Cyano aromatic ring derivative and pharmaceutical use thereof

Abstract

A cyano aromatic ring derivative and the pharmaceutical use thereof. Specifically, the present invention relates to a compound of general formula (I) or a stereoisomer, a tautomer, a deuterated substance, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or cocrystal thereof, an intermediate thereof, and the use thereof in diseases associated with the inhibition or degradation of AR, such as cancers. B-L-K (I).

Description

A cyano aromatic ring derivative and its application in medicine Technical Field

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

[0002] Prostate cancer is often diagnosed at an early stage, with its causes often linked to genetic factors, a high-fat diet, and endocrine factors. Generally speaking, the incidence of prostate cancer is higher in developed countries than in developing countries. In 2016, there were 120,000 new cases of prostate cancer in China, and by 2030, the number of new cases is expected to reach 237,000, with a market share of US$4.8 billion. For patients with early-stage prostate cancer, radical treatment is available, resulting in longer survival. However, for patients with advanced metastatic disease, castration combined with anti-androgen therapy is recommended, and the disease can progress to castration-resistant prostate cancer. Clinical studies have shown that most patients with castration-resistant prostate cancer overexpress the androgen receptor (AR). Inhibiting AR signaling has significant therapeutic effects in patients with hormone-refractory prostate disease, making AR inhibition an effective means of directly blocking this pathway.

[0003] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds can be recognized by the cell's proteasome, causing degradation of the target protein and effectively reducing the target protein's content in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology has become possible for the treatment of various diseases. This technology has also received widespread attention in recent years.

[0004] Therefore, it is necessary to develop new PROTAC drugs targeting androgen receptor (AR) for the treatment of androgen receptor-related tumor diseases.

[0005] Summary of the Invention

[0006] The object of the present invention is to provide a compound with novel structure, good efficacy, high bioavailability, greater safety, and the ability to inhibit or degrade AR, for the treatment of AR-related diseases such as cancer.

[0007] The compound of the present invention has good prostate cancer cell (such as VCaP cell) proliferation inhibition activity, has a good degradation effect on AR protein, shows good oral performance in in vivo pharmacokinetics, has no obvious inhibitory effect on hERG potassium channel current, has good liver microsomal stability, has no obvious inhibitory activity on human liver microsomal cytochrome P450, and has no significant inhibitory effect on CD34+ hematopoietic stem cell proliferation.

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

[0009] In some embodiments, L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl group are optionally replaced by -Ak- or -Cy-;

[0010] In some embodiments, L is selected from a bond or -C 1-20 Hydrocarbyl-, wherein 1 to 10 methylene units in the hydrocarbyl group 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 the CH, -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;

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

[0013] In some embodiments, R L Selected from H, C 1-4 Alkyl, C 3-7 Carbocyclyl, 4- to 10-membered heterocyclyl;

[0014] In some embodiments, each -Cy- is independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-8 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 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl;

[0015] In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, or Ak9;

[0016] In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4, or Ak5;

[0017] In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3, Cy4, or Cy5;

[0018] In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3, or Cy4;

[0019] In some embodiments, L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, 5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak 3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1 -Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-A k3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy 3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4- Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1- Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, - Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3 -Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2 -Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy 4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy 3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-,-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-、-Ak1-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-;、

[0020] In some embodiments, L is selected from a bond, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak2-, -Cy1-Ak1-Ak 2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1 -Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-,-Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3;

[0021] In some embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0022] In some embodiments, L is selected from -Cy1-, -Cy1-Ak2-, -Cy1-CH2-, -Ak1-Cy1-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-;

[0023] In some embodiments, L is selected from -Cy1-Ak2-Cy2-, -Cy1-O-Cy2-;

[0024] In some embodiments, L is selected from -Cy1-, -Cy1-Ak2-, -Cy1-CH2-, -Cy1-C(CH3)2-, -Ak1-Cy1-, -C≡C-Cy1-;

[0025] In some embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and 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 bond, wherein the -CH2- is optionally replaced by 1 to 2 atoms selected from deuterium, halogen, =O, OH, CN, C 1-4 Alkyl or C 3-6 substituted by a cycloalkyl substituent;

[0026] In some embodiments, q is selected from 0, 1, 2, or 3;

[0027] In some embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH(CH3)-, -CH2-, -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)-;

[0028] In some embodiments, Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -C≡C-, -C(CH3)2-, or -CH2-;

[0029] In some embodiments, R L Selected from H or C 1-4 alkyl;

[0030] In some embodiments, R L Selected from H, methyl or ethyl;

[0031] In some embodiments, Cy1, Cy2, Cy3, Cy4, or Cy5 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following groups substituted: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 7-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl;

[0032] In some embodiments, Cy5 is defined the same as Cy1;

[0033] In some embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, 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;

[0034] In some embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or 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, cyclopropyl;

[0035] In some embodiments, Cy1, Cy2, and Cy3 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, cyclopropyl;

[0036] In some embodiments, L is selected from one of the structural fragments shown in Table L-1:

[0037] Table L-1

[0038] In some embodiments, B is selected from

[0039] In some embodiments, B is selected from In some embodiments, B is selected from

[0040] In some embodiments, B is selected from

[0041] In some embodiments, B is selected from In some embodiments, B is selected from In some embodiments, Y1 and Y2 are each independently selected from -CR y1 R y2 -、-(CR y1 R y2 )2-、-(CR y1 R y2 )3-;

[0042] In some embodiments, Y1 and Y2 are each independently selected from -CR y1 Ry2 -、-(CR y1 R y2 )2-;

[0043] In some embodiments, Y1 and Y2 are each independently selected from -CH2-, -CH2CH2-, -C(CH3)2-;

[0044] In some embodiments, X1 is selected from N or CR x1 ; X2 is selected from N or CR x2 ; X3 is selected from N or CR x3 ; X4 is selected from N or CR x4 ; X5 is selected from N or CR x5 ; Up to 2 of X1, X2, X3, X4, and X5 are selected from N; In some embodiments, X3 is selected from CR x3 In some embodiments, one of X1, X2, X3, X4, and X5 is selected from N; In some embodiments, X1 is selected from CR x1 , X2 selected from CR x2 , X3 selected from CR x3 , X4 selected from CR x4 , X5 is selected from CR x5 ;

[0045] In some embodiments, X6 is selected from N or CH; in some embodiments, X7 is selected from NH or O; in some embodiments, X7 is selected from O;

[0046] In some embodiments, Z1 is selected from N or CR z1 ; Z2 is selected from N or CR z2 ; Z3 is selected from N or CR z3 ; Z4 is selected from N or CR z4 ; Up to 3 of Z1, Z2, Z3, and Z4 are selected from N; in some embodiments, up to 2 of Z1, Z2, Z3, and Z4 are selected from N; in some embodiments, 1 of Z1, Z2, Z3, and Z4 is selected from N; in some embodiments, 2 of Z1, Z2, Z3, and Z4 are selected from N; in some embodiments, Z1 is selected from CR z1 , Z2 is selected from CR z2 , Z3 is selected from CR z3 , Z4 is selected from CR z4 ;

[0047] In some embodiments, R x1 、R x2 、R x3 、R x4 、R x5 、R z1 、R z2 、Rz3 、R z4 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 Carbocyclic group, -O-4 to 6 membered heterocyclic group, the alkylene, alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, heteroaryl group are optionally substituted by 1 to 4 R s replaced by;

[0048] In some embodiments, R x1 、R x2 、R x3 、R x4 、R x5 、R z1 、R z2 、R z3 、R z4 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;

[0049] In some embodiments, R x1 、R x2 、R x3 、R x4 、R x5 、R z1 、R z2 、R z3 、Rz4 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;

[0050] In some embodiments, R x1 、R x2 、R x3 、R x4 Each independently selected from -S(=O)2NH2, -S(=O)2C 1-4 alkyl;

[0051] In some embodiments, R x1 、R x2 、R x3 、R x4 Each independently selected from -S(=O)2NH2, -S(=O)2methyl, -S(=O)2ethyl;

[0052] In some embodiments, R x2 、R x3 、R x4 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3, CF3, CHF2, CH2F, OCF3, OCH2F, OCD3, CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, -CH2-cyclopropyl, -O-cyclopropyl;

[0053] In some embodiments, R x3 、R x4 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3, CF3, CHF2, CH2F, OCF3, OCH2F, CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, -CH2-cyclopropyl, -O-cyclopropyl;

[0054] In some embodiments, R x2 、R x4 Each is independently selected from -S(=O)2CH3, -O-CH2-propynyl, -O-CH2-cyclopropyl, -O-CH2CH2-OCH3, -O-CH2CH2-O-cyclopropyl,

[0055] In some embodiments, R 2 、R 3 、R y1 、R y2 Each independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, the alkyl, alkenyl, alkynyl are optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0056] In some embodiments, R 2 、R 3 、R y1 、R y2 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio is replaced by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0057] In some embodiments, R 2 、R 3 Each independently selected from H, deuterium, F, Cl, Br;

[0058] In some embodiments, R y1 、R y2 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, methyl, ethyl, methoxy;

[0059] In some embodiments, R 1 Selected from H, deuterium, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH2, CN, C1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0060] In some embodiments, R 1 is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl is optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0061] In some embodiments, R 1 Selected from H, deuterium, CF3, CHF2, CH2F, CH2OH, methyl, ethyl, isopropyl, cyclopropyl;

[0062] In some embodiments, R x1 With R x2 、R x2 With R x3 、R x3 With R x4 、R x4 With R x5 、R 1 With R z3 、R 1 With R z1 Direct connection to form C 4-6 Carbocyclic group or 4 to 7 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R s replaced by;

[0063] In some embodiments, R x1 With R x2 、R x2 With R x3 、R x3 With R x4 、R x4 With R x5 Direct connection to form C 4-6 Carbocyclic group, 5-6 membered heteroaryl or 5 to 7 membered heterocyclic group, wherein the carbocyclic group, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 R s replaced by;

[0064] In some embodiments, R 1 With R z3 、R 1 With R z1 directly connected to form a 5- to 7-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R s replaced by;

[0065] In some embodiments, R x1 With Rx2 、R x2 With R x3 、R x3 With R x4 、R x4 With R x5 Direct connection to form optionally 1 to 3 R s substituted by one of the following groups: piperidinyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl; in some embodiments, R x1 With R x2 、R x2 With R x3 、R x3 With R x4 、R x4 With R x5 Direct connection to form optionally 1 to 3 R s One of the following substituted groups: pyrrolidinyl, oxalyl, oxaheryl, 1,3-dioxolane;

[0066] In some embodiments, R 1 With R z3 、R 1 With R z1 Direct connection to form optionally 1 to 4 R s The following structures are replaced:

[0067] In some embodiments, K is selected from The ring where the representative is located is an aromatic ring or a non-aromatic ring;

[0068] In some embodiments, K is selected from

[0069] In some embodiments, K is selected from

[0070] In some embodiments, K is selected from

[0071] In some embodiments, K is selected from

[0072] In some embodiments, K is selected from

[0073] In some embodiments, F1 is selected from N, NH, CH, CH2, CHR k1 NR k1 , CR k1、C(=O)、C(R k1 )2;

[0074] In some embodiments, F2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 NR k1 , CR k1 or C(R k1 )2;

[0075] In some embodiments, When the ring where the representative is located 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;

[0076] In some embodiments, The ring where the ring is located is aromatic, and F1 is selected from N, CH, CR k1 ,F2 is selected from bond, O, N, CH, CR k1 ;

[0077] In some embodiments, F6, F7, and F8 are each independently selected from N, C, CH, or CR. k1 , and F6, F7, and F8 contain at most 2 N; in some embodiments, one of F6, F7, and F8 is selected from N, and the remaining two are selected from CH or CR k1 ;

[0078] In some embodiments, G is selected from CH or N;

[0079] In some embodiments, E1 is selected from N or CH, preferably N;

[0080] In some embodiments, E2 is selected from C, N or CH, preferably N;

[0081] In some embodiments, each Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR q -;

[0082] In some embodiments, each Q is 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);

[0083] In some embodiments, each Q is independently selected from a bond, NH, N(CH3), O, S, NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3);

[0084] In some embodiments, each Q is independently selected from a bond, NH, C(=O)NH;

[0085] In some embodiments, Q and G cannot directly form a nitrogen-nitrogen bond or a nitrogen-oxygen bond;

[0086] In some embodiments, Selected from

[0087] In some embodiments, R q Each independently selected from H or C 1-4 alkyl;

[0088] In some embodiments, R q are each independently selected from H, methyl, ethyl or isopropyl;

[0089] In some embodiments, R q Selected from H or methyl;

[0090] 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, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 R s replaced by;

[0091] 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 is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, CF3, CN, NH2, C 1-4 substituted by an alkyl substituent;

[0092] In some embodiments, R k1Each is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, and NH2;

[0093] 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;

[0094] In some embodiments, 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;

[0095] In some embodiments, 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 0-2Alkylene-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;

[0096] In some embodiments, 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 substituted by an alkoxy substituent;

[0097] In some embodiments, R L2 、R s Each is 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, OCH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl;

[0098] In some embodiments, R s Each independently selected from -OC 3-6 Cycloalkyl;

[0099] In some embodiments, R s Each independently selected from propynyl, -O-cyclopropyl;

[0100] In some embodiments, p1 is each independently selected from 0, 1 or 2;

[0101] In some embodiments, p1 is independently selected from 0 and 1.

[0102] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

[0103] L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0104] 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 bond, wherein the -CH2- is optionally replaced by 1 to 2 atoms selected from deuterium, halogen, =O, OH, CN, C 1-4 Alkyl or C 3-6 substituted by a cycloalkyl substituent;

[0105] q is selected from 0, 1, 2 or 3;

[0106] R L Each independently selected from H or C 1-4 alkyl;

[0107] 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 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl;

[0108] B is selected from

[0109] X1 is selected from N or CR x1 ; X2 is selected from N or CR x2 ; X3 is selected from N or CR x3 ; X4 is selected from N or CR x4 ; X5 is selected from N or CR x5 ;

[0110] At most 2 of X1, X2, X3, X4, and X5 are selected from N;

[0111] Z1 is selected from N or CR z1 ; Z2 is selected from N or CR z2 ; Z3 is selected from N or CR z3 ; Z4 is selected from N or CR z4 ;

[0112] At most three of Z1, Z2, Z3, and Z4 are selected from N;

[0113] Y1 and Y2 are each independently selected from -CR y1 R y2 -、-(CR y1 R y2 )2-、-(CR y1 R y2 )3-;

[0114] R 1 Selected from H, deuterium, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0115] R x1 、R x2 、R x3 、R x4 、R x5 、R z1 、R z2 、R z3 、R z4 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 3-6Carbocyclic 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, the alkylene, alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, heteroaryl group are optionally substituted by 1 to 4 R s replaced by;

[0116] or R x1 、R x2 、R x3 、R x4 Each independently selected from -S(=O)2NH2, -S(=O)2C 1-4 alkyl;

[0117] Or, R x1 With R x2 、R x2 With R x3 、R x3 With R x4 、R x4 With R x5 、R 1 With R z3 、R 1 With R z1 Direct connection to form C 4-6 Carbocyclic group or 4 to 7 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R s replaced by;

[0118] R 2 、R 3 、R y1 、R y2 Each independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, the alkyl, alkenyl, alkynyl are optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0119] K is selected from

[0120] The ring where the representative is located is an aromatic ring or a non-aromatic ring;

[0121] F1 is selected from N, NH, CH, CH2, CHR k1 NR k1 , CRk1 、C(=O)、C(R k1 )2;

[0122] F2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 NR k1 , CR k1 or C(R k1 )2;

[0123] F6, F7, F8 are each independently selected from N, C, CH or CR k1 , and F6, F7, and F8 contain at most 2 Ns;

[0124] G is selected from CH or N;

[0125] E1 is selected from N or CH;

[0126] E2 is selected from C, N or CH;

[0127] Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q -;

[0128] Q and G cannot directly form a nitrogen-nitrogen bond or a nitrogen-oxygen bond;

[0129] R q Each independently selected from H or C 1-4 alkyl;

[0130] 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, the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 R s replaced by;

[0131] 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 1-4Alkoxy, -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;

[0132] p1 are each independently selected from 0, 1 or 2;

[0133] or R s Each independently selected from -OC 3-6 Cycloalkyl.

[0134] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

[0135] R x1 、R x2 、R x3 、R x4 、R x5 、R z1 、R z2 、R z3 、R z4 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;

[0136] or R x1 、R x2 、R x3 、R x4 Each independently selected from -S(=O)2NH2, -S(=O)2C 1-4alkyl;

[0137] Or, R x1 With R x2 、R x2 With R x3 、R x3 With R x4 、R x4 With R x5 Direct connection to form C 4-6 Carbocyclic group, 5-6 membered heteroaryl or 5 to 7 membered heterocyclic group, wherein the carbocyclic group, heteroaryl or heterocyclic group is optionally substituted by 1 to 4 R s replaced by;

[0138] Or, R 1 With R z3 、R 1 With R z1 directly connected to form a 5- to 7-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R s replaced by;

[0139] R L Selected from H, methyl or ethyl;

[0140] R q are each independently selected from H, methyl, ethyl or isopropyl;

[0141] Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl,

[0142] s1, s3, and s5 are each independently selected from 0, 1, or 2;

[0143] s2 and s4 are each independently selected from 0 or 1;

[0144] s6 is selected from 0, 1, 2 or 3;

[0145] s7 is selected from 1, 2 or 3;

[0146] 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, -SC1-4 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 substituted by an alkoxy substituent;

[0147] or R s Each independently selected from -OC 3-6 Cycloalkyl;

[0148] The remaining groups are defined the same as in the first embodiment of the present invention.

[0149] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

[0150] X3 selected from CR x3 ;

[0151] Y1 and Y2 are each independently selected from -CR y1 R y2 -、-(CR y1 R y2 )2-;

[0152] R 1 is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl is optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0153] R x1 、R x2 、R x3 、R x4 、R x5 、R z1 、R z2 、R z3 、R z4 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 ssubstituted by one of the following groups: methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -O-cyclopropyl, pyrazolyl;

[0154] or R x1 、R x2 、R x3 、R x4 Each independently selected from -S(=O)2NH2, -S(=O)2methyl, -S(=O)2ethyl;

[0155] Or, R x1 With R x2 、R x2 With R x3 、R x3 With R x4 、R x4 With R x5 Direct connection to form optionally 1 to 3 R s substituted by one of the following groups: piperidinyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl;

[0156] Or, R x1 With R x2 、R x2 With R x3 、R x3 With R x4 、R x4 With R x5 Direct connection to form optionally 1 to 3 R s One of the following substituted groups: pyrrolidinyl, oxalyl, oxaheryl, 1,3-dioxolane;

[0157] Or, R 1 With R z3 、R 1 With R z1 Direct connection to form optionally 1 to 4 R s The following structures are replaced:

[0158] R 2 、R 3 、R y1 、R y2 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio is replaced by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH2, CN, C1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0159] 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)-;

[0160] K is selected from

[0161] 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);

[0162] R k1 Each is independently selected from deuterium, F, Cl, Br, I, OH, NH2, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, and NH2;

[0163] 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 substituted by an alkoxy substituent;

[0164] or R sEach independently selected from propynyl, -O-cyclopropyl;

[0165] The remaining groups are defined the same as in the first or second embodiment of the present invention.

[0166] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein

[0167] B is selected from

[0168] Or B is selected from

[0169] X6 is selected from N or CH;

[0170] X7 is selected from NH or O;

[0171] At most 2 of Z1, Z2, Z3, and Z4 are selected from N;

[0172] R 2 、R 3 Each independently selected from H, deuterium, F, Cl, Br;

[0173] R y1 、R y2 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, methyl, ethyl, methoxy;

[0174] Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or 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, cyclopropyl;

[0175] K is selected from

[0176] Or K is selected from

[0177] The remaining groups are defined the same as in the first, second or third embodiment of the present invention.

[0178] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

[0179] B is selected from

[0180] Or B is selected from

[0181] R x2 、R x3 、R x4 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3, CF3, CHF2, CH2F, OCF3, OCH2F, OCD3, CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, -CH2-cyclopropyl, -O-cyclopropyl;

[0182] or R x2 、R x4 Each is independently selected from -S(=O)2CH3, -O-CH2-propynyl, -O-CH2-cyclopropyl, -O-CH2CH2-OCH3, -O-CH2CH2-O-cyclopropyl,

[0183] Q is independently selected from a bond, NH, N(CH3), O, S, NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3);

[0184] L is selected from -Cy1-, -Cy1-Ak2-, -Cy1-CH2-, -Ak1-Cy1-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-;

[0185] or L is selected from -Cy1-Ak2-Cy2-, -Cy1-O-Cy2-;

[0186] Cy1, Cy2, and Cy3 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, cyclopropyl;

[0187] The remaining groups are defined the same as in the first, second, third or fourth embodiment of the present invention.

[0188] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

[0189] K is selected from

[0190] Or K is selected from

[0191] Q is independently selected from a bond, NH, C(=O)NH;

[0192] 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;

[0193] L is selected from one of the structural fragments shown in Table L-1;

[0194] The remaining groups are defined the same as in the first, second, third, fourth or fifth embodiment of the present invention.

[0195] As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein:

[0196] B is selected from Z3 is selected from N or CR z3 ; Z4 is selected from N or CR z4 ; Preferably, B is selected from

[0197] L is selected from -Cy1-, -Cy1-Ak2-, -Cy1-Ak2-Cy2-; preferably, L is selected from -Cy1-, -Cy1-CH2-, -Cy1-C(CH3)2-, -Cy1-O-Cy2; further preferably, L is selected from

[0198] 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, and cyclopropyl; preferably, 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, cyclopropyl;

[0199] Ak2 is selected from -C(CH3)2- or -CH2-;

[0200] K is selected from Preferably, K is selected from

[0201] Selected from

[0202] The definitions of the remaining groups are consistent with those described in any embodiment of the present invention.

[0203] The present invention relates to the following compound or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table E below:

[0204] Table E

[0205] The present invention relates to a pharmaceutical composition comprising the above-mentioned compound of the present invention or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier.

[0206] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for treating diseases related to AR activity or expression.

[0207] The present invention relates to the use of a compound of the present invention or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof in the preparation of a medicament for treating and inhibiting or degrading AR-related diseases. In some embodiments, the disease associated with inhibiting or degrading AR is cancer, preferably prostate cancer.

[0208] The present invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in the unit dosage form is also referred to as the "drug strength").

[0209] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition thereof. In some embodiments, the mammal of the present invention comprises a human.

[0210] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., cancer). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3 -500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg , 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400 mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300- 400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 9 0-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40 -200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1500mg, 80-1000mg, 80-800mg;.

[0211] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1500 mg, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 1 25 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg, 1000 mg of a compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0212] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably cancer, more preferably prostate cancer.

[0213] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1500 mg / day, wherein the daily dose can be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 2 5-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day, 1500 mg / day.

[0214] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0215] The amount of the compound of the invention or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0216] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0217] The carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds of the present invention include their isotopes, that is, the carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. 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 11 C. 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 15 O. 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S. 35 S and 36 S, nitrogen isotopes include 13 N. 14 N and 15 N, fluorine isotopes include 17 F. 18 F and 19 F, chlorine isotopes include 35 Cl, 36 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br, Iodine isotopes include 123 I. 125 I, phosphorus isotopes include 31 P. 32 P.

[0218] "CN" refers to cyano.

[0219] "Halogen" refers to F, Cl, Br or I.

[0220] "Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0221] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0222] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, and adamantane. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0223] " Heterocycloalkyl " refers to a saturated cyclic hydrocarbon radical containing heteroatoms that is substituted or unsubstituted, including but not limited to 3 to 12 atoms, 3 to 8 atoms, comprising 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocycle, a ring, a bridged ring and a spirocycle. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, The heterocycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0224] "Alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-4-butenyl, 2-methyl-5-butenyl, 2-methyl-6-butenyl, 2-methyl-7-butenyl, 2-methyl-8-butenyl, 2-methyl-9-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3 ... -methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent or tetravalent.

[0225] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, and 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-pentynyl, 14-pentynyl, 15-pentynyl, 16-pentynyl, 17-pentynyl, 18-pentynyl, 19-pentynyl, 20-pentynyl, 21-pentynyl, 22-pentynyl, 23-pentynyl, 24-pentynyl, 25-pentynyl, 26-pentynyl, 27-pentynyl, 28-pentynyl, 29-pentynyl, 30-pentynyl, 31-pentynyl, 32-pentynyl, 33-pentynyl, 34-pentynyl, 35-pentynyl, 36-pentynyl, 37-pentynyl, 38-pentynyl, 39-pentynyl, 40-pentynyl, 41-pentynyl, 42-pentynyl, 43-pentynyl, 44-pentynyl, 45-pentynyl, 46-pentynyl, 47-pentynyl, 48-pentyn Alkynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, and the like; an alkynyl group may be monovalent, divalent, trivalent, or tetravalent.

[0226] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0227] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocycle, a 4-12 membered bicycle, a 10-15 membered tricycle, or a 12-18 membered quaternary system. The carbocyclyl can be attached to the aromatic or non-aromatic ring, and the ring can be optionally a monocycle, a cyclic ring, a bridged ring, or a spirocycle. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0228] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary ring, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se optionally substituted in the heterocyclyl ring 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 spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0229] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which the substituted or unsubstituted rings share an atom (called a spiro atom), and the number of ring atoms in the spirocycle system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 atoms selected from N, O or S (=O) n (n is 0, 1 or 2). Non-limiting examples include: "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0230] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0231] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in the bridged ring system may contain zero to five heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n or O, where n is 0, 1, or 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: "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0232] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0233] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0234] "Carbobridged ring," "bridged carbocyclic group," "bridged carbocyclic group," or "carbon-bridged cyclic group" refers to a "bridged ring" wherein the ring system consists of only carbon atoms.

[0235] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle".

[0236] "Heterocyclo", "heterocycloalkyl", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

[0237] "Heterospirocycle," "heterospirocyclyl," "spiroheterocyclyl," or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0238] "Heterobridged ring," "heterobridged cyclic group," "bridged ring heterocyclic group," or "bridged heterocyclic group" refers to a "bridged ring" containing a heteroatom.

[0239] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0240] "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 or Se(=O)n, where n is 0, 1 or 2). The number of ring atoms in the heteroaromatic ring is, but not limited to, 5 to 15, 5 to 10 or 5 to 6. The ring atoms C, N, and S are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connecting to the parent structure is an aryl ring, non-limiting examples of which include: When heteroaryl appears in this document, its definition is consistent with this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the ring with aromaticity.

[0241] "Substituted" or "substituted" refers to substitution by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, 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 (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c Can form five or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0242] "1 to X substituents selected from..." means substituted by 1, 2, 3, ..., X substituents selected from ..., where X is any integer from 1 to 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k Substitution. For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4, or 5 substituents selected from..." For example, "a heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3, or 4 substituents selected from H or F.

[0243] An XY-membered ring (X and Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes rings with X, X+1, X+2, X+3, X+4, ..., Y members. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10 membered heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring.

[0244] C x-y Carbocycles (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, fused carbocycle or bridged carbocycle) include C x 、C x+1 、C x+2 、C x+3 、C x+4 ….C y A ring of 1-membered ring (x is an integer, and 3≤x<y, y is selected from any integer between 4 and 20), for example. 3-6 "Cycloalkyl" refers to a C3, C4, C5 or C6 cycloalkyl group.

[0245] When a group has one or more bondable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are hydrogen atoms at the bondable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected, and the group will become a group with the corresponding valence. For example Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes For example, the general formula fragment is When X is selected from CH2 or NH, it means that the R group on the general fragment can be located on C or X. When X is selected from CH2, the general fragment can be When X is selected from NH, the general fragment can be

[0246] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in the reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0247] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0248] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0249] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0250] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0251] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0252] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0253] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0254] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0255] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0256] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers.

[0257] Synthesis method 1:

[0258] The compound of the general formula (Z-1) reacts with the compound of the general formula (Z-2) to generate the compound of the general formula (Z-3) through a nucleophilic substitution or coupling reaction;

[0259] The compound of the general formula (Z-3) undergoes a deprotection reaction to obtain the compound of the general formula (Z-4);

[0260] The compound of the general formula (Z-4) and the compound of the general formula (Z-5) undergo condensation reaction to obtain the compound of the general formula (Z-6);

[0261] The compound of the general formula (Z-6) is subjected to an oxidation reaction to obtain the compound of the general formula (Z-7);

[0262] The compound of the general formula (Z-7) and the compound of the general formula (Z-8) undergo reductive amination reaction to obtain the compound of the general formula (Z-9).

[0263] R x1 Selected from F, Cl, Br, I, OTf or borate;

[0264] R x2 Selected from Boc, Cbz, Fmoc, SEM and other protecting groups. DETAILED DESCRIPTION

[0265] 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 them.

[0266] The compounds used in the reactions described herein were prepared using 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" were obtained from reputable commercial sources, including suppliers such as Titan Technology, Anage Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and J&K Technology.

[0267] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0268] MS was determined using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0269] HPLC determination was performed using an Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 × 4.6 mm, 3.5 μM);

[0270] 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 for thin layer chromatography (TLC) were 0.15 mm to 0.20 mm, and the specifications used for thin layer chromatography separation and purification products were 0.4 mm to 0.5 mm.

[0271] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0272] Synthetic Reagent Abbreviations:

[0273] DMAP: CAS No.: 1122-58-3; NBS: CAS No.: 128-08-5; HATU: CAS No.: 148893-10-1;

[0274] Synthesis of intermediate 1:

[0275] Step 1: Preparation of 1-B

[0276] 1-A (2.8 g, 13.58 mmol) (synthesis method, see Bioorganic & Medicinal Chemistry Letters, 2016, 26, 5877-5882) was dissolved in dichloromethane (50 mL), and Boc2O (5.93 g, 27.17 mmol) and DMAP (3.32 g, 27.18 mmol) were added. The reaction was allowed to react at room temperature for 16 h. The reaction system was washed with 0.5 mol / L hydrochloric acid (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v) = 0:1-1:9) to obtain the racemate of 1-B (3.4 g, yield: 82%).

[0277] The racemate of 1-B was subjected to chiral separation as follows:

[0278] 1. Instrument: SFC Prep 150AP; Chromatographic column: Daicel IC-H (19 mm × 250 mm).

[0279] 2. Dissolve the sample in methanol and filter with a 0.45 μm filter to prepare a sample solution.

[0280] 3. Preparative chromatographic conditions: a. Mobile phases consisted of a system of A and B: mobile phase A: CO2; mobile phase B: methanol / isopropanol (v / v) = 1:1; b. Isocratic elution, mobile phase B content was 20%; c. Flow rate was 40 mL / min.

[0281] Peak time: chiral isomer 1 (compound 1-B): 5.7 min, chiral isomer 2 (compound 2-A): 6.47 min.

[0282] According to the MicroED structure determination of compound 2-B, compound 1-B is R-configuration and compound 2-A is S-configuration.

[0283] LCMS m / z=307.3[M+1] + .

[0284] Step 2: Preparation of 1-C

[0285] 1-B (1.8 g, 5.88 mmol) was dissolved in acetonitrile (50 mL), and NBS (1.05 g, 5.90 mmol) was added. The reaction was allowed to react at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v) = 0:1-1:9) to obtain 1-C (1.6 g, yield: 71%).

[0286] LCMS m / z=385.3[M+1] + .

[0287] Step 3: Preparation of 1-D

[0288] 1-C (0.77 g, 2.0 mmol), 1-C′ (1.67 g, 4.0 mmol) (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 mixture was reacted at 100°C under a nitrogen atmosphere for 20 h. The reaction system was cooled to room temperature, and 50 mL of water and 50 mL of ethyl acetate were added. The aqueous phase was extracted with 50 mL of ethyl acetate, and the organic phase was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and 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%).

[0289] Step 4: Preparation of 1-E

[0290] 1-D (0.70 g, 1.18 mmol) was dissolved in THF (20 mL), and 10% palladium on carbon (0.63 g) was added. The mixture was reacted at 45°C under a hydrogen balloon atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (MeOH:DCM (v / v) = 0:1-5:95) to obtain 1-E (0.25 g, yield: 51%).

[0291] LCMS m / z=418.1[M+1] + .

[0292] Step 5: Preparation of Intermediate 1

[0293] 1-E (250 mg, 0.6 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the mixture was allowed to react 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 crude intermediate 1 (190 mg).

[0294] LCMS m / z=318.3[M+1] + .

[0295] Synthesis of intermediate 2:

[0296] Step 1: Preparation of 2-B

[0297] 2-A (1.4 g, 4.57 mmol) was dissolved in acetonitrile (50 mL), and NBS (0.81 g, 4.55 mmol) was added. The reaction was allowed to react at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v) = 0:1-1:9) to obtain 2-B (1.6 g, yield: 92%).

[0298] LCMS m / z=385.3[M+1] + .

[0299] The compound 2-B was determined to be S-configuration by MicroED structure analysis.

[0300] Step 2: Preparation of 2-C

[0301] 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) were added to a reaction flask. 1,4-dioxane (50 mL) and water (5 mL) were added, and the mixture was reacted at 100°C under a nitrogen atmosphere for 20 h. The reaction system was cooled to room temperature, and 50 mL of water and 50 mL of ethyl acetate were added. The aqueous phase was extracted with ethyl acetate (50 mL), and the organic phase was washed with 30 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to obtain 2-C (1.4 g, yield: 56%).

[0302] Step 3: Preparation of 2-D

[0303] 2-C (1.4 g, 2.35 mmol) was dissolved in THF (50 mL), and 10% palladium on carbon (1.25 g) was added. The mixture was reacted at 45°C under a hydrogen balloon atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (MeOH:DCM (v / v) = 0:1-5:95) to obtain 2-D (0.85 g, yield: 87%).

[0304] LCMS m / z=418.1[M+1] + .

[0305] Step 4: Preparation of Intermediate 2

[0306] 2-D (620 mg, 1.49 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the mixture was allowed to react 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 crude intermediate 2 (460 mg).

[0307] LCMS m / z=318.3[M+1] + .

[0308] Preparation of intermediate 3:

[0309] Step 1: Preparation of 3-A

[0310] Under a nitrogen atmosphere, 1-C (7.00 g, 18.17 mmol) and 70 mL of tetrahydrofuran were added to a reaction flask. A 2.5 mol / L n-butyllithium solution 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, the carbon dioxide was replaced three times. The reaction was then placed under a carbon dioxide balloon, maintaining the temperature below -40°C for 0.5 h. The reaction system was returned to room temperature, and 20 mL of ethyl acetate was added. The pH was adjusted to 2 with 1 mol / L hydrochloric acid, and the reaction was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1-2:1) to afford 3-A (2.4 g, yield: 38%).

[0311] 1 H NMR(400MHz,DMSO-d6)δ7.42(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).

[0312] Step 2: Preparation of Intermediate 3

[0313] To a reaction flask, 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. After stirring at room temperature for 10 minutes, 3-amino-2,6-piperidinedione hydrochloride (1.35 g, 8.20 mmol) was added and allowed to react at room temperature for 30 minutes. The reaction mixture was poured into 100 mL of water and filtered. The filter cake was washed with 50 mL of water and dried under reduced pressure to obtain Intermediate 3 (2.0 g, yield: 63%).

[0314] LCMS m / z=461.2[M+1] +

[0315] Preparation of intermediate 4:

[0316] Intermediate 4 was obtained using compound 2-B as a raw material by referring to the synthetic method of intermediate 3.

[0317] LCMS m / z=461.2[M+1] +

[0318] Preparation of intermediate 5:

[0319] Step 1: Preparation of 5-B

[0320] 5-A (10 g, 42.02 mmol) was dissolved in 80 mL of DMSO, and 5-A′ (7.41 g, 46.25 mmol) and DIPEA (16.29 g, 126.03 mmol) were added. The reaction was allowed to react at 50°C for 3 h. The reaction system was cooled to room temperature, and 300 mL of water and 400 mL of ethyl acetate were added. The organic phase was washed with 300 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 5-B (6.2 g).

[0321] Step 2: Preparation of 5-C

[0322] The crude product 5-B (6.2 g) was added to 150 mL of methanol and 30 mL of water, followed by the addition of iron powder (9.15 g, 163.4 mmol) and ammonium chloride (8.77 g, 163.96 mmol). The reaction was allowed to proceed at 70°C for 20 h. The reaction system was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. 300 mL of water and 400 mL of ethyl acetate were added to the residue. The organic phase was washed with 300 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 0:1-1:9) to obtain 5-C (1.9 g, two-step yield: 13% based on compound 5-A).

[0323] Step 3: Preparation of 5-D

[0324] Dissolve 5-C (1.9 g, 5.46 mmol) and TEA (1.66 g, 16.40 mmol) in 20 mL of dichloromethane, add chloroacetyl chloride (0.99 g, 8.77 mmol) dropwise, and react at room temperature for 20 h. Add 50 mL of water to the reaction solution, dry the organic phase over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product 5-D (2.1 g).

[0325] Step 4: Preparation of 5-E

[0326] The crude product 5-D (0.95 g) was added to 15 mL of acetic acid and reacted at 50°C for 20 h. The reaction system was cooled to 0°C, the pH was adjusted to 8 with 25% aqueous ammonia, and extracted with 150 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 0:1-1:9) to obtain 5-E (0.85 g, two-step yield based on compound 5-C: 85%).

[0327] Step 5: Preparation of 5-F

[0328] 5-E (7.3 g, 17.95 mmol) was dissolved in 80 mL of THF, and 20 mL of a 1 mol / L solution of potassium tert-butoxide in tetrahydrofuran was added. The mixture was allowed to react at room temperature for 19 h. 30 mL of water and 50 mL of ethyl acetate were added to the reaction system. The organic phase was washed with 300 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (methanol:dichloromethane (v / v) = 0:1-1:9) to obtain 5-F (3.6 g, yield: 54%).

[0329] Step 6: Preparation of 5-G

[0330] 5-F (2.0 g, 5.4 mmol), 2,6-bis(benzyloxypyridine-3-boronic acid pinacol ester (3.4 g, 8.15 mmol), Pd(dppf)Cl2·DCM (0.44 g, 0.54 mmol), and cesium carbonate (3.5 g, 10.74 mmol) were added sequentially to a reaction flask. 1,4-dioxane (100 mL) and water (10 mL) were added, and the mixture was reacted at 100°C under a nitrogen atmosphere for 20 h. The reaction system was cooled to room temperature, and 300 mL of water and 300 mL of ethyl acetate were added. The organic phase was washed with 100 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to obtain 5-G (2.6 g, yield: 83%).

[0331] LCMS m / z=581.4[M+1] + .

[0332] Step 7: Preparation of 5-H

[0333] 5-G (2.6 g, 4.48 mmol) was dissolved in THF (10 mL) and methanol (30 mL), and 10% palladium on carbon (2.5 g) was added. The mixture was reacted at 40°C under a hydrogen balloon atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 5-H (0.98 g).

[0334] LCMS m / z=403.3[M+1] + .

[0335] Step 8: Preparation of Intermediate 5

[0336] The crude product 5-H (100 mg) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (1 mL) was added. The mixture was reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of methanol was added, and 150 mg of solid sodium bicarbonate was added. After stirring for 10 min, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain the crude intermediate 5 (80 mg).

[0337] Example 1: Preparation of trifluoroacetate salt of compound 1

[0338] 1a (0.23 g, 0.47 mmol) (synthesis method reference WO2021127443) was dissolved in 1,2-dichloroethane (10 mL), and the above-mentioned crude intermediate 2 (0.15 g) was added. 1 mL of acetic acid was added, and the mixture was stirred at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.30 g, 1.42 mmol) was added and reacted at room temperature for 16 h. 20 mL of saturated aqueous sodium bicarbonate solution was slowly added to the reaction solution, and the mixture was extracted with 50 mL of dichloromethane. The organic phase was washed with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 10:1). The crude product was subjected to HPLC preparation (preparation method: the DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 10% to 50% (elution time 15 min)) and lyophilized to give the trifluoroacetate salt of compound 1 (10 mg).

[0339] 1 H NMR (400MHz, CD3OD) δ7.80-7.72(m,2H),7.52(d,1H),7.08-7.00(m,2H),6.91(d,1H) ),6.71(d,1H),6.64-6.60(m,1H),6.55(dd,1H),4.26(s,1H),4.18-4.03(m,2H),4.0 2-3.83(m,6H),3.80-3.60(m,2H),3.43-3.30(m,1H),3.28-3.06(m,4H),3.04-2.57( m,7H),2.33-2.02(m,4H),2.01-1.70(m,3H),1.56-1.40(m,2H),1.36-1.19(m,12H).

[0340] LCMS m / z=791.4[M+1] +

[0341] The crude reaction solution obtained in this step can also be prepared by neutral HPLC (preparation method: the DMSO solution of the crude product is filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: 10 mmol / L ammonium bicarbonate aqueous solution / acetonitrile. Gradient elution method: acetonitrile gradient elution from 47% to 87% (elution time 28 min)) and lyophilized to obtain compound 1.

[0342] 1H NMR(400MHz, CDCl3)δ7.91(s,1H),7.73-7.64(m,2H),7.45(d,1H),6.95-6.87(m,2H),6.72 (d,1H),6.53-6.44(m,2H),6.40(dd,1H),6.10(d,1H),4.18-4.11(m,1H),4.04(s,1H),3.9 1(s,3H),3.89-3.72(m,3H),3.65-3.54(m,1H),3.14-3.00(m,1H),2.97-2.72(m,7H),2.70 -2.57(m,2H),2.32-2.11(m,5H),1.99-1.82(m,4H),1.81-1.65(m,2H),1.40-1.19(m,14H).

[0343] Compound 1 was subjected to chiral separation to obtain chiral isomer 1 and chiral isomer 2, respectively.

[0344] Conditions for the first chiral separation and purification:

[0345] 1. Instrument: SHIMADZU LC-20AP; Chromatographic column: Chiral Whelk column.

[0346] 2. Dissolve the sample in acetonitrile and filter with a 0.45 μm filter to prepare a sample solution.

[0347] 3. Preparative chromatographic conditions: a. Mobile phases consisted of a system A and B: Mobile phase A: n-hexane; Mobile phase B: a mixed solvent of ethanol / acetonitrile containing 0.1% ammonia; b. Isocratic elution, mobile phase B content was 70%; c. Flow rate was 100 mL / min.

[0348] Second chiral separation and purification conditions:

[0349] 1. Instrument: Waters 150Prep-SFC; Column: Chiral AD column.

[0350] 2. Dissolve the sample in acetonitrile and filter with a 0.45 μm filter to prepare a sample solution.

[0351] 3. Preparative chromatographic conditions: a. Mobile phases consisted of systems A and B: Mobile phase A: CO2; Mobile phase B: a mixed solvent of isopropanol / acetonitrile containing 0.1% ammonia; b. Isocratic elution with a mobile phase B content of 70%; c. Flow rate of 100 mL / min.

[0352] Chiral analysis method:

[0353] 1. Instrument: SHIMAZU LC-20AD; Chromatographic column: Chiral Whelk column.

[0354] 2. Analytical chromatographic conditions: a. Mobile phases consisted of a system of A and B: Mobile phase A: n-hexane; Mobile phase B: ethanol and acetonitrile solution containing 0.1% isopropylamine; b. Isocratic elution, mobile phase B content was 60%; c. Flow rate was 1 mL / min.

[0355] Peak time: chiral isomer 1: 2.594 min, chiral isomer 2: 5.557 min.

[0356] Example 3: Preparation of trifluoroacetate salt of compound 3

[0357] To intermediate 4 (160 mg, 0.35 mmol) was added 2 mL of dichloromethane and 1 mL of trifluoroacetic acid, and the mixture was allowed to react at room temperature for 2 h. The reaction system was concentrated under reduced pressure, and 5 mL of dichloromethane and 1 mL of triethylamine were added, followed by concentration under reduced pressure to afford crude product 1 (120 mg). 1a (0.160 g, 0.33 mmol) was dissolved in 1,2-dichloroethane (10 mL), and the crude product 1 (0.120 g) was added, along with 1 mL of acetic acid. After stirring at room temperature for 1 h, sodium triacetoxyborohydride (0.21 g, 0.99 mmol) was added and the mixture was allowed to react at room temperature for 16 h. 20 mL of saturated aqueous sodium bicarbonate solution was slowly added to the reaction solution, and the mixture was extracted with 50 mL of dichloromethane. The organic phase was washed with 50 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol (v / v) = 10:1). The crude product was subjected to HPLC preparation (preparation method: the DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 10% to 50% (elution time 15 min)) and lyophilized to give the trifluoroacetate salt of compound 3 (45 mg).

[0358] 1H NMR (400MHz, CD3OD) δ7.80-7.72(m,2H),7.60-7.48(m,2H),7.10-7.00(m,2H),6.76(d,1 H),6.65-6.60(m,1H),6.55(dd,1H),4.85-4.72(m,1H),4.30-4.10(m,3H),4.02-3.88(m, 5H),3.82-3.63(m,2H),3.60-3.43(m,1H),3.33-3.10(m,4H),3.07-2.62(m,7H),2.37-2 .06(m,4H),2.02-1.88(m,2H),1.85-1.72(m,1H),1.57-1.42(m,2H),1.35-1.17(m,12H).

[0359] LCMS m / z=834.6[M+1] +

[0360] Example 5: Preparation of Compound 5 Trifluoroacetate

[0361] Step 1: Preparation of 5A trifluoroacetate

[0362] 3-A (650 mg, 1.86 mmol) was dissolved in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of 5A (700 mg).

[0363] Step 2: Preparation of 5b trifluoroacetate

[0364] 5a (3.00 g, 11.75 mmol) was dissolved in 5 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of 5b (3.2 g).

[0365] Step 3: Preparation of 5c

[0366] The trifluoroacetic acid salt of the crude product 5b (3.2 g), ethyl 4-fluorobenzoate (1.85 g, 11.00 mmol), potassium carbonate (3.04 g, 22.0 mmol), and 15 mL of dimethyl sulfoxide were added to a reaction flask and reacted at 100°C for 16 h. The reaction system was cooled to room temperature, and 100 mL of water and 100 mL of ethyl acetate were added to the reaction solution. The layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, 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) = 1:0-1:1) to obtain 5c (2.40 g, yield: 72%).

[0367] Step 4: Preparation of 5d

[0368] To a reaction flask, 5c (2.40 g, 7.91 mmol), potassium hydroxide (1.78 g, 31.79 mmol), 10 mL of ethanol, 10 mL of tetrahydrofuran, and 10 mL of water were added and stirred at room temperature for 16 h. The reaction system was concentrated under reduced pressure, the pH was adjusted to 2 with 2 mol / L hydrochloric acid, and the filter cake was collected and dried under reduced pressure to obtain crude product 5d (1.50 g).

[0369] LCMS m / z=276.3[M+1] +

[0370] Step 5: Preparation of 5e

[0371] To a reaction flask, crude product 5d (0.6 g), HATU (0.99 g, 2.60 mmol), diisopropylethylamine (1.41 g, 10.91 mmol), and 10 mL of DMF were added. After stirring at room temperature for 0.5 h, trans-4-(3-amino-2,2,4,4-tetramethylcyclobutyloxy)-2-methoxybenzonitrile hydrochloride (0.66 g, 2.12 mmol) (synthesis method, see CN115175901) was added and stirred at room temperature for 2 h. To the reaction solution, 100 mL of water and 100 mL of ethyl acetate were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 to 0:1) to afford 5e (1.10 g, yield: 98%).

[0372] LCMS m / z=532.6[M+1] +

[0373] Step 6: Preparation of 5f

[0374] To a reaction flask, 5e (1.10 g, 2.07 mmol), Dess-Martin periodinane (1.05 g, 2.48 mmol), and 10 mL of dichloromethane were added and allowed to react at room temperature for 4 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-1:9) to afford 5f (0.52 g, 47% yield).

[0375] LCMS m / z=530.2[M+1] +

[0376] Step 7: Preparation of 5g

[0377] To a reaction flask, 5f (0.25 g, 0.47 mmol), the trifluoroacetate salt of crude 5A (0.18 g), 0.2 mL of glacial acetic acid, and 3 mL of DMAc were added. The mixture was allowed to react at room temperature for 1 h, followed by the addition of sodium triacetoxyborohydride (0.30 g, 1.42 mmol) and the reaction was continued at room temperature for 16 h. 20 mL of water and 20 mL of ethyl acetate were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-1:9) to afford 5g (0.20 g, 56% yield).

[0378] Step 8: Preparation of trifluoroacetate salt of compound 5

[0379] To a reaction flask, 5 g (0.10 g, 0.13 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (0.043 g, 0.26 mmol), EDCI (0.037 g, 0.19 mmol), HOBt (0.026 g, 0.19 mmol), N-methylmorpholine (0.065 g, 0.64 mmol), and 4 mL of DMF were added and allowed to react at room temperature for 16 h. The reaction solution was then subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The crude product in DMSO was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 10% to 50% (elution time 15 min), and lyophilized to obtain trifluoroacetic acid salt of compound 5 (20 mg).

[0380] 1H NMR(400MHz,CD3OD)δ7.74(d,2H),7.57-7.48(m,2H),7.02(d,2H),6.75(d,1H),6.62(d,1 H),6.55(dd,1H),4.82-4.74(m,1H),4.30-4.23(m,1H),4.23-4.17(m,1H),4.13(s,1H),3 .93(s,3H),3.68-3.49(m,2H),3.48-3.30(m,5H),3.28-3.08(m,4H),3.02-2.90(m,1H),2 .88-2.65(m,5H),2.35-2.05(m,5H),1.89-1.82(m,2H),1.82-1.65(m,5H),1.26(d,12H).

[0381] LCMS m / z=874.4[M+1] +

[0382] Example 7: Preparation of Compound 7 Trifluoroacetate

[0383] The trifluoroacetate salt of compound 7 was obtained using compound 4-A as a raw material by referring to the synthesis method of Example 5.

[0384] 1 H NMR (400MHz, CD3OD) δ7.81-7.71(m,2H),7.57-7.48(m,2H),7.13-7.01(m,2H),6.75(d ,1H),6.62(d,1H),6.55(dd,1H),4.80-4.74(m,1H),4.26(s,1H),4.24-4.16(m,1H),4 .13(s,1H),3.93(s,3H),3.67-3.50(m,2H),3.50-3.15(m,9H),3.01-2.91(m,1H),2.9 1-2.63(m,5H),2.35-2.07(m,5H),1.94-1.84(m,2H),1.84-1.67(m,5H),1.26(d,12H).

[0385] LCMS m / z=437.8[M / 2+1] +

[0386] The following compounds were obtained by referring to the synthesis methods of other examples:

[0387] Example 11: Preparation of Compound 11

[0388] Compound 11 was prepared from the trifluoroacetic acid salts of compounds 1a and 5A by referring to the synthesis method of Example 5 and lyophilized via neutral preparation (aqueous solution of ammonium acetate (5 mmol / L) / acetonitrile).

[0389] 1 H NMR(400MHz,DMSO-d6)δ10.82(s,1H),7.94(t,1H),7.78-7.69(m,2H),7.64(d,1H),7.47(d,1H ),7.36(d,1H),7.00-6.90(m,2H),6.73-6.61(m,2H),6.54(dd,1H),4.78-4.65(m,1H),4.27(s, 1H),4.05(d,1H),3.95-3.79(m,6H),3.16-3.06(m,1H),2.97-2.61(m,8H),2.57-2.50(m,1H),2 .26-2.14(m,2H),2.13-1.88(m,4H),1.87-1.72(m,4H),1.66-1.52(m,1H),1.28-1.09(m,14H).

[0390] LCMS m / z=418.0[M / 2+1] +

[0391] Example 13: Preparation of Compound 13

[0392] Compound 13 was prepared from compounds 1a and 7A by lyophilization using a neutral preparation method (aqueous solution of ammonium acetate (5 mmol / L) / acetonitrile) according to the synthesis method of Example 11.

[0393] 1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),7.94(t,1H),7.74(d,2H),7.64(d,1H),7.47(d,1H),7 .36(d,1H),6.95(d,2H),6.74-6.61(m,2H),6.54(dd,1H),4.82-4.60(m,1H),4.27(s,1H),4 .05(d,1H),3.95-3.79(m,6H),3.17-3.04(m,1H),2.97-2.87(m,2H),2.87-2.62(m,6H),2.5 7-2.52(m,1H),2.25-1.88(m,6H),1.88-1.70(m,4H),1.67-1.51(m,1H),1.29-1.08(m,14H).

[0394] LCMS m / z=418.0[M / 2+1] +

[0395] Example 15: Preparation of Compound 15

[0396] Step 1: Preparation of 15b

[0397] 15a (1.28 g, 3.48 mmol) (synthesis method, see Bioorg. Med. Chem. Lett. 2016, 26, 5877-5882), cesium carbonate (2.27 g, 6.97 mmol), palladium acetate (0.16 g, 0.71 mmol), XantPhos (0.20 g, 0.35 mmol), and 15A (0.89 g, 4.91 mmol) were added to a 1,4-dioxane solution (40 mL) and reacted at 105°C under a nitrogen atmosphere for 3 h. The reaction system was cooled to room temperature, water (100 mL) was added, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-7:3) to obtain 15b (1.30 g, 80% yield).

[0398] LCMS m / z=468.4[M+1] +

[0399] Step 2: Preparation of 15c

[0400] 15b (1.30 g, 2.78 mmol) was added to methanol (10 mL), followed by 10% palladium on carbon (1.33 g) and ammonium acetate (1.32 g, 17.13 mmol). The mixture was reacted at room temperature under a hydrogen balloon for 12 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:1) to afford 15c (0.76 g, 90% yield).

[0401] LCMS m / z=304.4[M+1] +

[0402] Step 3: Preparation of 15d

[0403] 15c (0.76 g, 2.55 mmol), 15B (0.75 g, 7.49 mmol), and DIPEA (0.97 g, 7.50 mmol) were added sequentially to ethanol (50 mL) and reacted at 100°C for 48 h. The reaction system was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-6:94) to afford 15d (0.70 g, 68% yield).

[0404] LCMS m / z=404.2[M+1] +

[0405] Step 4: Preparation of 15e

[0406] 15d (700 mg, 1.74 mmol) and DIPEA (671 mg, 5.19 mmol) were added to THF (20 mL), and triphosgene (565 mg, 1.90 mmol) was slowly added. The reaction was allowed to react at room temperature for 1 h. Aqueous ammonia (5 mL) was added to the reaction system, and the reaction was continued at 50°C for 2 h. The reaction system was cooled to room temperature, and water (50 mL) was added. The mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-1:9) to obtain 15e (700 mg, yield: 90%).

[0407] Step 5: Preparation of 15f

[0408] 15e (0.70 g, 1.57 mmol) was added to acetonitrile (30 mL), followed by a 40% benzyltrimethylammonium hydroxide solution in methanol (2 mL). The reaction was allowed to proceed at 60°C for 2 h. The reaction system was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-8:92) to afford 15f (530 mg, 84% yield).

[0409] LCMS m / z=401.4[M+1] +

[0410] Step 6: Preparation of compound 15

[0411] To a reaction flask, 15f (0.15 g, 0.37 mmol), 2 mL of trifluoroacetic acid, and 3 mL of dichloromethane were added and allowed to react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, triethylamine was added to adjust the pH to 7, and the solution was concentrated under reduced pressure. The residue was dissolved in 5 mL of DMA, and 1a (0.23 g, 0.47 mmol), 0.5 mL of acetic acid, and sodium triacetoxyborohydride (0.24 g, 1.13 mmol) were added sequentially. The reaction was allowed to react at room temperature for 16 h. 10 mL of methanol was added to the reaction solution, which was concentrated under reduced pressure. The reaction solution was then subjected to pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The crude product in DMSO was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was ammonium acetate (5 mmol / L) in water / acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 10% to 70% (elution time 12 min), and lyophilized to obtain compound 15 (0.20 g, yield: 70%).

[0412] 1 H NMR(400MHz,DMSO-d6)δ10.21(s,1H),7.74(d,2H),7.64(d,1H),7.47(d,1H),6.99-6.91(m,3H ),6.91-6.85(m,1H),6.85-6.77(m,1H),6.64(d,1H),6.54(dd,1H),4.27(s,1H),4.05(d,1H),3 .97-3.81(m,5H),3.80-3.72(m,1H),3.70-3.61(m,2H),2.99-2.73(m,6H),2.73-2.57(m,4H),2 .24-2.13(m,2H),2.13-2.02(m,1H),1.93-1.72(m,5H),1.69-1.54(m,1H),1.29-1.10(m,14H).

[0413] LCMS m / z=774.6[M+1] + .

[0414] Example 16: Preparation of Trifluoroacetate Salt of Compound 16

[0415] Step 1: Preparation of 16b trifluoroacetate

[0416] 16a (2.77 g, 11.48 mmol) was dissolved in 5 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the crude trifluoroacetate salt of 16b (3.0 g).

[0417] Step 2: Preparation of 16c

[0418] The trifluoroacetic acid salt of the crude product 16b (3.0 g), ethyl 4-fluorobenzoate (1.85 g, 11.00 mmol), potassium carbonate (3.04 g, 22.00 mmol), and 15 mL of dimethyl sulfoxide were added to a reaction flask and reacted at 100°C for 16 h. The reaction system was cooled to room temperature, and 100 mL of water and 100 mL of ethyl acetate were added to the reaction solution. The layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, 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) = 1:0-1:1) to obtain 16c (2.5 g, yield: 79%).

[0419] Step 3: Preparation of 16d

[0420] To a reaction flask, 16c (2.4 g, 8.29 mmol), potassium hydroxide (1.86 g, 33.21 mmol), 10 mL of ethanol, 10 mL of tetrahydrofuran, and 10 mL of water were added and allowed to react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, the pH was adjusted to 2 with 2 mol / L hydrochloric acid, and the filter cake was collected and dried under reduced pressure to afford crude product 16d (1.80 g).

[0421] LCMS m / z=262.1[M+1] +

[0422] Step 4: Preparation of 16e

[0423] To a reaction flask, the crude product 16d (0.68 g), HATU (0.99 g, 2.60 mmol), diisopropylethylamine (1.41 g, 10.91 mmol), and 10 mL of DMF were added, respectively. After stirring at room temperature for 0.5 h, trans-4-(3-amino-2,2,4,4-tetramethylcyclobutoxy)-2-methoxybenzonitrile hydrochloride (0.57 g, 1.83 mmol) (synthesis method, see CN115175901) was added, and the reaction was carried out at room temperature for 2 h. To the reaction solution were added 100 mL of water and 100 mL of ethyl acetate, the layers were separated, the aqueous phase was extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, 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) = 1:0-0:1) to give 16e (1.10 g, two-step yield based on compound 16c: 68%).

[0424] LCMS m / z=518.5[M+1] +

[0425] Step 5: Preparation of 16f

[0426] To a reaction flask, 16e (1.10 g, 2.13 mmol), Dess-Martin periodinane (1.08 g, 2.55 mmol), and 10 mL of dichloromethane were added and allowed to react at room temperature for 4 h. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-1:9) to afford 16f (0.9 g, 82% yield).

[0427] LCMS m / z=516.2[M+1] +

[0428] Step 6: Preparation of 16g

[0429] To a reaction flask, 16f (0.25 g, 0.485 mmol), the trifluoroacetate salt of crude product 5A (0.18 g), 0.2 mL of glacial acetic acid, and 3 mL of DMAc were added. The mixture was allowed to react at room temperature for 1 h, followed by the addition of sodium triacetoxyborohydride (0.30 g, 1.42 mmol) and the reaction was continued at room temperature for 16 h. 20 mL of water and 20 mL of ethyl acetate were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 0:1-1:9) to afford 16f (0.25 g, 69% yield).

[0430] LCMS m / z=750.4[M+1] +

[0431] Step 7: Preparation of trifluoroacetate salt of compound 16

[0432] To a reaction flask, 16 g (0.2 g, 0.27 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (0.069 g, 0.42 mmol), EDCI (0.13 g, 0.68 mmol), HOBt (0.073 g, 0.54 mmol), N-methylmorpholine (0.17 g, 1.68 mmol), and 4 mL of DMF were added and allowed to react at room temperature for 16 h. The reaction solution was then subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: The crude product in DMSO was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 10% to 50% (elution time 15 min), and lyophilized to obtain trifluoroacetic acid salt of compound 16 (50 mg).

[0433] 1 H NMR(400MHz,CD3OD)δ7.79-7.69(m,2H),7.59-7.47(m,2H),7.07-6.98(m,2H),6.76(d,1H),6.62(d,1H),6 .55(dd,1H),4.79-4.74(m,1H),4.29-4.18(m,2H),4.13(s,1H),3.93(s,3H),3.86-3.72(m,1H),3.67-3.54 (m,2H),3.51-3.40(m,1H),3.40-3.30(m,4H),3.26-3.15(m,1H),3.08-2.94(m,1H),2.89-2.74(m,4H),2. 74-2.65(m,1H),2.47-2.37(m,2H),2.35-2.25(m,1H),2.21-2.05(m,4H),1.87-1.70(m,5H),1.26(d,12H).

[0434] LCMS m / z=431.0[M / 2+1] +

[0435] The following compounds were obtained by referring to the synthesis methods of other examples:

[0436] Example 18: Preparation of Trifluoroacetate Salt of Compound 18

[0437] Compound 18 trifluoroacetate was obtained using compounds 16f and 7A as raw materials according to the synthetic method of Example 16.

[0438] 1 H NMR (400MHz, CD3OD) δ7.77-7.69(m,2H),7.59-7.47(m,2H),7.05-6.98(m,2H),6.76(d,1H),6.66-6.60(m,1H),6.55(dd,1H),4.79-4.74(m,1H), 4.28-4.18(m,2H),4.13(s,1H),3.93(s,3H),3.86-3.72(m,1H),3.67-3. 54(m,2H),3.51-3.40(m,1H),3.40-3.31(m,4H),3.27-3.15(m,1H),3.10 -2.94(m,1H),2.89-2.74(m,4H),2.74-2.63(m,1H),2.48-2.37(m,2H), 2.36-2.25(m,1H),2.21-2.05(m,4H),1.88-1.70(m,5H),1.26(d,12H).

[0439] LCMS m / z=860.4[M+1] +

[0440] Example 20: Preparation of Compound 20 Trifluoroacetate

[0441] Step 1: Preparation of 20b

[0442] Trans-4-(3-amino-2,2,4,4-tetramethylcyclobutyloxy)-2-methoxybenzonitrile hydrochloride (3.93 g, 12.64 mmol) (synthesis method, see CN115175901) was dissolved in 30 mL of DMF, and DIPEA (5.84 g, 45.18 mmol), HATU (5.16 g, 13.57 mmol), and 20a (2.0 g, 9.04 mmol) were added. The reaction was allowed to react at room temperature under a nitrogen atmosphere for 16 h. 50 mL of ethyl acetate and 50 mL of purified water were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (25 mL x 2). The organic phases were combined, washed with 25 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to obtain 20b (4.0 g, yield: 93%).

[0443] LCMS m / z=478.3[M+1] +

[0444] Step 2: Preparation of 20c

[0445] 20b (4.0 g, 8.38 mmol) was dissolved in 80 mL of dichloromethane, and Dess-Martin periodinane (4.27 g, 10.07 mmol) was added. The mixture was refluxed for 3 h. The reaction system was cooled to room temperature, and the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to obtain 20c (2.5 g, yield: 63%).

[0446] LCMS m / z=476.2[M+1] +

[0447] Step 3: Preparation of trifluoroacetate salt of compound 20

[0448] To a reaction flask, 1-E (0.3 g, 0.72 mmol), 1 mL of trifluoroacetic acid, and 3 mL of dichloromethane were added and allowed to react at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, and triethylamine was added to adjust the pH to 7. The solution was then concentrated under reduced pressure. To the residue was added 5 mL of N,N-dimethylacetamide, followed by 20c (0.34 g, 0.72 mmol), 0.3 mL of acetic acid, and sodium triacetoxyborohydride (0.31 g, 1.46 mmol). The reaction was continued at room temperature for 16 h. To the reaction solution, 15 mL of dichloromethane and 15 mL of saturated sodium bicarbonate aqueous solution were added. The aqueous phase was extracted with dichloromethane (15 mL x 3). The organic phases were combined, washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified using a silica gel column (dichloromethane:methanol (v / v) = 10:1). The crude product was subjected to Pre-HPLC (instrument and preparative column: Waters 2767 Preparative Liquid Phase, preparative column model: SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 10% to 50% (elution time 15 min). The product was lyophilized to obtain the trifluoroacetate salt of compound 20 (50 mg).

[0449] 1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),7.74(d,2H),7.64(d,1H),7.48(d,1H),6.97(d,2H),6.78 (d,1H),6.66-6.57(m,2H),6.54(dd,1H),4.27(s,1H),4.05(d,1H),3.97-3.85(m,5H),3.81(dd ,1H),3.77-3.68(m,1H),3.02-2.86(m,3H),2.86-2.75(m,2H),2.75-2.55(m,4H),2.50-2.39(m ,2H),2.35-2.22(m,1H),2.18-2.04(m,1H),2.03-1.80(m,5H),1.67-1.43(m,3H),1.19(d,12H).

[0450] LCMS m / z=389.4[M / 2+1] +

[0451] Example 21: Preparation of Trifluoroacetate Salt of Compound 21

[0452] The trifluoroacetate salt of compound 21 was obtained using compound 20c and 2-D as raw materials according to the synthetic method of Example 20.

[0453] 1 H NMR(400MHz,DMSO-d6)δ10.76(s,1H),7.79-7.70(m,2H),7.64(d,1H),7.48(d,1H),7.01-6.91 (m,2H),6.78(d,1H),6.67-6.49(m,3H),4.27(s,1H),4.05(d,1H),3.97-3.85(m,5H),3.81(dd, 1H),3.78-3.68(m,1H),3.01-2.86(m,3H),2.86-2.75(m,2H),2.75-2.54(m,4H),2.50-2.39(m, 2H),2.36-2.22(m,1H),2.18-2.04(m,1H),2.03-1.80(m,5H),1.67-1.43(m,3H),1.19(d,12H).

[0454] LCMS m / z=777.4[M+1] +

[0455] Example 22: Preparation of Compound 22 Trifluoroacetate

[0456] Step 1: Preparation of 22a

[0457] To a reaction flask, 3-A (0.5 g, 1.43 mmol), 2 mL of trifluoroacetic acid, and 6 mL of dichloromethane were added and allowed to react at room temperature for 3 h. The reaction solution was concentrated under reduced pressure, and to the residue was added 5 mL of N,N-dimethylacetamide, followed by 20c (0.68 g, 1.43 mmol), 0.3 mL of acetic acid, and sodium triacetoxyborohydride (0.61 g, 2.88 mmol). The reaction was allowed to react at room temperature for 16 h. 15 mL of dichloromethane and 15 mL of saturated sodium bicarbonate aqueous solution were added to the reaction solution. The aqueous phase was extracted with dichloromethane (15 mL x 3). The organic phases were combined, washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 10:1) to afford 22a (0.4 g, yield: 39%).

[0458] LCMS m / z=710.3[M+1] +

[0459] Step 2: Preparation of trifluoroacetate salt of compound 22

[0460] To a reaction flask were added 22a (0.2 g, 0.28 mmol), EDCI (0.11 g, 0.57 mmol), HOBt (0.038 g, 0.28 mmol), and N-methylmorpholine (0.14 g, 1.38 mmol). (S)-3-Aminopiperidine-2,6-dione hydrochloride (0.092 g, 0.56 mmol) was then added under nitrogen. The reaction mixture was allowed to react at room temperature under nitrogen for 16 h. 15 mL of dichloromethane and 15 mL of purified water were added to the reaction solution. The aqueous phase was extracted with dichloromethane (15 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then subjected to pre-HPLC (instrument and preparative column: Waters 2767 Preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation: Filter the crude product in DMSO through a 0.45 μm filter to prepare a sample solution. Mobile phase: water (containing 0.1% TFA) / acetonitrile. Gradient elution: 10% to 50% acetonitrile (elution time 15 min). Lyophilize to obtain compound 22 trifluoroacetate (50 mg).

[0461] 1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.93(t,1H),7.74(d,2H),7.64(d,1H),7.48(d,1H), 7.35(d,1H),6.97(d,2H),6.71-6.62(m,2H),6.54(dd,1H),4.78-4.61(m,1H),4.27(s,1H) ,4.05(d,1H),3.98-3.78(m,6H),3.13-3.02(m,1H),3.02-2.91(m,2H),2.87-2.62(m,6H), 2.57-2.41(m,2H),2.36-2.21(m,1H),2.17-1.80(m,6H),1.66-1.44(m,3H),1.19(d,12H).

[0462] LCMS m / z=820.4[M+1] +

[0463] The following compounds were obtained by referring to the synthesis methods of other examples:

[0464] Example 24: Preparation of Compound 24 Trifluoroacetate

[0465] Compound 24 trifluoroacetate was obtained using compound 20c and 4-A as raw materials according to the synthetic method of Example 22.

[0466] 1 H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.98-7.88(m,1H),7.78-7.70(m,2H),7.68-7.61(m,1H) ,7.49(d,1H),7.35(d,1H),6.97(d,2H),6.73-6.61(m,2H),6.54(dd,1H),4.79-4.61(m,1H),4. 27(s,1H),4.05(d,1H),3.98-3.81(m,6H),3.14-3.03(m,1H),3.02-2.90(m,2H),2.87-2.61(m, 6H),2.58-2.42(m,2H),2.36-2.22(m,1H),2.17-1.81(m,6H),1.66-1.43(m,3H),1.19(d,12H).

[0467] LCMS m / z=820.4[M+1] +

[0468] Example 26: Preparation of Compound 26

[0469] Step 1: Preparation of 26b

[0470] The hydrochloride salt of 26a (5.0 g, 29.48 mmol), ethyl 4-fluorobenzoate (4.96 g, 29.50 mmol), potassium carbonate (10.19 g, 73.7 mmol), and 50 mL of dimethyl sulfoxide were added to a reaction flask and reacted at 100°C for 16 h. The reaction system was cooled to room temperature, and 100 mL of water and 100 mL of ethyl acetate were added to the reaction solution. The layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, 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) = 1:0-1:1) to obtain 26b (5.0 g, yield: 60%).

[0471] Step 2: Preparation of 26c

[0472] To a reaction flask, 26b (5.0 g, 17.77 mmol), potassium hydroxide (4 g, 71.43 mmol), 50 mL of ethanol, 50 mL of tetrahydrofuran, and 50 mL of water were added and allowed to react at room temperature for 16 h. The reaction system was concentrated under reduced pressure, and the pH was adjusted to 2 with 2 mol / L hydrochloric acid. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product 26c (3.0 g).

[0473] LCMS m / z=254.1[M+1] +

[0474] Step 3: Preparation of 26d

[0475] To a reaction flask, crude product 26c (0.82 g), HATU (2.46 g, 6.47 mmol), diisopropylethylamine (2.09 g, 16.17 mmol), and 10 mL of DMF were added. After stirring at room temperature for 0.5 h, trans-4-(3-amino-2,2,4,4-tetramethylcyclobutyloxy)-2-methoxybenzonitrile hydrochloride (1.0 g, 3.22 mmol) (synthesis method, see CN115175901) was added and the mixture was allowed to react at room temperature for 2 h. To the reaction mixture, 100 mL of water and 100 mL of ethyl acetate were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 to 0:1) to afford 26d (1.5 g, yield: 91%).

[0476] LCMS m / z=510.3[M+1] +

[0477] Step 4: Preparation of 26e

[0478] To a reaction flask, 26d (0.9 g, 1.77 mmol), Dess-Martin periodinane (0.9 g, 2.12 mmol), and 10 mL of dichloromethane were added and reacted at room temperature for 4 h. The reaction solution was washed with 10 mL of saturated sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield crude product 26e (0.9 g).

[0479] Step 5: Preparation of compound 26

[0480] Crude product 26e (0.25 g), crude intermediate 1 (0.2 g), 0.2 mL of glacial acetic acid, and 3 mL of DMAc were added to a reaction flask. The mixture was allowed to react at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.31 g, 1.46 mmol) was added and allowed to react at room temperature for 16 h. The reaction solution was subjected to pre-HPLC (instrument and preparative column: Waters 2767 preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: A DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system consisted of water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile. Gradient elution was performed: 10% to 50% acetonitrile (elution time 15 min). The mixture was then lyophilized to afford compound 26 (91 mg, two-step yield: 23% based on compound 26d).

[0481] 1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),7.75(d,2H),7.64(d,1H),7.48(d,1H),7.00(d,2H),6.79(d,1 H),6.67-6.58(m,2H),6.54(dd,1H),4.27(s,1H),4.05(d,1H),3.91(s,3H),3.85-3.77(m,1H),3.75 -3.59(m,3H),3.19-3.07(m,2H),3.04-2.89(m,3H),2.80-2.64(m,3H),2.63-2.52(m,4H),2.31-2.2 1(m,1H),2.18-2.05(m,1H),2.04-1.88(m,4H),1.88-1.68(m,3H),1.64-1.51(m,1H),1.18(d,12H).

[0482] LCMS m / z=809.4[M+1] +

[0483] Example 28: Preparation of Compound 28

[0484] Compound 28 was prepared from compounds 1-C and 15A by lyophilization using a neutral preparation method (aqueous solution of ammonium bicarbonate (10 mmol / L) / acetonitrile) according to the synthesis method of Example 15.

[0485] 1 H NMR(400MHz,DMSO-d6)δ10.33(s,1H),7.74(d,2H),7.64(d,1H),7.47(d,1H),7.00-6.90(m,3H),6 .72(d,1H),6.64(d,1H),6.54(dd,1H),4.27(s,1H),4.05(d,1H),3.91(s,3H),3.89-3.81(m,2H),3 .79-3.71(m,1H),3.60(t,2H),3.04-2.95(m,1H),2.94-2.85(m,2H),2.84-2.57(m,7H),2.19(d,2H ),2.11-2.00(m,1H),1.94-1.85(m,1H),1.85-1.71(m,4H),1.67-1.54(m,1H),1.28-1.10(m,14H).

[0486] LCMS m / z=792.6[M+1] +

[0487] Example 29: Preparation of Compound 29

[0488] Compound 29 was prepared from compounds 2-B and 15A by lyophilization using a neutral preparation method (aqueous solution of ammonium bicarbonate (10 mmol / L) / acetonitrile) according to the synthesis method of Example 15.

[0489] 1 H NMR(400MHz,DMSO-d6)δ10.33(s,1H),7.77-7.70(m,2H),7.64(d,1H),7.47(d,1H),7.00-6.91(m,3H) ,6.76-6.68(m,1H),6.64(d,1H),6.54(dd,1H),4.27(s,1H),4.05(d,1H),3.91(s,3H),3.91-3.81(m, 2H),3.79-3.71(m,1H),3.60(t,2H),3.06-2.94(m,1H),2.94-2.85(m,2H),2.84-2.55(m,7H),2.19(d ,2H),2.11-2.00(m,1H),1.94-1.85(m,1H),1.85-1.71(m,4H),1.67-1.53(m,1H),1.29-1.11(m,14H).

[0490] Example 30: Preparation of Compound 30

[0491] Step 1: Preparation of 30b trifluoroacetate

[0492] 30a (2.00 g, 5.06 mmol) (synthesis method reference US2023135173) was dissolved in 20 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added. The reaction was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of crude product 30b (3.00 g).

[0493] LCMS m / z=296.2[M+1] +

[0494] Step 2: Preparation of 30c

[0495] To a reaction flask were added 30A (1.43 g, 6.07 mmol) (synthesis method reference CN115974840), HATU (2.87 g, 7.56 mmol), diisopropylethylamine (1.96 g, 15.18 mmol), and 10 mL of DMF. After stirring at room temperature for 0.5 h, the trifluoroacetic acid salt of the crude product 30b (3.00 g) was added and stirred at room temperature for 2 h. The reaction mixture was added with 100 mL of water and filtered. The filter cake was collected and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 to 0:1) to obtain 30c (1.50 g, yield: 58%).

[0496] LCMS m / z=513.2[M+1] +

[0497] Step 3: 30d preparation

[0498] To a reaction flask, 30c (1.50 g, 2.93 mmol), Dess-Martin periodinane (2.49 g, 5.86 mmol), and 20 mL of dichloromethane were added and reacted at room temperature for 30 min. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure to afford crude product 30d (2.00 g).

[0499] LCMS m / z=511.3[M+1] +

[0500] Step 4: Preparation of compound 30

[0501] Crude product 30d (0.20 g), crude intermediate 1 (0.15 g), 0.2 mL of glacial acetic acid, and 5 mL of DMAc were added to a reaction flask. The mixture was allowed to react at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.25 g, 1.17 mmol) was added and allowed to react at room temperature for 16 h. The reaction solution was subjected to pre-HPLC (instrument and preparative column: SHIMADZU LC-20AP preparative HPLC, C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The crude product DMF solution was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile. Gradient elution was performed: acetonitrile was eluted from 52% to 82% (elution time 15 min). The mixture was then lyophilized to obtain compound 30 (16.2 mg, two-step yield: 7% based on compound 30c).

[0502] 1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),9.13-9.08(m,1H),8.74(dd,1H),8.30(d,1H),7.80-7. 69(m,3H),7.52(d,1H),6.96(d,3H),6.79(d,1H),6.62(d,1H),4.49(s,1H),4.15(d,1H),3.90 -3.76(m,3H),3.76-3.66(m,1H),3.00-2.84(m,3H),2.84-2.64(m,5H),2.64-2.54(m,1H),2. 54-2.45(m,1H),2.25-1.99(m,4H),1.99-1.68(m,6H),1.66-1.51(m,1H),1.35-1.11(m,14H).

[0503] LCMS m / z=812.4[M+1] +

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

[0505] Example 36: Preparation of Compound 36

[0506] Step 1: Preparation of 36b

[0507] 36a (10.00 g, 52.32 mmol) was dissolved in 100 mL of DMF, and potassium carbonate (14.46 g, 104.64 mmol) and deuterated iodomethane (9.10 g, 62.78 mmol) were added. The reaction was allowed to react at room temperature for 19 h. The reaction solution was poured into 200 mL of water and extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1-2:1) to obtain crude product 36b (11.5 g).

[0508] Step 2: Preparation of 36c

[0509] The crude product 36b (11.5 g) was dissolved in 100 mL of NMP, and cuprous cyanide (11.30 g, 126.17 mmol) was added. The reaction was carried out at 180°C for 19 h. The reaction solution was cooled to room temperature, and 10 mL of concentrated aqueous ammonia and 200 mL of water were added. The product was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1-2:1) to obtain 36c (7.5 g, two-step yield: 93% based on compound 36a).

[0510] Step 3: Preparation of 36d

[0511] 36h (8.37 g, 34.38 mmol) was dissolved in 50 mL of THF, and 60% sodium hydride (1.65 g) was added at 0°C. After reacting at 0°C for 30 min, 36c (5.30 g, 34.38 mmol) was added and reacted at room temperature for 19 h. The reaction solution was poured into 100 mL of water and extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1-2:1) to obtain 36d (2.5 g, yield: 19%).

[0512] LCMS m / z=378.3[M+1] +

[0513] Step 4: Preparation of 36e hydrochloride

[0514] 36d (2.5 g, 6.62 mmol) was dissolved in 5 mL of ethyl acetate, and 10 mL of a 4 mol / L hydrochloric acid ethyl acetate solution was added. The reaction was allowed to react at room temperature for 5 h. The reaction system was filtered, and the filter cake was collected and dried under reduced pressure to give the crude hydrochloride salt of 36e (3.5 g).

[0515] LCMS m / z=278.2[M+1] +

[0516] Step 5: Preparation of 36f

[0517] To a reaction flask were added 30A (1.35 g, 5.74 mmol) (synthesis method, see CN115974840), HATU (2.73 g, 7.17 mmol), diisopropylethylamine (1.85 g, 14.34 mmol), and 10 mL of DMF. After stirring at room temperature for 0.5 h, the hydrochloride salt of the crude product 36e (2.5 g) was added and stirred at room temperature for 2 h. The reaction mixture was added with 100 mL of water and filtered. The filter cake was collected and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 to 0:1) to afford 36f (1.6 g, 68% yield over two steps based on compound 36d).

[0518] LCMS m / z=495.3[M+1] +

[0519] Step 6: Preparation of 36g

[0520] To a reaction flask, 36f (99 mg, 0.20 mmol), Dess-Martin periodinane (0.17 g, 0.40 mmol), and 3 mL of dichloromethane were added and allowed to react at room temperature for 30 min. The reaction system was then added with 10 mL of saturated aqueous sodium bicarbonate solution and extracted with 30 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 36 g (110 mg) of the crude product.

[0521] Step 7: Preparation of compound 36

[0522] To a reaction flask, 36 g (0.11 g) of the crude product, crude intermediate 1 (0.12 g), 0.1 mL of glacial acetic acid, and 5 mL of DMAc were added. The mixture was allowed to react at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.13 g, 0.6 mmol) was added and allowed to react at room temperature for 16 h. The reaction solution was subjected to pre-HPLC (instrument and preparative column: SHIMADZU LC-20AP preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: A DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system consisted of water (containing 10 mmol / L NH₄HCO₃) / acetonitrile. Gradient elution was performed: 53% to 83% acetonitrile (elution time 15 min). The elution was then lyophilized to afford compound 36 (46 mg, two-step yield: 29% based on compound 36f).

[0523] 1 H NMR(400MHz, CDCl3)δ7.89(s,1H),7.68(d,2H),7.45(d,1H),6.91(d,2H),6.78-6.65(m,1H),6.54 -6.43(m,2H),6.40(dd,1H),6.10(d,1H),4.15(d,1H),4.04(s,1H),3.93-3.71(m,3H),3.68-3.50 (m,1H),3.16-2.99(m,1H),2.99-2.71(m,7H),2.71-2.55(m,2H),2.35-2.07(m,5H),2.02-1.61(m,6H),1.39-1.17(m,14H).

[0524] LCMS m / z=794.7[M+1] +

[0525] The following compounds were obtained by referring to the synthesis methods of other examples:

[0526] Example 40: Preparation of Compound 40

[0527] Compound 40 was obtained using compound 36g and 5A trifluoroacetate as raw materials, referring to the synthetic method of Example 11.

[0528] 1 H NMR(400MHz,DMSO-d6)δ10.82(s,1H),7.94(t,1H),7.78-7.68(m,2H),7.64(d,1H),7.47 (d,1H),7.36(d,1H),6.95(d,2H),6.74-6.59(m,2H),6.54(dd,1H),4.79-4.65(m,1H),4. 27(s,1H),4.05(d,1H),3.93-3.76(m,3H),3.17-3.05(m,1H),3.00-2.61(m,8H),2.58-2 .44(m,1H),2.25-1.88(m,6H),1.87-1.70(m,4H),1.67-1.51(m,1H),1.28-1.11(m,14H).

[0529] LCMS m / z=419.3[M / 2+1] +

[0530] Example 42: Preparation of Compound 42

[0531] Compound 42 was obtained using the hydrochloride of compound 36e and 5d as raw materials, referring to the synthetic method of Example 36.

[0532] 1H NMR (400MHz, DMSO-d6) δ10.75(s,1H),7.72(d,2H),7.64(d,1H),7.47(d,1H),6.95(d,2H),6.78(d,1H),6. 65-6.57(m,2H),6.56-6.50(m,1H),4.26(s,1H),4.04(d,1H),3.81(dd,1H),3.74-3.62(m,1H),3.29-3.22 (m,2H),3.21-3.12(m,2H),2.99-2.78(m,3H),2.75-2.54(m,4H),2.54-2.45(m,2H),2.43-2.34(m,2H),2. 17-1.90(m,5H),1.89-1.72(m,2H),1.71-1.63(m,2H),1.63-1.50(m,3H),1.50-1.39(m,2H),1.18(d,12H).

[0533] LCMS m / z=834.7[M+1] +

[0534] The following compounds were obtained by referring to the synthesis methods of other examples:

[0535] Example 48: Preparation of Compound 48

[0536] Compound 48 was obtained using compound 48a (synthesis method reference WO2021231927) and intermediate 1 as raw materials, referring to the synthesis method of Example 36.

[0537] 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),7.90(d,1H),7.73(d,2H),7.45(d,1H),7.23-7.17(m,1 H),7.03-6.97(m,1H),6.95(d,2H),6.79(d,1H),6.62(d,1H),4.32(s,1H),4.05(d,1H),3.90 -3.77(m,3H),3.76-3.67(m,1H),2.99-2.85(m,3H),2.83-2.55(m,6H),2.54-2.45(m,1H),2. 21-2.14(m,2H),2.14-2.02(m,2H),1.98-1.73(m,6H),1.65-1.53(m,1H),1.26-1.08(m,14H).

[0538] LCMS m / z=795.3[M+1] +

[0539] The following compounds were obtained by referring to the synthesis methods of other examples:

[0540] Example 54: Preparation of Compound 54

[0541] Compound 54 was obtained using compound 54a hydrochloride (synthesis method reference WO2021231927) and 5d as raw materials, referring to the synthesis method of Example 42.

[0542] 1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),7.90(d,1H),7.72(d,2H),7.45(d,1H),7.20(d,1H),7.04-6.90(m,3H),6.78 (d,1H),6.60(d,1H),4.32(s,1H),4.04(d,1H),3.81(dd,1H),3.74-3.62(m,1H),3.28-3.23(m,2H),3.20-3.15(m, 2H),2.97-2.79(m,3H),2.74-2.56(m,4H),2.55-2.51(m,2H),2.42-2.36(m,2H),2.14-2.03(m,2H),2.00-1.90(m, 3H),1.89-1.81(m,1H),1.81-1.73(m,1H),1.71-1.63(m,2H),1.62-1.50(m,3H),1.50-1.40(m,2H),1.17(d,12H).

[0543] LCMS m / z=835.4[M+1] +

[0544] The following compounds were obtained by referring to the synthesis methods of other examples:

[0545] Example 60: Preparation of Compound 60 Trifluoroacetic Acid

[0546] Step 1: Preparation of 60b

[0547] 60a (0.51 g, 2.15 mmol) (synthesis method see WO2023066350) was dissolved in 15 mL of DMF. Under nitrogen protection, trans-4-(3-amino-2,2,4,4-tetramethylcyclobutyloxy)-2-methoxybenzonitrile hydrochloride (1.00 g, 3.22 mmol) (synthesis method see CN115175901), N,N-diisopropylethylamine (1.39 g, 10.75 mmol) and HATU (0.98 g, 2.58 mmol) were added respectively, and the reaction was carried out at room temperature for 16 h. To the reaction solution were added 30 mL of ethyl acetate and 30 mL of water, and the layers were separated. The aqueous phase was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to obtain 60b (0.8 g, yield: 75%).

[0548] LCMS m / z=494.2[M+1] +

[0549] Step 2: Preparation of 60c

[0550] Dissolve 60b (0.8 g, 1.62 mmol) in 15 mL of dichloromethane, add Dess-Martin periodinane (0.82 g, 1.94 mmol), and allow to react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to afford 60c (0.6 g, 75% yield).

[0551] LCMS m / z=492.4[M+1] +

[0552] Step 3: Preparation of trifluoroacetate salt of compound 60

[0553] Compound 60 trifluoroacetate was obtained using compound 60c and intermediate 1 as raw materials according to the synthetic method of Example 1.

[0554] 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.23(d,1H),7.86(d,1H),7.64(d,1H),7.42(d,1H),6.88(d,1H),6.80(d,1H ),6.67(d,1H),6.57(dd,1H),4.60-4.48(m,2H),4.40(s,1H),4.14-4.05(m,1H),4.04-3.98(m,1H),3.92(s,3H),3 .89-3.82(m,1H),3.70-3.57(m,2H),3.39-3.30(m,1H),3.19-2.98(m,6H),2.93-2.82(m,1H),2.81-2.62(m,3H),2 .56-2.52(m,1H),2.31-2.21(m,1H),2.20-2.06(m,1H),2.06-1.79(m,4H),1.70-1.56(m,1H),1.34-1.14(m,14H).

[0555] LCMS m / z=793.8[M+1] +

[0556] Example 62: Preparation of Compound 62 Trifluoroacetic Acid

[0557] Compound 62 trifluoroacetate was prepared from compounds 60c and 28f by the method of Example 15, followed by acidic preparation (water (containing 0.1% TFA) / acetonitrile) and lyophilization.

[0558] 1 H NMR (400MHz, DMSO-d6) δ10.36(s,1H),8.23(d,1H),7.86(d,1H),7.64(d,1H),7.42(d,1H),7.03(d,1H),6. 96-6.86(m,1H),6.67(d,1H),6.57(dd,1H),4.61-4.47(m,2H),4.40(s,1H),4.14-4.08(m,1H),4.04-3.98 (m,1H),3.91(s,3H),3.68-3.58(m,4H),3.43-3.33(m,1H),3.19-3.00(m,6H),2.95-2.82(m,1H),2.81-2. 61(m,4H),2.31-2.17(m,1H),2.08-1.97(m,1H),1.95-1.80(m,2H),1.72-1.57(m,1H),1.32-1.12(m,14H).

[0559] LCMS m / z=794.6[M+1]+

[0560] Example 64: Preparation of Compound 64 Trifluoroacetic Acid

[0561] Step 1: Preparation of 64b

[0562] 64a (1.12 g, 4.74 mmol) (synthesis method see WO2021249534A1) was dissolved in 30 mL of DMF. Under nitrogen protection, trans-4-(3-amino-2,2,4,4-tetramethylcyclobutyloxy)-2-methoxybenzonitrile hydrochloride (2.21 g, 7.11 mmol) (synthesis method see CN115175901), N,N-diisopropylethylamine (3.06 g, 23.70 mmol) and HATU (2.16 g, 5.69 mmol) were added respectively, and the reaction was carried out at room temperature for 16 h. To the reaction solution were added 50 mL of ethyl acetate and 50 mL of water, and the layers were separated. The aqueous phase was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to give 64b (1.5 g, yield: 64%).

[0563] LCMS m / z=493.2[M+1]+

[0564] Step 2: Preparation of 64c

[0565] 64b (1.5 g, 3.04 mmol) was dissolved in 30 mL of dichloromethane, and Dess-Martin periodinane (1.55 g, 3.65 mmol) was added. The reaction was allowed to react at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:2) to afford 64c (1.4 g, yield: 93%).

[0566] LCMS m / z=491.2[M+1] +

[0567] Step 3: Preparation of trifluoroacetate salt of compound 64

[0568] Compound 64 trifluoroacetate was obtained using compound 64c and intermediate 1 as raw materials according to the synthetic method of Example 1.

[0569] 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.63(d,1H),8.00(dd,1H),7.68-7.58(m,2H),6.97-6.91(m,1H) ,6.88(d,1H),6.80(d,1H),6.64(d,1H),6.54(dd,1H),4.48-4.37(m,2H),4.26(s,1H),4.13-4.02(m,2H ),3.91(s,3H),3.89-3.82(m,1H),3.68-3.57(m,2H),3.40-3.30(m,1H),3.19-2.81(m,7H),2.81-2.58( m,3H),2.57-2.45(m,1H),2.27-2.07(m,2H),2.05-1.79(m,4H),1.70-1.57(m,1H),1.27-1.10(m,14H).

[0570] LCMS m / z=396.8[M / 2+1] +

[0571] The following compounds were obtained by referring to the synthesis methods of other embodiments:

[0572] Example 72: Preparation of Compound 72

[0573] Step 1: Preparation of 72a

[0574] To a reaction flask, 5d (1.00 g, 3.63 mmol), HATU (2.07 g, 5.45 mmol), diisopropylethylamine (1.41 g, 10.89 mmol), and 8 mL of DMF were added. After stirring at room temperature for 0.5 h, the crude trifluoroacetate salt of 30b (1.0 g) was added and stirred at room temperature for 2 h. The reaction mixture was added with 100 mL of water and filtered. The filter cake was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 to 0:1) to afford 72a (0.97 g, 48% yield).

[0575] LCMS m / z=553.4[M+1] +

[0576] Step 2: Preparation of 72b

[0577] To a reaction flask, 72a (0.97 g, 1.76 mmol), Dess-Martin periodinane (1.49 g, 3.52 mmol), and 20 mL of dichloromethane were added and reacted at room temperature for 30 min. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to afford crude product 72b (1.50 g).

[0578] LCMS m / z=551.3[M+1] +

[0579] Step 3: Preparation of Compound 72

[0580] Crude product 72b (0.10 g), crude intermediate 1 (0.15 g), 0.2 mL of glacial acetic acid, and 5 mL of DMAc were added to a reaction flask. The mixture was allowed to react at room temperature for 1 h. Then, sodium triacetoxyborohydride (0.25 g, 1.17 mmol) was added and allowed to react at room temperature for 16 h. The reaction solution was then subjected to pre-HPLC (instrument and preparative column: SHIMADZU LC-20AP preparative HPLC, SunFire@Prep C18, 5 μm, i.d. x length = 19 mm x 250 mm). Preparation method: A DMSO solution of the crude product was filtered through a 0.45 μm filter to prepare the sample solution. The mobile phase system was water (containing 10 mmol / L NH₄HCO₃) / acetonitrile. Gradient elution method: acetonitrile was gradient eluted from 53% to 83% (elution time 15 min), and lyophilized to give compound 72 (27.0 mg, two-step yield based on compound 72a: 27%).

[0581] 1H NMR(400MHz,DMSO-d6)δ10.76(s,1H),9.10(dd,1H),8.74(dd,1H),8.30(d,1H),7.80-7.68(m,3H),7 .54(d,1H),7.01-6.90(m,3H),6.78(d,1H),6.61(d,1H),4.49(s,1H),4.15(d,1H),3.81(dd,1H),3.7 4-3.63(m,1H),3.30-3.24(m,4H),3.22-3.14(m,2H),2.98-2.78(m,3H),2.78-2.46(m,5H),2.44-2. 35(m,2H),2.19-1.72(m,7H),1.72-1.63(m,2H),1.63-1.51(m,2H),1.50-1.41(m,2H),1.26(d,12H).

[0582] LCMS m / z=426.8[M / 2+1] +

[0583] Example 78: Preparation of Compound 78

[0584] Compound 78 was prepared by freeze-drying from compound 78a (synthesis method reference WO2021127443) and intermediate 2 using the synthesis method of Example 1 and neutral preparation (aqueous solution of ammonium bicarbonate (10 mmol / L) / acetonitrile).

[0585] 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),7.73(d,2H),7.44(d,1H),6.95(d,2H),6.79(d,1 H),6.73(s,2H),6.62(d,1H),4.22(s,1H),4.03(d,1H),3.90-3.76(m,3H),3.76-3.67( m,1H),3.00-2.85(m,3H),2.84-2.64(m,5H),2.64-2.54(m,1H),2.54-2.46(m,1H),2.4 3(s,6H),2.25-2.00(m,4H),1.99-1.70(m,6H),1.67-1.52(m,1H),1.26-1.07(m,14H).

[0586] LCMS m / z=789.4[M+1] +

[0587] Example 83: Preparation of Compound 83

[0588] Step 1: Preparation of 83b

[0589] Compound 83a (3.3 g, 8.96 mmol) (synthesis method, see Tetrahedron Letters, 2018, 59, 2030-2033) was dissolved in 20 mL of methanol, and 10% palladium on carbon (2.38 g) was added. The hydrogen atmosphere was replaced three times, and the reaction was continued at 45°C under a hydrogen atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain crude product 83b (2.55 g).

[0590] LCMS m / z=290.2[M+1] +

[0591] Step 2: Preparation of 83c

[0592] The crude product 83b (2.55 g) was dissolved in 20 ml of acetonitrile, and NBS (1.54 g, 8.64 mmol) was added, followed by stirring at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether (v / v) = 0:1-1:9) to afford 83c (3.1 g, 98% yield).

[0593] Step 3: Preparation of 83d

[0594] To the reaction flask were added 83c (1.00 g, 2.72 mmol), 2,6-bis(benzyloxypyridine-3-boronic acid pinacol ester (1.70 g, 4.08 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.22 g, 0.27 mmol) and cesium carbonate (1.77 g, 5.44 mmol), respectively. The nitrogen atmosphere was replaced three times, and 30 mL of 1,4-dioxane and 3 mL of water were added. The reaction was carried out at 100 °C under nitrogen atmosphere for 20 h. The reaction system was cooled to room temperature, 50 mL of water and 50 mL of ethyl acetate were added, the layers were separated, the aqueous phase was extracted with 50 mL of ethyl acetate, the organic phases were combined, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, 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) = 1:0-9:1) to obtain 83d (1.10 g, yield: 70%).

[0595] LCMS m / z=579.3[M+1] +

[0596] Step 4: Preparation of 83e

[0597] 83d (1.10 g, 1.90 mmol) was dissolved in 20 mL of tetrahydrofuran, and 10% palladium on carbon (1.0 g) was added. The hydrogen atmosphere was replaced three times, and the reaction was allowed to proceed at 45°C for 20 h under a hydrogen atmosphere. The reaction system was cooled to room temperature, filtered through a pad of celite, and the filter cake was washed with 30 mL of tetrahydrofuran. The filtrate was collected and the filter cake was dried under reduced pressure to afford 83e (0.70 g, yield: 92%).

[0598] LCMS m / z=401.2[M+1] +

[0599] Step 5: Preparation of 83f

[0600] 83e (200 mg, 0.50 mmol) was dissolved in 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction was allowed to react at room temperature for 3 h. The reaction system was concentrated under reduced pressure, and 5 mL of dichloromethane and 1 mL of triethylamine were added, followed by concentration under reduced pressure to obtain crude product 83f (150 mg).

[0601] LCMS m / z=301.3[M+1] +

[0602] Step 6: Preparation of Compound 83

[0603] Compound 83 was prepared from crude products 83f and 1a by the synthesis method of Example 1 and lyophilized via neutral preparation (aqueous solution of ammonium bicarbonate (10 mmol / L) / acetonitrile).

[0604] 1 H NMR(400MHz,DMSO-d6)δ10.76(s,1H),7.80-7.69(m,3H),7.64(d,1H),7.46(d,1H),7.11-7.04(m,1H ),7.00-6.90(m,2H),6.64(d,1H),6.54(dd,1H),4.65-4.49(m,1H),4.27(s,1H),4.05(d,1H),3.93- 3.79(m,5H),3.68(dd,1H),3.27-3.17(m,1H),2.99-2.86(m,2H),2.85-2.56(m,6H),2.56-2.50(m,1 H),2.25-2.08(m,3H),2.02-1.87(m,3H),1.87-1.70(m,4H),1.66-1.52(m,1H),1.29-1.08(m,14H).

[0605] LCMS m / z=774.5[M+1] +

[0606] Example 85: Preparation of Compound 85

[0607] Compound 85 was prepared from compound 36e hydrochloride and compound 60a by referring to the synthesis method of Example 60 and freeze-dried via neutral preparation (aqueous solution of ammonium bicarbonate (10 mmol / L) / acetonitrile).

[0608] 1 H NMR(400MHz,DMSO-d6)δ10.76(s,1H),8.24(d,1H),7.82(d,1H),7.64(d,1H),7.36( d,1H),6.79(d,1H),6.69-6.52(m,3H),4.55-4.44(m,2H),4.40(s,1H),4.00(d,1H), 3.81(dd,1H),3.76-3.67(m,1H),3.09-2.84(m,5H),2.79-2.54(m,4H),2.54-2.44( m,1H),2.24-2.00(m,4H),1.99-1.70(m,6H),1.66-1.52(m,1H),1.28-1.05(m,14H).

[0609] LCMS m / z=796.6[M+1] +

[0610] The following compounds were obtained by referring to the synthesis methods of other examples:

[0611] Example 89: Preparation of Compound 89

[0612] Compound 89 was prepared from trifluoroacetate of compound 30b and compound 60a by referring to the synthesis method of Example 60 and freeze-drying from neutral preparation (water (containing 10 mmol / L ammonium bicarbonate) / acetonitrile).

[0613] 1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),9.10(d,1H),8.76(d,1H),8.33-8.2 4(m,2H),7.83(d,1H),7.79-7.72(m,1H),7.36(d,1H),7.01(d,1H),6.79( d,1H),6.62(d,1H),4.61(s,1H),4.56-4.44(m,2H),4.12(d,1H),3.85-3. 77(m,1H),3.76-3.69(m,1H),3.10-2.85(m,5H),2.78-2.64(m,3H),2.64- 2.45(m,2H),2.23-2.15(m,2H),2.14-2.01(m,2H),1.99-1.72(m,6H),1.67-1.53(m,1H),1.28(d,12H),1.20-1.07(m,2H).

[0614] LCMS m / z=814.6[M+1] +

[0615] Example 93: Preparation of Compound 93

[0616] Compound 93 was prepared using compound 93a (for the synthesis method, see Tetrahedron Letters, 2018, 59, 2030-2033) as a starting material and following the synthesis method of Example 83.

[0617] 1 H NMR(400MHz,DMSO-d6)δ10.76(s,1H),7.80-7.67(m,3H),7.64(d,1H),7.46(d,1H),7.11-7.03(m, 1H),6.95(d,2H),6.64(d,1H),6.54(dd,1H),4.66-4.49(m,1H),4.27(s,1H),4.05(d,1H),3.93-3. 78(m,5H),3.68(dd,1H),3.29-3.15(m,1H),2.99-2.87(m,2H),2.86-2.56(m,6H),2.56-2.45(m,1H ),2.25-2.06(m,3H),2.02-1.87(m,3H),1.87-1.69(m,4H),1.66-1.52(m,1H),1.29-1.08(m,14H).

[0618] The following compounds were obtained by referring to the synthesis methods of other examples:

[0619] Example 97: Preparation of Compound 97 Trifluoroacetic Acid

[0620] Step 1: Preparation of 97b

[0621] To a reaction flask, 97a (5.0 g, 36.47 mmol), 1-bromo-2-butyne (9.7 g, 72.94 mmol), potassium carbonate (10.08 g, 72.94 mmol), potassium iodide (0.61 g, 3.67 mmol), and 100 mL of acetone were added and reacted at room temperature for 12 h. 200 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-1:1) to afford 97b (5.0 g, yield: 72%).

[0622] The trifluoroacetate salt of compound 97 was prepared from compounds 97b, 36h and intermediate 2 using the synthetic method of Example 36 and lyophilized using acidic preparation (water (containing 0.1% TFA) / acetonitrile).

[0623] 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),7.76(d,2H),7.64(d,1H),7.46(d,1H),6.99(d,2H),6.88(d,1H),6. 80(d,1H),6.69(d,1H),6.60(dd,1H),5.00-4.92(m,2H),4.25(s,1H),4.10-4.03(m,2H),3.95-3.78(m,3H ),3.68-3.57(m,2H),3.41-3.28(m,1H),3.21-2.97(m,4H),2.93-2.77(m,3H),2.77-2.60(m,3H),2.58-2. 48(m,1H),2.20-2.06(m,2H),2.05-1.91(m,2H),1.91-1.76(m,5H),1.71-1.56(m,1H),1.38-1.09(m,14H).

[0624] LCMS m / z=829.6[M+1] +

[0625] The following compounds were obtained by referring to the synthesis methods of other examples:

[0626] Example 101: Preparation of Trifluoroacetate Salt of Compound 101

[0627] Step 1: Preparation of 101b

[0628] 101a (10 g, 72.93 mmol), 2-cyclopropyloxyethyl 4-methylbenzenesulfonate (22.62 g, 88.25 mmol), and cesium carbonate (35.64 g, 109.38 mmol) were dissolved in 100 mL of DMF and reacted at 90°C for 16 h. The reaction system was cooled to room temperature, added to 300 mL of water, and extracted with ethyl acetate (200 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 1:0-1:1) to obtain 101b (10 g, yield: 62%).

[0629] The trifluoroacetate salt of compound 101 was prepared from compounds 101b, 36h and intermediate 2 by lyophilization in acidic preparation (water (containing 0.1% TFA) / acetonitrile) according to the synthesis method of Example 36.

[0630] 1 H NMR(400MHz,DMSO-d6)δ10.79(s,1H),7.76(d,2H),7.64(d,1H),7.48(d,1H),6.99(d,2H),6.88(d,1H) ,6.80(d,1H),6.65(d,1H),6.55(dd,1H),4.29-4.20(m,3H),4.13-3.99(m,2H),3.95-3.74(m,5H),3.70 -3.56(m,2H),3.46-3.38(m,1H),3.38-3.28(m,1H),3.24-2.98(m,4H),2.93-2.59(m,6H),2.56-2.46( m,1H),2.21-2.05(m,2H),2.05-1.75(m,4H),1.70-1.55(m,1H),1.37-1.08(m,14H),0.55-0.38(m,4H).

[0631] LCMS m / z=861.6[M+1] +

[0632] Example 105: Preparation of Compound 105

[0633] Step 1: Preparation of 105b

[0634] To a reaction flask, 105a (1.6 g, 11.67 mmol), 1-bromo-2-methoxyethane (3.80 g, 15.18 mmol), potassium carbonate (4.84 g, 35.02 mmol), potassium iodide (0.19 g, 1.14 mmol), and 15 mL of DMF were added and reacted at room temperature for 12 h. 100 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-3:1) to afford 105b (1.1 g, 48% yield).

[0635] LCMS m / z=196.1[M+1] +

[0636] Compound 105 was prepared using compounds 105b and 36h as raw materials according to the synthetic method of Example 36.

[0637] 1 H NMR(400MHz,DMSO-d6)δ10.76(s,1H),7.73(d,2H),7.64(d,1H),7.46(d,1H),6.95(d,2H),6. 79(d,1H),6.70-6.58(m,2H),6.54(dd,1H),4.30-4.21(m,3H),4.04(d,1H),3.90-3.77(m,3H) ,3.76-3.66(m,3H),3.34(s,3H),3.00-2.85(m,3H),2.83-2.64(m,5H),2.64-2.54(m,1H),2. 54-2.46(m,1H),2.23-1.99(m,4H),1.99-1.72(m,6H),1.66-1.52(m,1H),1.27-1.09(m,14H).

[0638] LCMS m / z=835.3[M+1] +

[0639] The following compounds were obtained by referring to the synthesis methods of other examples:

[0640] Example 109: Preparation of Compound 109

[0641] Step 1: Preparation of 109b

[0642] To a reaction flask, 109a (5.0 g, 36.47 mmol), (bromomethyl)cyclopropane (6.4 g, 47.41 mmol), potassium carbonate (15.12 g, 109.41 mmol), potassium iodide (0.61 g, 3.67 mmol), and 50 mL of DMF were added and reacted at room temperature for 12 h. 200 mL of water was added to the reaction system, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-3:1) to afford 109b (6.2 g, yield: 89%).

[0643] LCMS m / z=192.1[M+1] +

[0644] Compound 109 was prepared using compounds 109b and 36h as raw materials according to the synthetic method of Example 36.

[0645] 1 H NMR(400MHz,DMSO-d6)δ10.76(s,1H),7.73(d,2H),7.63(d,1H),7.46(d,1H),6.95(d,2H),6.79( d,1H),6.66-6.58(m,2H),6.52(dd,1H),4.25(s,1H),4.04(d,1H),3.98(d,2H),3.89-3.77(m,3H ),3.76-3.67(m,1H),3.01-2.84(m,3H),2.83-2.64(m,5H),2.64-2.52(m,2H),2.24-1.98(m,4H) ,1.98-1.71(m,6H),1.66-1.51(m,1H),1.32-1.06(m,15H),0.64-0.57(m,2H),0.40-0.34(m,2H).

[0646] LCMS m / z=831.5[M+1] +

[0647] Example 113: Preparation of Compound 113 Trifluoroacetic Acid

[0648] Step 1: Preparation of 113b

[0649] 113a (5 g, 24.63 mmol) was dissolved in 100 mL of tetrahydrofuran and cooled to -78°C under nitrogen. A 1 mol / L solution of cyclopropylmagnesium bromide in tetrahydrofuran (24.63 mL) was added dropwise, and the temperature was slowly warmed to room temperature for 3 h. 100 mL of saturated aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 2:1) to obtain crude product 113b (3.3 g).

[0650] Step 2: Preparation of 113c

[0651] The crude product 113b (4.5 g) was dissolved in 20 mL of dichloromethane. Triethylsilane (3.20 g, 27.52 mmol) and trifluoroacetic acid (12.56 g, 110.16 mmol) were added at 0°C and reacted at 40°C for 2 h. The reaction solution was cooled to room temperature, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain 113c (4.0 g, two-step yield: 52% based on compound 113a).

[0652] Step 3: Preparation of 113d

[0653] 113c (4.0 g, 17.46 mmol) was added to 40 mL of DMF. Zinc cyanide (3.08 g, 26.23 mmol) and tetrakistriphenylphosphine palladium (2.02 g, 1.75 mmol) were added under nitrogen, and the reaction was carried out at 110°C for 2 h. The reaction solution was cooled to room temperature, and 60 mL of water and 60 mL of ethyl acetate were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1) to obtain 113d (2.2 g, yield: 72%).

[0654] LCMS m / z=176.1[M+1] +

[0655] The trifluoroacetate salt of compound 113 was prepared from compounds 113d and 36h by referring to the synthesis method of Example 36, and was prepared by acidic preparation (water (containing 0.1% TFA) / acetonitrile) and lyophilization.

[0656] 1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),7.81-7.65(m,3H),7.50(d,1H),7.04-6.93(m,3H),6.91-6.83 (m,2H),6.80(d,1H),4.25(s,1H),4.12-4.00(m,2H),3.96-3.79(m,3H),3.68-3.55(m,2H),3.41-3.2 7(m,1H),3.19-2.98(m,4H),2.93-2.59(m,8H),2.57-2.46(m,1H),2.21-2.05(m,2H),2.05-1.75(m, 4H),1.70-1.54(m,1H),1.38-1.09(m,14H),1.09-0.96(m,1H),0.57-0.47(m,2H),0.31-0.24(m,2H).

[0657] LCMS m / z=408.4[M / 2+1] +

[0658] The following compounds were obtained by referring to the synthesis methods of other examples:

[0659] Example 117: Preparation of Compound 117

[0660] Step 1: Preparation of 117b

[0661] To a reaction flask, 117a (5.00 g, 25.0 mmol), cyclopropylboronic acid (2.79 g, 32.48 mmol), palladium acetate (0.56 g, 2.49 mmol), tricyclohexylphosphine (0.76 g, 2.71 mmol), potassium phosphate (15.92 g, 75.0 mmol), and 100 mL of toluene were added. The mixture was reacted at 100°C for 3 h under nitrogen. The reaction system was cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to afford 117b (3.8 g, 94% yield).

[0662] Compound 117 was prepared using compounds 117b and 36h as raw materials according to the synthetic method of Example 36.

[0663] 1H NMR(400MHz,DMSO-d6)δ10.75(s,1H),7.79-7.60(m,3H),7.45(d,1H),6.95(d,2H),6.79(dd,2H),6.62(d, 1H),6.45(d,1H),4.24(s,1H),4.03(d,1H),3.93-3.76(m,3H),3.76-3.64(m,1H),3.00-2.84(m,3H),2.84 -2.55(m,6H),2.55-2.46(m,1H),2.25-2.00(m,5H),1.99-1.70(m,6H),1.68-1.52(m,1H),1.29-1.05(m,16H),0.86-0.74(m,2H).

[0664] LCMS m / z=801.4[M+1] +

[0665] Example 119: Preparation of Compound 119

[0666] Compound 119 was prepared from compound 117f by the synthesis method of Example 5, and was prepared by neutralization (10 mmol / L aqueous ammonium bicarbonate solution / acetonitrile) and lyophilization.

[0667] 1 H NMR(400MHz,DMSO-d6)δ10.82(s,1H),7.94(t,1H),7.79-7.63(m,3H),7.46(d,1H),7.36(d,1H), 6.95(d,2H),6.79(dd,1H),6.68(d,1H),6.45(d,1H),4.79-4.66(m,1H),4.24(s,1H),4.03(d,1H ),3.95-3.74(m,3H),3.17-3.05(m,1H),2.98-2.62(m,8H),2.58-2.48(m,1H),2.25-1.97(m,6H) ,1.97-1.87(m,1H),1.87-1.69(m,4H),1.68-1.51(m,1H),1.25-1.07(m,16H),0.85-0.75(m,2H).

[0668] LCMS m / z=844.5[M+1]+

[0669] The following compounds were obtained by referring to the synthesis methods of other examples:

[0670] Example 127: Preparation of Compound 127

[0671] Step 1: Preparation of 127b

[0672] 127a (4.98 g, 18.35 mmol) (synthesis method reference CN112912376) was dissolved in 20 mL of dichloromethane, and 10 mL of trifluoroacetic acid was added. The mixture was allowed to react at room temperature for 3 h. The reaction solution was concentrated under reduced pressure and dissolved in 50 mL of DMSO. DIPEA (11.86 g, 91.76 mmol) and tert-butyl 4-fluorobenzoate (3.6 g, 18.35 mmol) were added, respectively, and the mixture was allowed to react at 100°C for 19 h. The reaction solution was cooled to room temperature, and 100 mL of water and 100 mL of ethyl acetate were added. The layers were separated, and the aqueous phase was extracted with ethyl acetate (80 mL x 3). The organic phases were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate (v / v) = 5:1 to 1:1) to obtain 127b (2.75 g, yield: 43%).

[0673] Step 2: Preparation of 127c

[0674] Dissolve 127b (0.4 g, 1.15 mmol) in 2 mL of dichloromethane, add triethylamine (0.58 g, 5.73 mmol), cool the system to -50°C, and slowly add trifluoromethanesulfonic anhydride (0.39 g, 1.38 mmol) dropwise. Return the temperature to room temperature and allow to react for 3 h. The reaction solution is concentrated under reduced pressure to afford crude product 127c (1.0 g).

[0675] Step 3: Preparation of 127d

[0676] The crude product 127c (1.0 g) was dissolved in 5 mL of acetonitrile, and DIPEA (0.59 g, 4.6 mmol) and the crude intermediate 1 (0.30 g) were added, respectively, and the mixture was allowed to react at room temperature for 19 h. 10 mL of water and 20 mL of ethyl acetate were added to the reaction mixture, and the layers were separated. The aqueous phase was extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, 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) = 5:1-2:1) to afford 127d (0.45 g, two-step yield: 60% based on compound 127b).

[0677] Step 4: Preparation of 127e hydrochloride

[0678] Dissolve 127d (0.2 g, 0.31 mmol) in 2 mL of dichloromethane, add 4 mol / L hydrochloric acid in ethyl acetate (5 mL), and react at room temperature for 5 h. The reaction solution is concentrated under reduced pressure to obtain the crude hydrochloride of 127e (0.22 g).

[0679] LCMS m / z=591.3[M+1] +

[0680] Step 5: Preparation of Compound 127

[0681] The hydrochloride salt of the crude product 127e (0.22 g) was dissolved in 5 mL of DMF, and DIPEA (0.2 g, 1.55 mmol), HATU (0.18 g, 0.47 mmol), and the hydrochloride salt of 123A (96 mg, 0.31 mmol) were added, respectively. The mixture was reacted at room temperature under a nitrogen atmosphere for 16 h. 50 mL of ethyl acetate and 50 mL of purified water were added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (25 mL x 2). The organic phases were combined, washed with 25 mL of saturated brine, dried over anhydrous sodium sulfate, 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) = 1:2) to obtain compound 127 (110 mg, two-step yield: 42% based on compound 127d).

[0682] 1 H NMR(400MHz, CDCl3)δ7.88(s,1H),7.67(d,2H),7.45(d,1H),6.96-6.86(m,2H),6.72(d,1H) ,6.53-6.43(m,2H),6.40(dd,1H),6.10(d,1H),4.33-4.20(m,1H),4.18-4.10(m,1H),4.04(s ,1H),3.91(s,3H),3.84-3.72(m,1H),3.71-3.56(m,3H),3.56-3.46(m,1H),3.12-2.71(m,9H ),2.70-2.59(m,2H),2.32-2.07(m,6H),2.03-1.84(m,4H),1.79-1.62(m,4H),1.24(d,12H).

[0683] LCMS m / z=847.4[M+1] +

[0684] The following compounds were obtained by referring to the synthesis methods of other examples:

[0685] Biological test cases

[0686] 1. Detection of AR degradation in VCap cells

[0687] VCap is a human prostate cancer cell line purchased from ATCC. Culture conditions: DMEM + 10% FBS + 1% double-antibody, cultured at 37°C in a 5% CO2 incubator. Cells were plated in 6-well plates, 5×10 5 / well. After plating, different concentrations of compounds were added and cultured in a 37°C, 5% CO2 incubator for 24 hours. After the culture was completed, the cells were collected and lysed on ice for 15 minutes with RIPA lysis buffer (beyotime, Cat.P0013B). After centrifugation at 12000 rpm and 4°C for 10 minutes, the supernatant protein samples were collected and quantified using a BCA kit (Beyotime, Cat.P0009). The protein was diluted to 0.25 mg / mL and the expression of AR (CST, Cat.5153S) and the internal reference β-actin (CST, Cat.3700S) was detected using a fully automatic protein blot quantitative analyzer (Proteinsimple). The relative peak area of ​​AR was calculated using the "Compass for SW" software when the internal reference area was 10000. According to formula (1), the proportion of AR relative to the vehicle control group at different drug concentrations was calculated, where AR treat is the relative peak area of ​​the drug-treated group, AR solvent The data processed according to formula (1) were used to calculate DC using GraphPad Prism 8.3.0 software using a four-parameter nonlinear regression model. 50 The degradation rate at a specific concentration is 100-AR%; AR% = AR treat / AR solvent ×100% Formula 1

[0688] DCs that degrade AR protein in VCaP cells 50 The results are shown in Table 1.

[0689] Table 1 DCs of AR protein degradation in VCaP cells by the compounds of the present invention 50 value

[0690] Table 2 The degradation rate of AR protein in VCaP cells at a concentration of 30 nM by the compounds of the present invention

[0691] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good AR degradation activity.

[0692] 2. Pharmacokinetic Test in Rat

[0693] Experimental purpose: This study administered the test substance to SD rats by single-dose intravenous and oral gavage, determined the concentration of the test substance in rat plasma, and evaluated the pharmacokinetic characteristics of the test substance in rats.

[0694] Experimental animals: Male SD rats, 200-220 g, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0695] Experimental method: On the day of the experiment, 6 SD rats were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0696] Table 3 Dosing information for rat pharmacokinetic test *Dosage is based on the free base.

[0697] Sampling: Before and after drug administration, 0.1 mL of blood was collected from the eye socket under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. The tube was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma.

[0698] The time points for plasma collection in the IV&PO group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, 24, and 48 h.

[0699] All samples were stored at -60°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0700] Table 4 Pharmacokinetic parameters of the compounds of the present invention in rat plasma # Oral solvent is 5% DMSO + 5% Solutol + 30% PEG-400 + 60% (20% SBE-β-CD) ## Oral solvent is 5% DMSO + 5% Solutol + 10% PEG400 + 80% (20% SBE-β-CD) ### Oral solvent is 5% DMSO + 5% Solutol + 90% (20% SBE-β-CD)

[0701] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in rats.

[0702] 3. Inhibition of VCaP Cell Proliferation Experiment

[0703] Prostate cancer cells (VCaP) were purchased from ATCC and cultured in RPMI 1640 medium supplemented with 10% FBS at 37°C in a 5% CO2 incubator. Prior to the experiment, cells cultured in normal medium were passaged into phenol red-free RPMI 1640 supplemented with 10% charcoal-stripped FBS for 3 days. On day 4, cells were digested with phenol red-free digestion buffer (Trypsin LE trypsin) and discontinued with phenol red-free RPMI1640 medium supplemented with 1% charcoal-stripped FBS, 0.5% PS, and 0.1 nM R1881. Cells were resuspended by centrifugation and viable cells were counted using a Vi-Cell XR cell counter. The cell suspension was adjusted to the appropriate concentration using phenol red-free RPMI1640 medium supplemented with 1% charcoal-stripped FBS, 0.5% PS, and 0.1 nM R1881. 180 μl of the cell suspension was added to each well of a 96-well cell culture plate to a cell density of 7,500 cells per well. The plate was then plated and the T0 well was plated. The next day, R1881 was added to a final concentration of 0.1 nM and various concentrations of the compounds were added. The cells were then incubated in an incubator for an additional 7 days. The T0 plate was assayed using the CellTiter-Glo (CTG) (Promega, product number G7572) kit and recorded as RLU0. After the incubation period, 75 μl of pre-melted and room temperature CellTiter-Glo solution was added to each well and mixed for 2 minutes using a microplate shaker. After standing at room temperature for 10 minutes, the fluorescence signal was measured using an Envision 2104 plate reader. The results were processed according to formula (2) and the cell growth rate at each concentration of the compound was calculated in Excel. GraphPad software was used to calculate the compound concentration GI at which the proliferation rate reached 50%. 50 Value. compound The readings for the drug-treated groups, RLU control is the average value of the solvent control group. Growth%=(RLU compound -RLU0) / (RLU control -RLU0)×100% Formula (2)

[0704] GI inhibition of VCaP cell proliferation 50 The results are shown in Table 5.

[0705] Table 5 GI of the compounds of the present invention in inhibiting the proliferation of VCaP cells 50 value

[0706] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good VCaP cell proliferation inhibitory activity.

[0707] 4. Caco2 permeability test

[0708] The experiment used Caco-2 cell monolayers in 96-well Transwell plates, incubated in triplicate. Transport buffer (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing the compound of the invention (2 μM) or the control compounds digoxin (10 μM), nadolol (2 μM), and metoprolol (2 μM) was added to the apical or basolateral wells of the cell monolayer. Transport buffer containing DMSO was added to the corresponding receiving wells. After incubation at 37 ± 1°C for 2 hours, the cell plate was removed and appropriate samples were taken from the apical and basolateral wells to a new 96-well plate. Proteins were then precipitated by adding acetonitrile containing an internal standard. Samples were analyzed using LC-MS / MS to determine the concentrations of the compound of the invention and the control compound. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to basolateral side of the cell monolayer and from the basolateral to apical side, thereby calculating the efflux rate. The integrity of the cell monolayer after 2 hours of incubation was assessed by leakage of Lucifer Yellow.

[0709] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good Caco2 permeability.

[0710] 5. Pharmacokinetic Testing in Mice

[0711] Experimental purpose: This study administered the test substance to ICR mice by single-dose intravenous and oral gavage, measured the concentration of the test substance in mouse plasma, and evaluated the pharmacokinetic characteristics of the test substance in mice.

[0712] Experimental animals: Male ICR mice, 6 per compound, were purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0713] Experimental method: On the day of the experiment, 6 SD mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0714] Table 6 Dosing information for mouse pharmacokinetic test *Dosage is based on the free base.

[0715] Sampling: Before and after drug administration, 0.15 mL of blood was collected from the eye socket under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. The tube was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma.

[0716] The time points for plasma collection in the PO group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, 24, and 48 h.

[0717] The time points for plasma collection in group IV were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, 24, and 48 h.

[0718] All samples were stored at -60°C before analysis and quantitative analysis was performed using LC-MS / MS.

[0719] Table 7 Pharmacokinetic parameters of the compounds of the present invention in mouse plasma

[0720] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in mice.

[0721] 6. Pharmacokinetic Testing in Beagle Dogs

[0722] Experimental animals: Male beagle dogs, weighing about 8-10 kg, 6 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.

[0723] Experimental method: On the day of the experiment, 6 beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration.

[0724] Table 8. Dosing information for beagle dog pharmacokinetic study Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% NS; Oral (gavage) administration solvent: 5% DMSO + 5% Solutol + 10% PEG400 + 80% (20% SBE-CD); *Dosage is based on free base.

[0725] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected at the following time points for both the intravenous and oral administration groups: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0726] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in dogs.

[0727] 7. Monkey Pharmacokinetic Test

[0728] Test animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0729] Experimental method: On the day of the experiment, four monkeys were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration.

[0730] Table 9. Dosing information for monkey pharmacokinetic studies Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% NS; Oral (gavage) administration solvent: 5% DMSO + 5% Solutol + 10% PEG400 + 80% (20% SBE-CD); *Dosage is based on free base.

[0731] Before and after dosing, 1.0 mL of blood was collected from the jugular vein and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected at the following time points for both the intravenous and oral administration groups: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, and 48 hours. All samples were stored at -60°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0732] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in monkeys.

[0733] 8. hERG potassium channel effect test

[0734] Experimental platform: electrophysiology manual patch clamp system

[0735] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0736] Experimental methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. The tip resistance after perfusing the electrode liquid was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV to induce the hERG potassium current (I hERG ) was administered with a 2-second depolarization step from -80 mV to +20 mV, followed by repolarization to -50 mV for 1 second before returning to -80 mV. This voltage stimulus was administered every 10 seconds, and administration began after confirming that the hERG potassium current was stable (for at least 1 minute). Compounds were administered for at least 1 minute at each test concentration, and at least two cells (n ≥ 2) were tested for each concentration.

[0737] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula: Inhibition% = [1-(I / Io)] × 100%

[0738] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitudes of hERG potassium current before and after drug addition, respectively.

[0739] Compound IC 50 The results were calculated using GraphPad Prism 5 software by fitting the following equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0740] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0741] Conclusion: The compounds of the present invention, such as the example compounds, have no significant inhibitory effect on hERG potassium channel current. Specifically, the inhibitory activity IC of the trifluoroacetate of compound 1, trifluoroacetate of compound 2, trifluoroacetate of compound 3, trifluoroacetate of compound 4, compounds 11, 28, 30, 31, 34, 35, 73, 79, and 118 on hERG potassium channel current is 50 The values ​​were all greater than 40 μM.

[0742] 9. Liver microsome stability test

[0743] In this study, liver microsomes from five species, including humans, dogs, rats, and mice, were used as in vitro models to evaluate the metabolic stability of the test substances.

[0744] At 37°C, 1 μM of the test substance was incubated with microsomal proteins and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after a certain time (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. The T value was calculated based on the ln value of the drug residual rate in the incubation system and the incubation time. 1 / 2 , and further calculated the liver microsomal intrinsic clearance CL int(mic) and hepatic intrinsic clearance CL int(Liver) .

[0745] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good liver microsomal stability.

[0746] 10.CYP450 enzyme inhibition test

[0747] The purpose of this study was to evaluate the effects of test substances on the activities of five isoenzymes of cytochrome P450 (CYP) in human liver microsomes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) using an in vitro test system. Specific probe substrates for the CYP450 isoenzymes were incubated with human liver microsomes and varying concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and the IC values ​​were calculated. 50 The inhibitory potential of the test substance on each CYP enzyme isoform was evaluated.

[0748] Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on the five isoenzymes of CYP.

[0749] 11. Human CD34+ hematopoietic stem cell proliferation inhibition experiment

[0750] Human CD34+ hematopoietic stem cells (TPCS, Cat. hmPB34-P-2CW) were obtained from human PBMCs by immunomagnetic separation and expressed CD34. Culture conditions were: DPBS (Gibco, Cat. 14190-144) + StemSpan SFEMII (STEMCELL, Cat. 9655) + 1X StemSpan CD34+ Expansion Supplement (STEMCELL, Cat. 2691). 40 nL of DMSO, the positive control talazoparib, or the test compound were added to a 384-well plate (Corning, Cat. 3764). The cell suspension was then added at a density of 400 cells / 40 μL / well, resulting in a final concentration of 0.1% DMSO, 3 μM talazoparib, or various concentrations of the test compound. The cells were centrifuged at 1000 rpm for 1 minute at room temperature and then incubated at 37°C in a 5% CO2 incubator for 7 days. After the incubation, 20 μL of CellTiter-Glo Reagent (Promega, Cat. G7573) was added directly to each well, centrifuged at 1000 rpm for 1 minute at room temperature, and then incubated in the dark for 20 minutes. After the incubation, the chemiluminescent signal CFU was read and recorded using the Envision multi-mode microplate reader (PerkinElmer, Cat. 2104). The cell proliferation inhibition rate of different concentrations of compounds was calculated according to formula (3). high control is the average signal value of the DMSO group, CFU low control is the average signal value of Talazoparib group, CFU compound The data processed according to formula (3) were fitted with XLfit or GraphPad Prism software using four parameters to calculate the concentration IC of the compound when the inhibition rate was 50%. 50 value. Inhibiton%=(CFU high control -CFU compound ) / (CFU high control -CFU low control ) × 100% (Formula 3)

[0751] Conclusion: The compounds of the present invention, such as the example compounds, have no significant inhibitory effect on the proliferation of CD34+ hematopoietic stem cells. Specifically, the trifluoroacetic acid salt of compound 7, compound 11, and compound 31 have an inhibitory activity IC of CD34+ hematopoietic stem cell proliferation. 50 The values ​​were all greater than 10000nM.

[0752] 12. Study on AR degradation activity in MDA-PCA-2B cells

[0753] Human prostate cancer cells MDA-PCA-2B were cultured in a complete culture medium consisting of F-12K + 20% FBS + 25ng / ml cholera toxin + 10ng / ml mouse epidermal growth factor + 0.005mM phosphoethanolamine + 100pg / ml hydrocortisone + 45nM sodium selenite + 0.005mg / ml insulin at 37°C in a 5% CO2 incubator. Cells in the exponential growth phase were harvested and the cell suspension was adjusted to the appropriate concentration using hormone-deprived medium (containing 10% carbon-absorbed serum) for plating. Cells were plated in 12-well plates at 5×10 5 After plating, the cells were cultured in an incubator for 72 hours, then replaced with experimental medium (containing 1% carbon-adsorbed serum), and different concentrations of compounds were added, and cultured in an incubator at 37°C, 5% CO2 for 24 hours. After the incubation period, cells were washed with pre-chilled PBS and added with complete cell lysis buffer containing Protease / Phosphatase Inhibitor Cocktail (Cell Lysis Buffer Information: CST, Cat. 9803, diluted to 1X before use, Protease / Phosphatase Inhibitor Cocktail (100X) Information: Cat. 5872. The cocktail was then diluted 100-fold with 1X cell lysis buffer to obtain complete cell lysis buffer). After lysing on ice for 15 minutes, cells were scraped with a cell scraper into a new pre-chilled EP tube and centrifuged at 13,500 rpm at 4°C for 20 minutes. Supernatant protein samples were collected and quantified using a BCA kit (Thermofisher, Cat. 23225) and diluted to 2 mg / mL. The prepared sample was loaded into a 4-12% precast gel at a volume of 5 μL (10 μg). Androgen Receptor (D6F11) was detected using traditional Western blot method. Rabbit mAb (CST, Cat.5153S), and the internal reference β-Actin (CST, Cat.3700S) were used as secondary antibodies. HRP-labeled Anti-rabbit IgG Antibody (CST, Cat.7074V) and Anti-mouse IgG Antibody (CST, Cat.7076V) were used. The protein expression quantitative analysis software "Image Studio" was used to calculate the expression levels of AR and the internal reference. The degradation rate (% Degradation) of the compound at different concentrations was calculated according to formula (4), where R compound is the relative expression of AR in different concentrations of drug groups, AVE_R DMSO The relative expression of AR in the DMSO control group was averaged. GraphPad Prism software was then used to plot the inhibition curve and calculate DC 50 %Degradation=(AVE_R DMSO -R compound ) / AVE_R DMSO ×100% Formula (4)

[0754] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good degradation activity on AR protein in MDA-PCA-2B cells.

[0755] 13. Inhibition of MDA-PCA-2B cell proliferation experiment

[0756] Human prostate cancer cells (MDA-PCA-2B) were purchased from ATCC and cultured in a complete culture medium consisting of F-12K + 20% FBS + 25 ng / ml cholera toxin + 10 ng / ml mouse epidermal growth factor + 0.005 mM phosphoethanolamine + 100 pg / ml hydrocortisone + 45 nM sodium selenite + 0.005 mg / ml human recombinant insulin + 1% polysaccharide (PS) at 37°C in a 5% CO2 incubator. At the start of the experiment, cells were digested with 0.25% trypsin-EDTA (1x), phenol red, and the cells were then incubated with complete culture medium and centrifuged. The cells were resuspended in experimental culture medium (DMEM / F-12, without phenol red + 1% carbon-adsorbed FBS + 0.5% PS + 25ng / ml cholera toxin + 10ng / ml mouse epidermal growth factor + 0.005mM phosphoethanolamine + 100pg / ml hydrocortisone + 45nM sodium selenite + 0.005mg / ml human recombinant insulin), and the viable cells were counted using a cell counter. The cell suspension was adjusted to an appropriate concentration, and 100μl was seeded per well in a 96-well cell culture plate at a cell density of 30,000 cells / well, and incubated overnight. The next day, 100 μL of the diluted 2x working solution (containing test samples at different concentrations and exogenous androgen R1881) was added to make the total system 200 μL, and the final concentration of R1881 was 0.2 nM. The cells were placed in an incubator and incubated for 7 days. At the same time, the T0 well was set to detect the cell activity reading on Day 0 using the CellCounting-lite 2.0 (Vazyme, DD1101-03) kit on the day of compound treatment, and recorded as RLU0. After the incubation, 100 μL of the supernatant was discarded from each well, and 60 μL of CellCounting-lite 2.0 solution that had been melted and equilibrated to room temperature was added. The cells were mixed using a microplate shaker for 2 minutes, and then placed at room temperature for 30 minutes. The luminescence signal value was measured using a BMG multi-function microplate reader.

[0757] The results were processed according to formula (5), and the inhibition rate of each concentration of the compound was calculated in Excel. GraphPad software was used to calculate the concentration GI of the compound when the inhibition rate was 50%. 50Where RLU compound is the reading of the drug-treated group, and RLU control is the average value of the solvent control group. Inhibition% = 1-(RLU compound-RLU0) / (RLU control-RLU0)×100% Formula (5)

[0758] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity on the proliferation of MDA-PCA-2B cells.

[0759] 14. Inhibition of LNCaP AR F877L Cell proliferation assay

[0760] Prostate cancer cell LNCaP AR F877L The cells were constructed at WuXi AppTec using RPMI1640 medium supplemented with 10% FBS and cultured at 37°C in a 5% CO2 incubator. Prior to the experiment, cells cultured in normal medium were passaged into phenol red-free RPMI1640 supplemented with 10% charcoal-stripped FBS for 3 days. On day 4, cells were digested with phenol red-free digestion buffer (Trypsin LE trypsin) and discontinued with phenol red-free RPMI1640 medium containing 1% charcoal-stripped FBS, 0.5% PS, and 0.1 nM R1881. Cells were resuspended by centrifugation and viable cells were counted using a Vi-Cell XR cell counter. The cell suspension was adjusted to the appropriate concentration using phenol red-free RPMI1640 medium containing 1% charcoal-stripped FBS, 0.5% PS, and 0.1 nM R1881. 180 μl of the cell suspension was added to each well of a 96-well cell culture plate to a cell density of 2500 cells / well. The plate was then plated and the T0 well was plated. The next day, R1881 was added to a final concentration of 0.1 nM and various concentrations of the compounds were added. The cells were then incubated in an incubator for an additional 7 days. The T0 plate was assayed using the CellTiter-Glo (CTG) (Promega, product number G7572) kit and recorded as RLU0. After the incubation period, 75 μl of pre-melted and room temperature CellTiter-Glo solution was added to each well and mixed for 2 minutes using a microplate shaker. After standing at room temperature for 10 minutes, the fluorescence signal value (RLU) was measured using an Envision 2104 plate reader. The results were processed according to formula (6) and the inhibition rate (Inhibition%) of each compound concentration was calculated in Excel. GraphPad software was used to calculate the compound concentration at which the inhibition rate was 50%. 50 Value. compound The readings for the drug-treated groups, RLU control The average value of the solvent control group. Inhibition% = 1-(RLU compound -RLU0) / (RLUcontrol -RLU0)×100% Formula (6)

[0761] Conclusion: The compounds of the present invention, such as the compounds in the examples, have an effect on LNCaP AR F877L It has good inhibitory activity on cell proliferation.

[0762] 15.LNCaP AR F877L Study on AR degradation activity in cells

[0763] Prostate cancer cell LNCaP AR F877L This assay was constructed at WuXi AppTec, using RPMI1640 complete culture medium supplemented with 10% FBS and 1% PS, maintained at 37°C in a 5% CO2 incubator. Prior to the experiment, cells cultured in normal culture medium were passaged into phenol red-free RPMI1640 supplemented with 10% charcoal-stripped FBS for 3 days. On day 4, cells were digested with phenol red-free Trypsin LE and the cell suspension was adjusted to the appropriate concentration using hormone-deprived medium (containing 1% charcoal-stripped serum). Cells were plated in 24-well plates at a density of 50,000 cells per well. Following plating, cells were cultured in a humidified incubator for 24 hours before the addition of various compound concentrations. The cells were then incubated for an additional 24 hours at 37°C in a 5% CO2 incubator. After the culture, the cells were digested with phenol red-free digestion solution (Trypsin LE trypsin), and the digestion was stopped with phenol red-free RPMI1640 medium containing 1% activated carbon-adsorbed FBS + 0.5% PS. The cells were collected into 1.5 mL centrifuge tubes, resuspended by centrifugation, and washed twice with PBS. 20 μL of ice-cold complete cell lysis buffer containing Protease / Phosphatase Inhibitor Cocktail (cell lysis buffer RIPA information: Sigma, Cat. R0278; complete cell lysis buffer) was added to each tube. TM Mini protease inhibitor cocktail information: Roche, Cat. 04693124001; RIPA and cOmplete were mixed according to the instructions. TM After lysing cells on ice for 30 minutes using a complete cell lysis buffer prepared with a mini protease inhibitor cocktail, centrifuge at 12,000 × g at 4°C for 10 minutes, collect the supernatant protein sample, add SDS-PAGE protein loading buffer (5X), and heat the sample at 100°C for 10 minutes. A 15 μL load of the prepared sample was loaded onto a 4-12% precast gel and detected by traditional Western blotting for Androgen Receptor (D6F11). Rabbit mAb (CST, Cat. 5153S), and the expression of internal control β-Actin (CST, Cat. 3700S), the secondary antibody used was Anti-rabbit IgG (H+L) (DyLight TM 800 4X PEG Conjugate)(CST,Cat.5151), Anti-mouse IgG(H+L)(DyLight TM 680Conjugate) (CST, Cat. 5470). The protein expression quantitative analysis software "Image Studio" was used to calculate the expression levels of AR and internal reference, and the degradation rate (% Degradation) of the compound at different concentrations was calculated according to formula (7), where R compound is the relative expression of AR in different concentrations of drug groups, AVE_R DMSO The relative expression of AR in the DMSO control group was averaged. GraphPad Prism software was then used to plot the inhibition curve and calculate DC 50 %Degradation=(AVE_R DMSO -R compound ) / AVE_R DMSO ×100% Formula (7)

[0764] Conclusion: The compounds of the present invention, such as the compounds in the examples, have an effect on LNCaP AR F877L AR protein in cells has good degradation activity.

[0765] Reference compound structure:

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 the 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 X1 is selected from N or CR x1 ; X2 is selected from N or CR x2 ; X3 is selected from N or CR x3 ; X4 is selected from N or CR x4 ; X5 is selected from N or CR x5 ; At most 2 of X1, X2, X3, X4, and X5 are selected from N; Z1 is selected from N or CR z1 ; Z2 is selected from N or CR z2 ; Z3 is selected from N or CR z3 ; Z4 is selected from N or CR z4 ; At most 3 of Z1, Z2, Z3, and Z4 are selected from N; Y1 and Y2 are each independently selected from -CR y1 R y2 -、-(CR y1 R y2 )2-、-(CR y1 R y2 )3-; R 1 Selected from H, deuterium, C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R x1 , R x2 , R x3 , R x4 , R x5 , R z1 , R z2 , R z3 , R z4 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; or R x1 , R x2 , R x3 , R x4 Each independently selected from -S(=O)2NH2, -S(=O)2C 1-4 alkyl; Or, R x1 With R x2 , R x2 With R x3 , R x3 With R x4 , R x4 With R x5 , R 1 With R z3 , R 1 With R z1 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R s replaced by; R 2 , R 3 , R y1 , R y2 Each independently selected from H, deuterium, halogen, OH, NH2, CN, NO2, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, wherein the alkyl, alkenyl, alkynyl is optionally substituted by 1 to 4 deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; K is selected from The ring where the representative is located is an aromatic ring or a non-aromatic ring; 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 Ns; 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; or R s Each independently selected from -OC 3-6 Cycloalkyl.

2. The compound according to claim 1 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R x1 , R x2 , R x3 , R x4 , R x5 , R z1 , R z2 , R z3 , R z4 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; or R x1 , R x2 , R x3 , R x4 Each independently selected from -S(=O)2NH2, -S(=O)2C 1-4 alkyl; Or, R x1 With R x2 , R x2 With R x3 , R x3 With R x4 , R x4 With R x5 Direct connection to form C 4-6 A carbocyclic group, a 5-6 membered heteroaryl group or a 5-7 membered heterocyclic group, wherein the carbocyclic group, heteroaryl group or heterocyclic group is optionally substituted by 1 to 4 R s replaced by; Or, R 1 With R z3 , R 1 With R z1 directly connected to form a 5- to 7-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R s replaced by; 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 substituted by an alkoxy substituent; or R s Each independently selected from -OC 3-6 Cycloalkyl.

3. The compound according to claim 2 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: X3 Selected from CR x3 ; Y1 and Y2 are each independently selected from -CR y1 R y2 -、-(CR y1 R y2 )2-; R 1 is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R x1 , R x2 , R x3 , R x4 , R x5 , R z1 , R z2 , R z3 , R z4 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; or R x1 , R x2 , R x3 , R x4 Each independently selected from -S(=O)2NH2, -S(=O)2methyl, -S(=O)2ethyl; Or, R x1 With R x2 , R x2 With R x3 , R x3 With R x4 , R x4 With R x5 Direct connection is formed by 1 to 3 R s One of the following substituted groups: piperidinyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl; Or, R x1 With R x2 , R x2 With R x3 , R x3 With R x4 , R x4 With R x5 Direct connection is formed by 1 to 3 R s One of the following substituted groups: pyrrolidinyl, oxolanyl, oxhexyl, 1,3-dioxolane; Or, R 1 With R z3 , R 1 With R z1 Direct connection is formed by 1 to 4 R s The following structures are replaced: R 2 , R 3 , R y1 , R y2 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio is replaced by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; Ak1, Ak2, Ak3, Ak4, and 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 substituted by an alkoxy substituent; or R s Each is independently selected from propynyl and -O-cyclopropyl.

4. The compound according to claim 3 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B is selected from Or B is selected from X6 is selected from N or CH; X7 is selected from NH or O; At most 2 of Z1, Z2, Z3, and Z4 are selected from N; R 2 , R 3 Each is independently selected from H, deuterium, F, Cl, Br; R y1 , R y2 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio is substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2, CN, methyl, ethyl, methoxy; 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 Or 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: B is selected from Or B is selected from R x2 , R x3 , R x4 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, NH2, CN, NO2, COOH, CONH2, N(CH3)2, NHCH3, CF3, CHF2, CH2F, OCF3, OCH2F, OCD3, CH2OH, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, -CH2-cyclopropyl, -O-cyclopropyl; or R x2 , R x4 Each is independently selected from -S(=O)2CH3, -O-CH2-propynyl, -O-CH2-cyclopropyl, -O-CH2CH2-OCH3, -O-CH2CH2-O-cyclopropyl, 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 -Cy1-, -Cy1-Ak2-, -Cy1-CH2-, -Ak1-Cy1-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-; or L is selected from -Cy1-Ak2-Cy2-, -Cy1-O-Cy2-; Cy1, Cy2, and Cy3 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: K is selected from Or K is selected from Q is independently selected from a bond, NH, C(=O)NH; 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 one of the structural fragments shown in Table L-1.

7. The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in 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 a disease associated with AR activity or expression.

10. 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 drug for treating and inhibiting or degrading AR-related diseases.

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

12. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 7 or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition according to claim 8, the therapeutically effective amount preferably being 1-1500 mg, the disease preferably being cancer, preferably prostate cancer.

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