyl and deuterated C 1-6 alkyl; More preferably, L1 is a methylene group, the methylene group being replaced by one or more R B Substitution, the R B Selected from deuterium, halogen, C 1-3 alkyl, 3 to 6-membered cycloalkyl and 3 to 6-membered heterocycloalkyl, the C 1-3 The alkyl, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl groups are each independently optionally substituted with one or more R 1B Substitution, the R 1B Selected from Deuterium and halogens.

15. The compound according to any one of claims 7 to 11 and 14 or a pharmaceutically acceptable salt thereof, wherein: Ring A is phenyl; R 2 , R 3 , R 4 , R 5 and R 6 each independently is hydrogen; R 10 selected from the group consisting of methyl and -CD3; R 11 selected from the group consisting of methyl and -CD3; L1 is a methylene group, and the methylene group is replaced by one or more R B Substitution, the R B is selected from deuterium, halogen, methyl, ethyl, cyclopropyl and cyclobutyl, wherein the methyl, ethyl, cyclopropyl and cyclobutyl are each independently optionally substituted by one or more R 1B Substitution, the R 1B Selected from deuterium and halogen.

16. The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein: R 8 Selected from deuterium, halogen, hydroxyl, cyano, carboxyl, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy groups are each independently optionally substituted with one or more R D Substitution, the R D Selected from deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl are each independently optionally substituted with one or more deuterium or halogen; Preferably, R 8 is selected from deuterium, halogen, hydroxyl, cyano, carboxyl, methyl, ethyl, isopropyl, n-propyl, n-butyl, methoxy, ethoxy, isopropoxy and n-butoxy, wherein the methyl, ethyl, isopropyl, n-propyl, n-butyl, methoxy, ethoxy, isopropoxy and n-butoxy are each independently optionally replaced by one or more R D Substitution, the R D is selected from deuterium, halogen, hydroxy, methyl, ethyl, ethoxy and methoxy, wherein each of the methyl, ethyl, ethoxy and methoxy groups is independently optionally substituted with one or more deuterium or halogen; More preferably, R 8 is selected from deuterium, halogen, methyl, ethyl, methoxy and ethoxy, wherein the methyl, ethyl, methoxy and ethoxy are each independently optionally substituted by one or more R D Substitution, the R D is selected from the group consisting of deuterium, halogen and hydroxyl; n is selected from 0, 1, 2 and 3.

17. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from deuterium, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl, the C 1- 6 alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl and 3 to 6 membered heterocycloalkyl are each independently optionally substituted with one or more R A Substitution, the R A Selected from deuterium, halogen, hydroxy, amino, oxo, C 1-6 Alkyl and C 1-6 Alkoxy, the C 1-6 Alkyl and C 1-6 The alkoxy groups are each independently optionally substituted with one or more deuterium or halogen; Preferably, R 1 Selected from C 1-6 Alkyl and 3 to 6 membered cycloalkyl, the C 1-6 The alkyl group and the 3- to 6-membered cycloalkyl group are each independently optionally substituted with one or more R A Substitution, the R A is selected from the group consisting of deuterium, halogen, hydroxy, amino, oxo, methyl, ethyl, methoxy and ethoxy; More preferably, R 1 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl and cyclopentyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, The cyclobutyl and cyclopentyl groups are each independently optionally substituted with one or more R A Substitution, the R A is selected from the group consisting of deuterium, halogen and hydroxyl; The m is selected from 0, 1, 2 and 3.

18. The compound according to any one of claims 1, 2, 4 to 12, 14 to 17, or a pharmaceutically acceptable salt thereof, wherein: L1 is a methylene group, and the methylene group is replaced by one or more R B Substitution, the R B Deuterium or C 1-6 alkyl.

19. The compound according to any one of claims 1, 2, 4 to 12, 14 to 18, or a pharmaceutically acceptable salt thereof, wherein: Selected from 20. The compound according to any one of claims 1, 2, 4, 7 to 11, 14 to 19 or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (III-1), (III-2), (III-3), (III-4) or a pharmaceutically acceptable salt thereof, in, R 8 ,n,R 1 and m as defined in claim 1; said R B is selected from hydrogen, deuterium, methyl, ethyl, cyclopropyl and cyclobutyl, wherein the methyl, ethyl, cyclopropyl and cyclobutyl are each independently optionally substituted by one or more R 1B Substitution, the R 1B Selected from deuterium and halogen.

21. The compound according to claim 20 or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from deuterium, halogen, methyl, ethyl, methoxy and ethoxy, wherein the methyl, ethyl, methoxy and ethoxy are each independently optionally substituted by one or more R D Substitution, the R D is selected from the group consisting of deuterium, halogen and hydroxyl; R 1 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl and cyclopentyl, wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl and cyclopentyl are each independently optionally substituted by one or more R A Substitution, the R A selected from deuterium and halogen; m and n are each independently selected from 0, 1, 2 and 3.

22. The compound according to any one of claims 20 or 21, or a pharmaceutically acceptable salt thereof, wherein: R B is selected from methyl and cyclopropyl, wherein the methyl and cyclopropyl are each independently optionally substituted by one or more R 1B Substitution, the R 1B for deuterium; R 1 is selected from methyl and cyclopropyl, wherein the methyl and cyclopropyl are each independently optionally substituted by one or more R A Substitution, the R A selected from deuterium and halogen; m is selected from 0, 1, 2 and 3; n is 0.

23. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the compounds or pharmaceutically acceptable salts thereof shown below, Preferred are the compounds shown below or their pharmaceutically acceptable salts, 24. An isotope substitution of the compound according to any one of claims 1 to 23; preferably, the isotope substitution is a deuterated compound.

25. A method for preparing a compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, The method comprises the steps of reacting a compound represented by formula (IA) or a pharmaceutically acceptable salt thereof with a compound represented by formula (IB) or a pharmaceutically acceptable salt thereof in an alkaline environment, catalyzed by a catalyst selected from carbonyldiimidazole, phosgene and triphosgene; in, L2 is NH; R 1 ,m,L1,R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Ring A, R 8 ,n,R 9 , L3, R 10 and R 11 As defined in any one of claims 1 to 22.

26. A compound represented by formula (IA) or a pharmaceutically acceptable salt thereof, in, R 1 ,m,L1,R 2 , R 3 , R 4 , R 5 , R 6 and R 7 As defined in any one of claims 1 to 3.

27. A pharmaceutical composition comprising the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof or the isotope substitution according to claim 24 and a pharmaceutically acceptable excipient.

28. Use of the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, or the isotope substitution according to claim 24, or the pharmaceutical composition according to claim 27, in the preparation of a medicament for treating and / or preventing a disease or condition associated with abnormal activity of serine / threonine kinase.

29. Use of the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, the isotopic substitution according to claim 24 or the pharmaceutical composition according to claim 27 in the preparation of a medicament for treating and / or preventing a disease or condition associated with abnormal activity of CDK7; preferably, the disease or condition associated with abnormal activity of CDK7 is selected from proliferative diseases, inflammatory diseases, autoinflammatory diseases, autoimmune diseases and infectious diseases.

30. Use of a compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, an isotopic substitution according to claim 24 or a pharmaceutical composition according to claim 27 in the preparation of a medicament for treating and / or preventing a disease or condition selected from proliferative diseases, inflammatory diseases, autoinflammatory diseases, autoimmune diseases and infectious diseases.

31. The use according to any one of claims 29 or 30, wherein The proliferative disease is cancer; preferably, the cancer is selected from hematological tumors and solid tumors, the hematological tumor is selected from chronic lymphocytic leukemia, acute lymphocytic leukemia, T-cell acute lymphocytic leukemia, chronic myeloid leukemia and acute myeloid leukemia, and the solid tumor is selected from breast cancer, intestinal cancer, lung cancer, pancreatic cancer, prostate cancer, Ewing's sarcoma, osteoma, neuroblastoma, cervical cancer, ovarian cancer, gastric cancer and liver cancer.

32. The use according to claim 31, wherein The breast cancer is triple-negative breast cancer or ER / PR+HER2-breast cancer. Preferably, the ER / PR+HER2-breast cancer is ER / PR+HER2-breast cancer resistant to CDK4 / 6 inhibitors; the lung cancer is selected from non-small cell lung cancer and small cell lung cancer; the intestinal cancer is selected from colon cancer and rectal cancer.

33. Use of the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, or the isotope-substituted product according to claim 24 in the preparation of an antibody-drug conjugate or a protein-targeted degradation chimera. 34 . An antibody-drug conjugate comprising the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, or the isotope-substituted compound according to claim 24 .

35. A protein targeted degradation chimera comprising the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof or the isotope substitution according to claim 24.