CN114907406A

CN114907406A - Pyrimidine derivative, preparation method thereof and application thereof in medicine

Info

Publication number: CN114907406A
Application number: CN202210117358.7A
Authority: CN
Inventors: 杨方龙; 贾敏强; 王伟民; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2021-02-08
Filing date: 2022-02-08
Publication date: 2022-08-16

Abstract

The present disclosure relates to pyrimidine derivatives, processes for their preparation and their use in medicine. Specifically, the disclosure relates to a pyrimidine derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the derivative as a CDK7 inhibitor in treatment of diseases or symptoms related to CDK7 activity. Wherein each group in the general formula (I) is defined in the specification.

Description

Pyrimidine derivative, preparation method thereof and application thereof in medicine

Technical Field

The disclosure belongs to the field of medicines, and relates to a pyrimidine derivative, a preparation method thereof and application thereof in medicines. In particular, the present disclosure relates to pyrimidine derivatives of general formula (I), methods for their preparation, pharmaceutical compositions containing them, and their use as CDK7 inhibitors in the treatment of diseases or disorders associated with CDK7 activity.

Background

Cyclin kinases (CDKs) are an important class of kinases and play an important role in the regulation of division proliferation of cancer cells and oncogene transcription, and currently discovered cyclin kinases (CDKs) have more than 20 subtypes, and selective precise regulation of each subtype is an important challenge due to sequence and structural similarity of kinase domains that are members of the CDK family.

Cyclin-dependent kinase 7(CDK7) is a specific member of the CDK family, having dual functions in cell division regulation and transcriptional regulation. CDK7 binds to cyclin H and MAT1 to form trimerized cyclin-activated kinases (CAKs) which activate the activity of the corresponding CDK kinases to regulate the cell cycle by phosphorylating the relevant CDK's (including CDK1, CDK2, CDK4, CDK6) which control the cell cycle. CDK7 is also involved in the co-regulation of transcription as part of the common transcription factor II H (TFIIH), which is involved in the process of transcription initiation by phosphorylation of the Rbp1 subunit of RNA polymerase II (rnapii), and then elongation of transcription can be regulated by phosphorylation of the CDK9 complex.

An important feature of cancer is that cell proliferation is uncontrolled and deregulated in transcription, so inhibitors of CDK7 that inhibit both transcription and cell cycle progression are theoretically feasible targets of action for the treatment of cancer, and no drug that selectively regulates this target is currently on the market. We envisage the development of a highly selective inhibitor of CDK7 for the treatment of diseases associated with CDK7 activity.

Published patent applications for CDK7 inhibitors include WO2016058544a1, WO2018013867a1, WO2019143719a1, WO2019143730a1, WO2019099298a1, WO2020093006a1, and WO2020093011a1, among others.

Disclosure of Invention

The object of the present disclosure is to provide a compound represented by the general formula (I):

wherein:

g is CR ^1d Or an N atom;

R ^1d selected from-P (O) R ^m R ⁿ Alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy and hydroxyalkyl;

R ^m and R ⁿ Identical or different and are each independently methyl or ethyl;

y is CR ^2a Or an N atom;

R ^1a 、R ^1b and R ^1c The same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ² selected from the group consisting of hydrogen atoms, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;

R ^2a selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;

R ³ selected from the group consisting of hydrogen atoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;

R ⁴ selected from hydroxy, alkoxy and NR ^s R ^t ；

R ^s And R ^t Are the same or different and are each independently a hydrogen atom or an alkyl group;

R ⁶ 、R ⁷ 、R ¹² and R ¹³ The same or different, and the same or different,and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ⁵ 、R ⁸ 、R ⁹ 、R ¹⁰ and R ¹¹ The same or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or R ⁴ And R ⁵ 、R ⁴ And R ⁶ 、R ⁴ And R ⁸ 、R ⁸ And R ⁹ 、R ⁹ And R ¹⁰ 、R ¹⁰ And R ¹¹ One pair of which forms a cycloalkyl or heterocyclyl group, each independently optionally substituted with one or more groups selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, amino, hydroxy and hydroxyalkyl.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein G is CR ^1d ；R ^1d is-P (O) R ^m R ⁿ ；R ^m And R ⁿ As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is CR ^2a ；R ^2a Selected from hydrogen atom, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ^2a Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ² Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group; preferably, R ² Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is CR ^2a ；R ^2a Selected from hydrogen atoms, C _1-6 Alkyl radicalAnd C _1-6 A haloalkyl group; and/or, R ² Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ⁶ 、R ⁷ 、R ¹⁰ 、R ¹¹ 、R ¹² And R ¹³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy and C _1-6 A hydroxyalkyl group; preferably, R ⁶ 、R ⁷ 、R ¹⁰ 、R ¹¹ 、R ¹² And R ¹³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; more preferably, R ⁶ 、R ⁷ 、R ¹⁰ 、R ¹¹ 、R ¹² And R ¹³ Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II):

wherein:

R ^1a 、R ^1b 、R ^1c 、R ^m 、R ⁿ 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in formula (I).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof:

wherein:

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or the general formula (II) or a pharmaceutically acceptable salt thereof is a compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof:

wherein:

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (II) or the general formula (II-1), or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (III-1) or the general formula (III-2), or a pharmaceutically acceptable salt thereof,

wherein:

R ^1a 、R ^1b 、R ^1c 、R ^m 、R ⁿ 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in formula (I); with the proviso that R ⁴ And R ⁵ Different.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I), the general formula (II) or the general formula (II-2), or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (IV-1) or the general formula (IV-2), or a pharmaceutically acceptable salt thereof,

wherein:

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1) and formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R is ⁴ Is a hydroxyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1) and formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R is ⁵ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1) and formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R is ⁴ Is a hydroxyl group; and R is ⁵ Is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1) and formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R is ⁴ And R ⁵ The carbon atoms connected with the compound form 3-to 8-membered cycloalkyl or 3-to 8-membered heterocyclyl, and the 3-to 8-membered cycloalkyl or 3-to 8-membered heterocyclyl is independently selected from halogen and C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 Substituted with one or more of hydroxyalkyl; preferably, R ⁴ And R ⁵ Forms a 3 to 8 membered heterocyclic group with the carbon atom to which it is attached; more preferably, R ⁴ And R ⁵ The carbon atom to which it is attached forms a 3-to 8-membered heterocyclic group containing 1 nitrogen atom.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1) and formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R is ^m And R ⁿ Is methyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1) and formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R is ^1a Is cyano.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1) and formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R is ^1b And R ^1c Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; preferably, R ^1b And R ^1c Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1) and formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R is ^1a Is cyano; and R is ^1b And R ^1c Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; preferably, R ^1a Is cyano; and R is ^1b And R ^1c Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1) and formula (IV-2) or a pharmaceutically acceptable salt thereof, wherein R is ³ Is C _1-6 Alkyl or C _1-6 A haloalkyl group; preferably, R ³ Is C _1-6 A haloalkyl group; more preferably, R ³ Is trifluoromethyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), formula (II-1), formula (II-2), formula (II)I-1), a general formula (III-2), a general formula (IV-1) and a general formula (IV-2) or pharmaceutically acceptable salts thereof, wherein R ⁸ And R ⁹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; preferably, R ⁸ And R ⁹ Are the same or different and are each independently a hydrogen atom or a methyl group; more preferably, R ⁸ And R ⁹ Are all hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: g is CR ^1d ；R ^1d is-P (O) R ^m R ⁿ ；R ^m And R ⁿ Is methyl; y is CR ^2a ；R ^2a Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group; r ^1a Is cyano; r ^1b And R ^1c Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; r ² Is a hydrogen atom; r ³ Is C _1-6 A haloalkyl group; r ⁴ Is a hydroxyl group; r ⁵ Is a hydrogen atom; r ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² And R ¹³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: g is CR ^1d ；R ^1d is-P (O) R ^m R ⁿ ；R ^m And R ⁿ Is methyl; y is CR ^2a ；R ^2a Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group; r ^1a Is cyano; r ^1b And R ^1c Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group; r ² Is a hydrogen atom; r ³ Is C _1-6 A haloalkyl group; r is ⁴ And R ⁵ Forms a 3-to 8-membered heterocyclic group containing 1 nitrogen atom with the carbon atom to which it is attached; r ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ¹² And R ¹³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (II), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1) or formula (IV-2), or a pharmaceutically acceptable salt thereof, wherein: r ^m And R ⁿ Is methyl; r ^1a Is cyano; r ^1b And R ^1c Are each a hydrogen atom; r ³ Is C _1-6 A haloalkyl group; r ⁴ Is a hydroxyl group; r ⁵ Is a hydrogen atom; r ⁸ And R ⁹ Are all hydrogen atoms.

Table a typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a compound represented by general formula (IA):

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

Y、R ^1a 、R ^1b 、R ^1c and R ² To R ¹³ As defined in formula (I). Which is an intermediate for the preparation of the compounds of formula (I).

Another aspect of the disclosure relates to a compound represented by formula (IIA) or a salt thereof:

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

R ^1a 、R ^1b 、R ^1c 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in formula (II). Which is an intermediate for the preparation of the compound of formula (II).

Another aspect of the present disclosure relates to a compound represented by the general formula (II-1A):

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

R ^1a 、R ^1b 、R ^1c 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in the general formula (II-1). Which is an intermediate for the preparation of the compound represented by the general formula (II-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (II-2A):

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

R ^1a 、R ^1b 、R ^1c 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in the general formula (II-2). Which is an intermediate for preparing the compound represented by the general formula (II-2).

Another aspect of the present disclosure relates to a compound represented by the general formula (III-1A):

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

R ^1a 、R ^1b 、R ^1c 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in formula (III-1). Which is an intermediate for preparing the compound represented by the general formula (III-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (III-2A):

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

R ^1a 、R ^1b 、R ^1c 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in the general formula (III-2). Which is an intermediate for preparing the compound represented by the general formula (III-2).

Another aspect of the present disclosure relates to a compound represented by the general formula (IV-1A):

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

R ^1a 、R ^1b 、R ^1c 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in the general formula (IV-1). Which is an intermediate for preparing the compound represented by the general formula (IV-1).

Another aspect of the present disclosure relates to a compound represented by the general formula (IV-2A):

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

R ^1a 、R ^1b 、R ^1c 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in the general formula (IV-2). Which is an intermediate for preparing the compound represented by the general formula (IV-2).

Table B typical intermediate compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a method of preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising:

a compound represented by the general formula (IA) or a salt thereof and R ^1d -H is subjected to coupling reaction to obtain the compound shown in the general formula (I) or pharmaceutically acceptable salt thereof,

wherein:

g is CR ^1d ；

X is selected from Br, Cl and I; preferably, X is Br;

Y、R ^1a 、R ^1b 、R ^1c 、R ^1d and R ² To R ¹³ As defined in formula (I).

Another aspect of the present disclosure relates to a method of preparing a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

a compound represented by the general formula (IIA) or a salt thereof with R ^1d -H undergoes a coupling reaction to obtain a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

R ^1a 、R ^1b 、R ^1c 、R ^m 、R ⁿ 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in formula (II).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, the method comprising:

a compound represented by the general formula (II-1A) or a salt thereof and R ^1d -H undergoes a coupling reaction to obtain a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

R ^1a 、R ^1b 、R ^1c 、R ^m 、R ⁿ 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in the general formula (II-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof, the method comprising:

a compound represented by the general formula (II-2A) or a salt thereof and R ^1d -H undergoes a coupling reaction to obtain a compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof,

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

R ^1a 、R ^1b 、R ^1c 、R ^m 、R ⁿ 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in formula (II-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof, which comprises:

a compound represented by the general formula (III-1A) or a salt thereof and R ^1d Carrying out coupling reaction on the-H to obtain a compound shown as a general formula (III-1) or a pharmaceutically acceptable salt thereof,

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

R ^1a 、R ^1b 、R ^1c 、R ^m 、R ⁿ 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in the general formula (III-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof, which comprises:

a compound represented by the general formula (III-2A) or a salt thereof and R ^1d Carrying out coupling reaction on the-H to obtain a compound shown as a general formula (III-2) or a pharmaceutically acceptable salt thereof,

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

R ^1a 、R ^1b 、R ^1c 、R ^m 、R ⁿ 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in the general formula (III-2).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof, which comprises:

a compound represented by the general formula (IV-1A) or a salt thereof and R ^1d -H undergoes a coupling reaction to obtain a compound shown as a general formula (IV-1) or a pharmaceutically acceptable salt thereof,

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

R ^1a 、R ^1b 、R ^1c 、R ^m 、R ⁿ 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in the general formula (IV-1).

Another aspect of the present disclosure relates to a method for preparing a compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof, the method comprising:

a compound represented by the general formula (IV-2A) or a salt thereof and R ^1d -H undergoes a coupling reaction to obtain a compound shown as a general formula (IV-2) or a pharmaceutically acceptable salt thereof,

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

R ^1a 、R ^1b 、R ^1c 、R ^m 、R ⁿ 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in the general formula (IV-2).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound represented by the general formula (I), general formula (II-1), general formula (II-2), general formula (III-1), general formula (III-2), general formula (IV-1), general formula (IV-2), and table a of the present disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The present disclosure further relates to the use of a compound represented by formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2) and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting CDKs; preferably, wherein said CDK is CDK 7.

The present disclosure further relates to the use of a compound represented by formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of a disease or condition associated with abnormal activity of CDK 7; preferably, the disease or disorder is cancer.

The present disclosure further relates to the use of a compound represented by formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment and/or prevention of a disease or condition; wherein said disease or condition is preferably cancer; the cancer is preferably selected from breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, kidney cancer, bladder cancer, urothelial cancer, urinary tract cancer, prostate cancer, testicular cancer, colorectal cancer, sarcoma, bone cancer, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, nasopharyngeal cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, small intestine cancer, stomach cancer, esophageal cancer, pancreatic cancer, liver cancer, bile duct cancer, neurofibroma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland carcinoma, and gastrointestinal stromal tumor. Preferably, wherein said lymphoma is selected from hodgkin's disease and non-hodgkin's lymphoma (e.g. mantle cell lymphoma, diffuse large B-cell lymphoma, follicular central lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); wherein said lung cancer is non-small cell lung cancer (NSCLC) (including squamous cell carcinoma, adenocarcinoma, large cell carcinoma, etc.) or Small Cell Lung Cancer (SCLC); wherein said renal cancer is selected from the group consisting of renal cell carcinoma, clear cell and nephroeosinophilic tumor; wherein said leukemia is selected from the group consisting of Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), Chronic Myelogenous Leukemia (CML), and Acute Myelogenous Leukemia (AML); wherein said colorectal cancer is colon cancer or rectal cancer; wherein said sarcoma is chondrosarcoma.

The present disclosure further relates to a method of inhibiting CDKs comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, wherein said CDK kinase is CDK7 kinase.

The present disclosure further relates to a method of treating and/or preventing a disease or disorder associated with abnormal activity of CDK7, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2), and table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; preferably, the disease or disorder is cancer.

The present disclosure further relates to a method of treating and/or preventing a disease or disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II-1), formula (III-2), formula (IV-1), formula (IV-2), and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same. Wherein said disease or condition is preferably a cancer, preferably selected from the group consisting of breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, renal cancer, bladder cancer, urothelial cancer, urinary tract cancer, prostate cancer, testicular cancer, colorectal cancer, sarcoma, bone cancer, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, nasopharyngeal cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, small intestine cancer, stomach cancer, esophageal cancer, pancreatic cancer, liver cancer, bile duct cancer, neurofibroma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland cancer, and gastrointestinal stromal tumor. Preferably, wherein said lymphoma is selected from hodgkin's disease and non-hodgkin's lymphoma (e.g. mantle cell lymphoma, diffuse large B-cell lymphoma, follicular central lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); wherein said lung cancer is non-small cell lung cancer (NSCLC) (including squamous cell carcinoma, adenocarcinoma, large cell carcinoma, etc.) or Small Cell Lung Cancer (SCLC); wherein said renal cancer is selected from the group consisting of renal cell carcinoma, clear cell and nephroeosinophilic tumor; wherein said leukemia is selected from the group consisting of Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), Chronic Myelogenous Leukemia (CML), and Acute Myelogenous Leukemia (AML); wherein said colorectal cancer is colon cancer or rectal cancer; wherein said sarcoma is chondrosarcoma.

The present disclosure further relates to compounds of formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2) and Table A or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as a medicament.

The present disclosure further relates to a compound represented by formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a CDK inhibiting agent; preferably, wherein said CDK is CDK 7.

The present disclosure further relates to a compound represented by formula (I), formula (II-1), formula (II-2), formula (III-1), formula (III-2), formula (IV-1), formula (IV-2) and Table A, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of a disease or condition. Wherein said disease or condition is preferably a cancer, preferably selected from the group consisting of breast cancer, endometrial cancer, ovarian cancer, vaginal cancer, fallopian tube cancer, cervical cancer, renal cancer, bladder cancer, urothelial cancer, urinary tract cancer, prostate cancer, testicular cancer, colorectal sarcoma, bone cancer, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat cancer, nasopharyngeal cancer, oral cancer, lung cancer, alveolar cancer, lymphoma, mesothelioma, small intestine cancer, gastric cancer, esophageal cancer, pancreatic cancer, liver cancer, biliary tract cancer, neurofibroma, glioma, neuroblastoma, melanoma, skin cancer, basal cell carcinoma, squamous cell carcinoma, thyroid cancer, head and neck cancer, salivary gland carcinoma, and gastrointestinal stromal tumor. Preferably, wherein said lymphoma is selected from hodgkin's disease and non-hodgkin's lymphoma (e.g. mantle cell lymphoma, diffuse large B-cell lymphoma, follicular central lymphoma, marginal zone B-cell lymphoma, lymphoplasmacytic lymphoma and peripheral T-cell lymphoma); wherein said lung cancer is non-small cell lung cancer (NSCLC) (including squamous cell carcinoma, adenocarcinoma, large cell carcinoma, etc.) or Small Cell Lung Cancer (SCLC); wherein said renal cancer is selected from the group consisting of renal cell carcinoma, clear cell and nephroeosinophilic tumor; wherein said leukemia is selected from the group consisting of Chronic Lymphocytic Leukemia (CLL), Acute Lymphoblastic Leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), Chronic Myelogenous Leukemia (CML), and Acute Myelogenous Leukemia (AML); wherein said colorectal cancer is colon cancer or rectal cancer; wherein said sarcoma is chondrosarcoma.

The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers to formulate compositions of the disclosure by conventional methods. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure may also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

As a general guide, the active compound is preferably administered in a unit dose or in a manner such that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump of the model deltec add-plus.tm.5400.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound used, the severity of the disease, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment regimen, such as mode of treatment, daily dose, or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms (i.e., C) _1-20 Alkyl), preferably alkyl (i.e., C) containing 1 to 12 (e.g., 1,2,3, 4,5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms _1-12 Alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C) _1-6 Alkyl). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexylAnd various branched chain isomers thereof, and the like. Alkyl groups may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl radicals (i.e. C) containing from 2 to 12, for example 2,3, 4,5, 6, 7, 8, 9, 10, 11 and 12, carbon atoms are preferred _2-12 Alkenyl), more preferably alkenyl having 2 to 6 carbon atoms (i.e., C) _2-6 Alkenyl). The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 14 (e.g., 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, and 14) carbon atoms (i.e., 3 to 14 membered cycloalkyl groups), preferably 3 to 8 carbon atoms (i.e., 3 to 8 membered cycloalkyl groups), and more preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl groups). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered spirocycloalkyl) polycyclic group having a single ring sharing one carbon atom (referred to as a spiro atom) between the rings, which may contain one or more double bonds. Preferably 6 to 14 membered (i.e. 6 to 14 membered spirocycloalkyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered spirocycloalkyl). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group and a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered, mono-spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a 5 to 20 membered all carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds (i.e., a 5 to 20 membered fused cyclic alkyl). Preferably 6 to 14 (i.e. 6 to 14 fused ring alkyl) members, more preferably 7 to 10 (e.g. 7, 8, 9 or 10) members (i.e. 7 to 10 fused ring alkyl). They may be classified into polycyclic fused alkyl groups such as bicyclic, tricyclic, tetracyclic, etc., according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds (i.e., a 5 to 20 membered bridged cycloalkyl). Preferably 6 to 14 membered (i.e. 6 to 14 membered bridged cycloalkyl), more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered) (i.e. 7 to 10 membered bridged cycloalkyl). They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic bridged cycloalkyl groups according to the number of constituent rings, and preferably bicyclic, tricyclic and tetracyclic, more preferably bicyclic and tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes a cycloalkyl ring (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring as described above, wherein the ring(s) attached to the parent structure are cycloalkyl, non-limiting examples of which include indanyl

Tetrahydronaphthyl

Benzocycloheptalkyl radical

Etc.; indanyl is preferred

Tetrahydronaphthyl radical

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms (i.e., a 3 to 20 membered heterocyclyl group) wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., form an oxynitride; the sulfur may be optionally oxidized, i.e., form a sulfoxide or sulfone), but does not include a cyclic moiety of-O-, -O-S-, or-S-, the remaining ring atoms being carbon. Preferably 3 to 14 (e.g., 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13 and 14) ring atoms (i.e., 3 to 14 membered heterocyclyl), of which 1-4 (e.g., 1,2,3 and 4) are heteroatoms; more preferably 6 to 14 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14) (i.e., 6 to 14 membered heterocyclyl), wherein 1-3 are heteroatoms (e.g., 1,2 and 3); more preferably 3 to 8 ring atoms (i.e. 3 to 8 membered heterocyclyl), of which 1-3 (e.g. 1,2 and 3) are heteroatoms; most preferably 5 or 6 ring atoms (i.e. 5 or 6 membered heterocyclyl) are included, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3, 6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered spiroheterocyclyl) polycyclic heterocyclic group sharing one atom (referred to as a spiro atom) between single rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur (the nitrogen may be optionally oxidized, i.e., to form a nitrogen oxide; the sulfur may be optionally oxidized, i.e., to form a sulfoxide or sulfone), but excluding the ring portions of-O-, -O-S-or-S-, with the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably 6 to 14 (e.g. 6, 7, 8, 9, 10, 11, 12, 13 and 14) membered (i.e. 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 (e.g. 7, 8, 9 or 10) membered (i.e. 7 to 10 membered spiroheterocyclyl). Spiro heterocyclic groups are classified into a single spiro heterocyclic group, a double spiro heterocyclic group and a multi spiro heterocyclic group, preferably a single spiro heterocyclic group and a double spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, 5-membered/6-membered or 6-membered/6-membered mono spiroheterocyclyl group. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members (i.e., a 5 to 20 member fused heterocyclyl group) in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, and one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur (the nitrogen may optionally be oxidized, i.e., to form a nitrogen oxide; the sulfur may optionally be oxo, i.e., to form a sulfoxide or sulfone), but does not include the ring portion of-O-O-, -O-S-or-S-S-, and the remaining ring atoms are carbon. Preferably 6 to 14 (e.g., 6, 7, 8, 9, 10, 11, 12, 13 and 14) membered (i.e., 6 to 14 membered fused heterocyclyl), more preferably 7 to 10 (e.g., 7, 8, 9 or 10) membered (i.e., 7 to 10 membered fused heterocyclyl). They are classified into bicyclic, tricyclic, tetracyclic and other polycyclic fused heterocyclic groups according to the number of constituting rings, preferably bicyclic and tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 20 membered (i.e., 5 to 20 membered bridged heterocyclyl) polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, and sulfur and the remaining ring atoms are carbon. Preferably 6 to 14 (e.g. 6, 7, 8, 9, 10, 11, 12, 13 and 14) membered (i.e. 6 to 14 bridged heterocyclyl), more preferably 7 to 10 (e.g. 7, 8, 9 or 10) membered (i.e. 7 to 10 bridged heterocyclyl). They may be divided into polycyclic bridged heterocyclic groups such as bicyclic, tricyclic, tetracyclic, etc., depending on the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:

and so on.

The heterocyclyl group may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares an adjacent pair of carbon atoms) group (i.e., a 6 to 14 membered aryl group) having a conjugated pi-electron system, preferably a 6 to 10 membered (i.e., a 6 to 10 membered aryl group), such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system (i.e., 5-to 14-membered heteroaryl) containing 1 to 4 heteroatoms (e.g., 1,2,3, and 4), 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g., 5, 6, 7, 8, 9 or 10 membered) (i.e., 5 to 10 membered heteroaryl), more preferably 5 or 6 membered (i.e., 5 or 6 membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The above cycloalkyl, heterocyclyl, aryl and heteroaryl groups have 1 residue derived from the parent ring atom by removal of one hydrogen atom, or2 residues derived from the parent ring atom by removal of two hydrogen atoms from the same ring atom or two different ring atoms, i.e., "cycloalkylene", "heterocyclylene", "arylene", "heteroarylene".

The term "cycloalkyloxy" refers to cycloalkyl-O-, wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to the heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "alkylthio" refers to an alkyl-S-group wherein alkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

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

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to the group-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

The term "oxo" refers to "═ O".

The term "carbonyl" refers to C ═ O.

The term "carboxy" refers to-C (O) OH.

The term "carboxylate" refers to-C (O) O (alkyl), -C (O) O (cycloalkyl), (alkyl) C (O) O-or (cycloalkyl) C (O) O-, wherein alkyl and cycloalkyl are as defined above.

The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomers" refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Additional asymmetric atoms may be present in substituents in the compounds of the present disclosure. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers, and (D) -and (L) -isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. An isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or, when a basic functional group (e.g., amino group) or an acidic functional group (e.g., carboxyl group) is contained in a molecule, a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then diastereoisomeric resolution is performed by a conventional method known in the art to obtain a pure isomer. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

In the chemical structure of the compounds described in the present disclosure, a bond

Denotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structure

Can be that

Or at the same time contain

Two configurations.

The configuration is not specified, i.e., either the Z configuration or the E configuration, or both configurations are contemplated.

The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like. Examples of lactam-lactam equilibria are shown below:

when referring to pyrazolyl, it is understood to include any one of the following two structures or a mixture of two tautomers:

all tautomeric forms are within the scope of the disclosure, and the naming of the compounds does not exclude any tautomers.

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, and the like, for example, respectively ² H (deuterium, D), ³ H (tritium, T), ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ³² p、 ³³ p、 ³³ S、 ³⁴ S、 ³⁵ S、 ³⁶ S、 ¹⁸ F、 ³⁶ Cl、 ⁸² Br、 ¹²³ I、 ¹²⁴ I、 ¹²⁵ I、 ¹²⁹ I and ¹³¹ i, etc., preferably deuterium.

Compared with the non-deuterated drugs, the deuterated drugs have the advantages of reducing toxic and side effects, increasing the stability of the drugs, enhancing the curative effect, prolonging the biological half-life of the drugs and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, where replacement by deuterium may be partial or complete, partial replacement by deuterium meaning replacement of at least one hydrogen by at least one deuterium.

When a position is specifically designated as deuterium D, that position is understood to be deuterium having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e. at least 15% deuterium incorporation). The natural abundance of the compound in the examples can be deuterium at least 1000 times greater than deuterium (i.e., at least 15% deuterium incorporation), deuterium at least 2000 times greater than deuterium (i.e., at least 30% deuterium incorporation), deuterium at least 3000 times greater than deuterium (i.e., at least 45% deuterium incorporation), deuterium at least 3340 times greater than abundance of deuterium (i.e., at least 50.1% deuterium incorporation), deuterium at least 3500 times greater than abundance of deuterium (i.e., at least 52.5% deuterium incorporation), deuterium at least 4000 times greater than abundance of deuterium (i.e., at least 60% deuterium incorporation), deuterium at least 0 times greater than abundance of deuterium (i.e., at least 67.5% deuterium incorporation), deuterium at least 5000 times greater than abundance of deuterium (i.e., at least 75% deuterium incorporation), deuterium at least 5500 times greater than abundance of deuterium (i.e., at least 82.5% deuterium incorporation), deuterium at least 6000 times greater than abundance of deuterium (i.e., at least 90% deuterium incorporation), deuterium at least 6333.3 times greater than abundance of deuterium (i.e., at least 95% deuterium incorporation), deuterium at least 6466.7% greater than deuterium (i.e., at least 97% abundance of deuterium incorporation of deuterium) Deuterium at an abundance of at least 6600 times (i.e., deuterium incorporation of at least 99%), deuterium at an abundance of at least 6633.3 times (i.e., deuterium incorporation of at least 99.5%), or deuterium of higher abundance.

"optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example "C optionally substituted by halogen or cyano _1-6 Alkyl "means that halogen or cyano may, but need not, be present, and the description includes the case where alkyl is substituted with halogen or cyano and the case where alkyl is not substituted with halogen or cyano.

"substituted" means that one or more hydrogen atoms, preferably 1 to 6, more preferably 1 to 3, of the hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salt" refers to a salt of a compound of the disclosure, which may be selected from inorganic or organic salts. The salt has safety and effectiveness when used in a mammal body, and has due biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to an amount of drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate therapeutically effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.

As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be appreciated by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not limiting.

Synthesis of the Compounds of the disclosure

In order to achieve the purpose of the present disclosure, the following technical solutions are adopted in the present disclosure:

scheme one

The invention discloses a method for preparing a compound shown as a general formula (I) or a pharmaceutically acceptable salt thereof, which comprises the following steps:

a compound represented by the general formula (IA) or a salt thereof and R ^1d -H, in the presence of a catalyst under alkaline conditions, under microwave or heating conditions, to produce a coupling reaction to obtain a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof,

wherein:

g is CR ^1d ；

X is selected from Br, Cl and I; preferably, X is Br;

Scheme two

A process for preparing a compound of the general formula (II) or a pharmaceutically acceptable salt thereof, which comprises:

a compound represented by the general formula (IIA) or a salt thereof and R ^1d -H, in the presence of a catalyst under alkaline conditions, under microwave or heating conditions, to produce a coupling reaction to produce a compound of formula (II) or a pharmaceutically acceptable salt thereof,

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

Scheme three

A process for producing a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof, which comprises:

a compound represented by the general formula (II-1A) or a salt thereof and R ^1d -H, in the presence of a catalyst under alkaline conditions, in the presence of microwaves or heating conditions, to produce a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

Scheme four

A process for producing a compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof, which comprises:

a compound represented by the general formula (II-2A) or a salt thereof and R ^1d -H, under alkaline conditions, in the presence of a catalyst, under microwave or heating conditions, to produce a coupling reaction to obtain a compound represented by the general formula (II-2) or a pharmaceutically acceptable salt thereof,

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

R ^1a 、R ^1b 、R ^1c 、R ^m 、R ⁿ 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in the general formula (II-2).

Scheme five

A process for producing a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof, which comprises:

a compound represented by the general formula (III-1A) or a salt thereof and R ^1d -H, under alkaline conditions, in the presence of a catalyst, under microwave or heating conditions, to produce a coupling reaction to obtain a compound represented by the general formula (III-1) or a pharmaceutically acceptable salt thereof,

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

Scheme six

A process for producing a compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof, which comprises:

a compound represented by the general formula (III-2A) or a salt thereof and R ^1d -H, under alkaline conditions, in the presence of a catalyst, under microwave or heating conditions, to produce a coupling reaction to obtain a compound represented by the general formula (III-2) or a pharmaceutically acceptable salt thereof,

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

Scheme seven

A process for producing a compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof, which comprises:

a compound represented by the general formula (IV-1A) or a salt thereof and R ^1d -H, under alkaline conditions, in the presence of a catalyst, under microwave or heating conditions, to produce a compound represented by the general formula (IV-1) or a pharmaceutically acceptable salt thereof,

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

Scheme eight

A process for producing a compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof, which comprises:

a compound represented by the general formula (IV-2A) or a salt thereof and R ^1d -H, under alkaline conditions, in the presence of a catalyst, under microwave or heating conditions, to produce a coupling reaction to obtain a compound represented by the general formula (IV-2) or a pharmaceutically acceptable salt thereof,

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

The reagents that provide basic conditions in the above synthetic schemes include organic and inorganic bases, including but not limited to triethylamine, pyridine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide, or 1, 8-diazabicycloundecen-7-ene; the inorganic bases include, but are not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, and potassium hydroxide; preferably, the agent that provides alkaline conditions is potassium phosphate.

The catalysts in the above synthesis schemes include, but are not limited to, palladium acetate/4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene, tetrakis (triphenylphosphine) palladium, palladium dichloride, methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II), 1 '-bis (dibenzylphosphine) dichloropentairon palladium, [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, tris (dibenzylideneacetone) dipalladium, etc., preferably palladium acetate/4, 5-bis diphenylphosphine-9, 9-dimethylxanthene.

The above reaction is preferably carried out under microwave conditions; the microwave condition is that the reaction temperature is 100 to 200 ℃, and the reaction time is 0.5 to 6 hours; preferably, the microwave conditions are that the reaction temperature is 145 ℃ and the reaction time is 1 hour.

The reaction of the above step is preferably carried out in a solvent including, but not limited to: pyridine, ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1, 4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1, 2-dibromoethane and mixtures thereof.

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10 ^-6 The units in (ppm) are given. The NMR measurement wasUsing Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M, determining the solvent as deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS).

MS was measured using an Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid chromatograph-Mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), water ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: water ACQuity Qda Detector/waters SQ Detector), THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC assay using Agilent 1260DAD HPLC.

High performance liquid phase preparation Waters 2545-2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used.

Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument uses CombiFlash Rf200(TELEDYNE ISCO).

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Silica gel column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were determined with a NovoStar microplate reader (BMG, Germany).

Known starting materials of the present disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, J & K, Shaoyuan ChemBioInc (Accela ChemBio Inc), Shanghai Bide medicine, Darril Chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: n-hexane/ethyl acetate system. The volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine and acetic acid can be added for adjustment.

Example 1

7- (dimethylphosphoryl) -3- (2- (((1S,3R) -3-hydroxycyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile 1

First step of

7-bromo-3- (2- (((1S,3R) -3-hydroxycyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile 1c

The compound 7-bromo-3- (2-chloro-5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile 1a (100mg, 0.25mmol, prepared by the method disclosed in patent application "example 4 on page 58 of the specification in WO2020093006A 1"), compound (1R,3S) -3-aminocyclohexan-1-ol hydrochloride 1b (45mg, 0.30mmol, Nanjing Yam) was dissolved in N-methylpyrrolidone (6 mL). Diisopropylethylamine (160mg, 1.24mmol) was added, and the reaction was heated to 140 ℃ for 1 hour. The reaction was cooled to room temperature, water (15mL) was added, the reaction solution was extracted with ethyl acetate (40mL × 3), the organic phases were combined, the organic phase was washed with a saturated sodium chloride solution (50mL × 3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by column chromatography with eluent system a to give the title compound 1c (106mg, yield: 89%).

MS m/z(ESI)：480.1[M+1]，482.1[M+3]。

Second step of

Compound 1c (105mg, 0.22mmol), dimethylphosphine oxide (34mg, 0.44mmol) was dissolved in N, N-dimethylformamide (7 mL). 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene (25mg, 0.04mmol), palladium acetate (4.9mg, 0.02mmol) and potassium phosphate (69mg, 0.328mmol) were added, reacted at 145 ℃ for 1 hour with microwave, and cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Gilson GX-281, elution: 10mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 60% to 80%, flow rate: 30mL/min) to obtain the title compound 1(40mg, yield: 38%).

MS m/z(ESI)：478.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ12.15(s,1H),8.81-8.50(m,2H),8.21(s,1H),8.01(d,1H),7.79-7.64(m,1H),4.78-4.62(m,1H),3.87(s,1H),3.56-3.42(m,1H),2.21-2.10(m,1H),2.05(d,6H),1.95-1.65(m,3H),1.37-1.01(m,4H)。

Example 2

7- (dimethylphosphoryl) -3- (2- (((1S,3S) -3-hydroxycyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile 2

First step of

7-bromo-3- (2- (((1S,3S) -3-hydroxycyclohexyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -1H-indole-6-carbonitrile 2c

Compound 1a (100mg, 0.24mmol, prepared as disclosed in the patent application "WO 2020093006A1, page 58, example 4"), compound (1S,3S) -3-aminocyclohexane-1-ol hydrochloride 2b (45mg, 0.30mmol, Nanjing Yam) was dissolved in N-methylpyrrolidone (6 mL). Diisopropylethylamine (160mg, 1.24mmol) was added, and the reaction was heated to 140 ℃ for 1 hour. The reaction was cooled to room temperature, water (15mL) was added, the reaction solution was extracted with ethyl acetate (40 mL. times.3), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution (50 mL. times.3), dried over anhydrous sodium sulfate, filtered to remove the drying agent, the filtrate was concentrated under reduced pressure, and purified by column chromatography using eluent system A to give the title compound 2c (105mg, yield: 88%).

MS m/z(ESI)：480.1[M+1]，482.1[M+3]。

Second step of

Compound 2c (105mg, 0.22mmol), phosphorus dimethyl oxide (34mg, 0.44mmol) was dissolved in N, N-dimethylformamide (7 mL). 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene (25mg, 0.04mmol), palladium acetate (4.9mg, 0.02mmol) and potassium phosphate (69mg, 0.328mmol) were added, reacted at 145 ℃ for 1 hour by microwave, and cooled to room temperature. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by high performance liquid chromatography (Gilson GX-281, elution: 10mmol/L aqueous ammonium bicarbonate solution and acetonitrile, gradient of acetonitrile: 60% to 80%, flow rate: 30mL/min) to obtain the title compound 2(40mg, yield: 38%).

MS m/z(ESI)：478.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ12.12(s,1H),8.82-8.67(m,1H),8.65-8.50(m,1H),8.21(s,1H),7.98-7.80(m,1H),7.76-7.56(m,1H),4.56-4.43(m,1H),4.41-4.22(m,1H),4.03(s,1H),2.04(d,6H),1.93-1.78(m,2H),1.76-1.65(m,1H),1.64-1.46(m,3H),1.45-1.27(m,2H)。

Biological evaluation

The present disclosure is further described below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1 MDA-MB-468 proliferation assay

The following method was used to determine the inhibitory activity of the compounds of the present disclosure on MDA-MB-468 cell proliferation. The experimental method is briefly described as follows:

MDA-MB-468 cells (ATCC, HTB-132) were cultured in a complete medium, namely L15 medium (Gibco, 11415-114) containing 10% fetal bovine serum (Gibco, 10099-141). The first day of experiment, MDA-MB-468 cells were seeded in 96-well plates using complete medium at a density of 2500 cells/well, 180. mu.L cell suspension per well, placed at 37 ℃ and 5% CO ₂ The cell culture chamber was incubated overnight, and the next day 20. mu.L of test compound diluted in a gradient of complete medium was added to each well of the cell plate, the compound first being dissolved in DMSO at an initial concentration of 2mM or 0.2mM, diluted in a 3-fold concentration gradient for 10 concentration points, and the blank being 100% DMSO. Another 5. mu.L of the compound dissolved in DMSO was added to 95. mu.L of complete medium, i.e., the compound was diluted 20-fold with complete medium. To the cell suspension, 20. mu.L of each well of the compound diluted in complete medium was finally added, i.e., the compound was added to the cell suspension at a final concentration of 10 concentration points at which 3-fold gradient dilution was performed starting from 10. mu.M or 1. mu.M, a blank containing 0.5% DMSO was set, and the mixture was left at 37 ℃ and 5% CO ₂ The cell incubator was incubated for 6 days. On the seventh day, 96 well cell culture plates were removed and 90. mu.L of each well was added

The reagent for detecting the activity of the luminescent cells (Promega, G7573) was left at room temperature for 10 minutes, and then the luminescence signal value was read using a multifunctional microplate reader (BMG labtech, PHERAstar FS), and the IC of the inhibitory activity of the compound was calculated using Graphpad Prism software ₅₀ The values are shown in Table 1.

TABLE 1 Activity of compounds of this disclosure to inhibit MDA-MB-468 cell proliferation

Compound (I)	IC ₅₀ (nM)
		1	47.3
2	6.6

And (4) conclusion: the compound disclosed by the invention has good activity of inhibiting MDA-MB-468 cell proliferation.

Test example 2 CDK7 enzyme test

The following methods were used to determine the inhibitory activity of the compounds of the present disclosure on the enzymatic activity of CDK 7. The experimental method is briefly described as follows:

will be provided with

Enzymatic Buffer in CDKs Kinase (CDK1/4/6/7/12) Kit (Cisbio, 63ADK000CB11PEG) was formulated as 1 Xenzyme Buffer: DTT (Sigma, D0632) was first prepared as 1M mother liquor, then according to ddH ₂ O:Enzymatic Buffer:DTT：MgCl ₂ (Sigma, M1028): KCl (Sigma, 44675) ═ 689:200:1:10:100, was prepared as a1 Xenzyme buffer.

CDK7 (carba, 04-108) was diluted enzymatically with 1 Xenzyme buffer to 10 ng/. mu.L, 2. mu.L/well was added to a white 384-well plate (Corning, 4513), only 2. mu.L enzyme buffer was added to control wells, 4. mu.L test compound was added to wells diluted with a1 Xenzyme buffer gradient, compound was first dissolved in DMSO at an initial concentration of 50. mu.M, 3-fold concentration gradient was diluted for 11 concentration points, blank was 100% DMSO, 2. mu.L compound was added to 38. mu.L 1 Xenzyme buffer, enzyme and compound were pre-diluted in DMSO at room temperatureIncubate for 30 minutes. Then ATP (Sigma, A7699) was added at a concentration of 87.5. mu.M in 1 Xenzyme buffer and 1.25. mu.M

The mixed solution of CDKs Substrate-biotin in the CDKs Kinase (CDK1/4/6/7/12) Kit is 4 μ L/well, in this case, CDKs 7 enzyme concentration in the reaction plate well is 2ng/μ L, ATP concentration 35 μ M, CDKs Substrate-biotin concentration 0.5 μ M, compound 1 μ M first concentration 3-fold gradient dilution 11 concentrations, CDKs 7 enzyme concentration in the blank well is 2ng/μ L, ATP concentration 35 μ M, CDKsSubstrate-biotin concentration 0.5 μ M, compound 0 μ M, CDKs 7 enzyme concentration in the control blank well is 0ng/μ L, ATP concentration 35 μ M, CDKs Substrate-biotin concentration 0.5 μ M, compound 0 μ M. After mixing well, incubate at room temperature for 90 minutes. Then 5. mu.L/well of

CDKs Antibody-Cryptate 100-fold diluted with Detection buffer in CDKs Kinase (CDK1/4/6/7/12) Kit was added to 5. mu.L/well of Streptavidin-XL665 diluted to 250nM with Detection buffer, mixed well and incubated at room temperature for 1 hour. HTRF was read using a multifunctional microplate reader (BMG labtech, PHERAStar FS). IC of compound inhibitory activity was calculated using Graphpad Prism 5 software ₅₀ The values are shown in Table 2.

TABLE 2 inhibitory Activity of the presently disclosed Compounds on the enzymatic Activity of CDK7

Compound (I)	IC ₅₀ (nM)
		1	6.3
2	2.3

And (4) conclusion: the compounds disclosed in the present disclosure have excellent inhibitory activity against CDK 7.

Test example 3 CDK1 enzymological experiment

The following methods were used to determine the inhibitory activity of the compounds of the present disclosure on the enzymatic activity of CDK 1. The experimental method is briefly described as follows:

will be provided with

Enzymatic buffers in the CDKs Kinase (CDK1/4/6/7/12) Kit (Cisbio, 63ADK000CB11PEG) were formulated as 1 Xenzyme Buffer: DTT (Sigma, D0632) was first prepared as 1M mother liquor, then according to ddH ₂ O:Enzymatic Buffer:DTT：MgCl ₂ (Sigma, M1028) ═ 774:200:1:5 was prepared as a1 Xenzyme buffer.

CDK1 (carba, 04-102) was enzymatically diluted to 5 ng/. mu.L with 1 Xenzyme buffer, 2. mu.L/well was added to a white 384-well plate (Corning, 4513), only 2. mu.L of enzyme buffer was added to control wells, then 4. mu.L/well of test compound diluted with a1 Xenzyme buffer gradient was added, compound was first dissolved in DMSO at an initial concentration of 5mM, 3-fold concentration gradient dilution, 11 concentration points total, blank was 100% DMSO, 2. mu.L of compound dissolved in DMSO was added to 38. mu.L of 1 Xenzyme buffer, and enzyme and compound were preincubated at room temperature for 30 min. Then ATP (Sigma, A7699) was added at a concentration of 12.5. mu.M in 1 Xenzyme buffer and at a concentration of 0.75. mu.M

The mixed solution of CDKs Substrate-biotin in the CDKs Kinase (CDK1/4/6/7/12) Kit is 4 μ L/well, when the CDKs Substrate-biotin concentration in the reaction plate well is 1ng/μ L, ATP concentration of 5 μ M, the CDKs Substrate-biotin concentration is 0.3 μ M, the compound 100 μ M first concentration is 3-fold gradient diluted 11 concentrations, the CDK1 enzyme concentration in the blank well is 1ng/μ L, ATP concentration of 5 μ M, CDKsSubstrate-biotin concentration of 0.3 μ M, the compound is 0 μ M, the CDKs Substrate-biotin concentration in the control blank well is 0ng/μ L, ATP concentration of 5 μ M, and the CDKs Substrate-biotin concentration is 0.3 μ Mμ M, compound 0 μ M. After mixing well, incubate at room temperature for 60 minutes. Then 5. mu.L/well of

CDKs Antibody-Cryptate 100-fold diluted with Detection buffer in CDKs Kinase (CDK1/4/6/7/12) Kit was added to Streptavidin-XL665 diluted to 150nM with Detection buffer at 5. mu.L/well, mixed well and incubated at room temperature for 1 hour. HTRF was read using a multifunctional microplate reader (BMG labtech, PHERAStar FS). IC of compound inhibitory activity was calculated using Graphpad Prism 5 software ₅₀ The values are shown in Table 3.

TABLE 3 inhibitory Activity of compounds of the present disclosure on CDK1 enzymatic Activity

Compound (I)	IC ₅₀ (nM)
		2	>100000

And (4) conclusion: the compounds of the present disclosure had no significant inhibitory effect on CDK1 enzyme activity, and in combination with tables 2 and 3, it was seen that the compounds of the present disclosure were very selective (>1000 fold) for CDK 7.

Test example 4 CDK2 enzyme assay

The following methods were used to determine the inhibitory activity of the compounds of the present disclosure on the enzymatic activity of CDK 2. The experimental method is briefly described as follows:

will be provided with

Enzymic buffers in the CDKs Kinase (CDK2/5) Kit (Cisbio, 63ADK000CB12PEG) were formulated as 1 Xenzyme Buffer: DTT (Sigma, D0632) was first prepared as 1M mother liquor, thenddH ₂ O:Enzymatic Buffer:DTT：MgCl ₂ (Sigma，M1028):MnCl ₂ (Sigma, M1787) was prepared in 1 Xenzyme buffer at a ratio of 793:200:1:5: 1.

CDK2 (carba, 04-103) was enzymatically diluted to 10 ng/. mu.L with 1 Xenzyme buffer, 2. mu.L/well was added to a white 384-well plate (Corning, 4513), only 2. mu.L of enzyme buffer was added to control wells, then 4. mu.L/well of test compound diluted with a1 Xenzyme buffer gradient was added, compound was first dissolved in DMSO at an initial concentration of 5mM, 3-fold concentration gradient dilution, 11 concentration points total, blank was 100% DMSO, 2. mu.L of compound dissolved in DMSO was added to 38. mu.L of 1 Xenzyme buffer, and enzyme and compound were preincubated at room temperature for 30 min. Then ATP (Sigma, A7699) was added at a concentration of 2.5. mu.M in 1 Xenzyme buffer and at a concentration of 10. mu.M

The mixed solution of CDKs Substrate-biotin in the CDKs Kinase (CDK2/5) Kit is 4 μ L/well, in this case, CDKs 2 enzyme concentration in the reaction plate well is 2ng/μ L, ATP concentration is 1 μ M, CDKs Substrate-biotin concentration is 4 μ M, compound 100 μ M first concentration is 3-fold gradient diluted 11 concentrations, CDKs 2 enzyme concentration in the blank well is 2ng/μ L, ATP concentration is 1 μ M, CDKs Substrate-biotin concentration is 4 μ M, compound 0 μ M, CDKs 2 enzyme concentration in the control empty well is 0ng/μ L, ATP concentration is 1 μ M, CDKs Substrate-biotin concentration is 4 μ M, compound 0 μ M. After mixing well, incubate at room temperature for 60 minutes. Then 5. mu.L/well of

CDKs Antibody-Cryptate 100-fold diluted with Detection buffer in CDKs Kinase (CDK2/5) Kit was added to 5. mu.L/well of Streptavidin-XL665 diluted to 1000nM with Detection buffer, mixed well and incubated at room temperature for 1 hour. HTRF was read using a multifunctional microplate reader (BMG labtech, PHERAStar FS). IC of compound inhibitory activity was calculated using Graphpad Prism 5 software ₅₀ The values are shown in Table 4.

TABLE 4 inhibitory Activity of compounds of the present disclosure on CDK2 enzymatic Activity

Compound (I)	IC ₅₀ (nM)
		2	8986

And (4) conclusion: the compounds of the disclosure inhibited CDK2 enzyme activity weakly, and in combination with tables 2 and 4, the compounds of the disclosure were found to be very selective (>1000 fold) for CDK 7.

Test example 5 CDK4 enzyme assay

The following methods were used to determine the inhibitory activity of the compounds of the present disclosure on the enzymatic activity of CDK 4. The experimental method is briefly described as follows:

will be provided with

CDK4 (carba, 04-105) was enzymatically diluted to 5 ng/. mu.L with 1 Xenzyme buffer, 2. mu.L/well was added to a white 384-well plate (Corning, 4513), only 2. mu.L of enzyme buffer was added to control wells, then 4. mu.L/well of test compound diluted with a1 Xenzyme buffer gradient was added, compound was first dissolved in DMSO at an initial concentration of 5mM, 3-fold concentration gradient dilution, 11 concentration points total, blank was 100% DMSO, 2. mu.L of compound dissolved in DMSO was added to 38. mu.L of 1 Xenzyme buffer, and enzyme and compound were preincubated at room temperature for 30 min. Then ATP (Sigma, A7699) was added at a concentration of 25. mu.M in 1 Xenzyme buffer and 0.75. mu.M

The mixed solution of CDKs Substrate-biotin in the CDKs Kinase (CDK1/4/6/7/12) Kit is 4 μ L/well, in this case, the CDKs 4 enzyme concentration in the reaction plate well is 1ng/μ L, ATP concentration is 10 μ M, the CDKs Substrate-biotin concentration is 0.3 μ M, the compound 100 μ M first concentration is 3-fold gradient diluted 11 concentrations, the CDKs 4 enzyme concentration in the blank well is 1ng/μ L, ATP concentration is 10 μ M, CDKsSubstrate-biotin concentration is 0.3 μ M, the compound is 0 μ M, the CDKs 4 enzyme concentration in the control blank well is 0ng/μ L, ATP concentration is 10 μ M, the CDKs Substrate-biotin concentration is 0.3 μ M, and the compound is 0 μ M. After mixing well, incubate at room temperature for 90 minutes. Then 5. mu.L/well of

CDKs Antibody-Cryptate 100-fold diluted with Detection buffer in CDKs Kinase (CDK1/4/6/7/12) Kit was added to Streptavidin-XL665 diluted to 150nM with Detection buffer at 5. mu.L/well, mixed well and incubated at room temperature for 1 hour. HTRF was read using a multifunctional microplate reader (BMG labtech, PHERAStar FS). IC of compound inhibitory activity was calculated using Graphpad Prism 5 software ₅₀ The values are shown in Table 5.

TABLE 5 inhibitory Activity of the presently disclosed Compounds on the enzymatic Activity of CDK4

Compound (I)	IC ₅₀ (nM)
		2	3867

And (4) conclusion: the compounds of the disclosure inhibited CDK4 enzyme activity weakly, and in combination with tables 2 and 5, the compounds of the disclosure were found to be very selective (>1000 fold) for CDK 7.

Test example 6 CDK6 enzymological experiment

The following methods were used to determine the inhibitory activity of the compounds of the present disclosure on the enzymatic activity of CDK 6. The experimental method is briefly described as follows:

will be provided with

CDK6 (carba, 04-107) was enzymatically diluted to 12.5 ng/. mu.L with 1 Xenzyme buffer, 2. mu.L/well was added to a white 384-well plate (Corning, 4513), only 2. mu.L of enzyme buffer was added to control wells, then 4. mu.L/well of test compound diluted with a1 Xenzyme buffer gradient was added, compound was first dissolved in DMSO at an initial concentration of 5mM, 3-fold concentration gradient dilution, 11 concentration points total, blank was 100% DMSO, 2. mu.L of compound dissolved in DMSO was added to 38. mu.L of 1 Xenzyme buffer, and enzyme and compound were preincubated at room temperature for 30 minutes. ATP (Sigma, A7699) was then added at a concentration of 125. mu.M in 1 Xenzyme buffer and at a concentration of 0.75. mu.M

The mixed solution of CDKs Substrate-biotin in the CDKs Kinase (CDK1/4/6/7/12) Kit is 4 μ L/well, in this case, CDKs Substrate-biotin concentration in the reaction plate well is 50 μ M at 2.5ng/μ L, ATP concentration, CDKs Substrate-biotin concentration is 0.3 μ M, compound 100 μ M first concentration 3-fold gradient dilution 11 concentrations, CDKs 6 enzyme concentration in the blank well is 50 μ M at 2.5ng/μ L, ATP concentration, CDKs Substrate-biotin concentration is 0.3 μ M, compound 0 μ M, CDKs 6 enzyme concentration in the control blank well is 50 μ M at 0ng/μ L, ATP concentration, CDKs Substrate-biotin concentration is 0.3 μ M, compound 0 μ M. After mixing well, incubate for 180 minutes at room temperature. Then 5. mu.L/well of

CDKs Antibody-Cryptate 100-fold diluted with Detection buffer in CDKs Kinase (CDK1/4/6/7/12) Kit was added to Streptavidin-XL665 diluted to 150nM with Detection buffer at 5. mu.L/well, mixed well and incubated at room temperature for 1 hour. HTRF was read using a multifunctional microplate reader (BMG labtech, PHERAStar FS). IC of compound inhibitory activity was calculated using Graphpad Prism 5 software ₅₀ The values are shown in Table 6.

TABLE 6 inhibitory Activity of the presently disclosed Compounds on the enzymatic Activity of CDK6

Compound (I)	IC ₅₀ (nM)
		2	5885

And (4) conclusion: the compounds of the disclosure inhibited CDK6 enzyme activity weakly, and in combination with tables 2 and 6, the compounds of the disclosure were found to be very selective (>1000 fold) for CDK 7.

Test example 7 CDK9 enzyme test

The following methods were used to determine the inhibitory activity of the compounds of the present disclosure on the enzymatic activity of CDK 9. The experimental method is briefly described as follows:

will be provided with

Enzymatic buffers in the CDKs Kinase (CDK9) Kit (Cisbio, 63ADK000CB13PEG) were formulated as 1 Xenzyme Buffer: DTT (Sigma, D0632) was first prepared as 1M mother liquor, then according to ddH ₂ O:Enzymatic Buffer:DTT：MgCl ₂ (Sigma, M1028): KCl (Sigma, 44675) ═ 694:200:1:5:100 were mixed in 1 Xenzyme buffer.

Buffered with 1 XenzymeCDK9 (carba, 04-110) was diluted to 5 ng/. mu.L enzyme, 2. mu.L/well was added to a white 384-well plate (Corning, 4513), only 2. mu.L enzyme buffer was added to control wells, 4. mu.L test compound was added to wells diluted with a1 Xenzyme buffer gradient, compound was first dissolved in DMSO at an initial concentration of 5mM, 3-fold concentration gradient dilution, 11 concentration points total, blank was 100% DMSO, 2. mu.L compound was added to 38. mu.L 1 Xenzyme buffer, and enzyme and compound were preincubated at room temperature for 30 min. ATP (Sigma, A7699) was then added at a concentration of 175. mu.M in 1 Xenzyme buffer and at a concentration of 2.5. mu.M

The mixed solution of CDKs Substrate-biotin in the Kit of CDKs Kinase (CDK9) is 4 μ L/well, in this case, CDKs 9 enzyme concentration is 1ng/μ L, ATP concentration in the reaction plate well is 70 μ M, CDKsSubstrate-biotin concentration is 1 μ M, compound 100 μ M concentration is 3-fold gradient diluted 11 concentrations, CDKs 9 enzyme concentration is 1ng/μ L, ATP concentration is 70 μ M in the blank well, CDKs Substrate-biotin concentration is 1 μ M, compound 0 μ M, CDKs 9 enzyme concentration is 0ng/μ L, ATP concentration is 70 μ M in the control empty well, CDKs Substrate-biotin concentration is 1 μ M, compound 0 μ M. After mixing well, incubate at room temperature for 60 minutes. Then 5. mu.L/well of

CDKs Antibody-Cryptate 100-fold diluted with Detection buffer in CDKs Kinase (CDK9) Kit was added to 5. mu.L/well of Streptavidin-XL665 diluted to 250nM with Detection buffer, mixed well and incubated at room temperature for 1 hour. HTRF was read using a multifunctional microplate reader (BMG labtech, PHERAStar FS). IC of compound inhibitory activity was calculated using Graphpad Prism 5 software ₅₀ The values are shown in Table 7.

TABLE 7 inhibitory Activity of the presently disclosed Compounds on the enzymatic Activity of CDK9

Compound (I)	IC ₅₀ (nM)
		2	8303

And (4) conclusion: the disclosed compounds have weak inhibition effect on the enzyme activity of CDK9, and the disclosed compounds have good selectivity (>1000 times) on CDK7 as shown in table 2 and table 7.

Test example 8 CDK12 enzymological experiment

The following methods were used to determine the inhibitory activity of the compounds of the present disclosure on the enzymatic activity of CDK 12. The experimental method is briefly described as follows:

will be provided with

Enzymatic buffers in the CDKs Kinase (CDK1/4/6/7/12) Kit (Cisbio, 63ADK000CB11PEG) were formulated as 1 Xenzyme Buffer: DTT (Sigma, D0632) was first prepared as 1M mother liquor, then according to ddH ₂ O:Enzymatic Buffer:DTT：MgCl ₂ (Sigma, M1028): KCl (Sigma, 44675) ═ 694:200:1:5:100 were mixed in 1 Xenzyme buffer.

CDK12(Signalchem, C62-35BG-50) was enzymatically diluted to 50 ng/. mu.L with 1 Xenzyme buffer, 2. mu.L/well was added to a white 384-well plate (Corning, 4513), only 2. mu.L of enzyme buffer was added to control wells, then 4. mu.L/well of test compound diluted with a1 Xenzyme buffer gradient was added, compound was first dissolved in DMSO at an initial concentration of 5mM, 3-fold concentration gradient dilution for 11 concentration points, blank control was 100% DMSO, and 2. mu.L of compound dissolved in DMSO was added to 38. mu.L of 1 Xenzyme buffer, and enzyme and compound were preincubated at room temperature for 30 minutes. Then ATP (Sigma, A7699) at a concentration of 75. mu.M in 1 Xenzyme buffer and 1.25. mu.M was added

Of CDKs substrate-biotin in the CDKs Kit (CDK1/4/6/7/12) KitThe mixture was 4. mu.L/well, in which case the CDK12 enzyme concentration in the wells of the reaction plate was 10 ng/. mu. L, ATP concentration of 30. mu.M, the CDKs Substrate-biotin concentration was 0.5. mu.M, and the compound was 100. mu.M first concentration was 3-fold gradient diluted 11 concentrations, the CDK12 enzyme concentration in the blank well was 10 ng/. mu. L, ATP concentration of 30. mu.M, the CDKs Substrate-biotin concentration was 0.5. mu.M, the compound was 0. mu.M, the CDKs 12 enzyme concentration in the control blank well was 0 ng/. mu. L, ATP concentration of 30. mu.M, the CDKs Substrate-biotin concentration was 0.5. mu.M, and the compound was 0. mu.M. After mixing well, incubate at room temperature for 90 minutes. Then 5. mu.L/well of

CDKs Kinase (CDK1/4/6/7/12) Kit 100 times diluted CDKs Antibody-Cryptate with Detection buffer, 5. mu.L/well of Streptavidin-XL665 diluted to 250nM with Detection buffer were added, mixed well and incubated overnight at room temperature. HTRF was read using a multifunctional microplate reader (BMG labtech, PHERAStar FS). IC of compound inhibitory activity was calculated using Graphpad Prism 5 software ₅₀ The values are shown in Table 8.

TABLE 8 inhibitory Activity of compounds of the present disclosure on CDK12 enzymatic Activity

Compound (I)	IC ₅₀ (nM)
		2	1105

And (4) conclusion: the compounds of the disclosure inhibited CDK12 enzyme activity weakly, and in combination with tables 2 and 8, the compounds of the disclosure were found to be highly selective (>450 fold) for CDK 7.

Test example 9

Pharmacokinetic evaluation

First, second (Beagle) dog test

1. Abstract

The drug concentration in plasma of beagle dogs at various times after gavage (i.g.)/intravenous injection (i.v.) administration of the compound of example 2 and comparative example 1 was measured by LC/MS method using beagle dogs as test animals. The pharmacokinetic behavior of the compounds of the present disclosure in beagle dogs was studied and evaluated for their pharmacokinetic profile.

2. Test protocol

2.1 test drugs

The Compound of example 2 and comparative example 1 (see patent WO2020093011a1, Compound 101) have the following structure:

2.2 test animals

16 beagle dogs, half male and female, were divided into 4 groups on average, and were provided by Suzhou national Biotechnology GmbH. After fasting overnight, the administration was by gavage and intravenous injection, respectively.

2.3 pharmaceutical formulation

An amount of the compound of example 2 and comparative example 1 was weighed, and 5% by volume of DMSO + 20% by volume of PG + 20% by volume of PEG400+ 55% by volume of physiological saline was added to prepare a clear solution (gavage group) of 0.4mg/mL and a clear solution (intravenous group) of 0.25 mg/mL.

2.4 administration

And (3) intragastric administration group: the dose was 2.0mg/kg and the volume was 5.0 mL/kg.

Group for intravenous administration: the dose was 0.5mg/kg and the volume was 2.0 mL/kg.

3. Operation of

And (3) intragastric administration group: blood was collected from the jugular vein or the forelimb vein at 1.0mL for 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, and 24.0 hours before and after administration, and the blood was centrifuged at 10000rpm for 5 minutes (4 ℃) in an EDTA-K2 anticoagulation tube, and plasma was separated within 1 hour, and stored at-80 ℃ for testing. The blood collection to centrifugation process is operated under ice bath condition. Food was consumed 3 hours after dosing.

Group for intravenous administration: blood was collected before administration and 5 minutes after administration at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0 and 24 hours, and the group was treated with intragastric administration.

Determining the content of the test compound in the plasma of beagle dogs after administration of drugs with different concentrations: 20 μ L of beagle plasma samples were taken at various time points post-dose, each sample quenched with 20 μ L of IS (100% MeOH) and 100 μ L of methanol, vortexed for 10 minutes at 1000rmp, and centrifuged for 10 minutes at 2600g, 4 ℃. 50.0. mu.L of the supernatant was transferred to a solution containing 150. mu.L of 30% acetonitrile. 1 μ L of the supernatant was analyzed by LC/MS/MS.

4. Pharmacokinetic parameter results

Table 9 pharmacokinetic parameters for the compounds of this disclosure are as follows:

and (4) conclusion: the compound disclosed by the invention has good drug absorption activity in a beagle body and pharmacokinetic advantages.

Test example 10

The disclosed compound has inhibition effect on enzyme activity of human liver microsome CYP2D6 dextromethorphan metabolic site

The enzymatic activity of the disclosed compound on the metabolic site of human liver microsome CYP2D6 dextromethorphan is measured by adopting the following experimental method:

first, experimental material and instrument

1. Phosphate buffer (20 XPBS, purchased from Biotech),

2.NADPH(ACROS，A2646-71-1)，

3. human liver microsomes (Corning Gentest, Cat No, 452161, Lot No.9050002, Donor,35),

ABI QTrap 4000 liquid dual-purpose instrument (AB Sciex),

ZORBAX extended-C18, 3X 50mm,3.5 μm (Agilent, USA),

CYP probe substrate (dextromethorphan, Sigma, Cat No. D9684-5G) and positive control inhibitor (quinidine, SIGMA, Q0750-5G).

Second, the experimental procedure

100mM PBS buffer was prepared, and 7.5mM MgCl was prepared using this buffer ₂ And 5mM NADPH solution, followed by 7.5mM MgCl ₂ A0.25 mg/mL microsome solution was prepared, and a 30mM stock solution was diluted with DMSO to a 30mM, 10mM, 3mM, 1mM, 0.3mM, 0.03mM, 0.003mM, 0mM series of solutions I, which were then diluted 200-fold with Phosphate Buffered Saline (PBS) to give a series of test solutions II (150, 50, 15, 5, 1.5, 0.15, 0.015, 0. mu.M). Dextromethorphan working solution diluted to 20 μ M concentration with PBS.

40. mu.L of a 0.25mg/mL microsome solution prepared in 7.5mM MgCl2 was taken, and 20. mu.L of each of 15. mu.M dextromethorphan working solution and compound working solution (150, 50, 15, 5, 1.5, 0.15, 0.015, 0. mu.M) was taken and mixed uniformly. The positive control group replaced the compound with quinidine at the same concentration. 5mM NADPH solution were simultaneously preincubated for 5 minutes at 37 ℃. After 5 min 20. mu.L NADPH was added to each well, the reaction was started and incubated for 30 min. All incubated samples were set up in duplicate. After 30 minutes 250. mu.L of acetonitrile containing the internal standard was added to all samples, mixed well, shaken at 800rpm for 10 minutes, and then centrifuged at 3700rpm for 10 minutes. mu.L of the supernatant was mixed with 80. mu.L of ultrapure water and transferred to LC-MS/MS for analysis.

The value is calculated by Graphpad Prism to obtain the IC of the drug on CYP2D6 dextromethorphan metabolic site ₅₀ The values are shown in Table 10.

TABLE 10 IC of the compounds of this disclosure on the human liver microsome CYP2D6 dextromethorphan metabolic site ₅₀ Value of

Example numbering	IC ₅₀ (μM)
		2	>30
Comparative example 1	0.23

And (4) conclusion: the disclosed compound has weak inhibition effect on human liver microsome CYP2D6 dextromethorphan metabolic site, shows better safety, and prompts that metabolic drug interaction based on CYP2D6 dextromethorphan metabolic site does not occur; and the effect is significant compared to comparative example 1.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

g is CR ^1d Or an N atom;

y is CR ^2a Or an N atom;

R ³ selected from hydrogenAtoms, halogens, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cyano groups, amino groups, nitro groups, hydroxyl groups, hydroxyalkyl groups, cycloalkyl groups, and heterocyclic groups;

R ⁴ selected from hydroxy, alkoxy and NR ^s R ^t ；

R ⁶ 、R ⁷ 、R ¹² and R ¹³ The same or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein G is CR ^1d ；R ^1d is-P (O) R ^m R ⁿ ；R ^m And R ⁿ As defined in claim 1.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein Y is CR ^2a ；R ^2a Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 Alkyl halidesA group; and/or, R ² Selected from hydrogen atoms, C _1-6 Alkyl and C _1-6 A haloalkyl group.

4.A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R ⁶ 、R ⁷ 、R ¹⁰ 、R ¹¹ 、R ¹² And R ¹³ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, hydroxy and C _1-6 A hydroxyalkyl group; preferably, R ⁶ 、R ⁷ 、R ¹⁰ 、R ¹¹ 、R ¹² And R ¹³ Are all hydrogen atoms.

5. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof,

wherein:

R ^1a 、R ^1b 、R ^1c 、R ^m 、R ⁿ 、R ³ 、R ⁴ 、R ⁵ 、R ⁸ and R ⁹ As defined in claim 1.

6. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, which is a compound represented by the general formula (II-1) or a pharmaceutically acceptable salt thereof,

wherein:

7. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which is a compound represented by the general formula (III-1) or the general formula (III-2) or a pharmaceutically acceptable salt thereof,

wherein:

8. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R ⁴ Is a hydroxyl group; r is ⁵ Is a hydrogen atom.

9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R ⁴ And R ⁵ The carbon atoms connected with the compound form 3-to 8-membered cycloalkyl or 3-to 8-membered heterocyclyl, and the 3-to 8-membered cycloalkyl or 3-to 8-membered heterocyclyl is independently selected from halogen and C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy, cyano, amino, hydroxy and C _1-6 Substituted with one or more of hydroxyalkyl; preferably, R ⁴ And R ⁵ The carbon atom to which it is attached forms a 3-to 8-membered heterocyclic group.

10. The compound of formula (I) according to any one of claims 1 to 9, wherein R is ^m And R ⁿ Is methyl.

11. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein R ^1a Is cyano; r is ^1b And R ^1c Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group.

12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein R ³ Is C _1-6 Alkyl or C _1-6 A haloalkyl group.

13. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein R ⁸ And R ⁹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkyl group.

14. A compound of general formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

15. a compound represented by the general formula (IA):

wherein:

x is selected from Br, Cl and I; preferably, X is Br;

Y、R ^1a 、R ^1b 、R ^1c and R ² To R ¹³ As defined in claim 1.

16. A compound of formula (IA) or a salt thereof according to claim 15, selected from the following compounds:

17. a process for the preparation of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which comprises:

wherein:

g is CR ^1d ；

X is selected from Br, Cl and I; preferably, X is Br;

Y、R ^1a 、R ^1b 、R ^1c 、R ^1d and R ² To R ¹³ As defined in claim 1.

18. A pharmaceutical composition comprising a compound of general formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 14, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

19. Use of a compound of general formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 18 in the manufacture of a medicament for the inhibition of CDKs; preferably, wherein said CDK is CDK 7.

20. Use of a compound of general formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 18 in the manufacture of a medicament for the treatment and/or prevention of a disease or condition associated with abnormal activity of CDK 7; preferably, the disease or disorder is cancer.

21. Use of a compound of general formula (I) according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 18 for the preparation of a medicament for the treatment and/or prevention of a disease or condition; wherein said disease or condition is preferably cancer; the cancer is preferably selected from breast, endometrial, ovarian, vaginal, fallopian tube, cervical, kidney, bladder, urothelial, urinary, prostate, testicular, colorectal, sarcoma, bone, multiple myeloma, leukemia, myxoma, rhabdomyoma, leiomyoma, fibroma, lipoma, teratoma, throat, nasopharyngeal, oral, lung, alveolar, lymphoma, mesothelioma, small intestine, stomach, esophageal, pancreatic, liver, bile duct, neurofibroma, glioma, neuroblastoma, melanoma, skin, basal cell, squamous cell, thyroid, head and neck, salivary gland, and gastrointestinal stromal; wherein said colorectal cancer is preferably colon cancer or rectal cancer; wherein said sarcoma is preferably chondrosarcoma.