Benzene ring derivative and application thereof in medicine

Abstract

The invention discloses a benzene ring derivative and application thereof in medicine, and relates to a compound shown in a general formula (I) or a stereoisomer, a tautomer, a deuterated compound, a solvate, a prodrug, a metabolite, pharmaceutically acceptable salt or eutectic of the compound, an intermediate of the compound, and application of the compound in inhibiting or degrading AR / ARv7 related diseases such as cancers. And B-L-K (I).

Description

Technical Field

[0001] The present invention relates to a compound of general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods thereof, as well as uses thereof in AR / ARv7-related diseases such as cancer. Background Art

[0002] Androgen receptor (AR) is a hormone nuclear receptor, which can be divided into N-terminal activation domain (NTD), DNA binding domain (DBD) and ligand binding domain (LTD) in structure. It can regulate the gene expression that induces prostate cancer. Therefore, inhibiting androgen receptor is an effective method for treating prostate cancer. Currently available androgen receptor inhibitors such as enzalutamide and bicalutamide mainly exert their inhibitory effects by acting on the ligand binding domain (LTD) of androgen receptor, but some patients will develop drug resistance during treatment due to androgen receptor splice variants (AR-Vs) with missing LTD fragments. Preclinical studies have shown that androgen receptor splice mutants can accelerate the progression of enzalutamide-resistant prostate cancer. How to solve its drug resistance problem has become a focus of clinical medicine.

[0003] Small molecule degraders are drugs that use the body's ubiquitin-proteasome system (UPS) to degrade target proteins. Currently, small molecule degraders mainly include proteolysis targeted chimeras (PROTACs), molecular glues, and androgen receptor degraders (SARDs). With their unique catalytic mechanism, small molecule degraders can target difficult-to-drug targets and solve the problem of drug resistance. They are currently a hot topic in the field of drug research and development for tumors, autoimmune diseases, etc.

[0004] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. Such compounds can be recognized by the proteasome of the cell, causing the degradation of the target protein, and can effectively reduce the content of the target protein in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology can be applied to the treatment of various diseases. This technology has also received widespread attention in recent years.

[0005] Molecular glue is a class of small molecules that promote the contact between the target protein and the E3 ubiquitin ligase, induce the interaction between the two, and thus lead to the degradation of the target protein. From a functional perspective, molecular glue mainly fills the gap between the target protein and the E3 ubiquitin ligase, enhances the binding interface between the two, and promotes the strong interaction between the two. Compared with traditional small molecule inhibitors, molecular glue has the advantages of driving the degradation of target proteins in a catalytic form and not requiring a binding pocket on the target protein, and has the potential to act on undruggable targets.

[0006] Therefore, it is necessary to develop new PROTACs or other small molecule degrader drugs for androgen receptor splice variants (AR-Vs, especially AR-V7 mutants) to treat tumor diseases related to androgen receptor splice variants. Summary of the Invention

[0007] The purpose of the present invention is to provide a compound with a novel structure, good drug efficacy, high bioavailability, higher safety, and capable of inhibiting or degrading AR / ARv7 for the treatment of diseases related to AR / ARv7 such as cancer.

[0008] The present invention provides a compound or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the compounds represented by the general formula (I),

[0009] B-L-K (I);

[0010] In some embodiments, L is selected from a bond or -C 1-20 hydrocarbyl-, wherein 1 to 10 methylene units in the hydrocarbyl are optionally replaced by -Ak- or -Cy-;

[0011] 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) q C(=O)-, -(CH2) q-C(=O)NR L -、-C(=O)-、-C(=O)-(CH2) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L )2-、-Si(OH)(R L )-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-、-S-、-S(=O)-、-S(=O)2- or a bond, wherein CH and -CH2- are optionally substituted by 1 to 2 substituents selected from deuterium, halogen, =O, OH, CN, C 1-4 alkyl or C 3-6 cycloalkyl;

[0012] In some embodiments, q is independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0013] In some embodiments, R L is selected from H, C 1-4 alkyl, C 3-7 carbocyclic group, 4- to 10-membered heterocyclic group;

[0014] In some embodiments, each -Cy- is independently selected from a bond or one of the following groups optionally substituted by 1 to 4 R L2 : 4- to 8-membered heteromonocyclic group, 4- to 12-membered hetero-fused ring group, 5- to 13-membered heterospiro ring group, 7- to 12-membered heterobridged ring group, C 3-7 monocyclic alkyl group, C 4-7 monocyclic alkenyl group, C 4-12 fused ring alkyl group, C 5-13 spiroalkyl group, C 5-12 bridged ring alkyl group, 5- to 10-membered heteroaryl group or C 6-10 aryl group;

[0015] In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4 or Ak5;

[0016] In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3 or Cy4;

[0017] In some embodiments, -Cy- is selected from Cy1, Cy2;

[0018] In some embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0019] In some embodiments, L is selected from a bond, -Cy1-, -Cy1-Ak2-, -Ak1-Cy1-, -Ak1-, -Ak1-Cy1-Ak2-, -Cy1-Ak2-Cy2-, -Cy1-Cy2-Ak3-, -Ak1-Cy1-CH2-, -Ak1-Cy1-Cy2-, -Cy1-Ak2-Cy2-, -Cy1-Ak2-Cy2-Ak3-;

[0020] In some embodiments, L is selected from a bond, -Cy1-CH2-, -Cy1-, -C(=O)-Cy1-, -CH2-Cy1-, -C(=O)-Cy1-CH2-, -Cy1-CH2-Cy2-, -Cy1-Cy2-CH2-, -O-CH2-CH2-, -O-CH2-CH2-Cy1-, -O-CH2-Cy1-, -O-Cy1-, -O-Cy1-CH2-;

[0021] In some embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 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 substituents selected from deuterium, halogen, =O, OH, CN, C 1-4 alkyl or C 3-6 cycloalkyl;

[0022] In some embodiments, q is selected from 0, 1, 2, or 3;

[0023] In some embodiments, each of Ak1, Ak2, Ak3, Ak4, Ak5 is independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -CH(CH3)-, -CH2-, -C(CH3)2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH-, or -NHC(=O)-;

[0024] In some embodiments, each of Ak1, Ak2, Ak3, Ak4, Ak5 is independently selected from a bond, -C≡C-, -C(CH3)2-, or -CH2-;

[0025] In some embodiments, R L is selected from H or C 1-4 alkyl;

[0026] In some embodiments, R L is selected from H, methyl, or ethyl;

[0027] In some embodiments, each of Cy1, Cy2, Cy3, Cy4, or Cy5 is independently selected from a bond or one of the following groups optionally substituted with 1 to 4 R L2 : 4- to 7-membered nitrogen-containing monocyclic group, 4- to 12-membered nitrogen-containing fused ring group, 5- to 13-membered nitrogen-containing spiro ring group, 7- to 12-membered nitrogen-containing bridged ring group, C 3-7 monocyclic alkyl, C 4-7 monocyclic alkenyl, C 4-12 fused ring alkyl, C 5-13 spiroalkyl, C 7-12 bridged ring alkyl, 5- to 10-membered heteroaryl, or C 6-10 aryl;

[0028] In some embodiments, Cy5 is defined the same as Cy1;

[0029] In some embodiments, each of Cy1, Cy2, Cy3, Cy4 is independently selected from a bond or one of the following groups optionally substituted with 1 to 4 R L2 : phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl,

[0030]

[0031] s1, s3, and 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, and s7 is selected from 1, 2, or 3;

[0032] In some embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following optionally substituted groups:

[0033] When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, ═O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl;

[0034] In some embodiments, Cy1 and Cy2 are each independently selected from one of the following optionally substituted groups:

[0035]

[0036] When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, ═O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl;

[0037] In some embodiments, L is selected from one of the structural fragments shown in Table L-1:

[0038] Table L-1

[0039]

[0040]

[0041] In some embodiments, B is selected from wherein the represented ring is an aromatic ring or a non-aromatic ring;

[0042] In some embodiments, B is selected from

[0043] In some embodiments, W1 is each independently selected from -NR w1 -, -(CR w2 R w3 ) r -;

[0044] In some embodiments, W1 is each independently selected from -NR w1 -, -CR w2 Rw3 -, -(CR w2 R w3 )2-;

[0045] In some embodiments, each W1 is independently selected from -NR w1 -, -CR w2 R w3 -;

[0046] In some embodiments, each W1 is independently selected from -NH-, -C(CH3)2-;

[0047] In some embodiments, each V1 is independently selected from a bond, -O-, -S-, -(CR v2 R v3 ) t -, -NR v1 -, -NR v1 C(=O)-, -C(=O)NR v1 -, -NR v1 S(=O)2-, -NR v1 S(=O)2NR v1 -, which is directly connected to V2 on its right;

[0048] In some embodiments, each V1 is independently selected from a bond, -O-, -S-, -CR v2 R v3 -, -NR v1 -, -NR v1 C(=O)-, -C(=O)NR v1 -, which is directly connected to V2 on its right;

[0049] In some embodiments, each V2 is independently selected from a bond, -O-, -(CR v2 R v3 ) t -;

[0050] In some embodiments, each V2 is independently selected from a bond, -O-, -CR v2 R v3 -;

[0051] In some embodiments, -V1-V2- is independently selected from a bond, -CR v2 R v3 -, -O-, -S-, -NR v1 -, -NH-CR v2 R v3 -, -O-CR v2 R v3 -, -CR v2 R v3-O-, -NH-C(=O)-;

[0052] In some embodiments, each of -V1-V2- is independently selected from a bond, -C(CH3)2-, -O-, -S-, -NH, -NH-C(CH3)2--, -O-C(CH3)2--, -C(CH3)2--O-, -NH-C(=O)-;

[0053] In some embodiments, each of r and t is independently selected from 1, 2, 3, or 4;

[0054] In some embodiments, selected from

[0055] In some embodiments, selected from

[0056] In some embodiments, X1 is selected from O, N, NH, C(=O), CR x1 or CR x1 R x1 ; X2 is selected from O, N, NH, C(=O), CR x2 or CR x2 R x2 ; X3 is selected from O, N, NH, C(=O), CR x3 or CR x3 R x3 ; In some embodiments, X1 is selected from O, N, NH, CR x1 ; X2 is selected from O, N, NH, CR x2 ; X3 is selected from O, N, CR x3 ; In some embodiments, X3 is selected from CR x3 ;

[0057] In some embodiments, each of B3 is independently selected from a 5- to 10-membered heteroaryl or C 6-10 aryl;

[0058] In some embodiments, each of B3 is independently selected from phenyl, a 5- to 6-membered heteroaryl, benzocarbocyclic group, benzo 4- to 6-membered heterocyclic group, 5-fused 5-membered heteroaryl, 5-fused 6-membered heteroaryl, 6-fused 6-membered heteroaryl; 4-6 ;

[0059] In some embodiments, each B3 is independently selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furyl, thienyl, thiazolyl, isothiazolyl, benzimidazolyl, benzpyrazolyl, benzothiazolyl, benzoxazolyl, benzothienyl, benzofuryl, benzopyrrolyl, quinolinyl, isoquinolinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, pyrrolopyrrolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridyl, oxazolopyridyl, triazolopyridyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidinopyridyl, pyrimidinopyrazinyl, pyrimidinopyridazinyl, pyrimidinopyrimidinyl, pyridinopyridyl, pyridinopyrazinyl, pyridinopyridazinyl, pyridazinopyridazinyl, pyridazinopyrazinyl or pyrazinopyrazinyl;

[0060] In some embodiments, each B3 is independently selected from which is connected at a connection position to V2;

[0061] In some embodiments, each B4 is independently selected from a bond, C 3-12 carbocyclic group, 4- to 13-membered heterocyclic group, 5- to 6-membered heteroaryl group, and the B4 is optionally substituted with 1 to 4 Rs b4 ;

[0062] In some embodiments, each B4 is independently selected from a bond, 4- to 7-membered monocyclic heterocyclic group, 4- to 12-membered fused heterocyclic group, 5- to 13-membered spiro heterocyclic group, 7- to 12-membered bridged heterocyclic group, C 3-7 monocyclic alkyl group, C 4-7 monocyclic alkenyl group, C 4-12 fused cycloalkyl group, C 5-12 spirocycloalkyl group, C 5-12 bridged cycloalkyl group, phenyl, 5- to 6-membered heteroaryl group, and the B4 is optionally substituted with 1 to 4 Rs b4 ;

[0063] In some embodiments, each B4 is independently selected from a bond, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, oxolanyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, isoxazolyl, furyl, thienyl, thiazolyl, thiadiazolyl, isothiazolyl, and the B4 is optionally substituted with 1 to 4 Rs b4 ;

[0064] In some embodiments, each B4 is independently selected from a bond or B 4a ;

[0065] In some embodiments, B 4a is independently selected from 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furyl, thienyl, thiazolyl, isothiazolyl,

[0066] The B 4a is optionally substituted by 1 to 3 R b4 ;

[0067] In some embodiments, B 4a is independently selected from

[0068] In some embodiments, B5 is selected from C 3-12 carbocyclic group, 4- to 13-membered heterocyclic group, 5- to 10-membered heteroaryl group, and the B5 is optionally substituted by 1 to 4 R b5 ;

[0069] In some embodiments, B5 is selected from 4- to 7-membered heteromonocyclic group, 4- to 12-membered hetero-fused ring group, 5- to 13-membered heterospiro ring group, 7- to 12-membered heterobridged ring group, C 3-7 monocyclic alkyl group, C 4-7 monocyclic alkenyl group, C 4-12 fused ring alkyl group, C 5-12 spiroalkyl group, C 5-12 bridged ring alkyl group, phenyl, 5- to 6-membered heteroaryl group, benzo-C 4-6 carbocyclic group, benzo-4- to 6-membered heterocyclic group, 5-fused 5-membered heteroaryl group, 5-fused 6-membered heteroaryl group, 6-fused 6-membered heteroaryl group, and the B5 is optionally substituted by 1 to 4 R b5 ;

[0070] In some embodiments, B5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, 1,2,4-oxadiazolyl, isoxazolyl, furyl, thienyl, thiazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, quinolinyl, isoquinolinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, pyrrolopyrrolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridyl, oxazolopyridyl, triazolopyridyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidinopyridyl, pyrimidinopyrazinyl, pyrimidinopyridazinyl, pyrimidinopyrimidinyl, pyridinopyridyl, pyridinopyrazinyl, pyridinopyridazinyl, pyridazinopyridazinyl, pyridazinopyrazinyl or pyrazinopyrazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, The said B5 is optionally substituted by 1 to 4 R b5 ; in some embodiments, r1, r3, r5, r8 are each independently selected from 0, 1 or 2, and r1 and r8 on the same group are not both 2 at the same time; r2, r4 are each independently selected from 0 or 1; r6 is selected from 0, 1, 2 or 3; r7 is selected from 1, 2 or 3;

[0071] In some embodiments, B5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, furyl, thienyl, thiazolyl, isothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, quinolinyl, isoquinolinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,

[0072] The said B5 is optionally substituted by 1 to 3 R b5 ;

[0073] In some embodiments, B5 is selected from

[0074] In some embodiments, R x1 、R x2 、R x3 、Rb1 、R b2 、R b4 are each independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -C 0-4 alkylene-C 3-6 carbocyclic group, -C 0-4 alkylene-4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, -O-C 3-6 carbocyclic group, -O-4- to 6-membered heterocyclic group, and the alkylene, alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, heteroaryl are optionally substituted by 1 to 4 R s ;

[0075] In some embodiments, R x1 、R x2 、R x3 、R b1 、R b2 、R b4 are each independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -C 0-2 alkylene-C 3-6 cycloalkyl, -C 0-2 alkylene-4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, -O-C 3-6 cycloalkyl, -O-4- to 6-membered heterocyclic group, and the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, heteroaryl are optionally substituted by 1 to 4 R s ;

[0076] In some embodiments, R x1 、R x2 、R x3 、R b1 、R b2 、R b4Each independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3 or one of the following groups optionally substituted by 1 to 4 R s substituted: methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, pyrazolyl; in some embodiments, R x1 , R x2 , R x3 , R b1 , R b2 , R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3, CD3, CF3, CHF2, CH2F, OCF3, OCH2F, OCD3, CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, -CH2-cyclopropyl, -O-cyclopropyl; preferably selected from H, deuterium, F, Cl, CF3, CHF2, CH2F, OCF3, OCH2F, OCD3, methyl, methoxy; in some embodiments, R x1 , R x2 , R x3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, CD3, CF3, CHF2, CH2F, OCF3, OCH2F, OCD3, CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl;

[0077] In some embodiments, R b3 , R b5 Each independently selected from deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -C 0-4 alkylene-C 3-6 carbocyclic group, -C 0-4 alkylene-4 to 6-membered heterocyclic group, 5 to 6-membered heteroaryl, -O-C 3-6 carbocyclic group, -O-4 to 6-membered heterocyclic group, -C(=O)N(C 1-4 alkyl)2, -S(=O)2NH2, -S(=O)2N(C 1-4(alkyl)2, -S(=O)2C 1-4 alkyl, -C(=O)NHC 1-4 alkyl, -S(=O)2NHC 1-4 alkyl, -C(=O)C 1-4 alkyl, -C(=O)C 3-6 carbocyclic group, -NHC(=O)C 1-4 alkyl, -NHS(=O)2C 1-4 alkyl, wherein the alkylene, alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, heteroaryl are optionally substituted by 1 to 4 R s substituted;

[0078] In some embodiments, R b3 , R b5 are each independently selected from deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -C 0-2 alkylene-C 3-6 cycloalkyl, -C 0-2 alkylene-4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, -O-C 3-6 cycloalkyl, -O-4- to 6-membered heterocyclic group, -C(=O)N(C 1-4 alkyl)2, -S(=O)2NH2, -S(=O)2N(C 1-4 alkyl)2, -S(=O)2C 1-4 alkyl, -C(=O)NHC 1-4 alkyl, -S(=O)2NHC 1-4 alkyl, -C(=O)C 1-4 alkyl, -C(=O)C 3-6 cycloalkyl, -NHC(=O)C 1-4 alkyl, -NHS(=O)2C 1-4 alkyl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, heteroaryl are optionally substituted by 1 to 4 R s substituted;

[0079] In some embodiments, R b3 , R b5Each independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3, -S(=O)2NH2, -S(=O)2CH3, -C(=O)N(CH3)2, -S(=O)2N(CH3)2, -C(=O)NHCH3, -S(=O)2NHCH3, -C(=O)CH3, -C(=O)cyclopropyl, -NHC(=O)CH3, -NHS(=O)2CH3, -NHS(=O)2CH2CH3 or one of the following groups optionally substituted by 1 to 4 R s substituted: methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, pyrazolyl;

[0080] In some embodiments, R w1 or R v1 Each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, said alkyl or cycloalkyl optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, halogen-substituted C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;

[0081] In some embodiments, R w1 or R v1 Each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, said alkyl or cycloalkyl optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, CF3, CHF2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl; in some embodiments, R w1 or R v1 Selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, said methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, CF3, CHF2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;

[0082] In some embodiments, R w1 or R v1Selected from H, CD3, CF3, CHF2, CH2F, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl;

[0083] In some embodiments, R v2 , R v3 , R w2 or R w3 are each independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl or C 3-6 cycloalkyl, and the alkyl, alkenyl, alkynyl, cycloalkyl are optionally substituted by 1 to 4 deuterium, halogen, OH, =O, NH2, CN, NO2, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, C 3-6 cycloalkyl substituents;

[0084] In some embodiments, R v2 , R v3 , R w2 or R w3 are each independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, and the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl are substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;

[0085] In some embodiments, R v2 , R v3 , R w2 or R w3 are each independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, and the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl are substituted by 1 to 3 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, methyl, ethyl, methoxy, cyclopropyl;

[0086] In some embodiments, Rw2 With R w3 and the carbon atom to which both are attached together form a C 3-6 carbocyclic group or a 3- to 8-membered heterocyclic group, said carbocyclic group or heterocyclic group being optionally substituted by 1 to 4 R s ; in some embodiments, R w2 , R w3 and the carbon atom to which both are attached together form a cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, piperidinyl group, said cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl group being optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C 1-4 alkyl, C 1-4 alkoxy; in some embodiments, R w2 , R w3 and the carbon atom to which both are attached together form a cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, piperidinyl group, said cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl group being optionally substituted by 1 to 3 substituents selected from deuterium, F, Cl, Br, OH, NH2, CN, methyl, ethyl, methoxy;

[0087] In some embodiments, K is selected from wherein the ring represented is an aromatic ring or a non-aromatic ring;

[0088] In some embodiments, K is selected from

[0089] In some embodiments, K is selected from

[0090]

[0091] In some embodiments, K is selected from

[0092] In some embodiments, F1 is selected from N, NH, CH, CH2, CHR k1 , NR k1 , CR k1 , C(=O), C(R k1 )2;

[0093] In some embodiments, F2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 , NR k1 , CR k1or C(R k1 )2;

[0094] In some embodiments, when the represented ring is a non-aromatic ring, F1 is selected from NH, CH2, CHR k1 , NR k1 , C(=O), C(R k1 )2, F2 is selected from a bond, O, NH, CH2, CHR k1 , NR k1 or C(R k1 )2;

[0095] In some embodiments, when the represented ring is an aromatic ring, F1 is selected from N, CH, CR k1 , F2 is selected from a bond, O, N, CH, CR k1 ;

[0096] In some embodiments, F6, F7, F8 are each independently selected from N, C, CH or CR k1 , and F6, F7, F8 contain at most 2 Ns; in some embodiments, one of F6, F7, F8 is selected from N, and the other two are selected from CH or CR k1 ;

[0097] In some embodiments, G is selected from CH or N; in some embodiments, E1 is selected from N or CH, preferably N; in some embodiments, E2 is selected from C, N or CH, preferably N;

[0098] In some embodiments, Q is each independently selected from a bond, -O-, -S-, -CH2-, -NR q ]-, -CO-, -NR q CO-, -CONR q -;

[0099] In some embodiments, Q is each independently 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 some embodiments, Q is each independently selected from a bond, NH, N(CH3), O, S, NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3); in some embodiments, Q is each independently selected from a bond, NH, O, S, C(=O)NH; preferably from a bond, NH, C(=O)NH;

[0100] In some embodiments, Q and G cannot directly form a nitrogen-nitrogen bond or a nitrogen-oxygen bond;

[0101] In some embodiments, selected from

[0102] In some embodiments, R q each independently selected from H or C 1-4 alkyl; in some embodiments, R q each independently selected from H, methyl, ethyl or isopropyl; in some embodiments, R q selected from H or methyl;

[0103] In some embodiments, R k1 each independently selected from deuterium, halogen, OH, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 R s In some embodiments, R k1 each independently selected from deuterium, halogen, OH, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4- to 6-membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, CF3, CN, NH2, C 1-4 alkyl;

[0104] In some embodiments, R k1 each independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2; in some embodiments, R k1 each independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, CF3, CHF2, CH2F, OCF3, OCH2F, CH2OH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0105] In some embodiments, R L2 and R s each independently selected from deuterium, halogen, OH, CN, =O, CF3, SF5, NO2, NH2, NHC1-4 alkyl, N(C 1-4 alkyl)2, COOH, CONH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -S-C 1-4 alkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 6-membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy; in some embodiments, R L2 , R s are each independently selected from deuterium, halogen, OH, CN, =O, CF3, SF5, NO2, NH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, COOH, CONH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -S-C 1-4 alkyl, -C 0-2 alkylene-C 3-6 cycloalkyl, -C 0-2 alkylene-4- to 6-membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy;

[0106] In some embodiments, R L2 , R s are each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy;

[0107] In some embodiments, R L2 , R s are each independently selected from deuterium, F, Cl, Br, I, OH, ═O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, CHF2, CH2F, OCF3, OCH2F, OCHF2, CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl;

[0108] In some embodiments, p1 are each independently selected from 0, 1 or 2; in some embodiments, p1 are each independently selected from 0, 1;

[0109] In some embodiments, m1, m2, m3 are each independently selected from 0, 1, 2, 3 or 4;

[0110] In some embodiments, m1, m2, m3 are each independently selected from 0, 1, 2, 3.

[0111] As a first embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein,

[0112] L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0113] Ak1, Ak2, Ak3, Ak4, 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 key, wherein said -CH2- is optionally substituted by 1 to 2 substituents selected from deuterium, halogen, =O, OH, CN, C 1-4 alkyl or C 3-6 cycloalkyl;

[0114] q is selected from 0, 1, 2 or 3;

[0115] R L are each independently selected from H or C 1-4 alkyl;

[0116] Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or one of the following groups optionally substituted by 1 to 4 R L2 substituted: 4- to 7-membered hetero monocyclic group, 4- to 12-membered hetero fused ring group, 5- to 13-membered hetero spiro ring group, 7- to 12-membered hetero bridged ring group, C 3-7 monocyclic alkyl, C 4-7 monocyclic alkenyl, C 4-12 fused ring alkyl, C 5-13 spiroalkyl, C 5-12 bridged ring alkyl, 5- to 10-membered heteroaryl or C 6-10 aryl;

[0117] B is selected from

[0118] representing that the ring where it is located is an aromatic ring or a non-aromatic ring;

[0119] W1 are each independently selected from -NR w1 -, -(CR w2 R w3 ) r -;

[0120] V1 are each independently selected from a bond, -O-, -S-, -(CR v2 R v3 ) t -, -NR v1 -, -NR v1 C(=O)-, -C(=O)NR v1 -, -NR v1 S(=O)2-, -NR v1 S(=O)2NR v1 -, the right side of which is directly connected to V2;

[0121] V2 are each independently selected from a bond, -O-, -(CR v2 R v3 ) t -;

[0122] B3 are each independently selected from 5- to 10-membered heteroaryl or C 6-10 aryl;

[0123] B4 is independently selected from a bond, C 3-12 a carbocyclic group, a 4- to 13-membered heterocyclic group, a 5- to 6-membered heteroaryl group, and the B4 is optionally substituted by 1 to 4 Rs b4 ;

[0124] B5 is selected from C 3-12 a carbocyclic group, a 4- to 13-membered heterocyclic group, a 5- to 10-membered heteroaryl group, and the B5 is optionally substituted by 1 to 4 Rs b5 ;

[0125] X1 is selected from O, N, NH, C(=O), CR x1 or CR x1 R x1 ; X2 is selected from O, N, NH, C(=O), CR x2 or CR x2 R x2 ; X3 is selected from O, N, NH, C(=O), CR x3 or CR x3 R x3 ;

[0126] r and t are independently selected from 1, 2, 3 or 4;

[0127] m1, m2 and m3 are independently selected from 0, 1, 2, 3 or 4;

[0128] R w1 or R v1 is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, halogen-substituted C 1-4 alkyl, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;

[0129] R v2 , R v3 , R w2 or R w3 is independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl or C 3-6Cycloalkyl, and the alkyl, alkenyl, alkynyl, cycloalkyl are optionally substituted by 1 to 4 deuteriums, halogens, OH, ═O, NH2, CN, NO2, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, C 3-6 substituted by the substituents of cycloalkyl;

[0130] Optionally, R w2 together with R w3 and the carbon atom to which both are attached form a C 3-6 carbocyclic group or a 3- to 8-membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R s ;

[0131] R x1 , R x2 , R x3 , R b1 , R b2 , R b4 are each independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -C 0-4 alkylene-C 3-6 carbocyclic group, -C 0-4 alkylene-4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, -O-C 3-6 carbocyclic group, -O-4- to 6-membered heterocyclic group, and the alkylene, alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, heteroaryl are optionally substituted by 1 to 4 R s ;

[0132] R b3 , R b5 are each independently selected from deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -C 0-4 alkylene-C 3-6 carbocyclic group, -C 0-4 alkylene-4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, -O-C3-6 carbocyclic group, -O-4- to 6-membered heterocyclic group, -C(=O)N(C 1-4 alkyl)2, -S(=O)2NH2, -S(=O)2N(C 1-4 alkyl)2, -S(=O)2C 1-4 alkyl, -C(=O)NHC 1-4 alkyl, -S(=O)2NHC 1-4 alkyl, -C(=O)C 1-4 alkyl, -C(=O)C 3-6 carbocyclic group, -NHC(=O)C 1-4 alkyl, -NHS(=O)2C 1-4 alkyl, wherein the alkylene group, alkyl group, alkenyl group, alkynyl group, carbocyclic group, heterocyclic group, heteroaryl group are optionally substituted by 1 to 4 R s ;

[0133] K is selected from

[0134] F1 is selected from N, NH, CH, CH2, CHR k1 , NR k1 , CR k1 , C(=O), C(R k1 )2;

[0135] F2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 , NR k1 , CR k1 or C(R k1 )2;

[0136] F6, F7, F8 are each independently selected from N, C, CH or CR k1 , and at most 2 N's are contained in F6, F7, F8;

[0137] G is selected from CH or N;

[0138] E1 is selected from N or CH;

[0139] E2 is selected from C, N or CH;

[0140] Q is each independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q -;

[0141] Q and G cannot directly form a nitrogen-nitrogen bond or a nitrogen-oxygen bond;

[0142] R q are each independently selected from H or C1-4 alkyl;

[0143] R k1 each independently selected from deuterium, halogen, OH, NH2, CN, COOH, CONH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 cycloalkyl, 4- to 6-membered heteroalkyl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heteroalkyl are optionally substituted with 1 to 4 R s ;

[0144] R L2 , R s each independently selected from deuterium, halogen, OH, CN, =O, CF3, SF5, NO2, NH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, COOH, CONH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -S-C 1-4 alkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, -C 0-4 alkylene-4- to 6-membered heterocyclic group, and the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy;

[0145] p1 are each independently selected from 0, 1, or 2.

[0146] As a second embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein,

[0147] B3 are each independently selected from phenyl, 5- to 6-membered heteroaryl, benzoC 4-6 carbocyclic group, benzo-4- to 6-membered heterocyclic group, 5-fused 5-membered heteroaryl, 5-fused 6-membered heteroaryl, 6-fused 6-membered heteroaryl;

[0148] B4 are each independently selected from a bond, 4- to 7-membered hetero monocyclic group, 4- to 12-membered hetero fused ring group, 5- to 13-membered hetero spiro ring group, 7- to 12-membered hetero bridged ring group, C 3-7 monocyclic alkyl, C 4-7 monocyclic alkenyl, C 4-12 fused cycloalkyl, C5-12 Spiroalkyl, C 5-12 Bridged cycloalkyl, phenyl, 5- or 6-membered heteroaryl, where B4 is optionally substituted by 1 to 4 R b4 groups;

[0149] B5 is selected from 4- to 7-membered hetero monocyclic group, 4- to 12-membered hetero fused ring group, 5- to 13-membered hetero spiro ring group, 7- to 12-membered hetero bridged ring group, C 3-7 monocyclic alkyl, C 4-7 monocyclic alkenyl, C 4-12 fused cycloalkyl, C 5-12 spiroalkyl, C 5-12 bridged cycloalkyl, phenyl, 5- or 6-membered heteroaryl, benzo C 4-6 carbocyclic group, benzo 4- to 6-membered heterocyclic group, 5-fused 5-membered heteroaryl, 5-fused 6-membered heteroaryl, 6-fused 6-membered heteroaryl, where B5 is optionally substituted by 1 to 4 R b5 groups;

[0150] R x1 、R x2 、R x3 、R b1 、R b2 、R b4 are each independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -C 0-2 alkylene-C 3-6 cycloalkyl, -C 0-2 alkylene-4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, -O-C 3-6 cycloalkyl, -O-4- to 6-membered heterocyclic group, and the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, heteroaryl are optionally substituted by 1 to 4 R s groups;

[0151] R b3 、R b5 are each independently selected from deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, -SC 1-4 alkyl, -C0-2 Alkylene-C 3-6 Cycloalkyl, -C 0-2 Alkylene-4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl, -O-C 3-6 Cycloalkyl, -O-4- to 6-membered heterocyclic group, -C(=O)N(C 1-4 Alkyl)2, -S(=O)2NH2, -S(=O)2N(C 1-4 Alkyl), -S(=O)2C 1-4 Alkyl, -C(=O)NHC 1-4 Alkyl, -S(=O)2NHC 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -C(=O)C 3-6 Cycloalkyl, -NHC(=O)C 1-4 Alkyl, -NHS(=O)2C 1-4 Alkyl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, heteroaryl are optionally substituted by 1 to 4 R s substituents;

[0152] R w1 or R v1 each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, CF3, CHF2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;

[0153] Optionally, R w2 and R w3 and the carbon atom to which both are attached together form cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, piperidinyl, and the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl are optionally substituted by 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C 1-4 alkyl, C 1-4 alkoxy;

[0154] R L is selected from H, methyl or ethyl;

[0155] R q are each independently selected from H, methyl, ethyl or isopropyl;

[0156] Cy1, Cy2, Cy3, Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2One of the following substituted groups: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl,

[0157]

[0158] s1, s3, s5 are each independently selected from 0, 1 or 2;

[0159] s2, s4 are each independently selected from 0 or 1;

[0160] s6 is selected from 0, 1, 2 or 3;

[0161] s7 is selected from 1, 2 or 3;

[0162] R L2 、R s are each independently selected from deuterium, halogen, OH, CN, =O, CF3, SF5, NO2, NH2, NHC 1-4 alkyl, N(C 1-4 alkyl)2, COOH, CONH2, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -S-C 1-4 alkyl, -C 0-2 alkylene-C 3-6 cycloalkyl, -C 0-2 alkylene-4- to 6-membered heterocyclic group, and the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy;

[0163] The remaining definitions are the same as those in the first embodiment of the present invention.

[0164] As the third embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0165] W1 are each independently selected from -NR w1 -, -CR w2 R w3 -, -(CR w2 R w3 )2-;

[0166] V2 are each independently selected from a bond, -O-, -CR v2 R v3 -;

[0167] R w1 or R v1 selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, and the methyl, ethyl, isopropyl, cyclopropyl, and cyclobutyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, CF3, CHF2, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;

[0168] R x1 R x2 R x3 R b1 R b2 R b4 each independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3 or one of the following groups optionally substituted by 1 to 4 R s : methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, pyrazolyl;

[0169] R b3 R b5 each independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3, -S(=O)2NH2, -S(=O)2CH3, -C(=O)N(CH3)2, -S(=O)2N(CH3)2, -C(=O)NHCH3, -S(=O)2NHCH3, -C(=O)CH3, -C(=O)cyclopropyl, -NHC(=O)CH3, -NHS(=O)2CH3, -NHS(=O)2CH2CH3 or one of the following groups optionally substituted by 1 to 4 R s : methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, pyrazolyl;

[0170] R v2 R v3 R w2 or R w3Each independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl are substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl;

[0171] Alternatively, R w2 , R w3 and the carbon atom to which both are attached together form cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, piperidinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl are optionally substituted with 1 to 4 substituents selected from deuterium, halogen, OH, NH2, CN, C 1-4 alkyl, C 1-4 alkoxy;

[0172] Ak1, Ak2, Ak3, Ak4, Ak5 each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -CH(CH3)-, -CH2-, -C(CH3)2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

[0173] K is selected from

[0174] Q each independently 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);

[0175] R k1Each independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2;

[0176] R L2 、R s Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, and the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy;

[0177] The remaining definitions are the same as those in the first or second embodiment of the present invention.

[0178] As the fourth embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein

[0179] B3 are each independently selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furyl, thienyl, thiazolyl, isothiazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzoxazolyl, benzothienyl, benzofuryl, benzopyrrolyl, quinolinyl, isoquinolinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, pyrrolopyrrolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridyl, oxazolopyridyl, triazolopyridyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidinopyridyl, pyrimidinopyrazinyl, pyrimidinopyridazinyl, pyrimidinopyrimidinyl, pyridinopyridyl, pyridinopyrazinyl, pyridinopyridazinyl, pyridazinopyridazinyl, pyridazinopyrazinyl or pyrazinopyrazinyl;

[0180] B4 are each independently selected from a bond, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, oxolanyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, isoxazolyl, furyl, thienyl, thiazolyl, thiadiazolyl, isothiazolyl,

[0181] the said B4 is optionally substituted by 1 to 4 R b4 substituted;

[0182] r1, r3, r5, r8 are each independently selected from 0, 1 or 2, and r1 and r8 on the same group are not both 2 at the same time;

[0183] r2 and r4 are each independently selected from 0 or 1;

[0184] r6 is selected from 0, 1, 2 or 3;

[0185] r7 is selected from 1, 2 or 3;

[0186] B5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azolanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, oxolanyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, isoxazolyl, furyl, thienyl, thiazolyl, thiadiazolyl, isothiazolyl, benzothienyl, benzofuryl, benzopyrrolyl, quinolinyl, isoquinolinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, pyrrolopyrrolyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridyl, oxazolopyridyl, triazolopyridyl, pyrazolopyrimidinyl, pyrazolopyridazinyl, pyrazolopyrazinyl, pyrimidinopyridyl, pyrimidinopyrazinyl, pyrimidinopyridazinyl, pyrimidinopyrimidinyl, pyridinopyridyl, pyridinopyrazinyl, pyridinopyridazinyl, pyridazinopyridazinyl, pyridazinopyrazinyl or pyrazinopyrazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, the said B5 is optionally substituted by 1 to 4 R b5 substituted;

[0187] Cy1, Cy2, Cy3, Cy4 are each independently selected from a bond or one of the following optionally substituted groups: When substituted, it is substituted by 1 to 4 substituents selected from deuterium, F, CF3, OH, ═O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl;

[0188] K is selected from

[0189] The remaining definitions are the same as those in the first, second or third embodiment of the present invention.

[0190] As the fifth embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0191] W1 are each independently selected from -NR w1 -, -CR w2 R w3 -;

[0192] -V1-V2- are each independently selected from a bond, -CR v2 R v3 -, -O-, -S-, -NR v1 -, -NH-CR v2 R v3 -, -O-CR v2 R v3 -, -CR v2 R v3 -O-, -NH-C(═O)-;

[0193] Selected from

[0194] X1 is selected from O, N, NH, CR x1 ; X2 is selected from O, N, NH, CR x2 ;

[0195] R x1 、R x2 、R x3 are each independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, CD3, CF3, CHF2, CH2F, OCF3, OCH2F, OCD3, CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl;

[0196] R w1 or R v1 is selected from H, CD3, CF3, CHF2, CH2F, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl;

[0197] Rv2 , R v3 , R w2 or R w3 are each independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, and the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl are substituted with 1 to 3 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, methyl, ethyl, methoxy, cyclopropyl;

[0198] Optionally, R w2 , R w3 and the carbon atom to which both are attached together form cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, oxolanyl, pyrrolidinyl, piperidinyl, and the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl are optionally substituted with 1 to 3 substituents selected from deuterium, F, Cl, Br, OH, NH2, CN, methyl, ethyl, methoxy;

[0199] R s are each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, CHF2, CH2F, OCF3, OCH2F, OCHF2, CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl;

[0200] Q are each independently selected from a bond, NH, N(CH3), O, S, NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3);

[0201] L is selected from a bond, -Cy1-, -Cy1-Ak2-, -Ak1-Cy1-, -Ak1-, -Ak1-Cy1-Ak2-, -Cy1-Ak2-Cy2-, -Cy1-Cy2-Ak3-, -Ak1-Cy1-CH2-, -Ak1-Cy1-Cy2-, -Cy1-Ak2-Cy2-, -Cy1-Ak2-Cy2-Ak3-; preferably selected from a bond, -Cy1-CH2-, -Cy1-, -C(=O)-Cy1-, -CH2-Cy1-, -C(=O)-Cy1-CH2-, -Cy1-CH2-Cy2-, -Cy1-Cy2-CH2-, -O-CH2-CH2-, -O-CH2-CH2-Cy1-, -O-CH2-Cy1-, -O-Cy1-, -O-Cy1-CH2-;

[0202] Cy1 and Cy2 are each independently selected from one of the following optionally substituted groups: When substituted, it is substituted by 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl;

[0203] The remaining definitions are the same as those in the first, second, third, or fourth embodiment of the present invention.

[0204] As the sixth embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0205] B is selected from

[0206] Selected from

[0207] B 4a Each independently selected from 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furyl, thienyl, thiazolyl, isothiazolyl,

[0208]

[0209] The said B 4a Optionally substituted by 1 to 3 R b4 substituted;

[0210] B5 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, oxolanyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, furyl, thienyl, thiazolyl, isothiazolyl, benzothienyl, benzofuryl, benzopyrrolyl, quinolinyl, isoquinolinyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,

[0211] The said B5 is optionally substituted by 1 to 3 Rs b5 ;

[0212] K is selected from

[0213]

[0214] Each Q is independently selected from a bond, NH, O, S, C(=O)NH;

[0215] Preferably, selected from

[0216] R k1 Each is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, CF3, CHF2, CH2F, OCF3, OCH2F, CH2OH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0217] L is selected from a bond or one of the structural fragments shown in Table L-1;

[0218] The remaining definitions are the same as those in the first, second, third, fourth or fifth embodiment of the present invention.

[0219] The present invention relates to a compound as described below or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, wherein the compound is selected from one of the structures shown in Table E.

[0220] The present invention relates to a pharmaceutical composition comprising the compound as described above in the present invention or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and a pharmaceutically acceptable carrier.

[0221] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a drug for treating diseases related to AR / ARv7 activity or expression level.

[0222] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a drug for treating diseases related to the inhibition or degradation of AR / ARv7. In some embodiments, the diseases related to the inhibition or degradation of AR / ARv7 are cancers, preferably prostate cancer.

[0223] 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, tautomer, deuterated compound, 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 active ingredient in the unit preparation is also referred to as "preparation specification").

[0224] The present invention also provides a method for treating a disease in a mammal, which comprises administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or a pharmaceutical composition. In some embodiments, the mammal in the present invention includes humans.

[0225] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the therapeutically effective amount being preferably 1 - 1500 mg, and the disease being preferably cancer.

[0226] In the present invention, the amount of the compound of the present invention or its stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is converted in the form of the free base in each case.

[0227] Unless otherwise specified, the terms used in the specification and claims have the following meanings.

[0228] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotope situations, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 12 C, 13C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as superheavy hydrogen), and the isotopes of oxygen include 16 O, 17 O and 18 O, and the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, and the isotopes of fluorine include 17 F and 19 F, and the isotopes of chlorine include 35 Cl and 37 Cl, and the isotopes of bromine include 79 Br and 81 Br.

[0229] "CN" refers to the cyano group. "Halogen" refers to F, Cl, Br, or I.

[0230] "Halogen-substituted" means substituted by F, Cl, Br, or I, including but not limited to being substituted by 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is abbreviated as "halogenated".

[0231] "Alkyl" refers to a substituted or unsubstituted straight-chain or branched-chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups having 1 to 20 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, 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 their various branched isomers; alkyl can be monovalent, divalent, trivalent or tetravalent.

[0232] "Alkylene" refers to a substituted or unsubstituted straight-chain and branched-chain divalent saturated hydrocarbon group, including -(CH2) v -(where v is an integer from 1 to 10), and examples of alkylene include but not limited to methylene, ethylene, propylene, and butylene, etc.

[0233] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 12 carbon atoms, and cycloalkyl can be monocyclic, fused-ring, bridged-ring, and spiro-ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-fused-cyclobutyl, cyclobutyl-spiro-cyclobutyl, adamantane, etc. Cycloalkyl can be monovalent, divalent, trivalent or tetravalent.

[0234] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cycloalkyl group containing heteroatoms, including but not limited to cycloalkyl groups having 3 to 12 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O or S, and the C, N, S on the ring of the heterocycloalkyl group can be oxidized to various oxidation states. Heterocycloalkyl groups can be monocyclic, fused-ring, bridged-ring and spiro-ring. Heterocycloalkyl groups can be attached to heteroatoms or carbon atoms, and non-limiting examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,

[0235] Heterocycloalkyl groups can be monovalent, divalent, trivalent or tetravalent.

[0236] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched-chain unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include but 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.; alkenyl groups can be monovalent, divalent, trivalent or tetravalent.

[0237] "Alkynyl" refers to a substituted or unsubstituted straight-chain or branched-chain unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, with a main chain comprising 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms in the main chain, having 2 to 4 carbon atoms in the main chain. 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, 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, etc.; alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0238] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy and cyclobutoxy.

[0239] "Carbocyclic group" or "carbocycle" refers to a substituted or unsubstituted aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring, 4- to 12-membered bicyclic ring, 10- to 15-membered tricyclic ring, 12- to 18-membered tetracyclic system. The carbocyclic group can be attached to an aromatic ring or a non-aromatic ring, and the ring is optionally a monocyclic ring, fused ring, bridged ring or spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclic group" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

[0240] "Heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered tetracyclic system, and contains one or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O, S, or Se. The optionally substituted C, N, or S in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused, or spiro ring. Non-limiting examples include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridinyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiolyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuryl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclic group" or "heterocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0241] "Spiro ring" or "spiro group" refers to a polycyclic group in which a substituted or unsubstituted monocyclic ring shares an atom (called a spiro atom). The number of ring atoms in the spiro system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, and one or more of the rings can contain 0 or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally can contain 0 to 5 heteroatoms selected from N, O, S(=O) n or Se(=O) n (n is 0, 1, or 2).

[0242] "Spiro ring" or "spiro group" can be monovalent, divalent, trivalent, or tetravalent.

[0243] "Fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, where one or more rings may contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds, and may be substituted or unsubstituted. Each ring in the fused ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to selected from N, S(=O) n , Se(=O) n or O, and n is 0, 1, or 2). The number of ring atoms in the fused ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include:

[0244] "Fused ring" or "fused ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0245] "Bridged ring" or "bridged ring group" refers to a polycyclic group, substituted or unsubstituted, containing any two non-directly connected atoms, which may contain zero or more double bonds. Any ring in the bridged ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O)n, Se(=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" can be monovalent, divalent, trivalent, or tetravalent.

[0246] "Carbospirocycle", "spirocarbocyclic group", "spirocarbon group", or "carbospiro group" refers to a "spirocycle" whose ring system consists only of carbon atoms.

[0247] "Carbofused ring", "fused carbocyclic group", "carbofused group", or "carbofused ring group" refers to a "fused ring" whose ring system consists only of carbon atoms.

[0248] "Carbobridged ring", "bridged carbocyclic group", "bridged carbon group", or "carbobridged ring group" refers to a "bridged ring" whose ring system consists only of carbon atoms.

[0249] "Heteromonocycle", "monocyclic heterocyclic group", or "heteromonocyclic group" refers to a "heterocyclic group" or "heterocycle" of a monocyclic system,

[0250] "Heterofused ring", "heterofused ring group", "fused heterocyclic group", or "heterofused heterocyclic group" refers to a "fused ring" containing heteroatoms.

[0251] "Heterospirocycle", "heterospirocyclic group", "spiroheterocyclic group", or "heterospiro group" refers to a "spirocycle" containing heteroatoms.

[0252] "Spiroheterocycle", "spiroheterocyclic group", "bridged heterocyclic group" or "bridged hetero group" refers to a "bridged ring" containing heteroatoms.

[0253] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, and 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 ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection sites are located on the aryl ring.

[0254] "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, S(=O)n, Se(=O) n , where 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. The atoms C, N, S, Se on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1, 2). Non-limiting examples of heteroaryl include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, pyridone group, etc. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include The heteroaryl groups appearing in this text have the same definition as this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection sites are located on the aromatic ring.

[0255] "Substituted" or "substitution" means being substituted by one or more (including, but not limited to, 2, 3, 4 or 5) substituents, and the substituents include, but are not limited to, H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic group, bridged ring group, spiro ring group, fused ring group, 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) m S(=O) n R a , -(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c and other groups, where R b and R c are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl. Optionally, R b and R c can form a five- or six-membered cycloalkyl or heterocyclic group, R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, spiro ring group or fused ring group.

[0256] "substituted with 1 to X substituents selected from..." means substituted with 1, 2, 3... X substituents selected from.... X is any integer between 1 and 10. For example, "substituted with 1 to 4 R k " means substituted with 1, 2, 3 or 4 R k ". For example, "substituted with 1 to 5 substituents selected from..." means substituted with 1, 2, 3, 4 or 5 substituents selected from.... For example, "the heterobridged ring is optionally substituted with 1 to 4 substituents selected from H or F" means the heterobridged ring is optionally substituted with 1, 2, 3 or 4 substituents selected from H or F.

[0257] The X-Y membered ring (X, Y are integers, and 3 ≤ X < Y, X < Y ≤ 20 is any integer between 4 and 20) includes X, X + 1, X + 2, X + 3, X + 4... Y membered rings. The ring includes heterocyclic ring, carbocyclic ring, aromatic ring, aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heterofused ring, heterospiro ring or heterobridged ring. For example, "4-7 membered heteromonocyclic ring" means a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5-10 membered heterofused ring" means a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heterofused ring.

[0258] C x-y The carbocyclic ring (including aryl, cycloalkyl, monocyclic carbocyclic ring, spirocarbocyclic ring, fused carbocyclic ring or bridged carbocyclic ring) includes C x , C x+1 , C x+2 , C x+3 , C x+4 …C yRing of x yuan (x is an integer, and 3 ≤ x < y, y is any integer selected from 4 to 20), for example. Such as C 3-6 "Cycloalkyl" means C3, C4, C5 or C6 cycloalkyl;

[0259] When a certain group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the connection mode of the chemical bond is non-specific and there are hydrogen atoms at the connectable sites, then when connecting the chemical bond, the number of H atoms at this site will correspondingly decrease with the number of connected chemical bonds to become a group with the corresponding valence. For example Indicates that any connectable site on the piperidyl group can be connected to other groups through 1 chemical bond, including at least These 4 connection modes, even if H atoms are drawn on -N-, also includes For example Indicates that the R group on the piperidyl group can be located on C or on N, including at least

[0260] When the listed connecting groups do not specify their connection directions, their connection directions include the directions of the reading orders from left to right and from right to left for connection. For example, for A-L-B, when L is selected from -M-W-, it includes A-M-W-B and A-W-M-B.

[0261] "Optional" or "optionally" means that the subsequent described event or circumstance can but does not have to occur, and this description includes the occasions where the event or circumstance occurs or does not occur. For example: "Optionally F-substituted alkyl" means that the alkyl can but does not have to be substituted by F, and the description includes the situation where the alkyl is substituted by F and the situation where the alkyl is not substituted by F.

[0262] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention maintains the biological effectiveness and characteristics of the free acid or free base, and the salt obtained by reacting the free acid with a non-toxic inorganic base or organic base, and the free base with a non-toxic inorganic acid or organic acid.

[0263] "Pharmaceutical composition" means a mixture formed by one or more compounds of the present invention, or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals and other chemical components, wherein, "other chemical components" means pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0264] "Carrier" means a material that does not cause obvious irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound.

[0265] "Prodrug" refers to a compound of the present invention that can be metabolically converted in vivo into a bioactive compound. The prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compound of the present invention, and such 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 individual, the prodrug is cleaved to form a free amino group or carboxyl group.

[0266] "Co-crystal" refers to a crystal formed by the binding of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, where both the pure states of the API and the CCF are solids at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal, including binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0267] "Animal" refers to including mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0268] "Stereoisomer" refers to an isomer generated by the different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers, and conformational isomers.

[0269] "Tautomer" refers to a functional group isomer generated by the rapid movement of a certain atom in a molecule between two positions, such as keto-enol tautomerism and amide-imidol tautomerism.

[0270] Synthesis method 1:

[0271]

[0272] The general formula compound (Z-1) and the general formula compound (Z-2) are reacted through reductive amination or nucleophilic substitution reaction to obtain the general formula compound (Z-3);

[0273] The protecting group of the general formula compound (Z-3) is removed to obtain the general formula compound (Z-4);

[0274] The general formula compound (Z-4) and the general formula compound (Z-5) are reacted through nucleophilic substitution, condensation, or coupling reaction to obtain the general formula compound (I-a);

[0275] R m1 Each independently selected from protecting groups such as Boc, Cbz, Fmoc, SEM, MOM, TBS, THP, Trt and other groups;

[0276] R m2 Each independently selected from CHO, CH2Cl, CH2Br, CH2I, CH2OTf, CH2OMs, CH2OTs and other groups;

[0277] R m3 Each independently selected from groups such as Cl, Br, I, OMs, (C=O)Cl, (C=O)OH, etc.;

[0278] The definitions of the remaining groups are the same as those of the compound of general formula (I).

[0279] Synthesis method two:

[0280]

[0281] The general formula compound (Z-6) and the general formula compound (Z-7) are subjected to a nucleophilic substitution or coupling reaction to obtain the general formula compound (I-b);

[0282] R m4 Each independently selected from groups such as F, Cl, Br, I, OTf, etc.;

[0283] The definitions of the remaining groups are the same as those of the compound of general formula (I).

[0284] Synthesis method three:

[0285]

[0286] The general formula compound (Z-8) and the general formula compound (Z-7) are subjected to a nucleophilic substitution or coupling reaction to obtain the general formula compound (I-c);

[0287] R m5 Each independently selected from groups such as F, Cl, Br, I, OTf, etc.;

[0288] The definitions of the remaining groups are the same as those of the compound of general formula (I). Specific embodiments

[0289] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to this.

[0290] 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 the suppliers include: Titan Technology, Energy Chemical, Shanghai Dermer, Chengdu Kelong Chemical Industry, Shaoyuan Chemical Technology, Nanjing Pharmaron, WuXi AppTec, and J&K Scientific, etc.

[0291] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is in 10 -6Given in the unit of (ppm). The NMR measurement was performed using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometers. The solvents for measurement were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0292] The MS measurement was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI)).

[0293] The HPLC measurement was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0294] The thin-layer chromatography silica gel plates used were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used in thin-layer chromatography (TLC) were 0.15mm - 0.20mm, and the specifications of the silica gel plates used for thin-layer chromatography separation and purification of products were 0.4mm - 0.5mm.

[0295] Column chromatography generally used Yantai Huanghai silica gel with a mesh size of 200 - 300 as the carrier.

[0296] Abbreviations of synthetic reagents:

[0297] DMAP: CAS number: 1122 - 58 - 3; NBS: CAS number: 128 - 08 - 5; HATU: CAS number: 148893 - 10 - 1;

[0298] Synthesis of Intermediate 1:

[0299]

[0300] First step: Preparation of 1-B

[0301] Dissolve 1-A (2.8g, 13.58mmol) (the synthesis method refers to Bioorganic & Medicinal Chemistry Letters, 2016, 26, 5877 - 5882) in dichloromethane (50mL), add Boc2O (5.93g, 27.17mmol), add DMAP (3.32g, 27.18mmol), and react at room temperature for 16h. Wash the reaction system with 0.5mol / L hydrochloric acid (50mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1 - 1:9) to obtain the racemate of 1-B (3.4g, yield: 82%).

[0302] The racemate of 1-B is subjected to chiral resolution. The chiral resolution method is as follows:

[0303] 1. Instrument: SFC Prep 150AP; Chromatographic column: Daicel IC-H (19 mm × 250 mm).

[0304] 2. The sample is dissolved in methanol and filtered through a 0.45 μm filter head to prepare a sample solution.

[0305] 3. Preparation chromatographic conditions: a. The mobile phase consists of systems A and B: Mobile phase A: CO2; Mobile phase B: methanol / isopropanol (v / v) = 1:1; b. Isocratic elution, the content of mobile phase B is 20%; c. The flow rate is 40 mL / min.

[0306] Elution time: Chiral isomer 1 (compound 1-B): 5.7 min, chiral isomer 2 (compound 2-A): 6.47 min.

[0307] According to the MicroED structure determination of compound 2-B, compound 1-B is of the R configuration and compound 2-A is of the S configuration.

[0308] LCMS m / z = 307.3 [M+1] + 。

[0309] The second step: Preparation of 1-C

[0310] Dissolve 1-B (1.8 g, 5.88 mmol) in acetonitrile (50 mL), add NBS (1.05 g, 5.90 mmol), and react at room temperature for 1 h. Concentrate the reaction system under reduced pressure, and purify the crude product by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1 - 1:9) to obtain 1-C (1.6 g, yield: 71%).

[0311] LCMS m / z = 385.3 [M+1] + 。

[0312] The third step: Preparation of 1-D

[0313] 1-C (0.77 g, 2.0 mmol), 1-C′ (1.67 g, 4.0 mmol) (for the synthesis method, see WO2022235945), Pd(dppf)Cl2·DCM (0.16 g, 0.20 mmol) and cesium carbonate (1.30 g, 4.0 mmol) were added to a reaction flask, 1,4-dioxane (30 mL) and water (3 mL) were added, and the reaction was carried out at 100 °C for 20 h under a nitrogen atmosphere. The reaction system was cooled to room temperature, 50 mL of water and 50 mL of ethyl acetate were added, the aqueous phase was extracted with 50 mL of ethyl acetate, the organic phase was washed with 30 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 - 9:1) to obtain 1-D (0.70 g, yield: 59%).

[0314] Step 4: Preparation of 1-E

[0315] 1-D (0.70 g, 1.18 mmol) was dissolved in THF (20 mL), 10% palladium on carbon (0.63 g) was added, and the reaction was carried out at 45 °C for 20 h under a hydrogen balloon atmosphere. The reaction system was cooled to room temperature, filtered by suction, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (MeOH:DCM (v / v) = 0:1 - 5:95) to obtain 1-E (0.25 g, yield: 51%).

[0316] LCMS m / z = 418.1 [M+1] + 。

[0317] Step 5: Preparation of Intermediate 1

[0318] 1-E (250 mg, 0.6 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the mixture was concentrated under reduced pressure to obtain the crude Intermediate 1 (190 mg).

[0319] LCMS m / z = 318.3 [M+1] + 。

[0320] Synthesis of Intermediate 2:

[0321]

[0322] Step 1: Preparation of 2-B

[0323] Dissolve 2-A (1.4 g, 4.57 mmol) in acetonitrile (50 mL), add NBS (0.81 g, 4.55 mmol), and react at room temperature for 1 h. Concentrate the reaction system under reduced pressure, and purify the crude product by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1 - 1:9) to obtain 2-B (1.6 g, yield: 92%).

[0324] LCMS m / z = 385.3 [M+1] + 。

[0325] Compound 2-B was determined by MicroED to be in the S configuration.

[0326] Step 2: Preparation of 2-C

[0327] Add 2-B (1.6 g, 4.16 mmol), 2-B′ (3.46 g, 8.29 mmol), Pd(dppf)Cl2·DCM (0.34 g, 0.42 mmol), and cesium carbonate (2.70 g, 8.3 mmol) to a reaction flask, add 1,4-dioxane (50 mL) and water (5 mL), and react at 100 °C for 20 h under a nitrogen atmosphere. Cool the reaction system to room temperature, add 50 mL of water and 50 mL of ethyl acetate, extract the aqueous phase with ethyl acetate (50 mL), wash the organic phase with 30 mL of saturated sodium chloride aqueous solution, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 - 9:1) to obtain 2-C (1.4 g, yield: 56%).

[0328] Step 3: Preparation of 2-D

[0329] Dissolve 2-C (1.4 g, 2.35 mmol) in THF (50 mL), add 10% palladium on carbon (1.25 g), and react at 45 °C for 20 h under a hydrogen balloon atmosphere. Cool the reaction system to room temperature, filter by suction, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (MeOH:DCM (v / v) = 0:1 - 5:95) to obtain 2-D (0.85 g, yield: 87%).

[0330] LCMS m / z = 418.1 [M+1] + 。

[0331] Step 4: Preparation of Intermediate 2

[0332] Dissolve 2-D (620 mg, 1.49 mmol) in dichloromethane (5 mL), add trifluoroacetic acid (3 mL), and react at room temperature for 3 h. Concentrate the reaction system under reduced pressure, add 5 mL of dichloromethane and 1 mL of triethylamine, and concentrate under reduced pressure to obtain crude Intermediate 2 (460 mg).

[0333] LCMS m / z = 318.3 [M+1] + 。

[0334] Preparation of Intermediate 3:

[0335]

[0336] First step: Preparation of 3-A

[0337] Under a nitrogen atmosphere, 1-C (7.00 g, 18.17 mmol) and 70 mL of tetrahydrofuran were added to a reaction flask. A solution of 2.5 mol / L n-butyllithium in n-hexane (14.50 mL, 36.25 mmol) was slowly added dropwise at -78 °C. After stirring at -78 °C for 1.5 h, carbon dioxide was displaced three times, and the reaction was carried out under a carbon dioxide balloon atmosphere while controlling the system temperature below -40 °C for 0.5 h. The reaction system was restored to room temperature, 20 mL of ethyl acetate was added, the pH was adjusted to 2 with 1 mol / L hydrochloric acid, and extraction was carried out with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1 - 2:1) to obtain 3-A (2.4 g, yield: 38%).

[0338] 1 H NMR (400 MHz, DMSO-d6) δ 7.42 (d, 1H), 6.64 (d, 1H), 4.00–3.82 (m, 3H), 3.23–3.09 (m, 1H), 3.08–2.90 (m, 1H), 2.90–2.77 (m, 1H), 2.76–2.60 (m, 3H), 2.05–1.90 (m, 1H), 1.65–1.50 (m, 1H), 1.49–1.35 (m, 9H).

[0339] Second step: Preparation of Intermediate 3

[0340] 3-A (2.4 g, 6.85 mmol), HATU (3.13 g, 8.23 mmol), diisopropylethylamine (2.66 g, 20.58 mmol) and 10 mL of DMF were added to a reaction flask. After stirring at room temperature for 10 min, 3-amino-2,6-piperidinedione hydrochloride (1.35 g, 8.20 mmol) was added, and the reaction was carried out at room temperature for 30 min. The reaction solution was poured into 100 mL of water, filtered, and the filter cake was washed with 50 mL of water. The filter cake was dried under reduced pressure to obtain Intermediate 3 (2.0 g, yield: 63%).

[0341] LCMS m / z = 461.2 [M+1] +

[0342] Preparation of Intermediate 4:

[0343]

[0344] Intermediate 4 was obtained using compound 2-B as the raw material with reference to the synthesis method of Intermediate 3.

[0345] LCMS m / z = 461.2 [M+1] +

[0346] Example 1: Preparation of Compound 1

[0347]

[0348] First step: Preparation of chiral isomers 1 and 2 of 1a

[0349] 1a was subjected to chiral resolution. The preparation conditions were as follows:

[0350] 1. Instrument: Waters 150Prep-SFC E; Chromatographic column: Chiralcel AD column.

[0351] 2. The sample was dissolved in acetonitrile and filtered through a 0.45 μm filter head to prepare a sample solution.

[0352] 3. Preparation chromatographic conditions: a. The mobile phase consisted of systems A and B: Mobile phase A: CO2; Mobile phase B: methanol; b. Isocratic elution, with the content of mobile phase B being 10%; c. Flow rate: 120 mL / min.

[0353] The chiral analysis conditions were as follows:

[0354] 1. Instrument: SHIMADZU LC-30AD; Chromatographic column: Chiralcel AD column.

[0355] 2. Analytical chromatographic conditions: a. The mobile phase consisted of systems A and B: Mobile phase A: CO2; Mobile phase B: methanol (containing 0.05% diethylamine); b. Isocratic elution, with the content of mobile phase B being 5 - 40%; c. Flow rate: 3 mL / min.

[0356] Elution time: Chiral isomer 1: 0.60 min, chiral isomer 2: 0.78 min.

[0357] Chiral isomers 1 and 2 of compound 1a are each one of the isomers of structures 1a-1 or 1a-2.

[0358] Second step: Preparation of 1b

[0359] The chiral isomer 1 of 1a (250 mg, 0.99 mmol) was dissolved in 5 mL of dichloromethane, DIPEA (383 mg, 2.97 mmol) was added, and trifluoromethanesulfonic anhydride (418 mg, 1.48 mmol) was slowly added under an ice-water bath. The reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the crude product 1b (0.50 g).

[0360] Compound 1b is one of the isomers of structure 1b-1 or 1b-2.

[0361] Step 3: Preparation of 1c

[0362] 1A (500 mg, 0.95 mmol) (synthesis method referring to WO2022111526) was dissolved in 10 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure, and the obtained crude product was dissolved in 5 mL of acetonitrile. DIPEA (588 mg, 4.55 mmol) and the above crude product 1b (0.50 g) were added, and the reaction was carried out at room temperature for 18 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to obtain 1c (0.35 g, yield: 56%).

[0363] LCMS m / z = 659.5 [M+1] +

[0364] Compound 1c is one of the isomers of structure 1c-1 or 1c-2.

[0365] Step 4: Preparation of 1d trifluoroacetate

[0366] 1c (200 mg, 0.30 mmol) was dissolved in 4 mL of dichloromethane, 4 mL of trifluoroacetic acid was added, and the reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the crude product of 1d trifluoroacetate (0.35 g).

[0367] Compound 1d is one of the isomers of structure 1d-1 or 1d-2.

[0368] Step 5: Preparation of compound 1

[0369] The above crude product of 1d trifluoroacetate (0.35 g) was dissolved in 5 mL of DMF, potassium bicarbonate (232 mg, 2.32 mmol) and compound 1B (synthesis method referring to WO2022111526) (634 mg, 1.48 mmol) were added respectively, and the reaction was carried out at 80 °C for 18 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to obtain compound 1 (10 mg, two-step yield calculated from compound 1c: 4%).

[0370] 1 1H NMR (400 MHz, CDCl3) δ 8.32 (d, 1H), 8.01 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 7.14–7.05 (m, 2H), 6.91–6.84 (m, 2H), 6.77 (d, 1H), 6.71–6.61 (m, 3H), 5.40–5.00 (m, 2H), 4.96 (s, 2H), 4.92–4.75 (m, 1H), 4.04 (s, 3H), 3.64–3.51 (m, 2H), 3.40 (s, 3H), 3.21–2.56 (m, 11H), 2.28–2.17 (m, 2H), 2.08–1.72 (m, 6H), 1.70–1.54 (m, 9H), 1.52–1.19 (m, 5H).

[0371] LCMS m / z = 950.6 [M+1] +

[0372] Compound 1 is one of the isomers of Compound 1-1 or 1-2.

[0373] Referring to the synthesis methods of other examples, the following compounds were obtained:

[0374]

[0375]

[0376] Example 3: Preparation of Compound 3

[0377]

[0378] First step: Preparation of 3b trifluoroacetate

[0379] Dissolve 3a (1.0 g, 4.18 mmol) in 10 mL of dichloromethane, add 4 mL of trifluoroacetic acid, and react at room temperature for 3 h. Concentrate the reaction system under reduced pressure to obtain the crude trifluoroacetate of 3b (1.1 g).

[0380] Second step: Preparation of 3c

[0381] 1B (700 mg, 1.63 mmol) was dissolved in 5 mL of DMF. Potassium bicarbonate (820 mg, 8.15 mmol) and the trifluoroacetate salt (0.83 g) of the above crude product 3b were added respectively, and the reaction was carried out at 70 °C for 3 h. The reaction system was cooled to room temperature, poured into 250 mL of water, filtered, and the filter cake was collected. The filter cake was washed with water (5 mL × 2), dissolved in 80 mL of DCM, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 3:1) to obtain 3c (710 mg, yield: 82%).

[0382] Step 3: Preparation of Compound 3

[0383] 3A (150 mg, 0.36 mmol) (the synthesis method refers to WO2023232133) was added to a reaction flask, 5 mL of dichloromethane and 2 mL of trifluoroacetic acid were added, and the reaction was carried out at room temperature for 5 h. The reaction system was concentrated under reduced pressure. 3c (191 mg, 0.36 mmol), sodium bicarbonate (121 mg, 1.44 mmol), and 5 mL of DMA were added respectively. After reacting at room temperature for 0.5 h, acetic acid (65 mg, 1.08 mmol) was added. After reacting at room temperature for 2 h, sodium triacetoxyborohydride (229 mg, 1.08 mmol) was added, and the reaction was carried out at room temperature for 16 h. Water (30 mL) was added to the reaction system, and it was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was passed through Pre-HPLC (instrument and preparation column: using SHIMADZU LC-20AP preparative liquid phase, the preparation column model is C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The acetonitrile solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile. Gradient elution method: Acetonitrile was eluted from 63% to 93% (elution time 15 min), and the compound 3 was obtained by lyophilization (150 mg, yield: 50%).

[0384] 11H NMR (400 MHz, CDCl3) δ 8.29 (d, 1H), 7.87 (s, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 7.11–7.06 (m, 2H), 6.90–6.84 (m, 2H), 6.74–6.68 (m, 1H), 6.66 (d, 1H), 6.49 (d, 1H), 4.93 (s, 2H), 4.04 (s, 3H), 3.83–3.69 (m, 5H), 3.66–3.56 (m, 1H), 3.14–3.00 (m, 1H), 2.98–2.90 (m, 1H), 2.90–2.57 (m, 7H), 2.29–2.14 (m, 2H), 2.13–2.01 (m, 2H), 1.99–1.84 (m, 2H), 1.80–1.58 (m, 14H).

[0385] LCMS m / z = 832.5 [M+1] +

[0386] The following compound was synthesized by referring to the synthesis methods of other examples:

[0387]

[0388] Example 5: Preparation of Compound 5 Trifluoroacetate

[0389]

[0390] First step: Preparation of 5b Trifluoroacetate

[0391] Dissolve 5a (1.0 g, 3.92 mmol) in 10 mL of dichloromethane, add 4 mL of trifluoroacetic acid, and react at room temperature for 3 h. Concentrate the reaction system under reduced pressure to obtain the crude product of 5b trifluoroacetate (1.1 g).

[0392] Second step: Preparation of 5c

[0393] Dissolve 1B (651 mg, 1.52 mmol) in 10 mL of DMF, add potassium bicarbonate (760 mg, 7.60 mmol) and the above-mentioned crude product of 5b trifluoroacetate (0.82 g) respectively, and react at 70 °C for 3 h. Cool the reaction system to room temperature, pour it into 250 mL of water, filter, collect the filter cake, wash the filter cake with water (5 mL × 2), dissolve the filter cake with 80 mL of DCM, dry it over anhydrous sodium sulfate, concentrate it under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2:1) to obtain 5c (750 mg, yield: 90%).

[0394] Third step: Preparation of 5d

[0395] 5c (301 mg, 0.55 mmol) was dissolved in 8 mL of DCM and 2 mL of acetonitrile, and molecular sieve (0.5 g), NMO (130 mg, 1.10 mmol), and TPAP (39 mg, 0.11 mmol) were added respectively. The reaction was carried out at room temperature for 3 h. The reaction system was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to obtain 5d (190 mg, yield: 64%). Molecular sieve (0.5 g), NMO (130 mg, 1.10 mmol), and TPAP (39 mg, 0.11 mmol) were added respectively. The reaction was carried out at room temperature for 3 h. The reaction system was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to obtain 5d (190 mg, yield: 64%).

[0396] LCMS m / z = 545.4 [M+1] +

[0397] Step 4: Preparation of compound 5 trifluoroacetate

[0398] 4A (200 mg, 0.47 mmol) was added to a 50 mL single-necked flask, and dichloromethane (5 mL) and trifluoroacetic acid (2 mL) were added. The reaction was carried out at room temperature for 5 h. The reaction system was concentrated under reduced pressure, 5 mL of DMA, 5d (190 mg, 0.35 mmol), and sodium bicarbonate (118 mg, 1.40 mmol) were added. After stirring at room temperature for 0.5 h, acetic acid (63 mg, 1.05 mmol) was added. After reacting at room temperature for 2 h, sodium triacetoxyborohydride (220 mg, 1.05 mmol) was added, and the reaction was carried out at room temperature for 16 h. Water (30 mL) was added to the reaction system, and it was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (dichloromethane / methanol (v / v) = 12:1) to obtain the trifluoroacetate of compound 5 (120 mg).

[0399] 1 H NMR (400 MHz, CDCl3) δ 8.43–8.34 (m, 1H), 8.26–8.20 (m, 1H), 7.43 (d, 1H), 7.30 (d, 1H), 7.16–7.07 (m, 2H), 6.94–6.84 (m, 3H), 6.78 (t, 1H), 6.50 (d, 1H), 5.01 (s, 2H), 4.04 (s, 3H), 3.88–3.62 (m, 7H), 3.57–3.45 (m, 2H), 3.39–3.27 (m, 1H), 3.24–3.06 (m, 2H), 2.94–2.72 (m, 4H), 2.71–2.53 (m, 3H), 2.33–2.11 (m, 4H), 2.06–1.98 (m, 1H), 1.80–1.56 (m, 13H).

[0400] LCMS m / z = 846.6 [M+1]+

[0401] Example 6: Preparation of Compound 6 Trifluoroacetate

[0402]

[0403] First Step: Preparation of 6c

[0404] Dissolve 6a (2.33 g, 10.00 mmol) and 6b (1.91 g, 11.99 mmol) in 80 mL of 1,2-dichloroethane, add acetic acid (0.90 g, 14.98 mmol), react at room temperature for 2 h, then add sodium triacetoxyborohydride (4.22 g, 19.89 mmol), and react at room temperature for 16 h. Slowly add 100 mL of saturated sodium bicarbonate aqueous solution to the system, separate the layers, extract the aqueous phase with dichloromethane (80 mL × 3), combine the organic phases, wash the organic phase with 100 mL of water, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2:1) to obtain 6c (3.5 g, yield: 93%).

[0405] Second Step: Preparation of 6d

[0406] Dissolve 6c (3.5 g, 9.30 mmol) in 40 mL of methanol, add 10% Pd / C (1.0 g), and react at room temperature for 18 h under a hydrogen balloon atmosphere. Filter the reaction system, concentrate the filtrate under reduced pressure to obtain 6d (2.2 g, yield: 98%).

[0407] Third Step: Preparation of 6e

[0408] Dissolve 1B (500 mg, 1.17 mmol) in 10 mL of DMF, add potassium bicarbonate (590 mg, 5.85 mmol) and 6d (0.42 g, 1.75 mmol) respectively, and react at 70 °C for 3 h. Cool the reaction system to room temperature, pour it into 60 mL of water, filter, collect the filter cake, wash the filter cake with water (5 mL × 2), dissolve the filter cake with 80 mL of DCM, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to obtain 6e (490 mg, yield: 66%).

[0409] Fourth Step: Preparation of 6f Trifluoroacetate

[0410] Dissolve 6e (360 mg, 0.57 mmol) in 5 mL of DCM, add 2 mL of trifluoroacetic acid, and react at room temperature for 3 h. Concentrate the system under reduced pressure to obtain the crude product of 6f trifluoroacetate (480 mg).

[0411] LCMS m / z = 588.4 [M+1] +

[0412] The trifluoroacetate of compound 6 was obtained from the trifluoroacetate of the above-mentioned crude product 6f and 4A as raw materials with reference to the synthesis method of Example 5.

[0413] 1 H NMR (400 MHz, CDCl3) δ 8.41–8.28 (m, 2H), 7.43 (d, 1H), 7.29 (d, 1H), 7.15–7.05 (m, 2H), 6.90–6.85 (m, 2H), 6.84–6.81 (m, 1H), 6.81–6.75 (m, 1H), 6.56–6.41 (m, 1H), 5.04–4.93 (m, 4H), 4.03 (s, 3H), 3.88–3.65 (m, 3H), 3.61–3.26 (m, 6H), 3.07–2.57 (m, 12H), 2.44–2.31 (m, 1H), 2.29–2.08 (m, 6H), 2.06–1.89 (m, 3H), 1.80–1.66 (m, 3H), 1.65–1.52 (m, 6H).

[0414] LCMS m / z = 889.4 [M+1] +

[0415] The following compounds were obtained with reference to the synthesis methods of other examples:

[0416]

[0417] Example 8: Preparation of Compound 8

[0418]

[0419] First step: Preparation of 8b

[0420] 8a (3.0 g, 9.94 mmol) and methyl 5-chloropyrimidine-2-carboxylate (2.06 g, 11.93 mmol) were dissolved in 40 mL of DMSO. Potassium phosphate (6.33 g, 29.82 mmol), pyridine-2-carboxylic acid (0.37 g, 2.98 mmol), and copper(I) iodide (0.57 g, 2.98 mmol) were added respectively. The reaction was carried out at 100 °C for 3 h under a nitrogen atmosphere. The reaction system was cooled to room temperature, 80 mL of water was slowly added to the system, and it was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed with water (100 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 5:1) to obtain 8b (1.6 g, yield: 37%).

[0421] Step 2: Preparation of 8c

[0422] Dissolve 8b (1.6 g, 3.65 mmol) in 25 mL of THF and 5 mL of water, add lithium hydroxide monohydrate (0.31 g, 7.30 mmol), and react at room temperature for 18 h. Concentrate the reaction system under reduced pressure. Add 50 mL of water to the residue, adjust the pH to 3 with 2 mol / L hydrochloric acid, filter, dissolve the filter cake in 50 mL of DCM, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 8c (1.5 g, yield: 97%).

[0423] LCMS m / z = 424.1 [M+1] +

[0424] Step 3: Preparation of 8d

[0425] Dissolve 8c (300 mg, 0.71 mmol) and 7-azaspiro[3.5]nonan-2-one hydrochloride (150 mg, 0.85 mmol) in 8 mL of DCM, add HATU (403 mg, 1.06 mmol) and DIPEA (280 mg, 2.13 mmol) respectively, and react at room temperature for 18 h. Concentrate the reaction system under reduced pressure. Purify the crude product by silica gel column chromatography (dichloromethane / ethyl acetate (v / v) = 2:1) to obtain 8d (380 mg, yield: 98%).

[0426] LCMS m / z = 545.2 [M+1] +

[0427] Compound 8 was obtained from compound 8d and 3A as starting materials with reference to the synthesis method of Example 3.

[0428] 1 1H NMR (400 MHz, CDCl3) δ 8.54–8.48 (m, 2H), 8.22–8.15 (m, 1H), 7.46–7.42 (m, 1H), 7.37–7.32 (m, 1H), 7.26–7.22 (m, 2H), 7.07–7.00 (m, 2H), 6.83–6.75 (m, 1H), 6.54–6.47 (m, 1H), 4.06 (s, 3H), 3.89–3.64 (m, 5H), 3.55–3.46 (m, 2H), 3.44–3.21 (m, 4H), 2.89–2.59 (m, 5H), 2.50–2.34 (m, 3H), 2.34–2.12 (m, 4H), 2.08–1.99 (m, 1H), 1.78–1.62 (m, 11H).

[0429] LCMS m / z = 846.3 [M+1]+

[0430] Referring to the synthesis methods of other embodiments, the following compounds were obtained:

[0431]

[0432] Example 10: Preparation of Compound 10

[0433]

[0434] First step: Preparation of 10a

[0435] 8c (301 mg, 0.71 mmol) and 4 - dimethoxymethylpiperidine (135 mg, 0.85 mmol) were dissolved in 8 mL of DCM. HATU (403 mg, 1.06 mmol) and DIPEA (275 mg, 2.13 mmol) were added, and the reaction was carried out at room temperature for 18 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel chromatography column (dichloromethane / ethyl acetate (v / v) = 2:1) to obtain 10a (330 mg, yield: 82%).

[0436] LCMS m / z = 565.2 [M + 1] +

[0437] Compound 10 was obtained from 10a and 3A as raw materials, referring to the synthesis method of Example 6, and was obtained after neutral preparation (water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile) and lyophilization.

[0438] 1 H NMR (400 MHz, CDCl3) δ 8.51 (s, 2H), 8.26–8.11 (m, 1H), 7.44 (d, 1H), 7.35 (d, 1H), 7.26–7.20 (m, 2H), 7.07–7.00 (m, 2H), 6.83–6.74 (m, 1H), 6.51 (d, 1H), 4.84–4.69 (m, 1H), 4.10–4.02 (m, 3H), 3.86–3.74 (m, 2H), 3.72–3.52 (m, 4H), 3.46–3.35 (m, 1H), 3.15–2.97 (m, 2H), 2.96–2.74 (m, 5H), 2.72–2.54 (m, 3H), 2.34–2.13 (m, 3H), 2.08–1.86 (m, 3H), 1.80–1.60 (m, 7H), 1.55–1.31 (m, 2H).

[0439] LCMS m / z = 820.3 [M + 1] +

[0440] Refer to the synthesis methods of other embodiments to obtain the following compounds:

[0441]

[0442] Example 12: Preparation of Compound 12 Trifluoroacetate

[0443]

[0444] First step: Preparation of 12a

[0445] Dissolve 6b (5.0 g, 31.40 mmol) in 50 mL of DCM and 50 mL of water, add sodium carbonate (9.98 g, 94.20 mmol), and slowly add a DCM solution (30 mL) of bromocyan (4.32 g, 40.82 mmol) dropwise under an ice bath. React at room temperature for 18 h. Separate the reaction system by liquid-liquid extraction, extract the aqueous phase with DCM (50 mL × 2), combine the organic phases, wash the organic phase with water (50 mL × 2), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 2:1) to obtain 12a (5.6 g, yield: 97%).

[0446] Second step: Preparation of 12b

[0447] Dissolve 12a (5.5 g, 29.89 mmol) in 40 mL of isopropanol and 10 mL of water, add sodium bicarbonate (7.52 g, 89.55 mmol) and hydroxylamine hydrochloride (6.22 g, 89.55 mmol), and react at 80 °C for 6 h. Concentrate the reaction system under reduced pressure, stir the crude product with 200 mL of a mixed solvent (dichloromethane / methanol (v / v) = 10:1), filter, collect the filtrate, and concentrate the filtrate under reduced pressure to obtain 12b (6.1 g, yield: 94%).

[0448] LCMS m / z = 218.1 [M+1] +

[0449] Third step: Preparation of 12c

[0450] Dissolve 8c (500 mg, 1.18 mmol) and 12b (256 mg, 1.18 mmol) in 8 mL of DMF, add HOBt (320 mg, 2.36 mmol), EDCI (452 mg, 2.36 mmol), and DIPEA (760 mg, 5.90 mmol) respectively, and react at 45 °C for 18 h. Cool the system to room temperature, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (dichloromethane / methanol (v / v) = 20:1) to obtain 12c (250 mg, yield: 35%).

[0451] The trifluoroacetate of Compound 12 was obtained by referring to the synthesis method of Example 6, using 12c and 12A (synthesis method reference: WO2024026081) as raw materials.

[0452] 1 H NMR (400 MHz, CDCl3) δ 8.52 (s, 2H), 8.45 (s, 1H), 7.51 (d, 1H), 7.44 (d, 1H), 7.34 (d, 1H), 7.23 (d, 2H), 7.03 (d, 2H), 6.93–6.86 (m, 1H), 6.61 (s, 1H), 4.81–4.70 (m, 1H), 4.31–4.21 (m, 1H), 4.06 (s, 3H), 3.93 (s, 3H), 3.64–3.55 (m, 1H), 3.35–3.21 (m, 4H), 3.13–3.04 (m, 1H), 3.03–2.92 (m, 1H), 2.90–2.82 (m, 1H), 2.75–2.61 (m, 5H), 2.54–2.44 (m, 1H), 2.41–2.29 (m, 3H), 1.97–1.86 (m, 1H), 1.83–1.75 (m, 1H), 1.68 (s, 6H), 1.36–1.23 (m, 3H).

[0453] Referring to the synthesis methods of other examples, the following compounds were obtained:

[0454]

[0455] Example 17: Preparation of Compound 17

[0456]

[0457] Dissolve 17a (77 mg, 0.15 mmol) (synthesis method reference: WO2023056423) in 5 mL of DMA, add 17A (48 mg, 0.15 mmol) (synthesis method reference: WO2023232133), after reacting at room temperature for 1 h, add sodium triacetoxyborohydride (63 mg, 0.30 mmol), and react at room temperature for 15 h. Concentrate the reaction system under reduced pressure, and purify the crude product by silica gel column chromatography (dichloromethane / methanol (v / v) = 15:1) to obtain Compound 17 (10 mg, yield: 8%).

[0458] 11H NMR (400 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.61 (d, 1H), 7.50 (dd, 2H), 7.22–7.08 (m, 3H), 6.89–6.75 (m, 3H), 6.58 (d, 1H), 5.71 (s, 3H), 5.07 (s, 2H), 4.38–4.27 (m, 2H), 3.82–3.76 (m, 1H), 3.68–3.61 (m, 1H), 2.93–2.83 (m, 2H), 2.77–2.73 (m, 2H), 2.72–2.56 (m, 4H), 2.48–2.42 (m, 2H), 2.18–1.99 (m, 3H), 1.94–1.83 (m, 2H), 1.64–1.51 (m, 7H).

[0459] LCMS m / z = 816.2 [M+1] +

[0460] The following compound was synthesized by referring to the synthesis methods of other examples:

[0461]

[0462] Example 19: Preparation of Compound 19 Trifluoroacetate

[0463]

[0464] First step: Preparation of 19b

[0465] Dissolve 19a (9.0 g, 42.6 mmol) in 50 mL of ultra-dry THF and 50 mL of DMSO. Add 60% sodium hydride (5.1 g, 127.8 mmol) under an ice bath. After reacting at 0 °C for 30 min, add 3-bromopiperidine-2,6-dione (12.3 g, 64.0 mmol) and potassium iodide (5.7 g, 34.1 mmol), and react at room temperature for 12 h. Add 200 mL of ethyl acetate to the reaction system under an ice bath, add 400 mL of water, separate the layers, extract the aqueous phase with ethyl acetate (200 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1 - 0:1) to obtain 19b (11 g, yield: 80%).

[0466] LCMS m / z = 322.0 [M+1] +

[0467] Second step: Preparation of 19c

[0468] Dissolve 19b (3.0 g, 9.31 mmol) and 19B (3.75 g, 13.96 mmol) in 50 mL of dry 1,4-dioxane, add XPhos Pd G3 (1.58 g, 1.86 mmol) and cesium carbonate (9.10 g, 27.93 mmol), displace nitrogen three times, and react at 90 °C for 3 h. Cool the reaction solution to room temperature, add 50 mL of ethyl acetate under an ice bath, add 50 mL of saturated aqueous ammonium chloride solution, separate the layers, extract the aqueous phase with ethyl acetate (50 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1 - 0:1) to obtain 19c (3.3 g, yield: 70%).

[0469] LCMS m / z = 510.5 [M+1] +

[0470] Step 3: Preparation of 19d hydrochloride

[0471] Dissolve 19c (3.3 g, 6.48 mmol) in 5 mL of dichloromethane, add 4 mol / L hydrochloric acid 1,4-dioxane solution (15 mL), and react at room temperature for 3 h. Concentrate the reaction system under reduced pressure to obtain the crude product of 19d hydrochloride (5.2 g).

[0472] LCMS m / z = 410.5 [M+1] +

[0473] Step 4: Preparation of 19e

[0474] Dissolve the above crude product of 19d hydrochloride (400 mg) in 10 mL of DMA, add 0.3 mL of DIPEA, react at room temperature for 10 min, then add 19C (156 mg, 0.73 mmol), react at room temperature for 3 h, then add sodium triacetoxyborohydride (210 mg, 0.98 mmol), and react at room temperature for 16 h. Add 80 mL of water and 50 mL of ethyl acetate to the reaction system, separate the layers, extract the aqueous phase with ethyl acetate (50 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (dichloromethane / methanol (v / v) = 1:0 - 10:1) to obtain 19e (300 mg, two-step yield calculated from compound 19c: 99%).

[0475] LCMS m / z = 607.4 [M+1] +

[0476] Step 5: Preparation of 19f trifluoroacetate

[0477] Dissolve 19e (300 mg, 0.49 mmol) in 5 mL of dichloromethane, add 5 mL of trifluoroacetic acid, and react at room temperature for 3 h. Concentrate the reaction system under reduced pressure to obtain the trifluoroacetate salt of crude 19f (1.0 g).

[0478] LCMS m / z = 507.4 [M+1] +

[0479] The trifluoroacetate salt of compound 19 was obtained by freeze-drying after acidic preparation (water (containing 0.1% TFA) / acetonitrile) using the above-mentioned trifluoroacetate salt of crude 19f and 1B as raw materials with reference to the synthesis method of Example 1.

[0480] 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.86 (s, 1H), 8.36 (d, 1H), 7.58 (dd, 4H), 7.18 (d, 2H), 6.94 (d, 2H), 6.69 (d, 1H), 5.81–5.67 (m, 1H), 4.97 (s, 2H), 4.73–4.63 (m, 2H), 3.96 (s, 3H), 3.73–3.62 (m, 2H), 3.62–3.51 (m, 2H), 3.07–2.57 (m, 10H), 2.49–2.38 (m, 4H), 2.29–2.19 (m, 1H), 2.19–2.09 (m, 1H), 2.00–1.77 (m, 6H), 1.68–1.39 (m, 12H), 1.27–1.06 (m, 2H).

[0481] LCMS m / z = 898.6 [M+1] +

[0482] Example 20: Preparation of the trifluoroacetate salt of compound 20

[0483]

[0484] First step: Preparation of 20b

[0485] 20a (3.0 g, 6.0 mmol) (the synthesis method refers to WO2022261250) and 19B (1.93 g, 7.2 mmol) were dissolved in 50 mL of dry 1,4-dioxane. XPhos Pd G3 (0.51 g, 0.6 mmol) and cesium carbonate (5.86 g, 18.0 mmol) were added. Nitrogen was displaced three times, and the reaction was carried out at 100 °C for 20 h. The reaction solution was cooled to room temperature, 100 mL of ethyl acetate and 200 mL of water were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 - 1:1) to obtain 20b (3.2 g, yield: 78%).

[0486] LCMS m / z = 688.4 [M+1] +

[0487] Step 2: Preparation of 20c

[0488] 20b (2.0 g, 2.91 mmol) was dissolved in 20 mL of methanol. 10% palladium on carbon (1.0 g) was added. Hydrogen was displaced three times, and the reaction was carried out at room temperature under a hydrogen balloon atmosphere for 16 h. The reaction system was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 20c (1.8 g).

[0489] LCMS m / z = 510.2 [M+1] +

[0490] The trifluoroacetate of compound 20 was obtained using the above-mentioned crude product 20c and 1B as raw materials with reference to the synthesis method of Example 19.

[0491] 11H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.36 (d, 1H), 7.61 (d, 1H), 7.56 (d, 1H), 7.53 (d, 1H), 7.18 (d, 2H), 7.00–6.90 (m, 4H), 6.69 (d, 1H), 4.98 (s, 2H), 4.73–4.59 (m, 2H), 4.33–4.21 (m, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.85–3.82 (m, 2H), 3.57–3.54 (m, 2H), 3.04–2.84 (m, 6H), 2.83–2.73 (m, 2H), 2.65–2.61 (m, 1H), 2.55–2.45 (m, 1H), 2.38–2.24 (m, 1H), 2.24–2.08 (m, 2H), 1.97–1.86 (m, 2H), 1.85–1.76 (m, 4H), 1.63 (s, 6H), 1.59–1.47 (m, 2H), 1.46–1.31 (m, 4H), 1.22–1.10 (m, 2H).

[0492] LCMS m / z = 898.6 [M+1] +

[0493] Example 27: Preparation of Compound 27 Trifluoroacetate

[0494]

[0495] First step: Preparation of 27b

[0496] Dissolve 27a (12 g, 49.9 mmol) in 50 mL of DMF, add 6b (9.5 g, 59.9 mmol) and DIPEA (12.9 g, 99.8 mmol) respectively, and react at 80 °C for 16 h. Cool the reaction system to room temperature, add 400 mL of water and 100 mL of ethyl acetate, separate the layers, extract the aqueous phase with ethyl acetate (100 mL × 2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:0 - 4:1) to obtain 27b (16 g, yield: 88%).

[0497] LCMS m / z = 364.0 [M+1] +

[0498] Second step: Preparation of 27c

[0499] 27b (2.9 g, 8.0 mmol) and 27A (2.0 g, 6.6 mmol) were dissolved in 50 mL of dry 1,4-dioxane. CuI (1.5 g, 8 mmol), N,N-dimethylglycine hydrochloride (1.1 g, 8 mmol), and cesium carbonate (7.8 g, 23.9 mmol) were added respectively. The mixture was purged with nitrogen three times and reacted at 90 °C for 16 h. The reaction solution was cooled to room temperature, 100 mL of saturated ammonium chloride solution and 100 mL of ethyl acetate were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 - 4:1) to obtain 27c (1.0 g, yield: 28%).

[0500] LCMS m / z = 537.1 [M+1] +

[0501] The trifluoroacetate of compound 27 was obtained using 27c and 20d as starting materials with reference to the synthesis method of Example 12.

[0502] 1 H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.30 (s, 2H), 7.62 (d, 1H), 7.58 (d, 1H), 7.55–7.47 (m, 1H), 7.24–7.18 (m, 2H), 7.00–6.84 (m, 4H), 4.66–4.54 (m, 2H), 4.30–4.21 (m, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.87–3.78 (m, 2H), 3.61–3.50 (m, 2H), 3.03–2.58 (m, 10H), 2.35–2.24 (m, 1H), 2.22–2.08 (m, 2H), 1.96–1.73 (m, 6H), 1.63 (s, 6H), 1.58–1.26 (m, 6H), 1.25–1.11 (m, 2H).

[0503] LCMS m / z = 884.2 [M+1] +

[0504] The following compounds were obtained with reference to the synthesis methods of other examples:

[0505]

[0506]

[0507] Example 34: Preparation of Compound 34

[0508]

[0509] Step 1: Preparation of 34a

[0510] Dissolve 27A (10 g, 33.14 mmol) in 150 mL of dichloromethane, add triethylamine (6.71 g, 66.28 mmol), and slowly add trifluoromethanesulfonic anhydride (11.22 g, 39.77 mmol) dropwise at 0 °C. Restore to room temperature and react for 3 h. Add 200 mL of water to the reaction system, extract with dichloromethane (150 mL × 3), combine the organic phases, wash the organic phase with 200 mL of water, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the obtained crude product by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain 34a (9.5 g, yield: 66%).

[0511] Step 2: Preparation of 34b

[0512] Dissolve 34a (9.5 g, 21.90 mmol) and bis(pinacolato)diboron (8.34 g, 32.85 mmol) in 100 mL of 1,4-dioxane, add potassium acetate (6.45 g, 65.70 mmol), and under a nitrogen atmosphere, add Pd(dppf)Cl2 dichloromethane complex (1.79 g, 2.19 mmol), and react at 100 °C for 18 h. Cool the reaction system to room temperature, add 200 mL of DCM, stir for 10 min, filter, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 3:1) to obtain 34b (8.5 g, yield: 94%).

[0513] Step 3: Preparation of 34c

[0514] Dissolve 34b (9.02 g, 21.90 mmol) and 6-bromo-2-chloroquinazoline (8.0 g, 32.85 mmol) in 120 mL of 1,4-dioxane and 25 mL of water, add cesium carbonate (18.99 g, 58.29 mmol), and under a nitrogen atmosphere, add Pd(PPh3)2Cl2 (1.36 g, 1.94 mmol), and react at 80 °C for 4 h. Cool the reaction system to room temperature, add 800 mL of DCM, stir for 10 min, filter, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (PE:EA (v / v) = 4:1) to obtain 34c (2.4 g, yield: 24%).

[0515] Step 4: Preparation of 34e

[0516] Dissolve 34d (0.38 g, 0.91 mmol) (synthesis reference: WO2023232133) and 34A (0.36 g, 1.82 mmol) separately in 6 mL of DMAc. Add 0.26 mL of glacial acetic acid, stir at room temperature for 2 h, then add sodium triacetoxyborohydride (0.58 g, 2.73 mmol), and react at room temperature for 16 h. Add 30 mL of water to the reaction solution, extract with dichloromethane (50 mL × 3), combine the organic phases, wash the organic phase with 50 mL of water, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the obtained crude product by silica gel column chromatography (dichloromethane / methanol (v:v) = 15:1) to obtain 34e (160 mg, yield: 29%).

[0517] Compound 34 was prepared from 34e and 34c as raw materials with reference to the synthesis method of Example 19, and obtained after neutral preparation (water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile) and freeze-drying.

[0518] 1 H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 9.22 (s, 1H), 8.13–8.09 (m, 1H), 8.08–8.01 (m, 1H), 7.73–7.67 (m, 3H), 7.63 (d, 1H), 7.55 (d, 1H), 7.36 (d, 2H), 6.78 (d, 1H), 6.60 (d, 1H), 4.93–4.83 (m, 2H), 3.97 (s, 3H), 3.80 (dd, 1H), 3.73–3.64 (m, 1H), 3.02–2.79 (m, 7H), 2.77–2.63 (m, 3H), 2.62–2.51 (m, 3H), 2.21–2.06 (m, 5H), 2.03–1.93 (m, 2H), 1.90–1.79 (m, 3H), 1.73–1.65 (m, 8H), 1.63–1.32 (m, 5H), 1.14–1.01 (m, 2H).

[0519] LCMS m / z = 909.6 [M + 1] +

[0520] The following compounds were obtained with reference to the synthesis methods of other examples:

[0521]

[0522]

[0523] Degradation experiment of AR splice mutant 7 (AR-V7) in 22RV1 cells in biological test example

[0524] The prostate cancer cell line 22RV1 was purchased from ATCC. The cell culture medium was 1640 + 10% FBS, and the cells were cultured in an incubator at 37°C with 5% CO2. On the first day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the appropriate concentration with 1% css-FBS phenol red-free medium and plated. Each well of a 6-well plate was seeded with 1 mL of cell suspension containing 300,000 cells per well. The next day, 1% css-FBS phenol red-free medium containing the test compound was added. One well was added with 1% css-FBS phenol red-free medium containing 0.2% DMSO as a DMSO vehicle control. The 6-well plate was cultured in an incubator at 37°C with 5% CO2. After 24 hours, the cells were digested with trypsin and collected in 1.5 mL centrifuge tubes. 15 μL of RIPA lysis buffer (containing 1X protease inhibitor cocktail) was added to each well, and the cells were lysed on ice for 15 minutes. Then, the samples were centrifuged at 12,000 g at 4°C for 10 minutes. The supernatant protein samples were collected, and protein quantification was performed using the BCA method. To detect AR-V7 using an automated protein expression quantitative analysis, the experimental procedure was as follows: the concentration of the test protein sample was diluted to 2 mg / mL. 4 μL of the diluted protein sample was added to 1 μL of 5× Master Mix (provided by the kit), and the prepared sample was denatured at 95°C for 5 minutes and then placed on ice for use. The primary antibodies, AR V7 (CST, 19672S) and β-actin (CST, 3700), were diluted using Antibody Diluent II (provided by the kit) at dilution ratios of 1:10 and 1:500, respectively. The secondary antibody was a 1:1 mixture of goat anti-mouse and goat anti-rabbit secondary antibodies, and the chromogenic solution was a 1:1 mixture of Lumino-S and Peroxide. According to the kit instructions, the prepared reagents were added to the detection plate in sequence and then detected using the instrument. For Western blot band processing, the automated protein expression quantitative analysis software "Compass for SW" was used to automatically simulate Western blot bands based on the signal values. According to Equation (1), the degradation rate of AR-V7(1) relative to the vehicle control at different drug concentrations was calculated. Where AR-V7 compound is the relative peak area of AR-V7 in the drug-treated group, and AR-V7 solvent is the relative peak area of AR-V7 in the vehicle control group.

[0525] AR-V7% = (1 - AR-V7 compound / AR-V7 solvent ) × 100% Equation (1)

[0526] DC 50Calculation: Processed according to Equation (1), calculated using Graphpad software, and analyzed using the log(inhibitor) vs. response–Variable slope (four parameters) function to obtain the compound concentration DC when the AR-V7 degradation rate is 50%. 50 value.

[0527] Conclusion: The compound of the present invention has a good degradation effect on AR-V7 in prostate cancer cell line 22RV1.

[0528] 2. Experiment on inhibiting the proliferation of 22RV1 cells

[0529] Prostate cancer cell line 22RV1 was purchased from ATCC. The cell culture medium was RPMI 1640 + 10% FBS, and the cells were cultured in an incubator at 37 °C with 5% CO2. On the first day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the corresponding concentration with 1% css-FBS phenol red-free medium and plated at 2000 cells / well and incubated overnight. On the second day, compounds at different concentrations were added, and the cells were incubated in the incubator for another 7 days. After the culture, according to the operation instructions of the CellTiter-Glo kit (Promega, G7573), 50 μL of CellTiter-Glo reagent pre-melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and after standing at room temperature for 10 minutes, the fluorescence signal value was measured with a microplate reader (PHERAstar FSX). The results were processed according to Equation (2) to calculate the inhibition rate of each concentration of the compound, and using origin9.2 software, the IC 50 value when the compound inhibition rate was 50% was calculated. Where RLU compound is the reading of the drug treatment group, and RLU control is the average value of the DMSO solvent control group.

[0530] Inhibition % = [1 - RLU compound / RLU control × 100% Equation (2)

[0531] Conclusion: The compounds of the present invention, such as the compounds in the examples, have an inhibitory effect on prostate cancer cell line 22RV1. Specifically, the trifluoroacetate salts of compound 6 and compound 16 inhibit the IC 50 value of 22RV1 cells < 1 μM.

Claims

1. A compound or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: The compound is selected from the compounds represented by general formula (I), BLK(I); L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; Ak1, Ak2, Ak3, Ak4, 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 by 1 to 2 groups selected from deuterium, halogen, =O, OH, CN, C 1-4 Alkyl or C 3-6 substituted by a cycloalkyl substituent; q is selected from 0, 1, 2 or 3; R L Each independently selected from H or C 1-4 alkyl; Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-7 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl; B is selected from The ring where the representative is located is an aromatic ring or a non-aromatic ring; W1 is independently selected from -NR w1 -、-(CR w2 R w3 ) r -; V1 is independently selected from a bond, -O-, -S-, -(CR v2 R v3 ) t -、-NR v1 -、-NR v1 C(=O)-, -C(=O)NR v1 -、-NR v1 S(=O)2-、-NR v1 S(=O)2NR v1 -, its right side is directly connected to V2; V2 is independently selected from a bond, -O-, -(CR v2 R v3 ) t -; B3 is independently selected from 5-10 membered heteroaryl or C 6-10 Aryl; B4 are each independently selected from a bond, C 3-12 carbocyclic group, 4-13 membered heterocyclic group, 5-6 membered heteroaryl group, the B4 is optionally substituted by 1 to 4 R b4 replaced by; B5 is selected from C 3-12 carbocyclic group, 4-13 membered heterocyclic group, 5-10 membered heteroaryl group, said B5 is optionally substituted by 1 to 4 R b5 replaced by; X1 is selected from O, N, NH, C(=O), CR x1 or CR x1 R x1 ; X2 is selected from O, N, NH, C(=O), CR x2 or CR x2 R x2 ; X3 is selected from O, N, NH, C(=O), CR x3 or CR x3 R x3 ; r, t are each independently selected from 1, 2, 3 or 4; m1, m2, m3 are each independently selected from 0, 1, 2, 3 or 4; R w1 or R v1 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent; R v2 , R v3 , R w2 or R w3 Each independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkenyl, C 1-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl is optionally substituted with 1 to 4 deuterium, halogen, OH, =O, NH2, CN, NO2, C 1-4 Alkyl, C 1-4 Alkoxy, halogen substituted C 1-4 Alkyl, C 3-6 substituted by a cycloalkyl substituent; Alternatively, R w2 With R w3 Together with the carbon atoms connected to them, they form C 3-6 A carbocyclic group or a 3- to 8-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R s replaced by; R x1 , R x2 , R x3 , R b1 , R b2 , R b4 Each independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-4 to 6 membered heterocyclic group, 5 to 6 membered heteroaryl, -OC 3-6 The alkylene, alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, heteroaryl group are optionally substituted by 1 to 4 R s replaced by; R b3 , R b5 Each independently selected from deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Carbocyclic group, -C 0-4 Alkylene-4 to 6 membered heterocyclic group, 5 to 6 membered heteroaryl, -OC 3-6 carbocyclic group, -O-4 to 6-membered heterocyclic group, -C(=O)N(C 1-4 alkyl)2, -S(=O)2NH2, -S(=O)2N(C 1-4 Alkyl)2, -S(=O)2C 1-4 Alkyl, -C(=O)NHC 1-4 Alkyl, -S(=O)2NHC 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -C(=O)C 3-6 Carbocyclic group, -NHC(=O)C 1-4 Alkyl, -NHS(=O)2C 1-4 Alkyl, the alkylene, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, heteroaryl are optionally substituted by 1 to 4 R s replaced by; K is selected from F1 is selected from N, NH, CH, CH2, CHR k1 NR k1 , CR k1 , C(=O), C(R k1 )2; F2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 NR k1 , CR k1 or C(R k1 )2; F6, F7, F8 are each independently selected from N, C, CH or CR k1 , and F6, F7, and F8 contain at most 2 N; G is selected from CH or N; E1 is selected from N or CH; E2 is selected from C, N or CH; Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q -; Q and G cannot directly form a nitrogen-nitrogen bond or a nitrogen-oxygen bond; R q Each independently selected from H or C 1-4 alkyl; R k1 Each independently selected from deuterium, halogen, OH, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R s replaced by; R L2 , R s Each independently selected from deuterium, halogen, OH, CN, =O, CF3, SF5, NO2, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, -C 0-4 Alkylene-4 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl group is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; p1 is independently selected from 0, 1 or 2.

2. The compound according to claim 1 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B3 are each independently selected from phenyl, 5-6 membered heteroaryl, benzo 4-6 Carbocyclic group, benzo 4-6 membered heterocyclic group, 5- and 5-membered heteroaryl group, 5- and 6-membered heteroaryl group, and 6- and 6-membered heteroaryl group; B4 is independently selected from a bond, a 4-7 membered heteromonocyclic group, a 4-12 membered heterocyclic group, a 5-13 membered heterospirocyclic group, a 7-12 membered heterobridged ring group, a C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-12 Spirocycloalkyl, C 5-12 A bridged cycloalkyl group, a phenyl group, a 5-6 membered heteroaryl group, wherein B4 is optionally substituted by 1 to 4 R b4 replaced by; B5 is selected from 4-7 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-12 Spirocycloalkyl, C 5-12 Bridged cycloalkyl, phenyl, 5-6 membered heteroaryl, benzo C 4-6 carbocyclic group, benzo 4-6 membered heterocyclic group, 5- and 5-membered heteroaryl group, 5- and 6-membered heteroaryl group, 6- and 6-membered heteroaryl group, wherein B5 is optionally substituted by 1 to 4 R b5 replaced by; R x1 , R x2 , R x3 , R b1 , R b2 , R b4 Each independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, -C 0-2 Alkylene-4 to 6 membered heterocyclic group, 5 to 6 membered heteroaryl, -OC 3-6 Cycloalkyl, -O-4 to 6 membered heterocyclic group, the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, heteroaryl group are optionally substituted by 1 to 4 R s replaced by; R b3 , R b5 Each independently selected from deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, -C 0-2 Alkylene-4 to 6 membered heterocyclic group, 5 to 6 membered heteroaryl, -OC 3-6 Cycloalkyl, -O-4 to 6-membered heterocyclic group, -C(=O)N(C 1-4 alkyl)2, -S(=O)2NH2, -S(=O)2N(C 1-4 Alkyl)2, -S(=O)2C 1-4 Alkyl, -C(=O)NHC 1-4 Alkyl, -S(=O)2NHC 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -C(=O)C 3-6 Cycloalkyl, -NHC(=O)C 1-4 Alkyl, -NHS(=O)2C 1-4 Alkyl, the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, heteroaryl are optionally substituted by 1 to 4 R s replaced by; R w1 or R v1 Each independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, NH2, CN, CF3, CHF2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent; Alternatively, R w2 , R w3 and the carbon atoms connected to the two together form a cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, oxetanyl, pyrrolidinyl, piperidinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl is optionally substituted by 1 to 4 deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R L is selected from H, methyl or ethyl; R q Each is independently selected from H, methyl, ethyl or isopropyl; Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 Substituted by one of the following groups: phenyl, pyridyl, pyrimidinyl, 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; s7 is selected from 1, 2 or 3; R L2 , R s Each independently selected from deuterium, halogen, OH, CN, =O, CF3, SF5, NO2, NH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, -C 0-2 Alkylene-4 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl group is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

3. The compound according to claim 2 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: W1 is independently selected from -NR w1 -、-CR w2 R w3 -、-(CR w2 R w3 )2-; V2 is independently selected from a bond, -O-, -CR v2 R v3 -; R w1 or R v1 is selected from H, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, NH2, CN, CF3, CHF2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent; R x1 , R x2 , R x3 , R b1 , R b2 , R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3 or optionally substituted by 1 to 4 R s substituted by one of the following groups: methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, pyrazolyl; R b3 , R b5 each independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3, -S(=O)2NH2, -S(=O)2CH3, -C(=O)N(CH3)2, -S(=O)2N(CH3)2, -C(=O)NHCH3, -S(=O)2NHCH3, -C(=O)CH3, -C(=O)cyclopropyl, -NHC(=O)CH3, -NHS(=O)2CH3, -NHS(=O)2CH2CH3 or optionally substituted by 1 to 4 R s substituted by one of the following groups: methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, pyrazolyl; R v2 , R v3 , R w2 or R w3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl is replaced by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 substituted by a cycloalkyl substituent; Alternatively, R w2 , R w3 and the carbon atoms connected to the two together form a cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, oxetanyl, pyrrolidinyl, piperidinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl is optionally substituted by 1 to 4 deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -CH(CH3)-, -CH2-, -C(CH3)2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH- or -NHC(=O)-; K is selected from Q is each independently 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); R k1 Each independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2; R L2 , R s Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

4. The compound according to claim 3 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B3 is each independently selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, benzimidazolyl, benzopyrazolyl, benzothiazolyl, benzoxazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, quinolyl, isoquinolyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, pyrrolopyrrolyl, pyrrolopyridinyl, pyrrolo pyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, oxazolopyridinyl, triazolopyridinyl, pyrazolopyridinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl, or pyrazinopyrazinyl; B4 is each independently selected from a bond, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, oxolanyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazine, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, thiadiazolyl, isothiazolyl, The B4 is optionally replaced by 1 to 4 R b4 replaced by; R1, R3, R5, R8 are each independently selected from 0, 1 or 2, and R1 and R8 on the same group are not 2 at the same time; r2 and r4 are each independently selected from 0 or 1; r6 is selected from 0, 1, 2 or 3; r7 is selected from 1, 2 or 3; B5 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azopentyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, oxolanyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, thiadiazolyl, isothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, quinolyl, isoquinolyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, pyrrolo pyrrolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, imidazopyrimidinyl, imidazopyridinyl, imidazopyrazinyl, imidazopyridazinyl, pyrazolopyridinyl, oxazolopyridinyl, triazolopyridinyl, pyrazolopyridinyl, pyrazolopyrazinyl, pyrimidopyridinyl, pyrimidopyrazinyl, pyrimidopyridazinyl, pyrimidopyridinyl, pyridopyrazinyl, pyridopyridazinyl, pyridazinopyrazinyl or pyrazinopyrazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, The B5 is optionally replaced by 1 to 4 R b5 replaced by; 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 deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl; K is selected from 5. The compound according to claim 4 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: W1 is independently selected from -NR w1 -、-CR w2 R w3 -; -V1-V2- are each independently selected from a bond, -CR v2 R v3 -、-O-、-S-、-NR v1 -、-NH-CR v2 R v3 -、-O-CR v2 R v3 -、-CR v2 R v3 -O-, -NH-C(=O)-; Selected from X1 is selected from O, N, NH, CR x1 ; X2 is selected from O, N, NH, CR x2 ; R x1 , R x2 , R x3 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, CD3, CF3, CHF2, CH2F, OCF3, OCH2F, OCD3, CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl; R w1 or R v1 is selected from H, CD3, CF3, CHF2, CH2F, methyl, ethyl, cyclopropyl, -CH2-cyclopropyl; R v2 , R v3 , R w2 or R w3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl is substituted with 1 to 3 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, methyl, ethyl, methoxy, cyclopropyl; Alternatively, R w2 , R w3 and the carbon atoms connected to the two together form a cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, oxolyl, pyrrolidinyl, piperidinyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl is optionally substituted with 1 to 3 substituents selected from deuterium, F, Cl, Br, OH, NH2, CN, methyl, ethyl, methoxy; R s Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, CHF2, CH2F, OCF3, OCH2F, OCHF2, CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl; Q is each independently selected from a bond, NH, N(CH3), O, S, NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3); L is selected from a bond, -Cy1-, -Cy1-Ak2-, -Ak1-Cy1-, -Ak1-, -Ak1-Cy1-Ak2-, -Cy1-Ak2-Cy2-, -Cy1-Cy2-Ak3-, -Ak1-Cy1-CH2-, -Ak1-Cy1-Cy2-, -Cy1-Ak2-Cy2-, -Cy1-Ak2-Cy2-Ak3-; preferably from a bond , -Cy1-CH2-, -Cy1-, -C(=O)-Cy1-, -CH2-Cy1-, -C(=O)-Cy1-CH2-, -Cy1-CH2-Cy2-, -C y1-Cy2-CH2-, -O-CH2-CH2-, -O-CH2-CH2-Cy1-, -O-CH2-Cy1-, -O-Cy1-, -O-Cy1-CH2-; Cy1 and Cy2 are each independently selected from one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl.

6. The compound according to claim 5 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B is selected from Selected from B 4a Each independently selected from 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, The B 4a Optional 1 to 3 R b4 replaced by; B5 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azopentyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, oxolanyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, furanyl, thienyl, thiazolyl, isothiazolyl, benzothienyl, benzofuranyl, benzopyrrolyl, quinolyl, isoquinolyl, benzopyrazinyl, benzopyrimidinyl, benzopyridazinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, The B5 is optionally replaced by 1 to 3 R b5 replaced by; K is selected from Q is independently selected from a bond, NH, O, S, C(=O)NH; Preferably, Selected from R k1 Each independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, CF3, CHF2, CH2F, OCF3, OCH2F, CH2OH, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl; L is selected from a bond or one of the structural fragments shown in Table L-1.

7. The compound according to claim 1 or its stereoisomer, tautomer, 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 8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated form, 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 7 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

9. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and inhibiting or degrading AR-related diseases.

10. The use according to claim 9, characterized in that: The disease is selected from cancer, preferably prostate cancer.

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