CN116462676A

CN116462676A - Multi-condensed ring PRMT5 inhibitor and preparation method and application thereof

Info

Publication number: CN116462676A
Application number: CN202310035015.0A
Authority: CN
Inventors: 邓海兵; 杨飞; 喻红平; 陈椎; 徐耀昌
Original assignee: Abbisko Therapeutics Co Ltd
Current assignee: Abbisko Therapeutics Co Ltd
Priority date: 2022-01-20
Filing date: 2023-01-10
Publication date: 2023-07-21

Abstract

The invention relates to a multi-condensed ring PRMT5 inhibitor, and a preparation method and application thereof. In particular, the present invention relates to a PRMT5 inhibitor having the structure of formula (I), a method for preparing the same, a pharmaceutical composition containing the same, and the use thereof as a PRMT5 inhibitorAnd their use in the treatment and/or prophylaxis of PRMT5 mediated diseases. Wherein each substituent of formula (I) is as defined in the specification.

Description

Multi-condensed ring PRMT5 inhibitor and preparation method and application thereof

Technical Field

The invention belongs to the field of medicine synthesis, and particularly relates to a multi-condensed ring PRMT5 inhibitor, and a preparation method and application thereof.

Background

Epigenetic gene regulation is an important biological regulatory mechanism of protein synthesis and cell differentiation, playing an important role in many human diseases.

Epigenetic regulation involves the regulation of inheritable genetic material without altering its nucleic acid sequence. Typically, epigenetic regulation is controlled by selectively reversible modifications (e.g., methylation) of DNA and proteins (e.g., histones) to control the switching of transcriptionally active and inactive states in chromatin conformation. Modification of these covalent bonds can be controlled by enzymes such as methyltransferases (e.g., PRMT 5), many methyltransferases and many human pathogenic genes are associated with specific genetic changes. PRMT5 plays an important role in many diseases such as tumors, metabolic diseases and hematological diseases.

Homozygous deletion of the suppressor gene is a driver of the tumor, and often results in deletion of passenger genes in the vicinity of the suppressor gene. The loss of these passenger genes can bring about a weakness in tumor cell specificity that can be targeted for targeted therapy. Homozygous deletion of the chromosome 9p21 locus, which contains the well-known oncogene CDKN2A, occurs in 15% of tumors and frequently contains deletion of the passenger gene MTAP. MTAP is a key enzyme in the methionine and adenine reuse pathway. The absence of MTAP results in accumulation of its substrate, MTA. MTA and S-adenosylmethionine (SAM) share structural similarities, the latter being the methyl substrate donor for the dimethyl transferase PRMT 5. The increased MTA level due to MTAP deficiency can selectively compete with SAM for PRMT5 binding, placing methyltransferase in an disabled state, and is more susceptible to PRMT5 inhibition. The shRNA screen of a wide range of tumor cell lines has shown that MTAP deletions and cell lines have a correlation with PRMT5 dependence, i.e. the influence of this metabolic susceptibility is placed under a spotlight. However, studies of PRMT5 as a gene important for cells, conditional knockdown of PRMT5, or siRNA knockdown suggest that inhibition of PRMT5 has significant side effects in normal tissues. (e.g., cytopenia, infertility, skeletal muscle loss, myocardial hypertrophy, etc.). Thus, there is a need for new strategies to apply and explore this metabolic susceptibility, selectively targeting PRMT5 in MTAP-deficient tumors while avoiding effects on PRMT5 in normal tissues (MTAP wild type).

Small molecule inhibitors of PRMT5 that target co-operate with MTA can selectively target only PRMT5 in the MTA-bound state, whereas such PRMT5 is enriched only in MTAP-deficient tumor cells, and thus PRMT5 is not targeted when MTA levels are very low in normal MTAP-intact cells, thus providing a better therapeutic window.

Disclosure of Invention

The invention aims to provide a multi-condensed ring PRMT5 inhibitor, and a preparation method and application thereof. The series of compounds have strong inhibiting effect on PRMT5, and can be widely applied to preparing medicines for treating and/or preventing PRMT5 mediated diseases, thereby being hopeful to develop a new generation PRMT5 inhibitor.

The first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein X is CR _a Or N; y is CR _b Or N;

ring A is C ₅ Cycloalkyl, 5 membered heterocyclyl or 5 membered heteroaryl;

ring B is C _6-10 Aryl or 5-10 membered heteroaryl, said C _6-10 Aryl or 5-to 10-membered heteroaryl optionally condensed to C _3-6 Cycloalkyl or 4-10 membered heterocyclyl;

R ₁ 、R ₂ and R is ₃ Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Alternatively, R ₁ 、R ₂ And R is ₃ Any two of which together with the carbon atoms to which they are directly attached form a C _3-6 Cycloalkyl, 4-10 membered heterocyclyl, C _6-10 Aryl or 5-10 membered heteroaryl, said groups being independently optionally further substituted with one or more groups selected from deuterium,Halogen, cyano, nitro, azido, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, =o, =s, -C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

R ₄ 、R _a and R is _b Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ ；

Each R ₅ Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, =o, -C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, =o, =s, -C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

R ₆ And R is ₇ Each independently of the otherSelected from hydrogen, deuterium, hydroxy, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl and 3-12 membered heterocyclyl, alternatively, R ₆ And R is ₇ Together with the nitrogen atom to which it is directly attached, form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl group, which groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, hydroxy, = O, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _1-10 Alkoxy, C _3-12 Cycloalkyl, C _3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

R _8a and R is _8b Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, hydroxy and-NR ₁₃ R ₁₄ Alternatively, R _8a And R is _8b Together with the carbon atom to which it is directly attached form a C _3-6 Cycloalkyl or 4-10 membered heterocyclyl;

each R ₉ Each independently selected from C _3-12 Cycloalkyl-substituted C _1-10 Alkoxy, C _3-12 Cycloalkoxy, 3-12 membered hetero-epoxy, C _6-10 Aryloxy, 5-to 10-membered heteroaryloxy and-NR ₁₃ R ₁₄ The above groups are each independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, =o, =s, -C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

alternatively, when n.gtoreq.2, two adjacent R' s ₉ Together with the directly connected parts thereof form a C _4-6 Cycloalkyl or 4-10 membered heterocyclyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, =o, =s, -C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

each R ₁₀ Independently selected from hydrogen, deuterium, hydroxy, C _1-10 Alkyl, C _2-10 Alkenyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl and-NR ₁₃ R ₁₄ The above groups are independently optionallyFurther by one or more groups selected from deuterium, halogen, hydroxy, = O, C _1-10 Alkyl, C _1-10 Alkoxy, C _3-12 Cycloalkyl, C _3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _6-10 Aryl, C _6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

each R ₁₁ Independently selected from hydrogen, deuterium, C _1-10 Alkyl, C _2-10 Alkenyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl and 5-10 membered heteroaryl, the above groups being independently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, =o, cyano, C _1-10 Alkyl, C _1-10 Alkoxy, C _3-12 Cycloalkyl, C _3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _6-10 Aryl, C _6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

each R ₁₂ Independently selected from hydrogen, deuterium, hydroxy, C _1-10 Alkyl, C _1-10 Alkoxy, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, C _3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _6-10 Aryl, C _6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR ₁₃ R ₁₄ The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, =o, cyano, C _1-10 Alkyl, C _1-10 Alkoxy, C _3-12 Cycloalkyl, C _3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _6-10 Aryl, C _6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

each R ₁₃ And R is ₁₄ Each independently selected from hydrogen, deuterium, hydroxy, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C _1-10 Alkanoyl, said groups being independently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, = O, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, halo substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _1-10 Alkoxy, C _3-12 Cycloalkyl, C _3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _6-10 Aryl, C _6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, C _1-10 Alkyl monosubstituted amino, C _1-10 Alkyl disubstituted amino and C _1-10 Substituted by alkanoyl, or R ₁₃ And R is ₁₄ Together with the nitrogen atom to which it is directly attached, form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, said 4-10 membered heterocyclyl or 5-10 membered heteroaryl optionally being further substituted with one or more groups selected from deuterium, halogen, hydroxy, = O, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, halo substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _1-10 Alkoxy, C _3-12 Cycloalkyl, C _3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _6-10 Aryl, C _6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, C _1-10 Alkyl monosubstituted amino, C _1-10 Alkyl disubstituted amino and C _1-10 Substituted alkanoyl;

each r is independently 0, 1 or 2;

m is selected from 0, 1, 2, 3 or 4; and is also provided with

n is selected from 1, 2, 3 or 4.

Preferably, R in the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof _8a And R is _8b Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, halogen substituted C _1-4 Alkyl group,Deuterium substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, hydroxy and-NR ₁₃ R ₁₄ Alternatively, R _8a And R is _8b Together with the carbon atom to which it is directly attached form a C _3-4 Cycloalkyl or 4-6 membered heterocyclyl; wherein R is ₁₃ 、R ₁₄ As described for the compounds of formula (I).

As a further preferred embodiment, R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof _8a And R is _8b Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl and C _3-6 Cycloalkoxy, or R _8a And R is _8b Together with the carbon atom to which it is directly attached, forms a cyclopropyl group.

Preferably, R in the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof ₆ And R is ₇ Each independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl and 3-6 membered heterocyclyl, alternatively, R ₆ And R is ₇ Together with the nitrogen atom to which it is directly attached, form a 4-8 membered heterocyclyl or 5-8 membered heteroaryl group, which groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, hydroxy, = O, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

wherein R is ₁₃ 、R ₁₄ As described for the compounds of formula (I).

Preferably, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereofIn the acceptable salt, R ₄ Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅ 、-C _0-4 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-4 alkyl-S (O) _r R ₁₀ 、-C _0-4 alkyl-O-R ₁₁ 、-C _0-4 alkyl-C (O) OR ₁₁ 、-C _0-4 alkyl-C (O) SR ₁₁ 、-C _0-4 alkyl-S-C (O) R ₁₂ 、-C _0-4 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-4 alkyl-C (O) R ₁₂ 、-C _0-4 alkyl-O-C (O) R ₁₂ 、-C _0-4 alkyl-NR ₁₃ R ₁₄ 、-C _0-4 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-4 alkyl-N (R) ₁₃ )-C(O)R ₁₂ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ₁₀ 、R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ And r is as described for the compounds of formula (I).

As a further preferred embodiment, R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof ₄ Selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, C _3-6 Hetero-epoxy, C _6-8 Aryl, C _6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, hydroxy and-NR ₁₃ R ₁₄ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ₁₃ And R is ₁₄ As described for the compounds of formula (I).

As a still further preferred embodiment, R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof ₄ Selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl and C _3-6 A cycloalkoxy group.

Preferably, each R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof _a And R is _b Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅ 、-C _0-4 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-4 alkyl-S (O) _r R ₁₀ 、-C _0-4 alkyl-O-R ₁₁ 、-C _0-4 alkyl-C (O) OR ₁₁ 、-C _0-4 alkyl-C (O) SR ₁₁ 、-C _0-4 alkyl-S-C (O) R ₁₂ 、-C _0-4 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-4 alkyl-C (O) R ₁₂ 、-C _0-4 alkyl-O-C (O) R ₁₂ 、-C _0-4 alkyl-NR ₁₃ R ₁₄ 、-C _0-4 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-4 alkyl-N (R) ₁₃ )-C(O)R ₁₂ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ₁₀ 、R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ And r is as described for the compounds of formula (I).

As a further preferred embodiment, each R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof _a And R is _b Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, C _3-6 Hetero-epoxy, C _6-8 Aryl, C _6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, hydroxy and-NR ₁₃ R ₁₄ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ₁₃ And R is ₁₄ As described for compounds of formula (I);

as a still further preferred embodiment, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, each R _a And R is _b Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl and C _3-6 A cycloalkoxy group.

Preferably, R in the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof ₁ 、R ₂ And R is ₃ Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅ 、-C _0-4 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-4 alkyl-S (O) _r R ₁₀ 、-C _0-4 alkyl-O-R ₁₁ 、-C _0-4 alkyl-C (O) OR ₁₁ 、-C _0-4 alkyl-C (O) SR ₁₁ 、-C _0-4 alkyl-S-C (O) R ₁₂ 、-C _0-4 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-4 alkyl-C (O) R ₁₂ 、-C _0-4 alkyl-O-C (O) R ₁₂ 、-C _0-4 alkyl-NR ₁₃ R ₁₄ 、-C _0-4 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-4 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Alternatively, R ₁ 、R ₂ And R is ₃ Any two of which together with the carbon atoms to which they are directly attached form a C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-8 Aryl or 5-8 membered heteroaryl, said groups being independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -C _0-4 alkyl-SF ₅ 、-C _0-4 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-4 alkyl-S (O) _r R ₁₀ 、-C _0-4 alkyl-O-R ₁₁ 、-C _0-4 alkyl-C (O) OR ₁₁ 、-C _0-4 alkyl-C (O) SR ₁₁ 、-C _0-4 alkyl-S-C (O) R ₁₂ 、-C _0-4 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-4 alkyl-C (O) R ₁₂ 、-C _0-4 alkyl-O-C (O) R ₁₂ 、-C _0-4 alkyl-NR ₁₃ R ₁₄ 、-C _0-4 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-4 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

wherein R is ₁₀ 、R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ And r is as described for the compounds of formula (I).

In a preferred embodiment, in the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof, ring B is C _6-8 Aryl or 5-8 membered heteroaryl, said C _6-8 Aryl or 5-8 membered heteroaryl optionally condensed to C _3-6 Cycloalkyl or 4-6 membered heterocyclyl;

each R ₉ Each independently selected from C _3-6 Cycloalkyl-substituted C _1-4 Alkoxy, C _3-6 Cycloalkoxy, 3-6 membered hetero-epoxy, C _6-8 Aryloxy, 5-8 membered heteroaryloxy and-NR ₁₃ R ₁₄ The above groups are each independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -C _0-4 alkyl-SF ₅ 、-C _0-4 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-4 alkyl-S (O) _r R ₁₀ 、-C _0-4 alkyl-O-R ₁₁ 、-C _0-4 alkyl-C (O) OR ₁₁ 、-C _0-4 alkyl-C (O) SR ₁₁ 、-C _0-4 alkyl-S-C (O) R ₁₂ 、-C _0-4 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-4 alkyl-C (O) R ₁₂ 、-C _0-4 alkyl-O-C (O) R ₁₂ 、-C _0-4 alkyl-NR ₁₃ R ₁₄ 、-C _0-4 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-4 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

alternatively, when n.gtoreq.2, two adjacent R' s ₉ Together with the directly connected parts thereof form a C _4-6 Cycloalkyl or 4-10 membered heterocyclyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -C _0-4 alkyl-SF ₅ 、-C _0-4 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-4 alkyl-S (O) _r R ₁₀ 、-C _0-4 alkyl-O-R ₁₁ 、-C _0-4 alkyl-C (O) OR ₁₁ 、-C _0-4 alkyl-C (O) SR ₁₁ 、-C _0-4 alkyl-S-C (O) R ₁₂ 、-C _0-4 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-4 alkyl-C (O) R ₁₂ 、-C _0-4 alkyl-O-C (O) R ₁₂ 、-C _0-4 alkyl-NR ₁₃ R ₁₄ 、-C _0-4 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-4 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

As a further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ring B is furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl;

each R ₉ Each independently selected from-SF ₅ Trifluoromethyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, C _3-6 Cycloalkyl-substituted C _1-4 Alkoxy, C _3-6 Cycloalkoxy, 3-6 membered hetero-epoxy, C _6-8 Aryloxy, 5-8 membered heteroaryloxy and-NR ₁₃ R ₁₄ C above _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, C _3-6 Cycloalkoxy and-NR ₁₃ R ₁₄ Each independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

alternatively, when n.gtoreq.2, two adjacent R' s ₉ Together with the directly connected parts thereof form a C _4-6 Cycloalkyl or 4-8 membered heterocyclyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, nitro, azido, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、--NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

Preferably, each R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof ₅ Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, -C _0-4 alkyl-SF ₅ 、-C _0-4 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-4 alkyl-S (O) _r R ₁₀ 、-C _0-4 alkyl-O-R ₁₁ 、-C _0-4 alkyl-C (O) OR ₁₁ 、-C _0-4 alkyl-C (O) SR ₁₁ 、-C _0-4 alkyl-S-C (O) R ₁₂ 、-C _0-4 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-4 alkyl-C (O) R ₁₂ 、-C _0-4 alkyl-O-C (O) R ₁₂ 、-C _0-4 alkyl-NR ₁₃ R ₁₄ 、-C _0-4 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-4 alkyl-N (R) ₁₃ )-C(O)R ₁₂ The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -C _0-4 alkyl-SF ₅ 、-C _0-4 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-4 alkyl-S (O) _r R ₁₀ 、-C _0-4 alkyl-O-R ₁₁ 、-C _0-4 alkyl-C (O) OR ₁₁ 、-C _0-4 alkyl-C (O) SR ₁₁ 、-C _0-4 alkyl-S-C (O) R ₁₂ 、-C _0-4 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-4 alkyl-C (O) R ₁₂ 、-C _0-4 alkyl-O-C (O) R ₁₂ 、-C _0-4 alkyl-NR ₁₃ R ₁₄ 、-C _0-4 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-4 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

Preferably, each R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof ₁₀ Independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl, C _2-4 Alkenyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl and-NR ₁₃ R ₁₄ The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, = O, C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C _6-8 Aryl, C _6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

each R ₁₁ Independently selected from hydrogen, deuterium, C _1-4 Alkyl, C _2-4 Alkenyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl and 5-8 membered heteroaryl, the above groups being independently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, =o, cyano, C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C _6-8 Aryl, C _6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

each R ₁₂ Independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl, C _1-4 Alkoxy, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocycylEpoxy group, C _6-8 Aryl, C _6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR ₁₃ R ₁₄ The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, =o, cyano, C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C _6-8 Aryl, C _6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

each R ₁₃ And R is ₁₄ Each independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C _1-4 Alkanoyl, said groups being independently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, = O, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, halo substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C _6-8 Aryl, C _6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, C _1-4 Alkyl monosubstituted amino, C _1-4 Alkyl disubstituted amino and C _1-4 Substituted by alkanoyl, or R ₁₃ And R is ₁₄ Together with the nitrogen atom to which it is directly attached, form a 4-8 membered heterocyclyl or 5-8 membered heteroaryl, said 4-8 membered heterocyclyl or 5-8 membered heteroaryl optionally being further substituted with one or more groups selected from deuterium, halogen, hydroxy, = O, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, halo substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocycylEpoxy group, C _6-8 Aryl, C _6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, C _1-4 Alkyl monosubstituted amino, C _1-4 Alkyl disubstituted amino and C _1-4 The substituent of the alkanoyl group is substituted.

As a further preferred embodiment, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, has the structure of a compound of formula (iia):

wherein Y is ₁ CH or N; y is Y ₂ CH or N; z is Z ₁ Is C (R) _c R _d )、C(O)、N(R _e ) Or O; p is p ₁ 0, 1, 2 or 3; p is p ₂ 1, 2 or 3;

ring a, together with the portion to which it is attached, forms the structure:

x is CR _a Or N; y is CR _b Or N;

X ₁ is C (R) _5c R _5d )、C(O)、N(R _5e ) Or O, X ₂ And X ₃ Each independently is C (R) _5f R _5g )、C(O)、N(R _5h ) Or O, provided that X ₁ 、X ₂ And X ₃ O is not simultaneously used;

R ₁ and R is ₂ Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Alternatively, R ₁ And R is ₂ Together with the carbon atom to which it is directly attached form a C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-8 Aryl or 5-8 membered heteroaryl, said groups being independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

each R ₄ Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl and C _3-6 A cycloalkoxy group;

each R _a And R is _b Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl and C _3-6 A cycloalkoxy group;

R _c and R is _d Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl and 5-8 membered heteroaryl;

R _e selected from hydrogen, deuterium, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl and 3-6 membered heterocyclyl;

each R _5a Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

each R _5b Each independently selected from hydrogen, deuterium, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl and-O-R ₁₁ The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, hydroxy, = O, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

each R _5c And R is _5d Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Alternatively, R _5c And R is _5d Together with the carbon atom to which it is directly attached form a C _3-6 Cycloalkyl or 4-8 membered heterocyclyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

each R _5e Each independently selected from hydrogen, deuterium, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl and-O-R ₁₁ The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, hydroxy, = O, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

each R _5f And R is _5g Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Alternatively, R _5f And R is _5g Together with the carbon atom to which it is directly attached form a C _3-6 Cycloalkyl or 4-8 membered heterocyclyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

each R _5h Each independently selected from hydrogen, deuterium, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl and-O-R ₁₁ The above groups are independently optionally further substituted with one or more groups selected fromDeuterium, halogen, cyano, hydroxy, = O, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

R _8a selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl and C _3-6 A cycloalkoxy group;

wherein R is ₁₀ 、R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ M and r are as described for the compounds of formula (I).

As a still further preferred embodiment, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, has the structure of a compound of formula (iiia) as follows:

wherein Y is ₂ CH or N; z is Z ₁ Is C (R) _c R _d ) Or O; p is p ₁ 0, 1, 2 or 3; p is p ₂ 1, 2 or 3;

ring a, together with the portion to which it is attached, forms the structure:

x is CR _a Or N;

R ₁ selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridentate methyl, cyclopropyl and oxetanyl;

R ₂ Selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridentate methyl,Cyclopropyl, oxetanyl, phenyl, pyridinyl and pyrimidinyl;

R _a selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, tridentate methyl and cyclopropyl;

R _c selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, tridentate methyl and cyclopropyl;

R _d selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, tridentate methyl and cyclopropyl;

R _5a 、R _5g and R is _5f Each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, tridentate methyl and cyclopropyl;

R _5b selected from hydrogen, deuterium, methyl, trifluoromethyl, tridentate methyl and cyclopropyl;

R _8a selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, trifluoromethyl, tridentate methyl and cyclopropyl.

As a further preferred embodiment, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, has the structure of a compound of formula (iib):

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wherein Y is ₁ CH or N; y is Y ₂ CH or N;

ring a, together with the portion to which it is attached, forms the structure:

x is CR _a Or N; y is CR _b Or N;

R _f selected from C _3-6 Cycloalkyl C _1-4 Alkyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl and 5-8 membered heteroaryl, C as described above _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl and 5-8 membered heteroaryl are each independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

R ₁ and R is ₂ Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Alternatively, R ₁ And R is ₂ Together with the carbon atom to which it is directly attached form a C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-8 Aryl or 5-8 membered heteroaryl, said groups being independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl group,C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

each R _5a Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl、＝O、＝S、-SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

each R _5c And R is _5d Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Alternatively, R _5c And R is _5d Together with the carbon atom to which it is directly attached form a C _3-6 Cycloalkyl or 4-8 membered heterocyclyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 OlefinsRadical, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

each R _5f And R is _5g Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Alternatively, R _5f And R is _5g Together with the carbon atom to which it is directly attached form a C _3-6 Cycloalkyl or 4-8 membered heterocyclyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogenCyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

each R _5h Each independently selected from hydrogen, deuterium, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl and-O-R ₁₁ The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, hydroxy, = O, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

As a still further preferred embodiment, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, has the structure of a compound of formula (iiib) as follows:

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wherein Y is ₂ CH or N;

ring a, together with the portion to which it is attached, forms the structure:

x is CR _a Or N;

R _f selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl-substituted methyl, cyclobutyl-substituted methyl and cyclopentyl-substituted methyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, fluoro, chloro, cyano, methyl, trifluoromethyl and tridentate methyl;

R ₂ selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridentate methyl, cyclopropyl, oxetanyl, phenyl, pyridinyl, and pyrimidinyl;

As a most preferred embodiment, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, includes, but is not limited to, the following:

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in a second aspect the present invention provides a process for the preparation of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the process comprising the steps of:

wherein, ring A, ring B, X, Y, R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R _8a 、R _8b 、R ₉ M and n are as described for the compounds of formula (I).

In a third aspect the present invention provides a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In a fourth aspect, the present invention provides an application of the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof in preparing a medicament for treating MATP-related cancer or tumor.

Preferably, the tumor or cancer is selected from endometrial adenocarcinoma, granulosa-follicular cell carcinoma, testicular support cell carcinoma, germ cell carcinoma, malignant teratoma, squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, fallopian tube carcinoma, adenocarcinoma, wilms' cell carcinoma, lymphoma, leukemia, bladder carcinoma, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, prostate carcinoma, seminoma, teratoma, embryo carcinoma, teratoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, and lipoma; liver cancer, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gall bladder cancer, ampulla cancer, cholangiocarcinoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, nevi, dysplastic nevi, lipoma, hemangioma, acute and chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, and hodgkin's disease, non-hodgkin's lymphoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondral tumor, benign chondrioma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumor, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyomas, fibromas, lipomas and teratomas, bronchopulmonary carcinoma, alveolar carcinoma, bronchial adenomas, sarcomas, lymphomas, chondromatoid hamartoma, mesothelioma, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, gastric carcinoma, lymphoma, leiomyosarcoma, ductal adenocarcinoma, insulinoma, glucagon, gastrinoma, carcinoid tumors, venomous snake tumors, adenocarcinoma, lymphoma, carcinoid tumors, kaposi's sarcoma, smooth myomas, hemangiomas, lipomas, neurofibromas, fibromas, large intestine adenomas, tubular adenomas, villial adenomas, hamartoma, smooth myomas, craniocerebral adenomas, hemangiomas, granulomas, xanthomas, deforma osteomas, meningiomas, glioma diseases, astrocytomas, medulloblastomas, ependymomas, germ cell tumors, glioblastoma glioblastomas, glioblastoma multiforme, hemangiomas, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meningioma, glioma, and sarcoma.

More preferably, the cancer or tumor is selected from breast cancer, pancreatic cancer, skin cancer, bladder cancer, liver cancer or head and neck cancer.

The invention also relates to the compounds of formula (I), stereoisomers or pharmaceutically acceptable salts thereof, for use as PRMT5 inhibitor medicaments.

The invention also relates to the use of the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prophylaxis of PRMT5 mediated diseases.

Detailed Description

The inventor of the application researches widely and intensively to develop a PRMT5 inhibitor with the structure shown in the following formula (I) for the first time, and the series of compounds can be widely applied to preparing medicines for treating and/or preventing PRMT5 mediated diseases, and are expected to be developed into a new generation of PRMT5 inhibitor. On this basis, the present invention has been completed.

Detailed description: unless stated to the contrary or otherwise specified, the following terms used in the specification and claims have the following meanings.

"alkyl" refers to straight or branched chain saturated aliphatic hydrocarbon groups, preferably straight and branched chain alkyl groups comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl A group, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof, and the like. "C _1-10 Alkyl "refers to straight chain alkyl and branched alkyl groups comprising 1 to 10 carbon atoms," C _1-4 Alkyl "refers to straight chain alkyl groups and branched alkyl groups containing 1 to 4 carbon atoms," C _0-8 Alkyl "refers to straight chain alkyl and branched alkyl groups comprising from 0 to 8 carbon atoms," C _0-4 Alkyl "refers to straight chain alkyl groups and branched alkyl groups comprising from 0 to 4 carbon atoms.

The alkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, =o, =s, -C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2).

"cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has fully conjugated pi electronsThe system, cycloalkyl is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably cycloalkyl comprising 3 to 12 or 3 to 8 or 3 to 6 carbon atoms, e.g. "C _3-12 Cycloalkyl "refers to cycloalkyl groups comprising 3 to 12 carbon atoms," C _4-8 Cycloalkyl "refers to cycloalkyl groups comprising 4 to 8 carbon atoms," C _3-8 Cycloalkyl "refers to cycloalkyl groups comprising 3 to 8 carbon atoms," C _3-6 Cycloalkyl "refers to cycloalkyl groups comprising 3 to 6 carbon atoms, wherein:

monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.

Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "spirocycloalkyl" refers to a polycyclic group having one carbon atom (referred to as the spiro atom) shared between the monocyclic rings, which may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a fully conjugated pi-electron system. Spirocycloalkyl groups are classified as single-, double-, or multiple-spirocycloalkyl groups according to the number of common spiro atoms between rings, and include, but are not limited to:

"fused ring alkyl" refers to an all-carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system. The number of constituent rings can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused ring alkyl groups including, but not limited to:

"bridged cycloalkyl" refers to an all-carbon polycyclic group wherein any two rings share two carbon atoms that are not directly attached, and which may contain one or more (preferably 1, 2, or 3) double bonds, but no ring has a fully conjugated pi-electron system. Bridged cycloalkyl groups, which may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic depending on the number of constituent rings, include, but are not limited to:

the cycloalkyl ring may be fused to an aryl, heteroaryl, or heterocycloalkyl ring, wherein the ring attached to the parent structure is cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.

"cycloalkyl" or "carbocycle" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, =o, =s, -C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2).

"heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bondsNone of the rings has a fully conjugated pi-electron system, and one or more (preferably 1, 2, 3 or 4) ring atoms in the heterocyclic group are selected from N, O, N. O or S (O) _r (wherein r is a heteroatom of integers 0, 1, 2), but excluding the ring moieties of-O-O-, -O-S-, or-S-S-, the remaining ring atoms being carbon. Preferred is a heterocyclic group including 3 to 12 or 3 to 8 or 3 to 6 ring atoms, for example, "3-6 membered heterocyclic group" means a heterocyclic group including 3 to 6 ring atoms, "3-8 membered heterocyclic group" means a heterocyclic group including 3 to 8 ring atoms, "4-8 membered heterocyclic group" means a heterocyclic group including 4 to 8 ring atoms, "4-10 membered heterocyclic group" means a heterocyclic group including 4 to 10 ring atoms, "5-8 membered heterocyclic group" means a heterocyclic group including 5 to 8 ring atoms, "3-12 membered heterocyclic group" means a heterocyclic group including 3 to 12 ring atoms.

Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.

Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups. "spiroheterocyclyl" refers to a polycyclic heterocyclic group having a single ring sharing one atom (referred to as the spiro atom) between which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N. O or S (O) _r (wherein r is a heteroatom of integers 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but none of the rings has a fully conjugated pi-electron system. The spiroheterocyclyl groups are classified as single spiroheterocyclyl groups, double spiroheterocyclyl groups or multiple spiroheterocyclyl groups according to the number of common spiro atoms between rings. Spiroheterocyclyl groups include, but are not limited to:

"fused heterocyclyl" means a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more (preferably 1, 2, 3 or 4) of which may contain one or more (preferably 1, 2 or 3) double bonds, but none of which has a fully conjugated pi-electron system, in which one or more(preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N.O or S (O) _r (wherein r is a heteroatom of integers 0, 1, 2) and the remaining ring atoms are carbon. Depending on the number of constituent rings, they may be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclylalkyl groups, including but not limited to:

"bridged heterocyclyl" means a polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more (preferably 1, 2 or 3) double bonds, but none of which has a fully conjugated pi-electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N. O or S (O) _r (wherein r is a heteroatom of integers 0, 1, 2) and the remaining ring atoms are carbon. Depending on the number of constituent rings, bridged heterocyclyl groups that may be classified as bicyclic, tricyclic, tetracyclic, or polycyclic include, but are not limited to:

the heterocyclyl ring may be fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring attached to the parent structure is heterocyclyl, including but not limited to:

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"heterocyclyl" or "heterocycle" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, =o, =s,-C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Substituted by a substituent of (c).

"aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group, a polycyclic (i.e., ring bearing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably an all-carbon aryl group containing 6 to 10 or 6 to 8 carbons, e.g., "C _6-10 Aryl "refers to all-carbon aryl groups containing 6 to 10 carbons including, but not limited to, phenyl and naphthyl," C _6-8 Aryl "refers to an all-carbon aryl group containing 6-8 carbons. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, including but not limited to:

"aryl" or "aromatic ring" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, =o, =s, -C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2).

"heteroaryl" or "heteroaryl ring" refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including N, O, N-O and S (O) r (where r is an integer of 0, 1, 2) heteroatoms, preferably a heteroaromatic system containing 5 to 10 or 5 to 8 or 5 to 6 ring atoms, e.g., "5 to 8 membered heteroaryl" refers to a heteroaromatic system containing 5 to 8 ring atoms, and "5 to 10 membered heteroaryl" refers to a heteroaromatic system containing 5 to 10 ring atoms, including but not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, including but not limited to:

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"heteroaryl" or "heteroaryl ring" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, =o,＝S、-C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2).

"alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched alkenyl group containing 2 to 10 or 2 to 4 carbons, e.g., "C _2-10 Alkenyl "refers to straight or branched alkenyl groups containing 2 to 10 carbons," C _2-4 Alkenyl "refers to straight or branched alkenyl groups containing 2 to 4 carbons. Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like.

"alkenyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, =o, =s, -C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2).

"alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight or branched alkynyl group containing 2 to 10 or 2 to 4 carbons, e.g., "C _2-10 Alkynyl "refers to straight or branched chain alkynyl groups containing 2 to 10 carbons," C _2-4 Alkynyl "refers to straight or branched chain alkynyl groups containing 2 to 4 carbons. Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2-or 3-butynyl, and the like.

"alkoxy" refers to an-O-alkyl group, where alkyl is as defined above, e.g., "C _1-10 Alkoxy "refers to an alkyl oxy group containing 1 to 10 carbonsBase, "C _1-4 Alkoxy "refers to an alkyloxy group containing 1 to 4 carbons," C _1-2 Alkoxy "refers to an alkyl oxy group containing 1-2 carbons including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.

"alkoxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, =o, =s, -C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2).

"Cycloalkoxy" or "cycloalkyloxy" means-O-cycloalkyl, wherein cycloalkyl is as defined above, e.g., "C _3-12 Cycloalkoxy "refers to a cycloalkyloxy group of 3 to 12 carbons," C _3-6 Cycloalkoxy "refers to a cycloalkyloxy group having 3-6 carbons including, but not limited to, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.

"Cycloalkoxy" or "cycloalkyloxy" groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, =o, =s, -C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2).

"Heterocyclyloxy" or "heterocyclyloxy" refers to an-O-heterocyclyl group wherein heterocyclyl is defined as above, including but not limited to azetidinyloxy, oxetyloxy, azetidinyloxy, nitrogen, oxetyloxy, and the like.

"Heterocyclyloxy" or "heterocyclyloxy" may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1, 2, 3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, =o, =s, -C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2).

“C _1-10 Alkanoyl "means C _1-10 The monovalent radicals remaining after removal of the hydroxyl groups from the alkyl acid are also generally denoted as "C _0-9 alkyl-C (O) - ", e.g.," C ₁ alkyl-C (O) - "refers to acetyl; "C ₂ alkyl-C (O) - "refers to propionyl; "C ₃ alkyl-C (O) - "refers to butyryl or isobutyryl.

“-C _0-8 alkyl-O-S (O) ₂ R ₁₀ "means-O-S (O) ₂ R ₁₀ Wherein the oxygen atom is attached to C _0-8 On alkyl groups, where C _0-8 The definition of alkyl is as described above.

“-C _0-8 alkyl-S (O) _r R ₁₀ "finger-S (O) _r R ₁₀ Wherein the sulfur atom is attached to C _0-8 On alkyl groups, where C _0-8 The definition of alkyl is as described above.

“-C _0-8 alkyl-O-R ₁₁ "means-O-R ₁₁ Wherein the oxygen atom is attached to C _0-8 On alkyl groups, where C _0-8 The definition of alkyl is as described above.

“-C _0-8 alkyl-C (O) OR ₁₁ "means-C (O) OR ₁₁ Wherein the carbonyl group is attached to C _0-8 On alkyl groups, where C _0-8 The definition of alkyl is as described above.

“-C _0-8 alkyl-C (O) SR ₁₁ "means-C (O) SR ₁₁ Wherein the carbonyl group is attached to C _0-8 On alkyl groups, where C _0-8 The definition of alkyl is as described above.

“-C _0-8 alkyl-S-C (O) R ₁₂ "means-S-C (O) R ₁₂ Wherein the sulfur atom is attached to C _0-8 On alkyl groups, where C _0-8 The definition of alkyl is as described above.

“-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ "means-P (O) (R ₁₂ ) ₂ Wherein the phosphorus atom is attached to C _0-8 On alkyl groups, where C _0-8 The definition of alkyl is as described above.

“-C _0-8 alkyl-C (O) R ₁₂ "means-C (O) R ₁₂ Wherein the carbonyl group is attached to C _0-8 On alkyl groups, where C _0-8 The definition of alkyl is as described above.

“-C _0-8 alkyl-O-C (O) R ₁₂ "means-O-C (O) R ₁₂ Wherein the oxygen atom is attached to C _0-8 On alkyl groups, where C _0-8 The definition of alkyl is as described above.

“-C _0-8 alkyl-NR ₁₃ R ₁₄ "refer to-NR ₁₃ R ₁₄ Wherein nitrogen atoms are attached to C _0-8 On alkyl groups, where C _0-8 The definition of alkyl is as described above.

“-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ "means-C (O) NR ₁₃ R ₁₄ Wherein the carbonyl group is attached to C _0-8 On alkyl groups, where C _0-8 The definition of alkyl is as described above.

“-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ "means-N (R) ₁₃ )-C(O)R ₁₂ Wherein nitrogen atoms are attached to C _0-8 On alkyl groups, where C _0-8 The definition of alkyl is as described above.

"halogen substituted C _1-10 Alkyl "refers to 1-10 carbon alkyl groups optionally substituted with fluorine, chlorine, bromine, iodine atoms for hydrogen on the alkyl group, including, but not limited to, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

"halogen substituted C _1-10 Alkoxy "refers to a 1-10 carbon alkoxy group wherein the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.

"deuterium substituted C _1-10 Alkyl "refers to 1-10 carbon alkyl groups where the hydrogen on the alkyl is optionally substituted with deuterium atoms. Including but not limited to mono-, di-, tri-deuteromethyl, and the like.

"halogen" refers to fluorine, chlorine, bromine or iodine, "EA" refers to ethanol, "PE" refers to petroleum ether, "EtOAc" refers to ethyl acetate, "MeOH" refers to alcohol, "DCM" refers to dichloromethane, "DMSO" refers to dimethyl sulfoxide.

"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs or does not, i.e., instances where it is substituted or unsubstituted. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

"substituted" means that one or more "hydrogen atoms" in the group are substituted independently of each other with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, in line with the theory of chemical valence, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated bonds (e.g., olefins).

"stereoisomers", which are named stereisomer, refer to isomers produced by the different spatial arrangements of atoms in the molecule, and can be classified into cis-trans isomers, enantiomers, and enantiomers. Stereoisomers due to rotation of a single bond are known as conformational isomers (conformational stereo-isomers), sometimes also known as rotamers. Stereoisomers due to bond length, bond angle, double bonds in the molecule, rings, etc. are called configurational isomers (configuration stereo-isomers), which are classified into two types. Wherein isomers due to the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely become geometric isomers (also known as cis-trans isomers), fall into the Z, E configuration. For example: cis-2-butene and trans-2-butene are a pair of geometric isomers, and stereoisomers with different optical properties due to the lack of trans-axisymmetry in the molecule are called optical isomers (optical isomers) and are classified into R, S configurations. "stereoisomers" as used herein, unless otherwise indicated, are understood to include one or more of the enantiomers, configurational isomers and conformational isomers described above.

By "pharmaceutically acceptable salts" is meant in the present invention pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts, which salts may be prepared by methods known in the art.

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

The present invention will be described in more detail with reference to examples, but the present invention is not limited to the examples.

The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was performed using a Bruker AVANCE-400/500 nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated methanol (CD) ₃ OD) and deuterated chloroform (CDCl) ₃ ) The internal standard is Tetramethylsilane (TMS).

The LC-MS measurement was performed by using an Agilent 6120 mass spectrometer. HPLC was performed using Agilent 1200DAD high pressure liquid chromatography (Sunfire C18X 4.6mm column) and Waters 2695-2996 high pressure liquid chromatography (Gimini C18X 4.6mm column).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification adopted by TLC is 0.15 mm-0.20 mm, and the specification adopted by the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. Column chromatography generally uses tobacco stand yellow sea silica gel 200-300 mesh silica gel as a carrier.

The starting materials in the examples of the present invention are known and commercially available or may be synthesized using or according to methods known in the art.

All reactions of the invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being dry solvent and the reaction temperature being in degrees celsius (°c) without specific description.

Preparation of intermediate 1: preparation of 4-amino-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxylic acid

The first step: synthesis of methyl 4- ((tert-butoxycarbonyl) amino) -3- (4-cyano-1-methyl-1H-pyrazol-5-yl) benzoate

5-bromo-1-methyl-1H-pyrazole-4-carbonitrile (2.5 g,13.4 mmol) and methyl 4- ((tert-butoxycarbonyl) amino) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (5.0 g,13.4 mmol) were dissolved in dioxane (60 mL) and water (20 mL), sodium carbonate (4.26 g,40.2 mmol) and tetrakis triphenylphosphine palladium (155 mg,0.134 mmol) were added in portions, nitrogen displaced three times and stirred overnight at 80 ℃. After the completion of the reaction, it was diluted with water and extracted three times with ethyl acetate, and the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product (4.8 g) which was used directly in the next step. MS m/z (ESI): 357[ M+H ] ] ⁺ 。

And a second step of: synthesis of methyl 4-amino-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxylate

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Methyl 4- ((tert-Butoxycarbonyl) amino) -3- (4-cyano-1-methyl-1H-pyrazol-5-yl) benzoate (4.8 g,13.4 mmol) was dissolved in tetrahydrochyseneTo furan (10 mL) and 4N hydrogen chloride dioxane solution (10 mL) was added, stirred overnight at room temperature under nitrogen, filtered, the filter cake washed several times with N-pentane and the solid dried to give crude product (3.2 g) which was used directly in the next step. MS m/z (ESI): 257[ M+H ]] ⁺ 。

And a third step of: synthesis of 4-amino-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxylic acid

Methyl 4-amino-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxylate (3.2 g,13.4 mmol) was dissolved in methanol (30 mL), tetrahydrofuran (30 mL) and water (20 mL), lithium hydroxide monohydrate (1.69 g,40.2 mmol) was added and stirred overnight at room temperature. After the reaction, most of the organic solvent was concentrated and removed, the pH was adjusted to about 6 with dilute hydrochloric acid, filtered, washed several times with a large amount of clean water, and dried to give the product (2.4 g, three-step total yield: 74%). MS m/z (ESI): 243[ M+H ] +. Intermediate 2: preparation of 4-amino-1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxylic acid

The first step: synthesis of 4-oxo-tetrahydrofuran-3-carbonitrile

Potassium tert-butoxide (31.1 g, 274 mmol) was dissolved in 2-methyltetrahydrofuran (500 mL), and methyl glycolate (21.4 mL, 274 mmol) was added dropwise thereto with stirring at 0℃for 30 minutes, and after stirring, prop-2-enenitrile (18.4 mL, 274 mmol) was added dropwise thereto, and the temperature was returned to room temperature, and the stirring was continued for 3 hours, whereby the reaction was completed. 200mL of methyl tert-butyl ether was added to the solution, followed by stirring for 30 minutes, 500mL of water was added, extraction was performed 3 times with 500mL of ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered and spin-dried to give 4-oxo-tetrahydrofuran-3-carbonitrile (14.0 g, yield: 45%), and the crude product was used in the next reaction without purification.

And a second step of: synthesis of 4-cyano-2, 5-dihydrofuran-3-yl triflic acid

4-oxo-tetrahydrofuran-3-carbonitrile (17.7 g,159 mmol) was dissolved in methylene chloride (180 mL), diisopropylethylamine was added to the solution, and after cooling the mixture to-65℃trifluoromethanesulfonic anhydride (37.0 mL,223 mmol) was added dropwise thereto, and after completion of the reaction under stirring for 1 hour, the reaction was allowed to return to room temperature, quenched with clear water, extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered to give a crude product which was separated by silica gel column chromatography [0 to 30% ethyl acetate-petroleum ether system ] to give 4-cyano-2, 5-dihydrofuran-3-yl trifluoromethanesulfonic acid (17 g, yield: 44%).

And a third step of: synthesis of methyl 4-amino-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate

Methyl 4-amino-3-bromobenzoate (10 g,43.5 mmol), pinacol biborate (16.3 g,65.2 mmol), a [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex (1.77 g,2.17 mmol) and potassium acetate (8.53 g,86.9 mmol) were added to dimethylformamide (100 mL), and the mixture was reacted at 100℃under nitrogen for 3.5 hours. The reaction mixture was diluted with 800mL of ethyl acetate and 800mL of saturated brine, and after separation, the organic phase was dried over 600mL of saturated brine and dried over anhydrous sodium sulfate, and then dried by spin-drying to obtain a crude product. The crude product was charged with 100mL of methyl t-butyl ether, stirred for 1 hour, filtered, and the solid was drained to give methyl 4-amino-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate as a purple solid (5.50 g, yield: 45.7%).

Fourth step: synthesis of methyl 4-amino-1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxylate

Methyl 4-cyano-2, 5-dihydrofuran-3-yl trifluoromethanesulfonic acid (3.37 g,13.9 mmol), 4-amino-3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (3.20 g,11.5 mmol), was dissolved in a mixed solution of 1, 4-dioxane (128 mL) and water (10.0 mL), and potassium phosphate (7.35 g,34.65 mmol), [1,1' -bis (diphenylphosphine) ferrocene ] palladium dichloride dichloromethane complex (0.940 g,1.16 mmol) was added to the solution. The reaction was carried out at 100℃for 18 hours under nitrogen. The reaction mixture was diluted with 800mL of ethyl acetate and 800mL of saturated brine, and after separation, the organic phase was dried over 600mL of saturated brine and dried over anhydrous sodium sulfate, and then dried by spin-drying to obtain a crude product. The crude product was taken in 50mL of water and 100mL of methyl tert-butyl ether, stirred for 30 minutes, filtered, and the solid was drained to give methyl 4-amino-1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxylate (4.62 g, yield: 56.5%) as a black solid.

Fifth step: synthesis of 4-amino-1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxylic acid

Methyl 4-amino-1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxylate (4.11 g,16.8 mmol) was added to a mixed solution of methanol (20.0 mL), tetrahydrofuran (20.0 mL) and water (20.0 mL), lithium hydroxide hydrate (3.53 g,84.1 mmol) was added to the solution, and the mixture was stirred at 75℃for 2 hours. After the completion of the reaction, methanol and tetrahydrofuran were removed by rotary evaporation, and the remaining liquid was filtered, and the aqueous phase was separated by washing with ethyl acetate (100 mL) and water (100 mL), and the product was precipitated by adjusting the aqueous phase ph=7 with hydrochloric acid after washing with 300mL of ethyl acetate, and insoluble matter was collected by filtration to give 4-amino-1, 3-dihydrofuro [3,4-c ] quinoline-8-carboxylic acid (2.95 g, yield: 75.5%) as a brown solid.

Intermediate 3: preparation of N- ((5- (3, 3-difluoropyrrolidin-1-yl) pyridin-2-yl) methyl) -1- (pyrimidin-2-yl) ethane-1-amine

The first step: synthesis of 5- (3, 3-difluoropyrrolidin-1-yl) cyanopyridine

5-Fluorocyanopyridine (2.10 g,17.20 mmol) was dissolved in acetonitrile (50 mL), followed by addition of potassium carbonate (7.12 g,51.60 mmol), 3-difluoropyrrolidine (2.21 g,20.64 mmol), heating to 80℃under nitrogen protection, stirring overnight, completion of the reaction, quenching with clear water, extraction with ethyl acetate, drying the organic phase with anhydrous sodium sulfate and filtration to give crude product, which was purified by silica gel column chromatography [50% ethyl acetate-petroleum ether system ] ]5- (3, 3-difluoropyrrolidin-1-yl) cyanopyridine was isolated (3.30 g, yield: 80%). MS m/z (ESI) 210[ M+H ]] ⁺ 。

And a second step of: synthesis of (5- (3, 3-difluoropyrrolidin-1-yl) pyridin-2-yl) methylamine

Dissolving 5- (3, 3-difluoropyrrolidin-1-yl) cyanopyridine (1.00 g) in ethanol (20 mL), adding concentrated ammonia (1.00 mL) and Raney Ni (1.00 g), stirring overnight at room temperature under hydrogen atmosphere, filtering after the reaction, concentrating to obtain crude product, separating by silica gel column chromatography [10% methanol-dichloromethane system ]](5- (3, 3-difluoropyrrolidin-1-yl) pyridin-2-yl) methylamine was obtained (0.65 g, yield: 64%). MS m/z (ESI) 214[ M+H ]] ⁺ 。

And a third step of: synthesis of N- ((5- (3, 3-difluoropyrrolidin-1-yl) pyridin-2-yl) methyl) -1- (pyrimidin-2-yl) ethane-1-amine

(5- (3, 3-difluoropyrrolidin-1-yl) pyridin-2-yl) methylamine (650 mg,3.05 mmol) and 1- (azoxystrobin)Pyridin-2-yl) ethan-1-one (372 mg,3.05 mmol) was dissolved in dichloromethane (10 mL), sodium triacetoxyborohydride (970 mg,4.58 mmol) was added, 2 drops of acetic acid were added, stirred overnight at room temperature, after completion of the reaction, saturated aqueous sodium bicarbonate solution was quenched, dichloromethane extracted, the organic phase was dried over anhydrous sodium sulfate and filtered, and the crude product was separated by silica gel column chromatography [10% methanol-dichloromethane system ]N- ((5- (3, 3-difluoropyrrolidin-1-yl) pyridin-2-yl) methyl) -1- (pyrimidin-2-yl) ethane-1-amine (600 mg, yield: 67%) was obtained. MS m/z (ESI) 320[ M+H ]] ⁺ 。

Preparation of intermediate 4-5 the corresponding starting materials were selected for preparation with reference to the overall or partial synthesis of intermediate 3:

1. preparation of examples

Example 1: preparation of 4-amino-N- ((5- (3, 3-difluoropyrrolidin-1-yl) pyridin-2-yl) methyl) -1-methyl-N- (1- (pyrimidin-2-yl) ethyl) -1H-pyrazolo [4,3-c ] quinoline-8-carboxamide

N- ((5- (3, 3-difluoropyrrolidin-1-yl) pyridin-2-yl) methyl) -1- (pyrimidin-2-yl) ethan-1-amine (100 mg,0.31 mmol) and 4-amino-1-methyl-1H-pyrazolo [4, 3-c)]Quinoline-8-carboxylic acid (76 mg,0.31 mmol) was placed in DMA (5 mL), tripyrrolidinylphosphonium bromide hexafluorophosphate (173 mg,0.37 mmol), triethylamine (94 mg,0.93 mmol) were added sequentially, stirred overnight at room temperature, after the reaction was completed, clear water and ethyl acetate were added, the liquid was separated after filtration, the aqueous phase was extracted with ethyl acetate, the combined organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate and the crude product was filtered off by silica gel column chromatography [10% methanol-dichloromethane system ]]Then the mixture is separated by reversed phase (acetonitrile-10 mM ammonium bicarbonate system) to obtain 4-amino-N- ((5- (3, 3-difluoro-pyrrolidin-1-yl) pyridine-2-yl) methyl) -1-methyl-N- (1- (pyrimidine-2-yl) ethyl) -1H-pyrazolo [4, 3-c) ]Quinoline-8-carboxamide(45 mg, yield: 27%). MS m/z (ESI): 544[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.81(d,J＝4.9Hz,2H),8.45(s,1H),8.23(s,1H),7.88(s,1H),7.61(s,2H),7.41(t,J＝4.8Hz,1H),7.22(d,J＝8.6Hz,1H),7.11(s,2H),6.96(dd,J＝8.7,2.9Hz,1H),5.49(s,1H),4.79(d,J＝16.3Hz,1H),4.41-4.10(m,4H),3.71(t,J＝13.3Hz,2H),3.49(t,J＝7.3Hz,2H),2.59-2.54(m,2H),1.54(d,J＝7.1Hz,3H).

Examples 2 to 59 can be prepared by selecting the corresponding starting materials with reference to the whole or part of the synthesis method of example 1:

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the nuclear magnetic data of the compounds prepared in the above examples are as follows:

biological test evaluation

1. Human colon cancer HCT116 cell proliferation inhibition test

1. HCT116 MTAP knockout and MTAP wild type cells were plated in 96 well flat bottom plates and cultured with McCoy's 5A containing 10% fetal bovine serum+1% penicillin-streptomycin based on 5% CO at 37℃ ₂ Culturing under the conditionAnd (5) at night.

2. The next day, compounds were dissolved in DMSO, diluted in DMSO and medium sequentially and transferred to cell plates at a final concentration of 10 μm, 4-fold dilution, 9 concentration gradients plus DMSO control.

3. Cells untreated with the compound were removed, cell activity was detected with CellTiter-Glo Luminescent Cell Viability Assay (Promega), the procedure was as described with reference to the kit instructions, and the cell plates were then placed on EnVision Multilabel Reader to detect luminescence signals.

4. At the same time, the cell plates treated with the added compound were placed at 37℃and 5% CO ₂ The culture was continued for 6 days under the conditions.

5. Then, cell activity was also examined with CellTiter-Glo.

6. Finally, a four-parameter dose response curve module using GraphPad Prism v 9.2.0 software was used to draw the dose response curve and calculate proliferation inhibition IC ₅₀ (Unit: nM).

From the biological activity data of the compounds of the specific examples, the compounds of the invention have strong inhibition effect on the proliferation of human colon cancer HCT116 MTAP knockout cells at the cellular level, weak inhibition effect on MTAP wild type HCT116 cells and high selectivity.

All documents mentioned in this application are incorporated by reference as if each were individually incorporated by reference. Further, it will be understood that various changes and modifications may be made by those skilled in the art after reading the foregoing disclosure of the invention, and such equivalents are intended to fall within the scope of the claims appended hereto.

Claims

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

wherein X is CR _a Or N; y is CR _b Or N;

ring A is C ₅ Cycloalkyl, 5 membered heterocyclyl or 5 membered heteroaryl;

R ₁ 、R ₂ and R is ₃ Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, -C _0-8 alkyl-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Alternatively, R ₁ 、R ₂ And R is ₃ Any two of which together with the carbon atoms to which they are directly attached form a C _3-6 Cycloalkyl, 4-10 membered heterocyclyl, C _6-10 Aryl or 5-to 10-membered heteroaryl, said groups being independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-10 membered heteroaryl, =o, =s, -C _0-8 Alkyl group-SF ₅ 、-C _0-8 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-8 alkyl-S (O) _r R ₁₀ 、-C _0-8 alkyl-O-R ₁₁ 、-C _0-8 alkyl-C (O) OR ₁₁ 、-C _0-8 alkyl-C (O) SR ₁₁ 、-C _0-8 alkyl-S-C (O) R ₁₂ 、-C _0-8 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-8 alkyl-C (O) R ₁₂ 、-C _0-8 alkyl-O-C (O) R ₁₂ 、-C _0-8 alkyl-NR ₁₃ R ₁₄ 、-C _0-8 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-8 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

R ₆ and R is ₇ Each independently selected from hydrogen, deuterium, hydroxy, C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _3-12 Cycloalkyl and 3-12 membered heterocyclyl, alternatively, R ₆ And R is ₇ Together with the nitrogen atom to which it is directly attached, form a 4-10 membered heterocyclic group or a 5-10 membered heteroaryl group, which groups are independently optionally further substituted with one or more substituentsOne or more groups selected from deuterium, halogen, cyano, hydroxy, = O, C _1-10 Alkyl, halogen substituted C _1-10 Alkyl, deuterium substituted C _1-10 Alkyl, C _2-10 Alkenyl, C _2-10 Alkynyl, C _1-10 Alkoxy, C _3-12 Cycloalkyl, C _3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

each R ₁₀ Independently selected from hydrogen, deuterium, hydroxy, C _1-10 Alkyl, C _2-10 Alkenyl, C _3-12 Cycloalkyl, 3-12 membered heterocyclyl, C _6-10 Aryl, 5-to 10-membered heteroaryl and-NR ₁₃ R ₁₄ The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, = O, C _1-10 Alkyl, C _1-10 Alkoxy, C _3-12 Cycloalkyl, C _3-12 Cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C _6-10 Aryl, C _6-10 Aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

each r is independently 0, 1 or 2;

m is selected from 0, 1, 2, 3 or 4; and is also provided with

n is selected from 1, 2, 3 or 4.

2. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein R _8a And R is _8b Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, hydroxy and-NR ₁₃ R ₁₄ Alternatively, R _8a And R is _8b Together with the carbon atom to which it is directly attached form a C _3-4 Cycloalkyl or 4-6 membered heterocyclyl; wherein R is ₁₃ 、R ₁₄ The method of claim 1;

preferably, R _8a And R is _8b Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl and C _3-6 Cycloalkoxy, or R _8a And R is _8b Together with the carbon atom to which it is directly attached, forms a cyclopropyl group.

3. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₆ And R is ₇ Each independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl and 3-6 membered heterocyclyl, alternatively, R ₆ And R is ₇ Together with the nitrogen atom to which it is directly attached, form a 4-8 membered heterocyclyl or 5-8 membered heteroaryl group, which groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, hydroxy, = O, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

wherein R is ₁₃ 、R ₁₄ The method of claim 1.

4. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₄ Selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl group,3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅ 、-C _0-4 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-4 alkyl-S (O) _r R ₁₀ 、-C _0-4 alkyl-O-R ₁₁ 、-C _0-4 alkyl-C (O) OR ₁₁ 、-C _0-4 alkyl-C (O) SR ₁₁ 、-C _0-4 alkyl-S-C (O) R ₁₂ 、-C _0-4 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-4 alkyl-C (O) R ₁₂ 、-C _0-4 alkyl-O-C (O) R ₁₂ 、-C _0-4 alkyl-NR ₁₃ R ₁₄ 、-C _0-4 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-4 alkyl-N (R) ₁₃ )-C(O)R ₁₂ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ₁₀ 、R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ And r is as defined in claim 1;

preferably, R ₄ Selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, C _3-6 Hetero-epoxy, C _6-8 Aryl, C _6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, hydroxy and-NR ₁₃ R ₁₄ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ₁₃ And R is ₁₄ The method of claim 1;

more preferably, R ₄ Selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl and C _3-6 A cycloalkoxy group.

5. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 wherein each R _a And R is _b Each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl group,Deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅ 、-C _0-4 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-4 alkyl-S (O) _r R ₁₀ 、-C _0-4 alkyl-O-R ₁₁ 、-C _0-4 alkyl-C (O) OR ₁₁ 、-C _0-4 alkyl-C (O) SR ₁₁ 、-C _0-4 alkyl-S-C (O) R ₁₂ 、-C _0-4 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-4 alkyl-C (O) R ₁₂ 、-C _0-4 alkyl-O-C (O) R ₁₂ 、-C _0-4 alkyl-NR ₁₃ R ₁₄ 、-C _0-4 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-4 alkyl-N (R) ₁₃ )-C(O)R ₁₂ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ₁₀ 、R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ And r is as defined in claim 1;

preferably, each R _a And R is _b Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, hydroxy substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, C _3-6 Hetero-epoxy, C _6-8 Aryl, C _6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, hydroxy and-NR ₁₃ R ₁₄ The method comprises the steps of carrying out a first treatment on the surface of the Wherein R is ₁₃ And R is ₁₄ The method of claim 1;

more preferably, each R _a And R is _b Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl and C _3-6 A cycloalkoxy group.

6. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable thereof as claimed in claim 1 A salt characterized in that R ₁ 、R ₂ And R is ₃ Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅ 、-C _0-4 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-4 alkyl-S (O) _r R ₁₀ 、-C _0-4 alkyl-O-R ₁₁ 、-C _0-4 alkyl-C (O) OR ₁₁ 、-C _0-4 alkyl-C (O) SR ₁₁ 、-C _0-4 alkyl-S-C (O) R ₁₂ 、-C _0-4 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-4 alkyl-C (O) R ₁₂ 、-C _0-4 alkyl-O-C (O) R ₁₂ 、-C _0-4 alkyl-NR ₁₃ R ₁₄ 、-C _0-4 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-4 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Alternatively, R ₁ 、R ₂ And R is ₃ Any two of which together with the carbon atoms to which they are directly attached form a C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-8 Aryl or 5-8 membered heteroaryl, said groups being independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -C _0-4 alkyl-SF ₅ 、-C _0-4 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-4 alkyl-S (O) _r R ₁₀ 、-C _0-4 alkyl-O-R ₁₁ 、-C _0-4 alkyl-C (O) OR ₁₁ 、-C _0-4 alkyl-C (O) SR ₁₁ 、-C _0-4 alkyl-S-C (O) R ₁₂ 、-C _0-4 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-4 alkyl-C (O) R ₁₂ 、-C _0-4 alkyl-O-C (O) R ₁₂ 、-C _0-4 alkyl-NR ₁₃ R ₁₄ 、-C _0-4 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-4 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

wherein R is ₁₀ 、R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ And r is as defined in claim 1.

7. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 wherein ring B is C _6-8 Aryl or 5-8 membered heteroaryl, said C _6-8 Aryl or 5-8 membered heteroaryl optionally condensed to C _3-6 Cycloalkyl or 4-6 membered heterocyclyl;

each R ₉ Each independently selected from-SF ₅ Trifluoromethyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, C _3-6 Cycloalkyl-substituted C _1-4 Alkoxy, C _3-6 Cycloalkoxy, 3-6 membered hetero-epoxy, C _6-8 Aryloxy, 5-8 membered heteroaryloxy and-NR ₁₃ R ₁₄ C above _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, C _3-6 Cycloalkoxy and-NR ₁₃ R ₁₄ Each independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -C _0-4 alkyl-SF ₅ 、-C _0-4 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-4 alkyl-S (O) _r R ₁₀ 、-C _0-4 alkyl-O-R ₁₁ 、-C _0-4 alkyl-C (O) OR ₁₁ 、-C _0-4 alkyl-C (O) SR ₁₁ 、-C _0-4 alkyl-S-C (O) R ₁₂ 、-C _0-4 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-4 alkyl-C (O) R ₁₂ 、-C _0-4 alkyl-O-C (O) R ₁₂ 、-C _0-4 alkyl-NR ₁₃ R ₁₄ 、-C _0-4 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-4 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

wherein R is ₁₀ 、R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ And r is as defined in claim 1;

preferably, ring B is furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl;

each R ₉ Each independently selected from C _3-6 Cycloalkyl-substituted C _1-4 Alkoxy, C _3-6 Cycloalkoxy, 3-6 membered hetero-epoxy, C _6-8 Aryloxy, 5-8 membered heteroaryloxy and-NR ₁₃ R ₁₄ The above groups are each independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

8. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 wherein each R ₅ Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, -C _0-4 alkyl-SF ₅ 、-C _0-4 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-4 alkyl-S (O) _r R ₁₀ 、-C _0-4 alkyl-O-R ₁₁ 、-C _0-4 alkyl-C (O) OR ₁₁ 、-C _0-4 alkyl-C (O) SR ₁₁ 、-C _0-4 alkyl-S-C (O) R ₁₂ 、-C _0-4 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-4 alkyl-C (O) R ₁₂ 、-C _0-4 alkyl-O-C (O) R ₁₂ 、-C _0-4 alkyl-NR ₁₃ R ₁₄ 、-C _0-4 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-4 alkyl-N (R) ₁₃ )-C(O)R ₁₂ The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -C _0-4 alkyl-SF ₅ 、-C _0-4 alkyl-O-S (O) ₂ R ₁₀ 、-C _0-4 alkyl-S (O) _r R ₁₀ 、-C _0-4 alkyl-O-R ₁₁ 、-C _0-4 alkyl-C (O) OR ₁₁ 、-C _0-4 alkyl-C (O) SR ₁₁ 、-C _0-4 alkyl-S-C (O) R ₁₂ 、-C _0-4 alkyl-P (O) (R) ₁₂ ) ₂ 、-C _0-4 alkyl-C (O) R ₁₂ 、-C _0-4 alkyl-O-C (O) R ₁₂ 、-C _0-4 alkyl-NR ₁₃ R ₁₄ 、-C _0-4 alkyl-C (O) NR ₁₃ R ₁₄ and-C _0-4 alkyl-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

9. A compound of formula (I), its stereo according to claim 1An isomer or a pharmaceutically acceptable salt thereof, characterized in that each R ₁₀ Independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl, C _2-4 Alkenyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl and-NR ₁₃ R ₁₄ The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, = O, C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C _6-8 Aryl, C _6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

each R ₁₂ Independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl, C _1-4 Alkoxy, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C _6-8 Aryl, C _6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR ₁₃ R ₁₄ The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, =o, cyano, C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C _6-8 Aryl, C _6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

each R ₁₃ And R is ₁₄ Each independently selected from hydrogen, deuterium, hydroxy, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C _1-4 Alkanoyl, said groups being independently optionally further substituted with one or more groups selected from deuterium, halogen, hydroxy, = O, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, halo substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C _6-8 Aryl, C _6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, C _1-4 Alkyl monosubstituted amino, C _1-4 Alkyl disubstituted amino and C _1-4 Substituted by alkanoyl, or R ₁₃ And R is ₁₄ Together with the nitrogen atom to which it is directly attached, form a 4-8 membered heterocyclyl or 5-8 membered heteroaryl, said 4-8 membered heterocyclyl or 5-8 membered heteroaryl optionally being further substituted with one or more groups selected from deuterium, halogen, hydroxy, = O, C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, halo substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroepoxy, C _6-8 Aryl, C _6-8 Aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, C _1-4 Alkyl monosubstituted amino, C _1-4 Alkyl disubstituted amino and C _1-4 The substituent of the alkanoyl group is substituted.

10. The compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) has the structure of a compound of formula (iia):

wherein X is CR _a Or N; y is CR _b Or N; y is Y ₁ CH or N; y is Y ₂ CH or N; z is Z ₁ Is C (R) _c R _d )、C(O)、N(R _e ) Or O; p is p ₁ 0, 1, 2 or 3; p is p ₂ 1, 2 or 3;

ring a, together with the portion to which it is attached, forms the structure:

R ₁ and R is ₂ Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Alternatively, R ₁ And R is ₂ Together with the carbon atom to which it is directly attached form a C _3-6 Cycloalkyl, 4-8 membered heterocyclyl, C _6-8 Aryl or 5-8 membered heteroaryl, said groups being independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium extractionSubstitute C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

each R _5f And R is _5g Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl group,3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Alternatively, R _5f And R is _5g Together with the carbon atom to which it is directly attached form a C _3-6 Cycloalkyl or 4-8 membered heterocyclyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

R _8a selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl group,Halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl and C _3-6 A cycloalkoxy group;

wherein R is ₁₀ 、R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ M and r are as defined in claim 1.

11. The compound of formula (I), stereoisomer or pharmaceutically acceptable salt thereof according to claim 10, wherein the compound of formula (I) has the structure of a compound of formula (iiia):

wherein X is CR _a Or N; y is Y ₂ CH or N; z is Z ₁ Is C (R) _c R _d ) Or O; p is p ₁ 0, 1, 2 or 3; p is p ₂ 1, 2 or 3;

ring a, together with the portion to which it is attached, forms the structure:

R _d selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, and tri Fluoromethyl, tridentate methyl and cyclopropyl;

12. The compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound of formula (I) has the structure of a compound of formula (iib):

wherein X is CR _a Or N; y is CR _b Or N; y is Y ₁ CH or N; y is Y ₂ CH or N;

ring a, together with the portion to which it is attached, forms the structure:

R _f selected from C _3-6 Cycloalkyl-substituted C _1-4 Alkyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl and 5-8 membered heteroaryl, C as described above _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl and 5-8 membered heteroaryl are each independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Is substituted by a substituent of (2);

each R _5a Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o, =s, -SF ₅ 、-O-S(O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-C(O)SR ₁₁ 、-S-C(O)R ₁₂ 、-P(O)(R ₁₂ ) ₂ 、-C(O)R ₁₂ 、-O-C(O)R ₁₂ 、-NR ₁₃ R ₁₄ 、-C(O)NR ₁₃ R ₁₄ and-N (R) ₁₃ )-C(O)R ₁₂ Substituent of (2)Substituted;

13. The compound of formula (I), stereoisomer or pharmaceutically acceptable salt thereof according to claim 12, wherein the compound of formula (I) has the structure of a compound of formula (iiib):

wherein X is CR _a Or N; y is Y ₂ CH or N;

ring a, together with the portion to which it is attached, forms the structure:

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

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15. A process for the preparation of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in claim 1, comprising the steps of:

wherein, ring A, ring B, X, Y, R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R _8a 、R _8b 、R ₉ M and n are as defined in claim 1.

16. A pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14 and a pharmaceutically acceptable carrier.

17. Use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 14 for the manufacture of a medicament for the treatment of a MATP-related cancer or tumour; preferably, the tumor or cancer is selected from endometrial adenocarcinoma, granulosa-follicular cell carcinoma, testicular supporting cell carcinoma, germ cell carcinoma, malignant teratoma, squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma, clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, fallopian tube carcinoma, adenocarcinoma, wilms' cell carcinoma, lymphoma, leukemia, bladder carcinoma, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, prostate carcinoma, seminoma, teratoma, embryo carcinoma, teratoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma; liver cancer, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, gall bladder cancer, ampulla cancer, cholangiocarcinoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, kaposi's sarcoma, nevi, dysplastic nevi, lipoma, hemangioma, acute and chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome, and hodgkin's disease, non-hodgkin's lymphoma, osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, ewing's sarcoma, malignant lymphoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondral tumor, benign chondrioma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumor, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyomas, fibromas, lipomas and teratomas, bronchopulmonary carcinoma, alveolar carcinoma, bronchial adenomas, sarcomas, lymphomas, chondromatoid hamartoma, mesothelioma, squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma, gastric carcinoma, lymphoma, leiomyosarcoma, ductal adenocarcinoma, insulinoma, glucagon, gastrinoma, carcinoid tumors, venomous snake tumors, adenocarcinoma, lymphoma, carcinoid tumors, kaposi's sarcoma, smooth myomas, hemangiomas, lipomas, neurofibromas, fibromas, large intestine adenomas, tubular adenomas, villial adenomas, hamartoma, smooth myomas, craniocerebral adenomas, hemangiomas, granulomas, xanthomas, deforma osteomas, meningiomas, glioma diseases, astrocytomas, medulloblastomas, ependymomas, germ cell tumors, glioblastoma glioblastomas, glioblastoma multiforme, hemangiomas, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor, spinal neurofibroma, meningioma, glioma, and sarcoma.