Compound for inhibiting Bcl-2 or Bcl-xL and application of compound in medicine

Abstract

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal of the compound, an intermediate and a preparation method of the compound, and application of the compound in preparation of drugs for treating diseases related to activity or expression quantity of Bcl-2 or Bcl-xL. # imgabs0 #

Description

A compound for inhibiting Bcl-2 or Bcl-xL and its application in medicine

[0001] The present invention relates to a compound of general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, as well as intermediates and preparation methods thereof, and use of the compound in the preparation of drugs for treating diseases associated with the activity or expression of Bcl-2 or Bcl-xL.

[0002] Apoptosis is a gene-regulated, autonomous, and orderly death process of most cells in an organism at a certain developmental stage. It plays an important role in tissue evolution, organ development, and the maintenance of the body's own stability. In malignant tumors, anti-apoptosis is considered to be a key feature. Therefore, specifically targeting the anti-apoptotic pathway has potential application prospects in cancer treatment. The Bcl-2 protein family consists of pro-apoptotic and anti-apoptotic proteins, which can regulate the intrinsic apoptotic pathway of cancer cells. Among them, Bcl-2, Bcl-xL, and Mcl-1, members of the Bcl-2 protein family, have been identified as anti-tumor targets. Inhibition of these proteins can promote Bax / Bak oligomerization and ultimately induce mitochondrial outer membrane permeabilization, followed by the release of cytochrome C and the activation of caspases, thereby executing cancer cell apoptosis.

[0003] Preclinical studies have shown that inhibiting Bcl-2 cannot improve ischemic retinopathy, while selective inhibition of Bcl-xL can selectively kill senescent cells, inhibit the resulting aging-related secretory phenotype, inhibit pathological angiogenesis and enhance vascular recovery in avascular areas (Cell Metabolism 33, 818–832, April 6, 2021); at the same time, since Bcl-2 is a molecule that multiple cells depend on for survival, simultaneous inhibition of Bcl-xL and Bcl-2 may cause apoptosis of normal eye tissues and cells, causing further eye lesions; therefore, the development of selective Bcl-xL inhibitors for the treatment of retinopathy-related eye diseases is expected to bring greater clinical benefits and relatively smaller toxic side effects.

[0004] Therefore, it is necessary to develop novel Bcl-xL inhibitor drugs for the treatment of diseases related to apoptosis.

[0005] Summary of the invention

[0006] The purpose of the present invention is to provide a class of heterocyclic compounds or pharmaceutically acceptable salts thereof, which are applied to Bcl-2 or Bcl-xL inhibitors. The compounds of the present invention can effectively inhibit Bcl-2 or Bcl-xL and can be used to treat diseases such as tumors or eye diseases.

[0007] The compounds of the present invention have the effect of selectively inhibiting Bcl-xL and have good inhibitory activity on WI-38 senescent cells stained with SA-β-galactosidase induced by mitomycin C. The compounds of the present invention have good pharmacokinetic properties (such as better exposure and better t 1 / 2 , CL, etc.), and has better liver microsome stability. The compound of the present invention has good proliferation inhibition activity on MOLT-4 cells, NCI-H446 cells, and Kasumi-1 cells and has no obvious hERG and CYP inhibition activity.

[0008] The present invention provides a compound of general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein

[0009] In some embodiments, Ring A, Ring C, and Ring D are each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a The ring C is optionally substituted with 1 to 4 R c The ring D is optionally substituted with 1 to 4 R d replace;

[0010] In some embodiments, Ring A, Ring C, and Ring D are each independently selected from phenyl, benzo 4-6 carbocyclyl, benzo 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, 9- to 10-membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a The ring C is optionally substituted with 1 to 4 R c The ring D is optionally substituted with 1 to 4 R d replace;

[0011] In some embodiments, Ring A is selected from The ring A is optionally substituted with 1 to 4 R a replace;

[0012] In some embodiments, ring C and ring D are each independently selected from The ring C is optionally substituted with 1 to 4 R c The ring D is optionally substituted with 1 to 4 R d replace;

[0013] In some embodiments, B is selected from -B1-, -N(R n)-B1-、-B1-N(R n )-;

[0014] In some embodiments, B is selected from -B1-, -N(CH3)-B1-, -B1-N(CH3)-;

[0015] In some embodiments, B1 is selected from 4 to 12 membered heterocyclyl, which is optionally substituted with 1 to 10 R b replace;

[0016] In some embodiments, B1 is selected from a 4- to 7-membered nitrogen-containing monocyclic heterocyclic group, a 5- to 10-membered nitrogen-containing cyclic heterocyclic group, a 5- to 11-membered nitrogen-containing spirocyclic heterocyclic group, and a 5- to 11-membered nitrogen-containing bridged heterocyclic group, wherein B1 is optionally substituted by 1 to 8 R b replace;

[0017] In some embodiments, B1 is selected from azetidinyl, aziridine, azetidinyl, azetidinyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclopentyl, azetidinyl spirocyclopentyl, azetidinyl spirocyclohexyl, azetidinyl spirocyclohexyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl, azetidinyl spiroazetidinyl pentyl, azetidinylspiroazetidin ... Hexylcyclopentyl, azetidinylcyclohexyl, azetidinylcyclohexyl, azetidinylcyclohexyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, piperazinylcyclopropyl, piperazinylcyclobutyl, piperazinylcyclopentyl, piperazinylcyclohexyl, piperazinylspirocyclopropyl, piperazinylazetidinyl, piperazinylazetidinyl, piperazinylazetidinyl, 3 ,8-diazabicyclo[3.2.1]octyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 5-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 3-azabicyclo[3.3.1]nonyl, 3,7-diazabicyclo[3.3.1]nonyl, wherein B1 is optionally substituted by 1 to 8 R b replace;

[0018] In some embodiments, B1 is selected from The B1 is optionally replaced by 1 to 8 R b replace;

[0019] In some embodiments, Selected from The left side is connected to ring A;

[0020] In some embodiments, Selected from The left side is connected to ring C;

[0021] In some embodiments, X is selected from -N(R x )S(=O)2-、-S(=O)2N(R x )-、 The left side is connected to ring C;

[0022] In some embodiments, X is selected from -NHS(=O)2-, the left side is connected to ring C;

[0023] In some embodiments, K is selected from 5-membered heteroaryl, wherein K is substituted by 1 to 3 R k1 , 1 R k2 replace;

[0024] In some embodiments, K is selected from

[0025] In some embodiments, R x Selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0026] In some embodiments, R x Selected from H;

[0027] In some embodiments, R n Selected from H, C 1-6 Alkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene or cycloalkyl is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0028] In some embodiments, R n Selected from H, C 1-4 alkyl;

[0029] In some embodiments, R n is selected from H, methyl, ethyl;

[0030] In some embodiments, R a , R b , R c Each independently selected from deuterium, halogen, cyano, OH, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(CH2) q -C 3-10 Carbocyclic ring, -(CH2) q -4 to 10 membered heterocyclic ring, wherein the -CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 is substituted by a substituent of a carbocyclic group or a 4- to 10-membered heterocyclic group;

[0031] Or any R b With R c directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R a1 replace;

[0032] Or any R b With R a directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R a1 replace;

[0033] In some embodiments, R a , R b , R c Each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -(CH2) q -C 3-6 Carbocyclic ring, -(CH2) q -4 to 7 membered heterocyclic ring, wherein the -CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 is substituted by a substituent of a carbocyclic group or a 4- to 7-membered heterocyclic group;

[0034] Or any R b With R c directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R a1 replace;

[0035] Or any R b With R a directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R a1 replace;

[0036] In some embodiments, any R b With R c directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R a1 replace;

[0037] In some embodiments, any R b With R a directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R a1 replace;

[0038] In some embodiments, R a , R b , R c Each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl, wherein the alkyl, alkynyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0039] In some embodiments, R a , R b , R cEach independently selected from deuterium, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 halogens, OH, cyano, NH2, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0040] In some embodiments, R a1 Each independently selected from halogen, OH, cyano, NH2, =O, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 The alkyl, alkynyl, alkoxy, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 substituents selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 is substituted by a substituent of a carbocyclic group or a 4- to 10-membered heterocyclic group;

[0041] In some embodiments, R a1 Each independently selected from halogen, OH, cyano, NH2, =O, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the alkyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 is substituted by a substituent of a carbocyclic group or a 4- to 7-membered heterocyclic group;

[0042] In some embodiments, R a1Each independently selected from halogen, OH, cyano, NH2, =O, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl, wherein the alkyl, alkynyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0043] In some embodiments, R a1 Each independently selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0044] In some embodiments, R d , R k1 Each independently selected from deuterium, CD3, halogen, cyano, OH, NO2, COOH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -OC 3-6 Cycloalkyl, -(CH2) q -C 3-10 Carbocyclic ring, -(CH2) q -4 to 10 membered heterocyclic ring, -S(=O)2R 1 、-S(=O)2NR 1 R 2 、-C(=O)NR 1 R 2 、C(=O)NR 1 S(=O)2R 3 、-C(=O)R 1The -CH2-, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, CD3, halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 is substituted by a substituent of a carbocyclic group or a 4- to 10-membered heterocyclic group;

[0045] In some embodiments, R d , R k1 Each independently selected from deuterium, CD3, halogen, cyano, OH, NO2, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -OC 3-6 Cycloalkyl, -(CH2) q -C 3-6 Carbocyclic ring, -(CH2) q -4 to 7 membered heterocyclic ring, -S(=O)2R 1 、-S(=O)2NR 1 R 2 、-C(=O)NR 1 R 2 、C(=O)NR 1 S(=O)2R 3 、-C(=O)R 1 The -CH2-, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, CD3, halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 is substituted by a substituent of a carbocyclic group or a 4- to 7-membered heterocyclic group;

[0046] In some embodiments, R d , R k1 Each independently selected from deuterium, CD3, halogen, cyano, OH, NO2, COOH, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4Alkoxy, C 1-4 Alkylthio, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -S(=O)2NH2, -C(=O)NH2, -S(=O)2C 1-4 Alkyl, -S(=O)2-C 3-6 Cycloalkyl, -S(=O)2NHC 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -C(=O)-C 3-6 Cycloalkyl, -C(=O)NHC 1-4 Alkyl, wherein the -CH2-, alkyl, alkynyl, alkoxy, alkylthio, cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, CD3, halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0047] In some embodiments, R k1a is selected from COOH, S(=O)2NH2, -C(=O)NH2, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2NH-methyl, -S(=O)2NH-ethyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, wherein the methyl or ethyl group is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, CF3, hydroxymethyl, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0048] In some embodiments, R k1a Selected from COOH;

[0049] In some embodiments, R k1b is selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl is optionally substituted by 1 to 4 halogens, OH, cyano, NH2, CF3, hydroxymethyl, C1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0050] In some embodiments, R k1b Selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH2-cyclopropyl;

[0051] In some embodiments, R k1c is selected from deuterium, CD3, H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl is optionally substituted by 1 to 4 groups selected from deuterium, CD3, halogen, OH, cyano, NH2, CF3, hydroxymethyl, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0052] In some embodiments, R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH2-CF3, -CH2-cyclopropyl, cyclopropyl;

[0053] In some embodiments, R d each independently selected from F, Cl, Br, I, cyano, OH, NO2, COOH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, -S(=O)2NH2, -C(=O)NH2, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2NH-methyl, -S(=O)2NH-ethyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 halogen, OH, cyano, NH2, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0054] In some embodiments, R 1 , R 2 , R 3 Each independently selected from H, C 1-6 Alkyl, C 3-10A carbocyclic group or a 4- to 10-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 is substituted by a substituent of a carbocyclic group or a 4- to 10-membered heterocyclic group;

[0055] In some embodiments, R 1 , R 2 , R 3 Each independently selected from H, C 1-4 Alkyl, C 3-6 The alkyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 is substituted by a substituent of a carbocyclic group or a 4- to 7-membered heterocyclic group;

[0056] In some embodiments, Z is selected from -CH(R z1 )CH2-SR z2 or -CH(R z1 )CH2-Se-R z2 ;

[0057] In some embodiments, R z1 Selected from -C 1-4 Alkylene-Z1-R z3 ;

[0058] In some embodiments, R z1 Selected from -CH2CH2-Z1-R z3 ;

[0059] In some embodiments, Z1 is selected from 4 to 12 membered heterocyclyl, said Z1 being optionally substituted with 1 to 4 R z1a or is optionally substituted by 1 substituent selected from -OP(=O)(OH)2 or -CH2OP(=O)(OH)2;

[0060] In some embodiments, Z1 is selected from 4 to 7 membered nitrogen-containing monocyclic rings, 5 to 10 membered nitrogen-containing heterocyclic rings, 5 to 11 membered nitrogen-containing spirocyclic heterocyclic rings, and 5 to 11 membered nitrogen-containing bridged heterocyclic rings, wherein Z1 is optionally substituted by 1 to 4 R z1a or is optionally substituted by 1 substituent selected from -OP(=O)(OH)2 or -CH2OP(=O)(OH)2;

[0061] In some embodiments, Z1 is selected from azetidinyl, aziridine, azetidinyl, azetidinyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclopentyl, azetidinyl spirocyclopentyl, azetidinyl spirocyclohexyl, azetidinyl spirocyclohexyl, azetidinyl spirocyclohexyl, azetidinyl cyclopropyl, azetidinyl cyclopropyl, azetidinyl cyclobutyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclopentyl, azetidinyl spirocyclohexyl, azetidinyl spirocyclohexyl, azetidinyl cyclopropyl, azetidinyl cyclopropyl, azetidinyl cyclobutyl, azetidinyl cyclobutyl, azetidinyl cyclohexyl, 1-4-azabicyclo[3.3.1]nonyl, wherein Z1 is optionally substituted by 1 to 4 R z1a or is optionally substituted by 1 substituent selected from -OP(=O)(OH)2 or -CH2OP(=O)(OH)2;

[0062] In some embodiments, Z1 is selected from The Z1 is optionally replaced by 1 to 4 R z1a or is optionally substituted by 1 substituent selected from -OP(=O)(OH)2 or -CH2OP(=O)(OH)2;

[0063] In some embodiments, R k2 , R z2 Each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, said R k2 Optional 1 to 4 R k2a Substitution, the R z2 Optional 1 to 4 R z2a replace;

[0064] In some embodiments, R k2 , R z2 Each independently selected from phenyl, benzo 4-6 carbocyclic group, benzo 5- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl group, 9- to 10-membered heteroaryl group, wherein R k2 Optional 1 to 4 R k2a Substitution, the R z2 Optional 1 to 4 R z2a replace;

[0065] In some embodiments, R k2 , R z2 Each independently selected from phenyl, pyridine, The R k2 Optional 1 to 4 R k2a Substitution, the R z2 Optional 1 to 4 R z2a replace;

[0066] In some embodiments, R z1a , R k2a , R z2a Each independently selected from halogen, cyano, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(CH2) q -C 3-10 Carbocyclic ring, -(CH2) q -4 to 10 membered heterocyclic ring, wherein the -CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 is substituted by a substituent of a carbocyclic group or a 4- to 10-membered heterocyclic group;

[0067] In some embodiments, R z1a , R k2a , R z2a Each independently selected from halogen, cyano, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -(CH2)q -C 3-6 Carbocyclic ring, -(CH2) q -4 to 7 membered heterocyclic ring, wherein the -CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 is substituted by a substituent of a carbocyclic group or a 4- to 7-membered heterocyclic group;

[0068] In some embodiments, R z1a , R k2a , R z2a Each independently selected from F, Cl, Br, I, cyano, OH, CF3, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH2, CF3, hydroxymethyl, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0069] In some embodiments, R z1a , R k2a , R z2a Each independently selected from F, Cl, Br, I, cyano, OH, CF3, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0070] In some embodiments, R z3 Selected from -OH, -CH2OH, -OP(=O)(OH)2, -CH2OP(=O)(OH)2, -OP(=O)(OH)(OC 1-6 alkyl), -CH2OP(=O)(OH)(OC 1-6 alkyl), -OP(=O)(OC 1-6 alkyl)2, -CH2OP(=O)(OC 1-6 Alkyl)2;

[0071] In some embodiments, Rz3 Selected from -OH, -CH2OH, -OP(=O)(OH)2, -CH2OP(=O)(OH)2;

[0072] In some embodiments, q is each independently selected from 0, 1, 2, 3 or 4;

[0073] In some embodiments, q is each independently selected from 0, 1, 2;

[0074] In some embodiments, p1, p2, and p3 are each independently 0, 1, 2, or 3;

[0075] In some embodiments, Selected from

[0076] Arbitrarily,

[0077] 1) When B is selected from When B is replaced by 1 to 8 R b replace;

[0078] or 2) when B is selected from unsubstituted and Z1 is selected from a 4- to 7-membered monocyclic heterocyclic group connected to an alkylene group via a nitrogen atom, Z1 is replaced by 1 to 4 R z1a replace;

[0079] The compounds of general formula (I) are optionally substituted with 1 to 20 deuteriums.

[0080] As a first embodiment of the present invention, the compound represented by the following general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0081] Ring A, Ring C, and Ring D are each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a The ring C is optionally substituted with 1 to 4 R c The ring D is optionally substituted with 1 to 4 R d replace;

[0082] B is selected from -B1-, -N(R n )-B1-、-B1-N(R n )-;

[0083] B1 is selected from 4 to 12 membered heterocyclic groups, the heterocyclic groups are optionally substituted by 1 to 10 R b replace;

[0084] X is selected from -N(R x )S(=O)2-、-S(=O)2N(R x )-、 The left side is connected to ring C;

[0085] K is selected from a 5-membered heteroaryl group, wherein K is substituted by 1 to 3 R k1 , 1 R k2 replace;

[0086] R x Selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0087] R n Selected from H, C 1-6 Alkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene or cycloalkyl is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0088] R a , R b , R c Each independently selected from deuterium, halogen, cyano, OH, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(CH2) q -C 3-10 Carbocyclic ring, -(CH2) q -4 to 10 membered heterocyclic ring, wherein the -CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 is substituted by a substituent of a carbocyclic group or a 4- to 10-membered heterocyclic group;

[0089] Or any R b With R c directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R a1 replace;

[0090] Or any R b With Ra directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R a1 replace;

[0091] R a1 Each independently selected from halogen, OH, cyano, NH2, =O, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 The alkyl, alkynyl, alkoxy, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 substituents selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 is substituted by a substituent of a carbocyclic group or a 4- to 10-membered heterocyclic group;

[0092] R d , R k1 Each independently selected from deuterium, CD3, halogen, cyano, OH, NO2, COOH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -OC 3-6 Cycloalkyl, -(CH2) q -C 3-10 Carbocyclic ring, -(CH2) q -4 to 10 membered heterocyclic ring, -S(=O)2R 1 、-S(=O)2NR 1 R 2 、-C(=O)NR 1 R 2 、C(=O)NR 1 S(=O)2R 3 、-C(=O)R 1 The -CH2-, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, CD3, halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C3-10 is substituted by a substituent of a carbocyclic group or a 4- to 10-membered heterocyclic group;

[0093] R 1 , R 2 , R 3 Each independently selected from H, C 1-6 Alkyl, C 3-10 A carbocyclic group or a 4- to 10-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 is substituted by a substituent of a carbocyclic group or a 4- to 10-membered heterocyclic group;

[0094] Z is selected from -CH(R z1 )CH2-SR z2 or -CH(R z1 )CH2-Se-R z2 ;

[0095] R z1 Selected from -C 1-4 Alkylene-Z1-R z3 ;

[0096] Z1 is selected from 4 to 12 membered heterocyclic groups, said Z1 being optionally substituted by 1 to 4 R z1a or is optionally substituted by 1 substituent selected from -OP(=O)(OH)2 or -CH2OP(=O)(OH)2;

[0097] R k2 , R z2 Each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, said R k2 Optional 1 to 4 R k2a Substitution, the R z2 Optional 1 to 4 R z2a replace;

[0098] R z1a , R k2a , R z2a Each independently selected from halogen, cyano, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(CH2) q -C 3-10Carbocyclic ring, -(CH2) q -4 to 10 membered heterocyclic ring, wherein the -CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 is substituted by a substituent of a carbocyclic group or a 4- to 10-membered heterocyclic group;

[0099] R z3 Selected from -OH, -CH2OH, -OP(=O)(OH)2, -CH2OP(=O)(OH)2, -OP(=O)(OH)(OC 1-6 alkyl), -CH2OP(=O)(OH)(OC 1-6 alkyl), -OP(=O)(OC 1-6 alkyl)2, -CH2OP(=O)(OC 1-6 Alkyl)2;

[0100] q is each independently selected from 0, 1, 2, 3 or 4;

[0101] The condition is,

[0102] 1) When B is selected from When B is replaced by 1 to 8 R b replace;

[0103] or 2) when B is selected from unsubstituted and Z1 is selected from a 4- to 7-membered monocyclic heterocyclic group connected to an alkylene group via a nitrogen atom, Z1 is replaced by 1 to 4 R z1a replace;

[0104] The compounds of general formula (I) are optionally substituted with 1 to 20 deuteriums.

[0105] As a second embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0106] Ring A, Ring C, and Ring D are each independently selected from phenyl, benzo 4-6 carbocyclyl, benzo 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, 9- to 10-membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a The ring C is optionally substituted with 1 to 4 R c The ring D is optionally substituted with 1 to 4 R d replace;

[0107] B1 is selected from a 4- to 7-membered nitrogen-containing monocyclic heterocyclic group, a 5- to 10-membered nitrogen-containing cyclic heterocyclic group, a 5- to 11-membered nitrogen-containing spirocyclic heterocyclic group, and a 5- to 11-membered nitrogen-containing bridged heterocyclic group, wherein B1 is optionally substituted by 1 to 8 R b replace;

[0108] R n Selected from H, C 1-4 alkyl;

[0109] X is selected from -NHS(=O)2-, and the left side is connected to ring C;

[0110] R a , R b , R c Each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -(CH2) q -C 3-6 Carbocyclic ring, -(CH2) q -4 to 7 membered heterocyclic ring, wherein the -CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 is substituted by a substituent of a carbocyclic group or a 4- to 7-membered heterocyclic group;

[0111] Or any R b With R c directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R a1 replace;

[0112] Or any R b With R a directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R a1 replace;

[0113] R a1 Each independently selected from halogen, OH, cyano, NH2, =O, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the alkyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 is substituted by a substituent of a carbocyclic group or a 4- to 7-membered heterocyclic group;

[0114] R d , R k1 Each independently selected from deuterium, CD3, halogen, cyano, OH, NO2, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -OC 3-6 Cycloalkyl, -(CH2) q -C 3-6 Carbocyclic ring, -(CH2) q -4 to 7 membered heterocyclic ring, -S(=O)2R 1 、-S(=O)2NR 1 R 2 、-C(=O)NR 1 R 2 、C(=O)NR 1 S(=O)2R 3 、-C(=O)R 1 The -CH2-, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, CD3, halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 is substituted by a substituent of a carbocyclic group or a 4- to 7-membered heterocyclic group;

[0115] R 1 , R 2 , R 3 Each independently selected from H, C 1-4 Alkyl, C 3-6 The alkyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-4Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 is substituted by a substituent of a carbocyclic group or a 4- to 7-membered heterocyclic group;

[0116] Z1 is selected from 4 to 7 membered nitrogen-containing monocyclic heterocyclic rings, 5 to 10 membered nitrogen-containing heterocyclic rings, 5 to 11 membered nitrogen-containing spirocyclic heterocyclic rings, and 5 to 11 membered nitrogen-containing bridged heterocyclic rings, wherein Z1 is optionally substituted by 1 to 4 R z1a or is optionally substituted by 1 substituent selected from -OP(=O)(OH)2 or -CH2OP(=O)(OH)2;

[0117] R k2 , R z2 Each independently selected from phenyl, benzo 4-6 carbocyclic group, benzo 5- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl group, 9- to 10-membered heteroaryl group, wherein R k2 Optional 1 to 4 R k2a Substitution, the R z2 Optional 1 to 4 R z2a replace;

[0118] R z1a , R k2a , R z2a Each independently selected from halogen, cyano, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -(CH2) q -C 3-6 Carbocyclic ring, -(CH2) q -4 to 7 membered heterocyclic ring, wherein the -CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 is substituted by a substituent of a carbocyclic group or a 4- to 7-membered heterocyclic group;

[0119] R z3 Selected from -OH, -CH2OH, -OP(=O)(OH)2, -CH2OP(=O)(OH)2;

[0120] q is independently selected from 0, 1, and 2;

[0121] The remaining radicals are defined the same as in the first embodiment.

[0122] As a third embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0123] B1 is selected from the group consisting of azetidinyl, aziridine, azetidinyl, azetidinyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclopentyl, azetidinyl spirocyclopentyl, azetidinyl spirocyclohexyl, azetidinyl spirocyclohexyl, azetidinyl spiroazetidin ... spiroazacyclopentyl, azetidinyl spiroazacyclohexyl, azetidinyl spiroazacyclohexyl, azetidinyl spiroazacyclohexyl, azetidinyl spiroazacyclohexyl, azetidinyl spiroazacyclohexyl, azetidinyl spiroazacyclohexyl, piperazine spirocyclopropyl, piperazine spirocyclobutyl, piperazine spirocyclopentyl, piperazine spirocyclohexyl, piperazine spiroaziridine, piperazine spiroazetidinyl, piperazine spiroazacyclopentyl, piperazine spiroazacyclohexyl, azetidinyl and cyclopropyl, azetidinyl and cyclopropyl, azetidinyl and cyclopropyl, azetidinyl and cyclobutyl, azetidinyl and cyclopentyl, azetidinyl and cyclopentyl, azetidinyl and cyclopentyl, azetidinyl and cyclopentyl, azetidinyl and cyclopentyl, azetidinyl and cyclopentyl , azetidinyl and cyclohexyl, azetidinyl and cyclohexyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, azetidinyl and azetidinyl, piperazinyl and cyclopropyl, piperazinyl and cyclobutyl, piperazinyl and cyclopentyl, piperazinyl and cyclohexyl, piperazinyl and spiro and heterocyclopropyl, piperazinyl and azetidinyl, piperazinyl and azetidinyl, piperazinyl and azetidinyl, piperazinyl and azetidinyl, 3,8 -diazabicyclo[3.2.1]octanyl, 3-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 5-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 3-azabicyclo[3.3.1]nonyl, 3,7-diazabicyclo[3.3.1]nonyl, wherein B1 is optionally substituted by 1 to 8 R b replace;

[0124] Z1 is selected from azetidinyl, azetidinyl, azetidinyl, azetidinyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclopentyl, azetidinyl spirocyclopentyl, azetidinyl spirocyclohexyl, azetidinyl spirocyclohexyl, azetidinyl spirocyclohexyl, azetidinyl cyclopropyl, azetidinyl cyclopropyl, azetidinyl cyclopropyl, azetidinyl cyclobutyl, azetidinyl cyclobutyl, azetidinyl cyclobutyl , azetidinylcyclopentyl, azacyclopentylcyclopentyl, azacyclohexylcyclopentyl, azetidinylcyclohexyl, azacyclopentylcyclohexyl, azacyclohexylcyclohexyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.1]heptyl, 5-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.3.1]nonyl, 3-oxa-7-azabicyclo[3.3.1]nonyl, said Z1 is optionally substituted by 1 to 4 R z1a or is optionally substituted by 1 substituent selected from -OP(=O)(OH)2 or -CH2OP(=O)(OH)2;

[0125] R a , R b , R c Each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl, wherein the alkyl, alkynyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0126] R a1 Each independently selected from halogen, OH, cyano, NH2, =O, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl, wherein the alkyl, alkynyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0127] R d , R k1 Each independently selected from deuterium, CD3, halogen, cyano, OH, NO2, COOH, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -S(=O)2NH2, -C(=O)NH2, -S(=O)2C 1-4 Alkyl, -S(=O)2-C 3-6 Cycloalkyl, -S(=O)2NHC 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -C(=O)-C 3-6 Cycloalkyl, -C(=O)NHC 1-4 Alkyl, wherein the -CH2-, alkyl, alkynyl, alkoxy, alkylthio, cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, CD3, halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0128] The definitions of the remaining groups are the same as those of the first and second embodiments of the present invention.

[0129] As a fourth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0130] B is selected from -B1-, -N(CH3)-B1-, -B1-N(CH3)-;

[0131] B1 is selected from The B1 is optionally replaced by 1 to 8 R b replace;

[0132] Ring A is selected from The ring A is optionally substituted with 1 to 4 R a replace;

[0133] Ring C and ring D are each independently selected from The ring C is optionally substituted with 1 to 4 R c The ring D is optionally substituted with 1 to 4 R d replace;

[0134] or Selected from The left side is connected to ring A;

[0135] or Selected from The left side is connected to ring C;

[0136] R a , R b , R c Each independently selected from deuterium, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 halogens, OH, cyano, NH2, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0137] R a1 Each independently selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH2, C1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0138] R d each independently selected from F, Cl, Br, I, cyano, OH, NO2, COOH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, -S(=O)2NH2, -C(=O)NH2, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2NH-methyl, -S(=O)2NH-ethyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 halogen, OH, cyano, NH2, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0139] R z1 Selected from -CH2CH2-Z1-R z3 ;

[0140] Z1 is selected from The Z1 is optionally replaced by 1 to 4 R z1a or is optionally substituted by 1 substituent selected from -OP(=O)(OH)2 or -CH2OP(=O)(OH)2;

[0141] R z3 Selected from -OH, -CH2OH, -OP(=O)(OH)2, -CH2OP(=O)(OH)2;

[0142] K is selected from

[0143] R k1ais selected from COOH, S(=O)2NH2, -C(=O)NH2, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2NH-methyl, -S(=O)2NH-ethyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, wherein the methyl or ethyl group is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, CF3, hydroxymethyl, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0144] R k1b is selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl is optionally substituted by 1 to 4 halogens, OH, cyano, NH2, CF3, hydroxymethyl, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0145] R k1c is selected from deuterium, CD3, H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl is optionally substituted by 1 to 4 groups selected from deuterium, CD3, halogen, OH, cyano, NH2, CF3, hydroxymethyl, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0146] R k2 , R z2 Each independently selected from phenyl, pyridine, The R k2 Optional 1 to 4 R k2a Substitution, the R z2 Optional 1 to 4 R z2a replace;

[0147] R z1a , R k2a , R z2aEach independently selected from F, Cl, Br, I, cyano, OH, CF3, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH2, CF3, hydroxymethyl, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent;

[0148] p1, p2, p3 are each independently 0, 1, 2 or 3;

[0149] The remaining groups are defined the same as in the first, second or third embodiment of the present invention.

[0150] As a fifth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0151] R k1a Selected from COOH;

[0152] R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH2-CF3, -CH2-cyclopropyl, cyclopropyl;

[0153] R k1b Selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH2-cyclopropyl;

[0154] R z1a , R k2a , R z2a Each independently selected from F, Cl, Br, I, cyano, OH, CF3, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0155] Selected from

[0156] The remaining groups are defined the same as in any one of the first, second, third or fourth embodiments of the present invention.

[0157] As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by the general formula (I) is selected from the compound represented by the general formula (II-a),

[0158] B is selected from -B1-, -N(CH3)-B1-, -B1-N(CH3)-;

[0159] B1 is selected from The B1 is optionally replaced by 1 to 8 R b replace;

[0160] R b Each independently selected from deuterium, F;

[0161] or Selected from

[0162] Z1 is selected from Said Z1 is optionally substituted with 1 to 4 F;

[0163] R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH2-CF3, -CH2-cyclopropyl, cyclopropyl;

[0164] R k2a is selected from F, Cl, methyl, ethyl, cyclopropyl;

[0165] R z3 Selected from -OH, -CH2OH, -OP(=O)(OH)2, -CH2OP(=O)(OH)2.

[0166] As a seventh embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) is selected from the compound represented by general formula (III-a) or (III-b),

[0167] R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH2-CF3, -CH2-cyclopropyl, cyclopropyl;

[0168] Z1 is selected from Said Z1 is optionally substituted with 1 to 4 F;

[0169] R k2a is selected from F, Cl, methyl, ethyl, cyclopropyl;

[0170] R z3 Selected from -OH, -OP(=O)(OH)2.

[0171] The present invention relates to the compounds shown below or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein the compound is selected from one of the structures shown in Table E-1;

[0172] Table E-1

[0173] The present invention relates to a pharmaceutical composition, comprising any of the above-mentioned compounds or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1-1500 mg of the above-mentioned compounds or their stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals.

[0174] The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0175] In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation strength").

[0176] The "effective amount" or "therapeutically effective amount" described in this application refers to the administration of a sufficient amount of the compound disclosed in this application, which will alleviate one or more symptoms of the disease or condition being treated (e.g., inhibition of Bcl-2 or Bcl-xL related diseases such as tumors or eye diseases) to some extent. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms or causes of the disease, or any other desired changes in the biological system. For example, an "effective amount" for therapeutic use is the amount of the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 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. mg, 200-600mg, 1-500mg, 2-500mg, 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, 30-400mg, 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, 90-300mg, 100-300mg, 125-300mg, 150-300 mg, 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, 80-1000mg, 80-800mg.

[0177] In some embodiments, the pharmaceutical composition includes but is not limited to 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 , 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0178] 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, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably a disease related to the inhibition of Bcl-2 or Bcl-xL (such as a tumor or an eye disease).

[0179] A method for treating a disease in a mammal, the method comprising administering a drug compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof to a subject at a daily dose of 1-1000 mg / day, the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day , 25-400 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.

[0180] The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as that in the above-mentioned pharmaceutical composition.

[0181] The present invention relates to the use of any of the above-mentioned compounds or their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals for preparing drugs for treating diseases related to the activity or expression of Bcl-2 or Bcl-xL. Preferably, the disease is selected from tumors or eye diseases.

[0182] The present invention relates to the use of the above-mentioned pharmaceutical composition in the preparation of a drug for treating a disease associated with the activity or expression of Bcl-2 or Bcl-xL. Preferably, the disease is selected from a tumor or an eye disease, and more preferably, the disease is selected from a retinopathy-related eye disease.

[0183] The amount of the compound of the invention or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof is in each case calculated as the free base.

[0184] Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0185] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and81 Br.

[0186] "Halogen" refers to F, Cl, Br or I.

[0187] "Halogen substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen substituted" is abbreviated as "halo".

[0188] "Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; the alkyl groups appearing in this article are defined in accordance with this definition. Alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0189] "Heteroalkyl" refers to a substituted or unsubstituted alkyl group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X(CH2)vX(CH2)vX(CH2)vH (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom, the heteroatom includes but is not limited to N, O or S, and at least one X is selected from a heteroatom, and the N or S in the heteroatom can be oxidized to various oxidation states). The heteroalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0190] "Alkylene" refers to substituted or unsubstituted straight-chain or 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.

[0191] "Heteroalkylene" refers to a substituted or unsubstituted alkylene in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X(CH2)vX(CH2)vX(CH2)v-, v is an integer from 1 to 5, each X is independently selected from a bond, N, O or S, and at least one X is selected from N, O or S.

[0192] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyl groups appearing herein are defined as above. Cycloalkyl groups may be monovalent, divalent, trivalent or tetravalent.

[0193] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S, and the selectively substituted N and S in the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and heterocycloalkyl can be connected to an aromatic ring or a non-aromatic ring. Heterocycloalkyl can be connected to a bridge ring or a spiro ring, and non-limiting examples include oxirane, aziridine, oxadiazine, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl can be monovalent, divalent, trivalent or tetravalent.

[0194] "Alkenyl" refers to a substituted or unsubstituted straight chain or branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2- Methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl groups appearing in this article have the same definition as this definition. The alkenyl group can be monovalent, divalent, trivalent or tetravalent.

[0195] "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, including but not limited to 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone chain. 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, 1- Methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl and the like; the alkynyl group may be monovalent, divalent, trivalent or tetravalent.

[0196] "Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0197] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, or a 10-15-membered tricyclic ring system, and the carbocyclyl can be attached to the aromatic or non-aromatic ring, which can be a monocyclic ring, a bridged ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

[0198] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The N and S selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group may be connected to a heteroatom or a carbon atom, may be connected to an aromatic ring or a non-aromatic ring, may be connected to a bridged ring or a spiro ring, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, py ... furanyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

[0199] "Spiro" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called spiro atom), and the number of ring atoms in the spiro 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 selected from N, O or S (=O) n Non-limiting examples include: "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0200] "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 selected from N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0201] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, which may contain 0 or more double bonds, and any ring in the bridged ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S (=O) n or O, wherein n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include Cubane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent or tetravalent.

[0202] "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" whose ring system consists of only carbon atoms. "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" appearing in this article has the same definition as spirocycle.

[0203] "Carbocyclic ring", "cyclic carbocyclyl", "cyclic carbocyclyl" or "carbocyclic ring" refers to a "cyclic ring" whose ring system consists of only carbon atoms. "Carbocyclic ring", "cyclic carbocyclyl", "cyclic carbocyclyl" or "carbocyclic ring" appearing in this article have the same definition as cyclic ring.

[0204] "Carbobridge ring", "bridged ring carbocyclic group", "bridged carbocyclic group" or "carbon bridged cyclic group" refers to a "bridged ring" whose ring system consists of only carbon atoms. "Carbobridge ring", "bridged ring carbocyclic group", "bridged carbocyclic group" or "carbon bridged cyclic group" appearing in this article have the same definition as the bridged ring.

[0205] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclic group" refers to a "heterocyclic group" or "heterocycle" of a monocyclic ring system. The heterocyclic group, "monocyclic heterocyclyl" or "heteromonocyclic group" appearing in this document has the same definition as heterocycle.

[0206] "Heterocyclic ring", "heterocyclic ring group", "cyclic heterocyclic group" or "heterocyclic group" refer to a "cyclic ring" containing a heteroatom. The heterocyclic ring, "heterocyclic ring group", "cyclic heterocyclic group" or "heterocyclic group" appearing in this document have the same definition as cyclic ring.

[0207] "Heterospirocycle", "heterospirocyclyl", "spiro heterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" containing a heteroatom. Heterospirocycle, "heterospirocyclyl", "spiro heterocyclyl" or "heterospirocyclyl" appearing herein have the same definition as spirocycle.

[0208] "Heterobridged ring", "heterobridged ring group", "bridged heterocyclic group" or "heterobridged ring group" refers to a "bridged ring" containing a heteroatom. The heterobridged ring, "heterobridged ring group", "bridged heterocyclic group" or "heterobridged ring group" appearing herein have the same definition as the bridged ring.

[0209] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0210] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O or S(=O)n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of heteroaryl include but are not limited to pyridyl, furanyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include The heteroaryl groups appearing in this article have the same definition as this definition. The heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is located on the heteroaryl ring.

[0211] "5-membered ring and 5-membered heteroaromatic ring" refers to a 5-membered fused heteroaromatic ring, at least one of the two rings contains one or more heteroatoms (including but not limited to O, S or N), and the whole group is aromatic. Non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolofuran ring, pyrazolofuran ring, pyrrolothiophene ring, and pyrazolothiophene ring.

[0212] "5- and 6-membered heteroaromatic ring" refers to a 5- and 6-membered fused heteroaromatic ring, where at least one of the two fused rings contains one or more heteroatoms (including but not limited to O, S or N), and the entire group is aromatic. Non-limiting examples include benzo 5-membered heteroaromatic, 6-membered heteroaromatic ring and 5-membered heteroaromatic ring.

[0213] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, 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, silane or -NR b R c etc., where R b With R c is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R b With R c It can form a 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, spiro or paracyclic groups.

[0214] “Containing 1 to 5 heteroatoms selected from O, S, and N” means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, and N.

[0215] "Replaced by 1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from...", X is selected from any integer between 1 and 10. For example, "replaced by 1 to X substituents selected from..." means substituted by 1, 2, 3 or 4 substituents selected from..." For example, "replaced by 1 to 5 substituents" means substituted by 1, 2, 3, 4 or 5 substituents. For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from F.

[0216] The XY-membered ring (3≤X<Y, Y is any integer between 4 and 12) includes X, X+1, X+2, X+3, X+4...Y-membered rings. The ring includes a heterocyclic ring, a carbocyclic ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocyclic ring, a heterocyclic ring, a heterospirocyclic ring or a heterobridged ring. For example, "a 4-7-membered heteromonocyclic ring" refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "a 5-10-membered heterocyclic ring" refers to a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heterocyclic ring.

[0217] "Optional" or "optionally" or "arbitrarily" means that the event or circumstance described later may but need not occur, and the description includes occasions where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that alkyl may but need not be substituted with F, and the description includes the situation where alkyl is substituted with F and the situation where alkyl is not substituted with F.

[0218] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0219] "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.

[0220] "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.

[0221] "Preparation specification" refers to the weight of the main drug contained in each vial, tablet or other unit preparation. "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

[0222] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

[0223] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0224] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.

[0225] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.

[0226] “IC 50 ” is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of the process such as an enzyme, receptor, cell, etc.) by half.

[0227] The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0228] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were measured in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometer, the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS);

[0229] MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0230] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0231] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

[0232] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier;

[0233] In order to accomplish the purpose of the present invention, the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to technicians in the field, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., Tokyo Chemical Industry Development Co., Ltd., Anage Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

[0234] THF: tetrahydrofuran; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; HATU: CAS148893-10-1.

[0235] Example 1: Synthesis of Compound 1

[0236] Step 1: Synthesis of 1a

[0237] 2-Oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (5.0 g, 20.89 mmol) was dissolved in 30 mL of methanol, and under nitrogen protection, sodium borohydride (1.19 g, 31.34 mmol) was added in batches at 0°C, and the reaction was continued for 1 hour. 20 mL of water was added, and 30 mL of ethyl acetate was added to extract twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1a (4.5 g, yield: 89.26%).

[0238] LCMS m / z=186.1[M-55] +

[0239] Step 2: Synthesis of 1b

[0240] 1a (4.0 g, 16.57 mmol) was dissolved in 50 mL of tetrahydrofuran, and under nitrogen protection, sodium hydride (1.0 g, 41.42 mmol) was added in batches at 0°C, and stirring was continued for 30 minutes. Benzyl bromide (5.67 g, 33.14 mmol) was added, and stirring was continued at room temperature overnight. Water was added to quench the reaction, and the mixture was extracted twice with 50 mL of ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed to obtain 1b (4.6 g, yield: 83.76%).

[0241] LCMS m / z=332.2[M+H] +

[0242] Step 3: Synthesis of 1c

[0243] 1b (1.8 g, 5.43 mmol) was dissolved in 20 mL of acetonitrile, and 4 mL of 4N hydrochloric acid dioxane solution was added, and the mixture was reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and 5 mL of sodium bicarbonate aqueous solution was added to adjust the pH to about 8, and the mixture was extracted with dichloromethane for 5 times. The organic phases were combined and concentrated under reduced pressure to obtain 1c (1.0 g, yield: 79.61%).

[0244] LCMS m / z=232.2[M+H] +

[0245] Step 4: 1D synthesis

[0246] Intermediate A (1.3 g, 4.4 mmol) was dissolved in 20 mL of dichloromethane, 1c (1.1 g, 4.84 mmol) was added, and triethylamine (1.78 g, 17.6 mmol) was added after cooling in an ice-water bath under nitrogen protection, and stirred at 0°C for 30 minutes, sodium triacetoxyborohydride (1.4 g, 6.6 mmol) was added, and stirred at room temperature overnight. 30 mL of purified water was added, and the liquids were separated. The aqueous phase was extracted twice with 50 mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product, and 1d (1.45 g, yield: 64.52%) was obtained by column chromatography.

[0247] LCMS m / z=511.3[M+H] +

[0248] Step 5: Synthesis of 1e

[0249] 1d (0.5 g, 0.98 mmol) was dissolved in 5 mL of dichloromethane, and under nitrogen protection, boron tribromide (2 mL, 2 mmol) was added dropwise at -78°C, and stirred at room temperature for 2 hours. Aqueous sodium bicarbonate solution was added at low temperature to quench the reaction, and the pH was adjusted to about 8, extracted twice with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1e (40 mg, yield: 12.74%).

[0250] LCMS m / z=321.4[M+H] +

[0251] Step 6: Synthesis of Compound 1

[0252] Intermediate B (33 mg, 0.04 mmol) was dissolved in 2 mL of N,N-dimethylformamide, 1e (19 mg, 0.059 mmol) and N,N-diisopropylethylamine (16 mg, 0.12 mmol) were added, and stirred at room temperature for 2 hours. 30 mL of ethyl acetate was added, washed with water twice (20 mL × 2), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the product was obtained by column chromatography, and then the trifluoroacetate of compound 1 (10 mg, yield: 22.33%) was obtained by reverse phase column chromatography.

[0253] LCMS m / z=560.3[M / 2+H] +

[0254] Example 3: Synthesis of Compound 3

[0255] Step 1: Synthesis of 3a

[0256] Tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (1.0 g, 4.56 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain 3a (0.54 g, yield: 99.4%).

[0257] LCMS m / z=120.2[M+H] +

[0258] Step 2: Synthesis of 3b

[0259] Intermediate A (0.45 g, 1.52 mmol) was dissolved in 20 mL of dichloromethane, 3a (0.18 g, 1.52 mmol) was added, and triethylamine (0.62 g, 6.08 mmol) was added after cooling in an ice-water bath under nitrogen protection, and stirred at 0°C for 30 minutes, sodium triacetoxyborohydride (0.48 g, 2.28 mmol) was added, and stirred at room temperature overnight. 30 mL of purified water was added, and the liquid was separated, and the aqueous phase was extracted twice with 50 mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, and 3b (0.5 g, yield: 82.54%) was obtained by column chromatography.

[0260] LCMS m / z=399.3[M+H] +

[0261] Step 3: Synthesis of compound 3c

[0262] 3b (0.1 g, 0.25 mmol) was dissolved in 2 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain 3c (0.070 g, yield: 93.83%).

[0263] LCMS m / z=299.2[M+H] +

[0264] Step 4: Synthesis of compound 3

[0265] Intermediate B (30 mg, 0.037 mmol) was dissolved in 2 mL N,N-dimethylformamide, 3c (17 mg, 0.055 mmol) and N,N-diisopropylethylamine (14 mg, 0.11 mmol) were added, and stirred at room temperature for 2 hours. 30 mL of ethyl acetate was added, washed with water twice (20 mL × 2), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the product was obtained by column chromatography. The trifluoroacetate of compound 3 (22 mg, yield: 54.17%) was obtained by reverse phase column chromatography.

[0266] LCMS m / z=549.6[M / 2+H] +

[0267] 1 H NMR(400MHz,CF3COOD)δ8.28(d,1H),8.19(s,1H),8.00(dd,1H),7.93(d,1H),7.86(d,1H),7.8 3–7.76(m,3H),7.64–7.30(s,11H),6.80–6.73(m,1H),5.35–5.15(m,1H),4.83–4.68(m,1H),4. 66–4.48(m,8H),4.47–4.31(m,1H),4.13–3.99(m,2H),3.93–3.83(m,1H),3.66–3.42(m,3H),3 .36–3.21(m,3H),3.02(s,3H),2.71–2.51(m,2H),2.47–2.26(m,2H),1.73(d,3H),1.35(d,3H).

[0268] Example 4: Synthesis of Compound 4

[0269] Step 1: Synthesis of 4a

[0270] Tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (1.2 g, 5.47 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to obtain compound 4a (0.65 g, yield: 99.74%).

[0271] LCMS m / z=120.2[M+H] +

[0272] Step 2: Synthesis of compound 4b

[0273] Intermediate A (0.45 g, 1.52 mmol) was dissolved in 20 mL of dichloromethane, 3a (0.18 g, 1.52 mmol) was added, triethylamine (0.62 g, 6.08 mmol) was added in an ice-water bath under nitrogen protection, and the mixture was stirred at 0°C for 30 minutes; sodium triacetoxyborohydride (0.48 g, 2.28 mmol) was added, and the mixture was stirred at room temperature overnight. 30 mL of purified water was added, the mixture was separated, the aqueous phase was extracted twice with 50 mL of dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, and 4b (0.5 g, yield: 82.54%) was obtained by column chromatography.

[0274] LCMS m / z=399.3[M+H] +

[0275] Step 3: Synthesis of compound 4c

[0276] 4b (0.1 g, 0.25 mmol) was dissolved in 2 mL of dichloromethane, 0.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to obtain compound 4c (0.070 g, yield: 93.83%).

[0277] LCMS m / z=299.2[M+H] +

[0278] Step 4: Synthesis of compound 4

[0279] Intermediate B (50 mg, 0.061 mmol) was dissolved in 2 mL of N,N-dimethylformamide, and 4c (27 mg, 0.091 mmol) and N,N-diisopropylethylamine (24 mg, 0.18 mmol) were added, and stirred at room temperature for 2 hours. 30 mL of ethyl acetate was added, and the mixture was washed with water twice (20 mL × 2), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the product was obtained by column chromatography. The trifluoroacetate of compound 4 (20 mg, yield: 29.87%) was obtained by reverse phase column chromatography.

[0280] LCMS m / z=549.8[M / 2+H] +

[0281] 1 H NMR(400MHz,CF3COOD)δ8.26(s,1H),8.18(s,1H),7.98(dd,1H),7.91(d,1H),7.84(d,1H),7.8 1–7.73(m,3H),7.62–7.29(m,11H),6.80–6.69(m,1H),5.32–5.12(m,1H),4.81–4.65(m,1H),4. 63–4.46(m,8H),4.45–4.30(m,1H),4.10–3.97(m,2H),3.95–3.79(m,1H),3.69–3.41(m,3H),3 .38–3.21(m,3H),3.00(s,3H),2.71–2.49(m,2H),2.45–2.24(m,2H),1.71(d,3H),1.33(d,3H).

[0282] Example 5: Synthesis of Compound 5

[0283] Step 1: Synthesis of 5B

[0284] 5A (1.0 g, 1.91 mmol), 5A-1 (530 mg, 2.29 mmol), cuprous iodide (36 mg, 0.19 mmol), [(2,6-xylyl)amino](oxy)acetic acid (110 mg, 0.57 mmol) and potassium carbonate (790 mg, 5.73 mmol) were dissolved in 20 mL of dimethyl sulfoxide and reacted at 130°C in a sealed tube for 12 hours. Water was added, and the reaction was extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 5B (651 mg, 50.48%).

[0285] Step 2: Synthesis of 5C

[0286] 5B (610 mg, 0.90 mmol) was dissolved in 10 mL of ethanol and 2 mL of water, and iron powder (250 mg, 4.5 mmol) and ammonium chloride (240 mg, 4.5 mmol) were added, and the mixture was reacted at 90°C for 12 hours. The mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 5C (435 mg, 74.9%).

[0287] LCMS m / z=645.2[M+H] +

[0288] Step 3: 5D Synthesis

[0289] 5C-1 (350 mg, 1.06 mmol) was dissolved in 5 mL of dichloromethane, pyridine (170 mg, 2.13 mmol) was added at 0°C, stirred for 1 minute, 5C (460 mg, 0.71 mmol) was slowly added, and stirred at room temperature for 2 hours. Water was added, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 5D (410 mg, 61.73%).

[0290] LCMS m / z=935.4[M+H] +

[0291] Step 4: Synthesis of 5F

[0292] 5D (80 mg, 0.086 mmol) and 5E (48 mg, 0.13 mmol) were dissolved in 3 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (33 mg, 0.26 mmol) was slowly added, and stirred at room temperature for 2 hours. Water was added, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 5F (75 mg, 67.81%).

[0293] LCMS m / z=1285.4[M+H] +

[0294] Step 5: Synthesis of Compound 5

[0295] 5F (75 mg, 0.086 mmol) was dissolved in 5 mL of dichloromethane, and a dichloromethane solution of boron tribromide (1 mL, 10% v / v) was added at -78°C, and reacted at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography to obtain compound 5 (20 mg, 31.19%).

[0296] LCMS m / z=1105.3[M+H] +

[0297] Example 7: Synthesis of Compound 7

[0298] Step 1: Synthesis of 7B

[0299] 7A (5.0 g, 22.19 mmol) was dissolved in 30 mL of methanol, and under nitrogen protection, sodium borohydride (1.26 g, 33.29 mmol) was added in batches at 0°C, and the mixture was reacted for 1 hour at 0°C. 20 mL of water was added to quench the reaction, and 30 mL of ethyl acetate was added to extract twice, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7B (4.5 g, yield: 89.22%).

[0300] Ms m / z(ESI):228.3[M+H] +

[0301] Step 2: Synthesis of 7C

[0302] 7B (1.8 g, 7.92 mmol) was dissolved in 20 mL of acetonitrile, and 4 mL of 4N hydrochloric acid dioxane solution was added, and the mixture was reacted at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and 5 mL of sodium bicarbonate aqueous solution was added to adjust the pH to about 8, and the mixture was extracted with dichloromethane for 5 times. The organic phases were combined and concentrated under reduced pressure to obtain 7C (1.0 g, yield: 99.28%).

[0303] Ms m / z(ESI):128.2[M+H] +

[0304] Step 3: 7D Synthesis

[0305] Dissolve (R)-tert-butyl (4-oxo-1-(phenylthio)butan-2-yl)carbamate (1.3 g, 4.4 mmol) in 20 mL of dichloromethane, add 7C (0.84 g, 6.6 mmol), cool in an ice-water bath under nitrogen protection, add triethylamine (1.34 g, 13.2 mmol), stir at about 0°C for 30 minutes, add sodium triacetoxyborohydride (1.87 g, 8.8 mmol), stir at room temperature overnight. Add 30 mL of purified water, separate the liquids, extract the aqueous phase twice with 50 mL of dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is then subjected to column chromatography to obtain 7D (1.45 g, yield: 81.05%).

[0306] Ms m / z(ESI):407.3[M+H] +

[0307] Step 4: Synthesis of 7E

[0308] 7D (1 g, 2.46 mmol) was dissolved in 10 mL of DCM, and 3 mL of 4N hydrochloric acid dioxane solution was added. The mixture was reacted at room temperature for 2 hours and concentrated under reduced pressure to obtain 7E (500 mg, yield: 66.32%).

[0309] Step 5: Synthesis of compound 7

[0310] Intermediate B (50 mg, 0.061 mmol) was dissolved in 2 mL N,N-dimethylformamide, 7E (28 mg, 0.091 mmol) and N,N-diisopropylethylamine (24 mg, 0.18 mmol) were added, and stirred at room temperature for 2 hours. 30 mL of ethyl acetate was added, washed with water twice (20 mL × 2), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the product was obtained by column chromatography, and then the trifluoroacetate of compound 7 (10 mg, yield: 14.83%) was obtained by reverse phase column chromatography.

[0311] Ms m / z(ESI):1105.4[M+H] +

[0312] Example 8: Synthesis of Compound 8

[0313] Step 1: Synthesis of compound 8B

[0314] Compound 8A (0.4 g, 1.82 mmol) was dissolved in 20 mL of acetonitrile, and 2 mL of 4N hydrochloric acid dioxane solution was added, and the mixture was stirred at room temperature for 2 h. The solvent was removed by concentration under reduced pressure, and 5 mL of sodium bicarbonate aqueous solution was added to adjust the pH to 8, and the mixture was extracted 5 times with dichloromethane (20 mL×5), and the organic phases were combined and concentrated under reduced pressure to obtain 8B (0.21 g, yield: 96.85%).

[0315] Ms m / z(ESI):120.1[M+H] +

[0316] Step 2: Synthesis of compound 8C

[0317] Intermediate A (0.21 g, 0.71 mmol) was dissolved in 20 mL of dichloromethane, and compound 8B (0.13 g, 1.06 mmol) was added. Under nitrogen protection, triethylamine (0.39 g, 2.13 mmol) was added at 0°C, and the mixture was stirred at 0°C for 30 minutes. Sodium triacetoxyborohydride (0.3 g, 1.42 mmol) was added, and the mixture was heated to room temperature and reacted overnight. 30 mL of purified water was added, and the mixture was separated. The aqueous phase was extracted twice with (25 mL × 2) dichloromethane, and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain 8C (0.22 g, yield: 77.75%).

[0318] Ms m / z(ESI):343.2[M+H-56] +

[0319] Step 3: Synthesis of compound 8D

[0320] 8C (1 g, 2.51 mmol) was dissolved in 10 mL of dichloromethane, 3 mL of 4N hydrochloric acid dioxane solution was added, and the mixture was reacted at room temperature for 2 h. The solvent was removed by concentration under reduced pressure to obtain the hydrochloride of 8D, which was directly used for the next step without purification (500 mg, yield: 66.75%).

[0321] Step 4: Synthesis of Compound 8

[0322] Intermediate B (50 mg, 0.061 mmol) was dissolved in 2 mL of DMF, and compound 8D (27 mg, 0.09 mmol) and DIPEA (23 mg, 0.18 mmol) were added, and stirred at room temperature for 2 h. 30 mL of ethyl acetate was added, and the mixture was washed with water twice (20 mL × 2), and once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography and reverse column chromatography to obtain compound 8 (20 mg, yield: 29.87%).

[0323] Ms m / z(ESI):1097.4[M+H] +

[0324] 1 H NMR(400MHz,CF3COOD)δ8.27(s,1H),8.20(s,1H),8.03–7.96(m,1H),7.95–7.88(m,1H),7 .87–7.74(m,4H),7.63–7.46(m,7H),7.44–7.35(m,4H),6.82–6.70(m,1H),5.11–4.95(m, 1H),4.81–4.69(m,1H),4.63–4.44(m,8H),4.13–3.98(m,2H),3.94–3.82(m,1H),3.78–3.61(m,2H),3.58–3 .41(m,3H),3.33–3.23(m,2H),3.01(s,3H),2.69–2.44(m,2H),2.40–2.09(m,2H),1.71(d,3H),1.33(d,3H).

[0325] Example 9: Synthesis of Compound 9

[0326] Step 1: Synthesis of compound 9B

[0327] Compound 9A (0.7 g, 3.06 mmol) was dissolved in 10 mL of acetonitrile, and 3 mL of 4N hydrochloric acid dioxane solution was added, and the mixture was reacted at room temperature for 2 h. The solvent was removed by concentration under reduced pressure, and 5 mL of sodium bicarbonate aqueous solution was added to adjust the pH to about 8, and the mixture was extracted 5 times with dichloromethane (20 mL×5), and the organic phases were combined and concentrated under reduced pressure to obtain 9B (0.35 g, yield: 89.93%).

[0328] Ms m / z(ESI):128.2[M+H] +

[0329] Step 2: Synthesis of compound 9C

[0330] Dissolve intermediate A in 20 mL of dichloromethane, add 9B (0.19 g, 1.53 mmol), add triethylamine (0.31 g, 3.06 mmol) at 0°C under nitrogen protection, and stir at 0°C for 30 minutes. Add sodium triacetoxyborohydride (0.43 g, 2.04), warm to room temperature and stir overnight. Add 30 mL of purified water, separate the liquids, extract the aqueous phase twice with (25 mL × 2) dichloromethane, combine the organic phases, dry over anhydrous sodium sulfate, concentrate the filtrate under reduced pressure, and chromatograph the residue on a silica gel column to obtain 9C (0.3 g, yield: 72.34%).

[0331] Ms m / z(ESI):351.2[M+H-56] +

[0332] Step 3: Synthesis of compound 9D

[0333] Compound 9C (0.3 g, 0.74 mmol) was dissolved in 8 mL of dichloromethane, 3 mL of 4N hydrochloric acid dioxane solution was added, and the mixture was reacted at room temperature for 2 h. The solvent was removed by concentration under reduced pressure to obtain the hydrochloride of 9D, which was directly used for the next step without purification (200 mg, yield: 88.19%).

[0334] Ms m / z(ESI):306.2[M+H] +

[0335] Step 4: Synthesis of compound 9

[0336] Intermediate B (50 mg, 0.061 mmol) was dissolved in 3 mL of DMF, and compound 9D (28 mg, 0.091 mmol) and DIPEA (24 mg, 0.18 mmol) were added, and the mixture was reacted at room temperature for 2 h. 30 mL of ethyl acetate was added, and the mixture was washed with water twice (20 mL×2), and once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and reverse column chromatography to obtain compound 9 (21 mg, yield: 31.13%).

[0337] Ms m / z(ESI):1105.4[M+H] +

[0338] 1 H NMR(400MHz,CF3COOD)δ8.25(s,1H),8.21–8.16(m,1H),8.04–7.94(m,1H),7.93–7.87(m,1H),7.84–7.71(m,4H),7.62–7.44(m,7H),7.4 1–7.31(m,4H),6.85–6.69(m,1H),4.80–4.69(m,1H),4.64–4.42(m,8H),4.14–3.98(m,1H),3.91–3.65(m,1H),3.63–3.31(m,4H),3.30– 3.22(m,2H),2.99(s,3H),2.61–2.19(m,4H),1.70(d,3H),1.51–1.36(m,2H),1.32(d,3H),1.15–0.89(m,2H),0.87–0.68(m,2H).

[0339] Example 10: Synthesis of Compound 10

[0340] Step 1: Synthesis of compound 10B

[0341] Compound 10A (1.0 g, 4.2 mmol) was dissolved in 30 mL of methanol, and sodium borohydride (0.32 g, 8.4 mmol) was added in batches at 0°C under nitrogen protection, and the reaction was continued for 1 h. 20 mL of water was added to quench the reaction, and ethyl acetate (15 mL×2) was used for extraction twice. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain 10B (0.75 g, yield: 73.99%).

[0342] Ms m / z(ESI):242.3[M+H] +

[0343] Step 2: Synthesis of Compound 10C

[0344] Compound 10B (0.75 g, 3.11 mmol) was dissolved in 8 mL of acetonitrile, and 3 mL of 4N hydrochloric acid dioxane solution was added, and the mixture was reacted at room temperature for 2 h. The solvent was removed by concentration under reduced pressure, and 5 mL of sodium bicarbonate aqueous solution was added to adjust the pH to about 8, and the mixture was extracted 5 times with dichloromethane (20 mL×5), and the organic phases were combined and concentrated under reduced pressure to obtain 10C (0.35 g, yield: 79.7%).

[0345] Ms m / z(ESI):142.2[M+H] +

[0346] Step 3: Synthesis of compound 10D

[0347] Intermediate A was dissolved in 20 mL of dichloromethane, and compound 10C (0.22 g, 1.53 mmol) was added. Under nitrogen protection, triethylamine (0.31 g, 3.06 mmol) was added at 0°C, and stirred at 0°C for 30 min. Sodium triacetoxyborohydride (0.43 g, 2.04 mmol) was added to the reaction flask, and the mixture was heated to room temperature and stirred overnight. 30 mL of water was added to dilute, and the mixture was separated. The aqueous phase was extracted twice with (25 mL×2) dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain compound 10D (0.31 g, yield: 72.26%).

[0348] Ms m / z(ESI):365.3[M+H-56] +

[0349] Step 4: Synthesis of compound 10E

[0350] Compound 10D (0.31 g, 0.76 mmol) was dissolved in 8 mL of dichloromethane, 3 mL of 4N hydrochloric acid dioxane solution was added, and the mixture was reacted at room temperature for 2 h. The solvent was removed by concentration under reduced pressure to obtain the hydrochloride of 10E, which was directly used for the next step without purification (200 mg, yield: 85.87%).

[0351] Ms m / z(ESI):321.4[M+H] +

[0352] Step 5: Synthesis of compound 10

[0353] Intermediate B (50 mg, 0.061 mmol) was dissolved in 3 mL of DMF, and compound 10E (29 mg, 0.091 mmol) and DIPEA (23 mg, 0.18 mmol) were added, and stirred at room temperature for 2 h. 30 mL of ethyl acetate was added, and the mixture was washed with water twice (20 mL x 2), and once with 20 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 and reverse column chromatography to obtain compound 10 (18 mg, yield: 26.35%).

[0354] Ms m / z(ESI):1119.4[M+H] +

[0355] 1H NMR(400MHz,CF3COOD)δ8.30–8.24(m,1H),8.19(s,1H),8.03–7.96(m,1H),7.95–7.89(m,1H),7.87–7.74(m,4H),7 .63–7.53(m,4H),7.52–7.44(m,3H),7.43–7.34(m,4H),6.83–6.74(m,1H),4.82–4.70(m,1H),4.63–4.47(m,8H),4 .47–4.27(m,2H),4.13–3.98(m,2H),3.95–3.75(m,2H),3.54–3.41(m,2H),3.33–3.23(m,2H),3.01(s,3H),2.45–2 .34(m,1H),2.31–2.21(m,1H),2.20–2.01(m,4H),1.91–1.76(m,2H),1.72(d,3H),1.69–1.52(m,2H),1.33(d,3H).

[0356] Example 11: Synthesis of Compound 11

[0357] Step 1: Synthesis of compound 11B

[0358] (R)-1,1,1-trifluoroisopropylamine hydrochloride (8.02 g, 70.95 mmol) was dissolved in 10 mL of methanol, triethylamine was added to adjust the pH to about 7, 11A (3.0 g, 6.45 mmol) and acetic acid (4.26 g, 70.95 mmol) were added, and the mixture was placed in a sealed tube and reacted at 100°C for 16 h. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain 11B (2.64 g, yield: 70.9%).

[0359] Step 2: Synthesis of compound 11C

[0360] Compound 11B (0.60 g, 1.04 mmol) was added to 10 mL of dimethyl sulfoxide, and 1-(nitrophenyl)piperazine (0.65 g, 3.12 mmol), cuprous iodide (0.02 g, 0.1 mmol), 2,6-dimethylphenylcarbamoylcarbamic acid (0.20 g, 1.04 mmol), and potassium carbonate (0.43 g, 3.12 mmol) were added in sequence. The temperature was raised to 130° C. under a nitrogen atmosphere and the reaction was carried out for 12 h. The reaction solution was cooled to room temperature, and a saturated ammonium chloride solution was added to quench the reaction. The reaction was extracted 5 times with ethyl acetate (10 mL×5). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain 11C (0.12 g, yield: 17.77%).

[0361] Step 3: Synthesis of compound 11D

[0362] Compound 11C (0.6 g, 0.85 mmol) was dissolved in 20 mL of methanol, 100 mg of 10% palladium carbon was added, and the mixture was stirred at room temperature for 1 h under a hydrogen atmosphere. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain compound 11D (380 mg, yield: 76.68%).

[0363] Ms m / z(ESI):583.8[M+H] +

[0364] Step 4: Synthesis of compound 11E

[0365] 3-(Trifluoromethylsulfonyl)-4-fluorobenzenesulfonyl chloride (300 mg, 0.51 mmol) was dissolved in 10 mL of dichloromethane, and pyridine (200 mg, 0.61 mmol) and 10 mL of dichloromethane solution of 11D (200 mg, 2.55 mmol) were added at 0°C under nitrogen protection, and the reaction was continued for 1 hour after the addition was completed. The mixture was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain 11E (310 mg, yield: 69.61%).

[0366] Ms m / z(ESI):873.1[M+H] +

[0367] Step 5: Synthesis of compound 11

[0368] Compound 11E (50 mg, 0.057 mmol) was dissolved in 2 mL DMF, and 3c (26 mg, 0.086 mmol) and DIPEA (66 mg, 0.51 mmol) were added in sequence. After the addition, the mixture was stirred at room temperature for 2 h. 30 mL of ethyl acetate was added, and the mixture was washed with water twice (20 mL × 2), and washed once with 30 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and reverse column chromatography to obtain compound 11 (12 mg, yield: 6.13%).

[0369] Ms m / z(ESI):1151.3[M+H] +

[0370] 1 H NMR(400MHz,CF3COOD)δ8.34–8.21(m,1H),8.06–7.87(m,2H),7.86–7.74(m,3H),7 .67–7.18(m,13H),6.83–6.72(m,1H),5.43–5.17(m,1H),5.13–4.78(m,1H),4.68– 4.28(m,8H),4.16–4.01(m,2H),3.98–3.80(m,1H),3.73–3.42(m,3H),3.42–3.23( m,3H),3.20–2.87(m,2H),2.77–2.28(m,4H),2.11–1.78(m,3H),1.59–1.36(m,2H).

[0371] Example 12: Synthesis of Compound 12

[0372] Step 1: Synthesis of compound 12a

[0373] The raw material N-tert-butyloxycarbonyl-nortropinone (1.0 g, 4.44 mmol) was dissolved in 15 mL of methanol, and sodium borohydride (0.25 g, 6.66 mmol) was added in batches at 0°C under a nitrogen atmosphere, and the reaction was continued for 1 h. 20 mL of water was added to quench the reaction, and ethyl acetate (15 mL×2) was added to extract twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 12a (0.95 g, yield: 94.13%).

[0374] Ms m / z(ESI):172.2[M+H-56] +

[0375] Step 2: Synthesis of compound 12b

[0376] Compound 12a (0.95 g, 4.18 mmol) was dissolved in 10 mL of acetonitrile, 3 mL of 4N hydrochloric acid dioxane solution was added, and the mixture was reacted at room temperature for 2 h. The mixture was concentrated under reduced pressure to obtain compound 12b as a white solid (0.5 g, yield: 94.05%).

[0377] Ms m / z(ESI):128.2[M+H] +

[0378] Step 3: Synthesis of compound 12c

[0379] Intermediate A (0.5 g, 1.69 mmol) was dissolved in 20 mL of dichloromethane, and compound 12b (0.32 g, 2.54 mmol) was added. Under nitrogen atmosphere, triethylamine (0.68 g, 6.76 mmol) was added at 0°C, and stirred at 0°C for 30 min; sodium triacetoxyborohydride (0.54 g, 2.54 mmol) was added to the reaction flask, and the mixture was heated to room temperature and stirred overnight. 30 mL of purified water was added, and the liquid was separated. The aqueous phase was extracted twice with dichloromethane (25 mL×2), and the organic phases were combined and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain 12c, a colorless oil (0.4 g, yield: 58.21%).

[0380] Ms m / z(ESI):407.5[M+H] +

[0381] Step 4: Synthesis of compound 12d

[0382] Compound 12c (40 mg, 0.098 mmol) was dissolved in 5 mL of acetonitrile, and 1 mL of 4N hydrochloric acid dioxane solution was added, and the mixture was reacted at room temperature for 2 h. The mixture was concentrated under reduced pressure to obtain the hydrochloride of 12d (28 mg, yield: 93.23%).

[0383] Ms m / z(ESI):307.3[M+H] +

[0384] Step 5: Synthesis of compound 12

[0385] Intermediate B (50 mg, 0.061 mmol) was dissolved in 2 mL of DMF, 12d (28 mg, 0.091 mmol) and DIPEA (24 mg, 0.18 mmol) were added, and the mixture was stirred at room temperature for 2 h. 30 mL of ethyl acetate was added, and the mixture was washed with water twice (20 mL×2), and once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and reverse column chromatography to obtain trifluoroacetate of compound 12 (25 mg, yield: 37.06%).

[0386] Ms m / z(ESI):553.5[M / 2+H] +

[0387] 1 H NMR(400MHz,CF3COOD)δ8.27(s,1H),8.19(s,1H),8.04–7.97(m,1H),7.95–7.88 (m,1H),7.88–7.75(m,4H),7.63–7.53(m,4H),7.52–7.32(m,7H),6.86–6.74(m, 1H),4.84–4.70(m,1H),4.67–4.42(m,9H),4.33–4.16(m,2H),4.15–3.98(m,1H) ,3.41–3.19(m,4H),3.01(s,3H),2.68–2.18(m,10H),1.73(d,3H),1.34(d,3H).

[0388] Example 13: Synthesis of Compound 13

[0389] Step 1: Synthesis of compound 13a

[0390] The raw material (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.56 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added, and stirred at room temperature for 2 h. The solvent was removed by concentration under reduced pressure to obtain the trifluoroacetate salt of 13a (0.54 g, yield: 99.4%).

[0391] Ms m / z(ESI):120.2[M+H]

[0392] Step 2: Synthesis of compound 13b

[0393] Intermediate A was dissolved in 20 mL of dichloromethane, and compound 13a (0.18 g, 1.52 mmol) was added. Triethylamine (0.62 g, 6.08 mmol) was added at 0°C under a nitrogen atmosphere, and the mixture was stirred at about 0°C for 30 min. Sodium triacetoxyborohydride (0.48 g, 2.28 mmol) was added, and the mixture was reacted at room temperature overnight. 30 mL of purified water was added, and the mixture was separated. The aqueous phase was extracted twice with dichloromethane (25 mL×2), and the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain 13b (0.4 g, yield: 66.03%).

[0394] Ms m / z(ESI):399.3[M+H] +

[0395] Step 3: Synthesis of compound 13c

[0396] Compound 13b (0.1 g, 0.25 mmol) was dissolved in 2 mL of dichloromethane, 2 mL of dioxane hydrochloride was added, and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to obtain the hydrochloride of 13c (0.056 g, yield: 75.06%).

[0397] Ms m / z(ESI):299.2[M+H] +

[0398] Step 4: Synthesis of compound 13

[0399] Intermediate B (50 mg, 0.061 mmol) was dissolved in 2 mL of DMF, and the hydrochloride of compound 13c (27 mg, 0.091 mmol) and DIPEA (24 mg, 0.18 mmol) were added, and stirred at room temperature for 2 h. 30 mL of ethyl acetate was added, and the mixture was washed with water twice (20 mL×2), and once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and reverse column chromatography to obtain trifluoroacetate of compound 13 (23 mg, yield: 34.35%).

[0400] Ms m / z(ESI):549.3[M / 2+H] +

[0401] 1 H NMR(400MHz,CF3COOD)δ8.24(s,1H),8.16(s,1H),8.00–7.93(m,1H),7.92–7.86(m,1H),7.84–7.79(m,1H), 7.79–7.71(m,3H),7.59–7.50(m,4H),7.49–7.42(m,3H),7.41–7.31(m,4H),6.76–6.69(m,1H),5.09–4.92(m ,1H),4.80–4.66(m,1H),4.59–4.40(m,8H),4.07–3.95(m,1H),3.88–3.76(m,1H),3.72–3.38(m,5H),3.33–3 .20(m,2H),2.98(s,3H),2.69–2.44(m,2H),2.38–2.21(m,2H),2.04–1.95(m,1H),1.69(d,3H),1.30(d,3H).

[0402] Example 14: Synthesis of Compound 14

[0403] Step 1: Synthesis of compound 14a

[0404] The raw material (S)-1,1,1-trifluoroisopropylamine hydrochloride (1.5 g, 10.00 mmol) was dissolved in 10 mL of methanol, triethylamine was added to adjust the pH to about 7, and then 11A (1.0 g, 2.00 mmol) and acetic acid (1.32 g, 22 mmol) were added, and the mixture was placed in a sealed tube at 100°C for overnight reaction. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was subjected to column chromatography to obtain 14a (0.62 g, yield: 53.74%).

[0405] 1 H NMR (400MHz, CDCl3) δ7.30(dd,2H),7.25–7.16(m,6H),7.01–6.93(m,3H),6.92–6.88(m,2H),5.05(d,2H),4.63(dt,1H),2.74(s,3H),1.72(d,3H).

[0406] Step 2: Synthesis of compound 14b

[0407] Compound 14a (0.60 g, 1.04 mmol) was added to 10 mL of dimethyl sulfoxide, followed by 1-(nitrophenyl)piperazine (0.65 g, 3.12 mmol), cuprous iodide (0.02 g, 0.1 mmol), 2,6-dimethylphenylcarbamoylcarboxylic acid (0.20 g, 1.04 mmol), and potassium carbonate (0.43 g, 3.12 mmol), and the mixture was heated to 130°C for 12 h under a nitrogen atmosphere. The mixture was cooled to room temperature, saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×5). The organic phases were combined, washed, and dried over anhydrous magnesium sulfate. The crude product was separated and purified by silica gel column chromatography to obtain 14b (0.12 g, yield: 17.77%).

[0408] 1 H NMR(400MHz, CDCl3)δ8.14(d,2H),7.17(dd,3H),7.13–6.94(m,5H),6.94–6.88(m,2H),6.83(d,2H),6.70(dd, 1H),6.60(d,2H),5.08(s,2H),4.67(dt,1H),3.46–3.39(m,4H),3.12–3.03(m,4H),2.73(s,3H),1.73(d,3H).

[0409] Step 3: Synthesis of compound 14c

[0410] Compound 14b (0.12 g, 0.17 mmol) was dissolved in 20 mL of methanol, 50 mg of 10% palladium carbon was added, and the mixture was stirred at room temperature for 1 h under a hydrogen atmosphere. The mixture was filtered and the filtrate was directly concentrated to obtain compound 14c as a gray solid (90 mg, yield: 90.8%).

[0411] Ms m / z(ESI):583.8[M+H] +

[0412] Step 4: Synthesis of compound 14d

[0413] 3-(Trifluoromethylsulfonyl)-4-fluorobenzenesulfonyl chloride (20 mg, 0.061 mmol) was dissolved in 20 mL of dichloromethane, and pyridine (20 mg, 0.26 mmol) was added at 0°C under nitrogen atmosphere, and then 10 mL of dichloromethane solution of compound 14c (30 mg, 0.051 mmol) was added, and the reaction was continued for 1 h after the addition was complete. After direct concentration under reduced pressure, the residue was purified by silica gel chromatography to obtain 14d (27 mg, yield: 60.62%).

[0414] Ms m / z(ESI):873.1[M+H] +

[0415] Step 5: Synthesis of compound 14

[0416] Compound 14d (50 mg, 0.057 mmol) was dissolved in 2 mL DMF, and compound 4c (34 mg, 0.11 mmol) and DIPEA (37 mg, 0.29 mmol) were added, and stirred at room temperature for 2 h. 30 mL of ethyl acetate was added, and the mixture was washed with water twice (20 mL × 2), and once with 20 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and reverse column chromatography to obtain compound 14 (12 mg, yield: 18.28%).

[0417] Ms m / z(ESI):549.8[M / 2+H] +

[0418] 1H NMR(400MHz,CF3COOD)δ8.25(s,1H),7.97(d,1H),7.88–7.72(m,3H),7.60–7.2 9(m,13H),7.26–7.15(m,1H),6.76–6.69(m,1H),5.23(d,1H),4.90(dd,1H),4.5 6–4.32(m,8H),4.02(s,2H),3.94–3.85(m,1H),3.46(s,3H),3.29–2.95(m,5H), 2.69–2.52(m,2H),2.44–2.28(m,2H),2.02(d,1H),1.92(dd,2H),1.43(dd,2H).

[0419] Example 15: Synthesis of Compound 15

[0420] The raw material 14d (50 mg, 0.057 mmol) was dissolved in 2 mL of DMF, and 7E (26 mg, 0.085 mmol) and DIPEA (37 mg, 0.29 mmol) were added, and stirred at room temperature for 2 h. 30 mL of ethyl acetate was added, and the mixture was washed with water twice (20 mL × 2), and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and reverse column chromatography to obtain compound 15 (12 mg, yield: 18.15%).

[0421] Ms m / z(ESI):580.3[M / 2+H] +

[0422] 1 H NMR(400MHz,CF3COOD)δ8.20(s,1H),7.97–7.87(m,1H),7.77–7.65(m,2H),7.61– 7.26(m,13H),7.25–7.03(m,2H),6.73–6.60(m,1H),4.95–4.78(m,1H),4.73–4.6 3(m,1H),4.53–4.07(m,8H),4.02–3.88(m,1H),3.84–3.57(m,2H),3.48–3.14(m, 7H),3.03–2.72(m,3H),2.66–2.40(m,2H),2.35–2.11(m,3H),2.09–1.71(m,5H).

[0423] Example 17: Synthesis of Compound 17

[0424] Step 1: Synthesis of compound 17a

[0425] The raw material 1-cyclopropylethylamine hydrochloride (1.46 g, 12.00 mmol) was dissolved in 20 mL of methanol, triethylamine was added to adjust the pH to about 7, and then 11A (2.0 g, 4.00 mmol) and acetic acid (2.4 g, 40 mmol) were added, and the tube was sealed and reacted at 100°C overnight. After cooling to room temperature, the reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography to obtain compound 17a (1.2 g, yield: 56.65%).

[0426] 1 H NMR (400MHz, CDCl3) δ7.27–7.19(m,6H),7.19–7.14(m,1H),7.09–6.93(m,4H),6.94–6.87(m,2H),5.06(s,2H),3.33 –3.22(m,1H),2.75(s,3H),1.49(d,3H),0.96(dd,1H),0.65–0.55(m,1H),0.45(dd,1H),0.10(dd,1H),0.02(d,1H).

[0427] Step 2: Synthesis of compound 17b

[0428] Compound 17a (1.0 g, 1.82 mmol) was added to 10 mL of dimethyl sulfoxide, and 1-(nitrophenyl)piperazine (0.75 g, 3.64 mmol), cuprous iodide (0.035 g, 0.18 mmol), 2,6-dimethylphenylcarbamoylcarbamic acid (0.35 g, 1.82 mmol), and potassium carbonate (0.75 g, 5.46 mmol) were added in sequence. The mixture was heated to 130 °C under a nitrogen atmosphere for 12 h, cooled to room temperature, and saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate (10 mL×5), the organic phases were combined, washed, and dried over anhydrous magnesium sulfate. The crude product was separated and purified by silica gel column chromatography to obtain 17b (0.63 g, yield: 51.27%).

[0429] Step 3: Synthesis of compound 17c

[0430] The raw material 17b (0.63 g, 0.93 mmol) was dissolved in 20 mL of methanol, and 50 mg of 10% palladium carbon was added. The mixture was reacted at room temperature for 1 h under a hydrogen atmosphere. The filtrate was directly concentrated to obtain compound 17c. A gray solid (0.42 g, yield: 81.36%) was obtained.

[0431] Ms m / z(ESI):555.2[M+H] +

[0432] Step 4: Synthesis of compound 17d

[0433] The raw material 3-(trifluoromethylsulfonyl)-4-fluorobenzenesulfonyl chloride (0.3 g, 0.91 mmol) was dissolved in 20 mL of dichloromethane. Pyridine (0.3 g, 3.8 mmol) was added at 0°C under nitrogen atmosphere, and then 10 mL of dichloromethane solution of 17c (0.42 g, 0.76 mmol) was added. After the addition was complete, the reaction was continued for 1 h. After concentration under reduced pressure, the residue was separated and purified by column chromatography to obtain 17d as a yellow solid (0.27 g, yield: 42.03%).

[0434] Ms m / z(ESI):845.7[M+H] +

[0435] Step 4: Synthesis of compound 17

[0436] The raw material 17d (50 mg, 0.059 mmol) was dissolved in 2 mL of DMF, and 7E (27 mg, 0.087 mmol) and DIPEA (38 mg, 0.29 mmol) were added, and stirred at room temperature for 2 h. 30 mL of ethyl acetate was added, and the mixture was washed with water twice (20 mL × 2), and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography and reverse column chromatography to obtain compound 17 (14 mg, yield: 20.97%).

[0437] Ms m / z(ESI):566.3[M / 2+H] +

[0438] 1 H NMR(400MHz,CF3COOD)δ8.20(s,1H),8.14(s,1H),7.95–7.90(m,1H),7.89–7.84(m,1H),7.82–7.68(m, 4H),7.58–7.47(m,4H),7.46–7.39(m,3H),7.38–7.29(m,4H),6.75–6.63(d,1H),4.70–4.36(m,8H),4.1 7–3.90(m,2H),3.84–3.60(m,3H),3.45–3.14(m,8H),3.04–2.89(m,3H),2.57–2.45(m,1H),2.32–2.14 (m,3H),2.12–1.92(m,2H),1.74–1.66(m,1H),1.48–1.31(m,3H),1.03–0.63(m,2H),0.55–0.13(m,2H).

[0439] Compound 18: Synthesis of Compound 18

[0440] The raw material 17d (50 mg, 0.059 mmol) was dissolved in 2 mL of DMF, and 4c (19 mg, 0.064 mmol) and DIPEA (38 mg, 0.29 mmol) were added, and stirred at room temperature for 2 h. 30 mL of ethyl acetate was added, and the mixture was washed with water twice (20 mL × 2), and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography and reverse column chromatography to obtain compound 18 (13 mg, yield: 19.61%).

[0441] Ms m / z(ESI):1123.5[M+H] +

[0442] 1 H NMR(400MHz,CF3COOD)δ8.24–8.19(m,1H),8.16–8.10(m,1H),7.96–7.91(m,1H),7.89–7.84(m,1H),7.82–7.67 (m,4H),7.57–7.47(m,4H),7.46–7.38(m,3H),7.38–7.29(m,4H),6.74–6.69(d,1H),5.26–5.10(m,1H),4.57–4 .26(m,8H),4.04–3.92(m,2H),3.89–3.63(m,2H),3.61–3.35(m,4H),3.27–3.18(m,2H),2.96–2.89(m,3H),2.6 7–2.47(m,2H),2.40–2.21(m,2H),2.03–1.63(m,3H),1.44–1.31(m,2H),1.03–0.65(m,2H),0.53–0.13(m,2H).

[0443] Example 19: Preparation of Compound 19

[0444] The raw material 11E (50 mg, 0.057 mmol) was dissolved in 2 ml of DMF, 7E (26 mg, 0.086 mmol) and DIPEA (22 mg, 0.17 mmol) were added, and stirred at room temperature for 2 h. 30 ml of ethyl acetate was added, and the mixture was washed with water twice (20 mL × 2), washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and reverse column chromatography to obtain compound 19 (14 mg, 21.18%).

[0445] Ms m / z(ESI):1159.3[M+H] +

[0446] Example 20: Preparation of Compound 20

[0447] Step 1: Preparation of compound 20B

[0448] 20A (5.0 g, 46.24 mmol) was placed in a sealed tube, dissolved with 100 mL of N,N-dimethylformamide, and DIPEA (9 g, 50.86 mmol) and 3,4-difluoronitrobenzene (4.05 g, 50.86 mmol) were added. The system was heated to 120°C overnight under nitrogen protection, 300 mL of ethyl acetate was added to the system for dilution, and then the organic phase was washed three times with 150 mL of water and once with 150 mL of saturated brine. The organic phase was dried and spin-dried, and the residue was purified by column chromatography to obtain compound 20B (3.0 g, yield: 36.5%).

[0449] LCMS m / z=356.2[M+H] +

[0450] Step 2: Preparation of compound 20C

[0451] The intermediate 20B (3.0 g, 8.45 mmol) was dissolved in 30 mL of ultra-dry N,N-dimethylformamide, and the system was placed in an ice bath for 20 min under nitrogen protection, and then 60% sodium hydride (375 mg, 9.3 mmol) was added. After the addition, the system automatically warmed to room temperature and reacted for 3 h. The reaction solution was directly poured into 100 mL of ice water, and 200 mL of ethyl acetate was added to dilute it. The organic phase was washed three times with 100 mL of water and once with 100 mL of saturated salt water. The organic phase was dried and spin-dried, and the residue was purified by column chromatography to obtain compound 20C (2.8 g, yield: 99%).

[0452] LCMS m / z=336.2[M+H] +

[0453] Step 3: Preparation of compound 20D

[0454] Under nitrogen protection, intermediate 20C (0.8 g, 2.4 mmol) was dissolved in 20 mL of acetonitrile, and then 5 mL of 1,4-dioxane hydrochloride solution was added. The system then automatically warmed to room temperature and reacted for 1 h. The solvent was removed by concentration under reduced pressure to obtain the hydrochloride salt of product 20D (720 mg crude product), which was directly used in the next step reaction.

[0455] LCMS m / z=236.1[M+H] +

[0456] Step 4: Preparation of 20E

[0457] Compound 5A (800 mg, 1.53 mmol), 20D (720 mg, 3.06 mmol), cuprous iodide (170 mg, 0.92 mmol), [(2,6-xylyl)amino](oxy)acetic acid (570 mg, 3.06 mmol) and potassium carbonate (630 mg, 4.59 mmol) were dissolved in 15 mL of DMSO and reacted in a sealed tube at 130° C. for 10 hours. A certain amount of water was added to quench the reaction, and the reaction was extracted with EA, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 20E (320 mg, 29.15%).

[0458] Ms m / z(ESI):677.2[M+H]

[0459] Step 5: Preparation of 20F

[0460] Compound 20E (300 mg, 0.44 mmol) was dissolved in 10 mL of methanol and 10 mL of ethyl acetate, and then 10% palladium carbon (50 mg, 0.47 mmol) was added and stirred at room temperature for 1 hour. The filtrate was collected and concentrated under reduced pressure to obtain compound 20F (200 mg, 81.59%).

[0461] LCMS m / z=557.2[M+H] +

[0462] Step 3: Preparation of 20G

[0463] Compound 5C-1 (129 mg, 0.40 mmol) was dissolved in 5 mL of dichloromethane, and then pyridine (85 mg, 1.08 mmol) was added at 0°C, stirred for 10 minutes, and then 20F (200 mg, 0.36 mmol) was slowly added, and the whole system was stirred at room temperature for 2 hours. A certain amount of water was added to quench the reaction, extracted with ethyl acetate, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain product 20G (180 mg, 59.01%).

[0464] LCMS m / z=847.1[M+H] +

[0465] Step 4: Preparation of compound 20

[0466] 20G (80 mg, 0.094 mmol) was dissolved in 5 ml DMF, 10E (45.19 mg, 0.14 mmol) and DIPEA (36.45 mg, 0.28 mmol) were added, and stirred at room temperature for 2 h. 30 ml of ethyl acetate was added, and the mixture was washed with water twice (20 mL × 2), washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and reverse column chromatography to obtain compound 20 (15 mg, 13.9%).

[0467] Ms m / z(ESI):1147.3[M+H] +

[0468] Example 21: Preparation of Compound 21

[0469] Step 1: Preparation of 21C

[0470] The raw material 21A (2.2 g, 6.12 mmol) was dissolved in 20 mL of anhydrous ethanol, and compound 4-cyclopropylbenzaldehyde 21B (0.98 g, 6.73 mmol), triethylamine (1.55 g, 15.3 mmol), and 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazole bromide (0.77 g, 3.06 mmol) were added in sequence, and nitrogen was introduced. The system was heated to 75°C and stirred for 6 h. The reaction system was cooled to room temperature and concentrated. The organic phase was washed, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was subjected to column chromatography to obtain product 21C (1.8 g, yield: 58.2%).

[0471] Step 2: Preparation of 21D

[0472] The raw material (S)-1,1,1-trifluoroisopropylamine hydrochloride (1.6 g, 10.68 mmol) was dissolved in 10 mL of methanol, and triethylamine was added to adjust the pH to about 7, and then 21C (1.8 g, 3.5 6 mmol) and acetic acid (2.14 g, 35.6 mmol) were added, and the reaction was carried out overnight at 100°C in a sealed tube. After concentration, the residue was directly subjected to column chromatography to obtain the target product 21D (0.73 g, yield: 72%).

[0473] 1H NMR(400MHz, CDCl3)δ7.23(dd,4H),7.20–7.15(m,1H),7.03–6.94(m,5H),6.94–6.86(m,3H),5.06(s,2H ),4.73–4.69(m,1H),2.73(s,3H),1.89–1.83(m,1H),1.69(d,3H),1.02–0.94(m,2H),0.74–0.64(m,2H).

[0474] Step 3: Preparation of 21E

[0475] The raw material 21D (0.6 g, 1.03 mmol) was dissolved in a mixed solvent of 10 mL of dioxane and 2 mL of water, and N-Boc-1,2,5,6-tetrahydropyridine-4-boric acid pinacol ester (0.48 g, 1.54 mmol), cesium carbonate (0.67 g, 2.06 mmol), and Pd(dppf)Cl2 dichloromethane complex (0.084 g, 0.10 mmol) were added in sequence. After nitrogen substitution, the mixture was heated to 100°C and reacted for 2 h. The mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 21E (0.55 g, yield 78%).

[0476] Step 4: Preparation of 21F

[0477] The raw material 21E (0.55 g, 0.80 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of 4N hydrochloric acid-dioxane solution was added. The mixture was reacted at room temperature for 2 h and concentrated under reduced pressure to obtain the hydrochloride of 21F (0.45 g, yield: 96%).

[0478] LCMS m / z=585.3[M+H] +

[0479] Step 5: Preparation of 21G

[0480] The hydrochloride of the raw material 21F (0.45 g, 0.77 mmol) was dissolved in 5 mL of DMF, and p-fluoronitrobenzene (0.16 g, 1.16 mmol) and potassium carbonate (0.21 g, 0.54 mmol) were added in sequence, and the mixture was heated to 50°C for 16 h under a nitrogen atmosphere. 20 mL of ethyl acetate was added, and the mixture was washed with water 3 times (20 mL×3), and once with 30 mL of brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 21G (0.53 g, yield: 97%).

[0481] Step 6: Preparation of 21H

[0482] The raw material 21G (0.53 g, 0.75 mmol) was dissolved in 10 mL of methanol, and 50 mg of 10% palladium carbon was added. After replacing the hydrogen atmosphere, the mixture was reacted at room temperature for 2 h, filtered, and the filtrate was concentrated to obtain 21H (0.31 g, yield: 70%), which was directly used in the next step.

[0483] Ms m / z(ESI):588.3[M+H] +

[0484] Step 7: Preparation of 21I

[0485] The raw material compound 5C-1 (0.21 g, 0.64 mmol) was dissolved in 20 mL of dichloromethane, and the mixture was cooled to 0°C and pyridine (0.21 g, 2.65 mmol) was added. Then, 10 mL of dichloromethane solution of 21H (0.31 g, 0.53 mmol) was added. After the addition, the reaction was continued for 1 h. The mixture was directly concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 21I (0.15 g, yield: 32%).

[0486] Ms m / z(ESI):878.1[M+H] +

[0487] Step 8: Preparation of compound 21

[0488] The raw material 21I (60 mg, 0.071 mmol) was dissolved in 2 mL DMF, and 10E (34 mg, 0.11 mmol) and DIPEA (46 mg, 0.36 mmol) were added in sequence, and stirred at room temperature for 2 h. 30 ml of ethyl acetate was added, and the mixture was washed with water twice (20 mL × 2), and washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain a crude product, which was purified by silica gel column chromatography and reverse column chromatography to obtain a compound (23 mg, yield: 27.5%).

[0489] Ms m / z(ESI):1178.4[M+H] +

[0490] Example 22: Synthesis of Compound 22

[0491] Step 1: Synthesis of 22A

[0492] Under nitrogen atmosphere, 5A (1.0 g, 1.91 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (885 mg, 2.86 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (138 mg, 0.19 mmol), cesium carbonate (1.24 g, 3.82 mmol) were dissolved in 20 mL 1,4-dioxane and 4 mL water, and reacted at 100°C for 3 hours. Water was added for dilution, extracted with ethyl acetate (25 mL×3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 22A (1.1 g, 91.84%).

[0493] Step 2: Synthesis of 22B

[0494] 22A (1.1 g, 1.76 mmol) was dissolved in 10 mL of dichloromethane and 5 mL of 4N hydrochloric acid 1,4-dioxane solution, stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain the hydrochloride of 22B (800 mg, 86.66%).

[0495] LCMS m / z=525.3[M+H] +

[0496] Step 3: Synthesis of 22C

[0497] The hydrochloride of 22B (524 mg, 1.00 mmol) was dissolved in 15 mL of N,N-dimethylformamide, potassium carbonate (276 mg, 2.00 mmol), and p-fluoronitrobenzene (211 mg, 1.50 mmol), and the temperature was raised to 80°C and stirred for 2 hours. Water was added for dilution, and the mixture was extracted with ethyl acetate (25 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 22C (350 mg, 56.86%).

[0498] LCMS m / z=646.4[M+H] +

[0499] Step 4: 22D synthesis

[0500] 22C (350 mg, 0.54 mmol) was dissolved in 10 mL of methanol, 10% Pd / C (350 mg) was added, hydrogen was replaced for protection, and the mixture was stirred at room temperature for 2 hours. After filtration, the mixture was concentrated under reduced pressure to obtain 22D (200 mg, 69.93%).

[0501] LCMS m / z=528.3[M+H] +

[0502] Step 5: Synthesis of Compound 22E

[0503] 5C-1 (105 mg, 0.318 mmol) was dissolved in 5 mL of dichloromethane, pyridine (51 mg, 0.639 mmol) was added at 0°C, stirred for 1 minute, 22D (121 mg, 0.23 mmol) was slowly added, and stirred at room temperature for 2 hours. Water was added for dilution, and ethyl acetate (25 mL × 3) was extracted, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 22E (80 mg, 42.64%).

[0504] LCMS m / z=818.2[M+H] +

[0505] Step 6: Synthesis of compound 22

[0506] 22E (80 mg, 0.098 mmol) and 10E (48 mg, 0.15 mmol) were dissolved in 3 mL of N,N-dimethylformamide, and N,N-diisopropylethylamine (33 mg, 0.26 mmol) was slowly added, and stirred at room temperature for 2 hours. Water was added for dilution, and the mixture was extracted with ethyl acetate (25 mL×2), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain compound 22 (10 mg, 9.13%).

[0507] LCMS m / z=1118.4[M+H] +

[0508] 1 H NMR(400MHz,CF3COOD)δ8.23–8.11(m,1H),7.94(dd,1H),7.72–7.62(m,2H),7.5 7(s,1H),7.54–7.23(m,14H),6.74(d,1H),4.71–4.60(m,1H),4.41–4.22(m,2H) ,4.08–3.71(m,8H),3.51–3.34(m,2H),3.29–3.17(m,2H),3.16–3.04(m,1H),2. 90(s,3H),2.46–2.26(m,5H),2.25–1.72(m,8H),1.69–1.47(m,4H),1.26(d,3H).

[0509] Example 23: Preparation of Compound 23

[0510] Step 1: Preparation of compound 23C

[0511] Under nitrogen protection, compound 23A (1.5 g, 3.26 mmol), 23B (1.21 g, 6.52 mmol), cuprous iodide (370 mg, 1.96 mmol), [(2,6-xylyl)amino](oxy)acetic acid (1.26 g, 6.52 mmol) and potassium carbonate (2.25 g, 16.3 mmol) were dissolved in 20 mL of DMSO and reacted in a pressure bottle at 130° C. for 10 hours. Water was added to quench the reaction, EA was extracted (30 mL×2), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 23C (1.1 g, 59.6%).

[0512] Ms m / z(ESI):566.1[M+H] +

[0513] Step 2: Preparation of compound 23D

[0514] Under nitrogen protection, intermediate 23C (1.1 g, 1.94 mmol) was dissolved in 20 mL of acetonitrile, and 5 mL of 1,4-dioxane hydrochloride solution was slowly added under ice bath. The mixture was heated to room temperature for 1 h, and the solvent was removed by concentration under reduced pressure to obtain the hydrochloride salt of product 23D (880 mg crude product), which was directly used in the next step reaction.

[0515] LCMS m / z=466.1[M+H]+

[0516] Step 3: Preparation of compound 23E

[0517] The hydrochloride of intermediate 23D (0.3 g, 0.64 mmol) and p-fluoronitrobenzene (0.11 g, 0.77 mmol) were dissolved in 20 mL of DMF, and then cesium carbonate (0.83 g, 2.56 mmol) was added, and the temperature was raised to 80 ° C for 12 h. The reaction was quenched by adding water, extracted with EA (5 mL×2), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 23E (0.31 g, 82.5%).

[0518] LCMS m / z=587.2[M+H] +

[0519] Step 4: Preparation of compound 23F

[0520] Compound 23E (300 mg, 0.51 mmol) was dissolved in 10 mL of methanol and 2 mL of water, and ammonium chloride (140 mg, 2.56 mmol) and iron powder (150 mg, 2.63 mmol) were added. The temperature was raised to 80°C and reacted for 3 hours. The mixture was cooled to room temperature and silica gel was directly added to mix the sample. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain compound 23F (200 mg, 70.9%).

[0521] LCMS m / z=557.3[M+H] +

[0522] Step 5: Preparation of Compound 23G

[0523] Compound 5C-1 (140 mg, 0.43 mmol) was dissolved in 5 mL of dichloromethane, pyridine (85 mg, 1.08 mmol) was added at 0°C, stirred for 10 minutes, and then 23F (200 mg, 0.36 mmol) was slowly added, and stirred at room temperature for 2 hours. Water was added to quench the reaction, EA was extracted (5 mL × 2), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 23G (180 mg, 59.01%).

[0524] LCMS m / z=847.3[M+H] +

[0525] Step 6: Preparation of compound 23H

[0526] Dissolve 23G (180 mg, 0.21 mmol) in 5 ml DMF, add intermediate B (71 mg, 0.25 mmol) and DIPEA (81 mg, 0.63 mmol), stir at room temperature for 2 h, add 30 ml ethyl acetate, wash twice with water (20 mL × 2), wash once with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain product 23H (150 mg, 64.48%).

[0527] LCMS m / z=1107.2[M+H] +

[0528] Step 7: Preparation of compound 23

[0529] 23H (100 mg, 0.09 mmol) was dissolved in 10 mL of methanol and 2 mL of water, sodium hydroxide (18 mg, 0.45 mmol) was added, and the reaction was stirred at room temperature for 12 hours. The pH was adjusted to about 4 with dilute hydrochloric acid, diluted with water, extracted with ethyl acetate (25 mL × 2), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography and reverse column chromatography (mobile phase A: 0.5% NH4HCO3 aqueous solution, mobile phase B: acetonitrile, gradient elution from 10% of A to 40% of B solution) to obtain compound 23 (43 mg, 44.25%).

[0530] LCMS m / z=1080.2[M+H] +

[0531] Example 24: Synthesis of Compound 24

[0532] 22E (60 mg, 0.076 mmol) and intermediate 24A (21 mg, 0.076 mmol) were dissolved in 3 mL of DMF, and DIPEA (49 mg, 0.38 mmol) was slowly added and stirred at room temperature for 2 hours. Water was added for dilution, and the mixture was extracted with ethyl acetate (25 mL×2), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and reverse column chromatography (mobile phase A: 0.5% NH4HCO3 aqueous solution, mobile phase B: acetonitrile, gradient elution from 10% of A to 40% of B solution) to obtain compound 24 (23 mg, 28.05%).

[0533] LCMS m / z(ESI):540.0[M / 2+H] +

[0534] 1 H NMR(400MHz,CF3COOD)δ8.29(s,1H),8.08–7.98(m,1H),7.80–7.71(m,2H),7.70–7.62(m,1 H),7.62–7.51(m,9H),7.47–7.30(m,5H),6.86–6.77(m,1H),4.80–4.68(m,1H),4.51–4.27 (m,1H),4.21–3.99(m,3H),3.97–3.82(m,3H),3.75–3.62(m,1H),3.62–3.39(m,3H),3.38– 3.13(m,4H),2.99(s,3H),2.70-2.57(m,1H),2.55–2.12(m,9H),1.74(d,3H),1.35(d,3H).

[0535] Example 25: Synthesis of Compound 25

[0536] Step 1: Synthesis of 25A

[0537] Deuterated isopropylamine hydrochloride (0.65 g, 10.00 mmol) was dissolved in 10 mL of methanol, triethylamine was added to adjust the pH to about 7, 2-acetyl-3-(3-bromophenyl)-4-(4-chlorophenyl)-4-oxobutyric acid benzyl ester (1.0 g, 2.00 mmol) and acetic acid (1.2 g, 20 mmol) were added, and the mixture was reacted overnight at 100° C. in a pressure bottle. The reaction solution was concentrated, and the residue was separated and purified by column chromatography to obtain 25A (0.3 g, yield: 28.36%).

[0538] Step 2: Synthesis of 25B

[0539] Under nitrogen atmosphere, 25A (0.32 g, 0.61 mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (0.28 mg, 0.92 mmol), Pd(dppf)Cl2 (50 mg, 0.061 mmol), cesium carbonate (0.4 g, 1.22 mmol) were dissolved in 20 mL 1,4-dioxane and 4 mL water, and reacted at 100°C for 3 hours. Water was added for dilution, and ethyl acetate (25 mL × 3) was used for extraction, and the mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 25B (0.30 g, 77.91%).

[0540] Step 2: Synthesis of 25C

[0541] 25B (0.3 g, 0.48 mmol) was dissolved in 5 mL of dichloromethane and 2 mL of 4N hydrochloric acid 1,4-dioxane solution, stirred at room temperature for 2 hours, and concentrated under reduced pressure to obtain the hydrochloride of 25C (0.23 g, 90.22%).

[0542] LCMS m / z=531.7[M+H] +

[0543] Step 3: Synthesis of 25D

[0544] The hydrochloride of 25C (0.155 g, 0.29 mmol) was dissolved in 15 mL of N,N-dimethylformamide, cesium carbonate (0.19 g, 0.59 mmol), and p-fluoronitrobenzene (0.061 g, 0.43 mmol), and stirred at 50°C for 2 hours. Water was added for dilution, and the mixture was extracted with ethyl acetate (25 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 25D (0.145 g, 76.66%).

[0545] Step 4: Synthesis of 25E

[0546] 25D (145 mg, 0.22 mmol) was dissolved in 10 mL of methanol, 10% Pd / C (50 mg) was added, hydrogen was replaced for protection, and the mixture was stirred at room temperature for 2 hours. After filtration, the mixture was concentrated under reduced pressure to obtain 25E (108 mg, 91.91%).

[0547] LCMS m / z=534.6[M+H] +

[0548] Step 5: Synthesis of compound 25F

[0549] 5C-1 (98 mg, 0.30 mmol) was dissolved in 5 mL of dichloromethane, pyridine (48 mg, 0.60 mmol) was added at 0°C, stirred for 1 minute, 25E ​​(108 mg, 0.20 mmol) was slowly added, and stirred at room temperature for 2 hours. Water was added for dilution, and ethyl acetate (25 mL × 3) was extracted, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 25F (70 mg, 42.46%).

[0550] LCMS m / z=818.2[M+H] +

[0551] Step 6: Synthesis of compound 25

[0552] 25F (38 mg, 0.046 mmol) and intermediate 24A (39 mg, 0.14 mmol) were dissolved in 3 mL of DMF, and DIPEA (30 mg, 0.23 mmol) was slowly added and stirred at room temperature for 2 hours. Water was added for dilution, and the mixture was extracted with ethyl acetate (25 mL×2), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography and reverse column chromatography (mobile phase A: 0.5% NH4HCO3 aqueous solution, mobile phase B: acetonitrile, gradient elution from 10% of A to 40% of B solution) to obtain compound 25 (16 mg, 32.06%).

[0553] LC-Ms m / z(ESI):542.8[M / 2+H] +

[0554] 1 H NMR(400MHz,CF3COOD)δ8.28(s,1H),8.06–7.97(m,1H),7.84–7.71(m,2H),7.71 –7.63(m,2H),7.62–7.47(m,9H),7.47–7.35(m,4H),6.87–6.75(m,1H),4.76–4.5 2(m,1H),4.16–3.99(m,3H),3.98–3.81(m,3H),3.76–3.39(m,4H),3.38–3.13(m, 4H),3.01–2.95(m,3H),2.71-2.58(m,1H),2.57–2.29(m,8H),2.28–2.14(m,1H).

[0555] Example 26: Synthesis of Compound 26

[0556] Step 1: Synthesis of 26A

[0557] The raw materials N-Boc-piperazine-d8 (0.6 g, 3.09 mmol), 4-fluoronitrobenzene (0.65 g, 4.63 mmol) and cesium carbonate (2.03 g, 6.24 mmol) were dissolved in 15 mL DMF and heated to 50°C for 16 h. 20 mL of ethyl acetate was added, washed with water 3 times (20 mL×3), washed once with 30 mL of brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed to obtain the product 26A (0.78 g, yield: 80.04%).

[0558] Step 2: Synthesis of 26B

[0559] The raw material 26A (0.57 g, 1.81 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of 4N hydrochloric acid dioxane solution was added. The mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The residue was dissolved in 30 mL of dichloromethane and the pH was adjusted to about 8 with sodium bicarbonate aqueous solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product 26B (0.36 g, yield: 92.39%).

[0560] Step 3: Synthesis of 26C

[0561] 5A (0.60 g, 1.15 mmol) was dissolved in 10 mL of dimethyl sulfoxide, and 26B (0.36 g, 1.7 mmol), cuprous iodide (0.020 g, 0.11 mmol), 2,6-dimethylphenylcarbamoylcarboxylic acid (0.22 g, 1.15 mmol), and potassium carbonate (0.48 g, 3.45 mmol) were added in sequence, and the mixture was reacted at 130°C for 12 h under a nitrogen atmosphere. The mixture was cooled to room temperature, and a saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×5). The organic phases were combined, washed, and dried over anhydrous magnesium sulfate. The crude product was separated and purified by silica gel column chromatography to obtain 26C (0.2 g, yield: 26.46%).

[0562] Step 4: Synthesis of 26D

[0563] 26C (0.20 g, 0.30 mmol) was dissolved in 10 mL of methanol, 50 mg of 10% palladium carbon was added, and the mixture was reacted at room temperature for 1 h under a hydrogen atmosphere. The mixture was filtered and the filtrate was directly concentrated to obtain 26D (0.112 mg, yield: 69.51%).

[0564] LC-Ms m / z(ESI):537.8[M+H] +

[0565] Step 5: Synthesis of 26E

[0566] 3-(Trifluoromethylsulfonyl)-4-fluorobenzenesulfonyl chloride (78 mg, 0.24 mmol) was dissolved in 20 mL of dichloromethane, and pyridine (79 mg, 1.0 mmol) was added at 0°C under nitrogen atmosphere, and then 10 mL of dichloromethane solution of 26D (110 mg, 0.20 mmol) was added, and the reaction was continued for 1 h after the addition was complete. The residue was concentrated under reduced pressure and purified by column chromatography to obtain 26E (64 mg, yield: 38.68%).

[0567] Step 6: Synthesis of compound 26

[0568] 26E (55 mg, 0.066 mmol) was dissolved in 2 mL DMF, and intermediate 24A (56 mg, 0.20 mmol) and DIPEA (43 mg, 0.33 mmol) were added, and the mixture was stirred at room temperature for 2 h. 30 mL of ethyl acetate was added, and the organic layer was washed with water twice (20 mL×2), and once with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography and reverse column chromatography (mobile phase A: 0.5% NH4HCO3 aqueous solution, mobile phase B: acetonitrile, gradient elution from 10% of A to 40% of B solution) to obtain compound 26 (13 mg, 18.11%).

[0569] LC-Ms m / z(ESI):544.3[M / 2+H] +

[0570] 1 H NMR(400MHz,CF3COOD)δ8.33–8.28(m,1H),8.25–8.19(m,1H),8.06–8.00(m,1H),7.97–7.92(m,1H),7.90–7.86 (m,1H),7.85–7.78(m,3H),7.65–7.49(m,7H),7.48–7.37(m,4H),6.84–6.76(m,1H),4.85–4.73(m,1H),4.63–4 .27(m,1H),4.12–4.02(m,1H),3.96–3.82(m,1H),3.73–3.61(m,1H),3.59–3.39(m,3H),3.37–3.16(m,3H),3.0 4(s,3H),2.71–2.58(m,1H),2.57–2.46(m,1H),2.41–2.29(m,3H),2.28–2.15(m,1H),1.75(d,3H),1.37(d,3H).

[0571] Example 27: Synthesis of Compound 27

[0572] Step 1: Synthesis of compound 27B

[0573] 27A (5 g, 49.43 mmol) was dissolved in 50 mL THF and 5 mL water, and sodium carbonate (15.72 g, 148.23 mmol) was slowly added, and 9-fluorenylmethyl chloroformate (15.35 g, 59.34 mmol) was slowly added under ice bath, and the temperature was raised to room temperature and stirred for 2 hours. Water was added for dilution, and ethyl acetate (25 mL×3) was used for extraction, and the mixture was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 27B (11.2 g, 70.06%).

[0574] LCMS m / z=324.2[M+H] +

[0575] Step 2: Synthesis of compound 27C

[0576] 27B (5 g, 15.47 mmol) was dissolved in 15 mL of pyridine, and carbon tetrabromide (10.26 g, 30.94 mmol) was slowly added, and nitrogen was replaced 3 times. The mixture was stirred for 30 minutes, and trimethoxyphosphine (4.03 g, 32.49 mmol) was slowly added under ice bath, and the mixture was heated to room temperature and stirred for 2 hours. Water was added for dilution, and the mixture was extracted with ethyl acetate (25 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 27C (4.5 g, 67.43%).

[0577] LCMS m / z=432.2[M+H] +

[0578] Step 3: Synthesis of compound 27D

[0579] 27C (4.5 g, 1.61 mmol) was dissolved in 50 mL THF and 5 mL water, and lithium hydroxide (4.5 g, 1.61 mmol) was added. The reaction was carried out at room temperature for 12 h, and the filtrate was collected by filtration and concentrated under reduced pressure to obtain a crude product of 27D (0.78 g), which was directly used for the next step without further purification.

[0580] LCMS m / z=210.1[M+H] +

[0581] Step 4: Synthesis of compound 27E

[0582] Intermediate A (0.5 g, 1.69 mmol) was dissolved in 10 mL N,N-dimethylacetamide, 27D (0.42 g, 2.01 mmol) and acetic acid (0.1 g, 1.69 mmol) were added, and stirred for 30 minutes under nitrogen protection, sodium triacetoxyborohydride (0.72 g, 3.40 mmol) was added, and stirred at room temperature overnight. 30 mL of purified water was added, and the liquid was separated. The aqueous phase was extracted twice with 50 mL of dichloromethane, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, and 27E (0.61 g, yield: 73.88%) was obtained by column chromatography.

[0583] LCMS m / z=489.3[M+H] +

[0584] Step 5: Synthesis of compound 27F

[0585] Compound 27E (0.3 g, 0.61 mmol) was dissolved in DCM (10 mL), and then TMSI (0.73 g, 3.66 mmol) was added, and the mixture was reacted at room temperature for 2 h. The solvent was removed to obtain a crude product of 27F (0.21 g), which was used directly in the next step without further purification.

[0586] LCMS m / z=361.2[M+H] +

[0587] Step 6: Synthesis of compound 27

[0588] The crude product of 27F (110 mg, 0.31 mmol) was dissolved in 2 mL of DMF, and 22E (250 mg, 0.31 mmol) and DIPEA (120 mg, 0.93 mmol) were added, and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and acetonitrile was added to precipitate a solid, which was collected by filtration and separated and purified by preparative HPLC to obtain the trifluoroacetate salt of compound 27 (80 mg, yield: 22.27%).

[0589] HPLC preparation method: instrument: SHIMADZU LC-20AP; preparation column: C18; mobile phase: A is 0.1% TFA aqueous solution; B is acetonitrile;

[0590] Elution method: 32% to 62% of B solution A, gradient elution for 15 minutes; flow rate: 25mL / min; column temperature: room temperature; detection wavelength: 220nm;

[0591] LCMS m / z=1158.2[M+H] +

[0592] 1H NMR(400MHz,CF3COOD)δ8.34–8.27(m,1H),8.07–8.00(m,1H),7.82–7.72(m,2H),7 .69–7.64(m,1H),7.64–7.35(m,14H),6.86–6.77(m,1H),5.18–4.86(m,1H),4.82–4 .69(m,1H),4.14–4.01(m,3H),4.00–3.85(m,3H),3.80–3.68(m,1H),3.63–3.42(m, 3H),3.40–3.15(m,4H),3.00(s,3H),2.74–2.22(m,10H),1.76(d,3H),1.36(d,3H).

[0593] Example 28: Preparation of Compound 28

[0594] Step 1: Preparation of 28B

[0595] Under nitrogen protection, the raw material 28A (0.5 g, 2.07 mmol) and tetrabromomethane (1.37 g, 4.14 mmol) were dissolved in 5 mL of pyridine, cooled in an ice bath and trimethyl phosphite (541 mg, 4.35 mmol) was slowly added dropwise to form a precipitate immediately, and then slowly turned yellow, and continued to stir at 0°C for 30 minutes. Then at room temperature for 1.5 hours, the reaction solution was poured into water, 1N dilute hydrochloric acid was added to adjust the pH to about 7, and then 15 mL of ethyl acetate was added to extract twice, the organic layer was washed twice with 1N dilute hydrochloric acid, dried with Na2SO4, filtered, concentrated, and column chromatography to obtain 28B (0.6 g, yield: 83%).

[0596] LCMS m / z=350.2[M+H] +

[0597] Step 2: Preparation of 28C

[0598] Under nitrogen protection, intermediate 28B (84 mg, 0.241 mmol) was dissolved in 3 mL of dichloromethane, and then 21 mL of trifluoroacetic acid was added. The system was then reacted at room temperature for 1 h, and the solvent was removed by concentration under reduced pressure to obtain a crude product 28C (89 mg) which was directly used in the next step without further purification.

[0599] LCMS m / z=250.2[M+H] +

[0600] Step 3: Preparation of 28D

[0601] Under nitrogen protection, the crude intermediate 28D (89 mg, 0.241 mmol) was dissolved in a mixed solvent of 3 mL of ultra-dry 1.2-dichloroethane and 3 mL of ultra-dry methanol, and then sodium acetate (79 mg, 0.964 mmol), acetic acid (0.1 mL) and Molecular sieves (50 mg), stirred at room temperature for 15 min, then intermediate A (107 mg, 0.362 mmol) was added, and the system was reacted at room temperature for 1 h. Sodium triacetoxyborohydride (153 mg, 0.723 mmol) was added and stirred at room temperature overnight. The solvent was removed by concentration under reduced pressure, and the product 28D (124 mg, two-step yield: 97%) was obtained by column chromatography.

[0602] LCMS m / z=529.2[M+H] +

[0603] Step 4: Preparation of 28E

[0604] Under nitrogen protection, intermediate 28D (124 mg, 0.235 mmol) was dissolved in 5 mL of ultra-dry dichloromethane, and then trimethylsilyl iodide (0.2 mL, 1.41 mmol) was slowly added dropwise. The mixture was stirred at room temperature for 2 h and concentrated. The residue was dissolved in 10 mL of dichloromethane and concentrated again. After repeating the reaction twice, a crude product 28E (210 mg) was obtained, which was used directly in the next step.

[0605] LCMS m / z=401.2[M+H] +

[0606] Step 5: Preparation of compound 28

[0607] Under nitrogen protection, intermediate 28E (210 mg, 0.235 mmol) was dissolved in 5 mL of ultra-dry DMF, and then N,N-diisopropylethylamine (155 mg, 1.2 mmol) and intermediate 22E (160 mg, 0.2 mmol) were added in sequence. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The trifluoroacetate salt of compound 28 (20 mg, yield: 8.5%) was obtained by separation and purification by preparative HPLC.

[0608] HPLC preparation method:

[0609] Instrument: SHIMADZU LC-20AP;

[0610] Preparative column: C18;

[0611] Mobile phase: A is 0.1% TFA aqueous solution; B is acetonitrile;

[0612] Elution method: 48% to 68% of B solution A, gradient elution for 15 minutes;

[0613] Flow rate: 25 mL / min;

[0614] Column temperature: room temperature;

[0615] Detection wavelength: 220nm;

[0616] LCMS m / z=1199.3[M+H] +

[0617] 1 H NMR(400MHz,CF3COOD)δ8.37–8.27(m,1H),8.10–7.96(m,1H),7.85–7.72(m,2H),7 .69–7.30(m,15H),6.89–6.77(m,1H),4.85–4.66(m,2H),4.48–4.32(m,2H),4.17–3 .77(m,7H),3.61–3.45(m,2H),3.39–3.28(m,2H),3.27–3.14(m,1H),2.99(s,3H), 2.56–2.33(m,5H),2.31–2.11(m,3H),2.10–1.84(m,6H),1.75(d,3H),1.35(d,3H).

[0618] Example 29: Preparation of Compound 29

[0619] Under nitrogen protection, intermediate 27F (250 mg crude, 0.55 mmol) was dissolved in 10 mL ultra-dry DMF, and N,N-diisopropylethylamine (356 mg, 2.76 mmol) and intermediate 26E (377 mg, 0.46 mmol) were added in sequence. The mixture was reacted at room temperature overnight, and the excess solvent was removed under reduced pressure. The trifluoroacetate salt of compound 29 (97 mg, yield: 8.5%) was obtained by separation and purification by preparative HPLC.

[0620] HPLC preparation method: instrument: SHIMADZU LC-20AP; preparation column: C18; mobile phase: A is 0.1% TFA aqueous solution; B is acetonitrile; elution method: 25% to 60% of B in A solution, gradient elution for 15 minutes; flow rate: 25mL / min; column temperature: room temperature; detection wavelength: 220nm;

[0621] LCMS m / z=1167.3[M+H] +

[0622] 1H NMR(400MHz,CF3COOD)δ8.33–8.28(m,1H),8.25–8.19(m,1H),8.07–8.00(m,1H),7.99– 7.92(m,1H),7.91–7.78(m,4H),7.70–7.33(m,11H),6.84–6.75(m,1H),5.17–4.87(m,1H ),4.85–4.72(m,1H),4.13–4.01(m,1H),3.99–3.85(m,1H),3.79–3.66(m,1H),3.61–3. 24(m,6H),3.04(s,3H),2.71–2.46(m,3H),2.43–2.23(m,3H),1.76(d,3H),1.37(d,3H).

[0623] According to the synthesis method of the above embodiment, the following compounds were prepared:

[0624] Biological test cases

[0625] 1. Evaluation of compound affinity for Bcl-xL / Bcl-2 targets (TR-FRET)

[0626] Evaluation of compound affinity for Bcl-xL target (TR-FRET)

[0627] The test compounds were diluted 3-fold in a 384 dilution plate with DMSO (Sigma, D4540), and the final starting concentration of the test compounds was 10000 nM. 75 nL of the diluted compounds of different concentrations were transferred to the 384 reaction plate to ensure that the DMSO content was 0.5%. Then 5 μL of the diluted 3×Bcl-xL enzyme (BPS, 50273) solution was added to the 384 reaction plate to ensure that the final concentration of the reaction was 5 nM, centrifuged at 1000 rpm for 1 min, and incubated at 25°C for 10 min. 5 μL / well of 3×f-Bax substrate (GenScript) solution was transferred to the 384 reaction plate to ensure that the final concentration of the reaction was 30 nM, centrifuged at 1000 rpm for 1 min. 5 μL of 1×MAb-Anti-His-Tb (Cisbio, 61HISTLA) reagent was transferred to the 384 reaction plate, centrifuged at 1000 rpm for 1 min, and incubated at 25°C for 60 min. After the reaction, the HTRF (Homogeneous Time-Resolved Fluorescence) signal was read using a BMG microplate reader. The signal intensity was used to characterize the activity of the enzyme. The IC was calculated using the GraphPad nonlinear fitting formula (Formula 1).50 : Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope) Formula (1)

[0628] X: log value of compound concentration Y: inhibition rate (%inhibition)

[0629] Evaluation of compound affinity for Bcl-2 target (TR-FRET)

[0630] The positive compound (A-1210477) and the test compound were diluted 3-fold with DMSO (Sigma, D4540) in a 384 dilution plate, so that the final starting concentrations of the positive compound and the test compound were 1000nM and 10000nM, respectively. 75nL of the diluted compounds of different concentrations were transferred to the 384 reaction plate, ensuring that the DMSO content was 0.5%. Then 5μL / well 3×BCL-2 enzyme (BPS, 50272) solution was transferred to the 384 reaction plate, ensuring that the final concentration of the reaction was 2nM, centrifuged at 1000rpm for 1min, and incubated at 25℃ for 10min. 5μL / well 3×Bio-tin-BIM (GenScript) substrate solution was transferred to the 384 reaction plate, ensuring that the final concentration of the reaction was 30nM, and centrifuged at 1000rpm for 1min. Transfer 5 μL / well 1×His-Tb (Cisbio, 61HISTLA) & SA-d2 (Cisbio, 610SADLF) reagent to a 384 reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 60 min. Use a BMG microplate reader to read the HTRF (Homogeneous Time-Resolved Fluorescence) signal. The signal intensity is used to characterize the activity of the kinase. Calculate the IC using the GraphPad nonlinear fitting formula (Formula 1) 50 : Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)×HillSlope) Formula (2)

[0631] X: log value of compound concentration Y: inhibition rate (%inhibition)

[0632] The biological test results are shown in Table 1 and Table 2:

[0633] Table 1 TR-FRET IC of the affinity of the compounds for the Bcl-xL target 50 Note: A≤20nM

[0634] Table 2 TR-FRET IC of compound affinity for Bcl-xL / Bcl-2 target 50

[0635] Conclusion: The compounds of the present invention, such as the compounds of the examples, have a high binding ability to the Bcl-xL target. Relative to the Bcl-2 target, the compounds of the present invention have a high selectivity for the Bcl-xL target, and compared with the trifluoroacetate salts of the control compound 1 and the control compound 2, the compounds of the present invention have a better selectivity. In particular, the target affinity of compound 25 for Bcl-xL is 1207 times that of the Bcl-2 target, the target affinity of compound 22 for Bcl-xL is 893 times that of the Bcl-2 target, and the trifluoroacetate salts of compounds 21, 24, 27, and 28 have a target affinity for Bcl-xL that is more than 295 times that of the Bcl-2 target.

[0636] Structure of reference compound 1:

[0637] Control compound 2:

[0638] 2. Anti-aging test

[0639] Experimental method: Human fibroblast primary cell line WI-38 cells were obtained from ATCC (Cat. No.: CCL-75) and cultured in EMEM + 10% FBS + 1% double-antibody medium at 37°C in a 5% CO2 incubator. When the cells were in the exponential growth phase, the cells were collected, counted, and plated on 10 cm 2 After the cells adhered to the wall, the cells were treated with 200nM mitomycin C (MMC, manufacturer: Absin, catalog number: 47029279) for 48h to construct a cell senescence model. At the same time, a DMSO-treated cell group was set as a solvent control to ensure that the final concentration of DMSO was below 0.1%. The MMC / DMSO-treated cells were digested, centrifuged, resuspended, and plated into 384-well plates at a density of 5000 cells / well (MMC) and 1000 cells / well (DMSO) for 5 days. Then, the prepared compounds of different concentrations were added and incubated for 48h, followed by SA-β-gal staining. The staining steps are as follows:

[0640] a) Discard the culture medium, wash the cells twice with 1× PBS, and remove all the washing solution;

[0641] b) Fix the cells with 4% paraformaldehyde fixative, 15 μL / well, at room temperature for 15 minutes;

[0642] c) Wash the cells three times with 50 μL 1× PBS per well;

[0643] d) Prepare SA-β-gal staining solution according to the requirements of the kit (manufacturer: Sigma, catalog number: CS0030);

[0644] e) Add 10 μL of staining solution to each well, seal the plate, and incubate at 37°C for 3-6 hours, or overnight (depending on the actual staining situation);

[0645] f) Wash the cells twice with 1× PBS and stain with DAPI (1:400, manufacturer: Thermo; catalog number: 62248) and F-actin (manufacturer: Invitrogen, catalog number: A12380) at room temperature for 1 h;

[0646] g) Take photos and analyze using CQ1 (manufacturer: YOKOGAWA, catalog number: 1042288);

[0647] Data processing: The percentage of SA-β-gal+ cells in 2000 cells of each sample was counted and recorded as SA%, and the SA-β-gal+ percentage (Cpd%) of the compound group relative to the vehicle control was calculated according to formula (1). GraphPad Prism software was used to draw the dose-effect curve and the IC was calculated using the four-parameter analysis method. 50 value.

[0648] Cpd% = (SA% administration / SA% vehicle control)*100% Formula (1)

[0649] Table 3 IC values ​​of compounds on WI-38 senescent cells stained with SA-β-gal 50

[0650] Conclusion: The compounds of the present invention, such as the example compounds, especially compound 22, have good inhibitory activity on mitomycin C-induced SA-β-galactosidase staining of WI-38 senescent cells.

[0651] Senescent Cell Selective Killing Assay Protocol

[0652] Experimental method: Human fibroblast primary cell line WI-38 cells were obtained from ATCC (Cat. No.: CCL-75) and cultured in EMEM + 10% FBS + 1% double-antibody medium at 37°C in a 5% CO2 incubator. When the cells were in the exponential growth phase, the cells were collected, counted, and plated on 10 cm 2After the cells adhered to the wall, the cells were treated with 200nM mitomycin C (MMC, manufacturer: Absin, catalog number: 47029279) for 48h to construct a cell senescence model. At the same time, a DMSO-treated cell group was set as a solvent control to ensure that the final DMSO concentration was below 0.1%. The MMC / DMSO-treated cells were digested, centrifuged, resuspended, and plated into a 384-well plate at a density of 5000 cells / well (MMC treatment) and 1000 cells / well (DMSO treatment). The prepared compounds of different concentrations were added for co-incubation. After 7 days of compound treatment, the ATP level of the "senescent" cells in one plate treated with MMC and the non-"senescent" cells in another plate as a control was measured using CellTiter-Glo (manufacturer: Promega, catalog number: 18002030) as a surrogate indicator of cell activity to determine the selective killing effect of the compound on senescent cells.

[0653] The CTG test steps are as follows:

[0654] a) Equilibrate CTG reagent to room temperature and mix 1:1.

[0655] b) Add the reagents to the test plate at a ratio of 1:1, shake and mix. Detect on the Evision instrument.

[0656] Data processing: The luminescence readings were calculated using GraphPad Prism 8.0 software according to formula (1) and formula (2) to calculate the IC of the compound for inhibiting cell proliferation. 50 Value and maximum inhibition rate. T 给药 is the signal reading after 7 days of compound incubation, T 溶媒 The cell signal reading after 7 days of incubation with the vehicle control. Growth% = (T 给药 / T 溶媒 ×100)% Formula (1)

[0657] Max inhibition% calculation: According to formula (1), calculate the inhibition rate at the highest concentration of the compound. Max inhibition% = (100-Growth)% Formula (2)

[0658] Conclusion: The compounds of the present invention have good inhibitory activity on WI-38 senescent cells induced by mitomycin C.

[0659] 3. CYP450 enzyme inhibition test

[0660] The purpose of this study was to evaluate the effects of the test substances on the activities of two isoenzymes (CYP2C9 and CYP2D6) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system. Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the metabolites produced by the specific substrates were quantitatively detected by treating the samples and using liquid chromatography-tandem mass spectrometry (LC-MS / MS) to determine the changes in CYP enzyme activity and calculate the IC 50 The inhibitory potential of the test substance on each CYP enzyme subtype CYP2C9 and CYP2D6 was evaluated.

[0661] Table 4 CYP450 enzyme inhibition test results of compounds

[0662] Conclusion: The compounds of the present invention, such as the example compounds, especially compounds 22, 24, and 26, have weaker inhibition on CYP2C9 and CYP2D6 than the control compound 1, and the risk of drug interactions caused by CYP2C9 and CYP2D6 metabolism is lower. The compounds of the present invention have no obvious inhibitory effect on each subtype of CYP enzyme.

[0663] 4. Study on the inhibitory activity of compounds on MOLT-4 cell proliferation

[0664] MOLT-4 cells are human acute lymphoblastic leukemia cell lines. They were purchased from ATCC and cultured under the following conditions: RPMI-1640 + 10% FBS + 1% double antibody, cultured at 37°C, 5% CO2 incubator. Cells were plated in 96-well plates, 5×10 3 After plating, different concentrations of compounds were added and cultured for 72 hours in a 37°C, 5% CO2 incubator. After the culture, cell viability detection reagent (Promega, G7573) was added, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the luminescence signal was detected using a multifunctional microplate reader (BMG, PHERAstar FSX). The luminescence readings were calculated using GraphPad Prism 8.0 software according to formula (1) and formula (2) to calculate the IC of the compound to inhibit cell proliferation. 50 value and maximum inhibition rate. 给药 T is the cell signal reading after 72 hours of compound incubation. 溶 媒 This is the cell signal reading after 72 hours of incubation with the vehicle control. Growth% = T 给药 / T 溶媒 ×100 Formula (1)

[0665] Max inhibition% calculation: According to formula (2), calculate the inhibition rate at the highest concentration of the compound. Max inhibition% = 100% - Growth% Formula (2)

[0666] Conclusion: The compounds of the present invention, especially the compounds of the examples, have good proliferation inhibition activity on MOLT-4 cells.

[0667] 5. Study on the inhibitory activity of compounds on NCI-H446 cell proliferation

[0668] NCI-H446 cells (human small cell lung cancer cell line) were purchased from ATCC, cultured under the following conditions: RPMI-1640 + 10% FBS + 1% double antibody, cultured at 37°C, 5% CO2 incubator. Cells were plated in 96-well plates at a seeding density of 1×10 3 / well. On the second day, different concentrations of compounds were added to the well plate (the initial concentration of the compound was 10 μM, 5-fold dilution, and 9 concentration gradients), and the culture was continued in a 37°C, 5% CO2 incubator for 72 hours. After the culture was completed, the cell viability detection reagent (Promega, G7573) was added, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the luminescence signal was detected using a multifunctional microplate reader (BMG, PHERAstar FSX). The luminescence readings were calculated using GraphPad Prism 8.0 software according to formula (1) and formula (2) respectively to calculate the IC of the compound to inhibit cell proliferation 50 value and maximum inhibition rate. 给药 T is the cell signal reading after 72 hours of compound incubation. 溶媒 This is the cell signal reading after 72 hours of incubation with the vehicle control. Growth% = (T 给药 / T 溶媒 ×100)% Formula (1)

[0669] Max inhibition% calculation: According to formula (1), calculate the inhibition rate at the highest concentration of the compound. Max inhibition% = 100% - Growth% Formula (2)

[0670] Conclusion: The compounds of the present invention, especially the compounds of the examples, have good proliferation inhibition activity on NCI-H446 cells.

[0671] 6. Study on the inhibitory activity of compounds on Kasumi-1 cell proliferation

[0672] Kasumi-1 cells (human acute myeloblastic leukemia cell line) were purchased from ATCC. The culture conditions were: RPMI-1640 + 20% FBS + 1% double antibody, cultured at 37°C, 5% CO2 incubator. The cells were plated in 96-well plates at a density of 1.2×10 4 After plating, different concentrations of compounds were added (the initial concentration of the compound was 10 μM, 5-fold dilution, and 9 concentration gradients), and the culture was continued in a 37°C, 5% CO2 incubator for 72 hours. After the culture was completed, the cell viability detection reagent (Promega, G7573) was added, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the luminescence signal was detected using a multifunctional microplate reader (BMG, PHERAstar FSX). The luminescence readings were calculated using GraphPad Prism 8.0 software according to formula (1) and formula (2) respectively to calculate the IC of the compound to inhibit cell proliferation 50 value and maximum inhibition rate. 给药 T is the cell signal reading after 72 hours of compound incubation. 溶媒 This is the cell signal reading after 72 hours of incubation with the vehicle control. Growth% = (T 给药 / T 溶媒 ×100)% Formula (1)

[0673] Max inhibition% calculation: According to formula (1), calculate the inhibition rate at the highest concentration of the compound. Max inhibition% = 100% - Growth% Formula (2)

[0674] Conclusion: The compounds of the present invention, especially the compounds of the examples, have good proliferation inhibition activity on Kasumi-1 cells.

[0675] In the following pharmacokinetic tests, compounds containing phosphate esters (prodrugs) require quantitative analysis of both the test substance itself and its corresponding hydrolyzed compound (original drug). For example, for compound 27, it is necessary to simultaneously test compound 27 and its corresponding original drug compound 24.

[0676] 7. Pharmacokinetic test in mice

[0677] 1.1 Experimental animals: Male C57 mice, 20-25 g, 3-6 mice / compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0678] 1.2 Experimental design: On the day of the experiment, mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.

[0679] Table 5. Dosing Information

[0680] Note: Intravenous administration solvent: 5% DMSO + 95% (3% Tween 80 in PBS)

[0681] Before and after administration, 0.06 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and detection, all samples were stored at -80°C and quantitatively analyzed by LC-MS / MS. If the test compound was a prodrug molecule, the sample was quantitatively analyzed for both the prodrug and the original drug.

[0682] Conclusion: The compounds of the present invention, especially the example compounds, have good exposure in mice after intravenous administration. For example, after hydrolysis of compounds 27, 28, and 29, the original drugs are 24, 22, and 26, respectively, which have good exposure.

[0683] 8. Pharmacokinetic test in rats

[0684] 1.1 Experimental animals: Male SD rats, about 220 g, 6-8 weeks old, 3-6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0685] 1.2 Experimental design: On the day of the experiment, rats were randomly divided into groups according to their body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.

[0686] Table 6. Dosing Information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; or 5% DMSO + 95% (3% Tween 80 in PBS) (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline)

[0687] Before and after administration, 0.15 ml of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and detection, all samples were stored at -80°C and quantitatively analyzed by LC-MS / MS. If the test compound was a prodrug molecule, the sample was quantitatively analyzed for both the prodrug and the original drug.

[0688] Conclusion: The compounds of the present invention, especially the compounds of the examples, have good exposure in rats after intravenous administration. For example, the original drugs of compounds 27, 28, and 29 after hydrolysis are 24, 22, and 26, respectively, which have good exposure.

[0689] 9. Beagle dog pharmacokinetic test

[0690] Experimental animals: Male beagle dogs, about 8-11 kg, 3-6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

[0691] Test method: On the day of the test, beagle dogs were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration. Administration was performed according to Table 1.

[0692] Table 7. Dosing Information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; or 5% DMSO + 95% (3% Tween 80 in PBS) (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline)

[0693] Before and after administration, 1 ml of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS / MS. If the test compound was a prodrug molecule, the sample was quantitatively analyzed for both the prodrug and the original drug.

[0694] Conclusion: The compounds of the present invention, especially the compounds in the examples, have good exposure in beagle dogs after intravenous administration. For example, the original drugs of compounds 27, 28, and 29 after hydrolysis are 24, 22, and 26, respectively, which have good exposure.

[0695] 10. Monkey pharmacokinetic test

[0696] Experimental animals: male cynomolgus monkeys, 3-5 kg, 3-6 years old, 3-6 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0697] Test method: On the day of the test, monkeys were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours one day before administration and fed 4 hours after administration.

[0698] Table 8. Dosing Information Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; or 5% DMSO + 95% (3% Tween 80 in PBS) (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline)

[0699] Before and after administration, 1.0 mL of blood was collected from the limb veins and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS / MS. If the test compound was a prodrug molecule, the sample was quantitatively analyzed for both the prodrug and the original drug.

[0700] Conclusion: The compounds of the present invention, especially the compounds in the examples, have good exposure in monkeys after intravenous administration. For example, the original drugs of compounds 27, 28, and 29 after hydrolysis are 24, 22, and 26, respectively, which have good exposure.

[0701] 11. Liver microsome stability test

[0702] 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.

[0703] At 37°C, 1 μM of the test substance was incubated with microsomal protein and coenzyme NADPH. After a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS / MS. The ln value of the drug residual rate in the incubation system and the incubation time were used to calculate T. 1 / 2 , and further calculated the liver microsomal intrinsic clearance CL int(mic) and liver intrinsic clearance CL int(Liver) .

[0704] Conclusion: The compounds of the present invention, especially the compounds of the examples, have good liver microsome stability.

Claims

A compound or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the compound being selected from the compounds represented by general formula (I), wherein Ring A, Ring C, and Ring D are each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a The ring C is optionally substituted with 1 to 4 R c The ring D is optionally substituted with 1 to 4 R d Substituted; B is selected from -B1-, -N(R n )-B1-、-B1-N(R n )-; B1 is selected from a 4- to 12-membered heterocyclic group, the heterocyclic group is optionally substituted by 1 to 10 R b Substituted; X is selected from -N(R x )S(=O)2-、-S(=O)2N(R x )-、 The left side is connected to the ring C; K is selected from a 5-membered heteroaryl group, wherein K is 1 to 3 R k1 , 1 R k2 Replacement; R x Selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl; R n Selected from H, C 1-6 Alkyl, -C 1-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene or cycloalkyl is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 1-6 Alkoxy is substituted by a substituent; R a , R b , R c Each independently selected from deuterium, halogen, cyano, OH, =O, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(CH2) q -C 3-10 Carbocyclic ring, -(CH2) q -4 to 10 membered heterocyclic ring, wherein the -CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 is substituted by a substituent of a carbocyclic group or a 4- to 10-membered heterocyclic group; or any R b With R c directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R a1 Replace; or any R b With R a directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R a1 Replacement; R a1 Each independently selected from halogen, OH, cyano, NH2, =O, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 The alkyl, alkynyl, alkoxy, carbocyclic or heterocyclic group is optionally substituted by 1 to 4 substituents selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 is substituted by a substituent of a carbocyclic group or a 4- to 10-membered heterocyclic group; R d , R k1 Each independently selected from deuterium, halogen, cyano, OH, NO2, COOH, CD3, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, -OC 3-6 Cycloalkyl, -(CH2) q -C 3-10 Carbocyclic ring, -(CH2) q -4 to 10 membered heterocyclic ring, -S(=O)2R 1 、-S(=O)2NR 1 R 2 、-C(=O)NR 1 R 2 、C(=O)NR 1 S(=O)2R 3 、-C(=O)R 1 The -CH2-, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, CD3, halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 is substituted by a substituent of a carbocyclic group or a 4- to 10-membered heterocyclic group; R 1 , R 2 , R 3 Each independently selected from H, C 1-6 Alkyl, C 3-10 A carbocyclic group or a 4- to 10-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 is substituted by a carbocyclic group or a 4- to 10-membered heterocyclic group; Z is selected from -CH(R z1 )CH2-SR z2 or -CH(R z1 )CH2-Se-R z2 ; R z1 Selected from -C 1-4 Alkylene-Z1-R z3 ; Z1 is selected from 4 to 12 membered heterocyclic groups, wherein Z1 is optionally substituted by 1 to 4 R z1a or optionally substituted by 1 substituent selected from -OP(=O)(OH)2 or -CH2OP(=O)(OH)2; R k2 , R z2 Each independently selected from C 6-10 aryl or 5 to 10 membered heteroaryl, said R k2 Optional 1 to 4 R k2a Substitute, the R z2 Optional 1 to 4 R z2a Replacement; R z1a , R k2a , R z2a Each independently selected from halogen, cyano, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -(CH2) q -C 3-10 Carbocyclic ring, -(CH2) q -4 to 10 membered heterocyclic ring, wherein the -CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, hydroxy substituted C 1-6 Alkyl, cyano substituted C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-10 is substituted by a substituent of a carbocyclic group or a 4- to 10-membered heterocyclic group; R z3 Selected from -OH, -CH2OH, -OP(=O)(OH)2, -CH2OP(=O)(OH)2, -OP(=O)(OH)(OC 1-6 alkyl), -CH2OP(=O)(OH)(OC 1-6 alkyl), -OP(=O)(OC 1-6 alkyl)2, -CH2OP(=O)(OC 1-6 alkyl) 2; q are each independently selected from 0, 1, 2, 3 or 4; provided that 1) when B is selected from When B is replaced by 1 to 8 R b or 2) when B is selected from unsubstituted and Z1 is selected from a 4- to 7-membered monocyclic heterocyclic group connected to an alkylene group via a nitrogen atom, Z1 is replaced by 1 to 4 R z1a Substitution: The compound of formula (I) is optionally substituted with 1 to 20 deuteriums. The compound according to claim 1 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein Ring A, Ring C and Ring D are each independently selected from phenyl, benzo C 4-6 carbocyclyl, benzo 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, 9- to 10-membered heteroaryl, wherein the ring A is optionally substituted by 1 to 4 R a The ring C is optionally substituted with 1 to 4 R c The ring D is optionally substituted with 1 to 4 R d substituted; B1 is selected from a 4- to 7-membered nitrogen-containing monocyclic heterocyclic group, a 5- to 10-membered nitrogen-containing cyclic heterocyclic group, a 5- to 11-membered nitrogen-containing spirocyclic heterocyclic group, a 5- to 11-membered nitrogen-containing bridged heterocyclic group, and the B1 is optionally substituted by 1 to 8 R b Replacement; R n Selected from H, C 1-4 Alkyl; X is selected from -NHS(=O)2-, the left side is connected to the ring C; R a , R b , R c Each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -(CH2) q -C 3-6 Carbocyclic ring, -(CH2) q -4 to 7 membered heterocyclic ring, wherein the -CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 is substituted by a substituent of a carbocyclic group or a 4- to 7-membered heterocyclic group; or any R b With R c directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R a1 Replace; or any R b With R a directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R a1 Replacement; R a1 Each independently selected from halogen, OH, cyano, NH2, =O, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the alkyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 is substituted by a substituent of a carbocyclic group or a 4- to 7-membered heterocyclic group; R d , R k1 Each independently selected from deuterium, CD3, halogen, cyano, OH, NO2, COOH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -OC 3-6 Cycloalkyl, -(CH2) q -C 3-6 Carbocyclic ring, -(CH2) q -4 to 7 membered heterocyclic ring, -S(=O)2R 1 、-S(=O)2NR 1 R 2 、-C(=O)NR 1 R 2 、C(=O)NR 1 S(=O)2R 3 、-C(=O)R 1 The -CH2-, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 groups selected from deuterium, CD3, halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 is substituted by a substituent of a carbocyclic group or a 4- to 7-membered heterocyclic group; R 1 , R 2 , R 3 Each independently selected from H, C 1-4 Alkyl, C 3-6 carbocyclic or 4 to 7 membered heterocyclic rings, wherein the alkyl, carbocyclic or heterocyclic rings are optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 is substituted by a carbocyclic group or a 4- to 7-membered heterocyclic group; Z1 is selected from a 4- to 7-membered nitrogen-containing heteromonocyclic ring, a 5- to 10-membered nitrogen-containing heterocyclic ring, a 5- to 11-membered nitrogen-containing spirocyclic heterocyclic ring, and a 5- to 11-membered nitrogen-containing bridged heterocyclic ring, wherein Z1 is optionally substituted by 1 to 4 R z1a or optionally substituted by 1 substituent selected from -OP(=O)(OH)2 or -CH2OP(=O)(OH)2; R k2 , R z2 Each independently selected from phenyl, benzo 4-6 carbocyclic group, benzo 5- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl group, 9- to 10-membered heteroaryl group, wherein R k2 Optional 1 to 4 R k2a Substitution, the R z2 Optional 1 to 4 R z2a Replacement; R z1a , R k2a , R z2a Each independently selected from halogen, cyano, OH, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -(CH2) q -C 3-6 Carbocyclic ring, -(CH2) q -4 to 7 membered heterocyclic ring, wherein the -CH2-, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-6 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 is substituted by a substituent of a carbocyclic group or a 4- to 7-membered heterocyclic group; R z3 Selected from -OH, -CH2OH, -OP(=O)(OH)2, -CH2OP(=O)(OH)2; q is independently selected from 0, 1, 2. The compound according to claim 2 or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, B1 is selected from azetidinyl, aziridine, azetidinyl, azetidinyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclopentyl, azetidinyl spirocyclopentyl, azetidinyl spirocyclohexyl, azetidinyl spirocyclohexyl, azetidinyl spiroaza Cyclobutyl, azetyl spiroazetyl, azetyl spiroazetyl, azetyl spiroazetyl, azetyl spiroazetyl, azetyl spiroazetyl, azetyl spiroazetyl, azetyl spiroazetyl, azetyl spiroazetyl, azetyl spiroazetyl, azetyl spiroazetyl, piperazine spirocyclopropyl, piperazine spirocyclobutyl, piperazine spirocyclopentyl, piperazine spirocyclohexyl, piperazine spiroaziridine, piperazine spiroazetyl, piperazine spiroazetyl, piperazine spiroazetyl, piperazine spiroazetyl, piperazine spiroazetyl, piperazine spiroazetyl, piperazine spiroazetyl, azetyl and cyclopropyl, azetyl and cyclopropyl, azetyl and cyclopropyl, azetyl and cyclobutyl, azetyl and cyclobutyl, Azacyclohexyl and cyclobutyl, azetidin and cyclopentyl, azetidin and cyclopentyl, azetidin and cyclohexyl, azetidin and cyclohexyl, azetidin and cyclohexyl, azetidin and azetidin, azetidin and azetidin, azetidin and azetidin, azetidin and azetidin, azetidin and azetidin, azetidin and azetidin, azetidin and azetidin, azetidin and azetidin, azetidin and azetidin, azetidin and azetidin, azetidin and azetidin, azetidin and azetidin, azetidin and azetidin, azetidin and azetidin, azetidin and azetidin, azetidin and azetidin, piperazin and cyclopropyl, piperazin and cyclobutyl, piperazin and cyclopentyl, piperazin and cyclohexyl, piperazin and spiro and heterocyclopropyl, piperazin and azetidin, piperazine 1-8 R b substituted; Z1 is selected from azetidinyl, aziridine, azetidinyl, azetidinyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclopropyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclobutyl, azetidinyl spirocyclopentyl, azetidinyl spirocyclopentyl, azetidinyl spirocyclohexyl, azetidinyl spirocyclohexyl, azetidinyl spirocyclohexyl, azetidinyl cyclopropyl, azetidinyl cyclopropyl, azetidinyl cyclopropyl, azetidinyl cyclobutyl, azetidinyl cyclobutyl, azetidinyl cyclopentyl, azetidinyl spirocyclopentyl, azetidinyl spirocyclohexyl, azetidinyl spirocyclohexyl, azetidinyl cyclopropyl, azetidinyl cyclopropyl, azetidinyl cyclopropyl, azetidinyl cyclobutyl, azetidinyl cyclobutyl, azetidinyl cyclohexyl butyl, azetidinylcyclopentyl, azacyclopentylcyclopentyl, azacyclohexylcyclopentyl, azetidinylcyclohexyl, azacyclopentylcyclohexyl, azacyclohexylcyclohexyl, 3-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.1]heptyl, 5-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.3.1]nonyl, 3-oxa-7-azabicyclo[3.3.1]nonyl, wherein Z1 is optionally substituted by 1 to 4 R z1a or optionally substituted by 1 substituent selected from -OP(=O)(OH)2 or -CH2OP(=O)(OH)2; R a , R b , R c Each independently selected from deuterium, halogen, cyano, OH, =O, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl, wherein the alkyl, alkynyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent; R a1 Each independently selected from halogen, OH, cyano, NH2, =O, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl, wherein the alkyl, alkynyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent; R d , R k1 Each independently selected from deuterium, CD3, halogen, cyano, OH, NO2, COOH, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 1-4 Alkylthio, -OC 3-6 Cycloalkyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, -S(=O)2NH2, -C(=O)NH2, -S(=O)2C 1-4 Alkyl, -S(=O)2-C 3-6 Cycloalkyl, -S(=O)2NHC 1-4 Alkyl, -C(=O)C 1-4 Alkyl, -C(=O)-C 3-6 Cycloalkyl, -C(=O)NHC 1-4 Alkyl, wherein the -CH2-, alkyl, alkynyl, alkoxy, alkylthio, cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, CD3, halogen, OH, cyano, NH2, C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, hydroxy substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group is substituted with a substituent. The compound according to claim 3 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B is selected from -B1-, -N(CH3)-B1-, -B1-N(CH3)-; B1 is selected from The B1 is optionally replaced by 1 to 8 R b Substituted; Ring A is selected from The ring A is optionally substituted with 1 to 4 R a Ring C and ring D are each independently selected from The ring C is optionally substituted with 1 to 4 R c The ring D is optionally substituted with 1 to 4 R d replace; or Selected from The left side is connected to ring A; or Selected from The left side is connected to ring C; R a , R b , R c Each independently selected from deuterium, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 halogens, OH, cyano, NH2, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent; R a1 Each independently selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH2, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent; R d each independently selected from F, Cl, Br, I, cyano, OH, NO2, COOH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, -S(=O)2NH2, -C(=O)NH2, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2NH-methyl, -S(=O)2NH-ethyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 halogen, OH, cyano, NH2, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent; R z1 Selected from -CH2CH2-Z1-R z3 ; Z1 is selected from The Z1 is optionally replaced by 1 to 4 R z1a or optionally substituted by 1 substituent selected from -OP(=O)(OH)2 or -CH2OP(=O)(OH)2; R z3 is selected from -OH, -CH2OH, -OP(=O)(OH)2, -CH2OP(=O)(OH)2; K is selected from R k1a is selected from COOH, S(=O)2NH2, -C(=O)NH2, -S(=O)2-methyl, -S(=O)2-ethyl, -S(=O)2NH-methyl, -S(=O)2NH-ethyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, wherein the methyl or ethyl group is optionally substituted by 1 to 4 groups selected from halogen, OH, cyano, NH2, CF3, hydroxymethyl, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent; R k1b is selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl is optionally substituted by 1 to 4 halogens, OH, cyano, NH2, CF3, hydroxymethyl, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent; R k1c is selected from deuterium, CD3, H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl is optionally substituted by 1 to 4 groups selected from deuterium, CD3, halogen, OH, cyano, NH2, CF3, hydroxymethyl, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Substituted by a cycloalkyl substituent; R k2 , R z2 Each independently selected from phenyl, pyridine, The R k2 Optional 1 to 4 R k2a Substitution, the R z2 Optional 1 to 4 R z2a Replacement; R z1a , R k2a , R z2a Each independently selected from F, Cl, Br, I, cyano, OH, CF3, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH2, CF3, hydroxymethyl, C 1-4 Alkyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 The cycloalkyl group is substituted by a substituent; p1, p2, and p3 are each independently 0, 1, 2, or 3. The compound according to claim 4 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein R k1a Selected from COOH; R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH2-CF3, -CH2-cyclopropyl, cyclopropyl; R k1b is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH2-cyclopropyl; R z1a , R k2a , R z2a Each independently selected from F, Cl, Br, I, cyano, OH, CF3, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Selected from The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) is selected from the compound represented by general formula (II-a), B is selected from -B1-, -N(CH3)-B1-, -B1-N(CH3)-; B1 is selected from The B1 is optionally replaced by 1 to 8 R b Replacement; R b Each independently selected from deuterium, F; or Selected from Z1 is selected from The Z1 is optionally substituted with 1 to 4 F; R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH2-CF3, -CH2-cyclopropyl, cyclopropyl; R k2a is selected from F, Cl, methyl, ethyl, cyclopropyl; R z3 Selected from -OH, -CH2OH, -OP(=O)(OH)2, -CH2OP(=O)(OH)2. The compound according to claim 1 or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) is selected from the compounds represented by general formula (III-a) or (III-b), R k1c is selected from methyl, ethyl, propyl, isopropyl, -CH2-CF3, -CH2-cyclopropyl, cyclopropyl; Z1 is selected from The Z1 is optionally substituted with 1 to 4 F; R k2a is selected from F, Cl, methyl, ethyl, cyclopropyl; R z3 Selected from -OH, -OP(=O)(OH)2. The compound according to claim 1 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E-1. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition comprises 1 to 1500 mg of a compound according to any one of claims 1 to 8 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof. Use of the compound according to any one of claims 1 to 8 or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the composition according to claim 9 in the preparation of a medicament for treating a disease associated with the activity or expression of Bcl-2 or Bcl-xL. The use according to claim 10, wherein The disease is selected from tumors or eye diseases. 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 8 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or a composition according to claim 9, the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably a disease related to Bcl-2 or Bcl-xL activity or expression.

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