CN120813579A

CN120813579A - Synthesis of macrocyclic compounds and their use in medicine

Info

Publication number: CN120813579A
Application number: CN202480017010.8A
Authority: CN
Inventors: 陆洪福; 丁晓; 任峰
Original assignee: Insilicon Intelligent Technology Shanghai Co ltd
Current assignee: Insilicon Intelligent Technology Shanghai Co ltd
Priority date: 2023-06-19
Filing date: 2024-06-18
Publication date: 2025-10-17
Also published as: TW202500154A; WO2024260325A1

Abstract

本发明提供了一种大环类化合物的合成及其在医药上的用途，具体地，本发明提供了式(II)所示化合物、其立体异构体或其药学上可接受的盐，其可作为CDK7抑制剂。 The present invention provides a synthesis of a macrocyclic compound and its use in medicine. Specifically, the present invention provides a compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, which can be used as a CDK7 inhibitor.

Description

Synthesis of macrocyclic compounds and their use in medicine

The application claims priority from the prior application filed on 19 th 2023, 06 and to China national intellectual property agency, with patent application number 202310728137.8, entitled "synthesis of macrocyclic compounds and their use in medicine". The entirety of this prior application is incorporated by reference into the present application.

Technical Field

The invention belongs to the field of medicines, and particularly relates to synthesis of a macrocyclic compound and application of the macrocyclic compound in medicines.

Background

Cyclin Dependent Kinase (CDK)/cyclin complexes were identified as conserved components of the RNA polymerase II transcription machinery. Currently there are 20 mammalian CDKs. Of mammalian CDKs, CDK7 has a firm kinase activity, and only CDK7 has dual functions of regulating cell cycle progression and transcription. In the cytosol, CDK7 exists as a heterotrimeric complex and is thought to function as CDK 1/2/4/6-activated kinase (CAK), whereby phosphorylation of conserved residues in CDK1/2/4/6 by CDK7 is essential for full catalytic CDK activity and cell cycle progression. In the nucleus, CDK7 forms the kinase core of the RNA polymerase II transcription factor complex and is responsible for phosphorylating the C-terminal domain (CTD) of RNA polymerase II, an essential step in the initiation of gene transcription. Together, the two functions of CDK7 (i.e., CAK and CTD phosphorylation) support key aspects of cell proliferation, cell cycle and transcription.

CDK7 acts as a regulator of overall transcription and can be a therapeutic target for the treatment of many diseases and syndromes. CDK7 may interact in the transcriptional regulatory region and in multiple transcription factors, cofactors, chromatin regulatory factors, and non-coding RNAs to regulate transcription. Mutations in these transcription factors, cofactors, chromatin modulators or non-coding RNAs can lead to diseases such as cancer, autoimmune diseases, neurological disorders, developmental syndromes, diabetes, cardiovascular diseases and obesity. Some of these transcription factors control RNA polymerase II mediated transcription initiation and elongation and, when their expression or function is altered, can give rise to invasive tumor cells (e.g., caused by c-Myc) or some form of autoimmunity (e.g., caused by AIRE). Thus, CDK7 kinases can promote aberrant expression of certain transcription factors associated with tumors by regulating the overall transcription process, as well as promote tumor progression by regulating phosphorylation of cell cycle-critical kinases. More importantly, CDK7 regulates expression of oncogenic transcription factors more significantly than other housekeeping genes in cancer cells. Inhibition of CDK7 may differentially affect transcription of certain oncogenes and housekeeping genes, thus ensuring a therapeutic window. Transcriptional regulation and cell cycle regulation by modulating CDK 7-mediated phosphorylation modification are useful in the treatment of dysproliferative disorders, including cancer. As an overall regulator of transcription, CDK7 may also be a therapeutic target for the treatment of diseases such as inflammation, viral replication, e.g. HIV, EBV, cancer and cardiac hypertrophy.

The high sequence and structural similarity of the kinase domains of CDK family members hampers the discovery of CDK7 selective inhibitors. Thus, the development of selective CDK7 inhibitors is of great value for clinical use.

Disclosure of Invention

WO2018013867A1 discloses a CDK7 inhibitor, and researches show that the compound disclosed in the patent application has the problem of poor membrane permeability and poor excretion rate in a human Caco-2 single cell layer permeation experimental model.

It is an object of the present invention to provide a novel class of CDK7 inhibitors. In addition, the compound of the invention has at least one of the following technical effects of 1, better biological activity, 2, better membrane permeability, 3 and lower efflux rate (Efflux Ratio). Oral administration of drugs requires absorption through the gastrointestinal tract into the blood circulatory system and distribution to the corresponding tissues to exert pharmacological effects in the body. Thus, the permeabilities reflect the absorption and transport capacity of the compounds in vivo, which is critical for oral absorption of the drug. Meanwhile, the discharge rate of the oral medicine is low, which is more beneficial to the absorption of the medicine in the gastrointestinal tract.

In one aspect of the present invention, the present invention provides a compound of formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;

Wherein V is selected from a single bond or-O-;

Structural unit Selected from the group consisting of

X ₁ is selected from N or C (R _x1);

X ₂ is selected from N or C (R _x2);

X ₃ is selected from N or C (R _x3);

Y is selected from N or C (R _Y);

Z is selected from N or C (R _Z);

l is selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _2-8 alkenyl, or C _2-8 alkynyl, said C _1-8 alkyl, C _1-8 heteroalkyl, C _2-8 alkenyl, or C _2-8 alkynyl being optionally substituted with 1 or more R ^L;

R ^L is each independently selected from halogen, cyano, -NO ₂, hydroxy 、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C_1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, or heterocyclyl;

Or two R ^L are on the same atom and are linked together to form =o;

Or two R ^L are on two adjacent atoms and are linked together to form a single bond;

Or two R ^L are on the same or different atoms and are linked together to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, which cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with 1 or more R ^La;

R ^La is each independently selected from halogen, cyano, -NO ₂, hydroxy 、-OR^a、-NR^cR^d、-C(＝O)R^a、-C(＝O)OR^b、-C(＝O)NR^cR^d、C_1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, or C _1-6 heteroalkyl;

R ^a、R^b、R^c and R ^d are each independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, heterocyclyl, Aryl, heteroaryl, C _1-6 alkyl (cycloalkyl), C _1-6 alkyl (heterocyclyl), C _1-6 alkyl (aryl) or C _1-6 alkyl (heteroaryl), said C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 alkyl (cycloalkyl), C _1-6 alkyl (heterocyclyl), C _1-6 alkyl (aryl) or C _1-6 alkyl (heteroaryl) optionally substituted with 1 or more R;

Or R ^c and R ^d are linked together to form a heterocyclyl, said heterocyclyl optionally substituted with 1 or more R;

R _x1、R_x2、R_Y、R_Z、R₃ is independently selected from H, halogen, hydroxy, cyano, -C _2-4 alkenylene-phenyl, -C _2-4 alkynylene-phenyl, -S (=O) -OH, -S (=O) ₂-OH、-S-(C_1-6 alkyl), C _1-6 alkyl, -O-C _1-6 alkyl, -C _1-6 alkylene-O-C _1-6 alkyl, -O-C _1-6 alkylene-O-C _1-6 alkyl, -C _0-6 alkylene-NRR', -C _0-6 alkylene-C (=o) OH, -C _0-6 alkylene-C (=o) -C _1-6 alkyl, -C _0-6 alkylene-C (=o) -NRR', -C _0-6 alkylene-NR-C (=o) -C _1-6 alkyl, -C _0-6 alkylene-S (=o) ₂-C_1-6 alkyl, -C _0-6 alkylene-S (=o) (=nh) -C _1-6 alkyl, -C _0-6 alkylene-S (=o) ₂-NRR'、-C_0-6 alkylene-NR-S (=o) ₂-C_1-6 alkyl, -C _0-6 alkylene-NR-S (=o) ₂-NRR'、-C_0-6 alkylene-P (=o) O- (C _1-6 alkyl) ₂、-C_0-6 alkylene-P (=o) - (C _1-6 alkyl) (O-C _1-6 alkyl), -C _0-6 alkylene-P (=o) - (C _1-6 alkyl) ₂、-C_0-6 alkylene-3 to 14 membered cycloalkyl, -C _0-6 alkylene-3 to 14 membered heterocyclyl, -C _0-6 alkylene-5 to 12 membered heteroaryl, -C _0-6 alkylene-C _6-12 aryl, -C _0-6 alkylene-C (=o) -3 to 14 membered heterocyclyl, -C _0-6 alkylene-C (=o) -5 to 12 membered heteroaryl, -O-C _0-6 alkylene-O-C _1-6 alkyl, -O-C _0-6 alkylene-3 to 14 membered cycloalkyl, -O-C _0-6 alkylene-3 to 14 membered heterocyclyl, -O-C _0-6 alkylene-5 to 12 membered heteroaryl, -O-C _0-6 alkylene-C _6-12 aryl, -S (=o) -C _1-6 alkyl, wherein said C _1-6 alkyl, C _0-6 alkylene, C _2-4 alkenylene, A3 to 14 membered cycloalkyl, a3 to 14 membered heterocyclyl, a 5 to 12 membered heteroaryl, a C _6-12 aryl being independently unsubstituted or substituted with 1, 2,3, 4 or 5 groups selected from group S1, said 3 to 14 membered heterocycle having 1, 2,3 or 4 heteroatoms selected independently from nitrogen, oxygen and sulfur, said 5 to 12 membered heteroaryl having 1, 2,3 or 4 heteroatoms selected independently from nitrogen, oxygen and sulfur;

The group S1 comprises oxo (=O), halogen, hydroxy, cyano, C _1-6 alkyl, -O-C _1-6 alkyl, -C _1-6 alkylene-O-C _1-6 alkyl, -O-C _1-6 alkylene-O-C _1-6 alkyl, -C _0-6 alkylene-NRR', -C _0-6 alkylene-C (=o) OH, -C _0-6 alkylene-C (=o) -C _1-6 alkyl, -C _0-6 alkylene-C (=o) -NRR', -C _0-6 alkylene-NR-C (=o) -C _1-6 alkyl, -C _0-6 alkylene-S (=o) ₂-C_1-6 alkyl, -C _0-6 alkylene-S (=o) ₂-NRR'、-C_0-6 alkylene-NR-S (=o) ₂-C_1-6 alkyl, -C _0-6 alkylene-NR-S (=o) ₂-NRR'、-C_0-6 alkylene-P (=o) O- (C _1-6 alkyl) ₂、-C_0-6 alkylene-P (=o) - (C _1-6 alkyl) (O-C _1-6 alkyl), -C _0-6 alkylene-P (=o) - (C _1-6 alkyl) ₂、-C_0-6 alkylene-3 to 14 membered cycloalkyl, -C _0-6 alkylene-3 to 14 membered heterocyclyl, -C _0-6 alkylene-5 to 12 membered heteroaryl, -C _0-6 alkylene-C _6-12 aryl, -C _0-6 alkylene-C (=o) -3 to 14 membered heterocyclyl, -C _0-6 alkylene-C (=o) -5 to 12 membered heteroaryl, -O-C _0-6 alkylene-O-C _1-6 alkyl, -O-C _0-6 alkylene-3 to 14 membered cycloalkyl, -O-C _0-6 alkylene-3 to 14 membered heterocyclyl, -O-C _0-6 alkylene-5 to 12 membered heteroaryl, -O-C _0-6 alkylene-C _6-12 aryl, -S (=o) -C _1-6 alkyl;

R _x3 is independently selected from H, halogen, cyano, C _1-12 alkyl or C _1-12 haloalkyl;

R ₁ is selected from H, halogen, cyano, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 hydroxyalkyl, C _1-12 heteroalkyl, cycloalkyl, or heterocycloalkyl, said C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 hydroxyalkyl, cycloalkyl, or heterocycloalkyl being optionally substituted with 1 or more R ₁₁₁;

R ₂ is selected from H, halogen, cyano, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 hydroxyalkyl, C _1-12 heteroalkyl, cycloalkyl, or heterocycloalkyl, said C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 hydroxyalkyl, cycloalkyl, or heterocycloalkyl being optionally substituted with 1 or more R ₂₂₂;

Ring a is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl, optionally substituted with 1 or more R ^aa;

R ^aa is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, heterocyclyl, Aryl, heteroaryl, C _1-6 alkyl (cycloalkyl), C _1-6 alkyl (heterocyclyl), C _1-6 alkyl (aryl) or C _1-6 alkyl (heteroaryl), said C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 alkyl (cycloalkyl), C _1-6 alkyl (heterocyclyl), C _1-6 alkyl (aryl) or C _1-6 alkyl (heteroaryl) optionally substituted with 1 or more R;

R, R', R ₁₁₁、R₂₂₂ are each independently selected from halogen, cyano, hydroxy 、-OCH₃、-S(＝O)CH₃、-S(＝O)₂CH₃、-S(＝O)₂NH₂、-S(＝O)₂NHCH₃、-S(＝O)₂N(CH₃)₂、-NH₂、-NHCH₃、-N(CH₃)₂、-C(＝O)CH₃、-C(＝O)OH、-C(＝O)OCH₃、C_1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl or C _1-6 heteroalkyl;

The heteroalkyl, heteroaryl, or heterocyclyl contains 1,2, or 3 heteroatoms or groups of heteroatoms independently selected from O, NH, S, C (=o), C (=o) O, S (=o), S (=o) ₂, and N.

In another aspect of the present invention, the present invention also provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;

Wherein the structural unit Selected from the group consisting of

X ₁ is selected from N or C (R _x1);

X ₂ is selected from N or C (R _x2);

X ₃ is selected from N or C (R _x3);

Y is selected from N or C (R _Y);

Z is selected from N or C (R _Z);

L is selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _2-8 alkenyl, or C _2-8 alkynyl, said C _1-8 alkyl, C _1-8 heteroalkyl, C _2-8 alkenyl, or C _2-8 alkynyl being substituted with 1 or more optional R ^L;

Or two R ^L are on the same atom and are linked together to form =o;

R _x1、R_x2、R_Y、R_Z、R₃ is independently selected from H, halogen, hydroxy, cyano, -C _2-4 alkenylene-phenyl, -C _2-4 alkynylene-phenyl, -S (=O) -OH, -S (O) ₂-OH、-S-(C_1-6 alkyl), C _1-6 alkyl, -O-C _1-6 alkyl, -C _1-6 alkylene-O-C _1-6 alkyl, -O-C _1-6 alkylene-O-C _1-6 alkyl, -C _0-6 alkylene-NRR', -C _0-6 alkylene-C (=o) OH, -C _0-6 alkylene-C (=o) -C _1-6 alkyl, -C _0-6 alkylene-C (=o) -NRR', -C _0-6 alkylene-NR-C (=o) -C _1-6 alkyl, -C _0-6 alkylene-S (=o) ₂-C_1-6 alkyl, -C _0-6 alkylene-S (=o) (=nh) -C _1-6 alkyl, -C _0-6 alkylene-S (=o) ₂-NRR'、-C_0-6 alkylene-NR-S (=o) ₂-C_1-6 alkyl, -C _0-6 alkylene-NR-S (=o) ₂-NRR'、-C_0-6 alkylene-P (=o) O- (C _1-6 alkyl) ₂、-C_0-6 alkylene-P (=o) - (C _1-6 alkyl) (O-C _1-6 alkyl), -C _0-6 alkylene-P (=o) - (C _1-6 alkyl) ₂、-C_0-6 alkylene-3 to 14 membered cycloalkyl, -C _0-6 alkylene-3 to 14 membered heterocyclyl, -C _0-6 alkylene-5 to 12 membered heteroaryl, -C _0-6 alkylene-C _6-12 aryl, -C _0-6 alkylene-C (=o) -3 to 14 membered heterocyclyl, -C _0-6 alkylene-C (=o) -5 to 12 membered heteroaryl, -O-C _0-6 alkylene-O-C _1-6 alkyl, -O-C _0-6 alkylene-3 to 14 membered cycloalkyl, -O-C _0-6 alkylene-3 to 14 membered heterocyclyl, -O-C _0-6 alkylene-5 to 12 membered heteroaryl, -O-C _0-6 alkylene-C _6-12 aryl, -S (=o) -C _1-6 alkyl, wherein said C _1-6 alkyl, C _0-6 alkylene, C _2-4 alkenylene, A3 to 14 membered cycloalkyl, a3 to 14 membered heterocyclyl, a 5 to 12 membered heteroaryl, a C _6-12 aryl being independently unsubstituted or substituted with 1, 2,3, 4 or 5 groups selected from group S1, said 3 to 14 membered heterocycle having 1, 2,3 or 4 heteroatoms selected independently from nitrogen, oxygen and sulfur, said 5 to 12 membered heteroaryl having 1, 2,3 or 4 heteroatoms selected independently from nitrogen, oxygen and sulfur;

In some embodiments of the invention, the compound of formula (I) has a structure of formula (Ia);

wherein X ₁、X₂、X₃、Y、L、R₁、R₂、R₃, ring A are as defined herein.

In some embodiments of the present invention, the compound of formula (Ia) has a structure of formula (Iaa);

Wherein R _Z1、R_Z2 is independently selected from C _1-6 alkyl, L, R ₁、R₂、R₃ and ring A is defined in the invention.

In some embodiments of the present invention, the compound of formula (Iaa) has a structure of formula (Iaaa);

Wherein R _Z1、R_Z2 is independently selected from C _1-6 alkyl, L, R ₁、R₂ as defined herein.

In some embodiments of the present invention, the compound of formula (Iaaa) has a structure of formula (Iaaa-1) or formula (Iaaa-2);

Wherein R _Z1、R_Z2 is independently selected from C _1-6 alkyl, Y, L, R ₁、R₂ as defined herein.

In some embodiments of the invention, the compound of formula (Iaaa) has a structure of formula (Iaaaa);

Wherein R _Z1、R_Z2 is each independently selected from C _1-6 alkyl;

R _Z3 is independently selected from H, C _1-6 alkyl or C _3-12 cycloalkyl, said C _1-6 alkyl or C _3-12 cycloalkyl optionally substituted with 1,2 or 3 halogens or OH;

Lx is selected from L ^2A-L^3A-L^4A or L;

The L ^2A、L^3A or L ^4A are each independently selected from the group consisting of single bond, -O-, -C (=O) -, -S (=O) ₂ -, optionally substituted C _1-3 alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, -NR ^L4 -,

R ^L4 is selected from H, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl;

r ^L5 is selected from H, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl;

l, Y, R ₁、R₂ are as defined herein.

In some embodiments of the invention, the compound of formula (Iaaaa) has a structure of formula (Iaaaa-1) or formula (Iaaaa-2);

Wherein R _Z1、R_Z2、R_Z3、L_X、R₁、R₂ is as defined herein.

In some embodiments of the invention, the compound of formula (Ia) has a structure of formula (Iab);

Wherein Y, L, R ₁、R₂、R₃, ring A are as defined herein.

In some embodiments of the invention, the compound of formula (Iab) has the structure of formula (Iabb);

Wherein L, R ₁、R₂ is as defined herein.

In some embodiments of the invention, the compound of formula (Iabb) has a structure of formula (Iabb-1) or formula (Iabb-2);

Wherein L, R ₁、R₂ is as defined herein.

In some embodiments of the invention, the compound of formula (Iabb) has the structure of formula (Iabbb);

Wherein R _Z3 is independently selected from H, C _1-6 alkyl or C _3-12 cycloalkyl, said C _1-6 alkyl or C _3-12 cycloalkyl optionally substituted with 1,2 or 3 halogens or OH,

Lx is selected from L ^2A-L^3A-L^4A or L;

Y, R ₁、R₂ are as defined herein.

In some embodiments of the invention, the compound of formula (Iabbb) has a structure of formula (Iabbb-1) or formula (Iabbb-2);

Wherein R _Z3、L_X、R₁、R₂ is as defined herein. In some embodiments of the invention, R _c is each independently selected from H, C _1-3 alkyl or C _3-6 cycloalkyl, said C _1-3 alkyl or C _3-6 cycloalkyl optionally substituted with 1,2 or 3 halogens or OH, the remaining variables being as defined herein.

In some embodiments of the invention, R _Z3 is each independently selected from H, methyl, ethyl, cyclopropyl, CH ₂CF₃, or CH ₂CHF₂, the remaining variables being as defined herein.

In some embodiments of the invention, R _Z1、R_Z2 is independently selected from C _1-3 alkyl, the remaining variables being as defined herein.

In some embodiments of the invention, R _Z1、R_Z2 is independently selected from methyl or ethyl, respectively, with the remaining variables being as defined herein.

In some embodiments of the invention, -L-is selected from-L ^1A-L^2A-L^3A-L^4A-L^5A -, said L ^1A、L^2A、L^3A、L^4A or L ^5A are each independently selected from single bond, -O-, -C (=o) -, -S (=o) ₂ -, optionally substituted C _1-3 alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, -NR ^L4 -,R ^L4 is selected from H, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl, R ^L5 is selected from H, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl, and the remaining variables are as defined herein.

In some embodiments of the invention, the L ^1A、L^2A、L^3A、L^4A or L ^5A are each independently selected from the group consisting of single bond, -O-, -C (=o) -, -S (=o) ₂ -, optionally substituted C _1-3 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted 3-to 6-membered heterocyclyl, optionally substituted 5-to 12-membered heteroaryl, optionally substituted C _6-12 aryl, -NR ^L4 -,The remaining variables are as defined herein.

In some embodiments of the invention, the L ^1A、L^2A、L^3A、L^4A or L ^5A are each independently selected from the group consisting of single bond, -O-, -C (=O) -, -S (=O) ₂-、C_1-3 alkyl, C _3-6 cycloalkyl, 3-to 6-membered heterocyclyl, 5-to 6-membered heteroaryl, phenyl, -NR ^L4 -,The C _1-3 alkyl, C _3-6 cycloalkyl, 3 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, phenyl, -NR ^L4 -Optionally substituted with 1,2, 3 or 4R ^L6, R ^L4 is selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 3-to 6-membered heterocyclyl, R ^L5 is selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl or 3-to 6-membered heterocyclyl, R ^L6 is each independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, 3 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl or phenyl, said C _1-6 alkyl, C _3-6 cycloalkyl, 3 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl or phenyl optionally being substituted with 1, 2,3 or 4 halogen, 0H, CN, NH ₂ or C _1-6 alkyl, or two R ^L6 are on the same carbon atom and are joined together to form a C _3-6 cycloalkyl group or a 3-to 6-membered heterocyclic group, said C _3-6 cycloalkyl group or 3-to 6-membered heterocyclic group optionally being substituted with 1, 2. 3 or 4 halogen, 0H, CN, NH ₂ or C _1-6 alkyl groups, the remaining variables being as defined herein.

In some embodiments of the invention, the L ^1A、L^2A、L^3A、L^4A or L ^5A are each independently selected from a single bond, -O-, -C (=o) -, optionally substituted C _1-3 alkyl, optionally substituted C _3-6 cycloalkyl, optionally substituted 5-to 6-membered heteroaryl, optionally substituted phenyl, or-NR ^L4 -, with the remaining variables being as defined herein.

In some embodiments of the invention, the L ^1A、L^2A、L^3A、L^4A or L ^5A are each independently selected from a single bond, -O-, -C (=o) -, C _1-3 alkyl optionally substituted with halogen, optionally substituted C _3-6 cycloalkyl, optionally substituted 5-to 6-membered heteroaryl, or-NR ^L4 -, with the remaining variables being as defined herein.

In some embodiments of the invention, the L ^1A、L^2A、L^3A、L^4A or L ^5A are each independently selected from a single bond, -O-, -C (=o) -, C _1-3 alkyl, C _1-3 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cycloalkyl, imidazolyl, or-NR ^L4 -, with the remaining variables being as defined herein.

In some embodiments of the invention, R ^L4 is selected from H, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 haloalkyl or optionally substituted cycloalkyl, and the remaining variables are as defined herein.

In some embodiments of the invention, R ^L4 is selected from H, optionally substituted C _1-6 alkyl, and the remaining variables are as defined herein.

In some embodiments of the invention, R ^L4 is selected from H, optionally substituted C _1-3 alkyl, and the remaining variables are as defined herein.

In some embodiments of the invention, -L-is selected from the group consisting of:

-(O)_m2-(CR¹³R¹⁴)_m1-(NR¹²)_m3-、

-(NR¹¹)_m2-(CR¹³R¹⁴)_m1-(NR¹²)_m3-、

- (O) _m2-(CR¹³R¹⁴)_m5-(C_3-7 cycloalkyl) _m4-(CR¹³R¹⁴)_m6-(NR¹²)_m3 -,

- (NR ¹¹)_m2-(CR¹³R¹⁴)_m5-(C_3-7 cycloalkyl) _m4-(CR¹³R¹⁴)_m6-(NR¹²)_m3 -,

- (O) _m2-(CR¹³R¹⁴)_m5 - (3-to 7-membered heterocyclic group) _m4-(CR¹³R¹⁴)_m6-(NR¹²)_m3 -,

- (O) _m2-(CR¹³R¹⁴)_m5 - (3-to 7-membered heterocyclic group) )_m4-(CR¹³R¹⁴)_m6-NR¹⁰C(＝O)-(CR¹³R¹⁴)_m6-(NR¹²)_m3-、

- (NR ¹¹)_m2-(CR¹³R¹⁴)_m5 - (3-to 7-membered heterocyclic group) _m4-(CR¹³R¹⁴)_m6-(NR¹²)_m3 -,

- (O) _m2-(CR¹³R¹⁴)_m5 - (3-to 6-membered heteroaryl) _m4-(CR¹³R¹⁴)_m6-(NR¹²)_m3 -,

- (NR ¹¹)_m2-(CR¹³R¹⁴)_m5 - (3-to 6-membered heteroaryl) _m4-(CR¹³R¹⁴)_m6-(NR¹²)_m3 -,

-(O)_m2-(CR¹³R¹⁴)_m5-NR¹⁰-(CR¹³R¹⁴)_m6-(NR¹²)_m3-、

-(NR¹¹)_m2-(CR¹³R¹⁴)_m5-NR¹⁰-(CR¹³R¹⁴)_m6-(NR¹²)_m3-、

-(O)_m2-(CR¹³R¹⁴)_m5-NR¹⁰C(＝O)-(CR¹³R¹⁴)_m6-(NR¹²)_m3-、

-(NR¹¹)_m2-(CR¹³R¹⁴)_m5-NR¹⁰C(＝O)-(CR¹³R¹⁴)_m6-(NR¹²)_m3-、

-(O)_m2-(CR¹³R¹⁴)_m5-C(＝O)NR¹⁰-(CR¹³R¹⁴)_m6-(NR¹²)_m3-、

-(O)_m2-(CR¹³R¹⁴)_m5-C(＝O)NR¹⁰-(CR¹³R¹⁴)_m6-(O)_m2-(CR¹³R¹⁴)_m5、

-(NR¹¹)_m2-(CR¹³R¹⁴)_m5-C(＝O)NR¹⁰-(CR¹³R¹⁴)_m6-(NR¹²)_m3-、

-(O)_m2-(CR¹³R¹⁴)_m5-O-(CR¹³R¹⁴)_m6-(NR¹²)_m3-、

-(NR¹¹)_m2-(CR¹³R¹⁴)_m5-O-(CR¹³R¹⁴)_m6-(NR¹²)_m3-、

-(O)_m2-(CR¹³R¹⁴)_m5-OC(＝O)-(CR¹³R¹⁴)_m6-(NR¹²)_m3-、

-(NR¹¹)_m2-(CR¹³R¹⁴)_m5-OC(＝O)-(CR¹³R¹⁴)_m6-(NR¹²)_m3-、

-(O)_m2-(CR¹³R¹⁴)_m5-C(＝O)O-(CR¹³R¹⁴)_m6-(NR¹²)_m3-、

-(NR¹¹)_m2-(CR¹³R¹⁴)_m5-C(＝O)O-(CR¹³R¹⁴)_m6-(NR¹²)_m3-、

-(O)_m2-(CR¹³R¹⁴)_m5-(CH＝CH)_m7-(CR¹³R¹⁴)_m6-(NR¹²)_m3-、

-(NR¹¹)_m2-(CR¹³R¹⁴)_m5-(CH＝CH)_m7-(CR¹³R¹⁴)_m6-(NR¹²)_m3-;

R ¹⁰ is independently selected from H, C _1-6 alkyl, -C _3-7 cycloalkyl, -C (=O) -C _1-6 alkyl, -C (=O) -C _1-4 alkyl-C _1-6 alkoxy, -C (=O) -C _3-7 cycloalkyl, -C _1-4 alkyl-hydroxy, -C _1-4 alkyl-cyano, -C _1-4 alkyl-C _1-6 alkoxy, -C _1-4 alkyl-NHC (=O) -C _1-6 alkyl, -C _1-4 alkyl-NHC (=O) -C _1-4 alkyl-C _1-6 alkoxy, -C _1-4 alkyl-NHC (=O) -C _3-7 cycloalkyl or-C _1-4 alkyl-NRR';

R, R 'are each independently hydrogen, C _1-6 alkyl, or R, R' together with the nitrogen atom to which they are attached optionally form a 3 to 14 membered heterocyclyl or a 5 to 12 membered heteroaryl, wherein each of the heterocyclyl, heteroaryl independently contains 0,1 or 2 heteroatoms selected from N, O, S in addition to the existing nitrogen atom;

the 3-to 7-membered heterocyclyl groups each independently having 1, 2, or 3 heteroatoms selected independently from nitrogen, oxygen, and sulfur, the C _3-7 cycloalkyl groups each independently being unsubstituted or substituted with 1, 2,3, 4, or 5 groups selected from group S1;

c _3-7 cycloalkyl is independently selected from unsubstituted or substituted with 1,2,3, 4 or 5 groups selected from group S1;

r ¹¹ is independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3 to 7 membered heterocyclyl, said C _1-6 alkyl, C _3-7 cycloalkyl, or 3 to 7 membered heterocyclyl optionally substituted with 1,2, or 3 halogens, CN, OH, or C _1-6 alkyl;

R ¹² is independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl, or 3 to 7 membered heterocyclyl, said C _1-6 alkyl, C _3-7 cycloalkyl, or 3 to 7 membered heterocyclyl optionally substituted with 1,2, or 3 halogens, CN, OH, or C _1-6 alkyl;

r ¹³ is independently selected from H, cyano, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, -C _3-7 cycloalkyl, -C _0-6 alkylene-NRR', -C _1-6 alkylene-hydroxy, or-C _0-6 alkylene-cyano;

R ¹⁴ is independently selected from H, cyano, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, -C _3-7 cycloalkyl, -C _0-6 alkylene-NRR', -C _1-6 alkylene-hydroxy, or-C _0-6 alkylene-cyano;

Or R ¹³、R¹⁴ are linked together and taken together with the same carbon atom or different carbon atoms to which they are attached form a 3-6 membered heterocyclyl or C _3-6 cycloalkyl, said 3-6 membered heterocyclyl or C _3-6 cycloalkyl being optionally substituted with 1,2, 3,4 or 5 groups selected from group S1;

m1 is each independently 1,2, 3, 4, 5 or 6;

m2 is each independently 0 or 1;

m3 is each independently 0 or 1;

m4 is each independently 1 or 2;

m5 is each independently 0, 1,2, 3, 4, 5 or 6;

m6 is each independently 0, 1,2, 3, 4, 5 or 6;

m7 is each independently 1 or 2, and the remaining variables are as defined herein.

In some embodiments of the invention, R ¹³ is each independently selected from H, cyano, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, -C _3-7 cycloalkyl, -C _0-6 alkylene-NRR', -C _1-6 alkylene-hydroxy, or-C _0-6 alkylene-cyano, the remaining variables being as defined herein.

In some embodiments of the invention, R ¹³ is each independently selected from H, cyano, hydroxy, halogen, C _1-3 alkyl, C _1-3 alkoxy, halogenated C _1-3 alkyl, halogenated C _1-3 alkoxy, -5 to 6 membered cycloalkyl, -C _0-3 alkylene-NRR', -C _1-3 alkylene-hydroxy, or-C _0-3 alkylene-cyano, the remaining variables being as defined herein.

In some embodiments of the invention, R ¹³ is independently selected from H, F, cl, br, I, methyl or ethyl, the remaining variables being as defined herein.

In some embodiments of the invention, R ¹⁴ is each independently selected from H, cyano, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, -C _3-7 cycloalkyl, -C _0-6 alkylene-NRR', -C _1-6 alkylene-hydroxy, or-C _0-6 alkylene-cyano, the remaining variables being as defined herein.

In some embodiments of the invention, R ¹⁴ is each independently selected from H, cyano, hydroxy, halogen, C _1-3 alkyl, C _1-3 alkoxy, halogenated C _1-3 alkyl, halogenated C _1-3 alkoxy, -5 to 6 membered cycloalkyl, -C _0-3 alkylene-NRR', -C _1-3 alkylene-hydroxy, or-C _0-3 alkylene-cyano, the remaining variables being as defined herein.

In some embodiments of the invention, R ¹⁴ is independently selected from H, F, cl, br, I, methyl or ethyl, the remaining variables being as defined herein.

In some embodiments of the invention, R ¹¹ is each independently selected from H, C _1-3 alkyl, C _3-6 cycloalkyl or 3 to 6 membered heterocyclyl C _1-3 alkyl, C _3-6 cycloalkyl or 3 to 6 membered heterocyclyl optionally substituted with 1,2, or 3 halogens, CN, OH or C _1-6 alkyl, the remaining variables being as defined herein.

In some embodiments of the invention, R ¹² is each independently selected from H, C _1-3 alkyl, C _3-6 cycloalkyl or 3 to 6 membered heterocyclyl C _1-3 alkyl, C _3-6 cycloalkyl or 3 to 6 membered heterocyclyl optionally substituted with 1,2, or 3 halogens, CN, OH or C _1-6 alkyl, the remaining variables being as defined herein.

In some embodiments of the invention, R ¹¹ is independently selected from H, methyl, ethyl, cyclopropyl, CH ₂CF₃, or CH ₂CHF₂, with the remaining variables being as defined herein.

In some embodiments of the invention, R ¹² is independently selected from H, methyl, ethyl, cyclopropyl, CH ₂CF₃, or CH ₂CHF₂, with the remaining variables being as defined herein.

In some embodiments of the invention, R ¹³ is each independently selected from H, cyano, hydroxy, halogen, or C _1-6 alkyl, with the remaining variables being as defined herein.

In some embodiments of the invention, R ¹⁴ is each independently selected from H, cyano, hydroxy, halogen, or C _1-6 alkyl, with the remaining variables being as defined herein.

In some embodiments of the invention, R ¹³、R¹⁴ is linked together and taken together with the same carbon atom or different carbon atoms to which it is attached form a 3-6 membered heterocyclyl or C _3-6 cycloalkyl group, said 3-6 membered heterocyclyl or C _3-6 cycloalkyl group being optionally substituted with 1, 23 halogens or OH, the remaining variables being as defined herein.

In some embodiments of the invention, R ¹³、R¹⁴ is linked together and taken together with the same carbon atom to which it is attached form a C _3-6 cycloalkyl group, said C _3-6 cycloalkyl group optionally being substituted with 1, 23 halogens or OH, the remaining variables being as defined herein.

In some embodiments of the invention, R ¹³、R¹⁴ is taken together and taken together with the same carbon atom to which it is attached to form a C _3-6 cycloalkyl group, the remaining variables being as defined herein.

-(O)_m2-(CR¹³R¹⁴)_m5-C(＝O)NR¹⁰-(CR¹³R¹⁴)_m6-(NR¹²)_m3-、

-(O)_m2-(CR¹³R¹⁴)_m5-C(＝O)NR¹⁰-(CR¹³R¹⁴)_m6-(O)_m2-(CR¹³R¹⁴)_m5, The remaining variables are as defined herein.

- (3-to 7-membered heterocyclic group) _m4-(CR¹³R¹⁴)_m6-NR¹⁰ C (=o) -,

-C(=O)NR¹⁰-(CR¹³R¹⁴)_m6-、

-C (=o) NR ¹⁰-(CR¹³R¹⁴)_m6-(O)_m2-(CR¹³R¹⁴)_m5, the remaining variables being as defined in the present invention.

In some embodiments of the invention, L is-NR ¹¹-(CR¹³R¹⁴)_m1-NR¹²-;R¹¹、R¹² is independently hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, m1 is 1, 2,3, 4, 5 or 6, and the remaining variables are as defined herein.

In some embodiments of the invention, L is-O- (CR ¹³R¹⁴)_m1-NR¹²-;R¹² is hydrogen or methyl; each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl; m1 is 1, 2,3, 4, 5 or 6, the remaining variables are as defined herein.

In some embodiments of the invention, L is-NR ¹¹-(CR¹³R¹⁴)_m1-;R¹¹ is hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen, or methyl, m1 is 1,2, 3, 4, 5, or 6, and the remaining variables are as defined herein.

In some embodiments of the invention, L is- (CR ¹³R¹⁴)_m1-NR¹²-;R¹² is hydrogen or methyl; each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl; m1 is 1,2, 3, 4, 5 or 6, the remaining variables are as defined herein).

In some embodiments of the invention, L is- (CR ¹³R¹⁴)_m1 -; each R ¹³、R¹⁴ is independently hydrogen, halogen, or methyl; m1 is 1,2, 3, 4, 5, or 6, with the remaining variables being as defined herein.

In some embodiments of the invention, L is-NR ¹¹-(CR¹³R¹⁴)_m5-C_3-7 cycloalkyl- (CR ¹³R¹⁴)_m6-NR¹²-;R¹¹、R¹² is independently hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, m5 is 0,1,2,3 or 4, m6 is 0,1,2,3 or 4, said C _3-7 cycloalkyl is unsubstituted or substituted with 1,2,3, 4 or 5 groups selected from group S1, and the remaining variables are as defined herein.

In some embodiments of the invention, L is-O- (CR ¹³R¹⁴)_m5-C_3-7 cycloalkyl- (CR ¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl; each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl; m5 is 0,1,2,3 or 4; m6 is 0,1,2,3 or 4; the C _3-7 cycloalkyl is unsubstituted or substituted with 1,2,3, 4 or 5 groups selected from group S1, the remaining variables being as defined herein.

In some embodiments of the invention, L is- (CR ¹³R¹⁴)_m5-C_3-7 cycloalkyl- (CR ¹³R¹⁴)_m6-NR¹²-;R¹²) is hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, m5 is 0, 1,2, 3 or 4, m6 is 0, 1,2, 3 or 4, the C _3-7 cycloalkyl is unsubstituted or substituted with 1,2, 3, 4 or 5 groups selected from group S1 in some embodiments, the C _3-7 cycloalkyl is cyclobutyl, cyclopentyl or cyclohexyl, and the remaining variables are as defined herein.

In some embodiments of the invention, L is-NR ¹¹-(CR¹³R¹⁴)_m5 -3 to 7 membered heterocycle- (CR ¹³R¹⁴)_m6-NR¹²;R¹¹、R¹² is independently hydrogen or methyl; each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl; m5 is 0, 1,2, 3 or 4; m6 is 0, 1,2, 3 or 4; the 3 to 7 membered heterocycle is unsubstituted or substituted with 1,2, 3,4 or 5 groups selected from group S1, the remaining variables being as defined herein.

In some embodiments of the invention, L is-O- (CR ¹³R¹⁴)_m5 -3 to 7 membered heterocycle- (CR ¹³R¹⁴)_m6-NR¹²;R¹² is hydrogen or methyl), each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, m5 is 0, 1,2, 3 or 4, m6 is 0, 1,2, 3 or 4, the 3 to 7 membered heterocycle is unsubstituted or substituted with 1,2, 3,4 or 5 groups selected from group S1, and the remaining variables are as defined herein.

In some embodiments of the invention, L is- (CR ¹³R¹⁴)_m5 -3 to 7 membered heterocycle- (CR ¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl; each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl; m5 is 0, 1,2, 3 or 4; m6 is 0, 1,2, 3 or 4; the 3 to 7 membered heterocycle is unsubstituted or substituted with 1,2, 3,4 or 5 groups selected from group S1, the remaining variables being as defined herein.

In some embodiments of the invention, L is -NR¹¹-(CR¹³R¹⁴)_m5-NR¹⁰-(CR¹³R¹⁴)_m6-NR¹²-;R¹¹、R¹² is independently hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, R ¹⁰ is hydrogen or methyl, m5 is 0, 1,2, 3 or 4, m6 is 0, 1,2, 3 or 4, and the remaining variables are as defined herein.

In some embodiments of the invention, L is -O-(CR¹³R¹⁴)_m5-NR¹⁰-(CR¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, R ¹⁰ is hydrogen or methyl, m5 is 0, 1,2, 3 or 4, m6 is 0, 1,2, 3 or 4, and the remaining variables are as defined herein.

In some embodiments of the invention, L is -(CR¹³R¹⁴)_m5-NR¹⁰-(CR¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, R ¹⁰ is hydrogen or methyl, m5 is 0, 1,2, 3 or 4, m6 is 0, 1,2, 3 or 4, and the remaining variables are as defined herein.

In some embodiments of the invention, L is -NR¹¹-(CR¹³R¹⁴)_m5-NR¹⁰C(＝O)-(CR¹³R¹⁴)_m6-NR¹²-;R¹¹、R¹² is independently hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, R ¹⁰ is hydrogen or methyl, m5 is 0, 1,2, 3 or 4, m6 is 0, 1,2, 3 or 4, and the remaining variables are as defined herein.

In some embodiments of the invention, L is -O-(CR¹³R¹⁴)_m5-NR¹⁰C(＝O)-(CR¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, R ¹⁰ is hydrogen or methyl, m5 is 0, 1,2, 3 or 4, m6 is 0, 1,2, 3 or 4, and the remaining variables are as defined herein.

In some embodiments of the invention, L is -(CR¹³R¹⁴)_m5-NR¹⁰C(＝O)-(CR¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, R ¹⁰ is hydrogen or methyl, m5 is 0, 1,2, 3 or 4, m6 is 0, 1,2, 3 or 4, and the remaining variables are as defined herein.

In some embodiments of the invention, L is -NR¹¹-(CR¹³R¹⁴)_m5-C(＝O)NR¹⁰-(CR¹³R¹⁴)_m6-NR¹²-;R¹¹、R¹² is independently hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, R ¹⁰ is hydrogen or methyl, m5 is 0, 1,2, 3 or 4, m6 is 0, 1,2, 3 or 4, and the remaining variables are as defined herein.

In some embodiments of the invention, L is -O-(CR¹³R¹⁴)_m5-C(＝O)NR¹⁰-(CR¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, R ¹⁰ is hydrogen or methyl, m5 is 0, 1,2, 3 or 4, m6 is 0, 1,2, 3 or 4, and the remaining variables are as defined herein.

In some embodiments of the invention, L is -(CR¹³R¹⁴)_m5-C(＝O)NR¹⁰-(CR¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, R ¹⁰ is hydrogen or methyl, m5 is 0, 1,2, 3 or 4, m6 is 0, 1,2, 3 or 4, and the remaining variables are as defined herein.

In some embodiments of the invention, L is -NR¹¹-(CR¹³R¹⁴)_m5-O-(CR¹³R¹⁴)_m6-NR¹²-;R¹¹、R¹² is independently hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, m5 is 0, 1, 2, 3 or 4, m6 is 0, 1, 2, 3 or 4, and the remaining variables are as defined herein.

In some embodiments of the invention, L is-O- (CR ¹³R¹⁴)_m5-O-(CR¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl; each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl; m5 is 0, 1, 2, 3 or 4; m6 is 0, 1, 2, 3 or 4; and the remaining variables are as defined herein.

In some embodiments of the invention, L is- (CR ¹³R¹⁴)_m5-O-(CR¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl; each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl; m5 is 0, 1, 2, 3 or 4; m6 is 0, 1, 2, 3 or 4; and the remaining variables are as defined herein.

In some embodiments of the invention, L is -NR¹¹-(CR¹³R¹⁴)_m5-OC(＝O)-(CR¹³R¹⁴)_m6-NR¹²-;R¹¹、R¹² is independently hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, m5 is 0, 1, 2, 3 or 4, m6 is 0, 1, 2, 3 or 4, and the remaining variables are as defined herein.

In some embodiments of the invention, L is-O- (CR ¹³R¹⁴)_m5-OC(＝O)-(CR¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl; each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl; m5 is 0, 1, 2, 3 or 4; m6 is 0, 1, 2, 3 or 4; and the remaining variables are as defined herein.

In some embodiments of the invention, L is- (CR ¹³R¹⁴)_m5-OC(＝O)-(CR¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl; each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl; m5 is 0, 1, 2, 3 or 4; m6 is 0, 1, 2, 3 or 4; and the remaining variables are as defined herein.

In some embodiments of the invention, L is -NR¹¹-(CR¹³R¹⁴)_m5-C(＝O)O-(CR¹³R¹⁴)_m6-NR¹²-;R¹¹、R¹² is independently hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, m5 is 0, 1, 2, 3 or 4, m6 is 0, 1, 2, 3 or 4, and the remaining variables are as defined herein.

In some embodiments of the invention, L is-O- (CR ¹³R¹⁴)_m5-C(＝O)O-(CR¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl; each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl; m5 is 0, 1, 2, 3 or 4; m6 is 0, 1, 2, 3 or 4; and the remaining variables are as defined herein.

In some embodiments of the invention, L is- (CR ¹³R¹⁴)_m5-C(＝O)O-(CR¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl; each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl; m5 is 0, 1, 2, 3 or 4; m6 is 0, 1, 2, 3 or 4; and the remaining variables are as defined herein.

In some embodiments of the invention, L is -NR¹¹-(CR¹³R¹⁴)_m5-CH＝CH-(CR¹³R¹⁴)_m6-NR¹²-;R¹¹、R¹² is independently hydrogen or methyl, each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl, m5 is 0, 1, 2, 3 or 4, m6 is 0, 1, 2, 3 or 4, and the remaining variables are as defined herein.

In some embodiments of the invention, L is-O- (CR ¹³R¹⁴)_m5-CH＝CH-(CR¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl; each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl; m5 is 0, 1, 2, 3 or 4; m6 is 0, 1, 2, 3 or 4; and the remaining variables are as defined herein.

In some embodiments of the invention, L is- (CR ¹³R¹⁴)_m5-CH＝CH-(CR¹³R¹⁴)_m6-NR¹²-;R¹² is hydrogen or methyl; each R ¹³、R¹⁴ is independently hydrogen, halogen or methyl; m5 is 0, 1, 2, 3 or 4; m6 is 0, 1, 2, 3 or 4; and the remaining variables are as defined herein.

In some embodiments of the invention, the groups of group S1 include oxo, hydroxy, cyano, halogen, methyl, ethyl, propyl, the remaining variables being as defined herein.

In some embodiments of the invention, the C _3-7 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the remaining variables are as defined herein.

In some embodiments of the invention, the 3-to 7-membered heterocyclyl is azetidinyl, oxetanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl or piperazinyl, the remaining variables being as defined herein.

In some embodiments of the invention, L is selected from one of the following structures:

The remaining variables are as defined herein.

In some embodiments of the invention, L is selected from The upper end is connected to ring B and the lower end is connected to V, the remaining variables being as defined in the present invention.

In some embodiments of the invention, L is selected fromThe remaining variables are as defined herein.

In some embodiments of the invention, R _x1 is selected from H, halogen, hydroxy, cyano, -C _0-3 alkylene-P (O) - (C _1-3 alkyl) ₂、-C_0-3 alkylene-S (O) (=nh) -C _1-3 alkyl or-C _0-3 alkylene-S (O) ₂-C_1-3 alkyl, the remaining variables being as defined herein.

In some embodiments of the invention, R _x1 is selected from H, F, cl, br, I, hydroxy, cyano 、-P(O)-(CH₃)₂、-P(O)-(CH₂CH₃)₂、-S(O)₂-CH₃、-S(O)(＝NH)-CH₃, or-S (O) ₂-CH₂CH₃, the remaining variables being as defined herein.

In some embodiments of the invention, R _x1 is selected from H, F, cl, br, I, -P (O) - (CH ₃)₂), or-S (O) ₂-CH₃, the remaining variables being as defined herein.

In some embodiments of the invention, R ₁ is selected from H, halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl, or 3 to 6 membered heterocycloalkyl, said C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl, or 3 to 6 membered heterocycloalkyl being optionally substituted with 1, 2, or 3R ₁₁₁, the remaining variables being as defined herein.

In some embodiments of the invention, R ₁ is selected from H, halogen, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 heteroalkyl, C _5-6 cycloalkyl, or 5 to 6 membered heterocycloalkyl, said C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 heteroalkyl, C _5-6 cycloalkyl, or 5 to 6 membered heterocycloalkyl being optionally substituted with 1, 2, or 3R ₁₁₁, the remaining variables being as defined herein.

In some embodiments of the invention, R ₁ is selected from H, halogen, cyano, C _1-6 alkyl, or C _1-6 haloalkyl, said C _1-6 alkyl or C _1-6 haloalkyl being optionally substituted with 1,2, or 3R ₁₁₁, the remaining variables being as defined herein.

In some embodiments of the invention, R ₁ is selected from H, halogen, cyano, C _1-3 alkyl, or C _1-3 haloalkyl, said C _1-3 alkyl, C _1-3 haloalkyl being optionally substituted with 1,2, or 3R ₁₁₁, the remaining variables being as defined herein.

In some embodiments of the invention, R ₁ is selected from H or C _1-3 haloalkyl, the remaining variables being as defined herein.

In some embodiments of the invention, R ₁ is selected from H or CF ₃, the remaining variables being as defined herein.

In some embodiments of the invention, R ₁ is selected from CF ₃, the remaining variables being as defined herein.

In some embodiments of the invention, R ₂ is selected from H, halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl, or 3 to 6 membered heterocycloalkyl, said C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl, or 3 to 6 membered heterocycloalkyl being optionally substituted with 1, 2, or 3R ₂₂₂, the remaining variables being as defined herein.

In some embodiments of the invention, R ₂ is selected from H, halogen, cyano, C _1-6 alkyl, or C _1-6 haloalkyl, said C _1-6 alkyl or C _1-6 haloalkyl being optionally substituted with 1,2, or 3R ₂₂₂, the remaining variables being as defined herein.

In some embodiments of the invention, R ₂ is selected from H, halogen, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 heteroalkyl, C _5-6 cycloalkyl, or 5 to 6 membered heterocycloalkyl, said C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 hydroxyalkyl, C _1-3 heteroalkyl, C _5-6 cycloalkyl, or 5 to 6 membered heterocycloalkyl being optionally substituted with 1, 2, or 3R ₂₂₂, the remaining variables being as defined herein.

In some embodiments of the invention, R ₂ is selected from H, halogen, cyano, C _1-3 alkyl, or C _1-3 haloalkyl, said C _1-3 alkyl or C _1-3 haloalkyl being optionally substituted with 1,2, or 3R ₂₂₂, the remaining variables being as defined herein.

In some embodiments of the invention, R ₂ is selected from H or C _1-3 haloalkyl, the remaining variables being as defined herein.

In some embodiments of the invention, R ₂ is selected from H or CF ₃, the remaining variables being as defined herein.

In some embodiments of the invention, R ₂ is selected from H, and the remaining variables are as defined herein.

In some embodiments of the invention, ring a is selected from C _3-12 cycloalkyl, 3 to 12 membered heterocyclyl, C _6-12 aryl, or 5 to 12 membered heteroaryl, said C _3-12 cycloalkyl, 3 to 12 membered heterocyclyl, C _6-12 aryl, or 5 to 12 membered heteroaryl being optionally substituted with 1 or more R ^aa, the remaining variables being as defined herein.

In some embodiments of the invention, ring a is selected from C _3-12 cycloalkyl or 3-12 membered heterocyclyl, optionally substituted with 1 or more R ^aa, the remaining variables being as defined herein.

In some embodiments of the invention, ring a is selected from C _3-9 cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, said C _3-9 cycloalkyl, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl being optionally substituted with 1,2, or 3R ^aa, the remaining variables being as defined herein.

In some embodiments of the invention, ring a is selected from C _3-6 cycloalkyl or 5-to 6-membered heterocyclyl, optionally substituted with 1,2 or 3R ^aa, the remaining variables being as defined herein.

In some embodiments of the invention, ring a is selected from cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, tetrahydropyrrolyl, pyrazolyl, or imidazolyl, optionally substituted with 1, 2, or 3R ^aa, the remaining variables being as defined herein.

In some embodiments of the invention, ring a is selected from C _3-6 cycloalkyl or 5 to 6 membered heterocyclyl, the remaining variables being as defined herein.

In some embodiments of the invention, ring a is selected from C _3-6 cycloalkyl groups, the remaining variables being as defined herein.

In some embodiments of the invention, ring a is selected from C _5-6 cycloalkyl groups, the remaining variables being as defined herein.

In some embodiments of the invention, ring a is selected from cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted with 1,2 or 3R ^aa, the remaining variables being as defined herein.

In some embodiments of the invention, ring a is selected from cyclobutyl, cyclopentyl or cyclohexyl, the remaining variables being as defined herein.

In some embodiments of the invention, ring A is selected fromThe remaining variables are as defined herein.

In some embodiments of the invention, ring A is selected from The remaining variables are as defined herein.

In another aspect of the invention, the invention also provides a compound of the formula, stereoisomers or pharmaceutically acceptable salts thereof, selected from

In another aspect of the invention, the invention also provides a compound, stereoisomer or pharmaceutically acceptable salt thereof, having one of the structures in table 1 or table 2.

TABLE 1

TABLE 2

In another aspect of the invention, the invention also provides a pharmaceutical composition. In some embodiments of the invention, the pharmaceutical composition comprises a compound as described above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In a further aspect of the invention, the invention also provides the use of a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described for the manufacture of a medicament for the prophylaxis and/or treatment of a CDK7 related disorder.

In some embodiments of the invention, the CDK 7-related disorder is the treatment of a proliferative disorder (e.g., a tumor or cancer), an infectious disorder, an immune disorder, an autoimmune disorder, or an inflammatory disorder.

In a further aspect of the invention, the invention also provides the use of a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as hereinbefore described for the preparation of a CDK7 inhibitor.

In a further aspect of the invention, the invention also provides the use of a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described for the prevention and/or treatment of a CDK 7-related disorder.

In a further aspect of the invention also provides a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described for use in the prevention and/or treatment of a CDK 7-related disorder.

Advantageous effects

The invention has at least one of the following advantages:

1. The compound of the invention has novel structure;

2. The compound has better CDK7 inhibition activity;

3. The compound has higher film permeability, and is helpful for solving the problem of low permeability of oral absorption of the compound in the prior art;

4. The compounds of the present invention have a lower efflux rate (Efflux Ratio) and help to solve the problem of high efflux of the prior art compounds.

Definition and description of terms

Unless otherwise indicated, the radical and term definitions recited in the specification and claims of the present application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combinations of radical definitions and structures should be understood to be within the scope of the present description and/or claims.

The term "optional" (or "optionally", "optionally") in the definition of the general formula of the present application means that the situation is substituted by zero, one or more substituents, e.g. "optionally substituted by one or more R" means that it may be unsubstituted (unsubstituted) or optionally substituted by one, two, three or more R.

"Plurality" means two, three, four or more.

The numerical ranges recited in the specification and claims are equivalent to at least each specific integer number recited therein unless otherwise stated. For example, a numerical range of "1-12" corresponds to each integer number recited in the numerical range of "1-12," i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12.

When one of the variables is selected from a single bond, the two groups representing its attachment are directly linked, such as when L is selected from a single bond, the rings B and O are directly linked.

When the exemplified linking group does not indicate its linking direction, its linking direction is arbitrary, e.gThe linking group M is selected fromIn the time-course of which the first and second contact surfaces,Can be formed by connecting a cyclohexyl group and a phenyl group in the same direction as the reading sequence from left to rightOr can be formed by connecting a cyclohexyl group and a phenyl group in a direction opposite to the reading order from left to rightCombinations of such linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.

Halogen or "halo" means fluorine, chlorine, bromine, or iodine.

The term "alkyl" means a straight or branched chain saturated hydrocarbon containing 1 to 12 carbon atoms. The term "C _1-6 alkyl" denotes straight and branched alkyl groups having 1,2, 3,4, 5 or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl, or 1, 2-dimethylbutyl, or the like, or an isomer thereof. It may be monovalent (e.g., CH ₃), divalent (-CH ₂ -) or multivalent (e.g., secondary))。

The term "hydroxyalkyl" means an alkyl group substituted with one or more —oh groups. Wherein the alkyl groups mentioned have the same definition as the alkyl groups mentioned above. Examples of hydroxyalkyl groups include HO-CH ₂-、HO-CH₂CH₂ -and CH ₂ -CH (OH) -.

The term "haloalkyl" means an alkyl group substituted with one or more halogens. Wherein the alkyl groups mentioned have the same definition as the alkyl groups mentioned above. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

The term "alkenyl" means a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. The "alkenyl" group contains at least one double bond in the chain. The double bond of the alkenyl group may be unconjugated or conjugated to another unsaturated group. The term "C _2-6 alkenyl" denotes straight or branched chain unsaturated hydrocarbons having 2,3, 4,5 or 6 carbon atoms. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutylene, pentenyl, or hexenyl. The alkenyl group may be unsubstituted or substituted, and may be linear or branched.

The term "alkynyl" means a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. The term "C _2-6 alkynyl" denotes straight or branched chain unsaturated hydrocarbons having 2,3, 4,5 or 6 carbon atoms. The "alkynyl" group contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propargyl, n-butynyl, isobutynyl, pentynyl, or hexynyl. Alkynyl groups may be unsubstituted or substituted.

The term "heteroalkyl", by itself or in combination with another term, means a stable, straight or branched chain alkyl radical or combination thereof, consisting of a number of carbon atoms and at least one heteroatom or group of heteroatoms. In some embodiments, the heteroatoms are selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized. In other embodiments, the heteroatom is selected from-C (=o) O-, -C (=o) -, -C (=s) -, -S (=o) ₂-、-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)₂ N (H) -and-S (=o) N (H) -. In some embodiments, the heteroalkyl is a C _1-6 heteroalkyl, and in other embodiments, the heteroalkyl is a C _1-3 heteroalkyl. The heteroatom or heteroatom group may be located at any internal position of the heteroalkyl group, including where the alkyl group is attached to the remainder of the molecule, but the terms "alkoxy," "alkylamino" and "alkylthio" (or thioalkoxy) are conventional expressions and refer to those alkyl groups attached to the remainder of the molecule through an oxygen atom, amino group or sulfur atom, respectively. Examples of heteroalkyl groups include, but are not limited to -OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH₂(CH₃)₂、-CH₂-CH₂-O-CH₃、-NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₃)(CH₂CH₃)、-CH₂-CH₂-NH-CH₃、-CH₂-CH₂-N(CH₃)-CH₃、-SCH₃、-SCH₂CH₃、-SCH₂CH₂CH₃、-SCH₂(CH₃)₂、-CH₂-SCH₂-CH₃、-CH₂-CH₂、-S(＝O)-CH₃、-CH₂-CH₂-S(＝O)₂-CH₃. up to two heteroatoms may be contiguous, such as-CH ₂-NH-OCH₃.

The term "cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated non-aromatic carbocyclic ring containing 3 to 18 carbon atoms. In some embodiments, cycloalkyl is a saturated non-aromatic carbocyclic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl (norboranyl), norbornyl (norborenyl), bicyclo [2.2.2] octyl, or bicyclo [2.2.2] octenyl, and derivatives thereof. (C ₃-C₈) cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. Cycloalkyl groups may be fused (e.g., decalin) or bridged (e.g., norbornane (norbornane)). The term "C _3-12 cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (e.g. fused, bridged, spiro) hydrocarbon ring or tricyclic hydrocarbon ring having 3 to 12 carbon atoms, "C _3-10 cycloalkyl", more preferably "C _3-8 cycloalkyl". The term "C _3-12 cycloalkyl" is understood to mean a saturated monovalent monocyclic, bicyclic (e.g. bridged, spiro) hydrocarbon ring or tricyclic hydrocarbon ring having 3,4, 5,6,7, 8, 9, 10, 11 or 12 carbon atoms. The C _3-12 cycloalkyl group may be a monocyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as campholyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.1] heptenyl, 6-dimethylbicyclo [3.1.1] heptyl, 2, 6-trimethylbicyclo [3.1.1] heptyl, bicyclo [2.2.2] octyl, 2, 7-diazaspiro [3,5] nonyl, 2, 6-diazaspiro [3,4] octyl, or a tricyclic hydrocarbon group such as adamantyl.

The term "heterocyclyl" or "heterocycloalkyl" means a saturated or partially saturated monocyclic or polycyclic ring containing carbon and at least one heteroatom selected from oxygen, nitrogen or sulfur (O, N or S), and wherein there is no common delocalized n-electron (aromaticity) between the ring carbons or heteroatoms. The heterocycloalkyl ring structure may be substituted with one or more substituents. These substituents may themselves be optionally substituted. Examples of heterocycloalkyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxanyl, piperidinyl, morpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azaRadical, oxaBasic, diazaGroup, tolyl, oxazolidonyl, 1, 4-dioxanyl, dihydrofuranyl, 1, 3-dioxolanyl, imidazolidinyl, imidazolinyl, dithiolane, and homotropanyl (homotropanyl). Heterocyclyl may refer to a saturated or unsaturated, non-aromatic ring or ring system having 3 to 14 members, e.g., which is a 3-, 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic (e.g., fused, bridged, spiro) or 10-, 11-, 12-, 13-, or 14-membered tricyclic ring system, and contains at least one, e.g., 1, 2, 3, 4, 5, or more heteroatoms selected from O, S and N, wherein N and S may also optionally be oxidized to various oxidation states to form the nitrogen oxides, -S (O) -or-S (O) ₂ -state. Unless otherwise indicated, the heterocyclyl group may be a carbon or nitrogen group, and the-CH ₂ -group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. In some embodiments, the heterocyclyl is a 5-12 atom heterocyclyl, in other embodiments, the heterocyclyl is a 5-8 atom heterocyclyl, in still other embodiments, the heterocyclyl is a 5-7 atom heterocyclyl, and in still other embodiments, the heterocyclyl is a 5-6 atom heterocyclyl. The heterocyclyl may also be a bicyclic heterocyclyl, in some embodiments the heterocyclyl is a 7-12 atom bicyclic heterocyclyl, in other embodiments the heterocyclyl is a 7-10 atom bicyclic heterocyclyl, and in still other embodiments the heterocyclyl is a 8-10 atom bicyclic heterocyclyl.

The term "aryl" means a cyclic aromatic hydrocarbon group having 1 to 3 aromatic rings (including monocyclic or bicyclic groups), such as phenyl, biphenyl, or naphthyl. When two aromatic rings (bicyclic, etc.) are present, the aromatic rings of the aryl group are optionally attached (e.g., biphenyl) or fused (e.g., naphthyl) at a single point. The aryl group is optionally substituted at any point of attachment with one or more substituents, for example 1 to 5 substituents. The term "C _6-14 aryl" is understood to mean a mono-, bi-, such as fused, bridged, spiro-or tricyclic hydrocarbon ring of monovalent aromatic or partially aromatic nature having 6 to 14 carbon atoms, which may be a mono-aromatic ring or a poly-aromatic ring fused together, such as "C _6-10 aryl". The term "C _6-14 aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6,7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms ("C _6-14 aryl"), in particular a ring having 6 carbon atoms ("C ₆ aryl"), such as phenyl, or biphenyl, or a ring having 9 carbon atoms ("C ₉ aryl"), such as indanyl or indenyl, or a ring having 10 carbon atoms ("C ₁₀ aryl"), such as tetralin, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C ₁₃ aryl"), such as fluorenyl, or a ring having 14 carbon atoms ("C ₁₄ aryl"), such as anthracenyl. When the C _6-20 aryl group is substituted, it may be mono-substituted or poly-substituted. The substitution site is not limited, and may be, for example, ortho, para or meta substitution.

The term "heteroaryl" means a monovalent monocyclic aromatic group or polycyclic aromatic group of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. Heteroaryl as defined herein also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, or S. The aromatic groups are optionally independently substituted with one or more substituents described herein. The term "heteroaryl" is understood to include monovalent monocyclic, bicyclic (e.g., fused, bridged, spiro) or tricyclic aromatic ring systems, for example, having from 5 to 14 ring atoms and containing from 1 to 5 heteroatoms independently selected from N, O and S, such as "5-10 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems which have 5,6,7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which contain 1 to 5, or 1 to 3, heteroatoms which are each independently selected from N, O and S and which additionally may be benzofused in each case. "heteroaryl" also refers to groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherein the attached radical or point is on the heteroaromatic ring. non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl, 1-, 4-, 5-, 6-or, 6-, 7-or 8-phthalazinyl (phthalazinyl), 2-, 3-, 4-, 5-or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 6-or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-or 8-4 aH-carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-or 9-phenanthridinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-or 10-phenanthrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-or 10-phenazinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-or 10-phenazinyl, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-or 10-benzisoquinolinyl, 2-, 3-, 4-or thieno [2,3-b ] furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-or 11-7H-pyrazino [2,3-c ] carbazolyl, 2-, 3-, 5-, 6-or 7-2H-furo [3,2-b ] -pyranyl, 2-, 3-, 4-, 5-, 7-or 8-5H-pyrido [2,3-d ] -o-oxazinyl, 1-, 3-or 5-1H-pyrazolo [4,3-d ] -oxazolyl, 2-, 4-or 54H-imidazo [4,5-d ] thiazolyl, 3-, 5-or 8-pyrazino [2,3-d ] pyridazinyl, 2-, 3-, 5-or 6-imidazo [2,1-b ] thiazolyl, 1-, 3-, 6-, 7-, 8-or 9-furo [3,4-c ] cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10-or 11-4H-pyrido [2,3-c ] carbazolyl, 2-, 3-, 6-or 7-imidazo [1,2-b ] [1,2,4] triazinyl, 7-benzo [ b ] thienyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 2-, 4-, 5-, 6-or 7-benzimidazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-or 9-benzoxazolyl (benzoxapinyl), 2-, 4-, 5-, 6-, 7-or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-or 11-4H-pyrrolo [1,2-b ] [2] benzazepine (benzazapinyl). Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 2-, 3-, 4-, 5-, 6-or 7-benzo [ b ] thienyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 2-, 4-, 5-, 6-or 7-benzimidazolyl, and 2-, 4-, 5-, 6-or 7-benzothiazolyl. When the 5-14 membered heteroaryl is attached to other groups to form the compounds of the invention, the carbon atom on the 5-14 membered heteroaryl ring may be attached to other groups, or the heteroatom on the 5-14 membered heteroaryl ring may be attached to other groups. When the 5-14 membered heteroaryl is substituted, it may be mono-substituted or poly-substituted. And, the substitution site thereof is not limited, and for example, hydrogen attached to a carbon atom on a heteroaryl ring may be substituted, or hydrogen attached to a heteroatom on a heteroaryl ring may be substituted.

The term "spiro" refers to a ring system in which two rings share 1 ring-forming atom.

The term "fused ring" refers to a ring system in which two rings share 2 ring atoms.

The term "bridged ring" refers to a ring system in which two rings share more than 3 ring members.

The term "halogen" means fluorine, chlorine, bromine and iodine.

"Halo" refers to substitution with one or more halogens.

The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds may be labeled with a radioisotope, such as deuterium (² H), tritium (³ H), iodine-125 (¹²⁵ I) or C-14 (¹⁴ C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention. In some embodiments of the invention, H is deuterium or tritium.

By "salt" is meant the ionic form of the parent compound or the reaction between the parent compound and a suitable acid or base to produce the product of an acid or base salt of the parent compound. Salts of the compounds of the present disclosure may be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Typically, salts are prepared by reacting the free basic or acidic parent compound with a stoichiometric amount or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or different solvent combination.

By "pharmaceutically acceptable salt" is meant a salt of a compound of the present disclosure, which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, typically water-soluble or oil-soluble or dispersible, and are effective for its intended use. The term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. Since the compounds of the present disclosure are useful in both the free base form and the salt form, the use of the salt form in practice corresponds to the use of the base form. A list of suitable salts is found, for example, in S.M. Birge et al, J.Pharm.Sci. [ J.pharmaceutical sciences ],1977,66, pages 1-19, which is hereby incorporated by reference in its entirety.

By "pharmaceutically acceptable acid addition salts" is meant those salts which retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable, and which are formed with inorganic (e.g., hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, nitric, phosphoric, etc.) and organic (e.g., acetic, trichloroacetic, trifluoroacetic, adipic, alginic, ascorbic, aspartic, benzenesulfonic, benzoic, 2-acetoxybenzoic, butyric, camphoric, camphorsulfonic, cinnamic, citric, digluconic, ethanesulfonic, glutamic, glycolic, glycerophosphoric, hemisulfuric, heptanoic, caproic, formic, fumaric, 2-hydroxyethanesulfonic (hydroxyethanesulfonic), lactic, maleic, hydroxymaleic, malic, malonic, mandelic, mesitylene, methanesulfonic, naphthalenesulfonic, nicotinic, 2-naphthalenesulfonic, oxalic, pamoic, pectic, phenylacetic, 3-phenylpropionic, picric, pivalic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, p-toluenesulfonic, undecanesulfonic, and the like).

By "pharmaceutically acceptable base addition salts" is meant those salts which retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable, and which are formed with inorganic bases (e.g., ammonia or hydroxides, carbonates, or ammonium bicarbonate) or metal cations (e.g., sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc.). Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, quaternary amine compounds, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ion exchange resins such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N-dibenzylphenylamine, 1-dibenzenehydroxylamine, N' -dibenzylethylenediamine, polyamine resins and the like.

The compounds of the present disclosure, as discussed below, include the free base or acid or salt thereof, particularly the pharmaceutically acceptable forms thereof. Such forms (particularly pharmaceutically acceptable forms) are intended to be encompassed by the appended claims.

"Isomers" means compounds having the same number and kind of atoms, and therefore the same molecular weight, but differing in the arrangement or configuration of atoms in space. The term includes stereoisomers and geometric isomers.

"Stereoisomers" or "optical isomers" means stable isomers having at least one chiral atom or limited rotation resulting in a plane of perpendicular asymmetry (e.g., certain biphenyls, allenes, and spiro compounds) and which can rotate plane polarized light. Because asymmetric centers and other chemical structures are present in compounds of the present disclosure that can lead to stereoisomers, the present disclosure contemplates stereoisomers and mixtures thereof. The compounds of the present disclosure and salts thereof include asymmetric carbon atoms and thus may exist as individual stereoisomers, racemates, and mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture. However, if desired, such compounds may be prepared or isolated as stereoisomers, i.e., as individual enantiomers or diastereomers, or as a mixture of enriched stereoisomers. As discussed in more detail below, individual stereoisomers of the compounds are prepared by synthesis from optically active starting materials containing the desired chiral center, or by preparation of a mixture of enantiomeric products followed by separation or resolution (e.g., conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns). The starting compounds of a particular stereochemistry are commercially available or prepared by the methods described below and resolved by techniques well known in the art.

"Enantiomer" means a pair of stereoisomers that are not mirror images of each other in an overlapping manner.

"Diastereoisomers" or "diastereomers" mean optical isomers that do not form mirror images of one another.

"Racemic mixture" or "racemate" means a mixture containing equal parts of individual enantiomers.

"Non-racemic mixture" means a mixture containing unequal portions of individual enantiomers.

"Geometric isomer" means a stable isomer produced by rotational degree of freedom limitation in double bonds (e.g., cis-2-butene and trans-2-butene) or ring structures (e.g., cis-1, 3-dichlorocyclobutane and trans-1, 3-dichlorocyclobutane). Because carbon-carbon bis (olefinic) bonds, c=n double bonds, ring structures, and the like may be present in the compounds of the present disclosure, the present disclosure contemplates each of the different stable geometric isomers and mixtures thereof arising from the arrangement of substituents around these double bonds and in these ring structures. Substituents and isomers are indicated using cis/trans convention or using the E or Z system, where the term "E" means that the higher order substituents are on opposite sides of the double bond and the term "Z" means that the higher order substituents are on the same side of the double bond. A thorough discussion of E and Z isomerism is provided in J.March, advanced Organic Chemistry: reactions, MECHANISMS, and Structure [ higher organic chemistry: reactions, mechanisms and structures ], 4 th edition, john Wiley & Sons [ John Weil father-son publishing Co., ltd ],1992, which is hereby incorporated by reference in its entirety. The following examples represent individual E isomers, individual Z isomers, and mixtures of E/Z isomers. Determination of the E and Z isomers can be performed by analytical methods such as X-ray crystallography, ¹ H NMR, and ¹³ C NMR.

Some compounds of the present disclosure may exist in more than one tautomeric form. As mentioned above, the compounds of the present disclosure include all such tautomers.

As used herein, the term "pharmaceutical composition" refers to a compound of the present disclosure, or a pharmaceutically acceptable salt or stereoisomer thereof, in a form suitable for oral or parenteral administration, and at least one pharmaceutically acceptable carrier.

"Carrier" encompasses carriers, excipients, and diluents, and means materials, compositions, or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, that are involved in carrying or transporting a pharmaceutical agent from one organ or body part of a subject to another organ or body part of a subject.

The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.

The term "therapeutically effective amount" refers to that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought by a researcher, veterinarian, medical doctor or other clinician in a tissue, system, animal, individual or human, which includes one or more of (1) preventing a disease, disorder or condition, e.g., in an individual susceptible to the disease, disorder or condition but not yet experiencing or developing the pathology or symptomatology of the disease. (2) Inhibiting a disease, disorder or condition (i.e., preventing further development of pathology and/or symptoms), for example, in an individual experiencing or presenting with the pathology or symptoms of the disease, disorder or condition. (3) Alleviation of a disease, disorder or condition (i.e., reversing the pathology and/or symptomatology) such as in an individual experiencing or developing the pathology or symptomatology of the disease, disorder or condition.

Detailed Description

The technical scheme of the present disclosure will be described in further detail below with reference to specific embodiments. It should be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the present disclosure. All techniques implemented based on the foregoing disclosure are intended to be within the scope of the disclosure.

Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.

Abbreviations used herein extend throughout the present invention.

HATU stands for 2- (7-azabenzotriazol) -N, N' -tetramethylurea hexafluorophosphate.

Example 1

To a solution of compound 1-1 (50.0 g,203 mmol) in THF (300 mL) at-78deg.C was slowly added dropwise a solution of vinylmagnesium bromide in THF (1M, 812mL,812 mmol), after which the mixture was allowed to warm to room temperature naturally under nitrogen and stirred for 16 hours. The pH of the reaction solution was adjusted to 4 to 5 with 1M hydrochloric acid, and the reaction solution was extracted with ethyl acetate (300 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give crude compound 1-2 (50.0 g), which was used in the next reaction without purification.

To a solution of compound 1-2 (50.0 g,209 mmol) in DMF (250 mL) was added methyl iodide (32.5 g,229 mmol) and potassium carbonate (57.5 g,417 mmol) at 25 ℃. The reaction solution was stirred at 25 ℃ under nitrogen for 16 hours. The reaction mixture was added with water (500 mL), extracted with ethyl acetate (500 mL. Times.3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1-3 (27.5 g, yield 53%) as a crude product by silica gel column chromatography.

LCMS:m/z(ESI):253.7[M+H]⁺。

To a solution of compounds 1-3 (20.0 g,78.7 mmol) in dimethyl sulfoxide (250 mL) was added palladium acetate (2.65 g,11.8 mmol), 1, 4-bis (diphenylphosphine) butane (5.04 g,11.8 mmol), potassium phosphate (157 g,33.4 mmol) in this order at 25 ℃. Dimethyl phosphine oxide (12.3 g,157 mmol) was added and stirred under nitrogen for 5 minutes, warmed to 60 ℃ and stirred for 0.5 hours, and heated to 135 ℃ and stirred for 2 hours. The reaction mixture was diluted with water (200 mL), and extracted with ethyl acetate (200 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the crude product was purified by silica gel column chromatography to give compounds 1-4 (9.0 g, yield 45%). LCMS: m/z (ESI): 252.0[ M+H ] ⁺.

In a 50mL three-necked flask, aluminum trichloride (5.57 g,41.8 mmol) was added, nitrogen was replaced, a solution of compounds 1-4 (5.00 g,19.9 mmol) in 1, 2-dichloroethane (50 mL) was added, stirring was performed at 85℃for 30 minutes, a solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (4.75 g,21.9 mmol) in 1, 2-dichloroethane (5 mL) was added, and the reaction was continued at 85℃for 16 hours. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL. Times.3), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give compound 1-5 (4.2 g, yield 49%). LCMS: m/z (ESI): 431.7[ M+H ] ⁺.

To a solution of compounds 1-6 (500 mg,3.63 mmol) in DMF (10 mL) was added benzyl bromide (1.86 g,10.9 mmol) and potassium carbonate (2.05 g,14.8 mol). The reaction solution was stirred under nitrogen at 25 ℃ for 16 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (15 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product obtained was purified by silica gel column chromatography to give compounds 1 to 7 (800 mg, yield 58%).

LCMS:m/z(ESI):282.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆):δ7.36–7.27(m,8H),7.24–7.16(m,2H),4.50(d,J＝3.6Hz,1H),4.32–3.90(m,1H),3.62–3.49(m,4H),3.15–3.03(m,1H),1.97–1.88(m,1H),1.78–1.56(m,2H),1.54–1.36(m,3H).

To a solution of compounds 1-7 (51.0 g,181 mmol) in THF (500 mL) was added triphenylphosphine (95.1 g,362 mmol) and p-nitrobenzoic acid (60.6 g,362 mmol). The reaction solution was cooled to 0℃under nitrogen and diethyl azodicarboxylate (63.1 g,362 mmol) was added. Stirred at 25 ℃ for 3 hours. The reaction solution was poured into ice water (1L), extracted with ethyl acetate (500 mL. Times.2), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration, and the crude product was purified by silica gel column chromatography to give compounds 1-8 (57.0 g, yield 73％).LCMS:m/z(ESI):431.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆):δ8.31(d,J＝8.8Hz,2H),8.08(d,J＝8.8Hz,2H),7.39–7.27(m,8H),7.26–7.15(m,2H),5.41–5.31(m,1H),3.65–3.55(m,4H),3.51–3.39(m,1H),2.21–2.10(m,1H),2.01–1.93(m,2H),1.93–1.83(m,1H),1.76–1.56(m,2H).

To a mixed solution of compounds 1-8 (57.0 g,132 mmol) in water (50 mL), methanol (150 mL) and tetrahydrofuran (150 mL) was added lithium hydroxide monohydrate (27.8 g,62 mmol) at 25 ℃. The reaction was stirred at 50 ℃ for 3 hours. The reaction mixture was diluted with water (200 mL), extracted with ethyl acetate (50 mL. Times.3), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give compounds 1 to 9 (30.0 g, yield) 81％).LCMS:m/z(ESI):282.0[M+H]⁺.1H NMR(400MHz,DMSO-d₆):δ7.38–7.25(m,8H),7.24–7.16(m,2H),4.37(d,J＝3.2Hz,1H),4.17–4.03(m,1H),3.52(s,4H),3.43–3.35(m,1H),1.86–1.72(m,2H),1.70–1.55(m,2H),1.55–1.44(m,1H),1.44–1.31(m,1H).

Sodium hydride (7.11 g,178mmol,60% wt.) was slowly added to a solution of compounds 1-9 (5.00 g,17.8 mmol) in DMF (200 mL) under nitrogen at 0 ℃. After stirring at this temperature for 0.5 hours, 1, 4-diiodobutane (55.0 g,178 mmol) was added, followed by stirring at 50℃for 3 hours. The reaction solution was quenched by adding saturated aqueous ammonium chloride (500 mL. Times.3), extracted with ethyl acetate (300 mL. Times.3), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to give compounds 1 to 10 (1.90 g, yield) 23％).LCMS:m/z(ESI):464.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆):δ7.41–7.25(m,8H),7.25–7.14(m,2H),3.90–3.76(m,1H),3.57–3.50(m,4H),3.33–3.22(m,5H),2.08–1.61(m,6H),1.61–1.17(m,4H).

To a solution of compounds 1-10 (1.90 g,4.10 mmol) in DMF (50 mL) was added bis (t-butoxycarbonyl) amine (1.80 g,8.20 mmol) and cesium carbonate (4.00 g,12.3 mmol). The reaction solution was stirred at 25 ℃ for 16 hours. The reaction mixture was quenched with water (300 mL), extracted with ethyl acetate (100 mL. Times.3), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained was purified by silica gel column chromatography to give compounds 1 to 11 (2.20 g, yield 97%).

LCMS:m/z(ESI):553.6[M+H]⁺.¹H NMR(400MHz,DMSO-d₆):δ7.37–7.25(m,8H),7.23–7.16(m,2H),3.87–3.78(m,1H),3.53(s,4H),3.43(t,J＝7.2Hz,2H),3.27–3.18(m,3H),1.98–1.41(m,28H).

To a solution of compounds 1-11 (3.00 g,5.4 mmol) in isopropanol (30 mL) was added Pd/C (300 mg,10% wt.,55% water). The reaction solution was stirred under hydrogen at 80 ℃ for 18 hours. The reaction solution was concentrated by filtration to give compounds 1 to 12 (1.82 g, yield 90%). The crude product was used in the next reaction without purification. LCMS: m/z (ESI): 373.2[ M+H ] ⁺.

To a solution of 1-5 (2.10 g,4.83 mmol) and 1-12 (1.80 g,4.83 mmol) in NMP (20 mL) was added N, N-diisopropylethylamine (4.00 mL,24.2 mmol). After stirring at 130℃for 4 hours, cooling to room temperature, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (5 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product obtained was purified by silica gel column chromatography to give compound 1-13 (2.20 g, yield 47%).

LCMS:m/z(ESI):768.2[M+H]⁺。

Compounds 1-13 (2.20 g,2.87 mmol) were dissolved in a mixed solvent of THF (30 mL), methanol (30 mL) and water (10 mL), and lithium hydroxide monohydrate (0.60 g,14.3 mmol) was added. The reaction solution was stirred at 50 ℃ for 18 hours. After the completion of the reaction, the reaction mixture was concentrated by rotary evaporation to give compounds 1 to 14 (2.90 g). The crude product was used in the next reaction without purification.

LCMS:m/z(ESI):654.2[M+H]⁺。

To a solution of compounds 1-14 (2.90 g) in acetonitrile (30 mL) was added hydrochloric acid (30 mL,4M dioxane solution). The reaction solution was stirred at 45 ℃ for 1 hour. After completion of the reaction, the reaction mixture was concentrated and dried to give a residue, which was purified by reverse phase preparation (Xtimate C, 50*250mm,10um,10mM NH ₄HCO₃) to give compounds 1 to 15 (0.35 g). LCMS: m/z (ESI): 554.2[ M+H ] ⁺.

To a solution of compounds 1-15 (350 mg,0.63 mmol) in DMSO (20 mL) was added HATU (289 mg,0.80 mmol) and N, N-diisopropylethylamine (0.52 mL,3.16 mmol). The reaction solution was stirred at 60 ℃ for 18 hours. After completion of the reaction, water (1 mL) was added and the reaction was purified by reverse phase preparation (Xtimate C, 80 x 250mm,10um,0.1% TFA) to give compound 1 (79.5 mg, 24% yield).

LCMS:m/z(ESI):536.2[M+H]⁺.¹H NMR(400MHz,CD₃OD):δ8.81(d,J＝8.4Hz,1H),8.50(s,1H),8.11(s,1H),7.31(dd,J＝8.4,3.2Hz,1H),4.59–4.42(m,1H),4.05–3.91(m,1H),3.22–3.08(m,2H),2.92–2.78(m,2H),2.63–2.48(m,1H),2.26–2.13(m,2H),2.05–1.94(m,6H),1.89–1.70(m,2H),1.68–1.55(m,3H),1.48–1.38(m,1H),1.36–1.28(m,1H).

Example 2

Compound 2-1 (35 g,228 mmol) was added to a 33% solution of methylamine in ethanol (400 mL) at 25 ℃. The reaction solution was stirred at room temperature for 12 hours under nitrogen protection. After the reaction solution was concentrated to dryness by rotary evaporation, methylene chloride (500 mL), di-tert-butyl dicarbonate (102 mL, 4476 mmol) and triethylamine (93 mL,669 mmol) were added, and stirring was continued at room temperature for 16 hours. After the completion of the reaction, the reaction mixture was diluted with water (300 mL) and extracted with methylene chloride (500 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product obtained was purified by silica gel column chromatography to give compound 2-2 (21.0 g, yield 45%). LCMS: m/z (ESI): 226.0[ M+Na ] ⁺.

Triphenylphosphine (64.5 g,246 mmol) and imidazole (17 g,246 mmol) were added to a solution of compound 2-2 (21.0 g,92.9 mmol) in dichloromethane (300 mL) at 25 ℃. The reaction mixture was cooled to 0℃under nitrogen, and elemental iodine (62.0 g,246 mmol) was added thereto, followed by heating to 25℃and stirring for 2 hours. The reaction mixture was quenched with saturated sodium thiosulfate, and extracted with methylene chloride (500 mL. Times.2). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product obtained was purified by silica gel column chromatography to give compound 2-3 (30.0 g, yield 78%). LCMS: m/z (ESI): 258.2[ M-56] ⁺.

To a solution of compounds 1-9 (5.00 g,17.7 mmol) in DMF (100 mL) was added sodium hydride (3.60 g,88.8mmol,60% wt) at ice water bath temperature. The reaction solution was stirred under nitrogen for 1 hour. Compound 2-3 (6.70 g,21.3 mmol) was added and then warmed to 25℃and stirred for 18 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (30 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product obtained was purified by silica gel column chromatography to give compound 2-4 (2.75 g, yield) 33％).LCMS:m/z(ESI):467.2[M+1]⁺.1H NMR(400MHz,DMSO-d₆):δ7.33–7.18(m,10H),3.84–3.82(m,1H),3.55–3.50(m,4H),3.30–3.24(m,3H),3.11–3.08(m,2H),2.71(s,3H),1.86–1.60(m,4H),1.51–1.37(m,15H).

To a solution of compounds 2-4 (2.75 g,5.89 mmol) in isopropanol (30 mL) was added palladium on carbon (600 mg,5.89mmol,10% wt.,50% water) at 25 ℃. Heated to 80 ℃ and stirred under a hydrogen system for 16 hours. The crude compound 2-5 (1.60 g, yield 95%) was then concentrated by filtration and used in the next reaction without purification. LCMS: m/z (ESI): 287.4[ M+H ] ⁺.

In a 100mL single-necked flask, compound 2-5 (1.60 g,5.57 mmol), N-methylpyrrolidone (20 mL), N-diisopropylethylamine (0.580 mL,3.49 mmol) and compound 1-5 (1.50 g,3.49 mmol) were added sequentially. After reaction at 130℃for 2 hours, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration, and the obtained crude product was purified by silica gel column chromatography to give compound 2-6 (2.00 g, yield 84%). LCMS: m/z (ESI): 682.2[ M+H ] ⁺.

Compound 2-6 (2.00 g,2.93 mmol) was dissolved in a mixed system of water (15 mL), methanol (3 mL) and tetrahydrofuran (15 mL), then lithium hydroxide monohydrate (100 mg,2.93 mmol) was added, stirring was performed at 50℃for 6 hours, and after completion of the reaction, the solvent was directly spun dry to give crude compound 2-7 (2.00 g, yield 91%) which was used directly in the next reaction without purification. LCMS: m/z (ESI): 668.3[ M+H ] ⁺.

Compound 2-7 (2.00 g,2.99 mmol) was dissolved in hydrogen chloride/dioxane (20 mL, 4M) and stirred at 60℃for 1 hour, after which the solvent was directly spun dry to give the crude product which was purified by reverse phase preparation (Xtimate C, 50*250mm,5um,10mM NH ₄HCO₃) to give compound 2-8 (850 mg, yield 50%). LCMS: m/z (ESI): 568.2[ M+H ] ⁺.

To a solution of compound 2-8 (400 mg,0.700 mmol) in DMF (10 mL) was added HATU (321 mg,0.84 mmol) and N, N-diisopropylethylamine (0.35 mL,2.11 mmol) in sequence, and the reaction was stirred at 60℃for 2h. After the reaction, the crude product obtained by concentrating the reaction mixture was purified by reverse phase preparation (Xtimate C, 21.2 x 250mm,5um,0.1% TFA) to give compound 2 (123 mg, yield) 31％).LCMS:m/z(ESI):550.0[M+H]⁺.¹H NMR(400MHz,CD₃OD):δ8.71(d,J＝7.6Hz,1H),8.51(s,1H),8.10(s,1H),7.27(dd,J＝8.4,3.2Hz,1H),4.59–4.50(m,1H),4.01–3.94(m,1H),3.20–3.03(m,6H),2.93–2.85(m,1H),2.54–2.50(m,1H),2.24–2.11(m,2H),1.98–1.84(m,7H),1.80–1.31(m,6H).

Example 3

To a solution of compound 2-5 (2.23 g,7.79 mmol) in THF (40 mL) was added 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1.69 g,7.79 mmol) and N, N-diisopropylethylamine (3.02 g,23.4 mmol). The reaction solution was stirred at 20 ℃ for 18 hours. The reaction mixture was diluted with water (50 mL), and extracted with ethyl acetate (100 mL. Times.2). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. Purifying the crude product by silica gel column chromatography to obtain the compound 3-1(1.2g).LCMS:m/z(ESI):467.4[M+H]⁺.¹H NMR(400MHz,CDCl₃):δ8.53–8.30(m,1H),5.74–5.48(m,1H),4.53–4.41(m,1H),4.01–3.95(m,1H),3.38(t,J＝6.0Hz,2H),3.26–3.18(m,2H),2.83(s,1H),2.32–2.16(m,2H),2.03–1.94(m,1H),1.83–1.70(m,2H),1.67–1.60(m,1H),1.59–1.50(m,4H),1.45(s,9H).

To a 100mL single vial was added compound 3-2 (300 mg,1.96 mmol), DMF (5 mL), zinc cyanide (255 mg,2.16 mmol), and palladium tetraphenylphosphine (227 mg, 0.197mmol) in this order. The reaction was carried out at 120℃for 18 hours. After the completion of the reaction, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL. Times.3), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration, and the obtained crude product was purified by silica gel column chromatography to give compound 3-3 (100 mg, 35%).

LCMS:m/z(ESI):144.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆):δ12.25(s,1H),8.18(d,J＝8.0Hz,1H),7.84(d,J＝3.2Hz,1H),7.62(d,J＝8.0Hz,1H),6.64(d,J＝3.2Hz,1H).

To a solution of compound 3-3 (100 mg,0.699 mmol) in DMF (1 mL) was added N-iodosuccinimide (157 mg,0.699 mmol) at 25 ℃. The reaction solution was stirred under nitrogen for 18 hours. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (10 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product obtained was purified by silica gel column chromatography to give the compound 3-4(140mg,74％).LCMS:m/z(ESI):270.0[M+1]⁺.¹H NMR(400MHz,DMSO-d₆):δ12.70(s,1H),8.10(d,J＝2.4Hz,1H),7.91(d,J＝8.0Hz,1H),7.71(d,J＝8.0Hz,1H).

To a solution of compounds 3-4 (10.5 g,39.0 mmol) in dichloromethane (120 mL) under nitrogen, 4-dimethylaminopyridine (500 mg,3.90 mmol), triethylamine (11.9 g,117 mmol) and di-tert-butyl dicarbonate (10.2 g,46.8 mmol) were added. The reaction solution was stirred at 20 ℃ for 7 hours. After completion of the reaction, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (200 mL. Times.2), and the combined organic layers were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. Purifying the crude product by silica gel column chromatography to obtain the compound 3-5(12.0g,83％).LCMS:m/z(ESI):313.8[M+H-56]⁺.¹H NMR(400MHz,DMSO-d₆):δ8.30(s,1H),8.00(d,J＝8.0Hz,1H),7.94(d,J＝8.0Hz,1H),1.62(s,9H).

To a pressure-resistant tube was added a solution of compound 3-5 (2.00 g,5.42 mmol) in THF (20 mL) under nitrogen, pd ₂(dba)₃ (248 mg, 0.271mmol), XPhos (129 mg, 0.271mmol), triethylamine (2.74 g,27.1 mmol) and pinacol borane (3.47 g,27.1 mmol) in sequence. The reaction solution was stirred at 90 ℃ for 10 hours. After the completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product obtained was purified by silica gel column chromatography to give compound 3-6 (1.10 g, 55%).

LCMS:m/z(ESI):314.4[M+H-56]⁺.¹H NMR(400MHz,CDCl₃):δ8.35(d,J＝8.0Hz,1H),8.26(s,1H),7.61(d,J＝8.0Hz,1H),1.69(S,9H),1.37(s,12H).

To a mixed solvent of compound 3-6 (1.00 g,2.71 mmol) and tetrahydrofuran (10 mL) and water (2 mL) were added compound 3-1 (1.26 g,2.71 mmol), chloro [ (n-butylbis (1-adamantyl) phosphine) -2- (2-aminobiphenyl) ] palladium (II) (181 mg,0.27 mmol) and tripotassium phosphate (1.73 g,8.13 mmol). The reaction solution was stirred at 60 ℃ for 16 hours. After the completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product obtained was purified by silica gel column chromatography to give compound 3-7 (1.50 g, 82%).

LCMS:m/z(ESI):696.4[M+Na]⁺。

A mixed solution of compounds 3-7 (1.50 g,2.23 mmol) in acetic acid (10 mL) and concentrated hydrochloric acid (5 mL) was stirred at 120℃for 16h. After the reaction is completed, the reaction solution is directly dried by spin. The crude product obtained was prepared in reverse phase (Xtimate C, 80 x 250mm,10um,0.05% nh ₃.H₂ O) to give the compound 3-8(800mg,73％).LCMS:m/z(ESI):493.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆):δ8.89–8.69(m,1H),8.63–8.51(m,1H),8.19(s,1H),8.06–7.83(m,2H),7.30–7.09(m,2H),4.64–4.41(m,1H),4.04–3.90(m,1H),2.96–2.83(m,2H),2.56(s,3H),2.35–2.19(m,3H),2.15–1.90(m,2H),1.79–1.39(m,8H).

To a solution of compound 3-8 (500 mg,1.02 mmol) in DMF (30 mL) was added N, N-diisopropylethylamine (393 mg,3.05 mmol) and HATU (463 mg,1.22 mmol). The reaction solution was stirred at 60 ℃ for 24 hours. After the reaction was completed, the reaction solution was concentrated by filtration. The crude product obtained was prepared by reverse phase (Xtimate C, 21.2 x 250mm,5um,0.1% TFA) to give the compound 3(56mg,11％).LCMS:m/z(ESI):475.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆):δ12.39(d,J＝2.4Hz,1H),8.67(d,J＝8.0Hz,1H),8.58(s,1H),8.07(d,J＝5.6Hz,1H),7.91(d,J＝2.0Hz,1H),7.19(d,J＝8.0Hz,1H),4.23–4.12(m,1H),3.93–3.80(m,1H),2.97(s,3H),2.92–2.74(m,4H),2.44–2.35(m,1H),2.13–1.94(m,2H),1.83–1.69(m,1H),1.64–1.47(m,2H),1.45–1.35(m,1H),1.34–1.24(m,2H),1.19–1.06(m,1H).

Example 4

To a dry 500mL three-necked flask was added aluminum trichloride (38.0 g, 284 mmol) under nitrogen, a solution of Compound 4-1 (25.0 g,143 mmol) in 1, 2-dichloroethane (300 mL). After stirring at 80℃for 30 minutes, a solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (31.0 g,143 mmol) in 1, 2-dichloroethane (50 mL) was added. The reaction was continued at 80 ℃ for 16 hours. After completion of the reaction, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (300 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The obtained crude product is reversely prepared and purified to obtain the compound 4-2(20.0g,39％).LCMS:m/z(ESI):356.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆):δ12.51(s,1H),9.07(s,1H),8.39(d,J＝8.4Hz,1H),8.28(d,J＝2.4Hz,1H),8.21(d,J＝1.6Hz,1H),7.84(dd,J＝8.4,1.6HZ,1H),3.89(s,3H).

In a 250mL single vial, compound 4-2 (10.0 g,28.1 mmol), NMP (300 mL), N-diisopropylethylamine (13.9 mL,84.3 mmol), and tert-butyl ((1S, 3S) -3-aminocyclopentyl) carbamate (6.20 g,30.9 mmol) were added sequentially. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (200 mL. Times.3) at 130℃for 4 hours. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product obtained was purified by silica gel column chromatography to give compound 4-3 (8.00 g, 54%). LCMS: m/z (ESI): 520.2[ M+H ] ⁺.

To a solution of compound 4-3 (8.10 g,15.5 mmol) in methanol (40 mL) was added hydrogen chloride/ethyl acetate solution (40 mL, 4M) at room temperature. After 2 hours of reaction at 40 ℃, the reaction mixture was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (100 ml×3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product obtained was purified by silica gel column chromatography to give compound 4-4 (4.00 g, 61%). LCMS: m/z (ESI): 420.2[ M+H ] ⁺.

To a solution of compound 4-4 (2.00 g,4.76 mmol) in DMF (30 mL) were added tert-butyl (4-bromobutyl) carbamate (1.80 g,7.15 mmol), N-diisopropylethylamine (4.74 mL,28.6 mmol) and sodium iodide (71.4 mg,0.47 mmol) in this order. After stirring at 80℃for 12 hours, the mixture was cooled to room temperature, and the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product obtained was purified by silica gel column chromatography to give compound 4-5 (1.30 g, 46%). LCMS: m/z (ESI): 591.2[ M+H ] ⁺.

To a methanol solution (20 mL) of compound 4-5 (1.30 g,2.20 mmol) was added paraformaldehyde (660 mg,22.0 mmol), acetic acid (0.01 mL), palladium on carbon (400 mg,10% wt.,55% water) in this order. The reaction was stirred under hydrogen atmosphere at 70 ℃ for 2 hours. After completion of the reaction, palladium on carbon was filtered off, and the solvent in the filtrate was dried by spin-drying, diluted with water (20 mL), and extracted with ethyl acetate (20 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. Purifying the crude product by column chromatography to obtain the compound 4-6(1.20g,90％).LCMS:m/z(ESI):605.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆):δ12.27–12.02(m,1H),8.68–8.53(m,1H),8.49–8.28(m,2H),8.21–7.97(m,2H),7.84–7.73(m,1H),6.89–6.75(m,1H),4.46–4.34(m,1H),3.94–3.87(m,3H),3.19(s,3H),3.15–3.03(m,1H),2.96–2.87(m,2H),2.48–2.40(m,2H),2.28–2.17(m,3H),2.16–2.05(m,1H),2.00–1.89(m,4H),1.88–1.78(m,1H),1.68–1.56(m,1H),1.38–1.34(m,9H).

Compound 4-6 (1.20 g,1.98 mmol) was dissolved in a mixed solvent of water-methanol-tetrahydrofuran (21 mL, 1:3:3), followed by addition of lithium hydroxide monohydrate (416 mg,9.92 mmol). The reaction solution was stirred at 50 ℃ for 3 hours, and after the reaction was completed, the solvent was directly spin-dried. The crude compound 4-7 (1.20 g, 82%) was obtained and used in the next reaction without purification.

LCMS:m/z(ESI):591.2[M+H]⁺。

Compound 4-7 (1.20 g,2.03 mmol) was dissolved in dioxane hydrochloride solution (15 mL, 4M). After stirring at 50 ℃ for 1 hour, the solvent was directly spin-dried. The crude product obtained was purified by reverse phase preparation (Xtimate C, 50*250mm,10um,10mM NH ₄HCO₃) to give compound 4-8 (500 mg, 50%). LCMS: m/z (ESI): 491.2[ M+H ] ⁺.

To a solution of compound 4-8 (300 mg,0.61 mmol) in DMF (5 mL) was added HATU (279 mg,0.73 mmol) and N, N-diisopropylethylamine (0.30 mL,1.83 mmol) in sequence. The reaction solution was stirred at 60℃for 16h, and after the reaction was completed, the reaction solution was concentrated by rotary evaporation. The crude product obtained was purified by reverse phase preparation (Xtimate C, 50 x 250mm,10um,0.1% TFA) to give compound 4 (19.2 mg).

LCMS:m/z(ESI):473.0[M+H]⁺.¹H NMR(400MHz,CD₃OD):δ8.55(s,1H),8.31(d,J＝8.4Hz,1H),7.89(s,1H),7.64(s,1H),7.34(d,J＝8.4Hz,1H),4.37–4.23(m,1H),4.06–3.84(m,1H),3.20–2.96(m,3H),2.82–2.74(m,1H),2.73(s,3H),2.63–2.53(m,1H),2.32–2.19(m,2H),1.98–1.70(m,6H),1.63–1.53(m,1H).

Example 5

Synthesis of Compound 5 referring to the synthetic route of Compound 4, the synthetic raw material of intermediate 5-1, tert-butyl (4-iodobutyl) (methyl) carbamate, was substituted for the raw material of intermediate 4-5, tert-butyl (4-bromobutyl) carbamate.

Obtaining the compound 5(16.2mg).LCMS:m/z(ESI):487.2[M+H]⁺.¹H NMR(400MHz,CD₃OD):δ8.48(s,1H),8.38(d,J＝8.4Hz,1H),7.89(s,1H),7.57(d,J＝0.8Hz,1H),7.26(dd,J＝8.4,1.6Hz,1H),4.25–4.09(m,1H),3.29–3.25(m,2H),3.10(s,3H),3.08–2.98(m,1H),2.69–2.56(m,1H),2.53–2.40(m,1H),2.21–2.10(m,4H),2.08–1.95(m,3H),1.88–1.57(m,3H),1.54–1.31(m,3H).

Example 6

To a solution of compound 6-1 (20.0 g,114 mmol) in tetrahydrofuran (200 mL) was added carbonyldiimidazole (20.4 g,126 mmol) at 5℃under nitrogen. The reaction solution was stirred under these conditions for 14 hours. To the reaction mixture were added magnesium chloride (12.0 g,126 mmol) and monomethyl malonate potassium salt (17.8 g,114 mmol). The temperature was raised to 45℃and the reaction stirred for 4 hours. After completion of the reaction, the reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL. Times.3). The combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product was purified by column chromatography to give Compound 6-2 (25.3 g, yield) 96％).¹H NMR(400MHz,DMSO-d₆):δ7.12(t,J＝5.6Hz,1H),3.85(d,J＝6.0Hz,2H),3.63(s,3H),3.59(s,2H),1.38(s,9H).

To a solution of compound 6-2 (15.0 g,64.9 mmol) in DCM (200 mL) at 5℃under nitrogen was added diethylaminosulfur trifluoride (20.9 g,130 mmol). The reaction solution was stirred under these conditions for 18 hours. After completion of the reaction, the reaction mixture was diluted with water (200 mL), extracted with ethyl acetate (200 mL. Times.3), and the combined organic layers were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was subjected to reverse phase to give Compound 6-3 (2.3 g, yield) 14％).¹H NMR(400MHz,CDCl₃):δ4.89(s,1H),3.75(s,3H),3.69(dt,J＝13.6,6.8Hz,2H),2.97(t,J＝15.2Hz,2H),1.45(s,9H).

To a solution of compound 6-3 (1 g,3.95 mmol) in THF (10 mL) at-50℃was added dropwise a solution of lithium aluminum hydride in THF (1.9 mL,4.74mmol, 2.5M). After the completion of the dropwise addition, the reaction solution was stirred at 5℃for 2 hours. After completion of the reaction, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. Crude product 6-4 (725 mg, 82% yield) was obtained. LCMS: m/z (ESI): 170.0[ M-56+H ] ⁺.

To a solution of compound 6-4 (725 mg,3.22 mmol) in pyridine (10 mL) was added p-methylsulfonyl chloride (1.23 g,6.44 mmol). Stirred at 10 ℃ for 2 hours. After the reaction, concentrating and evaporating to dryness. The crude product was purified by silica gel column chromatography to give compound 6-5 (650 mg, yield 53%). LCMS: m/z (ESI): 280.0[ M-100+H ] ⁺.

Synthesis of Compound 6 referring to the synthetic route of Compound 4, intermediate raw material 6-5 for synthesizing intermediate 6-6 replaces tert-butyl (4-bromobutyl) carbamate, which is the raw material for synthesizing intermediate 4-5.

Obtaining the compound 6(9.3mg).LCMS:m/z(ESI):509.0[M+H]⁺.¹H NMR(400MHz,CD₃OD):δ8.55(s,1H),8.26(d,J＝9.2Hz,1H),7.87(s,1H),7.66(s,1H),7.33(d,J＝8.0Hz,1H),4.35–4.19(m,1H),3.99–3.90(m,1H),3.63–3.58(m,2H),3.11–3.05(m,1H),3.00–2.90(m,1H),2.81(s,3H),2.60–2.41(m,2H),2.33–2.18(m,3H),2.02–1.81(m,3H).

Example 7

Synthesis of Compound 7 referring to the synthetic route of Compound 6, synthetic intermediate 7-1 replaces raw material 6-1 of Compound 6.

Obtaining the compound 7(23.7mg).LCMS:m/z(ESI):523.0[M+H]⁺.¹H NMR(400MHz,DMSO-d₆):δ8.55(s,1H),8.33(d,J＝8.4Hz,1H),8.03(d,J＝5.6Hz,1H),7.91(d,J＝2.0Hz,1H),7.55(s,1H),7.18–7.10(m,1H),4.16–4.02(m,1H),3.85–3.51(m,4H),3.11(s,3H),2.66–2.56(m,1H),2.25–2.16(m,1H),2.03(s,3H),1.99–1.93(m,1H),1.90–1.80(m,2H),1.79–1.69(m,1H),1.60–1.41(m,2H),1.28–1.19(m,1H),1.16–1.06(m,1H).

Example 8

To a solution of compound 8-1 (10.0 g,49.6 mmol) in THF (120 mL) at-78℃under nitrogen, was slowly added dropwise a solution of vinylmagnesium bromide in THF (198mL, 39 mmol, 1M). After the completion of the dropwise addition, the reaction solution was stirred under these conditions for 3 hours. After the reaction, a saturated aqueous ammonium chloride solution (300 mL) was slowly added to the reaction mixture to quench the reaction mixture, the pH was adjusted to 4 to 5 with 1M hydrochloric acid, and the mixture was extracted with methylene chloride (300 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. Crude 8-2 (8.03 g, yield 83%) was obtained and used in the next reaction without purification.

LCMS:m/z(ESI):196.0[M+H]⁺。

To a solution of compound 8-2 (8.00 g,40.9 mmol) in DMF (85 mL) was added methyl iodide (6.97 g,49.1 mmol) and potassium carbonate (11.3 g,81.9 mmol) under nitrogen at 25 ℃. The reaction solution was stirred under these conditions for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (200 mL), extracted with ethyl acetate (150 mL. Times.3), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration. The crude product obtained was purified by silica gel column chromatography to give compound 8-3 (5.8 g, yield 67%).

LCMS:m/z(ESI):210.0[M+H]⁺.¹H NMR(400MHz,CDCl₃):δ8.67(s,1H),7.72(d,J＝8.4Hz,1H),7.55(d,J＝8.4Hz,1H),7.40(m,1H),6.62(dd,J＝3.2,2.0Hz,1H),3.95(s,3H).

In a dry 50mL three-necked flask, aluminum trichloride (1.27 g,9.54 mmol) was added and a solution of compound 8-3 (1.00 g,4.77 mmol) in 1.2-dichloroethane (10 mL) was added under a nitrogen system. The reaction solution was stirred at 80℃for 30 minutes, then a solution of 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (1.09 g,5.01 mmol) in 1, 2-dichloroethane (1 mL) was added. The reaction solution was reacted at 80℃for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated by filtration, and the obtained crude product was purified by silica gel column chromatography to give compound 8-4 (0.38 g, yield 20%).

LCMS:m/z(ESI):390.0.¹H NMR(400MHz,DMSO-d₆):δ12.86(s,1H),9.10(s,1H),8.25(d,J＝8.4Hz,1H),8.08(d,J＝2.4Hz,1H),7.73(d,J＝8.4Hz,1H),3.91(s,3H).

In a 10mL microwave tube, compound 8-4 (420 mg,1.08 mmol), NMP (2 mL), N-diisopropylethylamine (0.53 mL,3.23 mmol) and tert-butyl ((1S, 3S) -3-aminocyclopentyl) carbamate (237 mg,1.18 mmol) were added sequentially. The reaction solution was heated to 80 ℃ and stirred to become a solution, and then reacted at 130 ℃ for 2 hours under microwaves. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL. Times.3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained crude product was purified by silica gel column chromatography to give compound 8-6 (430 mg, yield 72%).

LCMS:m/z(ESI):554.0[M+H]⁺。

Compound 8-6 (430 mg,0.72 mmol) was dissolved in a mixed solution of hydrogen chloride/dioxane (4 mL, 4M) and MeOH (2 mL) at room temperature. The reaction was carried out at 15℃for 16 hours. After the completion of the reaction, a saturated sodium hydrogencarbonate solution (40 mL) was added to the reaction solution, and extracted with methylene chloride (20 mL. Times.3), and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and the crude product obtained by filtration concentration was purified by silica gel column chromatography to give compound 8-7 (320 mg, yield 89%).

LCMS:m/z(ESI):454.0[M+H]⁺。

Synthesis of Compound 8 referring to the synthetic route for Compound 7, synthetic intermediate 8-7 replaces intermediate 4-4 of synthetic Compound 7.

Obtaining the compound 8(10.9mg).LCMS:m/z(ESI):543.2[M+H]⁺.¹H NMR(400MHz,DMSO-d₆):δ12.63–11.85(m,1H),8.58(s,1H),8.46–8.18(m,1H),8.08(s,1H),7.89–7.62(m,1H),7.33–6.79(m,1H),4.21–3.72(m,1H),3.61–3.47(m,2H),3.12(s,3H),2.27–2.17(m,1H),2.14–1.85(m,5H),1.81–1.72(m,1H),1.68–1.43(m,2H),1.31–1.08(m,3H).

Test example 1 CDK7/Cyclin H Surface Plasmon Resonance (SPR) measurement method

CDK7/Cyclin H was purchased from soaper, lot number 20200309-BP487/492, MES buffer from BioRoYee, lot number 67GR9637, CM5 sensor chip from Cytiva, lot number 10305527, HEPES buffer from Cytiva, lot number 32349.

The kinetics and affinity parameters of CDK7/Cyclin H dimers and compounds were tested in this experiment using a Biacore S200 surface plasmon resonance apparatus (GE HEALTHCARE).

CDK7/Cyclin H dimer at a concentration of 50. Mu.g/mL was amino-coupled to CM5 sensor chip at a flow rate of 5. Mu.L/min in 10mM MES buffer pH 6.5. The target protein was immobilized on the chip channel within 600 seconds, typically reaching a 7000-10000 response. The compound was diluted 2-fold in a gradient 5 steps to a concentration range of 0.6-10nM in 10mM HEPES buffer pH7.4 with 150mM NaCl, 0.05% surfactant P20 and 2% DMSO. Each compound concentration cycle was run at 100. Mu.L/min, 180 second contact time and 1800 second dissociation time. For each compound, the binding of the 0nM compound control and the reference channel was subtracted to remove background signal and normalization data. The compound titration ensemble fit was performed using Biacore S200 evaluation software and kinetic model. The fit data was optimized and CDK7/Cyclin H binding rate and dissociation rate parameters were determined, and compound affinity parameter K _D.K_D(M)＝k_off(s^-1)/K_on(M^-1s^-1 was calculated using the following equation, where K _on (ka) is the binding rate, K _off (kd) is the dissociation rate, and s ^-1 (per second) and M ^-1s^-1 (per mole per second) are units of K _off and K _on. Based on the ratio of direct compound binding K _D (measured by SPR) to CDK7, the compound selectivity of CDK7 over CDK2, CDK9 or CDK12 was determined according to the following equation. Selectivity = K _{i, Off-target}/K_D,CDK7. The results show that the compounds of the invention have excellent selectivity for CDK7 over CDK2/CDK9/CDK12, and that the compounds of the invention are at least 100-fold or 300-fold more specific for CDK7 than for other CDKs, and may even be more than 500-fold. Results for some of the exemplified compounds are shown in table 3.

TABLE 3 CDK7/CYCLIN H SPR K of the Compounds of the invention _D

Test example 2 OVCAR-3 tumor cell proliferation inhibition Activity assay

OVCAR-3 was purchased from ATCC, cat# HTB-161, RPMI1640 from Gibco, cat# 22400-089, pancreatin (containing EDTA) from Gibco, cat# 25200-072, FBS from excel, FND500, cellTiter-Glo from Promega, cat# G7573, bovine insollin from Yeasen, cat# 40107ES25, DMSO from SIGMA, cat# D2650-1000ML, phosphate buffer (DPBS) from Corning, cat# 21-031-CVR, cytometer from Beckman, model Vi-CELLXR Cell Viability Analyzer, microplate reader from Perkinelmer, model 2105

OVCAR-3 was human ovarian adenocarcinoma cells cultured in an incubator containing 20% FBS and 0.01mg/mL Bovine insulin of RPMI-1640 medium at 37℃with 5% CO ₂. Cells in log phase were taken at plating, digested with 0.25% pancreatin-EDTA, collected and counted, 8000 OVCAR-3 cells/well inoculated in 96 well cell plates and incubated overnight in 5% CO ₂. Compound stock solution of 1000X was prepared 3-fold gradient concentration using DMSO, 100-fold to 10X compound stock solution was diluted using medium, 10X compound stock solution was added to each cell culture well the next day after cell inoculation at a final concentration of 1X and DMSO content of 0.1%. The DMSO-treated cell group was used as vehicle control (control), and the cell-free medium group was blank control (blank). After the addition of the compounds, the cells were further cultured for 3 days, 75 μ L CELLTITER-Glo working solution was added to each well, mixed well, incubated at room temperature for 20 minutes, and the luminescence values were read, and the Inhibition Ratio (IR) of the test compounds was calculated, IR (%) = (1- (RLU compound-RLU blank)/(RLU vehicle control-RLU blank). 100%). The Inhibition ratio of the compounds at different concentrations was calculated in Excel, and then the Inhibition graph and calculation of the relevant parameters were performed using GRAPHPAD PRISM software, including RELATIVE IC ₅₀,Bottom(％),Top(％);Absolute IC₅₀ and Max (%). The results showed that the compounds of the present invention had a strong inhibitory effect on OVCAR-3, human ovarian adenocarcinoma cell proliferation, the results of the exemplary compounds are shown in table 4 below, wherein "a" represents IC ₅₀ of less than 500nM, "B" represents < IC ₅₀ of 500nM to less than 2000nM, and "C" represents < IC ₅₀ of equal to or greater than 2000nM.

TABLE 4 OVCAR-3 tumor cell proliferation inhibitory Activity of the Compounds of the invention

As can be seen from table 4, the compounds of the present invention have excellent OVCAR3 cell inhibitory activity.

Test example 3 measurement of Caco-2 permeance and drainage

1. Preheating, i.e. the hanks balanced salt buffer (HBSS) is preheated in a 37 ℃ water bath.

2. Ultrasound, removing the compound from the-20 ℃ and performing ultrasound for several minutes (not less than 1 minute).

3. Preparation of blank solution

A) Drug administration side blank solution 1) drug administration side blank solution (A-B direction) transport buffer (pH 7.4) containing 0.3% DMSO and 5. Mu.M fluorescein (LY) 150. Mu.L DMSO and 50. Mu.L 5mM LY stock solution were added to 50mL HBSS, transport buffer (pH 7.4) containing 0.2% DMSO and 5. Mu.M LY 100. Mu.L DMSO and 50. Mu.L 5mM LY stock solution were added to 50mL HBSS, transport buffer (pH 7.4) containing 0.1% DMSO and 5. Mu.M LY 50. Mu.L 5mM LY stock solution were added to 50mL HBSS. 2) Drug administration side blank solution (B-A direction) was prepared by adding 150. Mu.L of DMSO to 50mL of HBSS in A transport buffer (pH 7.4) containing 0.3% DMSO, and adding 50. Mu.L of DMSO to 50mL of HBSS in A transport buffer (pH 7.4) containing 0.1% DMSO.

Receiving side blank solution 1) receiving side blank solution (A-B direction) transfer buffer containing 0.4% DMSO (pH 7.4) 200. Mu.L DMSO was added to 50mL HBSS, 2) receiving side blank solution (B-A direction) transfer buffer containing 0.4% DMSO and 5. Mu.M fluorescein LY (pH 7.4) 200. Mu.L DMSO and 50. Mu.L 5mM LY stock solution were added to 50mL HBSS, and transfer buffer containing 0.3% DMSO and 5. Mu.M fluorescein LY (pH 7.4) 150. Mu.L DMSO and 50. Mu.L 5mM LY stock solution were added to 50mL HBSS.

B) Preparation of working solutions of test Compound and reference Compound

TABLE 5

4. Centrifugation the test compound and the reference compound working fluid (step 3) were centrifuged at 4000 rpm for 5 minutes prior to dosing.

5. Dosing solutions were added according to the volumes listed in the table below (ensuring an additional 100 μl of dosing solution was used as T0 samples for the test and reference compounds).

TABLE 6

6. Top side LYT0 samples 100. Mu.L of sample per well from the top plate was placed into a black fluorescence measurement plate for preparing LY _T0 samples.

7. Preheating, namely placing the top side plate and the base side plate into a 37 ℃ incubator for preheating for 5 minutes respectively, and then combining the top side plate and the base side plate to start a transfer experiment.

8. Cell culture the cell plates were placed in an incubator for 90 minutes at 37 ℃.

9. Preparation of standard yeast solution

Preparing 20 times final concentration solution

A300. Mu.M working stock solution was prepared by adding 6. Mu.L of a10 mM test compound solution to 194. Mu.L of MeOH (MeOH/H ₂ O=v/v: 1/1).

TABLE 7

Preparing 1 Xfinal concentration solution

3. Mu.L (20X) +57. Mu.L of HBSS (0.4% DMSO) +60. Mu.L of ACN (imipramine) with internal standard.

10. After the completion of the 90-minute incubation, the transport experiment was terminated by separating the top plate from the bottom plate.

Measurement of LY 100. Mu.L of sample per well from the base side plate was placed in a black fluorescence measurement plate for preparing LY _T90 samples. The response values of LY _T0 and LY _T90 samples were determined with a microplate reader (excitation wavelength 485nm, emission wavelength 535 nm).

12. Samples were prepared for LC-MS/MS analysis 1) the drug side samples were diluted with HBSS (0.4% DMSO), 2) 60. Mu.L of diluted drug side samples or undiluted receiver side samples +60. Mu.L of ACN (imipramine) plus internal standard) +50. Mu.L of water.

The permeability (Papp, unit 10 ^-6, cm/s) and Efflux (ER) of the compounds in Caco-2 cells was calculated by the specific concentrations of the receiving and administration ends.

TABLE 8 Caco-2 permeabilities and efflux of the compounds of the invention

It can be seen from Table 8 that the compounds according to the invention have a higher Caco-2 permeance (Papp (A-B)) and a lower Efflux Rate (ER).

The embodiments of the technical solutions of the present disclosure have been described above by way of example. It should be understood that the protection scope of the present disclosure is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. which are within the spirit and principles of the present disclosure, by those skilled in the art, should be included in the scope of the present claims.

Claims

A compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;

Among them, the structural unit Selected from

_X1 is selected from N or C( _Rx1 );

_X2 is selected from N or C( _Rx2 );

_X3 is selected from N or C( _Rx3 );

Y is selected from N or C( _RY );

Z is selected from N or C (R _Z );

L is selected from C _1-8 alkyl, C _1-8 heteroalkyl, C _2-8 alkenyl or C _2-8 alkynyl, wherein the C _1-8 alkyl, C _1-8 heteroalkyl, C _2-8 alkenyl or C _2-8 alkynyl is optionally substituted with one or more ^RL ;

R and ^L are each independently selected from halogen, cyano, -NO ₂ , hydroxy, -OR ^a , -NR ^c R ^d , -C(═O)R ^a , -C(═O)OR ^b , -C(═O)NR ^c R ^d , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl or heterocyclyl;

Or two ^RLs are on the same atom and are linked together to form =O;

Or two ^RLs are on two adjacent atoms and are connected together to form a single bond;

or two ^RLs are on the same or different atoms and are linked together to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which is optionally substituted with one or more ^RLs ;

R ^La are each independently selected from halogen, cyano, -NO ₂ , hydroxy, -OR ^a , -NR ^c R ^d , -C(═O)R ^a , -C(═O)OR ^b , -C(═O)NR ^c R ^d , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl or C _1-6 heteroalkyl;

R ^a , R ^b , R ^c and R ^d are each independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 alkyl (cycloalkyl), C _1-6 alkyl (heterocyclyl), C _1-6 alkyl (aryl) or C _1-6 alkyl (heteroaryl), the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _{1-6 heteroalkyl, C 2-6} _{alkenyl, C 2-6} _alkynyl , cycloalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 alkyl (cycloalkyl), C _1-6 alkyl (heterocyclyl), C 1-6 alkyl (aryl) or C _1-6 alkyl (heteroaryl) _1-6 alkyl (heteroaryl) is optionally substituted with one or more R;

or R ^c and R ^d are linked together to form a heterocyclic group, which is optionally substituted by one or more R;

R _x1 , R _x2 , R _Y , R _Z , and R ₃ are each independently selected from H, halogen, hydroxy, cyano, -C _2-4 alkenylene-phenyl, -C _2-4 alkynylene-phenyl, -S(═O)-OH, -S(═O) ₂ -OH, -S-(C _1-6 alkyl), C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkylene-OC _1-6 alkyl, -OC _1-6 alkylene-OC _1-6 alkyl, -Co _0-6 alkylene-NRR′, -Co _0-6 alkylene-C(═O)OH, -Co _0-6 alkylene-C(═O)-Co _1-6 alkyl, -Co _0-6 alkylene-C(═O)-NRR′, -Co _0-6 alkylene-NR-C(═O)-Co _1-6 alkyl, -Co _0-6 alkylene-S(═O) ₂ -C _1-6 alkyl, -C _0-6 alkylene-S(═O)(═NH)-C _1-6 alkyl, -C 0-6 alkylene-S(═O) ₂ -NRR′, -C _0-6 alkylene-NR-S(═O) ₂ -C _1-6 alkyl, -C _0-6 alkylene-NR-S(═O) ₂ -NRR′, -C _0-6 alkylene-P(═O)O-(C _1-6 alkyl) ₂ , -C _0-6 alkylene-P(═O) _- (C _1-6 alkyl)(OC _1-6 alkyl), -C _0-6 alkylene-P(═O)-(C _1-6 alkyl) ₂ , -C _0-6 alkylene-3 to 14-membered cycloalkyl, -C _0-6 alkylene-3 to 14-membered heterocyclyl, -C _0-6 alkylene-5 to 12-membered heteroaryl, -C _0-6 alkylene-C _6-12 aryl, -C _0-6 alkylene-C (= O) -3 to 14 membered heterocyclyl, -C _0-6 alkylene-C (= O) -5 to 12 membered heteroaryl, -OC _0-6 alkylene-OC _1-6 alkyl, -OC _0-6 alkylene-3 to 14 membered cycloalkyl, -OC _0-6 alkylene-3 to 14 membered heterocyclyl, -OC _0-6 alkylene-5 to 12 membered heteroaryl, -OC _0-6 alkylene-C _6-12 aryl, -S (= O) -C _1-6 alkyl; wherein the C _1-6 alkyl, C _0-6 alkylene, C _2-4 alkenylene, 3 to 14 membered cycloalkyl, 3 to 14 membered heterocyclyl, 5 to 12 membered heteroaryl, C _{The 6-12} membered aryl groups are independently unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from Group S1; the 3 to 14 membered heterocyclyl group has 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; the 5 to 12 membered heteroaryl group has 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;

The groups of the S1 group include: oxo (=O), halogen, hydroxyl, cyano, C _1-6 alkyl, -OC _1-6 alkyl, -C _1-6 alkylene-OC _1-6 alkyl, -OC _1-6 alkylene-OC _1-6 alkyl, -C _0-6 alkylene-NRR', -C _0-6 alkylene-C(O)OH, -C _0-6 alkylene-C(=O)-C _1-6 alkyl, -C _0-6 alkylene-C(=O)-NRR', -C _0-6 alkylene-NR-C(=O)-C _1-6 alkyl, -C _0-6 alkylene-S(=O) ₂ -C _1-6 alkyl, -C _0-6 alkylene-S(=O) ₂ -NRR', -C _0-6 alkylene-NR-S(=O) ₂ -C _1-6 alkyl, -C -C _0-6 alkylene-NR-S(=O) ₂ -NRR', -C _0-6 alkylene-P(=O)O-(C _1-6 alkyl) ₂ , -C _0-6 alkylene-P(=O)-(C _1-6 alkyl)(OC _1-6 alkyl), -C _0-6 alkylene-P(=O)-(C _1-6 alkyl) ₂ , -C _0-6 alkylene-3 to 14-membered cycloalkyl, -C _0-6 alkylene-3 to 14-membered heterocyclyl, -C _0-6 alkylene-5 to 12-membered heteroaryl, -C _0-6 alkylene-C _6-12 aryl, -C _0-6 alkylene-C(=O)-3 to 14-membered heterocyclyl, -C _0-6 alkylene-C(=O)-5 to 12-membered heteroaryl, -OC _0-6 alkylene-OC _1-6 alkyl, -OC _0-6 alkylene-3 to 14-membered cycloalkyl, -OC _0-6 alkylene-3 to 14-membered heterocyclyl, -OC _0-6 alkylene-5 to 12-membered heteroaryl, -OC _0-6 alkylene-C _6-12 aryl, -S(═O)-C _1-6 alkyl;

R _x3 are each independently selected from H, halogen, cyano, C _1-12 alkyl or C _1-12 haloalkyl;

R ₁ is selected from H, halogen, cyano, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 hydroxyalkyl, C _1-12 heteroalkyl, cycloalkyl or heterocycloalkyl, wherein the C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 hydroxyalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R ₁₁₁ ;

R ₂ is selected from H, halogen, cyano, C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 hydroxyalkyl, C _1-12 heteroalkyl, cycloalkyl or heterocycloalkyl, wherein the C _1-12 alkyl, C _1-12 haloalkyl, C _1-12 hydroxyalkyl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more R ₂₂₂ ;

Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more R ^aa ;

R ^{aa is} each independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 alkyl(cycloalkyl), C _1-6 alkyl(heterocyclyl), C _1-6 alkyl(aryl) or C _1-6 alkyl(heteroaryl), wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, C _1-6 heteroalkyl, C _2-6 alkenyl, C _2-6 alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C _1-6 alkyl(cycloalkyl), C _1-6 alkyl(heterocyclyl), C _1-6 alkyl(aryl) or C _1-6 alkyl(heteroaryl) are optionally substituted with one or more R;

R, R', R ₁₁₁ , and R ₂₂₂ are each independently selected from halogen, cyano, hydroxy, -OCH ₃ , -S(=O)CH ₃ , -S(=O) ₂ CH ₃ , -S(=O) ₂ NH ₂ , -S(=O) ₂ NHCH ₃ , -S(=O) ₂ N(CH ₃ ) ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -C(=O)CH ₃ , -C(=O)OH, -C(=O)OCH ₃ , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 aminoalkyl, or C _1-6 heteroalkyl;

The heteroalkyl, heteroaryl or heterocyclyl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from O, NH, S, C(=O), C(=O)O, S(=O), S(=O) ₂ and N.

The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, which has the structure represented by formula (Ia);

The compound according to claim 1 or 2, its stereoisomer or pharmaceutically acceptable salt thereof, wherein:

-L- is selected from -L ^1A -L ^2A -L ^3A -L ^4A -L ^5A -, wherein L ^1A , L ^2A , L ^3A , L ^4A or L ^5A are independently selected from a single bond, -O-, -C(═O)-, -S-, -S(═O)-, -S(═O) ₂ -, optionally substituted C _1-3 alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted aryl, -NR ^L4 -,

^RL4 is selected from H, optionally substituted _C1-6 alkyl, optionally substituted _C1-6 haloalkyl, optionally substituted cycloalkyl or optionally substituted heterocyclyl;

Optionally, L ^1A , L ^2A , L ^3A , L ^4A or L ^5A are independently selected from a single bond, -O-, -C(=O)-, -S-, -S(=O)-, -S(=O) ₂ -, C _1-3 alkyl, C _3-6 cycloalkyl, 3 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, phenyl, -NR ^L4 -, The C _1-3 alkyl, C _3-6 cycloalkyl, 3 to 6 membered heterocyclic group, 5 to 6 membered heteroaryl, phenyl, -NR ^L4 -, Optionally substituted with 1, 2, 3 or 4 R ^L6 ,

^RL4 is selected from H, _C1-6 alkyl, _C1-6 haloalkyl, _C3-6 cycloalkyl or 3 to 6 membered heterocyclyl;

^RL5 is selected from H, _C1-6 alkyl, _C1-6 haloalkyl, _C3-6 cycloalkyl or 3 to 6 membered heterocyclyl;

R ^L6 are each independently selected from C _1-6 alkyl, C _3-6 cycloalkyl, 3 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl or phenyl, wherein the C _1-6 alkyl, C _3-6 cycloalkyl, 3 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl or phenyl is optionally substituted with 1, 2, 3 or 4 halogens, OH, CN, NH ₂ or C _1-6 alkyl,

or two ^RL6 are on the same carbon atom and are linked together to form a _C3-6 cycloalkyl or a 3 to 6 membered heterocyclyl, wherein the _C3-6 cycloalkyl or the 3 to 6 membered heterocyclyl is optionally substituted with 1, 2, 3 or 4 halogen, 0H, CN, _NH2 or _C1-6 alkyl.

-L- is selected from the following groups.

-(O) _m2 -(CR ¹³ R ¹⁴ ) _m1 -(NR ¹² ) _m3 -,

-(NR ¹¹ ) _m2 -(CR ¹³ R ¹⁴ ) _m1 -(NR ¹² ) _m3 -,

-(O) _m2 -(CR ¹³ R ¹⁴ ) _m5 -(C _3-7 cycloalkyl) _m4 -(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(NR ¹¹ ) _m2 -(CR ¹³ R ¹⁴ ) _m5 -(C _3-7 cycloalkyl) _m4 -(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(O) _m2 -(CR ¹³ R ¹⁴ ) _m5 -(3- to 7-membered heterocyclic group) _m4 -(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(O) _m2 -(CR ¹³ R ¹⁴ ) _m5 -(3- to 7-membered heterocyclic group) _m4 -(CR ¹³ R ¹⁴ ) _m6 -NR ¹⁰ C(O)-(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(NR ¹¹ ) _m2 -(CR ¹³ R ¹⁴ ) _m5 -(3- to 7-membered heterocyclic group) _m4 -(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(O) _m2 -(CR ¹³ R ¹⁴ ) _m5 -(3- to 6-membered heteroaryl) _m4 -(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(NR ¹¹ ) _m2 -(CR ¹³ R ¹⁴ ) _m5 -(3- to 6-membered heteroaryl) _m4 -(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(O) _m2 -(CR ¹³ R ¹⁴ ) _m5 -NR ¹⁰ -(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(NR ¹¹ ) _m2 -(CR ¹³ R ¹⁴ ) _m5 -NR ¹⁰ -(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(O) _m2 -(CR ¹³ R ¹⁴ ) _m5 -NR ¹⁰ C(O)-(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(NR ¹¹ ) _m2 -(CR ¹³ R ¹⁴ ) _m5 -NR ¹⁰ C(O)-(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(O) _m2 -(CR ¹³ R ¹⁴ ) _m5 -C(O)NR ¹⁰ -(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(O) _m2 -(CR ¹³ R ¹⁴ ) _m5 -C(O)NR ¹⁰ -(CR ¹³ R ¹⁴ ) _m6 -(O) _m2 -(CR ¹³ R ¹⁴ ) _m5 ,

-(NR ¹¹ ) _m2 -(CR ¹³ R ¹⁴ ) _m5 -C(O)NR ¹⁰ -(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(O) _m2 -(CR ¹³ R ¹⁴ ) _m5 -O-(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(NR ¹¹ ) _m2 -(CR ¹³ R ¹⁴ ) _m5 -O-(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(O) _m2 -(CR ¹³ R ¹⁴ ) _m5 -OC(O)-(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(NR ¹¹ ) _m2 -(CR ¹³ R ¹⁴ ) _m5 -OC(O)-(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(O) _m2 -(CR ¹³ R ¹⁴ ) _m5 -C(O)O-(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(NR ¹¹ ) _m2 -(CR ¹³ R ¹⁴ ) _m5 -C(O)O-(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(O) _m2 -(CR ¹³ R ¹⁴ ) _m5 -(CH＝CH) _m7 -(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -,

-(NR ¹¹ ) _m2 -(CR ¹³ R ¹⁴ ) _m5 -(CH＝CH) _m7 -(CR ¹³ R ¹⁴ ) _m6 -(NR ¹² ) _m3 -;

R ¹⁰ is each independently selected from H, C _1-6 alkyl, -C _3-7 cycloalkyl, -C(O)-C _1-6 alkyl, -C(O)-C _1-4 alkyl-C _1-6 alkoxy, -C(O)-C _3-7 cycloalkyl, -C _1-4 alkyl-hydroxy, -C 1-4 alkyl-cyano, -C _1-4 alkyl-C _1-6 alkoxy, -C _1-4 alkyl-NHC(O)-C 1-6 alkyl, -C _1-4 alkyl-NHC(O)-C _1-4 alkyl-C _1-6 alkoxy, -C 1-4 alkyl-NHC(O)-C _1-4 alkyl-C _1-6 alkoxy, -C _1-4 alkyl-NHC(O)-C _3-7 cycloalkyl or -C _1-4 alkyl-NRR';

R and R' are each independently hydrogen or C _1-6 alkyl; or R, R' optionally together with the nitrogen atom to which they are attached form a 3- to 14-membered heterocyclic group or a 5- to 12-membered heteroaryl group; wherein the heterocyclic group or heteroaryl group each independently contains 0, 1 or 2 heteroatoms selected from N, O and S in addition to the existing nitrogen atom;

The 3- to 7-membered heterocyclic groups each independently have 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; the C _3-7 cycloalkyl groups are each independently unsubstituted or substituted with 1, 2, 3, 4 or 5 groups selected from Group S1;

C _3-7 cycloalkyl groups are each independently selected from unsubstituted or substituted by 1, 2, 3, 4 or 5 groups selected from Group S1;

R ¹¹ is independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl or 3 to 7 membered heterocyclyl, wherein the C _1-6 alkyl, C _3-7 cycloalkyl or 3 to 7 membered heterocyclyl is optionally substituted with 1, 2, or 3 halogens, CN, OH or C _1-6 alkyl;

R ¹² is independently selected from H, C _1-6 alkyl, C _3-7 cycloalkyl or 3 to 7 membered heterocyclyl, wherein the C _1-6 alkyl, C _3-7 cycloalkyl or 3 to 7 membered heterocyclyl is optionally substituted with 1, 2, or 3 halogens, CN, OH or C _1-6 alkyl;

R ¹³ is independently selected from H, cyano, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, -C _3-7 cycloalkyl, -C _0-6 alkylene-NRR', -C _1-6 alkylene-hydroxy or -C _0-6 alkylene-cyano;

R ¹⁴ is independently selected from H, cyano, hydroxy, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, -C _3-7 cycloalkyl, -C _0-6 alkylene-NRR', -C _1-6 alkylene-hydroxy or -C _0-6 alkylene-cyano;

or R ¹³ and R ¹⁴ are linked together, and the same carbon atom or different carbon atoms to which they are linked together form a 3-6 membered heterocyclic group or a C _3-6 cycloalkyl group, wherein the 3-6 membered heterocyclic group or the C _3-6 cycloalkyl group is optionally substituted with 1, 2, 3, 4 or 5 groups selected from Group S1;

m1 is independently 1, 2, 3, 4, 5 or 6;

m2 are each independently 0 or 1;

m3 are each independently 0 or 1;

m4 are each independently 1 or 2;

m5 are each independently 0, 1, 2, 3, 4, 5 or 6;

m6 are each independently 0, 1, 2, 3, 4, 5 or 6;

m7 is independently 1 or 2.

The compound according to any one of claims 1 to 4, its stereoisomer or pharmaceutically acceptable salt thereof, wherein:

L is selected from The upper end is connected to ring B and the lower end is connected to V.

The compound according to any one of claims 1 to 5, its stereoisomer or pharmaceutically acceptable salt thereof, wherein:

R _x1 is selected from H, halogen, hydroxy, cyano, -C _0-3 alkylene-P(=O)-(C _1-3 alkyl) ₂ , -C _0-3 alkylene-S(=O) ₂ -C _1-3 alkyl, -C _0-3 alkylene-S(O)(=NH)-C _1-3 alkyl or -C _0-3 alkylene-S(=O)(=NH)-C _1-3 alkyl;

Optionally, R _x1 is selected from H, F, Cl, Br, I, hydroxy, cyano, -P(=O)-(CH ₃ ) ₂ , -P(=O)-(CH ₂ CH ₃ ) ₂ , -S(=O) ₂ -CH ₃ , -S(=O) ₂ -CH ₂ CH ₃ , -S(O)(=NH)-CH ₃ , or -S(=O)(=NH)CH ₃ .

The compound according to any one of claims 1 to 6, its stereoisomers and pharmaceutically acceptable salts thereof, wherein:

R ₁ is selected from H, halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with 1, 2 or 3 R ₁₁₁ ;

Optionally, R ₁ is selected from H, halogen, cyano, C _1-6 alkyl or C _1-6 haloalkyl, wherein the C _1-6 alkyl or C _1-6 haloalkyl is optionally substituted with 1, 2 or 3 R ₁₁₁ ;

Optionally, R ₂ is selected from H, halogen, cyano, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl, said C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 hydroxyalkyl, C _1-6 heteroalkyl, C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl optionally substituted with 1, 2 or 3 R ₂₂₂ ;

Optionally, R ₂ is selected from H, halogen, cyano, C _1-6 alkyl or C _1-6 haloalkyl, said C _1-6 alkyl or C _1-6 haloalkyl being optionally substituted with 1, 2 or 3 R ₂₂₂ ;

Optionally, R ₁ is selected from H or CF ₃ ;

Optionally, R ₂ is selected from H or CF ₃ .

The compound according to any one of claims 1 to 7, its stereoisomer or pharmaceutically acceptable salt thereof, wherein:

Ring A is selected from C _3-12 cycloalkyl or 3-12 membered heterocyclyl, wherein the C _3-12 cycloalkyl or 3-12 membered heterocyclyl is optionally substituted by one or more R ^aa ;

Optionally, Ring A is selected from C _3-6 cycloalkyl or 3-6 membered heterocyclyl, wherein the C _3-6 cycloalkyl or 3-6 membered heterocyclyl is optionally substituted with 1, 2 or 3 R ^aa ;

Optionally, Ring A is selected from C _5-6 cycloalkyl or 5-6 membered heterocyclyl, wherein the C _5-6 cycloalkyl or 5-6 membered heterocyclyl is optionally substituted with 1, 2 or 3 R ^aa ;

Optionally, ring A is selected from C _5-6 cycloalkyl or 5-6 membered heterocyclyl;

Optionally, Ring A is selected from

The compound of the following formula, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from

A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, having one of the structures in Table 1 or Table 2.

A pharmaceutical composition comprising the compound according to any one of claims 1 to 10, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

Use of the compound according to any one of claims 1 to 10, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 in the preparation of a medicament for preventing and/or treating CDK7-related diseases.

The use according to claim 12, characterized in that the CDK7-related disease is a proliferative disease, an infectious disease, an immune disease, an autoimmune disease or an inflammatory disease.

Use of the compound according to any one of claims 1 to 10, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11 in the preparation of a CDK7 inhibitor.