CN116462677A

CN116462677A - Multi-condensed ring PRMT5 inhibitor and preparation method and application thereof

Info

Publication number: CN116462677A
Application number: CN202310035415.1A
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 process for its preparation, pharmaceutical compositions containing it, its use as a PRMT5 inhibitor and its use in the treatment and/or prophylaxis of PRMT5 mediated disorders. 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, together with the directly attached portion thereof, forms the structure:

wherein X is ₁ Is CR (CR) _5a Or N, X ₂ Is CR (CR) _5a Or N, X ₃ Is CR (CR) _5a Or N, provided that X ₁ And X ₂ At least one of which is N;

X ₄ is CR (CR) _5b Or N; x is X ₅ Is CR (CR) _5b Or N;

each 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 _5a 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 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);

each R _5b 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 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);

each R _5c 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, 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 _5d 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);

each R _5e Each independently selected from 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);

each 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 attachedForming a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, said groups being 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);

ar 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, each of which is independently optionally further substituted with one or more substituents selected from 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 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, -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 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 group, 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 ₈ and R is ₉ 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 ₈ And R is ₉ Together with the carbon atom to which it is directly attached form a C _3-6 Cycloalkyl or 4-10 membered heterocyclyl;

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 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;

provided that each R _5b 、R ₄ 、R _a And R is _b At least one of which is other than hydrogen, or,

when each R _5b 、R ₄ 、R _a And R is _b When the two are all hydrogen,the structure is as follows:

each r is independently 0, 1 or 2.

Preferably, R in the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof ₈ And R is ₉ Each independently 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 _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 ₈ And R is ₉ 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 And R is 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 ₈ And R is ₉ 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 ₈ And R is ₉ Together with the carbon atom to which it is directly attached, forms a cyclopropyl group.

Preferably, each R in the compound of formula (I), a stereoisomer thereof 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 And R is ₁₄ As described for the compounds of formula (I).

As a preferred embodiment, the compounds of formula (I)In the compound, stereoisomer or pharmaceutically acceptable salt thereof, each R ₄ 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 _0-8 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 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, 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 、R ₁₄ 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, each R ₄ Each independently selected fromHydrogen, 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 _0-8 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, 5-8Meta-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 、R ₁₄ 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, 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 radicals3-6 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, ar is C in the compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt thereof _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 of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, 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 Substituted by 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, -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).

As a further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ar is furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl, which are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, 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 Substituted by 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, -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); wherein R is ₁₀ 、R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ And r is as described for the compounds of formula (I).

Preferably, each R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof _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, -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);

each R _5b 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 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);

each R _5c 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, 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);

each R _5d Each independently selected from hydrogen, deuteriumHalogen, cyano, 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);

each R _5e Each independently selected from deuterium, halogen, cyano, 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); wherein R is ₁₀ 、R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ And r is as described for the compounds of formula (I).

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 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.

In a 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 X is CR _a Or N; y is CR _b Or N;

X ₁ is CR (CR) _5a Or N, X ₂ Is CR (CR) _5a Or N, X ₃ Is CR (CR) _5a Or N, provided that X ₁ And X ₂ At least one of which is N;

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);

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;

ar is pyridyl, pyridazinylA pyrazinyl or phenyl group, which are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, 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 Substituted by 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, -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, 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 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;

R ₆ and R is ₇ Each independently 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;

R ₈ 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 And r is as described for the compounds of formula (I).

As a more 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):

wherein X is ₁ Is CR (CR) _5a ，X ₂ Is N; alternatively, X ₁ Is N, X ₂ Is CR (CR) _5a The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, X ₁ Is N, X ₂ Is N; x is X ₃ Is CR (CR) _5a Or N;

R _a selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl and C _3-6 Cycloalkyl;

each R _5a 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 _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -O-S (O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-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 ；

Ar is pyridinyl, pyridazinyl, pyrazinyl or phenyl, which 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 _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy, deuterium substituted 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, hydroxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

R ₁ 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 _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, -SF ₅ Amino, C _1-4 Alkyl monosubstituted amino, C _1-4 Alkyl disubstituted amino and C _1-4 An alkanoyl group;

R ₂ selected from hydrogen, deuterium, halogen, cyano, 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, 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 _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy, deuterium substituted C _1-4 Alkoxy, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o and-SF ₅ Is substituted by a substituent of (2);

alternatively, R ₁ And R is ₂ 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 _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy, deuterium substituted C _1-4 Alkoxy, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o and-SF ₅ Is substituted by a substituent of (2);

R ₄ selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl and C _3-6 Cycloalkyl;

R ₈ selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl group,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 And r is as described for the compounds of formula (IIa).

In a 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):

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

X ₄ is CR (CR) _5b Or N; x is X ₅ Is CR (CR) _5b Or N; provided that X ₄ And X ₅ At least one of which is N;

each R _5b 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);

ar is pyridinyl, pyridazinyl, pyrazinyl or phenyl, which are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, 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 Substituted by 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, -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);

As a more 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):

wherein X is ₄ Is CR (CR) _5b ，X ₅ Is N; alternatively, X ₄ Is N, X ₅ Is CR (CR) _5b The method comprises the steps of carrying out a first treatment on the surface of the Alternatively, X ₄ Is N; x is X ₅ Is N;

each R _5b 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 _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -O-S (O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-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 ；

wherein R is ₁₀ 、R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ And r is asA compound of formula (IIb).

In a preferred embodiment, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, has the structure of a compound of formula (ii c):

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

Provided that each R _5b When the two are all hydrogen,the structure is as follows:

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

wherein R is _a Selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl and C _3-6 Cycloalkyl;

each R _5b 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 _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -O-S (O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-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);

ar is pyridinyl, pyridazinyl, pyrazinyl or phenyl, which 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 _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy, deuterium substituted 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, hydroxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

alternatively, R ₁ And R is ₂ Together with the carbon atom to which it is directly attached form a C _3-6 Cycloalkyl and 4-8 membered heterocyclyl, 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 _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy, deuterium substituted C _1-4 Alkoxy, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o and-SF ₅ 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 compound of formula (IIc).

Preferably, each R in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof _5a Each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridecylmethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, aminoacyl, amino, methylamino and dimethylamino

R ₁ Selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridecyl, methoxy, ethoxy, n-propoxy, isopropoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopropyloxy, oxetanyl, azetidinyl, -SF ₅ Amino, C _1-4 Alkyl monosubstituted amino, C _1-4 Alkyl disubstituted amino and C _1-4 An alkanoyl group;

R ₂ selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridecylmethyl, methoxy, ethoxy, n-propoxy, isopropoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopropyloxy, oxetanyl, azetidinyl, phenyl, thiazolyl, triazolyl, pyridinyl and pyrimidinyl, each of which is independently optionally further substituted with one or more groups selected from the group consisting of deuterium, fluorine,chloro, bromo, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridecylmethyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, tridecylmethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopropoxy, oxetanyl, azetidinyl, =o and-SF ₅ Is substituted by a substituent of (2);

alternatively, R ₁ And R is ₂ And the carbon atoms to which they are directly attached form, independently, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and tetrahydro-2H-pyran, the groups being optionally further substituted independently by one or more groups selected from deuterium, fluoro, chloro, bromo, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridecylmethyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, tridecyloxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopropoxy, oxetanyl, azetidinyl, =o and-SF ₅ 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 _5b Each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridecylmethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, aminoacyl, amino, methylamino and dimethylamino

R ₂ selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridentate methyl, methoxyIndependently optionally further substituted with one or more groups selected from deuterium, fluoro, chloro, bromo, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridecylmethyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, tridecylmethoxy, ethenyl, ethynyl, cyclopropyl, cyclobutyl, cyclopropoxy, oxetanyl, azetidinyl, =o and-SF ₅ Is substituted by a substituent of (2);

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 the ring A, X, Y, ar, R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ 、R ₉ And m is 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 nerve fibroma, meningioma, glioma, sarcoma, 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, 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 groups 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 means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, and 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 bonds, but none of the rings has a fully conjugated pi electron system, one or more (preferably 1, 2, 3 or 4) ring atoms in the heterocyclyl being 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 comprising 3 to 12 or 3 to 8 or 3 to 6 ring atoms, for example, "3-6 membered heterocyclic group" means a heterocyclic group comprising 3 to 6 ring atoms, "3-8 membered heterocyclic group" means a heterocyclic group comprising 3 to 8 ring atoms, "4-8 membered heterocyclic group" means a heterocyclic group comprising 4 to 8 ring atoms"4-10 membered heterocyclic group" means a heterocyclic group containing 4 to 10 ring atoms, "5-8 membered heterocyclic group" means a heterocyclic group containing 5 to 8 ring atoms, "3-12 membered heterocyclic group" means a heterocyclic group containing 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 any twoThe rings sharing two polycyclic heterocyclic groups of atoms not directly attached, which may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings 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:

"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:

"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 means containing 2-1Straight or branched alkynyl of 0 carbon, "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 alkyloxy group containing 1 to 10 carbons," 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 extractionSubstitute 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 the alkyl group, the alkyl group is a hydroxyl group,wherein C is _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.

1. Preparation of intermediates

Intermediate 1: preparation of (R) -1- (pyrimidin-2-yl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) ethan-1-amine

The first step: synthesis of (R) -1- (pyrimidin-2-yl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) ethan-1-amine

2-Acetylpyrimidine (5.1 g,41.8mmol and 2-aminomethyl-5-trifluoromethylpyridine hydrochloride (9.77 g,45.9 mmol) were dissolved in DCM (50 mL), potassium acetate (4.92 g,50.1 mmol) was added and stirred at room temperature for 0.5h, sodium borohydride (8.81 g,41.8 mmol) was added and stirred at room temperature for 2h, DCM (500 mL) and water (300 mL) were added, 1M hydrochloric acid (300 mL) was added and the layers separated after stirring, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent, the residue was separated by column chromatography to give 1- (pyrimidin-2-yl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) ethane-1-amine, which was then resolved by SFC to give (S) -1- (pyrimidin-2-yl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) ethane-1-amine (ismer 1,3.9g, 33.1%)

¹ H NMR(400MHz,CDCl ₃ )δ8.81(s,1H)8.74(d,J＝5.02Hz,2H),7.88(dd,J＝8.28,1.76Hz,1H)7.54(d,J＝8.28Hz,1H)7.19(t,J＝4.77Hz,1H)4.09(q,J＝6.78Hz,1H)3.85-4.00(m,2H)1.52(d,J＝6.78Hz,3H).

And (R) -1- (pyrimidin-2-yl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) ethan-1-amine (isomer 2,3.91g, yield 33.2%)

¹ H NMR(400MHz,CDCl ₃ )δ8.80(s,1H)8.73(d,J＝5.02Hz,2H),7.87(dd,J＝8.28,2.01Hz,1H)7.53(d,J＝8.28Hz,1H)7.19(t,J＝4.89Hz,1H)4.08(q,J＝6.78Hz,1H)3.80-4.01(m,2H)1.52(d,J＝6.78Hz,3H).

Intermediate 2: preparation of 5-aminobenzo [ c ] [2,7] naphthyridine-9-carboxylic acid

The first step: synthesis of methyl 3-bromo-4- ((tert-butoxycarbonyl) amino) benzoate

To a solution of methyl 4-amino-3-bromobenzoate (4.00 g,17.39 mmol) in anhydrous tetrahydrofuran (80 mL) was added dropwise sodium bis (trimethylsilyl) amide (21.73 mL,2N,43.47 mmol) under ice-bath. The mixture was stirred under nitrogen for 15 minutes under an ice bath. Boc anhydride (3.98 g,18.26 mmol) was added and the mixture stirred overnight at room temperature. The reaction solution was quenched with 0.1N hydrochloric acid solution, extracted with ethyl acetate, and the organic phase was directly concentrated and separated by column chromatography [ developing solvent: EA/pe=0 to 10%]Methyl 3-bromo-4- ((tert-butoxycarbonyl) amino) benzoate (2.77 g, yield: 44%) was obtained. MS m/z (ESI): 274/276[ M+H-56 ]] ⁺ 。

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

Methyl 3-bromo-4- ((tert-butoxycarbonyl) amino) benzoate (2.77 g,8.41 mmol), duplex pinacol borate (3.20 g,12.61 mmol), potassium acetate (4.13 g,42.04 mmol) and [1,1' -bis (diphenylphosphino) ferrocene ]Palladium dichloride (310 mg,0.42 mmol) was placed in 1.4-dioxane (40 mL) and the mixture was stirred at 100deg.C for 18 hours under nitrogen. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography [ developer: EA/pe=10 to 80%]Methyl 4- ((tert-butoxycarbonyl) amino) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (3.90 g, purity: 75%, yield: 92%). MS m/z (ESI) 322[ M+H-56 ]] ⁺ 。

And a third step of: synthesis of methyl 5-aminobenzo [ c ] [2,7] naphthyridine-9-carboxylate

To a solution of methyl 4- ((tert-butoxycarbonyl) amino) -3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (200 mg,0.53 mmol), 3-bromoisonicotinic nitrile (97.0 mg,0.53 mmol), potassium phosphate (225 mg,1.06 mmol) in n-butanol (2.5 mL) and water (1 mL) was added tris (dibenzylideneacetone) dipalladium (38.8 mg,0.04 mmol) and 2-dicyclohexylphosphine-2 ',6' -dimethoxy-1, 1' -biphenyl (34.8 mg,0.08 mmol). The mixture was stirred at 100℃for 18 hours under nitrogen. The reaction was cooled to room temperature, diluted with water and extracted with EtOAc, concentrated and separated by column chromatography [ developer: meOH/dcm=5% ]To obtain methyl 5-aminobenzo [ c ]][2,7]Naphthyridine-9-carboxylate (120 mg, yield: 89%). MS m/z (ESI) 254[ M+H ]] ⁺ 。

Fourth step: synthesis of 5-aminobenzo [ c ] [2,7] naphthyridine-9-carboxylic acid

In methyl 5-aminobenzo [ c ]][2,7]To a mixture of naphthyridine-9-carboxylate (120 mg,0.47 mmol) in methanol (5 mL) and water (5 mL) was added lithium hydroxide (199mg, 4.74 mmol). The mixture was stirred at 40℃for 4 hours. Concentrating, diluting with water, regulating pH to 6-6.5 with diluted hydrochloric acid, and filtering to obtain 5-aminobenzo [ c ]][2,7]Naphthyridine-9-carboxylic acid, which is used directly in the next reaction without purification, MS m/z (ESI): 240[ M+H)] ⁺ 。

The intermediates can be prepared by selecting corresponding raw materials according to all or part of synthesis methods of 3-16 with reference to the intermediate 2:

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2. preparation of examples

Example 1: preparation of (R) -5-amino-N- (1- (pyrimidin-2-yl) ethyl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) benzo [ c ] [2,7] naphthyridine-9-carboxamide

In 5-aminobenzo [ c ]][2,6]To a solution of (R) -1- (pyrimidin-2-yl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) ethan-1-amine (56.7 mg,0.24 mmol) and triethylamine (60.0 mg,0.59 mmol) in anhydrous N, N-dimethylacetamide (3 mL) was added tripyrrolidinylphosphonium bromide hexafluorophosphate (132 mg,0.28 mmol). The reaction was stirred at room temperature for 4 hours. Diluted with water and extracted with EtOAc, the organic phase was concentrated and separated by column chromatography [ developing solvent: meOH/dcm=9% ]To give crude product, and preparing (R) -5-amino-N- (1- (pyrimidine-2-yl) ethyl) -N- ((5- (trifluoromethyl) pyridin-2-yl) methyl) benzo [ c ] by HPLC][2,7]Naphthyridine-9-carboxamide (4.4 mg, yield: 3.4%). MS m/z (ESI) 504[ M+H ]] ⁺ 。

¹ H NMR(400MHz,MeOH-d ₄ )δ9.96(s,1H),9.02(s,1H),8.81(s,1H),8.80(s,1H),8.79(s,1H),8.74(s,1H),8.18(d,J＝5.7Hz,1H),8.09-8.01(m,1H),7.87(d,J＝8.0Hz,1H),7.71(d,J＝8.6Hz,1H),7.64(d,J＝8.5Hz,1H),7.36(t,J＝4.9Hz,1H),5.62(s,1H),5.08(d,J＝16.8Hz,1H),4.91(s,1H),1.71(d,J＝7.0Hz,3H).

Examples 2 to 96 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:

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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 The culture was carried out overnight under the conditions.

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;

X ₄ is CR (CR) _5b Or N; x is X ₅ Is CR (CR) _5b Or N;

each 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 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);

ar 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, each of which is independently optionally further substituted with one or more substituents selected from 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 group-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 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, -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 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-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 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 NaphtheneRadical, 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.

2. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₈ And R is ₉ 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 ₈ And R is ₉ Together with the carbon atom to which it is directly attached form a C _3-4 Cycloalkyl or 4-6 membered heterocyclyl, wherein R ₁₃ And R is ₁₄ The method of claim 1;

preferably, R ₈ And R is ₉ 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 ₈ And R is ₉ 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 1Characterized in that each 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 And R is 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 each R ₄ 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 ₁₀ 、R ₁₁ 、R ₁₂ 、R ₁₃ 、R ₁₄ and r is as defined in claim 1;

preferably, 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, 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 、R ₁₄ The method of claim 1;

more preferably, 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.

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, 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 、R 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 salt thereof according to claim 1, wherein 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 Ar 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 of which is independently optionally further substituted with one or more substituents selected from deuterium, halogenElement, cyano, 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 Substituted by 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, -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 Ar is furyl, thienyl, or pyriA pyridyl, pyrrolyl, N-alkylpyrrolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl or phenyl group, which are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, 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 Substituted by 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, -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 _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, -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);

each R _5b 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 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);

each R _5c 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, 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 group5-8 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);

each R _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, =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);

each R _5e Each independently selected from deuterium, halogen, cyano, 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), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 wherein 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 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 Substituent of (2)Substituted;

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 moreFrom 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;

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 substitutionC _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);

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):

R ₂ selected from hydrogen, deuterium, halogen, cyano, 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, 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 _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy, deuterium substituted C _1-4 Alkoxy, C _2-4 Alkenyl, C _2-4 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, =o and-SF ₅ Substituted by substituents of (2)；

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

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;

ar is pyridinyl, pyridazinyl, pyrazinyl or phenyl, which are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 Alkyl group,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 Substituted by 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, -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);

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):

R _a selected from hydrogen, deuterium, halogen, cyano, C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkyl and C _3-6 Cycloalkyl; each R _5b 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 _3-6 Cycloalkyl, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, -O-S (O) ₂ R ₁₀ 、-S(O) _r R ₁₀ 、-O-R ₁₁ 、-C(O)OR ₁₁ 、-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 ；

Ar is pyridinyl, pyridazinyl, pyrazinyl or phenyl, which 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 _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy, deuterium substituted 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 group, 5-8Membered heteroaryl, 5-8 membered heteroaryloxy, hydroxy and-NR ₁₃ R ₁₄ Is substituted by a substituent of (2);

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

14. 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 (ii c):

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

ar is pyridinyl, pyridazinyl, pyrazinyl or phenyl, which are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, 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 、-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 Substituted by 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, -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);

15. The compound of formula (I), stereoisomer or pharmaceutically acceptable salt thereof according to claim 14, wherein the compound of formula (I) has the structure of a compound of formula (iii c):

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

16. Root of Chinese characterA compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 wherein each R _5a Each independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridecylmethyl, methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, aminoacyl, amino, methylamino and dimethylamino

R ₂ selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridecylmethyl, methoxy, ethoxy, n-propoxy, isopropoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopropyloxy, oxetanyl, azetidinyl, phenyl, thiazolyl, triazolyl, pyridinyl and pyrimidinyl, each of which is optionally further optionally substituted with one or more groups selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridecylmethyl, methoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, tridecyloxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopropyloxy, oxetanyl, azetidinyl, =o and-SF ₅ Is substituted by a substituent of (2);

alternatively, R ₁ And R is ₂ Together with the carbon atom to which it is directly attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and tetrahydro-2H-pyran, which are independently optionally further substituted with one or more groups selected from deuterium, fluoro, chloro, bromo, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridentatomethylMethoxy, ethoxy, n-propoxy, isopropoxy, trifluoromethoxy, tridecyloxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopropoxy, oxetanyl, azetidinyl, =o and-SF ₅ Is substituted by a substituent of (2).

17. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 wherein each R _5b Each independently selected from hydrogen, deuterium, halogen, cyano, and C _1-4 Alkyl, halogen substituted C _1-4 Alkyl, C _1-4 Alkoxy, halogen substituted C _1-4 Alkoxy, deuterium substituted C _1-4 Alkyl, deuterium substituted C _1-4 Alkoxy, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 3-6 membered heterocyclyl, C _6-8 Aryl, 5-8 membered heteroaryl, carboxyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, aminoacyl, amino, methylamino and dimethylamino;

R ₂ selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridecyl, methoxy, ethoxy, n-propoxy, isopropoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopropoxy, oxetanyl, azetidinyl, phenyl, thiazolyl, triazolyl, pyridinyl and pyrimidinyl, each of which is optionally further optionally substituted with one or more groups selected from the group consisting of deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridecyl, methoxy, ethoxy, n-propoxy, isopropoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopropoxy, oxetanylAzetidinyl, =o and-SF ₅ Is substituted by a substituent of (2);

Alternatively, R ₁ And R is ₂ Together with the carbon atom to which it is directly attached, form a cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane or tetrahydro-2H-pyran, which are independently optionally further substituted with one or more groups selected from deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, tridentatomethyl, methoxy, ethoxy, n-propoxy, isopropoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopropoxy, oxetanyl, azetidinyl, =o and-SF ₅ Is substituted by a substituent of (2).

18. A compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1, selected from the group consisting of:

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19. 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 the ring A, X, Y, ar, R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ 、R ₇ 、R ₈ 、R ₉ And m is as defined in claim 1.

20. 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 18 and a pharmaceutically acceptable carrier.

21. The 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 18 for the manufacture of a medicament for the treatment of a MATP-related cancer or tumour.

22. The use according to claim 21, wherein said tumor or cancer is selected from endometrial adenocarcinoma, granulosa-follicular 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, nephroblastoma, lymphoma, leukemia, bladder carcinoma, squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, prostate carcinoma, seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, adenoma, adenomatoid carcinoma, 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 nerve fibroma, meningioma, glioma, sarcoma, breast cancer, pancreatic cancer, skin cancer, bladder cancer, liver cancer, or head and neck cancer.