WO2022089444A1

WO2022089444A1 - Nitrogen-containing heterocyclic compound and application thereof

Info

Publication number: WO2022089444A1
Application number: PCT/CN2021/126482
Authority: WO
Inventors: 李元念; 王文义; 崔洪; 石峰
Original assignee: 恒元生物医药科技(苏州)有限公司
Priority date: 2020-10-28
Filing date: 2021-10-26
Publication date: 2022-05-05

Abstract

Provided are a nitrogen-containing heterocyclic compound or pharmaceutically acceptable salt thereof, and application thereof, said compound having a relatively high inhibitory effect on CDK7 kinase.

Description

A kind of nitrogen-containing heterocyclic compound and application thereof

technical field

The present invention provides a nitrogen-containing heterocyclic compound and its application.

Background technique

Cyclin-dependent kinases (CDKs) belonging to the serine/threonine kinase family combine with their corresponding cyclins to form dimer complexes that play various roles in different stages of the cell cycle. Key regulatory roles such as cell differentiation, DNA transcription, etc. Studies have found that abnormally highly expressed CDKs are found in various tumor cells, so targeting CDKs is considered to provide an efficient and feasible tumor therapy. There are nearly 20 kinds of CDKs discovered so far, which can be roughly divided into two categories according to their functions: CDKs that regulate the cell cycle and CDKs that control cell transcription. Among them, CDK1/2/4/6 are mainly related to the cell cycle, while CDK7/8/9/10/12 are related to cellular DNA transcription (Nature Review Drug Discovery, 2015(2):130-146) . So far, three small-molecule inhibitors targeting CDK4/6 have been approved clinically for the treatment of various tumors (Future Med Chem. 2018, 10:1369-1388). Although the CDKs related to DNA transcription are still in the early stage of development, more and more basic studies have shown that targeting this type of CDKs may provide a more effective and safer tumor therapy.

In the cytoplasm, CDK7 exists as a CDK7/Cyclin H/MAT1 heterotrimer and is considered to be an essential CDK1/2-activating kinase (CAK) that can phosphorylate its conserved amino acid residues and achieve its kinase catalytic activity and cell cycle progression. In the nucleus, CDK7 forms the kinase core of the RNA polymerase II universal transcription factor complex and is responsible for phosphorylation of the RNA polymerase II C-terminal domain (CTD), which is an essential step in the initiation of gene transcription. Collectively, the two major functions of CDK7, catalyzing the phosphorylation of CAK and CTD, play critical roles in cell proliferation, cell cycle, and DNA transcription. In addition, disrupting the phosphorylation of the RNA polymerase II CTD would first affect proteins with short half-lives, such as the anti-apoptotic BCL-2 family proteins. Tumor cells can survive and proliferate by upregulating BCL-2 family proteins to escape normal pro-cell death signals. Therefore, inhibition of CDK7 kinase activity may have anti-proliferative and pro-apoptotic effects on tumor cells.

However, due to the similarity in sequence and structure with the CDKs homologous kinases, the development of selective CDK7 inhibitors has encountered great challenges. So far, no selective CDK7 inhibitor has been approved for clinical use, so it is necessary to continue to develop highly druggable selective inhibitors. The present invention reports a series of CDK7 kinase inhibitors with high activity and high selectivity, which are expected to bring new treatment methods to related tumor patients in the future.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is that the structure of the CDK7 kinase inhibitor in the prior art is relatively simple. Therefore, the present invention provides a nitrogen-containing heterocyclic compound and its application. The compound has a high inhibitory effect on CDK7 kinase.

The present invention provides a nitrogen-containing heterocyclic compound as shown in formula I or a pharmaceutically acceptable salt thereof;

in,

is a single bond or a double bond;

Ring A is "5-membered or 6-membered heteroaryl group with 1 to 3 heteroatoms selected from one or more of N, O and S", "5-membered or 6-membered cycloalkenyl" or "5-membered or 6-membered heterocycloalkenyl with 1 to 3 heteroatoms selected from one or more of N, O and S";

n is 0, 1 or 2;

R ¹ is independently halogen, C ₁ -C ₆ alkyl or "C ₁ -C ₆ alkyl substituted with one or more halogens";

R is C ₃ -C ₆ cycloalkyl, "C ₃ -C ₆ cycloalkyl substituted by 1, 2 or 3 R ⁵ ", "the number of heteroatoms is 1 or 2, and the heteroatom is N , monocyclic or bicyclic 5- to 8-membered heterocycloalkyl "or "substituted by 1, 2 or 3 R ⁶ , the number of heteroatoms is 1 or 2, the heteroatom is N, the single 5- to 8-membered cyclic or bicyclic heterocycloalkyl";

R ⁵ is independently hydroxyl, C ₁ -C ₆ alkyl or "R ^5-1 -NH-"; R ^5-1 is independently C ₁ -C ₆ alkyl;

R ⁶ is independently C ₁ -C ₆ alkyl;

X is N or CH;

Z is N or CR ⁷ ; R ⁷ is halogen, -P(=O)(CH ₃ ) ₂ or -S(=O) ₂ -CH ₃ ;

R ³ is hydrogen, -CN, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, hydroxyl or amino.

In a certain scheme, in the nitrogen-containing heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, the definitions of some groups can be as follows, and the definitions of other groups can be as described in any of the above schemes (hereinafter referred to as "in a certain scheme"): Ring A is "a 5-membered heteroaryl group with 1 to 2 heteroatoms selected from one or more of N, O and S" or " 5- or 6-membered cycloalkenyl".

In one aspect, n is 0 or 1.

In one scheme, n is zero.

In a certain scheme, R is "C ₃ -C ₆ cycloalkyl substituted by 1, 2 or 3 R ⁵ ", "the number of heteroatoms is 1 or 2, and the heteroatom is N, a single Cyclic or bicyclic 5- to 8-membered heterocycloalkyl" or "substituted by 1, 2 or 3 R ⁶ , the number of heteroatoms is 1 or 2, the heteroatom is N, monocyclic or bicyclic 5- to 8-membered heterocycloalkyl".

In a certain scheme, R is "monocyclic or bicyclic 5- to 8-membered heterocycloalkyl with 1 or 2 heteroatoms and N heteroatoms" or "with 1, 2 or 3 heteroatoms" A monocyclic or bicyclic 5- to 8-membered heterocycloalkyl group substituted with R ⁶ , the number of heteroatoms is 1 or 2, and the heteroatom is N."

In a certain embodiment, R ⁵ is independently hydroxy or "R ^5-1 -NH-"; R ^5-1 is independently C ₁ -C ₆ alkyl.

In one aspect, X is CH.

In one embodiment, Z is ^CR7 ; ^R7 is halogen, -P(=O)( _CH3 ) ₂ or -S(=O) ₂ - _CH3 .

In one embodiment, Z is ^CR7 ; ^R7 is halogen or -P(=O)( _CH3 ) ₂ .

In one embodiment, ^R3 is hydrogen or -CN.

In a certain scheme, ring A is a "5-membered heteroaryl group with 1 to 2 heteroatoms selected from one or more of N, O and S", "5-membered or 6-membered ring" Alkenyl" or "5-membered heterocyclic alkenyl with one heteroatom selected from one of N, O and S";

n is 0 or 1;

R is "C ₃ -C ₆ cycloalkyl substituted by 1, 2 or 3 R ⁵ ", "the number of heteroatoms is 1 or 2, the heteroatom is N, monocyclic or bicyclic 5-membered to 8-membered heterocycloalkyl" or "substituted by 1, 2 or 3 R ⁶ , the number of heteroatoms is 1 or 2, the heteroatom is N, the monocyclic or bicyclic 5- to 8-membered Heterocycloalkyl";

R ⁵ is independently hydroxyl or "R ^5-1 -NH-"; R ^5-1 is independently C ₁ -C ₆ alkyl;

R ⁶ is independently C ₁ -C ₆ alkyl;

X is CH;

Z is CR ⁷ ; R ⁷ is halogen, -P(=O)(CH ₃ ) ₂ or -S(=O) ₂ -CH ₃ ;

R ³ is hydrogen or -CN.

In a certain scheme, Ring A is a "5-membered heteroaryl group with 1 to 2 heteroatoms selected from one or more of N, O and S" or "5- or 6-membered ring" alkenyl";

n is 0;

R is "the number of heteroatoms is 1 or 2, the heteroatom is N, a monocyclic or bicyclic 5- to 8-membered heterocycloalkyl" or "substituted by 1, ² or 3 R6, The number of heteroatoms is 1 or 2, and the heteroatom is N, a monocyclic or bicyclic 5- to 8-membered heterocycloalkyl";

X is CH;

R ⁶ is independently C ₁ -C ₆ alkyl

Z is CR ⁷ ; R ⁷ is halogen or -P(=O)(CH ₃ ) ₂ ;

R ³ is hydrogen or CN.

In a certain scheme, when the ring A is "5-membered or 6-membered heteroaryl with 1 to 3 heteroatoms, and the heteroatoms are selected from one or more of N, O and S" , the ring A can be

Its upper end is connected with N atom.

In a certain scheme, when the ring A is "5-membered or 6-membered cycloalkenyl", the ring A can be

In a certain scheme, when the ring A is "5-membered or 6-membered heterocycloalkenyl with 1 to 3 heteroatoms selected from one or more of N, O and S" , the ring A can be

Its upper end is connected with N atom.

In a certain scheme,

can be

In one embodiment, when said R ¹ is independently halogen, said halogen can be fluorine, chlorine, bromine or iodine, and can also be chlorine.

In a certain scheme, when the R ¹ is independently a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group may be a C ₁ -C ₄ alkyl group, or a methyl group, Ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also methyl or ethyl.

In a certain embodiment, when the R ¹ is independently "C ₁ -C ₆ alkyl substituted with multiple halogens", the multiple may be 2 or 3.

In a certain scheme, when the R ¹ is independently "C ₁ -C ₆ alkyl substituted by one or more halogens", the halogen can be fluorine, chlorine, bromine or iodine, or is fluorine.

In a certain scheme, when the R ¹ is independently "C ₁ -C ₆ alkyl substituted by one or more halogens", the C ₁ -C ₆ alkyl may be C ₁ -C ₄ Alkyl, which can be methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, and also methyl or ethyl.

In a certain embodiment, when said R ¹ is independently "C ₁ -C ₆ alkyl substituted with multiple halogens", the "C ₁ -C ₆ alkyl substituted with multiple halogens" Can be trifluoromethyl.

In a certain scheme,

can be

In a certain scheme, when the R is a C ₃ -C ₆ cycloalkyl group, the C ₃ -C ₆ cycloalkyl group can be cyclopropane, cyclobutane, cyclopentane or cyclohexane, It can also be cyclobutane, cyclopentane or cyclohexane.

In a certain scheme, when the R ⁵ is independently a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group may be a C ₁ -C ₄ alkyl group, or a methyl group, Ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also methyl or ethyl.

In a certain scheme, when the R ^5-1 is independently a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group may be a C ₁ -C ₄ alkyl group or a methyl group. , ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also methyl or ethyl.

In a certain scheme, when the R is "C ₃ -C ₆ cycloalkyl substituted with 1, 2 or 3 R ⁵ ," the C ₃ -C ₆ cycloalkyl may be Cyclopropane, cyclobutane, cyclopentane or cyclohexane can be cyclobutane, cyclopentane or cyclohexane.

In a certain scheme, when the said R is "C ₃ -C ₆ cycloalkyl substituted by 1, 2 or 3 R ⁵ ", the said "is substituted by 1, 2 or 3 R 5" The C ₃ -C ₆ cycloalkyl "substituted by R ⁵ " may be

In a certain scheme, when the R is "the number of heteroatoms is 1 or 2, and the heteroatom is N, a monocyclic 5- to 8-membered heterocycloalkyl group", the "heteroatom" The number is 1 or 2, the heteroatom is N, and the monocyclic 5- to 8-membered heterocycloalkyl "can be pyrrolidinyl or piperidinyl, or can be

In a certain scheme, when said R is "a bicyclic 5- to 8-membered heterocycloalkyl with 1 or 2 heteroatoms, and the heteroatom is N", said "the number of heteroatoms is 1 or 2, bicyclic 5- to 8-membered heterocycloalkyl with a heteroatom of N" can be 1-azaspiro[3.4]octyl or octahydrocyclopenta[b]pyrrolyl, or can be

In a certain scheme, when the R ⁶ is independently a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group may be a C ₁ -C ₄ alkyl group, or a methyl group, Ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also methyl or ethyl.

In a certain scheme, when the R is "substituted by 1, 2 or 3 R ⁶ , the number of heteroatoms is 1 or 2, the heteroatom is N, the monocyclic 5-membered to 8-membered In the case of "membered heterocycloalkyl", the "hetero-atom number is 1 or 2, the heteroatom is N, and the monocyclic 5- to 8-membered heterocycloalkyl" can be pyrrolidinyl or piperidinyl , can also be

In a certain scheme, when the R is "substituted by 1, 2 or 3 R ⁶ , the number of heteroatoms is 1 or 2, and the heteroatom is N, a bicyclic 5- to 8-membered heteroatom cycloalkyl", the "bicyclic 5- to 8-membered heterocycloalkyl with 1 or 2 heteroatoms and the heteroatom is N" may be 1-azaspiro[3.4]octyl or octahydrocyclopenta[b]pyrrolyl, or

In a certain scheme, when the R is "substituted by 1, 2 or 3 R ⁶ , the number of heteroatoms is 1 or 2, the heteroatom is N, the monocyclic 5-membered to 8-membered membered heterocycloalkyl", the "substituted by 1, 2 or 3 R ⁶ , the number of heteroatoms is 1 or 2, the heteroatom is N, the monocyclic 5- to 8-membered Heterocycloalkyl" can be

In a certain scheme, the R can be "C ₃ -C ₆ cycloalkyl substituted with 1, 2 or 3 R ⁵ ", pyrrolidinyl, piperidinyl, 1-azaspiro[ 3.4] Octyl or octahydrocyclopenta[b]pyrrolyl, which can also be

In one embodiment, when said ^R7 is independently halogen, said halogen can be fluorine, chlorine, bromine or iodine, and can also be bromine.

In a certain scheme, when the R ³ is halogen, the halogen can be fluorine, chlorine, bromine or iodine, and can also be bromine or fluorine.

In a certain scheme, when the R ³ is a C ₁ -C ₃ alkyl group, the C ₁ -C ₃ alkyl group may be methyl, ethyl, n-propyl or isopropyl.

In a certain scheme, when the R ³ is C ₁ -C ₃ alkoxy, the C ₁ -C ₃ alkoxy may be methoxy, ethoxy, n-propoxy or iso- propoxy.

In a certain scheme,

can be

In a certain scheme, the nitrogen-containing heterocyclic compound shown in formula I can be any of the following compounds:

The present invention also provides a pharmaceutical composition comprising substance X and pharmaceutical excipients;

The substance X is the above-mentioned nitrogen-containing heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof.

In the pharmaceutical composition, the substance X may be a therapeutically effective amount of the substance X.

The present invention also provides the application of a substance X in preparing a CDK7 kinase inhibitor, and the CDK7 kinase inhibitor is used in vitro;

The present invention also provides the application of a substance X in preparing a medicine for treating and/or preventing diseases related to CDK7 kinase;

In said application, said "disease associated with CDK7 kinase" may be a proliferative disease. The proliferative disease may be cancer, benign neoplasms, angiogenesis, inflammatory disease or autoimmune disease. The cancer can be one or more of leukemia, melanoma, multiple myeloma, breast cancer, brain cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, prostate cancer, uterine cancer, ovarian cancer and gastric cancer .

The present invention also provides the application of a substance X in the preparation of a medicine for treating and/or preventing proliferative diseases;

In such applications, the proliferative disease may be cancer, benign neoplasms, angiogenesis, inflammatory disease or autoimmune disease. The cancer can be one or more of leukemia, melanoma, multiple myeloma, breast cancer, brain cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, prostate cancer, uterine cancer, ovarian cancer and gastric cancer .

The present invention also provides a nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof;

Wherein, R ¹ is C ₄ -C ₆ cycloalkyl, "C ₄ -C ₆ cycloalkyl substituted by 1, 2 or 3 R ^1-1 ", "the number of heteroatoms is 1 or 2" , the heteroatom is selected from one or more of N, O and S, 5-membered or 6-membered heterocycloalkyl” or “substituted by 1 or 2 R ^1-2 , the number of heteroatoms is 1 or 2, the heteroatom is selected from one or more of N, O and S 5-membered or 6-membered heterocycloalkyl";

R ^1-1 is independently halogen, hydroxyl, NHR ^1-1-1 , cyano or C ₁ -C ₆ alkyl; R ^1-1-1 is independently C ₁ -C ₆ alkyl;

R ^1-2 is independently halogen, hydroxyl, NHR ^1-2-1 , cyano or C ₁ -C ₆ alkyl; R ^1-2-1 is independently C ₁ -C ₆ alkyl;

Alternatively, R ^1-1 on the same carbon or adjacent carbon and the C atom connected to it together form a 3- to 6-membered carbocyclic ring or "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N, O and one or more of S's 3- to 6-membered heterocycloalkyl";

Alternatively, R ^1-2 on the same carbon or adjacent carbon and the C atom connected to it together form a 3- to 6-membered carbocyclic ring or "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N, O and one or more of S's 3- to 6-membered heterocycloalkyl";

R ² is hydrogen, halogen, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkyl substituted by 1-3 fluorine atoms;

X is N or CH;

^R3 is

R ⁴ is hydrogen, hydroxy, cyano or halogen.

In a certain scheme, in the nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof, the definitions of some groups can be as follows, and the definitions of other groups can be as described in any of the above schemes (hereinafter referred to as "in a certain scheme"): R ¹ is "C ₄ -C ₆ cycloalkyl substituted with ¹ , 2 or 3 R 1-1s", "the number of heteroatoms is 1 or 2" 5-membered or 6-membered heterocycloalkyl group with heteroatoms selected from one or more of N, O and S" or "substituted by 1 or 2 R ^1-2 , the number of heteroatoms is 1 or 2, the heteroatoms are selected from one or more of N, O and S 5- or 6-membered heterocycloalkyl".

In a certain scheme, R ¹ is "a 5-membered or 6-membered heterocycloalkyl group in which the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S" or "are A 5- or 6-membered heterocycloalkyl group substituted with 1 or 2 R ^1-2 , the number of heteroatoms is 1 or 2, and the heteroatom is selected from one or more of N, O and S.

In a certain embodiment, R ^1-1 is independently hydroxyl, NHR ^1-1-1 ; R ^1-1-1 is independently C ₁ -C ₆ alkyl.

In one embodiment, R ^1-2 is independently hydroxy or C ₁ -C ₆ alkyl.

In one embodiment, R ² is hydrogen, chlorine, or C ₁ -C ₃ alkyl substituted with 1-3 fluorine atoms.

In one embodiment, R ² is chlorine or C ₁ -C ₃ alkyl substituted with 1-3 fluorine atoms.

In one aspect, X is CH.

In one scheme, R ³ is

^In one embodiment, R4 is hydrogen, halogen or cyano.

^In one embodiment, R4 is cyano or hydrogen.

In a certain scheme, R ¹ is "C ₄ -C ₆ cycloalkyl substituted by 1, 2 or 3 R ^1-1 ", "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from 5- or 6-membered heterocycloalkyl of one or more of N, O and S" or "substituted by 1 or 2 R ^1-2 , the number of heteroatoms is 1 or 2, the heteroatoms 5- or 6-membered heterocycloalkyl selected from one or more of N, O and S"

R ^1-1 is independently hydroxyl, NHR ^1-1-1 ; R ^1-1-1 is independently C ₁ -C ₆ alkyl;

R ^1-2 is independently hydroxyl or C ₁ -C ₆ alkyl;

R ² is hydrogen, chlorine or C ₁ -C ₃ alkyl substituted by 1-3 fluorine atoms;

X is CH;

^R3 is

R ⁴ is hydrogen, halogen or cyano.

In a certain scheme, R ¹ is "a 5-membered or 6-membered heterocycloalkyl group in which the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S" or "are 1 or 2 R ^1-2 substituted, the number of heteroatoms is 1 or 2, and the heteroatom is selected from one or more of N, O and S. 5-membered or 6-membered heterocycloalkyl”;

R ² is chlorine or C ₁ -C ₃ alkyl substituted by 1-3 fluorine atoms;

X is CH;

^R3 is

R ⁴ is cyano or hydrogen.

In a certain scheme, when the R ¹ is a C ₄ -C ₆ cycloalkyl group, the C ₄ -C ₆ cycloalkyl group may be cyclobutane, cyclopentane or cyclohexane.

In a certain scheme, when the R ¹ is "C ₄ -C ₆ cycloalkyl substituted by ¹ , 2 or 3 R 1-1s", the C ₄ -C ₆ cycloalkane is The radical can be cyclobutane, cyclopentane or cyclohexane.

In a certain scheme, when the R ^1-1-1 is independently a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group may be a C ₁ -C ₄ alkyl group, or may is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also methyl or ethyl.

In a certain embodiment, when the R ¹ is "C ₄ -C ₆ cycloalkyl substituted by ¹ , 2 or 3 R 1-1s", the " Or 3 R ^1-1 substituted C ₄ -C ₆ cycloalkyl" can be

In a certain scheme, when the R ¹ is "the number of heteroatoms is 1 or 2, the heteroatoms are selected from 5-membered or 6-membered heterocycloalkyl group of one or more of N, O and S. ", the "heteroatom number is 1 or 2, the heteroatom is selected from one or more of N, O and S 5-membered or 6-membered heterocycloalkyl" may be pyrrolidinyl or piperidinyl, which can also be

In a certain scheme, when the R ¹ is "substituted by 1 or 2 R ^1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one of N, O and S. or more 5-membered or 6-membered heterocycloalkyl”, the “heteroatoms are 1 or 2, and the heteroatoms are selected from one or more of N, O and S, 5-membered or 6-membered heterocycloalkyl" can be pyrrolidinyl or piperidinyl, or can be

In a certain scheme, when the R ^1-2 is independently a C ₁ -C ₆ alkyl group, the C ₁ -C ₆ alkyl group may be a C ₁ -C ₄ alkyl group or a methyl group , ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, also methyl or ethyl.

In a certain scheme, when the R ¹ is "substituted by 1 or 2 R ^1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one of N, O and S. or multiple 5-membered or 6-membered heterocycloalkyl", the "substituted by 1 or 2 R ^1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N, O and one or more of S 5- or 6-membered heterocycloalkyl" can be

In a certain scheme, the R ¹ can be "C ₄ -C ₆ cycloalkyl substituted by 1, 2 or 3 R ^1-1 ", pyrrolidinyl, piperidinyl, 1-nitrogen Heterospiro[3.4]octyl or octahydrocyclopenta[b]pyrrolyl, or

In a certain scheme, when the R ² is a C ₁ -C ₃ alkyl group substituted by 1-3 fluorine atoms, the C ₁ -C ₃ alkyl group can be methyl, ethyl, n- propyl or isopropyl.

In one embodiment, when the R ² is a C ₁ -C ₃ alkyl group substituted with 1-3 fluorine atoms, the C ₁ -C ₃ alkyl group substituted with 1-3 fluorine atoms Can be trifluoromethyl.

In a certain scheme, the nitrogen-containing heterocyclic compound shown in formula II can be any of the following compounds:

The present invention also provides a pharmaceutical composition, which comprises substance Z and pharmaceutical excipients;

The substance Z is the above-mentioned nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof.

In the pharmaceutical composition, the substance Z may be a therapeutically effective amount of the substance Z.

The present invention also provides the application of a substance Z in the preparation of a CDK7 kinase inhibitor, and the CDK7 kinase inhibitor is used in vitro;

The present invention also provides the application of a substance Z in the preparation of a medicine for treating and/or preventing diseases related to CDK7 kinase;

The present invention also provides the application of a substance Z in the preparation of a medicine for treating and/or preventing proliferative diseases;

The present invention provides a nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof;

in,

is a single bond or a double bond;

n is 0, 1 or 2;

R ⁶ is independently C ₁ -C ₆ alkyl;

X is N or CH;

In a certain scheme, in the nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, the definition of certain groups It can be as follows, and the definition of other groups can be as described in any of the above schemes (hereinafter referred to as "in a certain scheme"): Ring A is "the number of heteroatoms is 1 to 2, and the heteroatoms are selected from N, O and 5-membered heteroaryl" or "5- or 6-membered cycloalkenyl" of one or more of S.

In one aspect, n is 0 or 1.

In one scheme, n is zero.

In one aspect, X is CH.

In one embodiment, Z is ^CR7 ; ^R7 is halogen or -P(=O)( _CH3 ) ₂ .

In one embodiment, ^R3 is hydrogen or -CN.

n is 0 or 1;

R ⁶ is independently C ₁ -C ₆ alkyl;

X is CH;

Z is CR ⁷ ; R ⁷ is halogen, -P(=O)(CH ₃ ) ₂ or -S(=O) ₂ -CH ₃ ;

R ³ is hydrogen or -CN.

n is 0;

X is CH;

R ⁶ is independently C ₁ -C ₆ alkyl

Z is CR ⁷ ; R ⁷ is halogen or -P(=O)(CH ₃ ) ₂ ;

R ³ is hydrogen or CN.

Its upper end is connected with N atom.

In a certain scheme,

can be

In a certain scheme,

can be

In a certain scheme,

can be

The substance X is the above-mentioned nitrogen-containing heterocyclic compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.

The present invention also provides a method of treating and/or preventing a disease associated with CDK7 kinase, comprising administering to a patient a therapeutically effective amount of Substance X;

In the method, the "disease associated with CDK7 kinase" may be a proliferative disease. The proliferative disease may be cancer, benign neoplasms, angiogenesis, inflammatory disease or autoimmune disease. The cancer can be one or more of leukemia, melanoma, multiple myeloma, breast cancer, brain cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, prostate cancer, uterine cancer, ovarian cancer and gastric cancer .

The present invention also provides a method of treating and/or preventing a proliferative disease comprising administering to a patient a therapeutically effective amount of Substance X;

In the method, the proliferative disease can be cancer, benign neoplasms, angiogenesis, inflammatory disease or autoimmune disease. The cancer can be one or more of leukemia, melanoma, multiple myeloma, breast cancer, brain cancer, lung cancer, colorectal cancer, liver cancer, pancreatic cancer, prostate cancer, uterine cancer, ovarian cancer and gastric cancer .

The present invention also provides a nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof;

X is N or CH;

R ⁴ is hydrogen, hydroxyl, cyano or halogen;

^R3 is

In a certain scheme, in the nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, the definition of certain groups It can be as follows, and the definition of other groups can be as described in any of the above schemes (hereinafter referred to as "in a certain scheme"): R ¹ is "C ₄ substituted with 1, 2 or 3 R ^1-1 ~C ₆ cycloalkyl", "5- or 6-membered heterocycloalkyl with 1 or 2 heteroatoms, and the heteroatoms are selected from one or more of N, O and S" or "a 1- 5- or 6-membered heterocycloalkyl group substituted with one or two R ^1-2 , the number of heteroatoms is one or two, and the heteroatom is selected from one or more of N, O and S.

In one embodiment, R ^1-2 is independently hydroxy or C ₁ -C ₆ alkyl.

In one aspect, X is CH.

^In one embodiment, R4 is hydrogen, halogen or cyano.

^In one embodiment, R4 is cyano or hydrogen.

In one scheme, R ³ is

R ^1-2 is independently hydroxyl or C ₁ -C ₆ alkyl;

X is CH;

R ⁴ is hydrogen, halogen or cyano;

^R3 is

R ² is chlorine or C ₁ -C ₃ alkyl substituted by 1-3 fluorine atoms;

X is CH;

R ⁴ is cyano or hydrogen;

^R3 is

In a certain scheme, when the R ¹ is "C ₄ -C ₆ cycloalkyl substituted by ¹ , 2 or 3 R 1-1s", the " Or 3 R ^1-1 substituted C ₄ -C ₆ cycloalkyl" can be

The substance Z is the above-mentioned nitrogen-containing heterocyclic compound represented by formula II, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.

The present invention also provides a method of treating and/or preventing a disease associated with CDK7 kinase, comprising administering to a patient a therapeutically effective amount of Substance Z;

The present invention also provides a method of treating and/or preventing a proliferative disease comprising administering to a patient a therapeutically effective amount of Substance Z;

The present invention provides a nitrogen-containing heterocyclic compound represented by formula III or a pharmaceutically acceptable salt thereof;

in,

W, Y and Z are each independently N or C(R ² );

R ¹ is C ₄ -C ₆ cycloalkyl, "C ₄ -C ₆ cycloalkyl substituted by ¹ , 2 or 3 R 1-1s", "the number of heteroatoms is 1 or 2, heteroatoms Atoms selected from one or more of N, O and S 5- or 6-membered heterocycloalkyl" or "substituted by 1 or 2 R ^1-2 , the number of heteroatoms is 1 or 2 , the heteroatom is selected from one or more of N, O and S 5- or 6-membered heterocycloalkyl";

^R3 is

R ⁴ is hydrogen, hydroxy, cyano or halogen.

In certain aspects, the present invention provides a nitrogen-containing heterocyclic compound of formula III or a pharmaceutically acceptable salt thereof, wherein the nitrogen-containing heterocyclic compound is selected from the group consisting of:

In some schemes, R ¹ is "C ₄ -C ₆ cycloalkyl substituted by 1, 2 or 3 R ^1-1 ", "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from 5- or 6-membered heterocycloalkyl of one or more of N, O and S" or "substituted by 1 or 2 R ^1-2 , the number of heteroatoms is 1 or 2, the heteroatoms 5- or 6-membered heterocycloalkyl selected from one or more of N, O and S".

In certain schemes, R ¹ is "C ₄ -C ₆ cycloalkyl substituted with 1, 2 or 3 R ^1-1 " or "substituted with 1 or 2 R ^1-2 , hetero The number of atoms is 1 or 2, and the heteroatom is selected from one or more of N, O and S. 5- or 6-membered heterocycloalkyl".

In certain embodiments, R ^1-1 is independently hydroxyl, NHR ^1-1-1 ; R ^1-1-1 is independently C ₁ -C ₆ alkyl.

In certain embodiments, R ^1-2 is independently hydroxy or C ₁ -C ₆ alkyl.

In certain schemes, R1 is cyclopentane or cyclohexane substituted with ¹ , 2 or 3 R1-1, or piperidinyl substituted with 1 or ² ^R1-2 .

In certain embodiments, R ¹ is cyclopentane or cyclohexane substituted with 1, 2 or 3 R ^1-1 , and R ^1-1 is hydroxy.

In certain schemes, R ¹ is piperidinyl substituted with one or two R ^1-2 , and R ^1-2 is C ₁ -C ₆ alkyl.

In certain schemes, R ² is hydrogen, chlorine, or C ₁ -C ₃ alkyl substituted with 1-3 fluorine atoms.

In certain embodiments, R ² is hydrogen or C ₁ -C ₃ alkyl substituted with 1-3 fluorine atoms.

In certain schemes, R2 is ^hydrogen or trifluoromethyl.

^In certain schemes, R4 is hydrogen, halo, or cyano.

^In certain schemes, R4 is cyano or hydrogen.

^In certain schemes, R4 is cyano.

In certain schemes, the nitrogen-containing heterocyclic compound shown in formula III can be any of the following compounds:

The present invention provides a nitrogen-containing heterocyclic compound as shown in formula IV or a pharmaceutically acceptable salt thereof;

in,

W, Y and Z are each independently N or C(R ² );

^R3 is

R ⁴ is hydrogen, hydroxy, cyano or halogen.

In certain aspects, the present invention provides a nitrogen-containing heterocyclic compound of formula IV or a pharmaceutically acceptable salt thereof, wherein the nitrogen-containing heterocyclic compound has the following formula:

In certain embodiments, R ^1-2 is independently hydroxy or C ₁ -C ₆ alkyl.

In certain schemes, R1 is piperidinyl substituted with ¹ or ² R1-2.

^In certain schemes, R4 is hydrogen, halo, or cyano.

^In certain schemes, R4 is cyano or hydrogen.

^In certain schemes, R4 is cyano.

In certain schemes, the nitrogen-containing heterocyclic compound shown in formula IV can be as follows:

The substance Z is the above-mentioned nitrogen-containing heterocyclic compound represented by formula III or formula IV, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.

In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Substance Z.

Certain chemical groups defined herein are preceded by abbreviated symbols to indicate the total number of carbon atoms present in the group. For example, _C1 - _C6 alkyl refers to an alkyl group as defined below having a total of 1, 2, 3, 4, 5 or 6 carbon atoms. The total number of carbon atoms in the simplified notation does not include carbons that may be present in the substituents of the group.

The term "plurality" refers to 2, 3, 4 or 5.

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

The term "cycloalkyl" refers to a saturated monocyclic group consisting only of carbon atoms, preferably a saturated monocyclic group having 3-7 ring carbon atoms, more preferably 3-6 carbon atoms, such as cyclopropyl cyclobutyl, cyclopentyl or cyclohexyl.

The term "heterocycloalkyl" refers to a stable 4- to 11-membered saturated saturated alkyl group consisting of 3 to 7 carbon atoms and 1 to 3 heteroatoms (one or more selected from nitrogen, oxygen and sulfur). cyclic group. Unless specifically stated otherwise in this specification, heterocycloalkyl can be a monocyclic or bicyclic ring system, which can include spiro, bridged ring systems. A heterocycloalkyl group can be attached to the remainder of the molecule through a carbon atom or a heteroatom and through a single bond. For the purposes of this invention, examples of heterocycloalkyl include, but are not limited to: pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, azetidinyl, octahydrocyclopenta[b]pyrrole base, 2-azaspiro[3.3]heptane or 1-azaspiro[3.3]heptane and 1-azaspiro[3.4]octane, etc.

The term "cycloalkenyl" refers to an unsaturated, non-aromatic monocyclic group consisting of only carbon atoms, preferably an unsaturated, non-aromatic monocyclic group having 3-7 ring carbon atoms, For example cyclopentenyl.

The term "heterocycloalkenyl" denotes a stable 5- or 6-membered unsaturated composed of 3 to 5 carbon atoms and 1 to 2 heteroatoms (one or more selected from nitrogen, oxygen and sulfur) , non-aromatic cyclic group. A heterocycloalkenyl group can be attached to the rest of the molecule through a carbon atom or a heteroatom and through a single bond. For purposes of the present invention, examples of heterocycloalkenyl groups include, but are not limited to, dihydrothiophene and the like.

The term "heteroaryl" refers to an aromatic group containing a heteroatom, preferably containing 1, 2 or 3 aromatic 5-6 membered monocyclic rings independently selected from nitrogen, oxygen and sulfur, eg furyl, pyridyl , pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiazolyl Diazolyl, etc.

The compounds provided herein may exist in a number of different forms or derivatives, all of which are included within the scope of this application. These forms or derivatives include, for example, tautomers, stereoisomers, racemic mixtures, positional isomers, salts, prodrugs, solvated forms, different crystal or polymorphic forms, and active Metabolites.

The compounds provided herein may contain one or more asymmetric centers and thus may exist in various stereoisomeric forms. Accordingly, the compounds described herein are also intended to include all isomeric (eg, enantiomeric, diastereomeric, and geometric) forms of the compounds, including, for example, the R and S configurations for each asymmetric center form, Z and E double bond isomers and Z and E conformational isomers. Accordingly, the present application also encompasses compounds as individual isomers substantially free of other isomers, or as mixtures of various isomers (eg, racemic mixtures of enantiomers).

In some embodiments, when a particular enantiomer is preferred, the compounds of the present application may be provided substantially free of the opposite enantiomer and may be referred to as "optically enriched." "Optically enriched" as used herein means that a compound consists of a significantly greater proportion of one enantiomer. In some embodiments, the compound consists of at least about 90% by weight of the preferred enantiomer. In some embodiments, the compound consists of at least about 95%, 98%, or 99% by weight of the preferred enantiomer. Preferably the enantiomers can be separated from the racemic mixture by any method known in the art, including chiral high pressure liquid chromatography (HPLC), chiral salt formation and crystallization, or asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H. et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY , 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

The compounds of the present application also include prodrugs, active metabolic derivatives (active metabolites), active intermediates, and pharmaceutically acceptable salts thereof.

The term "prodrug" as used herein refers to a compound, or a pharmaceutically acceptable salt thereof, which, when metabolized under physiological conditions or when converted by solvolysis, yields the desired active compound. Prodrugs include, but are not limited to, esters, amides, carbamates, carbonates, ureides, solvates or hydrates of the active compound. Generally, prodrugs are inactive, or less active than the active compound, but can provide one or more advantageous handling, administration, and/or metabolic properties. For example, some prodrugs are esters of the active compound, and during metabolism, the ester group is cleaved to yield the active drug. Furthermore, some prodrugs are activated enzymatically to yield the active compound, or to yield compounds that upon further chemical reaction yield the active compound. A prodrug may be converted from the prodrug form to the active form in a single step, or may have one or more intermediate forms, which may or may not be active themselves. Preparation and use of prodrugs in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Described in Pergamon Press, 1987.

The term "metabolite", eg, active metabolite, as used herein, refers to a pharmacologically active compound or a compound that is further metabolized to a pharmacologically active compound that is a derivative obtained from a metabolic process in a subject. For example, such metabolites can be obtained from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic hydrolysis, etc. of the administered compound or salt or prodrug. Among them, the active metabolite is the pharmacologically active derivative compound. For prodrugs, the prodrug compound is generally inactive or has less activity than the metabolite. For active metabolites, the parent compound can be the active compound or can be an inactive prodrug.

Prodrugs and active metabolites can be identified using routine techniques in the art. See, e.g., Bertolini et al., 1997, J Med Chem 40:2011-2016; Shan et al., J Pharm Sci 86:756-757; Bagshawe, 1995, DrugDev Res 34:220-230.

The term "active intermediate" as used herein refers to an intermediate compound in a synthetic process that exhibits the same or substantially the same biological activity as the final synthesized compound.

The compounds of the present application may be formulated as or in the form of pharmaceutically acceptable salts. Unless indicated to the contrary, the compounds provided herein include pharmaceutically acceptable salts of the compounds.

The term "pharmaceutically acceptable" as used herein refers to compounds that are suitable for use in contact with human or animal tissue without undue toxicity, irritation, allergic reactions, other problems or complications, with a reasonable benefit/risk ratio, Materials, compositions and/or dosage forms. In some embodiments, a pharmaceutically acceptable compound, material, composition and/or dosage form is one that is approved by a regulatory agency (eg, the US Food and Drug Administration, the State Drug Administration of China, the European Medicines Agency) or Those compounds, materials, compositions and/or dosage forms listed in recognized pharmacopeias (eg, US Pharmacopoeia, Chinese Pharmacopoeia, European Pharmacopoeia) for use in animals, particularly humans.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed with a suitable non-toxic organic acid, inorganic acid, organic base or inorganic base with a nitrogen-containing heterocyclic compound of formula I or II, which retains as Biological activity of nitrogen-containing heterocyclic compounds represented by formula I or II. The organic acid can be various organic acids conventional in the art that can form salts, preferably methanesulfonic acid, trifluoromethanesulfonic acid, benzenemethanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, and succinic acid. , citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, phenylacetic acid, isethionic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid One or more of acid, mandelic acid, and salicylic acid. The inorganic acid can be various inorganic acids conventional in the art that can form salts, preferably one or more of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Described organic base can be various organic bases that can form salts conventional in the field, preferably one or more of pyridines, imidazoles, pyrazines, indoles, purines, tertiary amines and anilines. kind. The tertiary amine organic base is preferably triethylamine and/or N,N-diisopropylethylamine. The aniline organic base is preferably N,N-dimethylaniline. The pyridine organic base is preferably one or more of pyridine, picoline, 4-dimethylaminopyridine and 2-methyl-5-ethylpyridine. The inorganic base can be various inorganic bases that can form salts in the field, preferably alkali metal hydrides, alkali metal hydroxides, alkali metal alkoxides, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate , one or more of potassium bicarbonate and sodium bicarbonate. Said alkali metal hydride is preferably sodium hydride and/or potassium hydride. The alkali metal hydroxide is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide. The alkali metal alkoxide is preferably one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide.

It is also to be understood that the compounds of the present application may exist in unsolvated forms, solvated forms (eg, hydrated forms), and solid forms (eg, crystalline or polymorphic forms), all of which are intended to be encompassed by this application.

As used herein, the term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. The solvent includes, but is not limited to, water, methanol, ethanol, and the like.

"Pharmaceutically acceptable salts" and "solvates" in the term "solvates of pharmaceutically acceptable salts" are as described above, and refer to compounds of the present invention in combination with 1, a relatively non-toxic, pharmaceutically acceptable compound. 2. A substance formed in combination with a stoichiometric or non-stoichiometric solvent. Said "solvates of pharmaceutically acceptable salts" include, but are not limited to, hydrochloric acid monohydrates of the compounds of the present invention.

As used herein, the terms "crystalline form," "polymorphic form," and "polymorph" are used interchangeably and refer to crystal structures in which a compound (or a salt or solvate thereof) crystallizes in different crystal packings, which All have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility, etc. Recrystallization solvent, rate of crystallization, storage temperature and other factors may cause one crystalline form to dominate. Polymorphic forms of a compound can be prepared by crystallization under various conditions.

This application is also intended to include all isotopes of atoms in compounds. Isotopes of atoms include atoms with the same atomic number but different mass numbers. For example, unless otherwise indicated, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine or iodine in the compounds of the present application also include isotopes thereof, such as but not limited to ¹ H, ² H, ³ H, ¹¹ C, ¹² C, ¹³ C, ¹⁴ C, ¹⁴ N, ¹⁵ N, ¹⁶ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³² S, ³³ S, ³⁴ S, ³⁶ S, ¹⁷ F, ¹⁹ F, ^35Cl , ^37Cl , ^79Br , ^81Br , ^127I and ^131I . In some embodiments, the hydrogen includes protium, deuterium, tritium, or a combination thereof. In some embodiments, the carbon ^{includes12C,13C} ^, or a combination thereof. In some embodiments, the abundance of various isotopic atoms of an element may be the state in which the element naturally occurs in nature, or may be in a state enriched for a certain isotope.

The term "pharmaceutical excipients" refers to the excipients and additives used in the production of pharmaceuticals and the formulation of prescriptions, and are all substances contained in pharmaceutical preparations other than active ingredients. See the Pharmacopoeia of the People's Republic of China (2015 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).

The term "treatment" refers to therapeutic therapy. In relation to a specific disorder, treatment refers to: (1) ameliorating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disorder or (b) ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.

The term "prevention" refers to a reduced risk of acquiring or developing a disease or disorder.

The term "therapeutically effective amount" refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat the disease or disorder described herein. A "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.

The term "patient" refers to any animal, preferably a mammal, and most preferably a human, to whom the compound or composition is to be or has been administered according to embodiments of the present invention. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.

On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive improvement effect of the present invention is that the preliminary activity shows that the compound of the present invention has a higher inhibitory effect on CDK7 kinase.

Detailed ways

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.

Example 1

first step

Under nitrogen protection, a solution of compound 1a (100 mg, 0.49 mmol) and AlCl ₃ (130 mg, 0.98 mmol) in anhydrous 1,2-dichloroethane (5 mL) was placed at 80 °C for 30 minutes, and then compound 1b ( A solution of 115 mg, 0.59 mmol) in 1,2-dichloroethane (1 mL) was added dropwise to the above reaction solution. The resulting reaction solution was reacted at 80°C overnight. The reaction was completed, cooled, quenched with water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, passed, and concentrated to obtain a crude product, which was slurried with methanol (2 mL), and filtered to obtain Compound 1c (50 mg, 28%).

¹ H NMR (400HMz, DMSO-d6) δ 12.52 (s, 1H), 8.64-8.58 (m, 2H), 8.37 (s, 1H), 7.66 (d, J=4.8Hz, 1H), 7.56 (d , J=4.8Hz, 1H), 7.26 (t, J=8Hz, 1H).

second step

Under nitrogen protection, a solution of compound 1c (50 mg, 0.14 mmol), compound 1d (28 mg, 0.14 mmol) and DIEA (88 mg, 0.69 mmol) in NMP (1 mL) was heated to 150°C and reacted for 3 hours. The reaction was completed, cooled to room temperature, added with water (20 mL), extracted with ethyl acetate (20 mL x 2), combined with the organic phases, washed with water (20 mL x 1) and saturated brine (20 mL x 1) in turn, and dried over anhydrous sodium sulfate. , filtered and concentrated to give crude 1e (50 mg).

third step

Compound 1e (crude from previous step, 50 mg) was dissolved in dry DCM (5 mL) at room temperature. TFA (0.5 mL) was added dropwise. After the dropwise addition was completed, the reaction was continued for 2 hours. The reaction was completed, concentrated, and the crude product was subjected to reverse preparative HPLC to obtain the target compound 1 (5 mg, yield 9% for two steps).

¹ H NMR (400HMz, CDCl ₃ ) δ 8.70 (s, 1H), 8.49 (d, J=8.0 Hz, 1H), 8.08 (d, J=2.4 Hz, 1H), 7.00-7.85 (m, 1H) , 7.40(d, J=7.6Hz, 1H), 7.20-7.10(m, 2H), 4.66-4.53(m, 2H), 3.23-3.18(m, 1H), 3.02-2.93(m, 2H), 2.00 -1.96 (m, 1H), 1.82-1.79 (m, 1H), 1.39-1.26 (m, 2H).

LCMS(M+H)+m/z: 428/430

Example 2

first step

Under nitrogen protection, a solution of compound 2a (300 mg, 1.59 mmol) and AlCl ₃ (232 mg, 1.74 mmol) in anhydrous 1,2-dichloroethane (5 mL) was reacted at 80° C. for 30 minutes. A solution of compound 1b (312 mg, 1.59 mmol) in 1,2-dichloroethane (1 mL) was added dropwise to the above reaction solution. The resulting reaction solution was reacted at 80°C overnight. The reaction was completed, cooled, quenched with water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, passed, and concentrated to obtain a crude product, which was slurried with methanol (2 mL), and filtered to obtain Compound 2b (150 mg, 27%).

second step

Under nitrogen protection, a solution of compound 2b (150 mg, 0.43 mmol), compound 1d (86 mg, 0.43 mmol) and DIEA (277 mg, 2.15 mmol) in NMP (2 mL) was heated to 150°C and reacted for 3 hours. The reaction was completed, cooled to room temperature, added with water (20 mL), extracted with ethyl acetate (20 mL x 2), combined with the organic phases, washed with water (20 mL x 1) and saturated brine (20 mL x 1) in turn, and dried over anhydrous sodium sulfate. , filtered and concentrated to give crude 2c (150 mg).

third step

Compound 2c (crude from previous step, 150 mg) was dissolved in dry DCM (5 mL) at room temperature. TFA (0.5 mL) was added dropwise. After the dropwise addition was completed, the reaction was continued for 2 hours. The reaction was completed, concentrated, and the crude product was subjected to reverse preparative HPLC to obtain the target compound 2 (20 mg, two-step yield 11%).

¹ H NMR (400HMz, CDCl ₃ ) δ 8.64 (d, J=8.0 Hz, 1H), 7.74 (d, J=2.4 Hz, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.18 (t , J=8.0Hz, H), 4.68-4.54(m, 2H), 3.25-3.04(m, 1H), 3.02-2.90(m, 6H), 2.17-1.85(m, 4H), 1.44-1.28(m , 2H).

LCMS(M+H)+m/z: 412/414

Example 3

first step

According to the synthesis method of Example 1, starting from compound 3a and compound 1b, compound 3b is obtained through two-step reaction.

second step

Under nitrogen protection, compound 3b (300 mg, 0.56 mmol), K ₃ PO ₄ (130 mg, 0.61 mmol), Xantphos (97 mg, 0.17 mmol), Pd2(dba)3 (77 mg, 0.084 mmol) and dimethyl were oxidized A solution of phosphine (52 mg, 0.67 mmol) in DMF (2 mL) was heated to 140°C and reacted for 2 hours. The reaction was completed, cooled to room temperature, water (20 mL) was added to quench the reaction, extracted with ethyl acetate (20 mL x 2), the organic phases were combined, washed with water (20 mL x 1) and saturated brine (20 mL x 1) in turn, and anhydrous It was dried over sodium sulfate, filtered, and concentrated to obtain the crude product, which was subjected to column chromatography (MeOH/DCM=0-100%) to obtain the target compound 3c (190 mg, 64%).

third step

A solution of compound 3c (100 mg, 0.19 mmol) and Lawson's reagent (136 mg, 0.34 mmol) in toluene was heated to reflux for 3 hours under nitrogen protection. After the reaction was completed, it was cooled to room temperature, and the solvent was removed to obtain compound 3d (60 mg, 53%) by preparing a silica gel plate (petroleum ether/ethyl acetate=2/1).

the fourth step,

According to the synthetic method of the third step of Example 1, compound 3 (23 mg, 47%) was obtained from compound 3d (60 mg, 0.11 mmol).

¹ H NMR (400HMz, CDCl ₃ ) δ 11.54 (s, 1H), 8.61-8.45 (m, 2H), 7.90 (s, 1H), 7.34-7.25 (m, 2H), 6.29 (br s, 1H) , 4.35-4.15(m, 2H), 3.28-3.19(m, 1H), 3.02-2.85(m, 3H), 2.13(s, 3H), 2.10(s, 3H), 1.95-1.85(m, 2H) , 1.77-1.60 (m, 2H).

LCMS(M+H)+m/z: 454

Example 4

first step

Under nitrogen protection, a solution of compound 4a (300 mg, 1.39 mmol) and AlCl ₃ (202 mg, 1.52 mmol) in anhydrous 1,2-dichloroethane (5 mL) was reacted at 80° C. for 30 minutes. A solution of compound 4b (306 mg, 1.39 mmol) in 1,2-dichloroethane (5 mL) was added dropwise to the above reaction solution. The reaction solution was reacted at 80°C overnight. The reaction was completed, cooled, quenched with water (30 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was slurried with methanol (5 mL) and filtered to obtain the compound 4c (150 mg).

second step

Under nitrogen protection, compound 4c (100 mg, 0.19 mmol), K ₃ PO ₄ (43 mg, 0.20 mmol), Xantphos (32 mg, 0.06 mmol), Pd ₂ (dba) ₃ (26 mg, 0.028 mmol) and dimethyl A solution of phosphine oxide (18 mg, 0.22 mmol) in DMF (2 mL) was heated to 140°C and reacted for 2 hours. The reaction was completed, cooled to room temperature, water (20 mL) was added to quench the reaction, extracted with ethyl acetate (20 mL x 2), the organic phases were combined, washed with water (20 mL x 1) and saturated brine (20 mL x 1) in turn, and anhydrous It was dried over sodium sulfate, filtered and concentrated to obtain the crude product, which was subjected to column chromatography (MeOH/DCM=0-100%) to obtain the target compound 4d (63 mg).

third step

Under nitrogen protection, a solution of compound 4d (50 mg, 0.13 mmol), compound 4e (17 mg, 0.13 mmol) and DIEA (84 mg, 0.65 mmol) in NMP (2 mL) was heated to 150°C and reacted for 3 hours. The reaction was completed, cooled to room temperature, added with water (20 mL), extracted with ethyl acetate (20 mL x 2), combined with the organic phases, washed with water (20 mL x 1) and saturated brine (20 mL x 1) in turn, and dried over anhydrous sodium sulfate. , filtered, and the target compound 4 (30 mg) was obtained by column chromatography (MeOH/DCM=0-100%).

¹ H NMR (400HMz, CDCl ₃ ) δ 8.86-8.73 (m, 2H), 8.53-8.28 (m, 2H), 7.79-7.78 (m, 1H), 4.42-4.21 (m, 1H), 3.42-3.24 (m, 1H), 3.10-3.08 (s, 1H), 2.06-2.03 (m, 7H), 1.90-1.82 (m, 2H), 1.75-1.70 (m, 1H), 1.59-1.36 (s, 6H) .

LCMS(M+H)+m/z: 494

Example 5

first step

According to the synthesis method of compound 4d, compound 5b (129 mg) was obtained by one-step reaction from compound 5a (200 mg, 1.13 mmol).

second step

Under nitrogen protection, compound 5b (100 mg, 0.46 mmol), K ₂ CO ₃ (126 mg, 0.91 mmol), Xantphos (58 mg, 0.10 mmol), Pd ₂ (dba) ₃ (45 mg, 0.05 mmol) and 3a (99 mg) were combined , 0.46 mmol) in DMF (5 mL) was heated to 140 °C and reacted for 2 hours. The reaction was completed, cooled to room temperature, water (20 mL) was added to quench the reaction, extracted with ethyl acetate (20 mL x 2), the organic phases were combined, washed with water (20 mL x 1) and saturated brine (20 mL x 1) in turn, and anhydrous It was dried over sodium sulfate, filtered, and concentrated to obtain the crude product, which was subjected to column chromatography (MeOH/DCM=0-100%) to obtain the target compound 5c (74 mg).

third step

Referring to the synthesis method of compound 4e, compound 5 (20 mg) was obtained by one-step reaction from compound 5c (53 mg, 0.08 mmol).

LCMS(M+H)+m/z: 492

Example 6

first step

According to the synthesis method of compound 4c, compound 6a (112 mg) was obtained by one-step reaction from compound 3a (500 mg, 1.25 mmol) and 4b (275 mg, 1.25 mmol).

second step

According to the synthesis method of compound 4d, compound 6b (43 mg) was obtained by one-step reaction from compound 6a (100 mg, 0.25 mmol).

third step

Referring to the synthesis method of compound 4e, compound 6 (15 mg) was obtained by one-step reaction from compound 6b (30 mg, 0.08 mmol).

¹ H NMR (400HMz, CDCl ₃ ) δ 11.89 (s, 1H), 8.57 (s, 2H), 8.04 (s, 1H), 7.59-7.56 (m, 1H), 5.52-5.51 (m, 1H), 3.91-3.89(m, 1H), 3.59-3.48(m, 2H), 3.64-3.46(m, 1H), 2.13-2.01(m, 8H), 1.81-1.78(m, 2H), 1.37-1.32(m , 4H).

LCMS(M+H)+m/z: 478

Example 7

first step

According to the synthesis method of compound 4d, compound 7b (118 mg) was obtained by one-step reaction from compound 7a (200 mg, 1.14 mmol).

second step

According to the synthesis method of compound 5c, compound 7c (134 mg) was obtained by one-step reaction starting from compound 7b (85 mg, 0.39 mmol).

third step

Referring to the synthesis method of compound 4, compound 5 (45 mg) was obtained by one-step reaction from compound 5c (70 mg, 0.18 mmol).

¹ H NMR (400HMz, CDCl ₃ ) δ 8.86-8.73 (m, 2H), 8.34-8.23 (m, 2H), 7.83-7.75 (m, 1H), 7.51-7.42 (m, 1H), 4.34-4.15 (m, 1H), 3.38-3.19 (m, 1H), 3.05-2.97 (s, 1H), 2.16-2.08 (m, 7H), 1.85-1.80 (m, 2H), 1.79-1.72 (m, 1H) , 1.55-1.32 (s, 6H).

LCMS(M+H)+m/z: 491

Cell test

Experimental Materials:

CDK7/CyclinH/MAT1 kinase was purchased from Carna Company. Substrate (MBP) and other detection reagents were purchased from Promega. Nivo Multilabel Analyzer (PerkinElmer).

experimental method:

Dilute enzyme, substrate (MBP), adenosine triphosphate and inhibitor with the kinase buffer included in the kit.

The compound to be tested was diluted 5 times to the 8th concentration with a row gun, that is, from 50 μM to 0.65 nM, and the DMSO concentration was 5%, and a double-well experiment was set up. Add 1 μL of each concentration gradient of inhibitor, 2 μl CDK7/CyclinH/MAT1 enzyme (total 20ng), 2 μl mixture of substrate and ATP (125uM adenosine triphosphate, 0.1 μg/μl substrate) to the microtiter plate, and the final compound concentration gradient at this time Dilute to 0.13 nM for 10 μM. The reaction system was placed at 25 degrees for 120 minutes. After the reaction, 5 μl of ADP-Glo reagent was added to each well, and the reaction was continued at 25°C for 40 minutes. After the reaction was completed, 10 μL of kinase detection reagent was added to each well. After 30 minutes of reaction at 25°C, a multi-label analyzer was used to read chemiluminescence with an integration time of 0.5 Second.

data analysis:

Using the equation (Sample-Min)/(Max-Min)*100% to convert the raw data into inhibition rate, the IC50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response- in GraphPad Prism -Variable slope mode derived).

Table 1 provides the enzymatic inhibitory activity of the compounds of the present invention on CDK7/CyclinH/MAT1.

实施例Example	IC ₅₀(nM) _IC50 (nM)
化合物1Compound 1	232232
化合物2Compound 2	23272327
化合物3Compound 3	3.63.6
化合物4Compound 4	29.1829.18
化合物5Compound 5	4.84.8
化合物6Compound 6	21892189
化合物7Compound 7	7.17.1

The compounds of the present invention possess potent kinase inhibitory activity.

Claims

A nitrogen-containing heterocyclic compound as shown in formula I or a pharmaceutically acceptable salt thereof, characterized in that:

in,
is a single bond or a double bond;

Ring A is "5-membered or 6-membered heteroaryl group with 1 to 3 heteroatoms selected from one or more of N, O and S", "5-membered or 6-membered cycloalkenyl" or "5-membered or 6-membered heterocycloalkenyl with 1 to 3 heteroatoms selected from one or more of N, O and S";

n is 0, 1 or 2;

R 1 is independently halogen, C 1 -C 6 alkyl or "C 1 -C 6 alkyl substituted with one or more halogens";

R is C 3 -C 6 cycloalkyl, "C 3 -C 6 cycloalkyl substituted by 1, 2 or 3 R 5 ", "the number of heteroatoms is 1 or 2, and the heteroatom is N , monocyclic or bicyclic 5- to 8-membered heterocycloalkyl "or "substituted by 1, 2 or 3 R 6 , the number of heteroatoms is 1 or 2, the heteroatom is N, the single 5- to 8-membered cyclic or bicyclic heterocycloalkyl";

R 5 is independently hydroxyl, C 1 -C 6 alkyl or "R 5-1 -NH-"; R 5-1 is independently C 1 -C 6 alkyl;

R 6 is independently C 1 -C 6 alkyl;

X is N or CH;

Z is N or CR 7 ; R 7 is halogen, -P(=O)(CH 3 ) 2 or -S(=O) 2 -CH 3 ;

R 3 is hydrogen, -CN, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxyl or amino.
The nitrogen-containing heterocyclic compound represented by formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is "the number of heteroatoms is 1 to 2, and the heteroatoms are selected from N, 5-membered heteroaryl" or "5- or 6-membered cycloalkenyl" of one or more of O and S;

and/or, n is 0 or 1;

And/or, R is "C 3 -C 6 cycloalkyl substituted by 1, 2 or 3 R 5 ", "the number of heteroatoms is 1 or 2, and the heteroatom is N, monocyclic or Bicyclic 5- to 8-membered heterocycloalkyl" or "substituted by 1, 2 or 3 R6, the number of heteroatoms is 1 or 2, the heteroatom is N, the monocyclic or bicyclic 5 to 8-membered heterocycloalkyl";

And/or, R 5 is independently hydroxyl or "R 5-1 -NH-"; R 5-1 is independently C 1 -C 6 alkyl;

and/or, X is CH;

and/or, Z is CR 7 ; R 7 is halogen, -P(=O)(CH 3 ) 2 or -S(=O) 2 -CH 3 ;

And/or, R3 is hydrogen or -CN.
The nitrogen-containing heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 2, wherein n is 0;

And/or, R is "one or two heteroatoms and N, monocyclic or bicyclic 5- to 8-membered heterocycloalkyl" or "restricted by 1, 2 or 3 Rs" 6 -substituted, the number of heteroatoms is 1 or 2, and the heteroatom is N, a monocyclic or bicyclic 5- to 8-membered heterocycloalkyl";

and/or, Z is CR7 ; R7 is halogen or -P(=O)( CH3 ) 2 .
The nitrogen-containing heterocyclic compound represented by formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it is defined as described in any one of the following schemes:

plan 1:

Ring A is a "5-membered heteroaryl group with 1 to 2 heteroatoms selected from one or more of N, O and S", "5-membered or 6-membered cycloalkenyl" or "hetero A 5-membered heterocycloalkenyl with one atomic number and a heteroatom selected from one of N, O and S";

n is 0 or 1;

R 1 is independently halogen, C 1 -C 6 alkyl or "C 1 -C 6 alkyl substituted with one or more halogens";

R is "C 3 -C 6 cycloalkyl substituted by 1, 2 or 3 R 5 ", "the number of heteroatoms is 1 or 2, the heteroatom is N, monocyclic or bicyclic 5-membered to 8-membered heterocycloalkyl" or "substituted by 1, 2 or 3 R 6 , the number of heteroatoms is 1 or 2, the heteroatom is N, the monocyclic or bicyclic 5- to 8-membered Heterocycloalkyl";

R 5 is independently hydroxyl or "R 5-1 -NH-"; R 5-1 is independently C 1 -C 6 alkyl;

R 6 is independently C 1 -C 6 alkyl;

X is CH;

Z is CR 7 ; R 7 is halogen, -P(=O)(CH 3 ) 2 or -S(=O) 2 -CH 3 ;

R 3 is hydrogen or -CN;

Scenario 2:

Ring A is "5-membered heteroaryl with 1 to 2 heteroatoms selected from one or more of N, O and S" or "5- or 6-membered cycloalkenyl";

n is 0;

R is "the number of heteroatoms is 1 or 2, the heteroatom is N, a monocyclic or bicyclic 5- to 8-membered heterocycloalkyl" or "substituted by 1, 2 or 3 R6, The number of heteroatoms is 1 or 2, and the heteroatom is N, a monocyclic or bicyclic 5- to 8-membered heterocycloalkyl";

X is CH;

R 6 is independently C 1 -C 6 alkyl

Z is CR 7 ; R 7 is halogen or -P(=O)(CH 3 ) 2 ;

R 3 is hydrogen or CN.
The nitrogen-containing heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein when the ring A is "the number of heteroatoms is 1 ~3, when the heteroatom is selected from a 5-membered or 6-membered heteroaryl group of one or more of N, O and S, the ring A is

Its upper end is connected with N atom;

And/or, when the ring A is "5-membered or 6-membered cycloalkenyl", the ring A is

And/or, when the ring A is "5-membered or 6-membered heterocycloalkenyl with 1 to 3 heteroatoms selected from one or more of N, O and S", The ring A is
Its upper end is connected with N atom;

and/or, when said R 1 is independently halogen, said halogen is fluorine, chlorine, bromine or iodine;

And/or, when the R 1 is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group;

And/or, when the R 1 is independently "C 1 -C 6 alkyl substituted by multiple halogens", the multiple is 2 or 3;

And/or, when said R 1 is independently "C 1 -C 6 alkyl substituted by one or more halogens", said halogen is fluorine, chlorine, bromine or iodine;

And/or, when said R 1 is independently "C 1 -C 6 alkyl substituted by one or more halogens", said C 1 -C 6 alkyl is C 1 -C 4 alkyl ;

And/or, when the R is a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is cyclopropane, cyclobutane, cyclopentane or cyclohexane;

And/or, when the R 5 is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group;

And/or, when the R 5-1 is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group;

And/or, when the R is "C 3 -C 6 cycloalkyl substituted by 1, 2 or 3 R 5 ," the C 3 -C 6 cycloalkyl is cyclopropane, cyclobutane, cyclopentane or cyclohexane;

And/or, when said R is "the number of heteroatoms is 1 or 2, the heteroatom is N, a monocyclic 5- to 8-membered heterocycloalkyl group", the said "the number of heteroatoms is 1 or 2, the heteroatom is N, the monocyclic 5- to 8-membered heterocycloalkyl "is pyrrolidinyl or piperidinyl;

And/or, when said R is "the number of heteroatoms is 1 or 2, and the heteroatom is a bicyclic 5- to 8-membered heterocycloalkyl group with N", the said "the number of heteroatoms is 1" or 2, the bicyclic 5- to 8-membered heterocycloalkyl whose heteroatom is N" is 1-azaspiro[3.4]octyl or octahydrocyclopenta[b]pyrrolyl;

And/or, when the R 6 is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group;

And/or, when the R is "substituted by 1, 2 or 3 R 6 , the number of heteroatoms is 1 or 2, the heteroatom is N, the monocyclic 5- to 8-membered heteroatoms "Cycloalkyl", the "heteroatom number is 1 or 2, the heteroatom is N, and the monocyclic 5- to 8-membered heterocycloalkyl" is pyrrolidinyl or piperidinyl;

And/or, when said R is "substituted by 1, 2 or 3 R 6 , the number of heteroatoms is 1 or 2, and the heteroatom is a bicyclic 5- to 8-membered heterocycloalkane of N "base", the "bicyclic 5- to 8-membered heterocycloalkyl with 1 or 2 heteroatoms and the heteroatom is N" is 1-azaspiro[3.4]octyl or octahydro cyclopenta[b]pyrrolyl;

and/or, when said R 7 is independently halogen, said halogen is fluorine, chlorine, bromine or iodine;

And/or, when said R 3 is halogen, said halogen is fluorine, chlorine, bromine or iodine;

And/or, when the R 3 is a C 1 -C 3 alkyl group, the C 1 -C 3 alkyl group is methyl, ethyl, n-propyl or isopropyl;

And/or, when the R 3 is C 1 -C 3 alkoxy, the C 1 -C 3 alkoxy is methoxy, ethoxy, n-propoxy or isopropoxy .
The nitrogen-containing heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 5, wherein,
for

and/or, when said R 1 is independently halogen, said halogen is chlorine;

And/or, when the R 1 is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl , sec-butyl, isobutyl or tert-butyl;

And/or, when said R 1 is independently "C 1 -C 6 alkyl substituted by one or more halogens", said halogen is fluorine;

And/or, when the R 1 is independently "C 1 -C 6 alkyl substituted by one or more halogens", the C 1 -C 6 alkyl is methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

And/or, when the R is a C 3 -C 6 cycloalkyl group, the C 3 -C 6 cycloalkyl group is cyclobutane, cyclopentane or cyclohexane;

And/or, when the R 5 is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl , sec-butyl, isobutyl or tert-butyl;

And/or, when the R 5-1 is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-propyl Butyl, sec-butyl, isobutyl or tert-butyl;

And/or, when the R is "C 3 -C 6 cycloalkyl substituted by 1, 2 or 3 R 5 ," the C 3 -C 6 cycloalkyl is cyclobutane , cyclopentane or cyclohexane;

And/or, when said R is "the number of heteroatoms is 1 or 2, the heteroatom is N, a monocyclic 5- to 8-membered heterocycloalkyl group", the said "the number of heteroatoms is 1 or 2, the heteroatom is N, the monocyclic 5- to 8-membered heterocycloalkyl" is

And/or, when said R is "the number of heteroatoms is 1 or 2, and the heteroatom is a bicyclic 5- to 8-membered heterocycloalkyl group with N", the said "the number of heteroatoms is 1" or 2, bicyclic 5- to 8-membered heterocycloalkyl with heteroatom N" is

And/or, when the R 6 is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl , sec-butyl, isobutyl or tert-butyl;

And/or, when the R is "substituted by 1, 2 or 3 R 6 , the number of heteroatoms is 1 or 2, the heteroatom is N, the monocyclic 5- to 8-membered heteroatoms "cycloalkyl", the "heteroatoms with 1 or 2 heteroatoms, the heteroatom is N, and the monocyclic 5- to 8-membered heterocycloalkyl" is

And/or, when said R is "substituted by 1, 2 or 3 R 6 , the number of heteroatoms is 1 or 2, and the heteroatom is a bicyclic 5- to 8-membered heterocycloalkane of N In the case of "base", the "bicyclic 5- to 8-membered heterocycloalkyl group with the number of heteroatoms being 1 or 2 and the heteroatom being N" is

and/or, when said R 7 is independently halogen, said halogen is bromine;

And/or, when said R 3 is halogen, said halogen is fluorine or bromine.
The nitrogen-containing heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 6, wherein when said R 1 is independently "C substituted by one or more halogens" 1 -C 6 alkyl", the "C 1 -C 6 alkyl substituted by multiple halogens" is trifluoromethyl;

And/or, when said R is "C 3 -C 6 cycloalkyl substituted by 1, 2 or 3 R 5 ", the said "substituted by 1, 2 or 3 R 5 " Substituted C 3 -C 6 cycloalkyl" is

And/or, when the R is "substituted by 1, 2 or 3 R 6 , the number of heteroatoms is 1 or 2, the heteroatom is N, the monocyclic 5- to 8-membered heteroatoms Cycloalkyl", said "substituted by 1, 2 or 3 R 6 , the number of heteroatoms is 1 or 2, the heteroatom is N, a monocyclic 5- to 8-membered heterocycle Alkyl" is

and / or,
for
The nitrogen-containing heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 7, wherein,
for

and/or, R is
The nitrogen-containing heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein the nitrogen-containing heterocyclic compound represented by formula I is any of the following Compound:
A pharmaceutical composition comprising substance X and pharmaceutical excipients;

The substance X is the nitrogen-containing heterocyclic compound represented by formula I according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
An application of a substance X in the preparation of a CDK7 kinase inhibitor, the CDK7 kinase inhibitor being used in vitro;

The substance X is the nitrogen-containing heterocyclic compound represented by formula I according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
Application of a substance X in the preparation of a medicine for treating and/or preventing diseases related to CDK7 kinase;

The substance X is the nitrogen-containing heterocyclic compound represented by formula I according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
The use of a substance X in the preparation of a medicine for treating and/or preventing a proliferative disease;

The substance X is the nitrogen-containing heterocyclic compound represented by formula I according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
A nitrogen-containing heterocyclic compound as shown in formula II or a pharmaceutically acceptable salt thereof, characterized in that:

Wherein, R 1 is C 4 -C 6 cycloalkyl, "C 4 -C 6 cycloalkyl substituted by 1, 2 or 3 R 1-1 ", "the number of heteroatoms is 1 or 2" , the heteroatom is selected from one or more of N, O and S, 5-membered or 6-membered heterocycloalkyl” or “substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, the heteroatom is selected from one or more of N, O and S 5-membered or 6-membered heterocycloalkyl";

R 1-1 is independently halogen, hydroxyl, NHR 1-1-1 , cyano or C 1 -C 6 alkyl; R 1-1-1 is independently C 1 -C 6 alkyl;

R 1-2 is independently halogen, hydroxyl, NHR 1-2-1 , cyano or C 1 -C 6 alkyl; R 1-2-1 is independently C 1 -C 6 alkyl;

Alternatively, R 1-1 on the same carbon or adjacent carbon and the C atom connected to it together form a 3- to 6-membered carbocyclic ring or "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N, O and one or more of S's 3- to 6-membered heterocycloalkyl";

Alternatively, R 1-2 on the same carbon or adjacent carbon and the C atom connected to it together form a 3- to 6-membered carbocyclic ring or "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N, O and one or more of S's 3- to 6-membered heterocycloalkyl";

R 2 is hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted by 1-3 fluorine atoms;

X is N or CH;

R3 is

R 4 is hydrogen, hydroxy, cyano or halogen.
The nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof according to claim 14, wherein R 1 is "substituted by 1, 2 or 3 R 1-1 C 4 -C 6 cycloalkyl", "5-membered or 6-membered heterocycloalkyl with one or two heteroatoms selected from one or more of N, O and S" or " 5-membered or 6-membered heterocycloalkyl substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S";

And/or, R 1-1 is independently hydroxyl, NHR 1-1-1 ; R 1-1-1 is independently C 1 -C 6 alkyl;

And/or, R 1-2 is independently hydroxyl or C 1 -C 6 alkyl;

And/or, R 2 is hydrogen, chlorine or C 1 -C 3 alkyl substituted by 1-3 fluorine atoms;

and/or, X is CH;

and/or, R3 is

and/or, R4 is hydrogen, halogen or cyano.
The nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof according to claim 15, wherein R 1 is "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N , 5-membered or 6-membered heterocycloalkyl group of one or more of O and S" or "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from 5- or 6-membered heterocycloalkyl from one or more of N, O, and S";

And/or, R 2 is chlorine or C 1 -C 3 alkyl substituted by 1-3 fluorine atoms;

and/or, R3 is

and/or, R4 is cyano or hydrogen.
The nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof as claimed in claim 14, characterized in that, it is defined as described in any one of the following schemes:

Scheme A: R 1 is "C 4 -C 6 cycloalkyl substituted by 1 , 2 or 3 R 1-1s", "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N, O and one or more of S 5- or 6-membered heterocycloalkyl "or" substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N , 5- or 6-membered heterocycloalkyl of one or more of O and S"

R 1-1 is independently hydroxyl, NHR 1-1-1 ; R 1-1-1 is independently C 1 -C 6 alkyl;

R 1-2 is independently hydroxyl or C 1 -C 6 alkyl;

R 2 is hydrogen, chlorine or C 1 -C 3 alkyl substituted by 1-3 fluorine atoms;

X is CH;

R3 is

R 4 is hydrogen, halogen or cyano;

Scheme B: R 1 is "a 5- or 6-membered heterocycloalkyl group in which the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S" or "a 1 or 6-membered heterocycloalkyl group" 2 R 1-2 substituted, the number of heteroatoms is 1 or 2, the heteroatom is selected from one or more of N, O and S 5-membered or 6-membered heterocycloalkyl";

R 2 is chlorine or C 1 -C 3 alkyl substituted by 1-3 fluorine atoms;

X is CH;

R3 is

R 4 is cyano or hydrogen.
The nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof according to any one of claims 14 to 17, wherein when the R 1 is a C 4 -C 6 ring In the case of an alkyl group, the C 4 -C 6 cycloalkyl group is cyclobutane, cyclopentane or cyclohexane;

And/or, when the R 1 is "C 4 -C 6 cycloalkyl substituted by 1 , 2 or 3 R 1-1s", the C 4 -C 6 cycloalkyl is cyclobutane, cyclopentane or cyclohexane;

And/or, when the R 1-1-1 is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group;

And/or, when said R 1 is "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S. A 5-membered or 6-membered heterocycloalkyl group" , the described "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S. 5-membered or 6-membered heterocycloalkyl" is pyrrolidinyl or piperidinyl ;

And/or, when the R 1 is "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S. 5-membered or 6-membered heterocycloalkyl group”, said “the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more 5-membered or 6-membered heteroatoms of N, O and S. Heterocycloalkyl" is pyrrolidinyl or piperidinyl;

And/or, when the R 1-2 is independently a C 1 -C 6 alkyl group, the C 1 -C 6 alkyl group is a C 1 -C 4 alkyl group;

And/or, when the R 2 is a C 1 -C 3 alkyl group substituted by 1-3 fluorine atoms, the C 1 -C 3 alkyl group is methyl, ethyl, n-propyl or Isopropyl.
The nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof according to claim 18, wherein when said R 1-1-1 is independently C 1 -C 6 alkane When base, the C 1 -C 6 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

And/or, when said R 1 is "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S. A 5-membered or 6-membered heterocycloalkyl group" , the "heteroatoms are 1 or 2, and the heteroatoms are selected from one or more of N, O and S. 5-membered or 6-membered heterocycloalkyl" is

And/or, when the R 1 is "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S. 5-membered or 6-membered heterocycloalkyl group”, said “the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more 5-membered or 6-membered heteroatoms of N, O and S. Heterocycloalkyl" is

And/or, when said R 1-2 is independently C 1 -C 6 alkyl, said C 1 -C 6 alkyl is methyl, ethyl, n-propyl, isopropyl, n-propyl Butyl, sec-butyl, isobutyl or tert-butyl;

And/or, when the R 2 is a C 1 -C 3 alkyl group substituted with 1-3 fluorine atoms, the C 1 -C 3 alkyl group substituted with 1-3 fluorine atoms is a tri- Fluoromethyl.
The nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof according to claim 19, characterized in that when the R 1 is "by 1, 2 or 3 R 1 -1- substituted C 4 -C 6 cycloalkyl", the "C 4 -C 6 cycloalkyl substituted with 1, 2 or 3 R 1-1s " is

And/or, when the R 1 is "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S. 5-membered or 6-membered heterocycloalkyl group", said "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N, O and S One or more of the 5- or 6-membered heterocycloalkyl "are
The nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof according to claim 20, wherein the R 1 is
The nitrogen-containing heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof according to claim 14, wherein the nitrogen-containing heterocyclic compound represented by formula II is any of the following compounds :
A pharmaceutical composition comprising substance Z and pharmaceutical excipients;

The substance Z is the nitrogen-containing heterocyclic compound represented by formula II according to any one of claims 14 to 22 or a pharmaceutically acceptable salt thereof.
An application of a substance Z in the preparation of a CDK7 kinase inhibitor, the CDK7 kinase inhibitor being used in vitro;

The substance Z is the nitrogen-containing heterocyclic compound represented by formula II according to any one of claims 14 to 22 or a pharmaceutically acceptable salt thereof.
Application of a substance Z in the preparation of a medicine for treating and/or preventing diseases related to CDK7 kinase;

The substance Z is the nitrogen-containing heterocyclic compound represented by formula II according to any one of claims 14 to 22 or a pharmaceutically acceptable salt thereof.
Application of a substance Z in the preparation of a medicine for treating and/or preventing proliferative diseases;

The substance Z is the nitrogen-containing heterocyclic compound represented by formula II according to any one of claims 14 to 22 or a pharmaceutically acceptable salt thereof.
A nitrogen-containing heterocyclic compound or a pharmaceutically acceptable salt thereof as shown in formula III, characterized in that:

in,

W, Y and Z are each independently N or C(R 2 );

R 1 is C 4 -C 6 cycloalkyl, "C 4 -C 6 cycloalkyl substituted by 1 , 2 or 3 R 1-1s", "the number of heteroatoms is 1 or 2, heteroatoms Atoms selected from one or more of N, O and S 5- or 6-membered heterocycloalkyl" or "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2 , the heteroatom is selected from one or more of N, O and S 5- or 6-membered heterocycloalkyl";

R 1-1 is independently halogen, hydroxyl, NHR 1-1-1 , cyano or C 1 -C 6 alkyl; R 1-1-1 is independently C 1 -C 6 alkyl;

R 1-2 is independently halogen, hydroxyl, NHR 1-2-1 , cyano or C 1 -C 6 alkyl; R 1-2-1 is independently C 1 -C 6 alkyl;

Alternatively, R 1-1 on the same carbon or adjacent carbon and the C atom connected to it together form a 3- to 6-membered carbocyclic ring or "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N, O and one or more of S's 3- to 6-membered heterocycloalkyl";

Alternatively, R 1-2 on the same carbon or adjacent carbon and the C atom connected to it together form a 3- to 6-membered carbocyclic ring or "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N, O and one or more of S's 3- to 6-membered heterocycloalkyl";

R 2 is hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted by 1-3 fluorine atoms;

R3 is

R 4 is hydrogen, hydroxy, cyano or halogen.
The nitrogen-containing heterocyclic compound represented by formula III or a pharmaceutically acceptable salt thereof according to claim 27, wherein the nitrogen-containing heterocyclic compound is selected from the group consisting of:
The nitrogen-containing heterocyclic compound represented by the formula III or a pharmaceutically acceptable salt thereof according to claim 27 or 28, wherein R 1 is "by 1, 2 or 3 R 1-1 Substituted C 4 -C 6 cycloalkyl", "5-membered or 6-membered heterocycloalkyl with one or two heteroatoms selected from one or more of N, O and S" Or "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S. 5-membered or 6-membered heterocycloalkane base";

And/or, R 1-1 is independently hydroxyl, NHR 1-1-1 ; R 1-1-1 is independently C 1 -C 6 alkyl;

And/or, R 1-2 is independently hydroxyl or C 1 -C 6 alkyl;

And/or, R 2 is hydrogen, chlorine or C 1 -C 3 alkyl substituted by 1-3 fluorine atoms;

and/or, R4 is hydrogen, halogen or cyano.
The nitrogen-containing heterocyclic compound represented by the formula III or a pharmaceutically acceptable salt thereof according to claim 27 or 28, wherein R 1 is "by 1, 2 or 3 R 1-1 Substituted C 4 -C 6 cycloalkyl" or "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one of N, O and S or various 5- or 6-membered heterocycloalkyl";

And/or, R 2 is hydrogen or C 1 -C 3 alkyl substituted by 1-3 fluorine atoms;

and/or, R4 is hydrogen or cyano.
The nitrogen-containing heterocyclic compound represented by formula III or a pharmaceutically acceptable salt thereof according to claim 27 or 28, wherein R 1 is substituted by 1, 2 or 3 R 1-1 cyclopentane or cyclohexane, or piperidinyl substituted with 1 or 2 R 1-2 .
The nitrogen-containing heterocyclic compound represented by formula III or a pharmaceutically acceptable salt thereof according to claim 31, wherein R 1-1 is hydroxyl.
The nitrogen-containing heterocyclic compound represented by formula III or a pharmaceutically acceptable salt thereof according to claim 31, wherein R 1-2 is a C 1 -C 6 alkyl group.
The nitrogen-containing heterocyclic compound represented by formula III or a pharmaceutically acceptable salt thereof according to claim 27 or 28, wherein the nitrogen-containing heterocyclic compound is selected from the group consisting of:
A nitrogen-containing heterocyclic compound as shown in formula IV or a pharmaceutically acceptable salt thereof, characterized in that:

in,

W, Y and Z are each independently N or C(R 2 );

R 1 is C 4 -C 6 cycloalkyl, "C 4 -C 6 cycloalkyl substituted by 1 , 2 or 3 R 1-1s", "the number of heteroatoms is 1 or 2, heteroatoms Atoms selected from one or more of N, O and S 5- or 6-membered heterocycloalkyl" or "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2 , the heteroatom is selected from one or more of N, O and S 5- or 6-membered heterocycloalkyl";

R 1-1 is independently halogen, hydroxyl, NHR 1-1-1 , cyano or C 1 -C 6 alkyl; R 1-1-1 is independently C 1 -C 6 alkyl;

R 1-2 is independently halogen, hydroxyl, NHR 1-2-1 , cyano or C 1 -C 6 alkyl; R 1-2-1 is independently C 1 -C 6 alkyl;

Alternatively, R 1-1 on the same carbon or adjacent carbon and the C atom connected to it together form a 3- to 6-membered carbocyclic ring or "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N, O and one or more of S's 3- to 6-membered heterocycloalkyl";

Alternatively, R 1-2 on the same carbon or adjacent carbon and the C atom connected to it together form a 3- to 6-membered carbocyclic ring or "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from N, O and one or more of S's 3- to 6-membered heterocycloalkyl";

R 2 is hydrogen, halogen, C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted by 1-3 fluorine atoms;

R3 is

R 4 is hydrogen, hydroxy, cyano or halogen.
The nitrogen-containing heterocyclic compound of formula IV or a pharmaceutically acceptable salt thereof according to claim 35, wherein the nitrogen-containing heterocyclic compound has the following formula:
The nitrogen-containing heterocyclic compound represented by formula IV or a pharmaceutically acceptable salt thereof according to claim 35 or 36, characterized in that R 1 is "by 1, 2 or 3 R 1-1 Substituted C 4 -C 6 cycloalkyl", "5- or 6-membered heterocycloalkyl with 1 or 2 heteroatoms selected from one or more of N, O and S" Or "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S. 5-membered or 6-membered heterocycloalkane base";

And/or, R 1-1 is independently hydroxyl, NHR 1-1-1 ; R 1-1-1 is independently C 1 -C 6 alkyl;

And/or, R 1-2 is independently hydroxyl or C 1 -C 6 alkyl;

And/or, R 2 is hydrogen, chlorine or C 1 -C 3 alkyl substituted by 1-3 fluorine atoms;

and/or, R4 is hydrogen, halogen or cyano.
The nitrogen-containing heterocyclic compound represented by formula IV or a pharmaceutically acceptable salt thereof according to claim 37, wherein R 1 is "substituted by 1, 2 or 3 R 1-1 C 4 -C 6 cycloalkyl" or "substituted by 1 or 2 R 1-2 , the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S. 5- or 6-membered heterocycloalkyl";

And/or, R 2 is hydrogen or C 1 -C 3 alkyl substituted by 1-3 fluorine atoms;

and/or, R4 is cyano or hydrogen.
The nitrogen-containing heterocyclic compound represented by formula IV or a pharmaceutically acceptable salt thereof according to claim 38, wherein R 1 is piperidinyl substituted with one or two R 1-2 .
The nitrogen-containing heterocyclic compound represented by formula IV or a pharmaceutically acceptable salt thereof according to claim 39, wherein R 1-2 is a C 1 -C 6 alkyl group.
The nitrogen-containing heterocyclic compound of formula IV or a pharmaceutically acceptable salt thereof according to claim 35, wherein the nitrogen-containing heterocyclic compound is selected from the group consisting of:
A pharmaceutical composition comprising substance Z and pharmaceutical excipients;

The substance Z is the nitrogen-containing heterocyclic compound according to any one of claims 27 to 41 or a pharmaceutically acceptable salt thereof.
An application of a substance Z in the preparation of a CDK7 kinase inhibitor, the CDK7 kinase inhibitor being used in vitro;

The substance Z is the nitrogen-containing heterocyclic compound according to any one of claims 27 to 41 or a pharmaceutically acceptable salt thereof.
Application of a substance Z in the preparation of a medicine for treating and/or preventing diseases related to CDK7 kinase;

The substance Z is the nitrogen-containing heterocyclic compound according to any one of claims 27 to 41 or a pharmaceutically acceptable salt thereof.
Application of a substance Z in the preparation of a medicine for treating and/or preventing proliferative diseases;

The substance Z is the nitrogen-containing heterocyclic compound according to any one of claims 27 to 41 or a pharmaceutically acceptable salt thereof.