CN119013274A

CN119013274A - PRMT5 inhibitor, preparation method and pharmaceutical application thereof

Info

Publication number: CN119013274A
Application number: CN202380033442.3A
Authority: CN
Inventors: 邓海兵; 刘建; 杨飞; 喻红平; 陈椎; 徐耀昌
Original assignee: Abbisko Therapeutics Co Ltd
Current assignee: Abbisko Therapeutics Co Ltd
Priority date: 2022-07-26
Filing date: 2023-06-26
Publication date: 2024-11-22
Also published as: WO2024021957A1

Abstract

涉及一种PRMT5抑制剂及其制备方法和药学上的应用。特别地，涉及一种具有式(I)化合物结构的PRMT5抑制剂及其制备方法、含有其的药物组合物，以及其作为PRMT5抑制剂的用途和其在治疗和/或预防PRMT5介导的疾病中的用途。其中式(I)化合物的各取代基与说明书中的定义相同。 The invention relates to a PRMT5 inhibitor, a preparation method thereof and pharmaceutical applications. In particular, the invention relates to a PRMT5 inhibitor having a compound structure of formula (I), a preparation method thereof, a pharmaceutical composition containing the same, and its use as a PRMT5 inhibitor and its use in treating and/or preventing PRMT5-mediated diseases. The substituents of the compound of formula (I) are the same as those defined in the specification.

Description

PRMT5 inhibitor, preparation method and pharmaceutical application thereof

Technical Field

The invention belongs to the field of medicine synthesis, and particularly relates to a PRMT5 inhibitor, a preparation method thereof and pharmaceutical 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 PRMT5 inhibitor, a preparation method and pharmaceutical 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 ₁ is CR ₆ or N; x ₂ is CR ₇ or N; x ₃ is CR ₈ or N;

ring a is C _4-12 cycloalkyl, 4-12 membered heterocyclyl, C _6-10 aryl or 5-10 membered heteroaryl;

Ring B is selected from a 4-10 membered nitrogen containing heterocyclyl or a 5-10 membered nitrogen containing heteroaryl, said nitrogen atom being attached to the carbonyl group, wherein,

1) When ring B is selected from a 4-membered nitrogen-containing heterocyclic group, an 8-10 membered nitrogen-containing heterocyclic group or an 8-10 membered nitrogen-containing heteroaryl group,

Ring C is C _3-12 cycloalkyl, 4-12 membered heterocyclyl, C _6-10 aryl, or 5-10 membered heteroaryl, said C _3-12 cycloalkyl or 4-12 membered heterocyclyl optionally fused to C _6-10 aryl or 5-10 membered heteroaryl, said C _6-10 aryl or 5-10 membered heteroaryl optionally fused to C _3-12 cycloalkyl or 4-12 membered heterocyclyl;

Each R ₁ is independently selected from the group consisting of 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) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁, the above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, halo-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C _6-10 aryl, 5-to 10-membered heteroaryl, =O, =S, -C _0-8 alkyl-SF ₅、-C_0-8 alkyl-O-S (O) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁ substituents substituted;

2) When ring B is selected from a 5-7 membered nitrogen containing heterocyclyl or a 5-7 membered nitrogen containing heteroaryl,

Ring C forms together with- (R ₁)_m: Wherein,

A) When ring C is formed with- (R ₁)_m)When Y ₁、Y₂ is each independently CR ₁ or N, Y ₃ is O, S or NR ₁',Y₄、Y₅ is each independently CR ₁ "or N;

R ₁' is selected from hydrogen, deuterium, 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, -S (O) _rR₉、-O-R₁₀、-C(O)OR₁₀、-C(O)R₁₁ and-C (O) NR ₁₂R₁₃, the above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, halo-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) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁ substituents substituted;

Each R ₁' is 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) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁, the above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, halo-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C _6-10 aryl, 5-to 10-membered heteroaryl, =O, =S, -C _0-8 alkyl-SF ₅、-C_0-8 alkyl-O-S (O) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁ substituents substituted;

b) When ring C is formed with- (R ₁)_m) When Y ₆、Y₇、Y₈ and Y ₉ are each independently CR ₁ or N, and at least one is selected from CR ₁, Wherein at least one R ₁ is-C _0-8 alkyl-NR ₁₄R₁₅ or-O-C _1-4 alkyl-NR ₁₄R₁₅, Each R ₁ is independently selected from the group consisting of 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) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁, the above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, halo-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C _6-10 aryl, 5-to 10-membered heteroaryl, =O, =S, -C _0-8 alkyl-SF ₅、-C_0-8 alkyl-O-S (O) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁ substituents substituted;

Each R ₂ is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, halo-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, -C _0-8 alkyl-SF ₅、-C_0-8 alkyl-O-S (O) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁, or when p.gtoreq.2, wherein two R ₂ together with the moiety to which they are directly attached form a C (O);

r ₃ and R ₄ are 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, or R ₃ and R ₄ together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or a 5-10 membered heteroaryl, which are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxy, =o, = S, C _1-10 alkyl, halo 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 ₁₂R₁₃;

each R ₅ is independently selected from the group consisting of 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) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁, the above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, halo-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 12-membered heterocyclyl, C _6-10 aryl, 5-to 10-membered heteroaryl, =O, =S, -C _0-8 alkyl-SF ₅、-C_0-8 alkyl-O-S (O) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁ substituents substituted;

R ₆、R₇ and R ₈ are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, halo-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, and, -C _0-8 alkyl-SF ₅、-C_0-8 alkyl-O-S (O) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁;

each R ₉ is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and-NR ₁₂R₁₃, each of which is independently optionally further substituted with one or more substituents selected from the group consisting of 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 heteroaryloxy, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and-NR ₁₂R₁₃;

Each R ₁₀ is independently selected from the group consisting of 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, each of which is independently optionally further substituted with one or more substituents 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 heteroaryloxy, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and-NR ₁₂R₁₃;

each R ₁₁ is independently selected from the group consisting of 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 heteroaryl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and-NR ₁₂R₁₃, each of which is independently optionally further substituted with one or more substituents 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 heteroaryl, C _6-10 aryl, C _6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, and-NR ₁₂R₁₃;

each R ₁₂ and R ₁₃ is independently selected from hydrogen, deuterium, hydroxy, C _1-10 alkyl, C _2-10 alkenyl, c _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 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, Halogen 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 heteroepoxy, 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 alkanoyl, Or alternatively

R ₁₂ and R ₁₃ together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, said 4-10 membered heterocyclyl or 5-10 membered heteroaryl optionally further substituted with one or more substituents 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 heteroaryl, 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 alkanoyl;

R ₁₄ and R ₁₅ are each independently selected from hydrogen, deuterium, C _1-10 alkyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, c _6-10 aryl, 5-10 membered heteroaryl, and, -C _0-8 alkyl-SF ₅、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂ and-C _0-8 alkyl-C (O) NR ₁₂R₁₃, Or R ₁₄ and R ₁₅ together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or a 5-10 membered heteroaryl, said groups being independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, Halogen substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, =o, =s, -C _0-8 alkyl-SF ₅、-C_0-8 alkyl-O-S (O) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁ substituents substituted;

Each r is independently 0,1 or 2;

m is selected from 0,1, 2, 3, 4 or 5;

n is selected from 0,1, 2, 3, 4 or 5; and is also provided with

P is selected from 0,1, 2, 3, 4 or 5.

As a further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R ₃ and R ₄ are 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, or R ₃ and R ₄ together with the nitrogen atom to which they are directly attached form a 4-6 membered heterocyclyl or 5-8 membered heteroaryl, The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, hydroxy, =o, = S, C _1-4 alkyl, halo 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 a substituent of-NR ₁₂R₁₃; Wherein R ₁₂ and R ₁₃ are as described for the compounds of formula (I).

As a still further preferred embodiment, in the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkyl, halo 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.

As a further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, R ₆、R₇ and R ₈ are each independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halo-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, and, -C _0-4 alkyl-SF ₅、-C_0-4 alkyl-O-S (O) ₂R₉、-C_0-4 alkyl-S (O) _rR₉、-C_0-4 alkyl-O-R ₁₀、-C_0-4 alkyl-C (O) OR ₁₀、-C_0-4 alkyl-C (O) SR ₁₀、-C_0-4 alkyl-S-C (O) R ₁₁、-C_0-4 alkyl-C (O) R ₁₁、-C_0-4 alkyl-O-C (O) R ₁₁、-C_0-4 alkyl-P (O) (R ₁₁)₂、-C_0-4 alkyl-NR ₁₂R₁₃、-C_0-4 alkyl-C (O) NR ₁₂R₁₃ and-C _0-4 alkyl-N (R ₁₂)-C(O)R₁₁; wherein R ₉、R₁₀、R₁₁、R₁₂、R₁₃ and R are as described for the compounds of formula (I).

As a still further preferred embodiment, in the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R ₆、R₇ and R ₈ are each independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halo 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 、-SF₅、-O-S(O)₂R₉、-S(O)_rR₉、-O-R₁₀、-C(O)OR₁₀、-C(O)SR₁₀、-S-C(O)R₁₁、-C(O)R₁₁、-O-C(O)R₁₁、-P(O)(R₁₁)₂、-NR₁₂R₁₃、-C(O)NR₁₂R₁₃, and-N (R ₁₂)-C(O)R₁₁;

wherein R ₉、R₁₀、R₁₁、R₁₂、R₁₃ and R are 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, R ₁₄ and R ₁₅ are each independently selected from hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl, 5-8 heteroaryl, -C _0-4 alkyl-SF ₅、-C_0-4 alkyl-C (O) OR ₁₀、-C_0-4 alkyl-C (O) SR ₁₀、-C_0-4 alkyl-C (O) R ₁₁、-C_0-4 alkyl-P (O) (R ₁₁)₂ and-C _0-4 alkyl-C (O) NR ₁₂R₁₃, Or R ₁₄ and R ₁₅ together with the nitrogen atom to which they are directly attached form a 4-6 membered heterocyclyl or 5-8 membered heteroaryl, which are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, Halogen substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl, =o, =s, -C _0-4 alkyl-SF ₅、-C_0-4 alkyl-O-S (O) ₂R₉、-C_0-4 alkyl-S (O) _rR₉、-C_0-4 alkyl-O-R ₁₀、-C_0-4 alkyl-C (O) OR ₁₀、-C_0-4 alkyl-C (O) SR ₁₀、-C_0-4 alkyl-S-C (O) R ₁₁、-C_0-4 alkyl-C (O) R ₁₁、-C_0-4 alkyl-O-C (O) R ₁₁、-C_0-4 alkyl-P (O) (R ₁₁)₂、-C_0-4 alkyl-NR ₁₂R₁₃、-C_0-4 alkyl-C (O) NR ₁₂R₁₃ and-C _0-4 alkyl-N (R ₁₂)-C(O)R₁₁ substituents substituted; wherein R ₉、R₁₀、R₁₁、R₁₂、R₁₃ and R are as described for the compounds of formula (I).

As a still further preferred embodiment, in said compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R ₁₄ and R ₁₅ are each independently selected from the group consisting of hydrogen, deuterium, C _1-4 alkyl, halo 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, -SF ₅、-C(O)OR₁₀、-C(O)SR₁₀、-C(O)R₁₁、-P(O)(R₁₁)₂, and-C (O) NR ₁₂R₁₃; wherein R ₉、R₁₀、R₁₁、R₁₂、R₁₃ and R are as described for the compounds of formula (I).

As a further preferred embodiment, each R ₅ in the compound of formula (I), its stereoisomers or a pharmaceutically acceptable salt thereof, is independently 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, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅、-C_0-4 alkyl-O-S (O) ₂R₉、-C_0-4 alkyl-S (O) _rR₉、-C_0-4 alkyl-O-R ₁₀、-C_0-4 alkyl-C (O) OR ₁₀、-C_0-4 alkyl-C (O) SR ₁₀、-C_0-4 alkyl-S-C (O) R ₁₁、-C_0-4 alkyl-C (O) R ₁₁、-C_0-4 alkyl-O-C (O) R ₁₁、-C_0-4 alkyl-P (O) (R ₁₁)₂、-C_0-4 alkyl-NR ₁₂R₁₃、-C_0-4 alkyl-C (O) NR ₁₂R₁₃ and-C _0-4 alkyl-N (R ₁₂)-C(O)R₁₁, The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, halo 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) ₂R₉、-C_0-4 alkyl-S (O) _rR₉、-C_0-4 alkyl-O-R ₁₀、-C_0-4 alkyl-C (O) OR ₁₀、-C_0-4 alkyl-C (O) SR ₁₀、-C_0-4 alkyl-S-C (O) R ₁₁、-C_0-4 alkyl-C (O) R ₁₁、-C_0-4 alkyl-O-C (O) R ₁₁、-C_0-4 alkyl-P (O) (R ₁₁)₂、-C_0-4 alkyl-NR ₁₂R₁₃、-C_0-4 alkyl-C (O) NR ₁₂R₁₃ and-C _0-4 alkyl-N (R ₁₂)-C(O)R₁₁ substituents substituted; wherein R ₉、R₁₀、R₁₁、R₁₂、R₁₃ and R are as described for the compounds of formula (I).

As a still further preferred embodiment, each R ₅ in the compound of formula (I), its stereoisomers or a pharmaceutically acceptable salt thereof, is independently 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, 5-8 membered heteroaryl 、-SF₅、-O-S(O)₂R₉、-S(O)_rR₉、-O-R₁₀、-C(O)OR₁₀、-C(O)SR₁₀、-S-C(O)R₁₁、-C(O)R₁₁、-O-C(O)R₁₁、-P(O)(R₁₁)₂、-NR₁₂R₁₃、-C(O)NR₁₂R₁₃ and-N (R ₁₂)-C(O)R₁₁, The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, halo 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、-SF₅、-O-S(O)₂R₉、-S(O)_rR₉、-O-R₁₀、-C(O)OR₁₀、-C(O)SR₁₀、-S-C(O)R₁₁、-C(O)R₁₁、-O-C(O)R₁₁、-P(O)(R₁₁)₂、-NR₁₂R₁₃、-C(O)NR₁₂R₁₃ and-N (substituted by the substituents R ₁₂)-C(O)R₁₁; wherein R ₉、R₁₀、R₁₁、R₁₂、R₁₃ and R are as described for the compounds of formula (I).

As a further preferred embodiment, each R ₂ in the compound of formula (I), its stereoisomers or a pharmaceutically acceptable salt thereof, is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halo-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, and, -C _0-4 alkyl-SF ₅、-C_0-4 alkyl-O-S (O) ₂R₉、-C_0-4 alkyl-S (O) _rR₉、-C_0-4 alkyl-O-R ₁₀、-C_0-4 alkyl-C (O) OR ₁₀、-C_0-4 alkyl-C (O) SR ₁₀、-C_0-4 alkyl-S-C (O) R ₁₁、-C_0-4 alkyl-C (O) R ₁₁、-C_0-4 alkyl-O-C (O) R ₁₁、-C_0-4 alkyl-P (O) (R ₁₁)₂、-C_0-4 alkyl-NR ₁₂R₁₃、-C_0-4 alkyl-C (O) NR ₁₂R₁₃ and-C _0-4 alkyl-N (R ₁₂)-C(O)R₁₁, or when p.gtoreq.2, wherein two R ₂ together with the moiety to which they are directly attached form a C (O); wherein R ₉、R₁₀、R₁₁、R₁₂、R₁₃ and R are as described for the compounds of formula (I).

As a still further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ring B is selected from 4-membered nitrogen containing heterocyclyl;

Ring C is C _3-6 cycloalkyl, 4-8 membered heterocyclyl, C _6-8 aryl, or 5-8 membered heteroaryl, said C _3-6 cycloalkyl or 4-8 membered heterocyclyl optionally being fused to C _6-8 aryl or 5-8 membered heteroaryl, said C _6-8 aryl or 5-8 membered heteroaryl optionally being fused to C _3-6 cycloalkyl or 4-8 membered heterocyclyl;

Each R ₁ is independently 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, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅、-C_0-4 alkyl-O-S (O) ₂R₉、-C_0-4 alkyl-S (O) _rR₉、-C_0-4 alkyl-O-R ₁₀、-C_0-4 alkyl-C (O) OR ₁₀、-C_0-4 alkyl-C (O) SR ₁₀、-C_0-4 alkyl-S-C (O) R ₁₁、-C_0-4 alkyl-C (O) R ₁₁、-C_0-4 alkyl-O-C (O) R ₁₁、-C_0-4 alkyl-P (O) (R ₁₁)₂、-C_0-4 alkyl-NR ₁₂R₁₃、-C_0-4 alkyl-C (O) NR ₁₂R₁₃ and-C _0-4 alkyl-N (R ₁₂)-C(O)R₁₁, The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, halo 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) ₂R₉、-C_0-4 alkyl-S (O) _rR₉、-C_0-4 alkyl-O-R ₁₀、-C_0-4 alkyl-C (O) OR ₁₀、-C_0-4 alkyl-C (O) SR ₁₀、-C_0-4 alkyl-S-C (O) R ₁₁、-C_0-4 alkyl-C (O) R ₁₁、-C_0-4 alkyl-O-C (O) R ₁₁、-C_0-4 alkyl-P (O) (R ₁₁)₂、-C_0-4 alkyl-NR ₁₂R₁₃、-C_0-4 alkyl-C (O) NR ₁₂R₁₃ and-C _0-4 alkyl-N (R ₁₂)-C(O)R₁₁ substituents substituted;

As a still further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ring B is selected from 8-10 membered nitrogen containing heterocyclyl;

Each R ₁ is independently 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, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅、-C_0-4 alkyl-O-S (O) ₂R₉、-C_0-4 alkyl-S (O) _rR₉、-C_0-4 alkyl-O-R ₁₀、-C_0-4 alkyl-C (O) OR ₁₀、-C_0-4 alkyl-C (O) SR ₁₀、-C_0-4 alkyl-S-C (O) R ₁₁、-C_0-4 alkyl-C (O) R ₁₁、-C_0-4 alkyl-O-C (O) R ₁₁、-C_0-4 alkyl-P (O) (R ₁₁)₂、-C_0-4 alkyl-NR ₁₂R₁₃、-C_0-4 alkyl-C (O) NR ₁₂R₁₃ and-C _0-4 alkyl-N (R ₁₂)-C(O)R₁₁, The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, halo 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) ₂R₉、-C_0-4 alkyl-S (O) _rR₉、-C_0-4 alkyl-O-R ₁₀、-C_0-4 alkyl-C (O) OR ₁₀、-C_0-4 alkyl-C (O) SR ₁₀、-C_0-4 alkyl-S-C (O) R ₁₁、-C_0-4 alkyl-C (O) R ₁₁、-C_0-4 alkyl-O-C (O) R ₁₁、-C_0-4 alkyl-P (O) (R ₁₁)₂、-C_0-4 alkyl-NR ₁₂R₁₃、-C_0-4 alkyl-C (O) NR ₁₂R₁₃ and-C _0-4 alkyl-N (R ₁₂)-C(O)R₁₁ substituents substituted; wherein R ₉、R₁₀、R₁₁、R₁₂、R₁₃ and R are as described for the compounds of formula (I).

As a still further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ring B is selected from 5-7 membered nitrogen containing heterocyclyl and ring C forms together with- (R ₁)_m)Wherein each Y ₁、Y₂ is independently CR ₁ or N, each Y ₃ is O, S or NR ₁',Y₄、Y₅ is independently CR ₁ "or N;

R ₁' is selected from hydrogen, deuterium, 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, -S (O) _rR₉、-O-R₁₀、-C(O)OR₁₀、-C(O)R₁₁ and-C (O) NR ₁₂R₁₃, 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) ₂R₉、-C_0-4 alkyl-S (O) _rR₉、-C_0-4 alkyl-O-R ₁₀、-C_0-4 alkyl-C (O) OR ₁₀、-C_0-4 alkyl-C (O) SR ₁₀、-C_0-4 alkyl-S-C (O) R ₁₁、-C_0-4 alkyl-C (O) R ₁₁、-C_0-4 alkyl-O-C (O) R ₁₁、-C_0-4 alkyl-P (O) (R ₁₁)₂、-C_0-4 alkyl-NR ₁₂R₁₃、-C_0-4 alkyl-C (O) NR ₁₂R₁₃ and-C _0-4 alkyl-N (R ₁₂)-C(O)R₁₁ substituents substituted;

Each R ₁' is independently 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, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅、-C_0-4 alkyl-O-S (O) ₂R₉、-C_0-4 alkyl-S (O) _rR₉、-C_0-4 alkyl-O-R ₁₀、-C_0-4 alkyl-C (O) OR ₁₀、-C_0-4 alkyl-C (O) SR ₁₀、-C_0-4 alkyl-S-C (O) R ₁₁、-C_0-4 alkyl-C (O) R ₁₁、-C_0-4 alkyl-O-C (O) R ₁₁、-C_0-4 alkyl-P (O) (R ₁₁)₂、-C_0-4 alkyl-NR ₁₂R₁₃、-C_0-4 alkyl-C (O) NR ₁₂R₁₃ and-C _0-4 alkyl-N (R ₁₂)-C(O)R₁₁, The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, halo 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) ₂R₉、-C_0-4 alkyl-S (O) _rR₉、-C_0-4 alkyl-O-R ₁₀、-C_0-4 alkyl-C (O) OR ₁₀、-C_0-4 alkyl-C (O) SR ₁₀、-C_0-4 alkyl-S-C (O) R ₁₁、-C_0-4 alkyl-C (O) R ₁₁、-C_0-4 alkyl-O-C (O) R ₁₁、-C_0-4 alkyl-P (O) (R ₁₁)₂、-C_0-4 alkyl-NR ₁₂R₁₃、-C_0-4 alkyl-C (O) NR ₁₂R₁₃ and-C _0-4 alkyl-N (R ₁₂)-C(O)R₁₁ substituents substituted;

As a still further preferred embodiment, in the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ring B is selected from 5-7 membered nitrogen containing heterocyclyl and ring C forms together with- (R ₁)_m)Wherein Y ₆、Y₇、Y₈ and Y ₉ are each independently CR ₁ or N and at least one is CR ₁, Wherein, at least one R ₁ is-C _0-4 alkyl-NR ₁₄R₁₅ or-O-C _1-4 alkyl-NR ₁₄R₁₅, Each of the other R ₁ is independently 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, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅、-C_0-4 alkyl-O-S (O) ₂R₉、-C_0-4 alkyl-S (O) _rR₉、-C_0-4 alkyl-O-R ₁₀、-C_0-4 alkyl-C (O) OR ₁₀、-C_0-4 alkyl-C (O) SR ₁₀、-C_0-4 alkyl-S-C (O) R ₁₁、-C_0-4 alkyl-C (O) R ₁₁、-C_0-4 alkyl-O-C (O) R ₁₁、-C_0-4 alkyl-P (O) (R ₁₁)₂、-C_0-4 alkyl-NR ₁₂R₁₃、-C_0-4 alkyl-C (O) NR ₁₂R₁₃ and-C _0-4 alkyl-N (R ₁₂)-C(O)R₁₁, The above groups are independently optionally further substituted with one or more groups selected from deuterium, halogen, cyano, C _1-4 alkyl, halo 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) ₂R₉、-C_0-4 alkyl-S (O) _rR₉、-C_0-4 alkyl-O-R ₁₀、-C_0-4 alkyl-C (O) OR ₁₀、-C_0-4 alkyl-C (O) SR ₁₀、-C_0-4 alkyl-S-C (O) R ₁₁、-C_0-4 alkyl-C (O) R ₁₁、-C_0-4 alkyl-O-C (O) R ₁₁、-C_0-4 alkyl-P (O) (R ₁₁)₂、-C_0-4 alkyl-NR ₁₂R₁₃、-C_0-4 alkyl-C (O) NR ₁₂R₁₃ and-C _0-4 alkyl-N (R ₁₂)-C(O)R₁₁ substituents substituted;

Wherein R ₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅ and R are as described for the compounds of formula (I).

As a still further preferred embodiment, the compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, each R ₉ is independently selected from the group consisting of 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 ₁₂R₁₃, each of which is independently optionally further substituted with one or more substituents 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 heteroaryloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, and-NR ₁₂R₁₃;

each R ₁₀ is independently selected from the group consisting of 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, each of which is independently optionally further substituted with one or more substituents 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 heteroaryloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, and-NR ₁₂R₁₃;

Each R ₁₁ is independently selected from the group consisting of 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 heteroaryl, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, and-NR ₁₂R₁₃, each of which is independently optionally further substituted with one or more substituents 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 heteroaryl, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, and-NR ₁₂R₁₃;

Each R ₁₂ and R ₁₃ is independently selected from hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _2-4 alkenyl, c _2-4 alkynyl, C _3-6 cycloalkyl, 3-to 6-membered heterocyclyl, C _6-8 aryl, 5-to 8-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, 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, Halogen 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 alkanoyl, Or alternatively

R ₁₂ and R ₁₃ together with the nitrogen atom to which they are 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 substituents 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 heteroaryl, 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 alkanoyl.

As a still further preferred embodiment, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ring a forms together with the moiety to which it is directly attached the structure:

Wherein X ₁ is CR ₆ or N; x ₂ is CR ₇ or N;

each R _5a is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl, -SF ₅, and-O-R ₁₀, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C _1-4 alkyl, halo-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、-SF₅、-O-S(O)₂R₉、-S(O)_rR₉、-O-R₁₀、-C(O)OR₁₀、-C(O)SR₁₀、-S-C(O)R₁₁、-C(O)R₁₁、-O-C(O)R₁₁、-P(O)(R₁₁)₂、-NR₁₂R₁₃、-C(O)NR₁₂R₁₃, and-N (R ₁₂)-C(O)R₁₁;

Each R _5b is independently selected from hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, and-O-R ₁₀, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C _1-4 alkyl, halo-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、-SF₅、-O-S(O)₂R₉、-S(O)_rR₉、-O-R₁₀、-C(O)OR₁₀、-C(O)SR₁₀、-S-C(O)R₁₁、-C(O)R₁₁、-O-C(O)R₁₁、-P(O)(R₁₁)₂、-NR₁₂R₁₃、-C(O)NR₁₂R₁₃, and-N (R ₁₂)-C(O)R₁₁;

each R _5c is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl, -SF ₅, and-O-R ₁₀, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C _1-4 alkyl, halo-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、-SF₅、-O-S(O)₂R₉、-S(O)_rR₉、-O-R₁₀、-C(O)OR₁₀、-C(O)SR₁₀、-S-C(O)R₁₁、-C(O)R₁₁、-O-C(O)R₁₁、-P(O)(R₁₁)₂、-NR₁₂R₁₃、-C(O)NR₁₂R₁₃, and-N (R ₁₂)-C(O)R₁₁;

Each R ₆ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halo substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅, and-O-R ₁₀;

each R ₇ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halo substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅, and-O-R ₁₀;

each R ₈ is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halo substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅, and-O-R ₁₀;

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

Wherein Y ₁、Y₂ is each independently CR ₁ or N, Y ₃ is O, S or NR ₁';

ring a is C _4-8 cycloalkyl, 4-8 membered heterocyclyl, C _6-8 aryl, or 5-8 membered heteroaryl;

Ring B together with- (R ₂)_p) forms the following structure:

each R ₁ is independently selected from the group consisting of 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, 5-8 membered heteroaryl 、-SF₅、-O-S(O)₂R₉、-S(O)_rR₉、-O-R₁₀、-C(O)OR₁₀、-C(O)SR₁₀、-S-C(O)R₁₁、-C(O)R₁₁、-O-C(O)R₁₁、-P(O)(R₁₁)₂、-NR₁₂R₁₃、-C(O)NR₁₂R₁₃ and-N (R ₁₂)-C(O)R₁₁, which are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, halogen, cyano, C _1-4 alkyl, halo 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、-SF₅、-O-S(O)₂R₉、-S(O)_rR₉、-O-R₁₀、-C(O)OR₁₀、-C(O)SR₁₀、-S-C(O)R₁₁、-C(O)R₁₁、-O-C(O)R₁₁、-P(O)(R₁₁)₂、-NR₁₂R₁₃、-C(O)NR₁₂R₁₃ and-N (R ₁₂)-C(O)R₁₁;

R ₁' is selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl, each of which is independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, C _1-4 alkyl, halo-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、-SF₅、-O-S(O)₂R₉、-S(O)_rR₉、-O-R₁₀、-C(O)OR₁₀、-C(O)SR₁₀、-S-C(O)R₁₁、-C(O)R₁₁、-O-C(O)R₁₁、-P(O)(R₁₁)₂、-NR₁₂R₁₃、-C(O)NR₁₂R₁₃ and-N (R ₁₂)-C(O)R₁₁;

Each R ₂ is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halo 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 、-SF₅、-O-S(O)₂R₉、-S(O)_rR₉、-O-R₁₀、-C(O)OR₁₀、-C(O)SR₁₀、-S-C(O)R₁₁、-C(O)R₁₁、-O-C(O)R₁₁、-P(O)(R₁₁)₂、-NR₁₂R₁₃、-C(O)NR₁₂R₁₃, and-N (R ₁₂)-C(O)R₁₁;

R ₂' is selected from the group consisting of hydrogen, deuterium, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, halo substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _3-6 cycloalkyl, and 3-6 membered heterocyclyl;

Each R ₅ is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, halo 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 、-SF₅、-O-S(O)₂R₉、-S(O)_rR₉、-O-R₁₀、-C(O)OR₁₀、-C(O)SR₁₀、-S-C(O)R₁₁、-C(O)R₁₁、-O-C(O)R₁₁、-P(O)(R₁₁)₂、-NR₁₂R₁₃、-C(O)NR₁₂R₁₃, and-N (R ₁₂)-C(O)R₁₁;

R ₆ is selected from the group consisting of hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halo substituted C _1-4 alkyl, deuterium substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, halo substituted C _1-4 alkoxy, deuterium substituted C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heteroaryloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, hydroxy and-NR ₁₂R₁₃;

wherein R ₉、R₁₀、R₁₁、R₁₂、R₁₃, n, p and R are as described for the compounds of formula (I).

As a further preferred embodiment, in said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, ring a forms together with the moiety to which it is directly attached the structure:

Wherein X ₁ is CR ₆ or N; x ₂ is CH or N;

As a further preferred embodiment, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, has the structure of a compound of formula (iii ₁) or formula (iii ₂) as follows:

Wherein the compound of formula (III ₁) or formula (III ₂) has the structure The structure is that

Ring a, together with the directly attached portion thereof, forms the structure:

r ₁ is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, tridentate methyl, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino-substituted methyl, dimethylamino-substituted ethyl, dimethylaminoethoxy, cyclopropyl, cyclobutyl, piperidinyl, piperazinyl, morpholinyl, methyl-substituted piperidinyl, ethyl-substituted piperidinyl, cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl-substituted piperazine, and tetrahydropyranyl;

R ₁' is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, tridentate methyl, dimethylamino substituted ethyl, cyclopropyl, cyclobutyl, piperidinyl, methyl substituted piperidinyl, ethyl substituted piperidinyl, cyclopropyl substituted piperidinyl, and tetrahydropyranyl;

each R ₂ is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, tridentate methyl, and cyclopropyl;

Each R _5a is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, tridentate methyl, cyclopropyl, -SF ₅, and hydroxy;

Each R _5b is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, tridentate methyl, and cyclopropyl;

Each R _5c is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, tridentate methyl, cyclopropyl, -SF ₅, and hydroxy;

Each R ₆ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, tridentate methyl, cyclopropyl, -SF ₅, and hydroxy;

p is selected from 0,1 or 2.

As a further preferred embodiment, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, is a compound of formula (III ₁) or formula (III ₂)The structure is that

Wherein R ₁ is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, tridentate methyl, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino-substituted ethyl, dimethylamino-substituted ethoxy, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, methyl-substituted piperidinyl, ethyl-substituted piperidinyl, cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl-substituted piperazine, and tetrahydropyranyl;

Each R ₂ is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, tridentate methyl, and cyclopropyl;

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

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

Each R _5c is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, tridentate methyl, and cyclopropyl;

Each R ₆ is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, tridentate methyl, and cyclopropyl.

As a further preferred embodiment, the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, has the structure of a compound of formula (iv ₁), formula (iv ₂), formula (iv ₃) or formula (iv ₄) as follows:

Wherein,

Each R ₁ is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, tridentate methyl, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino-substituted ethyl, dimethylamino-substituted ethoxy, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, methyl-substituted piperidinyl, ethyl-substituted piperidinyl, cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl-substituted piperazinyl, and tetrahydropyranyl;

Each R _2a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, tridentate methyl, and cyclopropyl;

Each R _2b is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, tridentate methyl, and cyclopropyl;

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:

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, comprising the steps of: reacting a compound of formula (Ia) with a compound of formula (Ib) to form a compound of formula (I), the reaction formula being as follows:

Wherein X is hydroxy or halogen; ring a, ring B, ring C, R ₁、R₂、R₃、R₄、R₅、X₁、X₂、X₃, m, n and p are as defined 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 the use of a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a mat-related neoplasm.

As a further preferred embodiment, the tumor is selected from the group consisting of cytoma, lymphoma, leukemia, osteoma, malignant teratoma, intraepithelial carcinoma, adenoma, fibroma, melanoma, fallopian tube carcinoma, bladder carcinoma, teratoma, embryo carcinoma, choriocarcinoma, lipoma, liver cancer, cholangiocarcinoma, lung cancer, gastric cancer, hemangioma, gall bladder carcinoma, ampullate carcinoma, malignant melanoma, nevi, dysplastic nevi, myeloproliferative disease, hodgkin's disease, chordoma, myxoma, rhabdomyoma, smooth myoma, hamartoma, mesothelioma, insulinoma, glucagon tumor, gastrinoma, carcinoid tumor, venomocytoma, granuloma, xanthoma, anaplastic osteomyelitis, ependymoma, congenital tumor, meningioma, glioma, skin cancer, head and neck cancer and sarcoma.

As a further preferred embodiment, the cytoma is selected from the group consisting of granulosa-follicular cytoma, testicular supportive cytoma, germ cytoma, nephroblastoma, seminoma, hepatoblastoma, malignant fibrous histiocytoma, chondroblastoma, giant cell tumor, astrocytoma, medulloblastoma, glioblastoma multiforme, oligodendroglioma, retinoblastoma, squamous cell carcinoma, clear cell carcinoma, transitional cell carcinoma, interstitial cell carcinoma, and basal cell carcinoma;

the lymphoma is selected from malignant lymphoma and non-hodgkin's lymphoma;

the leukemia is selected from acute and chronic myeloid leukemia, acute lymphoblastic leukemia and chronic lymphoblastic leukemia;

The bone tumor is selected from the group consisting of a osteochondroma, a benign chondrioma, a osteoid osteoma, a chondroid tumor-like hamartoma, multiple myeloma, and a skull tumor;

The adenoma is selected from fibroadenoma, adenomatoid tumor, hepatocellular adenoma, bronchial adenoma, tubular adenoma, villous adenoma, breast cancer, pancreatic cancer, endometrial adenocarcinoma, prostate cancer, ductal adenocarcinoma, and large intestine adenocarcinoma;

the fibroids are selected from fibroids, chondromyxofibroids, neurofibromas and spinal neurofibromas;

the myeloproliferative disorder is selected from multiple myeloma and myelodysplastic syndrome;

The lung cancer is selected from bronchogenic cancer and alveolar cancer;

the sarcoma is selected from fibrosarcoma, botryoid sarcoma, hemangiosarcoma, kaposi's sarcoma, osteosarcoma, chondrosarcoma, ewing's sarcoma, rhabdomyosarcoma, liposarcoma, leiomyosarcoma, and meningioma.

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.

The present invention also relates to a method of treating and/or preventing PRMT5 mediated diseases, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

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 application 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 and branched alkyl groups comprising from 1 to 10 carbon atoms, "C _1-4 alkyl" refers to straight chain and branched alkyl groups comprising from 1 to 4 carbon atoms, "C _0-8 alkyl" refers to straight chain and branched alkyl groups comprising from 0 to 8 carbon atoms, "C _0-4 alkyl" refers to straight chain and branched alkyl groups comprising from 0 to 4 carbon atoms.

The alkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more (preferably 1,2,3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, halo-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 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) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁ substituents.

"Cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which refers to a cyclic hydrocarbon that may contain one or more (preferably 1,2, or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, and cycloalkyl is classified as monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 or 3 to 8 or 3 to 6 carbon atoms, e.g., "C _3-12 cycloalkyl" refers to cycloalkyl including 3 to 12 carbon atoms, "C _4-8 cycloalkyl" refers to cycloalkyl including 4 to 8 carbon atoms, "C _3-8 cycloalkyl" refers to cycloalkyl including 3 to 8 carbon atoms, and "C _3-6 cycloalkyl" refers to cycloalkyl including 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, halo substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 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) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁ substituents.

"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 heteroatoms N, O, N-O or S (O) _r (where r is an integer 0, 1, 2), but excluding the ring portion of-O-, -O-S-or-S-with the remaining ring atoms being carbon. Preferred is a heterocyclic group including 3 to 12 or 3 to 8 or 3 to 6 ring atoms, for example, "3-6 membered heterocyclic group" means a heterocyclic group including 3 to 6 ring atoms, "3-8 membered heterocyclic group" means a heterocyclic group including 3 to 8 ring atoms, "4-8 membered heterocyclic group" means a heterocyclic group including 4 to 8 ring atoms, "4-10 membered heterocyclic group" means a heterocyclic group including 4 to 10 ring atoms, "5-8 membered heterocyclic group" means a heterocyclic group including 5 to 8 ring atoms, "3-12 membered heterocyclic group" means a heterocyclic group including 3 to 12 ring atoms.

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

Polycyclic heterocyclyl groups include spiro, fused and bridged heterocyclic groups. "spiroheterocyclyl" refers to a polycyclic heterocyclic group having one atom (referred to as the spiro atom) in common between monocyclic rings, wherein one or more (preferably 1, 2,3 or 4) ring atoms are selected from the group consisting of N, O, N-O or S (O) _r (where r is an integer 0, 1, 2) heteroatoms, 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, wherein 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 an integer 0, 1, 2) heteroatom 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" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly attached, which may contain one or more (preferably 1,2, or 3) double bonds, but none of which have a fully conjugated pi-electron system, wherein one or more (preferably 1,2,3, or 4) ring atoms are selected from N, O, N-O or S (O) _r (where r is an integer of 0,1, 2) heteroatoms 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, halo-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 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) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁) substituted substituents.

"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 with adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably an all-carbon aryl group containing 6-10 or 6-8 carbons, e.g., "C _6-10 aryl" refers to an all-carbon aryl group containing 6-10 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, halo substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 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) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁ substituents.

"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 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, halo-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 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) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁ substituents.

"Alkenyl" refers to 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 a straight or branched alkenyl group containing 2 to 10 carbons, and "C _2-4 alkenyl" refers to a straight or branched alkenyl group 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 substituent(s) are preferably one or more (preferably 1,2,3 or 4) groups independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, halo substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, deuterium, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 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) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁ substituents.

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

"Alkynyl" may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more (preferably 1,2,3 or 4) of the following groups, independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, halo-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 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) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁ substituents.

"Alkoxy" refers to an-O-alkyl group wherein alkyl is as defined above, for example, "C _1-10 alkoxy" refers to an alkyl oxy group containing 1-10 carbons, "C _1-4 alkoxy" refers to an alkyl oxy group containing 1-4 carbons, and "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 substituent(s), preferably one or more (preferably 1,2,3 or 4) independently selected from deuterium, halogen, cyano, nitro, azido, C _1-10 alkyl, halo substituted C _1-10 alkyl, deuterium substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 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) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁ substituents.

"Cycloalkoxy" or "cycloalkyloxy" refers to-O-cycloalkyl, wherein cycloalkyl is as defined above, e.g., "C _3-12 Cycloalkoxy" refers to cycloalkyloxy having 3-12 carbons, and "C _3-6 Cycloalkoxy" refers to cycloalkyloxy 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, halo-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 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) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁ substituents.

"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, halo-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, 3-to 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) ₂R₉、-C_0-8 alkyl-S (O) _rR₉、-C_0-8 alkyl-O-R ₁₀、-C_0-8 alkyl-C (O) OR ₁₀、-C_0-8 alkyl-C (O) SR ₁₀、-C_0-8 alkyl-S-C (O) R ₁₁、-C_0-8 alkyl-C (O) R ₁₁、-C_0-8 alkyl-O-C (O) R ₁₁、-C_0-8 alkyl-P (O) (R ₁₁)₂、-C_0-8 alkyl-NR ₁₂R₁₃、-C_0-8 alkyl-C (O) NR ₁₂R₁₃ and-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁ substituents.

"C _1-10 alkanoyl" refers to a monovalent radical remaining after removal of the hydroxyl group of a C _1-10 alkyl acid, also commonly referred to 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) ₂R₉" means that the oxygen atom in-O-S (O) ₂R₉ is attached to a C _0-8 alkyl group, wherein C _0-8 alkyl is as defined above.

"-C _0-8 alkyl-S (O) _rR₉" means that the sulfur atom in-S (O) _rR₉ is attached to a C _0-8 alkyl group, wherein C _0-8 alkyl is as defined above.

"-C _0-8 alkyl-O-R ₁₀" means that the oxygen atom in-O-R ₁₀ is attached to a C _0-8 alkyl group, wherein C _0-8 alkyl is as defined above.

"-C _0-8 alkyl-C (O) OR ₁₀" means that the carbonyl group in-C (O) OR ₁₀ is attached to a C _0-8 alkyl group, wherein C _0-8 alkyl is as defined above.

"-C _0-8 alkyl-C (O) SR ₁₀" means that the carbonyl group in-C (O) SR ₁₀ is attached to a C _0-8 alkyl group, wherein C _0-8 alkyl is as defined above.

"-C _0-8 alkyl-S-C (O) R ₁₁" means that the sulfur atom in-S-C (O) R ₁₁ is attached to a C _0-8 alkyl group, wherein C _0-8 alkyl is as defined above.

"-C _0-8 alkyl-C (O) R ₁₁" means that the carbonyl group in-C (O) R ₁₁ is attached to a C _0-8 alkyl group, wherein C _0-8 alkyl is as defined above.

"-C _0-8 alkyl-O-C (O) R ₁₁" means that the oxygen atom in-O-C (O) R ₁₁ is attached to a C _0-8 alkyl group, wherein C _0-8 alkyl is as defined above.

"-C _0-8 alkyl-P (O) (R ₁₁)₂" means-P (O) (the phosphorus atom in R ₁₁)₂ is attached to a C _0-8 alkyl group, wherein C _0-8 alkyl is as defined above).

"-C _0-8 alkyl-NR ₁₂R₁₃" means that the nitrogen atom in-NR ₁₂R₁₃ is attached to a C _0-8 alkyl group, wherein C _0-8 alkyl is as defined above.

"-C _0-8 alkyl-C (O) NR ₁₂R₁₃" means that the carbonyl group in-C (O) NR ₁₂R₁₃ is attached to a C _0-8 alkyl group, wherein C _0-8 alkyl is as defined above.

"-C _0-8 alkyl-N (R ₁₂)-C(O)R₁₁" means that the nitrogen atom in R ₁₂)-C(O)R₁₁ is attached to a C _0-8 alkyl group, wherein C _0-8 alkyl is as defined above).

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

"Halo-substituted C _1-10 alkoxy" refers to a 1-10 carbon alkoxy group wherein the hydrogen on the alkyl group is optionally substituted with a fluorine, chlorine, bromine, or iodine atom. 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 group is optionally substituted with a deuterium atom. 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).

"Stereoisomer" is named stereoisomer, and refers to an isomer produced by the different spatial arrangements of atoms in a molecule, and can be classified into cis-trans isomers and enantiomers, and also into enantiomers and diastereomers. Stereoisomers due to rotation of single bonds are known as conformational isomers (conformational stereo-isomers), sometimes also known as rotamers (rotamer). 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 the isomer due to the inability of the double bond or single bond of the ring-forming carbon atom to rotate freely becomes the geometric isomer (geometric isomer), also known as cis-trans isomer (cis-trans isomer), and is classified into two configurations of Z, E. 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) as solvents and Tetramethylsilane (TMS) as internal standard.

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

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

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

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

Preparation of intermediates

Intermediate 1:2- (1-methylpiperidin-4-yl) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] thiazole, first step: synthesis of 5-chloro-2- (1-methylpiperidin-4-yl) benzo [ d ] thiazole

2-Amino-4-chlorobenzenethiol (3.00 g,18.8 mmol), 1-methylpiperidine-4-carboxylic acid (2.69 g,18.8 mmol), N-diisopropylethylamine (6.55 mL,37.6 mmol) and 50% 1-propylphosphoric anhydride (12.0 g,18.8 mmol) were dissolved in a 100mL round bottom flask, nitrogen replaced three times and stirred overnight at 100 ℃. The reaction solution was cooled to room temperature, pH was adjusted to 9 to 10 with saturated sodium hydrogencarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation to give 5-chloro-2- (1-methylpiperidin-4-yl) benzo [ d ] thiazole (4.50 g, yield: 90%). MS m/z (ESI): 267[ M+H ] ⁺.

And a second step of: synthesis of 2- (1-methylpiperidin-4-yl) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] thiazole

5-Chloro-2- (1-methylpiperidin-4-yl) benzo [ d ] thiazole (1.80 g,6.75 mmol) and pinacol biborate (2.57 g,10.12 mmol) were dissolved in dioxane (40 mL), potassium acetate (1.66 g,16.87 mmol), tricyclohexylphosphine (305 mg,1.09 mmol) and bis (dibenzylideneacetone) palladium (313 mg,0.54 mmol) were added, nitrogen was displaced three times and stirred overnight at 105 ℃. After the reaction is finished, filtering, washing a filter cake by ethyl acetate, and concentrating the filtrate by rotary evaporation. The residue was separated by column chromatography to give 2- (1-methylpiperidin-4-yl) -5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] thiazole (1.93 g, yield: 80%). MS m/z (ESI): 359[ M+H ] ⁺.

The intermediates 2 to 6 can be prepared by selecting corresponding raw materials according to a full or partial synthesis method of the intermediate 1:

Intermediate 7: preparation of 2-methyl-5- (4-methylpiperidin-2-yl) benzo [ d ] thiazole

The first step: synthesis of 4-methylpiperidin-2-one

4-Methylpyridin-2 (1H) -one (25.0 g,0.23 mol) was dissolved in acetic acid (30 mL), 10% palladium on carbon (4.88 g) was added, and the reaction mixture was stirred under a hydrogen atmosphere at 70℃for 24 hours. After the reaction, the mixture was filtered, and the filtrate was concentrated by direct rotary evaporation to give a crude 4-methylpiperidin-2-one (25.4 g). MS m/z (ESI) 114[ M+H ] ⁺.

And a second step of: synthesis of tert-butyl 4-methyl-2-oxopiperidine-1-carboxylate

4-Methylpiperidin-2-one (23.0 g,0.20 mol) was dissolved in tetrahydrofuran (30 mL), and di-tert-butyl dicarbonate (47.8 mL,0.22 mol), 4-dimethylaminopyridine (4.97 g,40.6 mmol) and triethylamine (28.2 mL,0.20 mol) were added and stirred at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate and water, the separated solution was concentrated by rotary evaporation, and the residue was subjected to column chromatography to give tert-butyl 4-methyl-2-oxopiperidine-1-carboxylate (7.0 g, yield: 16%). MS m/z (ESI) 158[ M-56+H ] ⁺. And a third step of: synthesis of tert-butyl 4-methyl-6- (((trifluoromethyl) sulfonyl) oxy) -3, 4-dihydropyridine-1 (2H) -carboxylate

Tert-butyl 4-methyl-2-oxopiperidine-1-carboxylate (1.00 g,4.69 mmol) was dissolved in dry tetrahydrofuran (40 mL), cooled to-78℃and a solution of potassium bis (trimethylsilyl) amide in tetrahydrofuran (6.1 mL,6.10 mmol) was slowly added. After the completion of the addition, the reaction was continued at-78℃for 1 hour with stirring, and N-phenylbis (trifluoromethanesulfonyl) imide (2.177 g,6.10 mmol) was added thereto, and the reaction mixture was continued at-78℃with stirring for 2 hours. The reaction solution was diluted with ethyl acetate and water, the separated solution was concentrated by rotary evaporation, and the residue was subjected to column chromatography to give tert-butyl 4-methyl-6- (((trifluoromethyl) sulfonyl) oxy) -3, 4-dihydropyridine-1 (2H) -carboxylate (900 mg, yield: 54%). MS m/z (ESI): 290[ M-56+H ] ⁺.

Fourth step: synthesis of tert-butyl 4-methyl-6- (2-methylbenzo [ d ] thiazol-5-yl) -3, 4-dihydropyridine-1 (2H) -carboxylate

Tert-butyl 4-methyl-6- (((trifluoromethyl) sulfonyl) oxy) -3, 4-dihydropyridine-1 (2H) -carboxylate (319 mg,1.16 mmol) and 2-methyl-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] thiazole (400 mg,1.16 mmol) were dissolved in dioxane (9 mL) and water (3 mL), sodium carbonate (365 mg,3.48 mmol) and 1, 1-bis (diphenylphosphine) iron-palladium dichloride (85 mg,0.12 mmol) were added, nitrogen replaced three times and stirred overnight at 90 ℃. After the reaction was completed, it was diluted with water, extracted twice with ethyl acetate, and the organic phases were combined and concentrated by rotary evaporation. Column chromatography of the residue gave tert-butyl 4-methyl-6- (2-methylbenzo [ d ] thiazol-5-yl) -3, 4-dihydropyridine-1 (2H) -carboxylic acid ester (180 mg, yield: 45%). MS m/z (ESI): 345[ M+H ] ⁺.

Fifth step: synthesis of 2-methyl-5- (4-methyl-3, 4,5, 6-tetrahydropyridin-2-yl) benzo [ d ] thiazole

Tert-butyl 4-methyl-6- (2-methylbenzo [ d ] thiazol-5-yl) -3, 4-dihydropyridine-1 (2H) -carboxylate (180 mg,0.52 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 1 hour. After the reaction, the solvent was removed by concentration. The residue was diluted with dichloromethane, the pH was adjusted to 8-9 with saturated sodium carbonate solution and extracted twice with dichloromethane. The organic phases were combined and concentrated by rotary evaporation to give 2-methyl-5- (4-methyl-3, 4,5, 6-tetrahydropyridin-2-yl) benzo [ d ] thiazole (127 mg, yield: 100%). MS m/z (ESI): 245[ M+H ] ⁺.

Sixth step: synthesis of 2-methyl-5- (5-methylpiperidin-2-yl) benzo [ d ] thiazole

2-Methyl-5- (5-methyl-3, 4,5, 6-tetrahydropyridin-2-yl) benzo [ d ] thiazole (128 mg,0.52 mmol) was dissolved in methanol (5 mL), cooled in an ice bath, and sodium borohydride (53 mg,1.57 mmol) was added thereto and the reaction was stirred in an ice bath for 1 hour. After the reaction, the solvent was removed by concentration. Column chromatography of the residue gave 2-methyl-5- (5-methylpiperidin-2-yl) benzo [ d ] thiazole (95 mg, yield: 74%). MS m/z (ESI) 247[ M+H ] ⁺.

The intermediates 8 to 15 can be prepared by selecting corresponding raw materials according to all or partial synthesis methods of the intermediate 7:

Intermediate 16: preparation of 3- (2- (1-methylpiperidin-4-yl) benzo [ d ] thiazol-5-yl) morpholine

The first step: synthesis of tert-butyl 5- ((diphenoxyphosphoryl) oxy) -2, 3-dihydro-4H-1, 4-oxazine-4-carboxylate

Tert-butyl 3-oxomorpholine-4-carboxylate (1.00 g,4.97 mmol) was dissolved in dry tetrahydrofuran (40 mL), cooled to-40℃and a solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran (5.47 mL,5.47 mmol) was slowly added. After the completion of the addition, the reaction was continued at-40℃for 1 hour with stirring, diphenyl phosphoryl chloride (1.09 mL,5.22 mmol) was added, and the reaction mixture was continued at-40℃with stirring for 2 hours. The reaction solution was diluted with ethyl acetate and saturated ammonium chloride solution, the separated solution was concentrated by rotary evaporation, and the residue was separated by column chromatography to give tert-butyl 5- ((diphenoxyphosphoryl) oxy) -2, 3-dihydro-4H-1, 4-oxazine-4-carboxylate (1550 mg, yield: 72%). MS m/z (ESI): 334[ M-Boc+H ] ⁺.

And a second step of: synthesis of tert-butyl 5- (2-methylbenzo [ d ] thiazol-5-yl) -2, 3-dihydro-4H-1, 4-oxazine-4-carboxylate

Tert-butyl 5- ((diphenoxyphosphoryl) oxy) -2, 3-dihydro-4H-1, 4-oxazine-4-carboxylate (750 mg,1.38 mmol) and 2-methyl-5- (4, 5-tetramethyl-1, 2-dioxaborolan-2-yl) benzo [ d ] thiazole (381 mg,1.38 mmol) were dissolved in dioxane (15 mL) and water (3 mL), sodium carbonate (587 mg,5.54 mmol) and 1, 1-bis (diphenylphosphine) iron palladium dichloride (101 mg,0.14 mmol) were added, nitrogen replaced three times and stirred overnight at 95 ℃. After the reaction was completed, it was diluted with water, extracted twice with ethyl acetate, and the organic phases were combined and concentrated by rotary evaporation. The residue was subjected to column chromatography to give tert-butyl 5- (2-methylbenzo [ d ] thiazol-5-yl) -2, 3-dihydro-4H-1, 4-oxazine-4-carboxylate (400 mg, yield: 87%). MS m/z (ESI): 333[ M+H ] ⁺.

And a third step of: synthesis of 5- (2-methylbenzo [ d ] thiazol-5-yl) -3, 6-dihydro-2H-1, 4-oxazine

Tert-butyl 5- (2-methylbenzo [ d ] thiazol-5-yl) -2, 3-dihydro-4H-1, 4-oxazine-4-carboxylate (390 mg,1.17 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the reaction was carried out at room temperature for 3 hours. The reaction solution was diluted with dichloromethane, the pH was adjusted to 8-9 with saturated sodium carbonate solution, and extraction was performed twice with dichloromethane. The organic phases were combined and concentrated by rotary evaporation to give 5- (2-methylbenzo [ d ] thiazol-5-yl) -3, 6-dihydro-2H-1, 4-oxazine (270 mg, yield: 84%, purity: 85%). MS m/z (ESI): 233[ M+H ] ⁺.

Fourth step: synthesis of 3- (2-methylbenzo [ d ] thiazol-5-yl) morpholine

5- (2-Methylbenzo [ d ] thiazol-5-yl) -3, 6-dihydro-2H-1, 4-oxazine (270 mg, purity: 85%,0.99 mmol) was dissolved in methanol (10 mL), and sodium borohydride (100 mg,2.97 mmol) was added thereto, and the reaction was stirred at room temperature for 1 hour. After the reaction, the solvent was removed by concentration. Column chromatography of the residue gave 3- (2-methylbenzo [ d ] thiazol-5-yl) morpholine (205 mg, yield: 86%). MS m/z (ESI): 235[ M+H ] ⁺.

Intermediates 17 to 19 can be prepared by selecting the corresponding starting materials with reference to the overall or partial synthesis of intermediate 16:

Intermediate 20: preparation of 4-amino-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxylic acid

The first step: synthesis of methyl 4-amino-5-bromo-2-fluorobenzoate

Methyl 4-amino-2-fluorobenzoate (20.8 g,123.0 mmol) was dissolved in chloroform (500 mL), N-bromosuccinimide (21.89 g,123.0 mmol) was added at 0deg.C, and the reaction was stirred at 20deg.C for 16 hours. The reaction solution was concentrated by rotary evaporation, and the crude product was separated by a normal phase column to give methyl 4-amino-5-bromo-2-fluorobenzoate (27.9 g, yield 91%). MS m/z (ESI) 248,250[ M+H ] ⁺.

¹H NMR(400MHz,CDCl₃)δ8.04(d,J＝7.2Hz,1H),6.46(d,J＝12.2Hz,1H),4.62(s,2H),3.88(s,3H).

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

Methyl 4-amino-5-bromo-2-fluorobenzoate (27.9 g,112.5 mmol) and pinacol diboronate (35 mL,135 mmol) were dissolved in dioxane (300 mL) and potassium acetate (33.12 g,337.4 mmol) and 1,1' -bis (diphenylphosphino) ferrocene palladium (II) dichloride (8.23 g,11.2 mmol) were added. The mixture was stirred at 100℃for 18 hours. The reaction solution was filtered and dried. The crude product is diluted with water, extracted three times with ethyl acetate, the organic phase is washed with saturated saline, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated by rotary evaporation. The crude product was separated by normal phase column to give methyl 4-amino-2-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (25.2 g, 76%). MS m/z (ESI): 296[ M+H ] ⁺.

¹H NMR(400MHz,CDCl₃)δ8.25(d,J＝9.2Hz,1H),6.24(d,J＝13.2Hz,1H),5.29(s,2H),3.86(s,3H),1.34(s,12H).

And a third step of: synthesis of methyl 4-amino-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxylate

5-Bromo-1-methyl-1H-pyrazole-4-carbonitrile (9.1 g,48.9 mmol), methyl 4-amino-2-fluoro-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzoate (14.4 g,48.9 mmol), potassium carbonate (27.04 g,195.7 mmol) and tetrakis (triphenylphosphine) palladium (7.35 g,6.4 mmol) were added to 1, 4-dioxane (100 mL) and water (100 mL) and reacted at 100℃for 16H under nitrogen. The organic solvent was evaporated under reduced pressure, filtered, and the filter cake was washed with ethanol (50 mL), and the filter cake was dried to give methyl 4-amino-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxylate (13.28 g, yield 99%). MS m/z (ESI): 275[ M+H ] ⁺.

Fourth step: synthesis of 4-amino-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxylic acid

Methyl 4-amino-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxylate (13.28 g,48.4 mmol) was added to tetrahydrofuran (100 mL) and water (100 mL), followed by lithium hydroxide monohydrate (4.06 g,96.8 mmol) and reacted at 50℃for 16 hours. After completion of the reaction the organic phase was dried and diluted with water and extracted with ethyl acetate (200 ml x 6). The aqueous phase was adjusted to ph=2 with saturated potassium bisulfate, a large amount of solids precipitated, filtered and the cake was washed with water (100 mL) and acetonitrile (100 mL) and dried to give 4-amino-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxylic acid (6.7 g, yield 53%). MS m/z (ESI): 261[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ8.73(d,J＝8.0Hz,1H),8.27(s,1H),7.54(s,2H),7.27(d,J＝13.2Hz,1H),4.38(s,3H).

Intermediates 21-26 can be prepared by selecting the corresponding starting materials with reference to the overall or partial synthetic method of intermediate 20:

intermediate 27: preparation of 5- ((2R, 5S) -5-methylpiperidin-2-yl) benzo [ d ] thiazole

The first step: synthesis of methyl 4-methyl-5-oxopentanoate

To potassium carbonate (4.76 g,34.43 mmol) was added propionaldehyde (5.0 g,86.09 mmol) under an ice-water bath, and the mixture was stirred vigorously at room temperature for 18 hours. The mixture was filtered, the mother liquor was dried over anhydrous sodium sulfate, filtered again, and the filtrate was concentrated and dissolved in acetonitrile (50 mL), and methyl acrylate (14.82 g,172.2 mmol) was slowly added dropwise. The reaction solution was heated under reflux for 24 hours. Glacial acetic acid (10.34 g,172.2 mmol) and water (50 mL) are added and refluxed for an additional 24 hours. The reaction mixture was diluted with water, extracted with t-butyl methyl ether, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation. The crude product was isolated by normal phase column to give methyl 4-methyl-5-oxopentanoate (6.22 g, 47.6% yield).

¹H NMR(400MHz,CDCl₃)δ9.63(d,J＝1.6Hz,1H),3.68(s,3H),2.48-2.40(m,1H),2.41-2.35(m,2H),2.10-2.02(m,1H),1.71(dq,J＝14.3,7.3Hz,1H),1.14(d,J＝7.2Hz,3H). And a second step of: synthesis of (3R, 8S) -8-methyl-3-phenylhexahydro-5H-oxazolo [3,2-a ] pyridin-5-one

To toluene (100 mL) of methyl 4-methyl-5-oxopentanoate (6.222 g,43.16 mmol) was added (R) -2-amino-2-phenylethan-1-ol (5.92 g,43.16 mmol), and the mixture was heated under reflux for 24 hours and water was removed by a water separator. The reaction solution was concentrated, and the crude product was separated by normal phase column to give (3R, 8S) -8-methyl-3-phenylhexahydroo-5H-oxazolo [3,2-a ] pyridin-5-one (4.866 g, yield 46.3%). MS m/z (ESI) 232[ M+H ] ⁺.

¹H NMR(400MHz,CDCl₃)δ7.33-7.20(m,5H),4.93(dd,J＝6.8,1.3Hz,1H),4.44(d,J＝8.8Hz,1H),4.17-4.08(m,2H),4.01(dd,J＝9.0,1.3Hz,1H),2.46-2.28(m,2H),2.02-1.87(m,2H),1.60-1.45(m,1H),1.21(d,J＝6.4Hz,3H).

And a third step of: synthesis of (S) -1- ((R) -2-hydroxy-1-phenylethyl) -5-methylpiperidin-2-one

To a solution of (3R, 8S) -8-methyl-3-phenylhexahydro-5H-oxazolo [3,2-a ] pyridin-5-one (4.866 g,21.04 mmol) in dry dichloromethane (200 mL) was added triethylsilane (7.34 g,63.12 mmol) and titanium tetrachloride (17.96 g,94.68 mmol), and the mixture was reacted at 50℃for 24 hours. Triethylsilane (7.34 g,63.12 mmol) and titanium tetrachloride (17.96 g,94.68 mmol) were added and the reaction was continued at 50℃for 24 hours. The reaction solution was slowly poured into saturated sodium bicarbonate solution (500 mL), and the aqueous phase was filtered and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was isolated by normal phase column to give (S) -1- ((R) -2-hydroxy-1-phenylethyl) -5-methylpiperidin-2-one (1.54 g, 31.4% yield). MS m/z (ESI): 234[ M+H ] ⁺.

Fourth step: synthesis of (S) -5-methyl-1- (1-phenylvinyl) piperidin-2-one

To a solution of (S) -1- ((R) -2-hydroxy-1-phenylethyl) -5-methylpiperidin-2-one (10.3 g,44.15 mmol) in DMSO (150 mL) was added lithium hydroxide monohydrate (37.05 g,882.9 mmol). The mixture was reacted at 135℃for 4 days. Poured into water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give (S) -5-methyl-1- (1-phenylvinyl) piperidin-2-one (7.383 g, yield 66.0%). MS m/z (ESI): 216.3[ M+H ] ⁺.

Fifth step: synthesis of (S) -5-methylpiperidin-2-one

To a solution of (S) -5-methyl-1- (1-phenylvinyl) piperidin-2-one (7.28 g,33.81 mmol) in methylene chloride (30 mL) was added TFA (30 mL) and water (3 mL). The reaction was carried out overnight at 40 ℃. After concentration, crude product was isolated by reverse phase column, lyophilized, added with ammonia (3 mL), concentrated to dryness, and filtered with ethyl acetate (2.52 g, 62.6% yield) to give (S) -5-methylpiperidin-2-one. MS m/z (ESI) 114[ M+H ] ⁺.

¹H NMR(400MHz,MeOD)δ3.30-3.24(m,1H),2.86(dd,J＝12.2,10.1Hz,1H),2.39-2.26(m,2H),1.96-1.80(m,2H),1.54-1.40(m,1H),1.01(d,J＝6.5Hz,3H).

Sixth step: synthesis of tert-butyl (S) -5-methyl-2-oxopiperidine-1-carboxylate

To a solution of (S) -5-methylpiperidin-2-one (2.02 g,17.85 mmol) in tetrahydrofuran (25 mL) was added DMAP (327 mg,2.68 mmol) and di-tert-butyl dicarbonate (6.22 g,26.78 mmol). The reaction was carried out overnight at 25 ℃. The reaction mixture was concentrated, which was then diluted with methylene chloride, followed by washing with a 5% potassium hydrogen sulfate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give tert-butyl (S) -5-methyl-2-oxopiperidine-1-carboxylate (3.48 g,12.55mmol, 70.3%). MS m/z (ESI) 214[ M+H ] ⁺.

¹H NMR(400MHz,CDCl₃)δ3.83-3.75(m,1H),3.11(dd,J＝12.7,10.4Hz,1H),2.63-2.53(m,1H),2.53-2.41(m,1H),2.01-1.93(m,1H),1.92-1.83(m,1H),1.53(s,9H),1.46-1.40(m,1H),1.04(d,J＝6.6Hz,3H).

Seventh step: synthesis of tert-butyl (S) -3-methyl-6- (((trifluoromethyl) sulfonyl) oxy) -3, 4-dihydropyridine-1 (2H) -carboxylate

To a solution of tert-butyl (S) -5-methyl-2-oxopiperidine-1-carboxylate (1.00 g,4.69 mmol) in anhydrous tetrahydrofuran (25 mL) was added sodium bis (trimethylsilyl) amide (3.52 mL,7.03 mmol) at-78deg.C. The reaction solution was reacted at this temperature for 1 hour. N-phenyl bis (trifluoromethanesulfonyl imide) (2.18 g,6.10 mmol) was then added. The reaction solution was slowly warmed up and stirred at room temperature for 3.5 hours. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was isolated by normal phase column to give tert-butyl (S) -3-methyl-6- (((trifluoromethyl) sulfonyl) oxy) -3, 4-dihydropyridine-1 (2H) -carboxylate (1.05 g, 62.4% yield). MS m/z (ESI): 290[ M+H-56] ⁺.

¹H NMR(400MHz,CDCl₃)δ5.25(t,J＝3.8Hz,1H),3.87(dd,J＝12.8,3.3Hz,1H),3.00(dd,J＝12.7,9.1Hz,1H),2.44-2.34(m,1H),1.98-1.88(m,1H),1.88-1.78(m,1H),1.49(s,9H),0.99(d,J＝6.6Hz,3H).

Eighth step: synthesis of tert-butyl (S) -6- (benzo [ d ] thiazol-5-yl) -3-methyl-3, 4-dihydropyridine-1 (2H) -carboxylate

Tert-butyl (S) -3-methyl-6- (((trifluoromethyl) sulfonyl) oxy) -3, 4-dihydropyridine-1 (2H) -carboxylate (1.39 g,4.02 mmol), 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] thiazole (1.00 g,3.83 mmol), sodium carbonate (1.01 g,9.57 mmol) and 1,1' -bis-diphenylphosphino ferrocene palladium dichloride (140 mg,0.191 mmol) were added to 1, 4-dioxane (30 mL) and water (10 mL) and reacted at 90℃for 18 hours under nitrogen. The reaction solution was diluted with ethyl acetate, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was isolated by normal phase column to give tert-butyl (S) -6- (benzo [ d ] thiazol-5-yl) -3-methyl-3, 4-dihydropyridine-1 (2H) -carboxylate (1.01 g, yield 74.9%). MS m/z (ESI): 331[ M+H ] ⁺.

Ninth step: synthesis of (S) -5- (5-methyl-3, 4,5, 6-tetrahydropyridin-2-yl) benzo [ d ] thiazole

To a solution of tert-butyl (S) -6- (benzo [ d ] thiazol-5-yl) -3-methyl-3, 4-dihydropyridine-1 (2H) -carboxylate (1.01 g,3.05 mmol) in dichloromethane (9 mL) was added trifluoroacetic acid (3 mL,2.68 mmol). The reaction was carried out overnight at 25 ℃. The reaction mixture was concentrated, diluted with water, adjusted to pH8 with aqueous ammonia, and extracted with methylene chloride. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give (S) -5- (5-methyl-3, 4,5, 6-tetrahydropyridin-2-yl) benzo [ d ] thiazole (0.70 g, yield 91.7%). MS m/z (ESI) 231[ M+H ] ⁺.

Tenth step: synthesis of 5- ((2R, 5S) -5-methylpiperidin-2-yl) benzo [ d ] thiazole

To a solution of (S) -5- (5-methyl-3, 4,5, 6-tetrahydropyridin-2-yl) benzo [ d ] thiazole (0.70 g,3.04 mmol) in methanol (5 mL) was added sodium borohydride (308 mg,9.12 mmol) under an ice-water bath. The reaction was stirred at room temperature for 45 minutes. The reaction mixture was concentrated, diluted with water, adjusted to pH 8 with aqueous ammonia, and extracted with methylene chloride. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 5- ((2R, 5S) -5-methylpiperidin-2-yl) benzo [ d ] thiazole (0.69 g, yield 97.6%). MS m/z (ESI): 233[ M+H ] ⁺.

¹H NMR(400MHz,CDCl₃)δ8.98(s,1H),8.15(d,J＝1.7Hz,1H),7.88(d,J＝8.3Hz,1H),7.56(dd,J＝8.3,1.7Hz,1H),3.78(dd,J＝11.4,2.6Hz,1H),3.22-3.13(m,1H),2.48(t,J＝11.4Hz,1H),1.97-1.87(m,2H),1.86-1.68(m,2H),1.30-1.19(m,1H),0.92(d,J＝6.6Hz,3H).

Preparation of examples

Example 1: preparation of (4-amino-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinolin-8-yl) (2- (2- (1-methylpiperidin-4-yl) benzo [ d ] thiazol-5-yl) piperidin-1-yl) methanone

2- (1-Methylpiperidin-4-yl) -5- (piperidin-2-yl) benzo [ d ] thiazole (74 mg,0.15 mmol) and 4-amino-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinoline-8-carboxylic acid (40 mg,0.15 mmol) were dissolved in N, N-dimethylformamide (3 mL), triethylamine (71 mg,0.70 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (80 mg,0.21 mmol) were added, and nitrogen was replaced three times at room temperature and stirred overnight. The reaction mixture was directly subjected to reverse phase separation to give (4-amino-7-fluoro-1-methyl-1H-pyrazolo [4,3-c ] quinolin-8-yl) (2- (2- (1-methylpiperidin-4-yl) benzo [ d ] thiazol-5-yl) piperidin-1-yl) methanone (13 mg, yield: 15%). MS m/z (ESI): 558[ M+H ] ⁺.

¹H NMR(400MHz,DMSO-d₆)δ8.33-7.72(m,4H),7.49-7.35(m,2H),7.29(s,2H),6.09-5.08(m,1H),4.60-4.42(m,3H),3.80-3.48(m,1H),3.17-2.58(m,6H),2.20(s,3H),2.10-2.00(m,4H),1.88-1.76(m,2H),1.70-1.40(m,4H).

Resolution of the compound of example 1 (940 mg,1.69 mmol) obtained according to the above preparation method by chiral SFC preparation (column: AS-H4.6 x 100mm,5um; mobile phase: methanol [0.2% ammonia (7M in methanol) ]/acetonitrile=30%; flow rate: 3.0mL/min; column temperature: 40 ℃ C.; detection wavelength: 214 nm) gave examples 1-1 (411 mg peak 1, retention time: 1.391 min) and examples 1-2 ((448 mg, peak 2, retention time: 1.890 min).

Examples 2 to 87 can be prepared by selecting the corresponding starting materials with reference to the whole or partial synthesis methods of examples 1, 1-2:

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

Biological test evaluation

1. Human colon cancer HCT116 cell proliferation inhibition test

1. HCT 116MTAP knockout and MTAP wild type cells were plated in 96-well flat bottom plates and cultured overnight at 37 ℃ with McCoy's 5A containing 10% fetal bovine serum +1% penicillin-streptomycin under 5% co ₂ 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 referred to kit instructions, and the cell plates were then placed on EnVision Multilabel Reader to detect luminescence signals.

4. The cell plates treated with the addition of the compound were simultaneously incubated at 37℃for 6 days under 5% CO ₂.

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

6. Finally, a four-parameter dose-response curve module of GRAPHPAD PRISM V9.2.0 software was used to plot 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.

2. Mouse pharmacokinetic assay

1. Purpose of investigation

The aim of this test was to study the pharmacokinetic behavior of a part of the compounds of the invention, administered in the following manner: ICR mice were dosed via single oral administration (PO): 10mg/kg.

2. Test protocol

2.1 Test drug

The compounds used in this test are derived from the compounds of the specific examples of the present invention.

2.2 Test animals

ICR mice male n=3 original source: shanghai Sipuler-BiKai laboratory animal Co., ltd.

2.3 Pharmaceutical formulation and administration

Weighing the compounds, respectively dissolving in 20%PG+10%Solutol HS15+70%pH3 citrate buffer solvents, shaking, and performing ultrasonic treatment to obtain colorless clear solution or suspension. 9 mice were orally administered after one night of fasting. The administration dose is 10mg/kg.

2.4 Sample collection:

1) About 90 μl/time point was taken via submandibular vein, heparin sodium was anticoagulated, placed on ice after collection, and plasma was centrifuged within 1 hour (centrifugation conditions: 8000 rpm, 6 minutes, 2-8 degrees).

2) The time point of blood collection was 1,4,24 hours. The sample was stored in a minus 20 degree refrigerator.

3) Plasma samples 40. Mu.L were added 160. Mu.L of ice-cold acetonitrile containing an internal standard, vortexed for 3 minutes and centrifuged at 11000 rpm for 5 minutes.

4) 100. Mu.L of the supernatant was added to 100. Mu.L of water, and 5. Mu.L of the mixture was sampled to LC/MS/MS for analysis.

3. Blood brain barrier penetration analysis in mice

Kp is calculated by AUC or concentration in brain or plasma measured by the method described above. Kp refers to the relationship between brain and drug concentration in the blood and is used to assess the ability of a drug to penetrate the blood brain barrier. Kp after administration was calculated by the following formula:

Kp= [ AUC (brain)/AUC (plasma) ], or kp= [ drug concentration (brain)/drug concentration (plasma) ].

Table 2: kp data for example compounds and comparative compounds

From the above data, the compounds of examples 82 and 83 of the present invention have very high Kp and excellent blood brain barrier penetration properties.

All documents mentioned in this disclosure are incorporated by reference in this disclosure 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 application, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims

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

Wherein, _X1 is _CR6 or N; _X2 is _CR7 or N; _X3 is _CR8 or N;

Ring A is a C _4-12 cycloalkyl group, a 4-12 membered heterocyclyl group, a C _6-10 aryl group, or a 5-10 membered heteroaryl group;

Ring B is selected from a 4-10 membered nitrogen-containing heterocyclic group or a 5-10 membered nitrogen-containing heteroaryl group, wherein the nitrogen atom is connected to the carbonyl group, wherein

1) When ring B is selected from a 4-membered nitrogen-containing heterocyclic group, an 8-10-membered nitrogen-containing heterocyclic group or an 8-10-membered nitrogen-containing heteroaryl group,

Ring C is a C _3-12 cycloalkyl, a 4-12 membered heterocyclyl, a C _6-10 aryl or a 5-10 membered heteroaryl, wherein the C _3-12 cycloalkyl or the 4-12 membered heterocyclyl is optionally fused to a C _6-10 aryl or a 5-10 membered heteroaryl, wherein the C _6-10 aryl or the 5-10 membered heteroaryl is optionally fused to a C _3-12 cycloalkyl or a 4-12 membered heterocyclyl;

each R ₁ is 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-OS(O) ₂ R ₉ , -C _0-8 alkyl-S(O) _r R ₉ , -C _0-8 alkyl-OR ₁₀ , -C _0-8 alkyl-C(O)OR ₁₀ , -C _0-8 alkyl-C(O)SR ₁₀ , -C _0-8 alkyl-SC(O)R ₁₁ , -C _0-8 alkyl-C(O)R ₁₁ , -C _0-8 alkyl-OC(O)R ₁₁ , -C _0-8 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-8 alkyl-NR ₁₂ R ₁₃ , -C _0-8 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-8 alkyl-N(R ₁₂ )-C(O)R ₁₁ , the above groups are independently optionally further substituted by one or more 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-OS(O) ₂ R ₉ , -C _{-C 0-8} alkyl-S(O) _r R ₉ , -C _0-8 alkyl-OR ₁₀ , -C _0-8 alkyl-C(O)OR ₁₀ , -C 0-8 alkyl-C(O) _SR ₁₀ , -C _0-8 alkyl-SC(O)R ₁₁ , -C _0-8 alkyl-C(O)R ₁₁ , -C _0-8 alkyl-OC(O)R ₁₁ , -C _0-8 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-8 alkyl-NR ₁₂ R ₁₃ , -C _0-8 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-8 alkyl-N(R ₁₂ )-C(O)R ₁₁ ;

2) When ring B is selected from a 5-7 membered nitrogen-containing heterocyclic group or a 5-7 membered nitrogen-containing heteroaryl group,

Ring C together with -(R ₁ ) _m forms: in,

a) When ring C and -(R ₁ ) _m form , Y ₁ and Y ₂ are each independently CR ₁ or N, Y ₃ is O, S or NR ₁ ', and Y ₄ and Y ₅ are each independently CR ₁ ' or N;

R ₁ 'is selected from hydrogen, deuterium, 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, -S(O) _r R ₉ , -OR ₁₀ , -C(O)OR ₁₀ , -C(O)R ₁₁ and -C(O)NR ₁₂ R ₁₃ , the above groups are independently optionally further substituted by one or more 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, -S(O) r R 9, -OR 10, -C(O)OR 10, -C(O)R 11 and -C(O)NR 12 R 13, the above groups are independently optionally further substituted by one or more 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 membered aryl, 5-10 membered heteroaryl, =O, =S, -C _0-8 alkyl-SF ₅ , -C _0-8 alkyl-OS(O) ₂ R ₉ , -C _0-8 alkyl-S(O) _r R ₉ , -C _0-8 alkyl-OR ₁₀ , -C _0-8 alkyl-C(O)OR ₁₀ , -C _0-8 alkyl-C(O)SR ₁₀ , -C _0-8 alkyl-SC(O)R ₁₁ , -C _0-8 alkyl-C(O)R ₁₁ , -C _0-8 alkyl-OC(O)R ₁₁ , -C _0-8 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-8 alkyl-NR ₁₂ R ₁₃ , -C 0-8 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-8 alkyl- _0-8 alkyl-N(R ₁₂ )-C(O)R ₁₁ ;

each R ₁ " is 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-OS(O) ₂ R ₉ , -C _0-8 alkyl-S(O) _r R ₉ , -C _0-8 alkyl-OR ₁₀ , -C _0-8 alkyl-C(O)OR ₁₀ , -C _0-8 alkyl-C(O)SR ₁₀ , -C _0-8 alkyl-SC(O)R ₁₁ , -C _0-8 alkyl-C(O)R ₁₁ , -C _0-8 alkyl-OC(O)R ₁₁ , -C _0-8 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-8 alkyl-NR ₁₂ R ₁₃ , -C _0-8 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-8 alkyl-N(R ₁₂ )-C(O)R ₁₁ , the above groups are independently optionally further substituted by one or more 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-OS(O) ₂ R ₉ , -C _{-C 0-8} alkyl-S(O) _r R ₉ , -C _0-8 alkyl-OR ₁₀ , -C _0-8 alkyl-C(O)OR ₁₀ , -C 0-8 alkyl-C(O) _SR ₁₀ , -C _0-8 alkyl-SC(O)R ₁₁ , -C _0-8 alkyl-C(O)R ₁₁ , -C _0-8 alkyl-OC(O)R ₁₁ , -C _0-8 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-8 alkyl-NR ₁₂ R ₁₃ , -C _0-8 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-8 alkyl-N(R ₁₂ )-C(O)R ₁₁ ;

b) When ring C and -(R ₁ ) _m form When Y ₆ , Y ₇ , Y ₈ and Y ₉ are each independently CR ₁ or N, and at least one is selected from CR ₁ , wherein at least one R ₁ is -C _0-8 alkyl-NR ₁₄ R ₁₅ or -OC _1-4 alkyl-NR ₁₄ R ₁₅ , and each of the other R ₁ is 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-OS(O) ₂ R ₉ , -C _0-8 alkyl-S(O) _r R ₉ , -C _0-8 alkyl-OR ₁₀ , -C _{-C 0-8} alkyl-C(O)OR ₁₀ , -C _0-8 alkyl-C(O)SR ₁₀ , -C _0-8 alkyl-SC(O)R ₁₁ , -C _0-8 alkyl-C(O)R ₁₁ , -C _0-8 alkyl-OC(O)R ₁₁ , -C _0-8 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-8 alkyl-NR ₁₂ R ₁₃ , -C _0-8 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-8 alkyl-N(R ₁₂ )-C(O)R ₁₁ , the above groups are independently optionally further substituted with one or more 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 _{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-OS(O) ₂ R ₉ , -C _0-8 alkyl-S(O) _r R ₉ , -C _0-8 alkyl-OR ₁₀ , -C _0-8 alkyl-C(O)OR ₁₀ , -C _0-8 alkyl-C(O)SR ₁₀ , -C _0-8 alkyl-SC(O)R ₁₁ , -C _0-8 alkyl-C(O)R ₁₁ , -C _0-8 alkyl-OC(O)R ₁₁ , -C _0-8 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-8 alkyl-NR ₁₂ R ₁₃ , -C _0-8 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-8 alkyl-N(R ₁₂ )-C(O)R ₁₁ ;

each R ₂ is 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-OS(O) ₂ R ₉ , -C _0-8 alkyl-S(O) _r R ₉ , -C _0-8 alkyl-OR ₁₀ , -C _0-8 alkyl-C(O)OR ₁₀ , -C _0-8 alkyl-C(O)SR ₁₀ , -C _0-8 alkyl-SC(O)R ₁₁ , -C _0-8 alkyl-C(O)R -C _0-8 _alkyl -OC(O)R ₁₁ , -C _0-8 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-8 alkyl-NR ₁₂ R ₁₃ , -C _0-8 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-8 alkyl-N(R ₁₂ )-C(O)R ₁₁ , or, when p ≥ 2, wherein two R ₂ together with the part to which they are directly attached form a C(O);

_R3 and _R4 are each independently selected from hydrogen, deuterium, hydroxyl, _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C3-12 cycloalkyl and 3-12 membered heterocyclyl, or, _R3 and _R4 together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, which groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, =O, =S, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, _C2-10 alkenyl, _C2-10 alkynyl, _C1-10 alkoxy, _C3-12 cycloalkyl, _C3-12 cycloalkyloxy, _3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy and _-NR12R13 ;

each R ₅ is 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-OS(O) ₂ R ₉ , -C _0-8 alkyl-S(O) _r R ₉ , -C _0-8 alkyl-OR ₁₀ , -C _0-8 alkyl-C(O)OR ₁₀ , -C _0-8 alkyl-C(O)SR ₁₀ , -C _0-8 alkyl-SC(O)R ₁₁ , -C _0-8 alkyl-C(O)R ₁₁ , -C _0-8 alkyl-OC(O)R ₁₁ , -C _0-8 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-8 alkyl-NR ₁₂ R ₁₃ , -C _0-8 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-8 alkyl-N(R ₁₂ )-C(O)R ₁₁ , the above groups are independently optionally further substituted by one or more 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-OS(O) ₂ R ₉ , -C _{-C 0-8} alkyl-S(O) _r R ₉ , -C _0-8 alkyl-OR ₁₀ , -C _0-8 alkyl-C(O)OR ₁₀ , -C 0-8 alkyl-C(O) _SR ₁₀ , -C _0-8 alkyl-SC(O)R ₁₁ , -C _0-8 alkyl-C(O)R ₁₁ , -C _0-8 alkyl-OC(O)R ₁₁ , -C _0-8 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-8 alkyl-NR ₁₂ R ₁₃ , -C _0-8 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-8 alkyl-N(R ₁₂ )-C(O)R ₁₁ ;

_R6 , _R7 and _R8 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, _C1-10 alkyl, halogen-substituted _C1-10 alkyl, deuterium-substituted _C1-10 alkyl, C2-10 alkenyl, _C2-10 alkynyl, _C3-12 cycloalkyl, _3-12 membered heterocyclyl, _C6-10 aryl, 5-10 membered heteroaryl, _-C0-8 alkyl- _SF5 , _-C0-8 alkyl-OS( _O ) _2R9 , _-C0-8 alkyl-S(O) _rR9 , _-C0-8 alkyl- _OR10 , _-C0-8 alkyl- _C (O) _OR10 , _-C0-8 alkyl-C(O) _SR10 , _-C0-8 alkyl-SC(O) _R11 , _-C0-8 alkyl -C(O)R ₁₁ , -C _0-8 alkyl-OC(O)R ₁₁ , -C _0-8 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-8 alkyl-NR ₁₂ R ₁₃ , -C _0-8 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-8 alkyl-N(R ₁₂ )-C(O)R ₁₁ ;

each R ₉ is independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C _2-10 alkenyl, C _3-12 cycloalkyl, 3-12 membered heterocyclyl, C _6-10 aryl, 5-10 membered heteroaryl, and -NR ₁₂ R ₁₃ , which are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, =O, C _1-10 alkyl, C _1-10 alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkyloxy, 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 ₁₂ R ₁₃ ;

each R ₁₀ is 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, which groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, =0, cyano, C _1-10 alkyl, C _1-10 alkoxy, C 3-12 cycloalkyl, C _3-12 cycloalkyloxy, _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 ₁₂ R ₁₃ ;

Each R ₁₁ is independently selected from hydrogen, deuterium, hydroxyl, C _1-10 alkyl, C 1-10 alkoxy, C _2-10 alkenyl, C _2-10 alkynyl, C _3-12 cycloalkyl, C _3-12 cycloalkyloxy, _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 ₁₂ R ₁₃ , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, =O, cyano, C 1-10 alkyl, C _1-10 alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkyloxy, 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 12 R 13 substituted by a substituent selected from the group consisting of _{a 6- to} 10-membered aryloxy group, a 5- to 10-membered heteroaryl group, a 5- to 10-membered heteroaryloxy group, and -NR ₁₂ R ₁₃ ;

Each of R ₁₂ and R ₁₃ is independently selected from hydrogen, deuterium, hydroxyl, 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, sulfinyl, sulfonyl, methylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C _1-10 alkanoyl, and the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, =0, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _1-10 alkoxy, C _3-12 cycloalkyl, C substituted by a _{C 3-12} cycloalkyloxy group, a 3-12 membered heterocyclyl group, a 3-12 membered heterocyclyl group, a C _6-10 aryl group, a C _6-10 aryloxy group, a 5-10 membered heteroaryl group, a 5-10 membered heteroaryloxy group, an amino group, a C _1-10 alkyl monosubstituted amino group, a C _1-10 alkyl disubstituted amino group, and a C _1-10 alkanoyl group, or,

R ₁₂ and R ₁₃ together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, which is optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, =O, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, halogen-substituted C _1-10 alkyl, deuterium-substituted C _1-10 alkyl, C _1-10 alkoxy, C _3-12 cycloalkyl, C _3-12 cycloalkyloxy, 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 alkanoyl;

R ₁₄ and R ₁₅ are each independently selected from hydrogen, deuterium, C _1-10 alkyl, 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-C(O)OR ₁₀ , -C _0-8 alkyl-C(O)SR ₁₀ , -C _0-8 alkyl-C(O)R ₁₁ , -C _0-8 alkyl-P(O)(R ₁₁ ) ₂ and -C _0-8 alkyl-C(O)NR ₁₂ R ₁₃ , or, R ₁₄ and R ₁₅ together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, and the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azido, C 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-OS(O) ₂ R ₉ , -C _0-8 alkyl-S(O) _r R ₉ , -C _0-8 alkyl-OR ₁₀ , -C _0-8 alkyl-C(O)OR ₁₀ , -C _0-8 alkyl-C(O)SR ₁₀ , -C _0-8 alkyl-SC(O)R ₁₁ , -C _0-8 alkyl-C(O)R ₁₁ , -C _0-8 alkyl-OC(O)R ₁₁ , -C _0-8 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-8 alkyl-NR ₁₂ R ₁₃ , -C _0-8 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-8 alkyl-N(R ₁₂ )-C(O)R ₁₁ ;

Each r is independently 0, 1 or 2;

m is selected from 0, 1, 2, 3, 4 or 5;

n is selected from 0, 1, 2, 3, 4 or 5; and

p is selected from 0, 1, 2, 3, 4 or 5.

The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that _R3 and _R4 are each independently selected from hydrogen, deuterium, hydroxyl, _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl and 3-6 membered heterocyclyl, or, _R3 and _R4 together with the nitrogen atom to which they are directly connected form a 4-6 membered heterocyclyl or 5-8 membered heteroaryl, and the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, hydroxyl, =O, =S, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, _C3-6 cycloalkyl, _C3-6 cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy and _-NR12R ₁₃ ; wherein R ₁₂ and R ₁₃ are as described in claim 1;

Preferably, R ₃ and R ₄ are each independently selected from hydrogen, deuterium, hydroxyl, 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.

The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that R ₆ , R ₇ and R ₈ are each independently selected from hydrogen, 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-OS(O) ₂ R ₉ , -C _0-4 alkyl-S(O) _r R ₉ , -C _0-4 alkyl-OR ₁₀ , -C _0-4 alkyl-C(O)OR ₁₀ , -C _0-4 alkyl-C(O)SR ₁₀ , -C _0-4 alkyl-SC(O)R ₁₁ , -C _0-4 alkyl-C(O)R ₁₁ , -C _0-4 alkyl-OC(O)R ₁₁ , -C _0-4 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-4 alkyl-NR ₁₂ R ₁₃ , -C _0-4 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-4 alkyl-N(R ₁₂ )-C(O)R ₁₁ ;

Preferably, _R6 , _R7 and _R8 are each independently selected from hydrogen, deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C3-6 cycloalkyl, 3-6 membered heterocyclyl, _C6-8 aryl, 5-8 membered heteroaryl, _-SF5 , -OS(O) _2R9 , -S(O) _rR9 , _-OR10 , -C(O) _OR10 , -C(O ₎ _SR10 , -SC(O) _R11 , -C(O) _R11 , _-OC(O)R11 _, -P(O)( _R11 ) ₂ , _-NR12R13 , -C( _O _)NR12R13 _and -N( _R12 )-C(O)R ₁₁ ;

wherein R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ and r are as described in claim 1.

The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that R ₁₄ and R ₁₅ are each independently selected from hydrogen, deuterium, C _1-4 alkyl, 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-C(O)OR ₁₀ , -C _0-4 alkyl-C(O)SR ₁₀ , -C _0-4 alkyl-C(O)R ₁₁ , -C _0-4 alkyl-P(O)(R ₁₁ ) ₂ and -C _0-4 alkyl-C(O)NR ₁₂ R ₁₃ , or, R ₁₄ and R ₁₅ together with the nitrogen atom to which they are directly connected form a 4-6 membered heterocyclyl or 5-8 membered heteroaryl, and the above groups are independently optionally further selected from one or more deuterium, halogen, cyano, nitro, azido, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl, =O, =S, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-OS(O) ₂ R ₉ , -C _0-4 alkyl-S(O) _r R ₉ , -C _0-4 alkyl-OR ₁₀ , -C _0-4 alkyl-C(O)OR ₁₀ , -C _0-4 alkyl-C(O)SR ₁₀ , -C _0-4 alkyl-SC(O)R ₁₁ , -C _0-4 alkyl-C(O)R ₁₁ , _{-C 0-4} alkyl-OC(O)R ₁₁ , -C _0-4 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-4 alkyl-NR ₁₂ R ₁₃ , -C _0-4 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-4 alkyl-N(R ₁₂ )-C(O)R ₁₁ ;

Preferably, R ₁₄ and R ₁₅ are each independently selected from hydrogen, deuterium, 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, -SF ₅ , -C(O)OR ₁₀ , -C(O)SR ₁₀ , -C(O)R ₁₁ , -P(O)(R ₁₁ ) ₂ and -C(O)NR ₁₂ R ₁₃ ;

The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that each R ₅ is independently 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, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-OS(O) ₂ R ₉ , -C _0-4 alkyl-S(O) _r R ₉ , -C _0-4 alkyl-OR ₁₀ , -C _0-4 alkyl-C(O)OR ₁₀ , -C _0-4 alkyl-C(O)SR ₁₀ , -C _0-4 alkyl-SC(O)R ₁₁ , -C _0-4 alkyl-C(O)R ₁₁ , _{-C 0-4} alkyl-OC(O)R ₁₁ , -C _0-4 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-4 alkyl-NR ₁₂ R ₁₃ , -C _0-4 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-4 alkyl-N(R ₁₂ )-C(O)R ₁₁ , the above groups are independently optionally further substituted by one or more 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-OS(O) ₂ R ₉ , -C _{-C 0-4} alkyl-S(O) _r ₉ , -C _0-4 alkyl-OR ₁₀ , -C _0-4 alkyl-C(O)OR ₁₀ , -C 0-4 alkyl-C(O)SR ₁₀ , -C _0-4 alkyl-SC(O) _R ₁₁ , -C _0-4 alkyl-C(O)R ₁₁ , -C _0-4 alkyl-OC(O)R ₁₁ , -C _0-4 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-4 alkyl-NR ₁₂ R ₁₃ , -C _0-4 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-4 alkyl-N(R ₁₂ )-C(O)R ₁₁ ;

Preferably, each R ₅ is independently 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, 5-8 membered heteroaryl, -SF ₅ , -OS(O) ₂ R ₉ , -S(O) _r R ₉ , -OR ₁₀ , -C(O)OR ₁₀ , -C(O)SR ₁₀ , -SC(O)R ₁₁ , -C(O)R ₁₁ , -OC(O)R ₁₁ , -P(O)(R ₁₁ ) ₂ , -NR ₁₂ R ₁₃ , -C(O)NR ₁₂ R ₁₃ and -N(R ₁₂ )-C(O)R ₁₁ The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, _C6-8 aryl, 5-8 membered heteroaryl, =O, = _S , _-SF5 , -OS(O) _2R9 , -S(O) _rR9 , _-OR10 , -C(O _)OR10 _, -C(O) _SR10 , -SC(O) _R11 , -C(O) _R11 , -OC(O) _R11 , -P(O)( _R11 ) ₂ _, _-NR12R13 _, -C(O) _NR12R13 and -N( _R12 )-C(O)R ₁₁ is substituted;

The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that each R ₂ is independently selected from hydrogen, 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-OS(O) ₂ R ₉ , -C _0-4 alkyl-S(O) _r R ₉ , -C _0-4 alkyl-OR ₁₀ , -C _0-4 alkyl-C(O)OR ₁₀ , -C _0-4 alkyl-C(O)SR ₁₀ , -C _0-4 alkyl-SC(O)R ₁₁ , -C _{-C 0-4} alkyl-C(O)R ₁₁ , -C _0-4 alkyl-OC(O)R ₁₁ , -C _0-4 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-4 alkyl-NR ₁₂ R ₁₃ , -C _0-4 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-4 alkyl-N(R ₁₂ )-C(O)R ₁₁ , or, when p ≥ 2, wherein two R ₂ together with the part to which they are directly attached form a C(O);

The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that ring B is selected from a 4-membered nitrogen-containing heterocyclic group;

Ring C is C _3-6 cycloalkyl, 4-8 membered heterocyclyl, C _6-8 aryl or 5-8 membered heteroaryl, the C _3-6 cycloalkyl or 4-8 membered heterocyclyl is optionally fused to C _6-8 aryl or 5-8 membered heteroaryl, the C _6-8 aryl or 5-8 membered heteroaryl is optionally fused to C _3-6 cycloalkyl or 4-8 membered heterocyclyl;

each R ₁ is independently 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, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-OS(O) ₂ R ₉ , -C _0-4 alkyl-S(O) _r R ₉ , -C _0-4 alkyl-OR ₁₀ , -C _0-4 alkyl-C(O)OR ₁₀ , -C _0-4 alkyl-C(O)SR ₁₀ , -C _0-4 alkyl-SC(O)R ₁₁ , -C _0-4 alkyl-C(O)R ₁₁ , -C _0-4 alkyl-OC(O)R ₁₁ , -C _0-4 alkyl-P(O)(R -C _0-4 alkyl-NR ₁₂ R ₁₃ , -C _0-4 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-4 alkyl-N(R ₁₂ )-C(O)R ₁₁ ) ₂ , _the above groups are independently optionally further substituted by one or more 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-OS(O) ₂ R ₉ , -C _0-4 alkyl-S(O) _r R ₉ , -C _0-4 alkyl-OR ₁₀ , -C _{-C 0-4} alkyl-C(O)OR ₁₀ , -C _0-4 alkyl-C(O)SR ₁₀ , -C _0-4 alkyl-SC(O)R ₁₁ , -C _0-4 alkyl-C(O)R ₁₁ , -C _0-4 alkyl-OC(O)R ₁₁ , -C _0-4 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-4 alkyl-NR ₁₂ R ₁₃ , -C _0-4 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-4 alkyl-N(R ₁₂ )-C(O)R ₁₁ ;

The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that ring B is selected from an 8-10 membered nitrogen-containing heterocyclic group;

The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that ring B is selected from a 5-7 membered nitrogen-containing heterocyclic group, and ring C and -(R ₁ ) _m together form wherein Y ₁ and Y ₂ are each independently CR ₁ or N, Y ₃ is O, S or NR ₁ ', and Y ₄ and Y ₅ are each independently CR ₁ ' or N;

R ₁ 'is selected from hydrogen, deuterium, 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, -S(O) _r R ₉ , -OR ₁₀ , -C(O)OR ₁₀ , -C(O)R ₁₁ and -C(O)NR ₁₂ R ₁₃ , the above groups are independently optionally further substituted by one or more 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 _{-C 0-4} alkyl-OS(O) ₂ R ₉ , -C _0-4 alkyl-S(O) _r ₉ , -C _0-4 alkyl-OR ₁₀ , -C _0-4 alkyl-C(O)OR ₁₀ , -C _0-4 alkyl-C(O)SR ₁₀ , -C _0-4 alkyl-SC(O)R ₁₁ , -C _0-4 alkyl-C(O)R ₁₁ , -C _0-4 alkyl-OC(O)R ₁₁ , -C _0-4 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-4 alkyl-NR ₁₂ R ₁₃ , -C _0-4 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-4 alkyl-N(R ₁₂ )-C(O)R ₁₁ ;

each R ₁ ″ is independently 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, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-OS(O) ₂ R ₉ , -C _0-4 alkyl-S(O) _r R ₉ , -C _0-4 alkyl-OR ₁₀ , -C _0-4 alkyl-C(O)OR ₁₀ , -C _0-4 alkyl-C(O)SR ₁₀ , -C _0-4 alkyl-SC(O)R ₁₁ , -C _0-4 alkyl-C(O)R ₁₁ , -C _0-4 alkyl-OC(O)R ₁₁ , -C _0-4 alkyl-P(O)(R -C _0-4 alkyl-NR ₁₂ R ₁₃ , -C _0-4 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-4 alkyl-N(R ₁₂ )-C(O)R ₁₁ ) ₂ , _the above groups are independently optionally further substituted by one or more 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-OS(O) ₂ R ₉ , -C _0-4 alkyl-S(O) _r R ₉ , -C _0-4 alkyl-OR ₁₀ , -C _{-C 0-4} alkyl-C(O)OR ₁₀ , -C _0-4 alkyl-C(O)SR ₁₀ , -C _0-4 alkyl-SC(O)R ₁₁ , -C _0-4 alkyl-C(O)R ₁₁ , -C _0-4 alkyl-OC(O)R ₁₁ , -C _0-4 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-4 alkyl-NR ₁₂ R ₁₃ , -C _0-4 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-4 alkyl-N(R ₁₂ )-C(O)R ₁₁ ;

The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that ring B is selected from a 5-7 membered nitrogen-containing heterocyclic group, and ring C and -(R ₁ ) _m together form wherein Y ₆ , Y ₇ , Y ₈ and Y ₉ are each independently CR ₁ or N, and at least one is CR ₁ , wherein at least one R ₁ is -C _0-4 alkyl-NR ₁₄ R ₁₅ or -OC _1-4 alkyl-NR ₁₄ R ₁₅ , and each of the other R ₁ is each independently 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, 5-8 membered heteroaryl, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-OS(O) ₂ R ₉ , -C _0-4 alkyl-S(O) _r R ₉ , -C _0-4 alkyl-OR ₁₀ , -C _0-4 alkyl-C(O)OR ₁₀ , -C _{-C 0-4} alkyl-C(O)SR ₁₀ , -C _0-4 alkyl-SC(O)R ₁₁ , -C _0-4 alkyl-C(O)R ₁₁ , -C 0-4 alkyl-OC(O) _R ₁₁ , -C _0-4 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-4 alkyl-NR ₁₂ R ₁₃ , -C _0-4 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-4 alkyl-N(R ₁₂ )-C(O)R ₁₁ , the above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, C _0-4 alkyl, halogen-substituted C _{0-4 alkyl, deuterium-substituted C 0-4} _alkyl , C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 membered aryl, 5-8 membered heteroaryl, =O, =S, -C _0-4 alkyl-SF ₅ , -C _0-4 alkyl-OS(O) ₂ R ₉ , -C _0-4 alkyl-S(O) _r R ₉ , -C _0-4 alkyl-OR ₁₀ , -C _0-4 alkyl-C(O)OR ₁₀ , -C _0-4 alkyl-C(O)SR ₁₀ , -C _0-4 alkyl-SC(O)R ₁₁ , -C _0-4 alkyl-C(O)R ₁₁ , -C _0-4 alkyl-OC(O)R ₁₁ , -C _0-4 alkyl-P(O)(R ₁₁ ) ₂ , -C _0-4 alkyl-NR ₁₂ R ₁₃ , -C 0-4 alkyl-C(O)NR ₁₂ R ₁₃ and -C _0-4 alkyl- _0-4 alkyl-N(R ₁₂ )-C(O)R ₁₁ ;

wherein R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ and r are as described in claim 1.

The compound of formula (I) according to claim 1, its stereoisomer or pharmaceutically acceptable salt thereof, characterized in that each R ₉ is independently selected from hydrogen, deuterium, hydroxyl, 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 ₁₂ R ₁₃ , and the above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxyl, =O, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₂ R ₁₃ ;

each R ₁₀ is 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, which groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, =O, cyano, C _1-4 alkyl, C _1-4 alkoxy, C 3-6 cycloalkyl, C _3-6 cycloalkyloxy, _3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₂ R ₁₃ ;

each R ₁₁ is 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 cycloalkyloxy, _3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₂ R ₁₃ , the above groups are independently optionally further substituted with one or more substituents selected from deuterium, halogen, hydroxy, =0, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR ₁₂ R ₁₃ ;

Each of R ₁₂ and R ₁₃ is independently selected from hydrogen, deuterium, hydroxyl, 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, and the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, hydroxyl, =0, C _1-4 alkyl, C _{2-4 alkenyl, C 2-4} _alkynyl , halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C 1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkyloxy, _3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C substituted by a C _6-8 aryl, a C _6-8 aryloxy, a 5-8 membered heteroaryl, a 5-8 membered heteroaryloxy, an amino, a C _1-4 alkyl monosubstituted amino, a C _1-4 alkyl disubstituted amino and a C _1-4 alkanoyl substituent, or

_R12 and _R13 together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein the 4-8 membered heterocyclyl or 5-8 membered heteroaryl is optionally further substituted by one or more substituents selected from deuterium, halogen, hydroxy, =O, _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C1-4 alkoxy, _C3-6 cycloalkyl, C3-6 cycloalkyloxy, _3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, _C6-8 aryl, _C6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, amino, _C1-4 alkyl monosubstituted amino, _C1-4 alkyl disubstituted amino and _C1-4 alkanoyl.

The compound of formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that ring A together with the part directly connected thereto forms the following structure:

Wherein, _X1 is _CR6 or N; _X2 is _CR7 or N;

each R _5a is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl, -SF ₅ and -OR ₁₀ , and the above groups are independently optionally further substituted by one or more 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 , -OS(O) ₂ R ₉ , -S(O) _r R ₉ , -OR ₁₀ , -C(O)OR ₁₀ , -C(O)SR ₁₀ , -SC(O)R ₁₁ , -C(O)R ₁₁ , -OC(O)R ₁₁ , -P(O)(R ₁₁ ) ₂ , -NR ₁₂ R ₁₃ , -C(O)NR ₁₂ R ₁₃ and -N(R ₁₂ )-C(O)R ₁₁ ;

each R _5b is independently selected from hydrogen, deuterium, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl and -OR ₁₀ , the above groups are independently optionally further substituted by one or more 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 , -OS(O) ₂ R ₉ , -S(O) _r R ₉ , -OR ₁₀ , -C(O)OR ₁₀ , -C(O)SR ₁₀ , -SC(O)R ₁₁ , -C(O)R ₁₁ , -OC(O)R ₁₁ , -P(O)(R ₁₁ ) ₂ , -NR ₁₂ R ₁₃ , -C(O)NR ₁₂ R ₁₃ and -N(R ₁₂ )-C(O)R ₁₁ ;

each R _5c is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, C _6-8 aryl, 5-8 membered heteroaryl, -SF ₅ and -OR ₁₀ , and the above groups are independently optionally further substituted by one or more 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 , -OS(O) ₂ R ₉ , -S(O) _r R ₉ , -OR ₁₀ , -C(O)OR ₁₀ , -C(O)SR ₁₀ , -SC(O)R ₁₁ , -C(O)R ₁₁ , -OC(O)R ₁₁ , -P(O)(R ₁₁ ) ₂ , -NR ₁₂ R ₁₃ , -C(O)NR ₁₂ R ₁₃ and -N(R ₁₂ )-C(O)R ₁₁ ;

Each R ₆ is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ and -OR ₁₀ ;

Each R ₇ is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ and -OR ₁₀ ;

Each R ₈ is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _3-6 cycloalkyl, 3-6 membered heterocyclyl, -SF ₅ and -OR ₁₀ ;

The compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound of formula (I) has the following compound structure of formula (II):

wherein Y ₁ and Y ₂ are each independently CR ₁ or N, and Y ₃ is O, S or NR ₁ ';

Ring A is C _4-8 cycloalkyl, 4-8 membered heterocyclyl, C _6-8 aryl or 5-8 membered heteroaryl;

Ring B and -(R ₂ ) _p together form the following structure:

each R ₁ is independently 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, 5-8 membered heteroaryl, -SF ₅ , -OS(O) ₂ R ₉ , -S(O) _r R ₉ , -OR ₁₀ , -C(O)OR ₁₀ , -C(O)SR ₁₀ , -SC(O)R ₁₁ , -C(O)R ₁₁ , -OC(O)R ₁₁ , -P(O)(R ₁₁ ) ₂ , -NR ₁₂ R ₁₃ , -C(O)NR ₁₂ R ₁₃ and -N(R ₁₂ )-C(O)R ₁₁ The above groups are independently optionally further substituted with one or more selected from deuterium, halogen, cyano, _C1-4 alkyl, halogen-substituted _C1-4 alkyl, deuterium-substituted _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, C3-6 cycloalkyl, _3-6 membered heterocyclyl, _C6-8 aryl, 5-8 membered heteroaryl, =O, = _S , _-SF5 , -OS(O) _2R9 , -S(O) _rR9 , _-OR10 , -C(O _)OR10 _, -C(O) _SR10 , -SC(O) _R11 , -C(O) _R11 , -OC(O) _R11 , -P(O)( _R11 ) ₂ _, _-NR12R13 _, -C(O) _NR12R13 and -N( _R12 )-C(O)R ₁₁ is substituted;

R ₁ 'is selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl, the above groups are independently optionally further substituted by one or more 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 , -OS(O) ₂ R ₉ , -S(O) _r R ₉ , -OR ₁₀ , -C(O)OR ₁₀ , -C(O)SR ₁₀ , -SC(O)R ₁₁ , -C(O)R ₁₁ , -OC(O)R ₁₁ , -P(O)(R ₁₁ ) ₂ , -NR ₁₂ R ₁₃ , -C(O)NR ₁₂ R ₁₃ and -N(R ₁₂ )-C(O)R ₁₁ ;

each R ₂ is independently selected from hydrogen, 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 , -OS(O) ₂ R ₉ , -S(O) _r R ₉ , -OR ₁₀ , -C(O)OR ₁₀ , -C(O)SR ₁₀ , -SC(O)R ₁₁ , -C(O)R ₁₁ , -OC(O)R ₁₁ , -P(O)(R ₁₁ ) ₂ , -NR ₁₂ R ₁₃ , -C(O)NR ₁₂ R ₁₃ and -N(R ₁₂ )-C(O)R ₁₁ ;

R ₂ ′ is selected from hydrogen, deuterium, hydroxyl, C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, deuterium-substituted C _1-4 alkyl, C _3-6 cycloalkyl and 3-6 membered heterocyclyl;

each R ₅ is independently selected from hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, hydroxy substituted 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 , -OS(O) ₂ R ₉ , -S(O) _r R ₉ , -OR ₁₀ , -C(O)OR ₁₀ , -C(O)SR ₁₀ , -SC(O)R ₁₁ , -C(O)R ₁₁ , -OC(O)R ₁₁ , -P(O)(R ₁₁ ) ₂ , -NR ₁₂ R ₁₃ , -C(O)NR ₁₂ R ₁₃ and -N(R ₁₂ )-C(O)R ₁₁ ;

R ₆ is selected from hydrogen, 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 _1-4 alkoxy, halogen-substituted C _1-4 alkoxy, deuterium-substituted C _1-4 alkoxy, C _3-6 cycloalkyl, C _3-6 cycloalkoxy, 3-6 membered heterocyclyl, 3-6 membered heterocyclyloxy, C _6-8 aryl, C _6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy, hydroxyl and -NR ₁₂ R ₁₃ ;

wherein R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , n, p and r are as described in claim 1.

Wherein, _X1 is _CR6 or N; _X2 is CH or N;

The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound of formula (I) has the following compound structure of formula (III ₁ ) or formula (III ₂ ):

Wherein, in the structure of the compound of formula (III ₁ ) or formula (III ₂ ) The structure is

Ring A and its directly connected parts together form the following structure:

_R is selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, dimethylamino-substituted methyl, dimethylamino-substituted ethyl, dimethylaminoethoxy, cyclopropyl, cyclobutyl, piperidinyl, piperazinyl, morpholinyl, methyl-substituted piperidinyl, ethyl-substituted piperidinyl, cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl-substituted piperazine, and tetrahydropyranyl;

R ₁ ′ is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl, dimethylamino-substituted methyl, dimethylamino-substituted ethyl, cyclopropyl, cyclobutyl, piperidinyl, methyl-substituted piperidinyl, ethyl-substituted piperidinyl, cyclopropyl-substituted piperidinyl, and tetrahydropyranyl;

Each R ₂ is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuterium and cyclopropyl;

Each R _5a is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriummethyl, cyclopropyl, -SF ₅ and hydroxyl;

Each R _5b is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl and cyclopropyl;

Each R _5c is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriummethyl, cyclopropyl, -SF ₅ and hydroxyl;

Each R ₆ is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuterium, cyclopropyl, -SF ₅ and hydroxyl;

p is selected from 0, 1 or 2.

The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 15, characterized in that in the structure of the compound of formula (III ₁ ) or formula (III ₂ ) The structure is

Ring A and its directly connected parts together form the following structure:

wherein _R is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl, methoxy, trifluoromethoxy, amino, methylamino, ethyl substituted with dimethylamino, ethoxy substituted with dimethylamino, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, methyl substituted piperidinyl, ethyl substituted piperidinyl, cyclopropyl substituted piperidinyl, methyl substituted piperazinyl, cyclopropyl substituted piperazine, and tetrahydropyranyl;

Each R ₂ is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuterium and cyclopropyl;

Each R _5a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteriummethyl and cyclopropyl;

Each R _5b is independently selected from hydrogen, deuterium, methyl, trifluoromethyl, trideuteriomethyl and cyclopropyl;

Each R _5c is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteriummethyl and cyclopropyl;

Each R ₆ is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteriummethyl and cyclopropyl.

The compound of formula (I), its stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, characterized in that the compound of formula (I) has the following compound structure of formula (IV ₁ ), formula (IV ₂ ), formula (IV ₃ ) or formula (IV ₄ ):

in,

each R ₁ is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteriomethyl, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino substituted ethyl, dimethylamino substituted ethoxy, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, methyl substituted piperidinyl, ethyl substituted piperidinyl, cyclopropyl substituted piperidinyl, methyl substituted piperazinyl, cyclopropyl substituted piperazinyl and tetrahydropyranyl;

Each R _2a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteriummethyl and cyclopropyl;

Each R _2b is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteriummethyl and cyclopropyl;

The compound of formula (I) according to any one of claims 1 to 17, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the following compounds:

A method for preparing a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that it comprises the following steps: a compound of formula (Ia) reacts with a compound of formula (Ib) to generate a compound of formula (I), and the reaction formula is as follows:

wherein X is hydroxyl or halogen; and ring A, ring B, ring C, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , m, n and p are as described in claim 1.

A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 18, a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Use of the compound of formula (I) according to any one of claims 1 to 18, its stereoisomers or pharmaceutically acceptable salts thereof in the preparation of a drug for treating MATP-related tumors.

The use according to claim 21 is characterized in that the tumor is selected from the group consisting of cell tumors, lymphomas, leukemias, osteomas, malignant teratomas, intraepithelial carcinomas, adenomas, fibromas, melanomas, fallopian tube cancer, bladder cancer, teratomas, embryonal carcinomas, choriocarcinomas, lipomas, liver cancer, bile duct cancer, lung cancer, gastric cancer, hemangiomas, gallbladder cancer, ampullary cancer, malignant melanomas, nevi, dysplastic nevi, myeloproliferative diseases, Hodgkin's disease, chordomas, myxomas, rhabdomyomas, leiomyomas, hamartomas, mesotheliomas, insulinomas, glucagonomas, gastrinomas, carcinoid tumors, viper tumors, granulomas, xanthomas, deforming osteitis, ependymomas, schwannomas, congenital tumors, meningiomas, gliomas, skin cancers, head and neck cancers, and sarcomas.

The use according to claim 22, characterized in that the cell tumor is selected from granulosa-thecoma cell tumor, Sertoli cell tumor, germ cell tumor, Wilms tumor, seminoma, hepatoblastoma, malignant fibrous histiocytoma, chondroblastoma, giant cell tumor, astrocytoma, medulloblastoma, glioblastoma multiforme, oligodendroglioma, retinoblastoma, squamous cell carcinoma, clear cell carcinoma, transitional cell carcinoma, interstitial cell carcinoma and basal cell carcinoma;

The lymphoma is selected from malignant lymphoma and non-Hodgkin's lymphoma;

The leukemia is selected from acute and chronic myeloid leukemia, acute lymphocytic leukemia and chronic lymphocytic leukemia;

The bone tumor is selected from osteochondroma, benign enchondroma, osteoid osteoma, enchondromatous hamartoma, multiple myeloma and skull tumor;

The adenoma is selected from the group consisting of fibroadenoma, adenomatoid tumor, hepatocellular adenoma, bronchial adenoma, tubular adenoma, villous adenoma, breast cancer, pancreatic cancer, endometrial adenocarcinoma, prostate cancer, ductal adenocarcinoma and colorectal adenocarcinoma;

The fibroma is selected from the group consisting of fibroma, chondromyxofibroma, neurofibroma and spinal neurofibroma;

The myeloproliferative disease is selected from multiple myeloma and myelodysplastic syndrome;

The lung cancer is selected from bronchogenic carcinoma and alveolar carcinoma;

The sarcoma is selected from the group consisting of fibrosarcoma, botryoid sarcoma, angiosarcoma, Kaposi's sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, liposarcoma, leiomyosarcoma and meningeal sarcoma.

The compound of formula (I) according to any one of claims 1 to 18, its stereoisomer or a pharmaceutically acceptable salt thereof, which is used as a PRMT5 inhibitor.