CN118206558A - A compound for inhibiting and degrading Aurora A, its pharmaceutical composition and pharmaceutical application - Google Patents

Abstract

The present invention relates to a compound of formula (I) or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and intermediates thereof, and their use in the inhibition or degradation AuroraA associated diseases such as cancer. B-L-K (I).

Description

A compound that inhibits and degrades AuroraA, its pharmaceutical composition, and pharmaceutical applications

Technical Field

The present invention relates to a compound of general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, as well as intermediates and preparation methods thereof, and use thereof in Aurora A-related diseases such as tumors or autoimmune system diseases.

Background Art

Aurora kinase (laser kinase) is a serine/threonine protease involved in cell mitosis, mainly acting on centrioles and spindles to maintain the normal progress of cell division. Human Aurora kinase includes three subtypes: A, B, and C.

Aurora A was originally discovered to be a mitotic kinase that phosphorylates specific substrates and regulates centrosome and spindle activity during mitosis (J Cell Sci. 2015, 128: 4035-4038.); Aurora A was later discovered to be an oncogene that showed gene amplification and overexpression in a variety of human tumors (such as small cell lung cancer, neuroblastoma, breast cancer, ovarian cancer, gastric cancer, etc.) (J Dermatol, 2018, 45: 507-508.).

In addition to its good catalytic activity, Aurora A also has non-catalytic functions. For example, Aurora A binds to the proto-oncoproteins of the MYC family and protects N-MYC and c-MYC from proteasomal degradation (Cancer Cell, 2013, 24: 75–89; Nat Med, 2016, 22: 744–53.), and this effect is independent of the kinase activity of Aurora A. These non-catalytic functions suggest that Aurora A kinase inhibitors may not be able to eliminate all the oncogenic activities of Aurora A.

PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to targeted proteins and E3 ubiquitin ligases. Such compounds can be recognized by the proteasome of the cell, causing degradation of the targeted protein, and can effectively reduce the content of the targeted protein in the cell. By introducing ligands that can bind to different targeted proteins in PROTAC molecules, PROTAC technology can be applied to the treatment of various diseases. This technology has also received widespread attention in recent years (Drug Discovery Today Technol. 2019, 31: 15-27; Nat. Rev. Drug Discovery, 2022, 21: 181-200.).

The development of new PROTAC drugs that bind Aurora A protein and E3 ubiquitin ligase, targeting both the catalytic and non-catalytic functions of Aurora A protein and used to treat diseases related to Aurora A protein will be full of application prospects.

Summary of the invention

The object of the present invention is to provide a compound with novel structure, good efficacy, high bioavailability, greater safety, and the ability to inhibit or degrade Aurora A, for use in treating Aurora A-related diseases such as autoimmune diseases, inflammatory diseases or cancer.

The present invention provides a compound or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compounds represented by general formula (I),

B-L-K(I);

In some embodiments, the compound of formula (I) is selected from (Ia), (Ib), (Ib-1)

In some embodiments, L is selected from a bond or -C _1-50 alkyl-, wherein 1 to 20 methylene units in the alkyl are optionally replaced by -Ak-, -Cy-;

In some embodiments, each -Ak- is independently selected from -( _CH2 ) _q- , -( _CH2 ) _q -O-, -O-( _CH2 ) _q- , -( _CH2 ) _q -S-, -S-( _CH2 ) _q- , -( _CH2 ) _q -NR ^L- , -NR L-( _CH2 ) _q- , -( _CH2 ) _q -NR ^{L C} (＝O)-, -NR ^L ( _CH2 )qC(＝O)-, -( _CH2 ) _{q -} C(＝O)NR ^L- , -C(＝O)-, -C(＝O)-( _CH2 ) _q -NR ^L- , -(C≡C) _q- , -CH＝CH-, -Si( ^RL ) _2- , -Si(OH)( ^RL )-, -Si(OH) _2- , -P(＝O)(OR ^L )-, or -NH-NH-NH-. )-, -P(=O)(R ^L )-, -S-, -S(=O)-, -S(=O) ₂ -, or a bond, wherein the -CH ₂ - is optionally substituted by 1 to 2 R ^z ;

In some embodiments, q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;

In some embodiments, ^RL is selected from H, _C1-4 alkyl, _C3-7 carbocyclyl, 4 to 10 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 ^Rz ;

In some embodiments, each -Cy- is independently selected from a bond or one of the following groups optionally substituted with 1 to 4 R ^L2 : a 4-7 membered heteromonocyclyl, a 4-12 membered heterocycloalkyl, a 5-13 membered heterospirocyclyl, a 7-12 membered heterobridged cyclyl, a 3-7 membered monocycloalkyl, a 4-12 membered cycloalkyl, a 5-13 membered spirocycloalkyl, a 5-12 membered bridged cycloalkyl, a 5-10 membered heteroaryl, or a C _6-10 aryl;

In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, or Ak9;

In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4, or Ak5;

In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3, Cy4 or Cy5;

In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3 or Cy4;

In some embodiments, L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, k1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak 1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3 -Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5- , -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2 -Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4- Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-A k5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Ak1- Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-, -Ak1-Cy1-Ak2-Ak3-A k4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-C y2-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-, -A k1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-, -Ak1-Ak2-Ak 3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-, -Ak1-Ak2-Ak3-Ak4-Cy1-Cy2 -Cy3-Ak5-Cy4-, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Ak1-Ak2-Ak3- Ak4-Ak5-Ak6-Ak7-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-;

In certain embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

In certain embodiments, L is selected from -C(＝O)-Cy1-, -C(＝O)-Cy1-Cy2-, -C(＝O)-Cy1-CH ₂ -Cy2-, -C(＝O)-Cy1-Cy2-Cy3-, -C(＝O)-Cy1-CH ₂ -Cy2-Cy3-, -C(＝O)-Cy1-Cy2-CH ₂ -Cy3-, -C(＝O)-Cy1-Cy2-CH 2 -Cy3-, -C(＝O)NH-Cy1-, -C(＝O)NH-Cy1-Cy2-, -C(＝O)NH-Cy1-CH ₂ -Cy2-;

In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 are each independently selected from -(CH ₂ ) _q -, -(CH ₂ ) _q -O-, -O-(CH ₂ ) _q -, -(CH ₂ ) _q -S-, -S-(CH ₂ ) _q -, -(CH ₂ ) _q -NR ^L -, -NR ^L -(CH ₂ ) _q -, -(CH ₂ ) _q -NR ^L C(＝O)-, -(CH ₂ ) _q -C(＝O)NR ^L -, -C(＝O)-, -C(＝O)-(CH ₂ ) _q -NR ^L -, -(C≡C) _q -, or a bond, and the -CH ₂ - is optionally substituted with 1 to 2 R ^z ;

In certain embodiments, Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -( _CH2 ) _q- , -( _CH2 ) _q -O-, -O-( _CH2 )q-, -(CH2) _q - _S- , -S-( _CH2 ) _q- , -( _CH2 ) _q -NR ^L -, -NR ^L -( _{CH2 ) q-} , -( _CH2 ) _q -NR ^L C(＝O)-, -( _CH2 ) _q -C(＝O)NR ^L -, -C(＝O)-, -C(＝O)-( _CH2 ) _q -NR ^L -, -(C≡C) _q- , or a bond, wherein the _-CH2- is optionally substituted with 1 to 2 R ^z ;

In certain embodiments, Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from a bond, -O-, -S-, _-OCH2- , _-CH2O- , _-OCH2CH2- , -CH2CH2O-, -C≡C-, _-C ( _CH3 ) _2- , _{-CH2- , -C} (CH3) _2- , -CH2CH2-, _-CH2CH2CH2- , _-N (CH3)-, -NH- _{, -CH2N} ( _CH3 )- _{, -CH2NH-} , _{-NHCH2- , -CH2CH2N ( CH3} )-, _{-CH2CH2NH- , -NHCH2CH2-} , _-C (=O)-, _-C (= _{O ) CH2NH-} , _-CH2 C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

In certain embodiments, ^RL is selected from H or _C1-4 alkyl;

In certain embodiments, ^RL is selected from H, methyl or ethyl;

In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups optionally substituted by 1 to 4 ^RL2 : a 4-7 membered nitrogen-containing heteromonocyclic group, a 4-12 membered nitrogen-containing heterocycloalkyl group, a 5-13 membered nitrogen-containing heterospirocyclic group, a 7-12 membered nitrogen-containing heterobridged ring group, a C _3-7 monocycloalkyl group, a C _4-12 cycloalkyl group, a C _5-13 spirocycloalkyl group, a C _7-12 bridged cycloalkyl group, a 5-10 membered heteroaryl group or a C _6-10 aryl group;

In certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following groups optionally substituted with 1 to 4 R ^L2 : phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, s1, s3, s5 are each independently selected from 0, 1 or 2, s2, s4 are each independently selected from 0 or 1, s6 is selected from 0, 1, 2 or 3, s7 is selected from 1, 2 or 3;

In certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following groups which are optionally substituted:

When substituted, it is substituted by 1 to 4 substituents selected from F, CF ₃ , OH, methyl, =0, hydroxymethyl, methoxy, COOH, CN or NH ₂ ;

In certain embodiments, Cy1, Cy2, and Cy3 are each independently selected from one of the following optionally substituted groups:

When substituted, it is substituted by 1 to 4 substituents selected from F, CF ₃ , OH, methyl, =0, hydroxymethyl, methoxy, COOH, CN or NH ₂ ;

In certain embodiments, Ya, Yb, Yc, Yd, and Ye are each independently selected from N or CH;

In certain embodiments, Cy2 is selected from 4 to 6-membered nitrogen-containing heterocycloalkyl or C _3-6 cycloalkyl, said Cy2 being optionally substituted with 1 to 4 R ^L2a ;

In certain embodiments, Cy2 is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, cyclobutyl, cyclopentyl, cyclohexyl, and said Cy2 is optionally substituted with 1 to 4 R ^L2a ;

In certain embodiments, ^RL2a , ^RL2b are each independently selected from H, deuterium, halogen, OH, COOH, CN, _NH2 , =O, _C1-4 alkyl or _C1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl, _C1-4 alkoxy substituents;

In certain embodiments, ^RL2a , ^RL2b are each independently selected from H, F, Cl, Br, I, OH, COOH, CN, _NH2 , =O, _CF3 , methyl, ethyl, isopropyl, methoxy, ethoxy, or isopropoxy;

In certain embodiments, R ^k1 is each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, CONH ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^k1 is each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CF ₃ , CN, COOH, CONH ₂ , methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH ₂ ;

In certain embodiments, ^RL2 and ^Rz are each independently selected from deuterium, F, Cl, Br, I, OH, =O, _CF3 , CN, _NH2 , COOH, _CONH2 , _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, _-C0-4 alkylene- _C3-6 cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl, _C1-4 alkoxy;

In certain embodiments, ^RL2 is selected from ^RL2a , ^RL2b ;

In certain embodiments, R ^L2b is directly connected to R ^b1 , R ^L2a is directly connected to R ^k1 , R ^L2b is directly connected to R ^L2a , and R ^k1 is directly connected to R ^k1 to form a C _4-6 carbocyclic ring or a 4- to 6-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^L2b and R ^b1 are directly connected, R ^L2a and R ^k1 are directly connected, R ^L2b and R ^L2a are directly connected, and R ^k1 and R ^k1 are directly connected to form a C ₄ carbocyclyl, a C ₅ carbocyclyl, a C ₆ carbocyclyl, a 4-membered heterocyclyl, a 5-membered heterocyclyl, or a 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^z is independently selected from deuterium, halogen, OH, CN, NH ₂ , ═O, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

In certain embodiments, R ^z is independently selected from deuterium, F, Cl, Br, , OH, COOH, CN, NH ₂ , =O, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl;

In certain embodiments, p3 is selected from 0, 1, 2, 3, 4;

In certain embodiments, m1, m2, and m3 are each independently selected from 0, 1, 2, 3, 4

In certain embodiments, L is selected from the group shown in Table L-1, wherein the left side of the group is connected to B;

Table L-1L Group

In certain embodiments, B is selected from

In certain embodiments, B is selected from

In certain embodiments, ^Ba , ^Bb are each independently selected from N or ^CRb5 ;

In certain embodiments, ^Ba , ^Bb are selected from N or CH;

In certain embodiments, B ₁ is selected from C _3-10 carbocyclyl or 4 to 10 membered heterocyclyl, said B ₁ being optionally substituted with 1 to 4 R ^b1 ;

In certain embodiments, B ₁ is selected from phenyl, benzo C _4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5 to 10 membered heteroaryl, C _3-7 cycloalkyl, C _5-10 cycloalkyl, C _5-10 spirocycloalkyl, C _5-10 bridged cycloalkyl, said B ₁ is optionally substituted with 1 to 4 R ^b1 ;

In certain embodiments, B1 is selected from cyclohexyl, phenyl, naphthyl, pyridine, pyrimidine, Bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl;

In certain embodiments, _B1 is selected from

In certain embodiments, Selected from

Optionally, B1 is selected from L is selected from a bond or contains at least one ring structure;

In certain embodiments, R ^b1 is each independently selected from halogen, =O, OH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , CN, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -OC _0-4 alkylene-C _3-6 carbocyclyl, -OC _0-4 alkylene-4 to 10 membered heterocyclyl, -NH-C _0-4 alkylene-C _3-6 carbocyclyl, -NH-C _0-4 alkylene-4 to 10 membered heterocyclyl, -C _0-4 alkylene-C _3-6 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl, heterocyclyl is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^b1 is each independently selected from F, Cl, Br, I, =O, OH, NH ₂ , CN, methyl, ethyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, and the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^b2 is selected from H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -C _0-4 alkylene-C _3-8 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^b2 is selected from H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -C _0-4 alkylene-C _3-8 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkylene, cycloalkyl is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^b2 is selected from methyl, ethyl, propyl, isopropyl, -CH ₂ -vinyl, -CH ₂ -ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, said methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl being optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^b3 is selected from H, -C(=O)NR ^b3a R ^b3b ;

In certain embodiments, R ^b3 is selected from -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ ,

In certain embodiments, R ^b3a , R ^b3b are each independently selected from H, OH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, -C _0-4 alkylene-C _3-6 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^b3a , R ^b3b are each independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, —CH ₂ -cyclopropyl, —CH ₂ -cyclobutyl, —CH _{2 -cyclopentyl, —CH 2 -cyclohexyl} ;

In certain embodiments, R ^b3a and R ^b3b are directly linked to form a 4- to 7-membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^b3a and R ^b3b are directly linked to form azetidinyl, pyrrolidinyl, piperazinyl, piperidinyl or morpholinyl;

In certain embodiments, R ^b4 and R ^b5 are each independently selected from H, halogen, =O, OH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , CN, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -OC _0-4 alkylene-C _3-6 carbocyclyl, -OC _0-4 alkylene-4 to 10 membered heterocyclyl, -NH-C _0-4 alkylene-C _3-6 carbocyclyl, -NH-C _0-4 alkylene-4 to 10 membered heterocyclyl, -C _0-4 alkylene-C _3-6 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl, heterocyclyl is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^b4 and R ^b5 are each independently selected from H, F, and methyl;

In certain embodiments, K is selected from K1, K2, K3, K4;

In certain embodiments, K1 is selected from

In certain embodiments, K1 is selected from

In certain embodiments, K2 is selected from

In certain embodiments, K2 is selected from

In certain embodiments, K3 is selected from In certain embodiments, K3 is selected from

In certain embodiments, K4 is selected from

In certain embodiments, K4 is selected from

In certain embodiments, each Q is independently selected from a bond, -O-, -S-, _-CH2- , ^-NRq- , -CO-, ^-NRqCO- , ^-CONRq- , or a 3-12 membered heterocyclyl group optionally substituted with 1 to 4 groups selected from ^Rz ;

In certain embodiments, each Q is independently selected from a bond, -O-, -S-, _-CH2- , ^-NRq- , -CO-, ^-NRqCO- , ^-CONRq- , or a 4-7 membered heterocyclyl optionally substituted with 1 to 4 ^Rz ;

In certain embodiments, Q is selected from a bond, C(═O);

In certain embodiments, Q is selected from Q1 or Q2;

In certain embodiments, Q1 is selected from a bond, _CH2 , NH, N( _CH3 ), O, S, C(=O), NHC(=O), C(=O)NH, N( _CH3 )C(=O), C(=O)N( _CH3 ),

In certain embodiments, Q2 is selected from a bond, _CH2 , O, S, C(=O), NHC(=O), N( _CH3 )C(=O);

In certain embodiments, R ^q is selected from H or C _1-4 alkyl;

In certain embodiments, ^Rq is selected from H, methyl or ethyl;

In certain embodiments, A is selected from C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl;

In certain embodiments, A is selected from C _3-8 carbocyclyl, phenyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl;

In certain embodiments, each F is independently selected from C _3-20 carbocyclyl, C _6-20 aryl, 3-20 membered heterocyclyl, or 5-20 membered heteroaryl;

In certain embodiments, each F is independently selected from C _3-7 monocyclic group, C _4-10 cycloalkyl group, C _5-12 spirocyclic group, C _5-10 bridged cyclyl group, 4-7 membered heteromonocyclic group, 4-10 membered heterocycloalkyl group, 8-15 membered tricyclic heterocycloalkyl group, 12-17 membered tetracyclic heterocycloalkyl group, 5-17 membered heterospirocyclic group, 5-10 membered heterobridged cyclyl group, C _6-14 aryl group, 5-10 membered heteroaryl group,

indicates that the ring is selected from an aromatic ring or a non-aromatic ring;

In certain embodiments, each E is independently selected from C _3-10 carbocyclyl, phenyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl;

In certain embodiments, each F is independently selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolidinyl, benzothiazolyl, benzothiophenyl ... yl, benzopyridinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, indolopyridine, indolothiophene, indolofuran, Its left side is directly connected to L;

In certain embodiments, E and A are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl;

In certain embodiments, each R ^k2 is independently selected from a bond, -CO-, -SO ₂ -, -SO-, or -C(R ^k3 ) ₂ -;

In certain embodiments, R ^k1 is each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, CONH ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, R ^k7a , wherein the alkyl, alkoxy or cycloalkyl is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^k7a is selected from H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 4 selected from R ^z ;

In certain embodiments, R ^k3 is each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, CONH ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl, or 3 to 8 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 selected from R ^z ;

In certain embodiments, R ^k1 , R ^k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CF ₃ , CN, COOH, CONH ₂ , C _1-4 alkyl or C _1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH or NH ₂ ;

In certain embodiments, two R ^k3 and the carbon atom or ring skeleton directly connected to the two together form a C _3-8 carbocyclyl or a 3-8 membered heterocyclyl, and two R ^k1 and the carbon atom or ring skeleton directly connected to the two together form a C _3-8 carbocyclyl or a 3-8 membered heterocyclyl, and the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 selected from R ^z ;

In certain embodiments, two R ^k3 and the carbon atom or ring skeleton directly connected to the two together form a C _3-6 carbocyclyl or a 3-7 membered heterocyclyl, two R ^k1 and the carbon atom or ring skeleton directly connected to the two together form a C _3-6 carbocyclyl or a 3-7 membered heterocyclyl, and the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 selected from R ^z ;

In certain embodiments, R ^k4 is each independently selected from H, OH, NH ₂ , CN, CONH ₂ , C _1-4 alkyl, C _3-8 cycloalkyl, or 3-8 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^k4 is each independently selected from H, OH, NH ₂ , CF ₃ , CN or C _1-4 alkyl;

In certain embodiments, each R ^k5 is independently selected from C(CH ₃ ) ₂ , CO, CH ₂ , CH ₂ CH ₂ , SO ₂ ,

In certain embodiments, each R ^k6 is independently selected from CO, CH, SO, SO ₂ , CH ₂ or N;

In certain embodiments, R ^k7 is each independently selected from C(CH ₃ ) ₂ , CO, CH, N, CH ₂ , O, S, NR ^k7a ;

In certain embodiments, R ^k7 is selected from NR ^k7a ;

In certain embodiments, each R ^k7 is independently selected from C(CH ₃ ) ₂ , CH ₂ , O, N(CH ₃ ), N(CH ₂ CH ₃ ), N(cyclopropyl) or NH;

In certain embodiments, R ^k8 is each independently selected from C, N or CH;

In certain embodiments, each ^Rk9 is independently selected from a bond, C(CH ₃ ) ₂ , CO, CH ₂ , CH ₂ CH ₂ or SO ₂ ;

In certain embodiments, ^Rka is selected from O, S or NH;

In certain embodiments, R ^k7a is selected from H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, said alkyl, cycloalkyl, heterocycloalkyl is optionally substituted with 1 to 4 selected from R ^z ;

In certain embodiments, R ^k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C _3-6 cycloalkyl

In certain embodiments, ^Rk14 is selected from

In certain embodiments, M ₁ is selected from a bond, -CH ₂ -C(=O)NH-, or -C(=O)CH ₂ NH-;

In certain embodiments, _M2 is selected from -NHC(=O) _-C1-4 alkyl, -NHC(=O) _-C3-6 cycloalkyl, or 4-10 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with 1 to 4 ^Rz ;

In certain embodiments, _M3 is selected from -NH- or -O-;

In certain embodiments, R ^k10 is selected from C _1-4 alkyl, which is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^k11 is each independently selected from H, F, Cl, Br, I, =O, OH, SH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio or -OC(=O)-C _1-4 alkyl, wherein the alkyl, alkoxy or alkylthio is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^k12 and R ^k13 are each independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, R ^k14 is selected from 5-6 membered heteroaryl, which is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, G is selected from a C _6-10 aromatic ring or a 5-10 membered heteroaromatic ring, wherein the aromatic ring or heteroaromatic ring is optionally substituted with 1 to 4 R ^z ;

In certain embodiments, ^RL2 and ^Rz are each independently selected from deuterium, F, Cl, Br, I, OH, =O, _CF3 , CN, _NH2 , COOH, _CONH2 , _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, _-C0-4 alkylene- _C3-6 cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl, _C1-4 alkoxy;

^RL2 and ^Rz are each independently selected from deuterium, F, Cl, Br, I, OH, =O, _CF3 , CN, _NH2 , COOH, _CONH2 , methyl, ethyl _, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, _-CH2 -cyclobutyl, _-CH2 -cyclopentyl, _-CH2 -cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl, _C1-4 alkoxy;

In certain embodiments, in certain embodiments, R ^L2 and R ^k1 are directly connected to form a C _4-6 carbocyclyl or a 4 to 7 membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R ^z ;

In certain embodiments, in certain embodiments, R ^L2 and R ^k1 are directly connected to form a C ₄ carbocyclyl, a C ₅ carbocyclyl, a C ₆ carbocyclyl, a 4-membered heterocyclyl, a 5-membered heterocyclyl, a 6-membered heterocyclyl, or a 7-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R ^z ;

In certain embodiments, n1, n2, and n3 are each independently selected from 0, 1, 2, or 3;

In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;

In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2 or 3

In certain embodiments, K is selected from one of the structural fragments shown in Table K-1;

In certain embodiments, K is selected from one of the structural fragments shown in Table K-2;

Table K-1

Table K-2

As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

L is selected from a bond or -C _1-50 hydrocarbon group-, wherein 1 to 20 methylene units in the hydrocarbon group are optionally replaced by -Ak-, -Cy-;

Each -Ak- is independently selected from -( _CH2 ) _q- , -( _CH2 ) _q -O-, -O-( _CH2 ) _q- , -( _CH2 ) _q -S-, -S-( _CH2 ) _q- , -( _CH2 ) _q -NR ^L- , -NR ^{L-(CH2)q-, -(CH2)q-NR L} _{C ( ＝ O} ⁾ -, -NR ^L ( _CH2 ) _qC (＝O)-, -( _CH2 ) _q -C(＝O)NR ^L -, -C(＝O)-, -C(＝O)-( _CH2 ) _q -NR ^L -, -(C≡C) _q- , -CH＝CH-, -Si( ^RL )2-, -Si(OH)( ^RL )-, _{-Si(OH)2- ,} -P(＝O)(OR ^L )-, -P(=O)(R ^L )-, -S-, -S(=O)-, -S(=O) ₂ -, or a bond, wherein the -CH ₂ - is optionally substituted by 1 to 2 R ^z ;

q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;

^RL is selected from H, _C1-4 alkyl, _C3-7 carbocyclyl, 4 to 10 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 ^Rz ;

Each -Cy- is independently selected from a bond or one of the following groups optionally substituted with 1 to 4 R ^L2 : a 4-7 membered heteromonocyclic group, a 4-12 membered heterocycloalkyl group, a 5-13 membered heterospirocyclic group, a 7-12 membered heterobridged cyclyl group, a 3-7 membered monocycloalkyl group, a 4-12 membered cycloalkyl group, a 5-13 membered spirocycloalkyl group, a 5-12 membered bridged cycloalkyl group, a 5-10 membered heteroaryl group or a C _6-10 aryl group;

B is selected from

^Ba and ^Bb are each independently selected from N or ^CRb5 ;

B ₁ is selected from C _3-10 carbocyclyl or 4 to 10 membered heterocyclyl, said B ₁ is optionally substituted by 1 to 4 R ^b1 ;

R ^b1 is each independently selected from halogen, =O, OH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , CN, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -OC _0-4 alkylene-C _3-6 carbocyclyl, -OC _0-4 alkylene-4 to 10-membered heterocyclyl, -NH-C _0-4 alkylene-C _3-6 carbocyclyl, -NH-C _0-4 alkylene-4 to 10-membered heterocyclyl, -C _0-4 alkylene-C _3-6 carbocyclyl, -C _0-4 alkylene-4 to 10-membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl, heterocyclyl is optionally substituted by 1 to 4 R ^z ;

R ^b2 is selected from H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -C _0-4 alkylene-C _3-8 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl is optionally substituted by 1 to 4 R ^z ;

R ^b3 is selected from H, -C(=O)NR ^b3a R ^b3b ;

R ^b3a , R ^b3b are each independently selected from H, OH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, -C _0-4 alkylene-C _3-6 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl is optionally substituted by 1 to 4 R ^z ;

Alternatively, R ^b3a and R ^b3b are directly linked to form a 4- to 7-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R ^z ;

R ^b4 and R ^b5 are each independently selected from H, halogen, =O, OH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , CN, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -OC _0-4 alkylene-C _3-6 carbocyclyl, -OC _0-4 alkylene-4 to 10 membered heterocyclyl, -NH-C _0-4 alkylene-C _3-6 carbocyclyl, -NH-C _0-4 alkylene-4 to 10 membered heterocyclyl, -C _0-4 alkylene-C _3-6 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl and heterocyclyl are optionally substituted by 1 to 4 R ^z ;

The condition is that B1 is selected from L is selected from a bond or contains at least one ring structure;

K is selected from K1, K2, K3, K4;

K1 is selected from

K2 is selected from

K3 is selected from

K4 is selected from

Q is each independently selected from a bond, -O-, -S-, _-CH2- , ^-NRq- , -CO-, ^-NRqCO- , ^-CONRq- or a 3-12 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1 to 4 groups selected from ^Rz ;

^Rq is selected from H or _C1-4 alkyl;

A is selected from C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl;

F is each independently selected from C _3-20 carbocyclyl, C _6-20 aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl;

R ^k2 are each independently selected from a bond, -CO-, -SO ₂ -, -SO- or -C(R ^k3 ) ₂ -;

R ^k1 is each independently selected from H, F, Cl, Br, I, OH, ═O, NH ₂ , CN, COOH, CONH ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, R ^k7a , wherein the alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R ^z ;

R ^k7a is selected from H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 selected from R ^z ;

R ^k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, CONH ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl or 3 to 8 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 groups selected from R ^z ;

or two R ^k3 and the carbon atom or ring skeleton directly connected to the two together form a C _3-8 carbocyclic group or a 3-8 membered heterocyclic group, and two R ^k1 and the carbon atom or ring skeleton directly connected to the two together form a C _3-8 carbocyclic group or a 3-8 membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 selected from R ^z ;

R ^k4 is each independently selected from H, OH, NH ₂ , CN, CONH ₂ , C _1-4 alkyl, C _3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 R ^z ;

_M1 is selected from a bond, -CH2 _- C(=O)NH- or -C(=O) _CH2NH- ;

_M2 is selected from -NHC(=O) _-C1-4 alkyl, -NHC(=O) _-C3-6 cycloalkyl or 4-10 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 ^Rz ;

_M3 is selected from -NH- or -O-;

R ^k10 is selected from C _1-4 alkyl, wherein the alkyl is optionally substituted with 1 to 4 R ^z ;

R ^k11 is each independently selected from H, F, Cl, Br, I, ＝O, OH, SH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio or -OC(＝O)-C _1-4 alkyl, wherein the alkyl, alkoxy or alkylthio is optionally substituted by 1 to 4 R ^z ;

R ^k12 and R ^k13 are each independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with 1 to 4 R ^z ;

R ^k14 is selected from 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted with 1 to 4 R ^z ;

G is selected from C _6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1 to 4 R ^z ;

^RL2 and ^Rz are each independently selected from deuterium, F, Cl, Br, I, OH, =O, _CF3 , CN, _NH2 , COOH, _CONH2 , _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, _-C0-4 alkylene- _C3-6 cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl and alkynyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl and _C1-4 alkoxy;

Alternatively, R ^L2 and R ^k1 are directly linked to form a C _4-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R ^z ;

n1, n2, n3 are each independently selected from 0, 1, 2 or 3;

p1 and p2 are each independently selected from 0, 1, 2, 3, 4 or 5.

As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

B ₁ is selected from phenyl, benzo C _4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5 to 10 membered heteroaryl, C _3-7 cycloalkyl, C _5-10 cycloalkyl, C _5-10 spirocycloalkyl, C _5-10 bridged cycloalkyl, and B ₁ is optionally substituted by 1 to 4 R ^b1 ;

R ^b2 is selected from H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -C _0-4 alkylene-C _3-8 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkylene and cycloalkyl are optionally substituted by 1 to 4 R ^z ;

Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -(CH ₂ ) _q -, -(CH ₂ ) _q -O-, -O-(CH ₂ ) _q -, -(CH ₂ ) _q -S-, -S-(CH ₂ ) _q -, -(CH ₂ ) _q -NR ^L -, -NR ^L -(CH ₂ ) _q -, -(CH ₂ ) _q -NR ^L C(＝O)-, -(CH ₂ ) _q -C(＝O)NR ^L -, -C(＝O)-, -C(＝O)-(CH ₂ ) _q -NR ^L -, -(C≡C) _q -, or a bond, and the -CH ₂ - is optionally substituted with 1 to 2 R ^z ;

R ^L are each independently selected from H or C _1-4 alkyl;

Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or one of the following groups optionally substituted by 1 to 4 ^RL2 : a 4-7 membered nitrogen-containing heteromonocyclic group, a 4-12 membered nitrogen-containing heterocycloalkyl group, a 5-13 membered nitrogen-containing heterospirocyclic group, a 7-12 membered nitrogen-containing heterobridged ring group, a _C3-7 monocycloalkyl group, a _C4-12 cycloalkyl group, a _C5-13 spirocycloalkyl group, a _C7-12 bridged cycloalkyl group, a 5-10 membered heteroaryl group or a _C6-10 aryl group;

K2 is selected from

K3 is selected from

A is selected from C _3-8 carbocyclyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl;

F is independently selected from C _3-7 monocyclic group, C _4-10 cycloalkyl group, C _5-12 spirocyclic group, C _5-10 bridged cyclyl group, 4-7 membered heteromonocyclic group, 4-10 membered heterocycloalkyl group, 8-15 membered tricyclic heterocycloalkyl group, 12-17 membered tetracyclic heterocycloalkyl group, 5-17 membered heterospirocyclic group, 5-10 membered heterobridged cyclyl group, C _6-14 aryl group, 5-10 membered heteroaryl group,

represents that the ring is selected from an aromatic ring or a non-aromatic ring;

E is each independently selected from C _3-10 carbocyclyl, phenyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl;

Q is each independently selected from a bond, -O-, -S-, _-CH2- , ^-NRq- , -CO-, ^-NRqCO- , ^-CONRq- or a 4-7 membered heterocyclic group, said heterocyclic group being optionally substituted with 1 to 4 ^Rz ;

^Rq is selected from H or _C1-4 alkyl;

R ^k1 and R ^k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CF ₃ , CN, COOH, CONH ₂ , C _1-4 alkyl or C _1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH or NH ₂ ;

or two R ^k3 and the carbon atom or ring skeleton directly connected to the two together form a C _3-6 carbocyclic group or a 3-7 membered heterocyclic group, two R ^k1 and the carbon atom or ring skeleton directly connected to the two together form a C _3-6 carbocyclic group or a 3-7 membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 selected from R ^z ;

R ^k4 are each independently selected from H, OH, NH ₂ , CF ₃ , CN or C _1-4 alkyl;

R ^k5 are each independently selected from C(CH ₃ ) ₂ , CO, CH ₂ , CH ₂ CH ₂ , SO ₂ ,

R ^k6 are each independently selected from CO, CH, SO, SO ₂ , CH ₂ or N;

R ^k7 are each independently selected from C(CH ₃ ) ₂ , CO, CH, N, CH ₂ , O, S, NR ^k7a ;

R ^k8 are each independently selected from C, N or CH;

R ^k9 are each independently selected from a bond, C(CH ₃ ) ₂ , CO, CH ₂ , CH ₂ CH ₂ or SO ₂ ;

^Rka is selected from O, S or NH;

R ^k7a is selected from H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 groups selected from R ^z ;

R ^k14 is selected from

The remaining definitions are the same as those of the first embodiment of the present invention.

As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

^RL is selected from H, methyl or ethyl;

Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following groups optionally substituted by 1 to 4 R ^L2 : phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl,

s1, s3, s5 are each independently selected from 0, 1 or 2;

s2 and s4 are each independently selected from 0 or 1;

s6 is selected from 0, 1, 2 or 3;

s6 is selected from 1, 2 or 3;

B1 is selected from cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, Bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl;

^Ba and ^Bb are selected from N or CH;

R ^b1 is each independently selected from F, Cl, Br, I, =O, OH, NH ₂ , CN, methyl, ethyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, and the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted with 1 to 4 R ^z ;

R ^b2 is selected from methyl, ethyl, propyl, isopropyl, -CH ₂ -vinyl, -CH ₂ -ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl is optionally substituted with 1 to 4 R ^z ;

R ^b3 is selected from -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ ,

R ^b4 and R ^b5 are each independently selected from H, F, and methyl;

K1 is selected from

K4 is selected from

Q is selected from a bond, C(═O);

Q1 is selected from a bond, _CH2 , NH, N( _CH3 ), O, S, C(=O), NHC(=O), C(=O)NH, N( _CH3 )C(=O), C(=O)N( _CH3 ),

Q2 is selected from a bond, _CH2 , O, S, C(=O), NHC(=O), N( _CH3 )C(=O);

E and A are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl;

F is independently selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthryl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridinonyl, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridine yl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, indolopyridinyl, indolothienyl, indolofuranyl,

The left side is directly connected to L;

^Rka is selected from O, S or NH;

R ^k7 are each independently selected from C(CH ₃ ) ₂ , CH ₂ , O, N(CH ₃ ), N(CH ₂ CH ₃ ), N(cyclopropyl) or NH;

R ^k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C _3-6 cycloalkyl;

^RL2 and ^Rz are each independently selected from deuterium, F, Cl, Br, I, OH, =O, _CF3 , CN, _NH2 , COOH, _CONH2 , methyl, ethyl _, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, _-CH2 -cyclobutyl, _-CH2 -cyclopentyl, _-CH2 -cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl, _C1-4 alkoxy;

Alternatively, R ^L2 and R ^k1 are directly linked to form a C _4-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R ^z ;

p1 or p2 are each independently selected from 0, 1, 2 or 3;

The remaining definitions are the same as those of the first or second embodiment of the present invention.

As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from _a bond, -O-, -S-, _-OCH2- , _-CH2O- , _-OCH2CH2- , _-CH2CH2O- , _-C≡C- , _-C ( _CH3 ) _2- , -CH2-, _-C (CH3)2-, -CH2CH2- _{, -CH2CH2CH2-} , _{-N ( CH3} )-, _{-NH- , -CH2N} ( _CH3 )-, _{-CH2NH- , -NHCH2-} , _-CH2CH2N ( _CH3 )- _{, -CH2CH2NH- ,} -NHCH2CH2-, -C(=O)-, -C(= _O ) _CH2NH- , _-CH2 C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups which are optionally substituted: When substituted, it is substituted by 1 to 4 substituents selected from F, CF ₃ , OH, methyl, =0, hydroxymethyl, methoxy, COOH, CN or NH ₂ ;

The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

B is selected from

L is selected from -C(=O)-Cy1-, -C(=O)-Cy1-Cy2-, -C(=O)-Cy1-CH ₂ -Cy2-, -C(=O)-Cy1-Cy2 -Cy3-, -C(=O)-Cy1-CH ₂ -Cy2-Cy3-, -C(=O)-Cy1-Cy2-CH ₂ -Cy3-, -C(=O)NH-Cy1-,- C(=O)NH-Cy1-Cy2-, -C(=O)NH-Cy1-CH ₂ -Cy2-;

Cy1, Cy2, and Cy3 are each independently selected from one of the following optionally substituted groups: When substituted, it is substituted by 1 to 4 substituents selected from F, CF ₃ , OH, methyl, =0, hydroxymethyl, methoxy, COOH, CN or NH ₂ ;

The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

K is selected from one of the structural fragments shown in Table K-1 or Table K-2;

L is selected from the group shown in Table L-1, wherein the left side of the group is connected to B;

The remaining definitions are the same as those of the first, second, third, fourth or fifth embodiment of the present invention.

As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by the general formula (I) is selected from (Ia), (Ib), (Ib-1)

Ya, Yb, Yc, Yd, and Ye are each independently selected from N or CH;

B ₂ is absent or is selected from C _4-6 carbocyclyl or 4 to 6 membered heterocyclyl;

Cy2 is selected from 4 to 6-membered nitrogen-containing heterocycloalkyl or C _3-6 cycloalkyl, and the Cy2 is optionally substituted by 1 to 4 R ^L2a ;

^RL2a and ^RL2b are each independently selected from H, deuterium, halogen, OH, COOH, CN, _NH2 , =O, _C1-4 alkyl or _C1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl or _C1-4 alkoxy substituents;

R ^k1 is each independently selected from H, F, Cl, Br, I, OH, ＝O, NH ₂ , CN, COOH, CONH ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R ^z ;

Alternatively, R ^L2b and R ^b1 are directly connected, R ^L2a and R ^k1 are directly connected, R ^L2b and R ^L2a are directly connected, and R ^k1 and R ^k1 are directly connected to form a C _4-6 carbocyclic group or a 4 to 6-membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R ^z ;

R ^z is independently selected from deuterium, halogen, OH, CN, NH ₂ , ═O, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

p3 is selected from 0, 1, 2, 3, 4;

m1, m2, and m3 are each independently selected from 0, 1, 2, 3, and 4;

L is selected from the group shown in Table L-1, wherein the left side of the group is connected to B;

The remaining definitions are the same as those of the first, second, third, fourth, fifth or sixth embodiment of the present invention.

As an eighth embodiment of the present invention, the compound represented by (Ia), (Ib), (Ib-1) above or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

Selected from

^RL2a , ^RL2b are each independently selected from H, F, Cl, Br, I, OH, COOH, CN, _NH2 , =O, _CF3 , methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy;

R ^k1 is each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CF ₃ , CN, COOH, CONH ₂ , methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH ₂ ;

Alternatively, R ^L2b and R ^b1 are directly connected, R ^L2a and R ^k1 are directly connected, R ^L2b and R ^L2a are directly connected, and R ^k1 and R ^k1 are directly connected to form a C ₄ carbocyclyl, a C ₅ carbocyclyl, a C ₆ carbocyclyl, a 4-membered heterocyclyl, a 5-membered heterocyclyl, or a 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R ^z ;

^Rz is independently selected from deuterium, F, Cl, Br, , OH, COOH, CN, _NH2 , =O, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl;

Cy2 is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, cyclobutyl, cyclopentyl, cyclohexyl, and said Cy2 is optionally substituted by 1 to 4 R ^L2a .

The remaining definitions are the same as those of the first, second, third, fourth, fifth, sixth or seventh embodiment of the present invention.

The present invention relates to the following compound or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures in Table E.

The present invention relates to a pharmaceutical composition, comprising the above-mentioned compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

The present invention relates to use of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a drug for treating diseases related to Aurora A activity or expression.

The present invention relates to use of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in preparing a drug for treating and inhibiting or degrading Aurora A-related diseases.

In some embodiments, the disease associated with the inhibition or degradation of Aurora A is cancer.

The present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal and a pharmaceutical excipient. The pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").

The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition. In some embodiments, the mammal of the present invention includes a human.

"Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition (e.g., cancer) being treated to some extent. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3 -500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500 mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400 mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-3 00mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg , 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1500mg, 80-1000mg, 80-800mg;

In some embodiments, the pharmaceutical composition includes but is not limited to 1-1500 mg, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg g, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg, 1000 mg of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being an autoimmune disease, an inflammatory disease or a cancer.

A method for treating a disease in a mammal, the method comprising administering to a subject a drug compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1500 mg/day, the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, 100-800 mg/day, 200-800 mg/day, 25-4 In some embodiments, the daily dose includes but is not limited to 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200 mg/day, 300 mg/day, 320 mg/day, 400 mg/day, 480 mg/day, 600 mg/day, 640 mg/day, 800 mg/day, 1000 mg/day, 1500 mg/day.

The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as its amount in the above-mentioned pharmaceutical composition.

The amount of the compound of the invention or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

In order to accomplish the purpose of the present invention, the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Anage Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

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

The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include ¹² C, ¹³ C and ¹⁴ C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include ¹⁶ O, ¹⁷ O and ¹⁸ O, sulfur isotopes include ³² S, ³³ S, ³⁴ S and ³⁶ S, nitrogen isotopes include ¹⁴ N and ¹⁵ N, fluorine isotopes include ¹⁷ F and ¹⁹ F, chlorine isotopes include ³⁵ Cl and ³⁷ Cl, and bromine isotopes include ⁷⁹ Br and ⁸¹ Br.

"CN" refers to cyano.

"Halogen" refers to F, Cl, Br or I.

"Halogen substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen substituted" is abbreviated as "halo".

"Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; the alkyl groups appearing herein are defined in accordance with this definition. Alkyl groups may be monovalent, divalent, trivalent, or tetravalent.

"Heteroalkyl" refers to a substituted or unsubstituted alkyl group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X( _CH2 )vX( _CH2 )vX( _CH2 )vH (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom, the heteroatom includes but is not limited to N, O or S, and at least one X is selected from a heteroatom, and the N or S in the heteroatom can be oxidized to various oxidation states). The heteroalkyl group can be monovalent, divalent, trivalent or tetravalent.

"Alkylene" refers to a substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon group, including -(CH ₂ ) _v - (v is an integer from 1 to 10). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene.

"Heteroalkylene" refers to a substituted or unsubstituted alkylene in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X( _CH2 )vX( _CH2 )vX( _CH2 )v-, v is an integer from 1 to 5, each X is independently selected from a bond, N, O or S, and at least one X is selected from N, O or S.

"Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, etc. Cycloalkyl groups appearing herein are defined as above. Cycloalkyl groups can be monovalent, divalent, trivalent or tetravalent.

"Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S. The N and S selectively substituted in the ring of the heterocycloalkyl can be oxidized to various oxidation states. The heterocycloalkyl can be connected to a heteroatom or a carbon atom, the heterocycloalkyl can be connected to an aromatic ring or a non-aromatic ring, and the heterocycloalkyl can be connected to a bridge ring or a spiro ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. The heterocycloalkyl can be monovalent, divalent, trivalent or tetravalent.

"Alkenyl" refers to a substituted or unsubstituted straight chain and branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2- Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl groups appearing in this article have the same definition as this definition. The alkenyl group can be monovalent, divalent, trivalent or tetravalent.

"Alkynyl" refers to a substituted or unsubstituted straight or branched monovalent unsaturated hydrocarbon radical having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, 2 to 4 carbon atoms in the backbone, examples of alkynyl include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-pentynyl, 14-pentynyl, 15-pentynyl, 16-pentynyl, 17-pentynyl, 18-pentynyl, 19-pentynyl, 20-pentynyl, 21-pentynyl, 22-pentynyl, 23-pentynyl, 24-pentynyl, 25-pentynyl, 26-pentynyl, 27-pentynyl, 28-pentynyl, 29-pentynyl, 30-pentynyl, 31-pentynyl, 32-pentynyl, 33-pentynyl, 34-pentynyl, 35-pentynyl, 36-pentynyl, 37-pentynyl, 38-pentynyl, 39-pentynyl, 40-pentynyl, 41-pentynyl, 42-pentynyl, 43-pentynyl, 44-pentynyl, 45-pentynyl, 46-pentynyl, 47-pentynyl, 48-pent Alkynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl and the like; the alkynyl group can be monovalent, divalent, trivalent or tetravalent.

"Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

"Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, or a 10-15-membered tricyclic ring system, and the carbocyclyl can be attached to the aromatic or non-aromatic ring, which can be a monocyclic ring, a bridged ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The N and S selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group may be connected to a heteroatom or a carbon atom, may be connected to an aromatic ring or a non-aromatic ring, may be connected to a bridged ring or a spiro ring, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, py ... pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, pyridazinyl, py furanyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

"Spiro" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called spiro atom), and the number of ring atoms in the spiro ring system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 heteroatoms selected from N, O or S(=O) _n . Non-limiting examples include:

"Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

"Cyclic" or "Cyclic radical" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or unsubstituted, and each ring in the cyclic system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to selected from N, S(=O) _n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:

"Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

"Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, which may contain 0 or more double bonds, and any ring in the ring system may contain 0 to 5 groups selected from heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12 or 5 to 10. Non-limiting examples include Cubane, adamantane. "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

"Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" whose ring system consists of only carbon atoms. "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" appearing in this article has the same definition as spirocycle.

"Carbocyclic ring", "cyclic carbocyclyl", "cyclic carbocyclyl" or "carbocyclic ring" refers to a "cyclic ring" whose ring system consists of only carbon atoms. "Carbocyclic ring", "cyclic carbocyclyl", "cyclic carbocyclyl" or "carbocyclic ring" appearing in this article have the same definition as cyclic ring.

"Carbobridge ring", "bridged ring carbocyclic group", "bridged carbocyclic group" or "carbon bridged cyclic group" refers to a "bridged ring" whose ring system consists of only carbon atoms. "Carbobridge ring", "bridged ring carbocyclic group", "bridged carbocyclic group" or "carbon bridged cyclic group" appearing in this article have the same definition as the bridged ring.

"Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclic group" refers to a "heterocyclic group" or "heterocycle" of a monocyclic ring system. The heterocyclic group, "monocyclic heterocyclyl" or "heteromonocyclic group" appearing in this document has the same definition as heterocycle.

"Heterocyclic ring", "heterocyclic ring group", "cyclic heterocyclic ring group" or "heterocyclic ring group" refer to a "cyclic ring" containing a heteroatom. The heterocyclic ring, "heterocyclic ring group", "cyclic heterocyclic ring group" or "heterocyclic ring group" appearing in this document have the same definition as cyclic ring.

"Heterospirocycle", "heterospirocyclyl", "spiro heterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" containing a heteroatom. Heterospirocycle, "heterospirocyclyl", "spiro heterocyclyl" or "heterospirocyclyl" appearing herein have the same definition as spirocycle.

"Heterobridged ring", "heterobridged ring group", "bridged heterocyclic group" or "heterobridged ring group" refers to a "bridged ring" containing a heteroatom. The heterobridged ring, "heterobridged ring group", "bridged heterocyclic group" or "heterobridged ring group" appearing herein have the same definition as the bridged ring.

"Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring,

"Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

"Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O or S(=O)n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl include but are not limited to pyridyl, furanyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include The heteroaryl groups appearing in this article have the same definition as this definition. The heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is located on the heteroaryl ring.

"5-membered ring and 5-membered heteroaromatic ring" refers to a 5-membered fused heteroaromatic ring, at least one of the two rings contains one or more heteroatoms (including but not limited to O, S or N), and the whole group is aromatic. Non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolofuran ring, pyrazolofuran ring, pyrrolothiophene ring, and pyrazolothiophene ring.

"5- and 6-membered heteroaromatic ring" refers to a 5- and 6-membered fused heteroaromatic ring, where at least one of the two fused rings contains one or more heteroatoms (including but not limited to O, S or N), and the entire group is aromatic. Non-limiting examples include benzo 5-membered heteroaromatic, 6-membered heteroaromatic ring and 5-membered heteroaromatic ring.

"Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring group, spirocyclyl, cyclocyclyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -( _CH2 ) _m -C(=O)-R ^a , -O-( _CH2 ) _m -C(=O)-R ^a , -( _CH2 ) _m -C(=O)-NR ^b R ^c , -( _CH2 ) _mS (=O) _nR ^a , -( _CH2 ) _m -alkenyl-R ^a , OR ^d , or -( _CH2 ) _m -alkynyl-R ^a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR ^b R ^c , wherein R ^b and R ^c are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R ^b and R ^c can form a five- or six-membered cycloalkyl or heterocyclyl.

“Containing 1 to 5 heteroatoms selected from O, S, and N” means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, and N.

"0 to X substituents are substituted" means substituted by 0, 1, 2, 3 ... X substituents, X is selected from any integer between 1 and 10. For example, "0 to 4 substituents are substituted" means substituted by 0, 1, 2, 3 or 4 substituents. For example, "0 to 5 substituents are substituted" means substituted by 0, 1, 2, 3, 4 or 5 substituents. For example, "the heterobridged ring is optionally further substituted by 0 to 4 substituents selected from H or F" means that the heterobridged ring is optionally further substituted by 0, 1, 2, 3 or 4 substituents selected from H or F.

X-Y membered rings (X is selected from an integer less than Y and greater than or equal to 3, and Y is selected from any integer between 4 and 12) include X, X+1, X+2, X+3, X+4...Y membered rings. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings or heterobridged rings. For example, "4-7 membered heteromonocyclic rings" refer to 4-, 5-, 6- or 7-membered heteromonocyclic rings, and "5-10 membered heterocyclic rings" refer to 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic rings.

"Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes situations where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

"Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.

"Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

"Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

"Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

"Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

"Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

"Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

"Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.

" _IC50 " is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of such a process, such as an enzyme, receptor, cell, etc.) by half.

DETAILED DESCRIPTION

The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology.

The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in units of 10 ^-6 (ppm). NMR measurements were performed using (Bruker Avance III 400 and Bruker Avance 300) NMR spectrometers, with deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) as the solvent, and tetramethylsilane (TMS) as the internal standard;

MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

Reagent and Solvent Abbreviations:

Dess-Martin oxidant: (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzimidoyl-3(1H)-one (CAS No. 87413-09-0);

TBSOTf: tert-butyldimethylsilyl trifluoromethanesulfonate; BINAP (1,1'-binaphthyl-2,2'-bis(diphenylphosphine), CAS: 98327-87-8); Pd ₂ (dba) ₃ : tris(dibenzylideneacetone)dipalladium (CAS No.: 51364-51-3); DMA: N,N-dimethylacetamide; DMF: N,N-dimethylformamide;

DCM: dichloromethane; MeOH: methanol; NMI: N-methylimidazole; HATU: CAS: 148893-10-1;

TCFH:N,N,N',N'-Tetramethylchloroformamidine hexafluorophosphate

Embodiment 1:

Step 1: Preparation of 1A

Intermediate 1 (6 g, 20.49 mmol), tert-butyl 4-aminobenzoate (5.54 g, 28.67 mmol), palladium acetate (0.92 g, 4.10 mmol), BINAP (2.81 g, 4.51 mmol) and cesium carbonate (16.69 g, 51.22 mmol) were added to 1,4-dioxane (90 mL), and the mixture was reacted at 95° C. under nitrogen protection for about 18 h. The reaction solution was cooled to room temperature, ethyl acetate (150 mL) was added, and the mixture was washed with saturated aqueous sodium chloride solution (100 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered, and an appropriate amount of silica gel was added to concentrate under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-2/98). Ethyl acetate (12 mL) was added to the obtained product and stirred, and petroleum ether (24 mL) was added dropwise. The mixture was stirred for 1 h and then filtered. The filter residue was rinsed with a small amount of petroleum ether and dried in vacuo to obtain 1A (4 g, yield: 43%).

Step 2: Preparation of 1B

1A (3.5 g, 7.79 mol) was added to dichloromethane (15 mL), trifluoroacetic acid (7 mL) was added, and the mixture was reacted at room temperature for 2 h, trifluoroacetic acid (8 mL) was added, and the reaction was continued for 2 h. The reaction solution was concentrated under reduced pressure, methyl tert-butyl ether (40 mL) was added to the residue, and the mixture was stirred for 30 minutes and filtered. The filter residue was washed with a small amount of methyl tert-butyl ether and dried under vacuum to obtain 1B (3.06 g, yield: 99%).

LCMS m/z＝394.50[M+H] ⁺

Step 3: Preparation of 1C

1B (0.3 g, 0.76 mmol), N-BOC piperazine (0.14 g 0.76 mmol), HATU (0.43 g, 1.14 mmol) were added to DMF (5 mL), and N,N-diisopropylethylamine (0.20 g, 1.52 mmol) was added dropwise, and the mixture was reacted at room temperature for 20 h. Ethyl acetate (50 mL) was added to the reaction solution, and the mixture was washed with a saturated sodium chloride aqueous solution (50 mL × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 1C (0.39 g, yield: 91%).

Step 4: 1D preparation

1C (0.39 g, 0.69 mmol) was added to dichloromethane (5 mL), and trifluoroacetic acid (4.59 g, 40.25 mmol) was added dropwise, and stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, and dichloromethane (20 mL) was added to the residue, and the pH was adjusted to 8-9 with 0.5 N sodium hydroxide aqueous solution. After separation, the aqueous layer was extracted with dichloromethane (20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 1D (0.3 g, yield: 94%).

Step 5: Preparation of Compound 1

1D (0.27 g, 0.58 mmol) and 1E (0.19 g, 0.69 mmol) were added to DMSO (5 mL), and N,N-diisopropylethylamine (0.15 g, 1.16 mmol) was added, and the mixture was reacted at 90°C-100°C for 6 h. The mixture was cooled to room temperature, and methanol (2.5 mL) and water (15 mL) were added. The mixture was stirred for 30 minutes and filtered. The filter cake was washed with water and dissolved in dichloromethane/methanol. An appropriate amount of silica gel was added and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to give compound 1 (0.2 g, yield: 48%).

LCMS m/z＝718.3[M+H] ⁺

Embodiment 2:

Step 1: Preparation of 2A

CBZ-piperazine (4.4 g, 19.98 mmol) and 1-Boc-3-azetidinone (3.42 g, 19.98 mmol) were added to dichloromethane (100 mL), sodium triacetoxyborohydride (8.47 g, 39.96 mmol) and glacial acetic acid (2.40 g, 39.98 mmol), and the mixture was reacted at room temperature for 3 h. The reaction solution was washed with saturated sodium chloride solution (100 mL×2), washed once with saturated sodium bicarbonate solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA/PE (V/V) = 0/100-50/50) to obtain 2A (4.5 g, yield: 60%).

Step 2: Preparation of 2B

2A (4.5 g, 11.99 mol) and palladium carbon (1.28 g) were added to methanol (30 mL) and reacted under a hydrogen balloon at room temperature for about 20 h. Appropriate amount of celite was spread, filtered, washed with a small amount of ethyl acetate, and the filtrate was concentrated under reduced pressure to dryness to obtain 2B (2.89 g, yield: 100%).

Step 3: Preparation of 2C

1B (0.3 g, 0.76 mmol), compound 2B (0.18 g 0.76 mmol), HATU (0.43 g, 1.14 mmol) and DMF (5 mL) were added dropwise with N, N-diisopropylethylamine (0.20 g, 1.52 mmol) and reacted at room temperature for 20 h. Ethyl acetate (50 mL) was added to the reaction solution, which was washed with saturated sodium chloride aqueous solution (50 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 2C (0.38 g, yield: 81%).

Step 4: 2D preparation

2C (0.38 g, 0.62 mmol) was added to dichloromethane (5 mL), and trifluoroacetic acid (4.59 g, 40.25 mmol) was added dropwise, and stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, and dichloromethane (20 mL) was added to the residue, and the pH was adjusted to 8-9 with 0.5 N sodium hydroxide aqueous solution. After separation, the aqueous layer was extracted with dichloromethane (20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 2D (0.27 g, yield: 84%).

Step 5: Preparation of Compound 2

2D (0.27 g, 0.52 mmol), 1E (0.17 g, 0.62 mmol), N,N-diisopropylethylamine (0.13 g, 1.00 mmol) were added to DMSO (5 mL) and reacted at 95°C for 3 h. After cooling to room temperature, methanol (2.5 mL) was added, water (15 ml) was added dropwise, and the mixture was stirred for crystallization for 30 minutes, filtered, and the filter cake was washed with water. The filter cake was dissolved with dichloromethane-methanol, and an appropriate amount of silica gel was added. After concentrating under reduced pressure, the mixture was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain compound 2 (0.18 g, yield: 45%).

LCMS m/z＝773.9[M+H] ⁺

Embodiment 3:

Step 1: Preparation of 3A

CBZ-piperazine (4.4 g, 19.98 mmol) and tert-butyl 3-formylazetidine-1-carboxylate (3.70 g, 19.98 mmol) were added to dichloromethane (60 mL), and sodium triacetoxyborohydride (8.47 g, 39.96 mmol) and glacial acetic acid (2.40 g, 39.98 mmol) were added. The reaction was carried out at room temperature for about 18 h. The reaction solution was washed with saturated sodium chloride solution (100 mL×2), washed with saturated sodium bicarbonate solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM (V/V)=0/100-5/95) to obtain 3A (4.3 g, yield: 55%).

Step 2: Preparation of 3B

3A (4.3 g, 11.04 mol) and palladium carbon (0.86 g) were added to methanol (60 mL) and reacted at room temperature under a hydrogen balloon for about 18 h. Appropriate amount of celite was spread, filtered, washed with a small amount of ethyl acetate, and the filtrate was concentrated under reduced pressure to dryness to obtain 3B (2.81 g, yield: 100%).

Step 3: Preparation of 3C

1B (0.3 g, 0.76 mmol), 3B (0.19 g, 0.76 mmol), HATU (0.43 g, 1.14 mmol) and DMF (5 mL) were added dropwise with N, N-diisopropylethylamine (0.20 g, 1.52 mmol) and reacted at room temperature for 20 h. Ethyl acetate (50 mL) was added to the reaction solution, which was washed with a saturated sodium chloride aqueous solution (50 mL × 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 3C (0.29 g, yield: 60%).

Step 4: 3D preparation

3C (0.29 g, 0.46 mmol) was added to dichloromethane (5 mL), stirred to dissolve, and then trifluoroacetic acid (4.59 g, 40.25 mmol) was added dropwise. The mixture was stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure to dryness. Dichloromethane (20 mL) was added to the residue, and the pH was adjusted to 8-9 with 0.5 N aqueous sodium hydroxide solution. After separation, the aqueous layer was extracted with dichloromethane (20 mL), the organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain 3D (0.24 g, yield: 98%).

Step 5: Preparation of compound 3

3D (0.24 g, 0.45 mmol), 1E (0.14 g, 0.51 mmol), N,N-diisopropylethylamine (0.12 g, 0.93 mmol) were added to DMSO (5 mL), and the mixture was reacted at 95 °C for 3 h. The mixture was cooled to room temperature, and methanol (2.5 mL) was added. Water (15 ml) was added dropwise, and the mixture was stirred for crystallization for 30 minutes. The mixture was filtered, and the filter cake was washed with water, dried, and dissolved in dichloromethane-methanol. An appropriate amount of silica gel was added, and the mixture was concentrated under reduced pressure and chromatographed on a silica gel column (MeOH/DCM (V/V) = 0/100-5/95) to obtain compound 3 (0.2 g, yield: 56%).

LCMS m/z＝787.9[M+H] ⁺

Embodiment 4:

Step 1: Preparation of 4A

4-Fluoronitrobenzene (0.42 g, 2.98 mmol), 2B (0.72 g, 2.98 mmol), N,N-diisopropylethylamine (0.77 g, 5.96 mmol) were added to DMSO (10 mL), reacted at 95 ° C for 3 h, cooled to room temperature, added with ethyl acetate (50 mL), washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, added with appropriate amount of silica gel, concentrated under reduced pressure, and purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 4A (0.67 g, yield: 62%)

Step 2: Preparation of 4B

4A (0.57 g, 1.57 mmol), zinc powder (1.03 g, 15.75 mmol), ammonium chloride (0.84 g, 15.70 mmol) were added to tetrahydrofuran (9 mL) and water (3 mL), and reacted at room temperature for 2 h. Saturated sodium bicarbonate solution (20 mL) was added, stirred for 5 minutes, filtered, the filter cake was washed with dichloromethane, the layers were separated, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 4B (0.50 g, yield: 96%).

Step 3: Preparation of 4C

Intermediate 1 (0.4 g, 1.37 mmol), 4B (0.50 g, 1.51 mmol), palladium acetate (0.062 g, 0.27 mmol), BINAP (0.19 g, 0.30 mmol), cesium carbonate (1.12 g, 3.43 mmol) were added to 1,4-dioxane (10 mL), purged with nitrogen three times, and reacted at 95 ° C for about 18 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and an appropriate amount of silica gel was added to the filtrate. After reduced pressure concentration, it was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 4C (0.65 g, yield: 81%).

Step 4: 4D preparation

4C (0.40 g, 0.68 mmol) was added to dichloromethane (5 mL), and trifluoroacetic acid (4.59 g, 40.25 mmol) was added dropwise, and stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, and dichloromethane (20 mL) was added to the residue, and the pH was adjusted to 8-9 with 0.5 N sodium hydroxide aqueous solution. After separation, the aqueous layer was extracted once with dichloromethane (20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 4D (0.29 g, yield: 87%).

Step 5: Preparation of compound 4

4D (0.29 g, 0.59 mmol), 1E (0.18 g, 0.65 mmol), N,N-diisopropylethylamine (0.16 g, 1.21 mmol) were added to DMSO (5 mL), and the mixture was reacted at 95 °C for 3 h. The mixture was cooled to room temperature, and methanol (2.5 mL) was added. Water (15 ml) was added dropwise, and the mixture was stirred for crystallization for 30 minutes. The mixture was filtered, and the filter cake was washed with water. After being drained, the mixture was dissolved in dichloromethane-methanol, and an appropriate amount of silica gel was added. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain a crude product. Methanol (10 mL) was added, and the mixture was stirred at 60 °C for 1 h, stirred at room temperature for 2 h, filtered, and the filter cake was washed with an appropriate amount of methanol. The mixture was concentrated under reduced pressure to obtain compound 4 (0.21 g, yield: 48%).

LCMS m/z＝745.3[M+H] ⁺

Embodiment 5:

Step 1: Preparation of 5A

Intermediate 1 (10 g, 34.16 mmol), 4-aminobicyclo[2.2.2]octane-1-carboxylic acid methyl ester hydrochloride (11.26 g, 51.24 mmol), and N,N-diisopropylethylamine (13.24 g, 102.48 mmol) were added to NMP (50 mL), and the mixture was reacted at 120° C. for 10 h. The mixture was cooled to room temperature, and ethyl acetate (100 mL) was added. The organic layer was washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5A (15 g, yield: 100%).

Step 2: Preparation of 5B

5A (15.00 g, 34.13 mmol), sodium hydroxide (1.37 g, 34.13 mmol) were added to tetrahydrofuran (100 mL) and water (30 mL), and the mixture was reacted at 60°C for about 18 h. The mixture was concentrated under reduced pressure to remove THF, methanol (100 mL) was added, the mixture was reacted at 60°C for 3 h, the mixture was cooled to room temperature, concentrated under reduced pressure, water (100 mL) was added, the reaction solution was extracted with ethyl acetate (100 mL×2), the aqueous layer was cooled with ice water, concentrated hydrochloric acid was added dropwise to adjust the pH to 2-3, and a solid was gradually precipitated. After stirring for 30 minutes, the mixture was filtered, the filter cake was washed with water, the filter cake was dissolved in methanol-dichloromethane solution, silica gel was added, the mixture was concentrated under reduced pressure, and the mixture was purified by silica gel column chromatography (MeOH/DCM (V/V)=0/100-10/90) to obtain 5B (0.9 g, yield: 6%).

LCMS m/z＝426.5[M+H] ⁺

Step 3: Preparation of 5C

5B (0.192 g, 0.45 mmol), 2B (0.129 g, 0.53 mmol), and HATU (0.256 g, 0.67 mmol) were added to DMF (5 mL), and N,N-diisopropylethylamine (0.116 g, 0.90 mmol) was added dropwise. The reaction was carried out at room temperature for 18 h. Ethyl acetate (30 mL) was added to the reaction solution, and the mixture was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 5C (0.24 g, yield: 82%).

Step 4: 5D preparation

5C (0.24 g, 0.37 mmol) was added to dichloromethane (5 mL), and trifluoroacetic acid (4.59 g, 40.25 mmol) was added dropwise, and stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, and dichloromethane (20 mL) was added to the residue, and the pH was adjusted to 8-9 with 0.5 N sodium hydroxide aqueous solution. After separation, the aqueous layer was extracted once with dichloromethane (20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 5D (0.27 g, yield: 84%).

Step 5: Preparation of compound 5

5D (0.17 g, 0.31 mmol), 1E (0.094 g, 0.34 mmol), N,N-diisopropylethylamine (0.080 g, 0.62 mmol) were added to DMSO (5 mL), and the mixture was reacted at 95 °C for 3 h. The mixture was cooled to room temperature, and methanol (2.5 mL) was added. Water (15 ml) was added dropwise, and the mixture was stirred for crystallization for 30 minutes. The mixture was filtered, and the filter cake was washed with water, dried, and dissolved in dichloromethane-methanol. An appropriate amount of silica gel was added, and the mixture was concentrated under reduced pressure and chromatographed on a silica gel column (MeOH/DCM (V/V) = 0/100-5/95) to obtain compound 5 (0.09 g, yield: 36%).

LCMS m/z＝805.4[M+H] ⁺

Embodiment 6:

Step 1: Preparation of 6A

4-Fluoronitrobenzene (0.45 g, 3.19 mmol), 3B (0.81 g, 3.19 mmol), N,N-diisopropylethylamine (0.82 g, 6.38 mmol) were added to DMSO (5 mL), reacted at 95 ° C for about 3 h, cooled to room temperature, added with ethyl acetate (30 mL), washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, added with appropriate amount of silica gel, concentrated under reduced pressure, and purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 6A (1 g, yield: 83%)

Step 2: Preparation of 6B

6A (1.00 g, 2.66 mmol), zinc powder (1.74 g, 26.60 mmol), ammonium chloride (1.43 g, 26.60 mmol) were added to tetrahydrofuran (15 mL) and water (5 mL), and the mixture was stirred at room temperature for 2 h. Saturated sodium bicarbonate solution (30 mL) was added, and the mixture was stirred for 5 minutes. The mixture was filtered by spreading an appropriate amount of diatomaceous earth, and the filter cake was washed with dichloromethane (30 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6B (0.75 g, yield: 81%).

Step 3: Preparation of 6C

Intermediate 1 (0.58 g, 1.98 mmol), 6B (0.75 g, 2.18 mmol), palladium acetate (0.089 g, 0.40 mmol), BINAP (0.27 g, 0.43 mmol), cesium carbonate (1.61 g, 4.94 mmol) were added to 1,4-dioxane (15 mL), and the mixture was reacted at 80° C. under nitrogen protection for about 18 h. The reaction solution was cooled to room temperature, filtered, and an appropriate amount of silica gel was added to the filtrate, and the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95). Methyl tert-butyl ether (20 mL) was added to the obtained crude product, and the mixture was stirred at room temperature for crystallization for 1 h, filtered, and the filter cake was washed with a small amount of methyl tert-butyl ether, and concentrated under reduced pressure to obtain 6C (0.78 g, yield: 65%).

Step 4: Preparation of 6D

6C (0.40 g, 0.68 mmol) was added to dichloromethane (5 mL), and trifluoroacetic acid (4.59 g, 40.25 mmol) was added dropwise, and stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, and dichloromethane (20 mL) was added to the residue, and the pH was adjusted to 8-9 with 0.5 N sodium hydroxide aqueous solution. After separation, the aqueous layer was extracted with dichloromethane (20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 6D (0.3 g, yield: 90%).

Step 5: Preparation of compound 6

6D (0.30 g, 0.60 mmol), 1E (0.18 g, 0.65 mmol), N,N-diisopropylethylamine (0.16 g, 1.21 mmol) were added to DMSO (5 mL), and the mixture was reacted at 95 °C for 3 h. The mixture was cooled to room temperature, and methanol (2.5 mL) was added. Water (15 ml) was added dropwise, and the mixture was stirred for crystallization for 30 minutes. The mixture was filtered, and the filter cake was washed with water. The filter cake was dissolved with dichloromethane-methanol, and an appropriate amount of silica gel was added. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain compound 6 (0.21 g, yield: 46%).

LCMS m/z＝760.0[M+H] ⁺

Embodiment 7:

Step 1: Preparation of 7A

5B (0.19 g, 0.45 mmol), 3B (0.13 g, 0.51 mmol), HATU (0.26 g, 0.68 mmol) were added to DMF (5 mL), and N,N-diisopropylethylamine (0.12 g, 0.93 mmol) was added dropwise, and the mixture was reacted at room temperature for 18 h. Ethyl acetate (30 mL) was added to the reaction solution, and the mixture was washed twice with a saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 7A (0.22 g, yield: 74%).

Step 2: Preparation of 7B

7A (0.22 g, 0.33 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (4.59 g, 40.25 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, and dichloromethane (20 mL) was added to the residue, and the pH was adjusted to 8-9 with 0.5 N sodium hydroxide aqueous solution. After separation, the aqueous layer was extracted once with dichloromethane (20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 7B (0.16 g, yield: 86%).

Step 3: Preparation of compound 7

7B (0.16 g, 0.28 mmol), 1E (0.085 g, 0.31 mmol), N,N-diisopropylethylamine (0.072 g, 0.56 mmol) were dissolved in DMSO (5 mL) and reacted at 95°C for 3 h. After cooling to room temperature, methanol (2.5 mL) was added, water (15 ml) was added dropwise, and the mixture was stirred for crystallization for 30 minutes, filtered, and the filter cake was washed with water, dried, and dissolved in dichloromethane-methanol, and an appropriate amount of silica gel was added. After concentrating under reduced pressure, the mixture was chromatographed on a silica gel column (MeOH/DCM (V/V) = 0/100-5/95) to obtain compound 7 (0.04 g, yield: 17%).

LCMS m/z＝820.0[M+H] ⁺

Embodiment 8:

Step 1: Preparation of 8A

3-(Methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (24 g, 141.04 mmol), benzyl alcohol (30.50 g, 282.08 mmol), and triethylamine (21.41 g, 211.56 mmol) were added to toluene (300 mL), and diphenylphosphoryl azide (46.58 g, 169.25 mmol) was added, and the mixture was reacted at 100°C for about 18 h, cooled to room temperature, and ethyl acetate (300 mL) was added. The mixture was quenched with a saturated ammonium chloride solution (400 mL), and the organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and an appropriate amount of silica gel was added. The mixture was concentrated under reduced pressure and purified by column chromatography (EA/PE (V/V) = 0/100-20/80) to obtain 8A (28 g, yield: 72%).

Step 2: Preparation of 8B

8A (28 g, 101.71 mmol) and palladium carbon (5.6 g) were added to methanol (300 mL), and the mixture was hydrogenated under a hydrogen balloon for about 20 h. Appropriate amount of celite was applied, the mixture was filtered, and washed with appropriate amount of methanol. The filtrate was concentrated under reduced pressure to obtain 8B (12.5 g, yield: 87%).

Step 3: Preparation of 8C

Intermediate 1 (13 g, 44.40 mmol), 8B (12.54 g, 88.8 mmol), N,N-diisopropylethylamine (17.21 g, 133.20 mmol) were added to NMP (130 mL), reacted at 120 ° C for about 10 h, cooled to room temperature, added ethyl acetate (200 mL), the organic layer was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 8C (15 g, yield: 85%).

Step 4: Preparation of 8D

8C (15.00 g, 37.74 mmol), lithium hydroxide monohydrate (7.74 g, 188.75 mmol), tetrahydrofuran (150 mL) and water (30 mL) were reacted at room temperature for about 4 h, water (50 mL) and ethyl acetate (100 mL) were added, and the layers were separated by stirring; dichloromethane (100 mL) was added to the aqueous layer, and the pH was adjusted to 3-4 with concentrated hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, filtered, and an appropriate amount of silica gel was added. After concentration under reduced pressure, the mixture was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 8D (0.7 g, yield: 5%).

LCMS m/z＝384.3[M+H] ⁺

Step 5: Preparation of 8E

8D (0.1 g, 0.26 mmol), 2B (0.069 g, 0.29 mmol), and HATU (0.15 g, 0.39 mmol) were added to DMF (3 mL), and N,N-diisopropylethylamine (0.067 g, 0.52 mmol) was added dropwise. The reaction was carried out at room temperature for 4 h. Ethyl acetate (20 mL) was added to the reaction solution, which was washed with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and an appropriate amount of silica gel was added to the filtrate. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 8E (0.1 g, yield: 63%).

Step 6: Preparation of 8F

8E (0.1 g, 0.17 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (3.06 g, 26.84 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, and dichloromethane (20 mL) was added to the residue, and the pH was adjusted to 8-9 with 0.5 N aqueous sodium hydroxide solution. After separation, the aqueous layer was extracted with dichloromethane (20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 8F (0.07 g, yield: 81%).

Step 7: Preparation of Compound 8

8F (0.07 g, 0.14 mmol), 1E (0.043 g, 0.16 mmol), N,N-diisopropylethylamine (0.036 g, 0.28 mmol) were added to DMSO (5 mL), reacted at 95 ° C for 4 h, cooled to room temperature, added with ethyl acetate (20 mL), washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, added with appropriate amount of silica gel, concentrated under reduced pressure, and purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain compound 5 (0.10 g, yield: 94%).

LCMS m/z＝764.0[M+H] ⁺

Embodiment 9:

Step 1: Preparation of 9A

CBZ-piperazine (5 g, 22.72 mmol) and N-tert-butyloxycarbonyl-4-piperidone (6.79 g, 34.08 mmol) were dissolved in 1,2-dichloroethane (80 mL), and sodium triacetoxyborohydride (14.45 g, 68.16 mmol) and two drops of glacial acetic acid were added. The mixture was reacted at room temperature for 15 h. The reaction solution was washed with saturated sodium chloride solution (100 mL×2), washed with saturated sodium bicarbonate solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA/PE (V/V) = 0/100-50/50) to obtain 9A (6.2 g, yield: 68%).

Step 2: Preparation of 9B

9A (6 g, 14.87 mmol) was dissolved in methanol (80 mL), palladium carbon (0.7 g) was added, and the mixture was reacted at room temperature for about 20 h under a hydrogen balloon. Appropriate amount of celite was applied, the mixture was filtered, and washed with a small amount of ethyl acetate. The filtrate was concentrated under reduced pressure to dryness to obtain 9B (4 g, yield: 100%).

Step 3: Preparation of 9C

1B (0.3 g, 0.76 mmol), 9B (0.20 g, 0.76 mmol), HATU (0.43 g, 1.14 mmol) and DMF (5 mL) were added dropwise with N,N-diisopropylethylamine (0.20 g, 1.52 mmol) and reacted at room temperature for 20 h. Ethyl acetate (50 mL) was added to the reaction solution, which was washed with saturated aqueous sodium chloride solution (50 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 9C (0.32 g, yield: 65%).

Step 4: Preparation of 9D

9C (0.32 g, 0.50 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to dryness, water (20 mL) was added to the residue, and the pH was adjusted to 8-9 with solid potassium carbonate. The mixture was extracted twice with dichloromethane (20 mL), the organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure after filtration to obtain 9D (0.25 g, yield: 92%).

LCMS m/z＝545.3[M+H] ⁺

Step 5: Preparation of compound 9

9D (0.25 g, 0.46 mmol), 1E (0.19 g, 0.69 mmol), N,N-diisopropylethylamine (0.18 g, 1.38 mmol) and DMSO (5 mL) were reacted at 95 °C for 3 h, cooled to room temperature, methanol (2.5 mL) was added, water (15 ml) was added dropwise, stirred for crystallization for 30 minutes, filtered, the filter cake was washed with water, drained and dissolved in dichloromethane-methanol, an appropriate amount of silica gel was added, and the mixture was concentrated under reduced pressure and chromatographed on a silica gel column (MeOH/DCM (V/V) = 0/100-5/95) to obtain compound 9 (0.22 g, yield: 60%).

LCMS m/z＝801.3[M+H] ⁺

Embodiment 10:

Step 1: Preparation of 10A

CBZ-piperazine (5 g, 22.72 mmol) and 1-tert-butyloxycarbonylpiperidine-4-carboxaldehyde (4.85 g, 22.74 mmol) were dissolved in dichloromethane (80 mL), sodium triacetoxyborohydride (5.06 g, 23.87 mmol) was added, and the mixture was reacted at room temperature for 15 h. The reaction solution was washed with a saturated sodium chloride solution (100 mL×2), washed once with a saturated sodium bicarbonate solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EA/PE (V/V) = 0/100-50/50) to obtain 10A (7.6 g, yield: 80%).

Step 2: Preparation of 10B

10A (7.6 g, 18.20 mmol) was dissolved in methanol (80 mL), palladium carbon (0.9 g) was added, and the mixture was reacted at room temperature for about 20 h under a hydrogen balloon. Appropriate amount of celite was applied, the mixture was filtered, and washed with a small amount of ethyl acetate. The filtrate was concentrated under reduced pressure to dryness to obtain 10B (4.9 g, yield: 95%).

Step 3: Preparation of 10C

1B (0.2 g, 0.51 mmol), 10B (0.14 g, 0.51 mmol), HATU (0.29 g, 0.77 mmol) and DMF (5 mL) were added dropwise with N,N-diisopropylethylamine (0.13 g, 1.02 mmol), and the mixture was stirred at room temperature for 20 h. Ethyl acetate (50 mL) was added to the reaction solution, and the mixture was washed with saturated aqueous sodium chloride solution (50 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 10C (0.14 g, yield: 42%).

Step 4: Preparation of 10D

10C (0.14 g, 0.21 mmol) was dissolved in dichloromethane (4 mL), trifluoroacetic acid (2 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to dryness, water (20 mL) was added to the residue, and the pH was adjusted to 8-9 with potassium carbonate. The mixture was extracted with dichloromethane (20 mL), the organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain 10D (0.11 g, yield: 94%).

LCMS m/z＝559.4[M+H] ⁺

Step 5: Preparation of compound 10

10D (0.11 g, 0.20 mmol), 1E (0.083 g, 0.30 mmol), N,N-diisopropylethylamine (0.077 g, 0.60 mmol) were added to DMSO (5 mL), reacted at 95 ° C for 3 h, cooled to room temperature, methanol (2.5 mL) was added, water (15 ml) was added dropwise, stirred for crystallization for 30 minutes, filtered, the filter cake was washed with water, drained and dissolved in dichloromethane-methanol, an appropriate amount of silica gel was added, and the mixture was concentrated under reduced pressure and chromatographed on a silica gel column (MeOH/DCM (V/V) = 0/100-5/95) to obtain compound 10 (0.11 g, yield: 67%).

LCMS m/z＝816.10[M+H] ⁺

Embodiment 11:

Step 1: Preparation of 11A

4-Fluoronitrobenzene (0.17 g, 1.22 mmol), 9B (0.30 g, 1.11 mmol), and N,N-diisopropylethylamine (0.43 g, 3.33 mmol) were added to DMSO (8 mL), and the mixture was reacted at 95 °C for about 3 h. The mixture was cooled to room temperature, and ethyl acetate (50 mL) was added. The mixture was washed twice with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. An appropriate amount of silica gel was added. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 11A (0.43 g, yield: 99%).

Step 2: Preparation of 11B

11A (0.43 g, 1.10 mmol), zinc powder (0.72 g, 11.01 mmol), ammonium chloride (0.59 g, 11.03 mmol) were added to tetrahydrofuran (12 mL) and water (4 mL), and the mixture was reacted at room temperature for 1 h. Saturated sodium bicarbonate solution (20 mL) was added, stirred for 5 minutes, filtered, and the filter cake was washed with dichloromethane, separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 11B (0.39 g, yield: 98%).

Step 3: Preparation of 11C

Intermediate 1 (0.3 g, 1.02 mmol), 11B (0.44 g, 1.22 mmol), palladium acetate (0.046 g, 0.20 mmol), BINAP (0.14 g, 0.22 mmol), cesium carbonate (0.83 g, 2.55 mmol) were added to 1,4-dioxane (10 mL), and reacted at 95° C. for about 18 h under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and an appropriate amount of silica gel was added to the filtrate. After reduced pressure concentration, it was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 11C (0.36 g, yield: 57%).

Step 4: Preparation of 11D

11C (0.36 g, 0.58 mmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (4 mL) was added dropwise, and the mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the residue, and the pH was adjusted to 8-9 with solid potassium carbonate. The mixture was extracted twice with dichloromethane (20 mL), the organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure after filtration to obtain 11D (0.28 g, yield: 95%).

Step 5: Preparation of compound 11

11D (0.28 g, 0.54 mmol), 1E (0.22 g, 0.81 mmol), N,N-diisopropylethylamine (0.21 g, 1.62 mmol) were added to DMSO (5 mL), and the mixture was reacted at 95 °C for 3 h. The mixture was cooled to room temperature, and methanol (2.5 mL) was added. Water (15 ml) was added dropwise, and the mixture was stirred for crystallization for 30 minutes. The mixture was filtered, and the filter cake was washed with water, dried, and dissolved in dichloromethane-methanol. An appropriate amount of silica gel was added, and the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain compound 11 (0.16 g, yield: 38%).

LCMS m/z＝774.1[M+H] ⁺

Embodiment 12:

Step 1: Preparation of 12A

4-Fluoronitrobenzene (0.17 g, 1.22 mmol), 10B (0.30 g, 1.06 mmol), and N,N-diisopropylethylamine (0.41 g, 3.18 mmol) were added to DMSO (8 mL), and the mixture was reacted at 95 °C for about 3 h. The mixture was cooled to room temperature, and ethyl acetate (50 mL) was added. The mixture was washed twice with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. An appropriate amount of silica gel was added. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 12A (0.30 g, yield: 70%).

Step 2: Preparation of 12B

12A (0.30 g, 0.74 mmol), zinc powder (0.48 g, 7.40 mmol), ammonium chloride (0.40 g, 7.40 mmol) were added to tetrahydrofuran (9 mL) and water (3 mL) and reacted at room temperature for 1 h. Saturated sodium bicarbonate solution (20 mL) was added, stirred for 5 minutes, filtered, the filter cake was washed with dichloromethane, separated, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 12B (0.27 g, yield: 97%).

Step 3: Preparation of 12C

Intermediate 1 (0.18 g, 0.61 mmol), 12B (0.27 g, 0.73 mmol), palladium acetate (0.027 g, 0.12 mmol), BINAP (0.084 g, 0.13 mmol), cesium carbonate (0.50 g, 1.52 mmol) were added to 1,4-dioxane (10 mL), and the mixture was reacted at 95° C. for 18 h under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and an appropriate amount of silica gel was added to the filtrate. After concentration under reduced pressure, the mixture was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 12C (0.30 g, yield: 78%).

Step 4: Preparation of 12D

12C (0.30 g, 0.48 mmol) was added to dichloromethane (8 mL), and trifluoroacetic acid (4 mL) was added dropwise. The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure, and water (20 mL) was added to the residue. The pH was adjusted to 8-9 with solid potassium carbonate. The mixture was extracted twice with dichloromethane (20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 12D (0.24 g, yield: 94%).

Step 5: Preparation of compound 12

12D (0.24 g, 0.45 mmol), 1E (0.19 g, 0.68 mmol), N,N-diisopropylethylamine (0.17 g, 1.35 mmol) were added to DMSO (5 mL), and the mixture was reacted at 95 °C for 3 h. The mixture was cooled to room temperature, and methanol (2.5 mL) was added. Water (15 ml) was added dropwise, and the mixture was stirred for crystallization for 30 minutes. The mixture was filtered, and the filter cake was washed with water, dried, and dissolved in dichloromethane-methanol. An appropriate amount of silica gel was added, and the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain compound 12 (0.22 g, yield: 62%).

LCMS m/z＝788.1[M+H] ⁺

Embodiment 13:

Step 1: Preparation of 13A

9B (0.11 g, 0.41 mmol), 5B (0.15 g, 0.35 mmol), HATU (0.20 g, 0.52 mmol) were added to DMF (5 mL), and N,N-diisopropylethylamine (0.090 g, 0.70 mmol) was added dropwise, and the mixture was reacted at room temperature for 18 h. Ethyl acetate (20 mL) was added to the reaction solution, and the mixture was washed twice with a saturated sodium chloride aqueous solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 13A (0.168 g, yield: 71%).

Step 2: Preparation of 13B

13A (0.16 g, 0.24 mmol) was added to dichloromethane (4 mL), and trifluoroacetic acid (2 mL) was added dropwise, and stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and water (20 mL) was added to the residue, and the pH was adjusted to 8-9 with potassium carbonate. It was extracted twice with dichloromethane (20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 13B (0.13 g, yield: 94%).

Step 3: Preparation of compound 13

13B (0.13 g, 0.23 mmol), 1E (0.095 g, 0.35 mmol), N,N-diisopropylethylamine (0.090 g, 0.69 mmol) were added to DMSO (5 mL), and the mixture was reacted at 95 °C for 3 h. The mixture was cooled to room temperature, and methanol (2.5 mL) was added. Water (15 ml) was added dropwise, and the mixture was stirred for crystallization for 30 minutes. The mixture was filtered, and the filter cake was washed with water, dried, and dissolved in dichloromethane-methanol. An appropriate amount of silica gel was added. The mixture was concentrated under reduced pressure and chromatographed on a silica gel column (MeOH/DCM (V/V) = 0/100-5/95) to obtain compound 13 (0.09 g, yield: 47%).

LCMS m/z＝833.4[M+H] ⁺

Embodiment 14:

Step 1: Preparation of 14A

10B (0.12 g, 0.42 mmol), 5B (0.15 g, 0.35 mmol), HATU (0.20 g, 0.52 mmol) were added to DMF (5 mL), and N,N-diisopropylethylamine (0.090 g, 0.70 mmol) was added dropwise, and the mixture was reacted at room temperature for 18 h. Ethyl acetate (20 mL) was added, and the mixture was washed twice with a saturated sodium chloride aqueous solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (MeOH/DCM (V/V) = 0/100-5/95) to obtain 14A (0.095 g, yield: 39%).

Step 2: Preparation of 14B

14A (0.095 g, 0.14 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added dropwise, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, water (20 mL) was added to the residue, and the pH was adjusted to 8-9 with solid potassium carbonate. The mixture was extracted twice with dichloromethane (20 mL), the organic phases were combined and dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure after filtration to obtain 14B (0.07 g, yield: 85%).

Step 3: Preparation of compound 14

14B (0.07 g, 0.12 mmol), 1E (0.050 g, 0.18 mmol), N,N-diisopropylethylamine (0.047 g, 0.36 mmol) were added to DMSO (3 mL), and the mixture was reacted at 95 °C for 3 h. The mixture was cooled to room temperature, and methanol (1 mL) was added. Water (10 ml) was added dropwise, and the mixture was stirred for crystallization for 30 minutes. The mixture was filtered, and the filter cake was washed with water and dissolved in dichloromethane-methanol. An appropriate amount of silica gel was added, and the mixture was concentrated under reduced pressure and chromatographed on a silica gel column (MeOH/DCM (V/V) = 0/100-5/95) to obtain compound 14 (0.05 g, yield: 49%).

LCMS m/z＝847.4[M+H] ⁺

Biological test cases

Test Example 1: Study on proliferation activity of NCI-H446 cells

NCI-H446 cells (human small cell lung cancer cell line) were purchased from ATCC, culture conditions: RPMI-1640 + 10% FBS + 1% double antibody, cultured at 37 ° C, 5% CO ₂ incubator. Cells were plated in 96-well plates with a seeding density of 1×10 ³ cells/well. On the second day, different concentrations of compounds were added to the well plate (compound starting concentration 10 μM, 5-fold dilution, 9 concentration gradients), and cultured in a 37 ° C, 5% CO ₂ incubator for 72 hours. After the culture, cell viability detection reagent (Promega, G7573) was added, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the luminescence signal was detected by a multifunctional microplate reader (BMG, PHERAstar FSX). The luminescence readings were calculated using GraphPad Prism 8.0 software according to formula (1) and formula (2) to calculate the IC ₅₀ value and maximum inhibition rate of the compound to inhibit cell proliferation. _Tdosage is the cell signal reading after 72 hours of compound incubation, and _Tvehicle is the cell signal reading after 72 hours of vehicle control incubation.

Growth % = ( _Tdose / _Tsolvent ×100)% Formula (1)

Max inhibition% calculation: According to formula (1), the inhibition rate at the highest concentration of the compound was calculated.

Max inhibition%=(100-Growth)% Formula (2)

Conclusion: The compounds of the present invention have a good inhibitory effect on the proliferation of NCI-H446 cells.

Test Example 2: Study on the proliferation activity of IMR-32 cells

IMR-32 cells (human neuroblastoma cells, purchased from ATCC), culture conditions: EMEM + 10% FBS + 1% PS, cultured at 37 ° C, 5% CO ₂ incubator. Cells were plated in 96-well plates, with a seeding density of 1×10 ³ cells/well/180uL. On the second day, different concentrations of compounds were added to the well plate (the initial concentration of the compound was 10μM, 5-fold dilution, 9 concentration gradients, 20uL/well, and the negative control was a medium containing 0.1% DMSO), and cultured for 48h in a 37 ° C, 5% CO ₂ incubator. After the culture was completed, the cell viability detection reagent (Promega, G755B, 50uL/well) was added, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the luminescent signal was detected using a multifunctional microplate reader (BMG, PHERAstar FSX). The luminescence readings were calculated using GraphPad Prism 8.1 software according to formula (3) and formula (4) to calculate the IC ₅₀ value and the maximum inhibition rate of the compound in inhibiting cell proliferation, respectively. T _{administration} is the cell signal reading after 48 hours of compound incubation, and T _{negative control} is the cell signal reading after 48 hours of DMSO control incubation.

Growth% = (Tdrug _{administration} /Tnegative _control ×100)% Formula (3)

Max inhibition% calculation: According to formula (1), the inhibition rate at the highest concentration of the compound was calculated.

Max inhibition%=(100-Growth)% Formula (4)

Table 1 Results of the inhibitory activity of the test compounds on IMR-32 cell proliferation

Compound No. IC ₅₀ (nM) Compound 2 A Compound 3 A Compound 6 A Compound 10 A Compound 12 A

Note: A＜100nM, 100nM≤B＜500nM, 500nM≤C＜1000nM

Conclusion: The compounds of the present invention have a good inhibitory effect on the proliferation of IMR-32 cells.

Test Example 3: Mouse Pharmacokinetic Test

Experimental purpose: This study administered the test substance to ICR mice by single-dose intravenous and oral gavage, determined the concentration of the test substance in mouse plasma, and evaluated the pharmacokinetic characteristics and bioavailability of the test substance in mice.

Experimental animals: Male ICR mice, 20-25 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

Experimental method: On the day of the experiment, ICR mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-16 hours one day before administration, and food was resumed 4 hours after administration.

Table 2

^* Dosage is based on free base;

Sampling: Blood was collected from the eye socket under isoflurane anesthesia before and after administration and placed in an EDTAK ₂ centrifuge tube. The tube was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma.

Plasma collection time points in G1&G2 groups: 5, 15, 30 min, 1, 2, 4, 7, 24 and 48 h;

Plasma collection time points in G3 group: 5, 15, 30 min, 1, 2, 4, 7, 24 and 48 h;

All samples were stored at -60°C before analysis. The samples were quantitatively analyzed by LC-MS/MS.

Table 3 Oral absorption results of test compounds in mice (administration method i.g. (10 mg/kg))

Compound No. Bioavailability (F) Compound 2 23.9% Compound 3 30.6% Compound 6 68.5% Compound 10 27.9% Compound 12 36.0%

*Note: Compounds were administered i.g. (orally).

Conclusion: The compound synthesized by the technology of the present invention has good oral absorption performance in mice.

Claims (10)

1. A compound or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compounds represented by general formula (I), B-L-K(I); L is selected from a bond or -C _1-50 hydrocarbon group-, wherein 1 to 20 methylene units in the hydrocarbon group are optionally replaced by -Ak-, -Cy-; Each -Ak- is independently selected from -( _CH2 ) _q- , -( _CH2 ) _q -O-, -O-( _CH2 ) _q- , -( _CH2 ) _q -S-, -S-( _CH2 ) _q- , -( _CH2 ) _q -NR ^L- , -NR ^{L-(CH2)q-, -(CH2)q-NR L} _{C ( ＝ O} ⁾ -, -NR ^L ( _CH2 ) _qC (＝O)-, -( _CH2 ) _q -C(＝O)NR ^L -, -C(＝O)-, -C(＝O)-( _CH2 ) _q -NR ^L -, -(C≡C) _q- , -CH＝CH-, -Si( ^RL )2-, -Si(OH)( ^RL )-, _{-Si(OH)2- ,} -P(＝O)(OR ^L )-, -P(=O)(R ^L )-, -S-, -S(=O)-, -S(=O) ₂ -, or a bond, wherein the -CH ₂ - is optionally substituted by 1 to 2 R ^z ; q is each independently selected from 0, 1, 2, 3, 4, 5 or 6; ^RL is selected from H, _C1-4 alkyl, _C3-7 carbocyclyl, 4 to 10 membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 ^Rz ; Each -Cy- is independently selected from a bond or one of the following groups optionally substituted with 1 to 4 R ^L2 : a 4-7 membered heteromonocyclic group, a 4-12 membered heterocycloalkyl group, a 5-13 membered heterospirocyclic group, a 7-12 membered heterobridged cyclyl group, a 3-7 membered monocycloalkyl group, a 4-12 membered cycloalkyl group, a 5-13 membered spirocycloalkyl group, a 5-12 membered bridged cycloalkyl group, a 5-10 membered heteroaryl group or a C _6-10 aryl group; B is selected from ^Ba and ^Bb are each independently selected from N or ^CRb5 ; B ₁ is selected from C _3-10 carbocyclyl or 4 to 10 membered heterocyclyl, said B ₁ is optionally substituted by 1 to 4 R ^b1 ; R ^b1 is each independently selected from halogen, =O, OH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , CN, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -OC _0-4 alkylene-C _3-6 carbocyclyl, -OC _0-4 alkylene-4 to 10 membered heterocyclyl, -NH-C _0-4 alkylene-C _3-6 carbocyclyl, -NH-C _0-4 alkylene-4 to 10 membered heterocyclyl, -C _0-4 alkylene-C _3-6 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl, heterocyclyl is optionally substituted by 1 to 4 R ^z ; R ^b2 is selected from H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -C _0-4 alkylene-C _3-8 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl is optionally substituted by 1 to 4 R ^z ; R ^b3 is selected from H, -C(=O)NR ^b3a R ^b3b ; R ^b3a , R ^b3b are each independently selected from H, OH, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, -C _0-4 alkylene-C _3-6 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl is optionally substituted by 1 to 4 R ^z ; Alternatively, R ^b3a and R ^b3b are directly linked to form a 4- to 7-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R ^z ; R ^b4 and R ^b5 are each independently selected from H, halogen, =O, OH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , CN, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -OC _0-4 alkylene-C _3-6 carbocyclyl, -OC _0-4 alkylene-4 to 10 membered heterocyclyl, -NH-C _0-4 alkylene-C _3-6 carbocyclyl, -NH-C _0-4 alkylene-4 to 10 membered heterocyclyl, -C _0-4 alkylene-C _3-6 carbocyclyl, -C _0-4 alkylene-4 to 10 membered heterocyclyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclyl and heterocyclyl are optionally substituted by 1 to 4 R ^z ; The condition is that B1 is selected from L is selected from a bond or contains at least one ring structure; K is selected from K1, K2, K3, K4; K1 is selected from K2 is selected from K3 is selected from K4 is selected from Q is each independently selected from a bond, -O-, -S-, _-CH2- , ^-NRq- , -CO-, ^-NRqCO- , ^-CONRq- or a 3-12 membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1 to 4 groups selected from ^Rz ; ^Rq is selected from H or _C1-4 alkyl; A is selected from C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl or 5-10 membered heteroaryl; F is each independently selected from C _3-20 carbocyclyl, C _6-20 aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl; R ^k2 are each independently selected from a bond, -CO-, -SO ₂ -, -SO- or -C(R ^k3 ) ₂ -; R ^k1 is each independently selected from H, F, Cl, Br, I, OH, ═O, NH ₂ , CN, COOH, CONH ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, R ^k7a , wherein the alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R ^z ; R ^k7a is selected from H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 selected from R ^z ; R ^k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, CONH ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-8 cycloalkyl or 3 to 8 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 groups selected from R ^z ; or two R ^k3 and the carbon atom or ring skeleton directly connected to the two together form a C _3-8 carbocyclic group or a 3-8 membered heterocyclic group, and two R ^k1 and the carbon atom or ring skeleton directly connected to the two together form a C _3-8 carbocyclic group or a 3-8 membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 selected from R ^z ; R ^k4 is each independently selected from H, OH, NH ₂ , CN, CONH ₂ , C _1-4 alkyl, C _3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 R ^z ; _M1 is selected from a bond, -CH2 _- C(=O)NH- or -C(=O) _CH2NH- ; _M2 is selected from -NHC(=O) _-C1-4 alkyl, -NHC(=O) _-C3-6 cycloalkyl or 4-10 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally substituted by 1 to 4 ^Rz ; _M3 is selected from -NH- or -O-; R ^k10 is selected from C _1-4 alkyl, wherein the alkyl is optionally substituted with 1 to 4 R ^z ; R ^k11 is each independently selected from H, F, Cl, Br, I, ＝O, OH, SH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio or -OC(＝O)-C _1-4 alkyl, wherein the alkyl, alkoxy or alkylthio is optionally substituted by 1 to 4 R ^z ; R ^k12 and R ^k13 are each independently selected from H, C _1-4 alkyl or C _3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with 1 to 4 R ^z ; R ^k14 is selected from 5-6 membered heteroaryl, wherein the heteroaryl is optionally substituted with 1 to 4 R ^z ; G is selected from C _6-10 aryl or 5-10 membered heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1 to 4 R ^z ; ^RL2 and ^Rz are each independently selected from deuterium, F, Cl, Br, I, OH, =O, _CF3 , CN, _NH2 , COOH, _CONH2 , _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, _-C0-4 alkylene- _C3-6 cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl and alkynyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl and _C1-4 alkoxy; Alternatively, R ^L2 and R ^k1 are directly linked to form a C _4-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R ^z ; n1, n2, n3 are each independently selected from 0, 1, 2 or 3; p1 and p2 are each independently selected from 0, 1, 2, 3, 4 or 5. 2. The compound according to claim 1 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; B ₁ is selected from phenyl, benzo C _4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5 to 10 membered heteroaryl, C _3-7 cycloalkyl, C _5-10 cycloalkyl, C _5-10 spirocycloalkyl, C _5-10 bridged cycloalkyl, and B ₁ is optionally substituted by 1 to 4 R ^b1 ; R ^b2 is selected from H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, -C _0-4 alkylene-C _3-8 cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkylene and cycloalkyl are optionally substituted by 1 to 4 R ^z ; Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -(CH ₂ ) _q -, -(CH ₂ ) _q -O-, -O-(CH ₂ ) _q -, -(CH ₂ ) _q -S-, -S-(CH ₂ ) _q -, -(CH ₂ ) _q -NR ^L -, -NR ^L -(CH ₂ ) _q -, -(CH ₂ ) _q -NR ^L C(＝O)-, -(CH ₂ ) _q -C(＝O)NR ^L -, -C(＝O)-, -C(＝O)-(CH ₂ ) _q -NR ^L -, -(C≡C) _q -, or a bond, and the -CH ₂ - is optionally substituted with 1 to 2 R ^z ; R ^L are each independently selected from H or C _1-4 alkyl; Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or one of the following groups optionally substituted by 1 to 4 ^RL2 : a 4-7 membered nitrogen-containing heteromonocyclic group, a 4-12 membered nitrogen-containing heterocycloalkyl group, a 5-13 membered nitrogen-containing heterospirocyclic group, a 7-12 membered nitrogen-containing heterobridged ring group, a _C3-7 monocycloalkyl group, a _C4-12 cycloalkyl group, a _C5-13 spirocycloalkyl group, a _C7-12 bridged cycloalkyl group, a 5-10 membered heteroaryl group or a _C6-10 aryl group; K2 is selected from K3 is selected from A is selected from C _3-8 carbocyclyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl; F is independently selected from C _3-7 monocyclic group, C _4-10 cycloalkyl group, C _5-12 spirocyclic group, C _5-10 bridged cyclyl group, 4-7 membered heteromonocyclic group, 4-10 membered heterocycloalkyl group, 8-15 membered tricyclic heterocycloalkyl group, 12-17 membered tetracyclic heterocycloalkyl group, 5-17 membered heterospirocyclic group, 5-10 membered heterobridged cyclyl group, C _6-14 aryl group, 5-10 membered heteroaryl group, represents that the ring is selected from an aromatic ring or a non-aromatic ring; E is each independently selected from C _3-10 carbocyclyl, phenyl, 4-12 membered heterocyclyl, 5-12 membered heteroaryl; Q is each independently selected from a bond, -O-, -S-, _-CH2- , ^-NRq- , -CO-, ^-NRqCO- , ^-CONRq- or a 4-7 membered heterocyclic group, said heterocyclic group being optionally substituted with 1 to 4 ^Rz ; ^Rq is selected from H or _C1-4 alkyl; R ^k1 and R ^k3 are each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CF ₃ , CN, COOH, CONH ₂ , C _1-4 alkyl or C _1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH or NH ₂ ; or two R ^k3 and the carbon atom or ring skeleton directly connected to the two together form a C _3-6 carbocyclic group or a 3-7 membered heterocyclic group, two R ^k1 and the carbon atom or ring skeleton directly connected to the two together form a C _3-6 carbocyclic group or a 3-7 membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 selected from R ^z ; R ^k4 are each independently selected from H, OH, NH ₂ , CF ₃ , CN or C _1-4 alkyl; R ^k5 are each independently selected from C(CH ₃ ) ₂ , CO, CH ₂ , CH ₂ CH ₂ , SO ₂ , R ^k6 are each independently selected from CO, CH, SO, SO ₂ , CH ₂ or N; R ^k7 are each independently selected from C(CH ₃ ) ₂ , CO, CH, N, CH ₂ , O, S, NR ^k7a ; R ^k8 are each independently selected from C, N or CH; R ^k9 are each independently selected from a bond, C(CH ₃ ) ₂ , CO, CH ₂ , CH ₂ CH ₂ or SO ₂ ; ^Rka is selected from O, S or NH; R ^k7a is selected from H, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, wherein the alkyl, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 groups selected from R ^z ; R ^k14 is selected from 3. The compound according to claim 2 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: ^RL is selected from H, methyl or ethyl; Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following groups optionally substituted by 1 to 4 R ^L2 : phenyl, pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, s1, s3, s5 are each independently selected from 0, 1 or 2; s2 and s4 are each independently selected from 0 or 1; s6 is selected from 0, 1, 2 or 3; s6 is selected from 1, 2 or 3; B1 is selected from cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, Bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptyl; ^Ba and ^Bb are selected from N or CH; R ^b1 is each independently selected from F, Cl, Br, I, =O, OH, NH ₂ , CN, methyl, ethyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, and the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted with 1 to 4 R ^z ; R ^b2 is selected from methyl, ethyl, propyl, isopropyl, -CH ₂ -vinyl, -CH ₂ -ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH ₂ -cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octyl is optionally substituted with 1 to 4 R ^z ; R ^b3 is selected from -C(=O)N(CH ₃ ) ₂ , -C(=O)N(CH ₂ CH ₃ ) ₂ , R ^b4 and R ^b5 are each independently selected from H, F, and methyl; K1 is selected from K4 Selection Q is selected from a bond, C(=O); Q1 is selected from a bond, _CH2 , NH, N( _CH3 ), O, S, C(=O), NHC(=O), C(=O)NH, N( _CH3 )C(=O), C(=O)N( _CH3 ), Q2 is selected from a bond, _CH2 , O, S, C(=O), NHC(=O), N( _CH3 )C(=O); E and A are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl; F is independently selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthryl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridinonyl, benzoxazolyl, pyridoimidazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, benzopyridine yl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, benzotriazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyrimidinyl, pyridopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl, pyrazinopyrazinyl, indolopyridinyl, indolothienyl, indolofuranyl, Its left side is directly connected to L; ^Rka is selected from O, S or NH; R ^k7 are each independently selected from C(CH ₃ ) ₂ , CH ₂ , O, N(CH ₃ ), N(CH ₂ CH ₃ ), N(cyclopropyl) or NH; R ^k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, CN, CF ₃ , C _1-4 alkyl, C _1-4 alkoxy, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, C _3-6 cycloalkyl; ^RL2 and ^Rz are each independently selected from deuterium, F, Cl, Br, I, OH, =O, _CF3 , CN, _NH2 , COOH, _CONH2 , methyl, ethyl _, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, _-CH2 -cyclobutyl, _-CH2 -cyclopentyl, _-CH2 -cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl, _C1-4 alkoxy; Alternatively, R ^L2 and R ^k1 are directly linked to form a C _4-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R ^z ; p1 and p2 are each independently selected from 0, 1, 2 or 3. 4. The compound according to claim 3 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from _a bond, -O-, -S-, _-OCH2- , _-CH2O- , _-OCH2CH2- , _-CH2CH2O- , _-C≡C- , _-C ( _CH3 ) _2- , -CH2-, _-C (CH3)2-, -CH2CH2- _{, -CH2CH2CH2-} , _{-N ( CH3} )-, _{-NH- , -CH2N} ( _CH3 )-, _{-CH2NH- , -NHCH2-} , _-CH2CH2N ( _CH3 )- _{, -CH2CH2NH- ,} -NHCH2CH2-, -C(=O)-, -C(= _O ) _CH2NH- , _-CH2 C(=O)NH-, -C(=O)NH- or -NHC(=O)-; Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups which are optionally substituted: When substituted, it is substituted with 1 to 4 substituents selected from F, _CF3 , OH, methyl, =0, hydroxymethyl, methoxy, COOH, CN or _NH2 . 5. The compound according to claim 4 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B is selected from L is selected from -C(=O)-Cy1-, -C(=O)-Cy1-Cy2-, -C(=O)-Cy1-CH ₂ -Cy2-, -C(=O)-Cy1-Cy2 -Cy3-, -C(=O)-Cy1-CH ₂ -Cy2-Cy3-, -C(=O)-Cy1-Cy2-CH ₂ -Cy3-, -C(=O)NH-Cy1-, - C(=O)NH-Cy1-Cy2-, -C(=O)NH-Cy1-CH ₂ -Cy2-; Cy1, Cy2, and Cy3 are each independently selected from one of the following optionally substituted groups: When substituted, it is substituted by 1 to 4 substituents selected from F, CF ₃ , OH, methyl, =0, hydroxymethyl, methoxy, COOH, CN or NH ₂ ; Preferably, K is selected from one of the structural fragments shown in Table K-1 or Table K-2; Preferably, L is selected from the groups shown in Table L-1, wherein the left side of the group is connected to B. 6. The compound according to claim 1 or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound of general formula (I) is selected from (Ia), (Ib), (Ib-1), Ya, Yb, Yc, Yd, and Ye are each independently selected from N or CH; B ₂ is absent or is selected from C _4-6 carbocyclyl or 4 to 6 membered heterocyclyl; Cy2 is selected from 4 to 6-membered nitrogen-containing heterocycloalkyl or C _3-6 cycloalkyl, and the Cy2 is optionally substituted by 1 to 4 R ^L2a ; ^RL2a and ^RL2b are each independently selected from H, deuterium, halogen, OH, COOH, CN, _NH2 , =O, _C1-4 alkyl or _C1-4 alkoxy, wherein the alkyl or alkoxy is optionally substituted with deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl or _C1-4 alkoxy substituents; R ^k1 is each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, CONH ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, wherein the alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 R ^z ; Alternatively, R ^L2b and R ^b1 are directly connected, R ^L2a and R ^k1 are directly connected, R ^L2b and R ^L2a are directly connected, and R ^k1 and R ^k1 are directly connected to form a C _4-6 carbocyclic group or a 4 to 6-membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R ^z ; R ^z is independently selected from deuterium, halogen, OH, CN, NH ₂ , ═O, C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl; p3 is selected from 0, 1, 2, 3, 4; m1, m2, and m3 are each independently selected from 0, 1, 2, 3, and 4; The remaining groups are as defined in claims 1 to 5. 7. The compound according to claim 6, or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, Selected from ^RL2a , ^RL2b are each independently selected from H, F, Cl, Br, I, OH, COOH, CN, _NH2 , =O, _CF3 , methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy; R ^k1 is each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CF ₃ , CN, COOH, CONH ₂ , methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy is optionally substituted with 1 to 4 substituents selected from F, Cl, Br, I, OH, NH ₂ ; Alternatively, R ^L2b and R ^b1 are directly connected, R ^L2a and R ^k1 are directly connected, R ^L2b and R ^L2a are directly connected, and R ^k1 and R ^k1 are directly connected to form a C ₄ carbocyclyl, a C ₅ carbocyclyl, a C ₆ carbocyclyl, a 4-membered heterocyclyl, a 5-membered heterocyclyl, or a 6-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R ^z ; ^Rz is independently selected from deuterium, F, Cl, Br, , OH, COOH, CN, _NH2 , =O, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl; Cy2 is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, cyclobutyl, cyclopentyl, cyclohexyl, and said Cy2 is optionally substituted by 1 to 4 R ^L2a . 8. The compound according to claim 1 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E: Table E 9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of a compound according to any one of claims 1 to 8 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof. 10. Use of the compound according to any one of claims 1 to 8 or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal for preparing a medicament for treating a disease associated with the activity or expression of Aurora A; preferably, use of the compound according to any one of claims 1 to 8 or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal for preparing a medicament for treating a disease associated with the inhibition or degradation of Aurora A; preferably, the disease is selected from cancer.