TW202415647A - Compounds that inhibit Bcl-2 or Bcl-xL and their application in medicine - Google Patents

Abstract

The present invention relates to a compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods thereof, as well as use thereof in the preparation of drugs for treating diseases related to the activity or expression of Bcl-2 or Bcl-xL. .

Description

Compounds that inhibit Bcl-2 or Bcl-xL and their medical applications

The present invention relates to a compound of general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods thereof, as well as use thereof in the preparation of drugs for treating diseases related to the activity or expression of Bcl-2 or Bcl-xL.

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 anti-apoptotic pathways has potential application prospects in cancer treatment. The Bcl-2 protein family consists of pro-apoptotic proteins and anti-apoptotic proteins, which can regulate the intrinsic apoptotic pathways of cancer cells. Among them, Bcl-2 protein family members Bcl-2, Bcl-xL and Mcl-1 have been identified as anti-tumor targets. Inhibition of these proteins can promote Bax/Bak polymerization and ultimately induce mitochondrial outer membrane permeabilization, subsequently causing the release of cytochrome C and activation of caspase, thereby executing cancer cell apoptosis.

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 many cells depend on for survival, inhibiting Bcl-xL and Bcl-2 at the same time 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 eye diseases related to retinal lesions is expected to bring greater clinical benefits and relatively less toxic side effects.

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

The purpose of the present invention is to provide a class of heterocyclic compounds or pharmaceutically acceptable salts thereof, which are used as 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.

The compound of the present invention has the effect of selectively inhibiting Bcl-xL, and has good inhibitory activity on WI-38 senescent cells stained with SA-β-galactosidase induced by mitomycin C. The compound of the present invention has good pharmacokinetic properties (such as better exposure, better t _1/2 , CL, etc.) in mice, rats, dogs, and monkeys, and has better liver microsomal stability. The compound of the present invention has good proliferation inhibitory activity on MOLT-4 cells, NCI-H446 cells, and Kasumi-1 cells, and has no obvious hERG and CYP inhibitory activity.

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 (I)

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, Ring A is optionally substituted with 1 to 4 ^Ra , Ring C is optionally substituted with 1 to 4 ^Rc , and Ring D is optionally substituted with 1 to 4 ^Rd ;

In some embodiments, Ring A, Ring C, and Ring D are each independently selected from phenyl, benzo _C4-6 carbocyclyl, benzo 5-6 membered heterocyclyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl, and Ring A is optionally substituted with 1 to 4 ^Ras , Ring C is optionally substituted with 1 to 4 ^Rcs , and Ring D is optionally substituted with 1 to 4 ^Rds ;

In some embodiments, Ring A is selected from , , , , , , , , , , , , , , , , , , , the ring A is optionally substituted with 1 to 4 ^Ra ;

In some embodiments, Ring C and Ring D are each independently selected from , , , , , , , , , , , , , , , , , , , , the ring C is optionally substituted by 1 to 4 R ^c , and the ring D is optionally substituted by 1 to 4 R ^d ;

In some embodiments, B is selected from -B ₁ -, -N(R ⁿ )-B ₁ -, -B ₁ -N(R ⁿ )-;

In some embodiments, B is selected from -B ₁ -, -N(CH ₃ )-B ₁ -, -B ₁ -N(CH ₃ )-;

In some embodiments, B ₁ is selected from a 4- to 12-membered heterocyclic group, which is optionally substituted with 1 to 10 R ^b ;

In some embodiments, B ₁ is selected from a 4- to 7-membered nitrogen-containing monocyclic heterocyclic group, a 5- to 10-membered nitrogen-containing bicyclic heterocyclic group, a 5- to 11-membered nitrogen-containing spirocyclic heterocyclic group, and a 5- to 11-membered nitrogen-containing bridged heterocyclic group, and B ₁ is optionally substituted with 1 to 8 R ^b ;

In some embodiments, _B1 is selected from azidocyclobutyl, azidocyclopentyl, azidocyclohexyl, azidocyclohexenyl, azidocycloheptyl, azidocyclobutylspirocyclopropyl, azidocyclopentylspirocyclopropyl, azidocyclohexylspirocyclopropyl, azidocyclobutylspirocyclobutyl, azidocyclopentylspirocyclobutyl, azidocyclohexylspirocyclobutyl, azidocyclobutylspiro ... cyclopentyl, spirocyclopentyl, cyclohexyl, spirocyclopentyl, cyclobutyl, spirocyclohexyl, cyclopentyl, spirocyclohexyl, cyclohexyl, cyclobutyl, spiroazacyclobutyl, cyclopentyl, spiroazacyclobutyl, cyclohexyl, spiroazacyclobutyl, cyclopentyl, spiroazacyclobutyl, cyclohexyl, spiroazacyclobutyl, cyclobutyl, spiroazacyclopentyl, cyclopentyl, cyclobutyl Pentylspiroazacyclopentyl, azacyclohexylspiroazacyclopentyl, azacyclobutylspiroazacyclohexyl, azacyclopentylspiroazacyclohexyl, azacyclohexylspiroazacyclohexyl, piperazinespirocyclopropyl, piperazinespirocyclobutyl, piperazinespirocyclopentyl, piperazinespirocyclohexyl, piperazinespiroazacyclopropyl, piperazinespirocyclobutyl , piperazine spiroazacyclopentyl, piperazine spiroazacyclohexyl, azacyclobutyl and cyclopropyl, azacyclopentyl and cyclopropyl, azacyclohexyl and cyclopropyl, azacyclobutyl and cyclobutyl, azacyclopentyl and cyclobutyl, azacyclohexyl and cyclobutyl, azacyclobutyl and cyclopentyl, azacyclopentyl and cyclopentyl, azacyclohexyl and cyclobutyl azacyclopentyl, azacyclobutyl and azacyclohexyl, azacyclopentyl and azacyclohexyl, azacyclohexyl and azacyclohexyl, azacyclobutyl and azacyclobutyl, azacyclopentyl and azacyclobutyl, azacyclohexyl and azacyclobutyl, azacyclobutyl and azacyclopentyl, azacyclopentyl and azacyclopentyl, azacyclohexyl and azacyclobutyl, azacyclobutyl and azacyclopentyl, azacyclopentyl and azacyclopentyl, azacyclohexyl and azacyclohexyl Azacyclopentyl, Azacyclobutyl and Azacyclohexyl, Azacyclopentyl and Azacyclohexyl, Azacyclohexyl and Azacyclohexyl, Piperazinylcyclopropyl, Piperazinylcyclobutyl, Piperazinylcyclopentyl, Piperazinylcyclohexyl, Piperazinylspirocyclopropyl, Piperazinylcyclobutyl, Piperazinylcyclopentyl, Piperazinylcyclohexyl, Piperazinylspirocyclopropyl, Piperazinylcyclobutyl, Piperazinylcyclopentyl, Piperazinylcyclo hexyl, 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, said B ₁ is optionally substituted by 1 to 8 R ^b ;

In some embodiments, _B1 is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , said B ₁ is optionally substituted with 1 to 8 R ^b ;

In some implementations, Selected from , , , , , , , , , , , , , the left side is connected to ring A;

In some implementations, Selected from , , , , , , , , , , , , , the left side is connected to ring C;

In some embodiments, X is selected from -N(R ^x )S(=0) ₂ -, -S(=0) ₂ N(R ^x )-, , , , , the left side is connected to ring C;

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

In some embodiments, K is selected from a 5-membered heteroaryl group, wherein K is substituted with 1 to 3 R ^k1 and 1 R ^k2 ;

In some embodiments, K is selected from ;

In some embodiments, ^Rx is selected from H, _C1-6 alkyl or _C3-6 cycloalkyl;

In some embodiments, ^Rx is selected from H;

In some embodiments, ^Rn is selected from H, _C1-6 alkyl, _-C1-4 alkylene- _C3-6 cycloalkyl, wherein the alkyl, alkylene or cycloalkyl is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-6 alkyl, halogen-substituted _C1-6 alkyl, hydroxyl-substituted _C1-6 alkyl, cyano-substituted _{C1-6 alkyl, and C1-6 alkoxy} ;

In some embodiments, ^Rn is selected from H, _C1-4 alkyl;

In some embodiments, ^Rn is selected from H, methyl, ethyl;

In some embodiments, ^Ra , ^Rb , and ^Rc are each independently selected from deuterium, halogen, cyano, OH, =O, _C1-6 alkyl, C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, -( _CH2 ) _q - _C3-10 carbocycle, -( _CH2 ) _q -4 to 10 membered heterocycle, wherein the _-CH2- , alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle is optionally substituted with 1 to 4 members selected from halogen, OH, cyano, NH2, _C1-6 alkyl, _C1-6 alkyl substituted with halogen, _C1-6 alkyl substituted with hydroxyl, _C1-6 alkyl substituted with cyano, _C2-6 alkynyl, _C1-6 alkoxy, _C3-10 carbocycle, and -( _CH2 )q-4 to 10 membered heterocycle. substituted by a substituent of a _3-10- membered carbocyclic group or a 4- to 10-membered heterocyclic group;

Or any R ^b and R ^c are directly linked to form a 4- to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R ^a1 ;

Or any R ^b and ^Ra are directly linked to form a 4- to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 ^Ra1 ;

In some embodiments, ^Ra , ^Rb , and ^Rc are each independently selected from deuterium, halogen, cyano, OH, =O, _C1-4 alkyl, C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, -( _CH2 ) _q - _C3-6 carbocycle, -( _CH2 ) _q -4 to 7 membered heterocycle, wherein the _-CH2- , alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle is optionally substituted with 1 to 4 members selected from halogen, OH, cyano, NH2, _C1-6 alkyl, _C1-4 alkyl substituted with halogen, _C1-4 alkyl substituted with hydroxyl, _C1-4 alkyl substituted with cyano, _C2-4 alkynyl, _C1-4 alkoxy, _C3-6 carbocycle, and -(CH2)q- ₄ to 7 membered heterocycle. substituted by a substituent of a _3-6- membered carbonyl or 4- to 7-membered heterocyclic group;

Or any R ^b and R ^c are directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted with 1 to 4 R ^a1 ;

Or any R ^b and R ^a are directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R ^a1 ;

In some embodiments, any R ^b and R ^c are directly linked to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted with 1 to 4 R ^a1 ;

In some embodiments, any R ^b and ^Ra are directly linked to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted with 1 to 4 ^Ra1 ;

In some embodiments, ^Ra , ^Rb , and ^Rc are each independently selected from deuterium, halogen, cyano, OH, =O, _C1-4 alkyl, _C2-4 alkynyl, _C1-4 alkoxy, or _C3-6 cycloalkyl, wherein the alkyl, alkynyl, alkoxy, or cycloalkyl is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-4 alkyl, halogen-substituted _C1-4 alkyl, hydroxyl-substituted _C1-4 alkyl, cyano-substituted _C1-4 alkyl, _C2-4 alkynyl, _C1-4 alkoxy, or _C3-6 cycloalkyl;

In some embodiments, ^Ra , ^Rb , and ^Rc are each independently selected from deuterium, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-4 alkyl, _C2-4 alkynyl, _C1-4 alkoxy, and _C3-6 cycloalkyl;

In some embodiments, each ^Ra1 is independently substituted with a substituent selected from halogen, OH, cyano, _NH2 , =O, _C1-6 alkyl, _C2-6 alkynyl, _C1-6 alkoxy, _C3-10 carbocyclic group, or 4-10 membered heterocyclic group, wherein the alkyl, alkynyl, alkoxy, carbocyclic group, or heterocyclic group is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-6 alkyl, halogen-substituted _C1-6 alkyl, hydroxyl-substituted _C1-6 alkyl, cyano-substituted _C1-6 alkyl, _C2-6 alkynyl, _C1-6 alkoxy, _C3-10 carbocyclic group, or 4-10 membered heterocyclic group;

In some embodiments, each ^Ra1 is independently selected from halogen, OH, cyano, _NH2 , =O, _C1-4 alkyl, _C2-4 alkynyl, _C1-4 alkoxy, _C3-6 carbocyclic group or 4-7 membered heterocyclic group, wherein the alkyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-4 alkyl, halogen-substituted _C1-4 alkyl, hydroxyl-substituted _C1-4 alkyl, cyano-substituted _C1-4 alkyl, _C2-4 alkynyl, _C1-4 alkoxy, _C3-6 carbocyclic group or 4-7 membered heterocyclic group;

In some embodiments, ^Ra1 is independently selected from halogen, OH, cyano, _NH2 , =O, _C1-4 alkyl, _C2-4 alkynyl, _C1-4 alkoxy or _C3-6 cycloalkyl, wherein the alkyl, alkynyl, alkoxy or cycloalkyl is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-4 alkyl, halogen-substituted _C1-4 alkyl, hydroxyl-substituted _C1-4 alkyl, cyano _- substituted C1-4 alkyl, _C2-4 alkynyl, _C1-4 alkoxy, _C3-6 cycloalkyl;

In some embodiments, ^Ra1 is independently selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-4 alkyl, _C2-4 alkynyl, _C1-4 alkoxy, _C3-6 cycloalkyl;

In some embodiments, R ^d and R ^k1 are each independently selected from deuterium, CD ₃ , halogen, cyano, OH, NO ₂ , 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, -(CH ₂ ) _q -C _3-10 carbocycle, -(CH ₂ ) _q -4 to 10 membered heterocycle, -S(=O) ₂ R ¹ , -S(=O) ₂ NR ¹ R ² , -C(=O)NR ¹ R ² , C(=O)NR ¹ S(=O) ₂ R ³ , -C(=O)R ¹ , wherein the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic optionally substituted with 1 to 4 substituents selected from deuterium, CD ₃ , halogen, OH, cyano, NH ₂ , 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 carbocyclic or 4-10 membered heterocyclic;

In some embodiments, R ^d and R ^k1 are each independently selected from deuterium, CD ₃ , halogen, cyano, OH, NO ₂ , 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, -(CH ₂ ) _q -C _3-6 carbocycle, -(CH ₂ ) _q -4 to 7 membered heterocycle, -S(=O) ₂ R ¹ , -S(=O) ₂ NR ¹ R ² , -C(=O)NR ¹ R ² , C(=O)NR ¹ S(=O) ₂ R ³ , -C(=O)R ¹ , wherein the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic optionally substituted with 1 to 4 substituents selected from deuterium, CD ₃ , halogen, OH, cyano, NH ₂ , 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 carbocyclic or 4-7 membered heterocyclic;

In some embodiments, R ^d and R ^k1 are each independently selected from deuterium, CD ₃ , halogen, cyano, OH, NO ₂ , 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, -CH ₂ -C _3-6 cycloalkyl, -S(=O) ₂ NH ₂ , -C(=O)NH ₂ , -S(=O) ₂ C _1-4 alkyl, -S(=O) ₂ -C _3-6 cycloalkyl, -S(=O) ₂ NHC _1-4 alkyl, -C(=O)C _1-4 alkyl, -C(=O)-C _3-6 cycloalkyl, -C(=O)NHC _1-4 alkyl, wherein the -CH ₂ -, alkyl, alkynyl, alkoxy, alkylthio, cycloalkyl optionally substituted with 1 to 4 substituents selected from deuterium, CD ₃ , halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

In some embodiments, R ^k1a is selected from COOH, S(=O) ₂ NH ₂ , -C(=O)NH ₂ , -S(=O) ₂ -methyl, -S(=O) ₂ -ethyl, -S(=O) ₂ NH-methyl, -S(=O) ₂ NH-ethyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, wherein the methyl or ethyl is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , CF ₃ , hydroxymethyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

In some embodiments, R ^k1a is selected from COOH;

In some embodiments, R ^k1b is selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , CF ₃ , hydroxymethyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

In some embodiments, R ^k1b is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH ₂ -cyclopropyl;

In some embodiments, R ^k1c is selected from deuterium, CD ₃ , H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, CD ₃ , halogen, OH, cyano, NH ₂ , CF ₃ , hydroxymethyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

In some embodiments, R ^is selected from methyl, ethyl, propyl, isopropyl, , , , , -CH ₂ -CF ₃ , -CH ₂ -cyclopropyl, cyclopropyl;

In some embodiments, each R ^d is independently selected from F, Cl, Br, I, cyano, OH, NO ₂ , COOH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, -S(=O) ₂ NH ₂ , -C(=O)NH ₂ , -S(=O) ₂ -methyl, -S(=O) ₂ -ethyl, -S(=O) ₂ NH-methyl, -S(=O) ₂ NH-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 with 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-4 alkyl, _C2-4 alkynyl, _C1-4 alkoxy, _C3-6 cycloalkyl;

In some embodiments, R ¹ , R ² , and R ³ are each independently selected from H, C _1-6 alkyl, C _3-10 carbocyclic group, or 4- to 10-membered heterocyclic group, wherein the alkyl, carbocyclic group, or heterocyclic group is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, halogen-substituted C _1-6 alkyl, hydroxyl-substituted C _1-6 alkyl, cyano-substituted C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-10 carbocyclic group, or 4- to 10-membered heterocyclic group;

In some embodiments, R ¹ , R ² , and R ³ are each independently selected from H, C _1-4 alkyl, C _3-6 carbocyclic ring, or 4-7 membered heterocyclic ring, wherein the alkyl, carbocyclic ring, or heterocyclic ring is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 carbocyclic ring, or 4-7 membered heterocyclic ring;

In some embodiments, Z is selected from -CH( ^Rz1 ) _CH2 - ^SRz2 or -CH( ^Rz1 ) _CH2 -Se- ^Rz2 ;

In some embodiments, R ^z1 is selected from -C _1-4 alkylene- _{Z 1} -R ^z3 ;

In some embodiments, R ^z1 is selected from -CH ₂ CH ₂ -Z ₁ -R ^z3 ;

In some embodiments, Z ₁ is selected from a 4- to 12-membered heterocyclic group, and said Z ₁ is optionally substituted with 1 to 4 R ^z1a or optionally substituted with 1 substituent selected from -OP(=O)(OH) ₂ or -CH ₂ OP(=O)(OH) ₂ ;

In some embodiments, Z ₁ is selected from a 4- to 7-membered nitrogen-containing monocyclic heterocyclic group, a 5- to 10-membered nitrogen-containing cycloheterocyclic group, a 5- to 11-membered nitrogen-containing spirocyclic heterocyclic group, and a 5- to 11-membered nitrogen-containing bridged heterocyclic group, and said Z ₁ is optionally substituted with 1 to 4 R ^z1a or optionally substituted with 1 substituent selected from -OP(=O)(OH) ₂ or -CH ₂ OP(=O)(OH) ₂ ;

In some embodiments, _Z is selected from azidocyclobutyl, azidocyclopentyl, azidocyclohexyl, azidocyclohexenyl, azidocycloheptyl, azidocyclobutylspirocyclopropyl, azidocyclopentylspirocyclopropyl, azidocyclohexylspirocyclopropyl, azidocyclobutylspirocyclobutyl, azidocyclopentylspirocyclobutyl, azidocyclohexylspirocyclobutyl, azidocyclobutylspirocyclopentyl, Azacyclopentylspirocyclopentyl, Azacyclohexylspirocyclopentyl, Azacyclobutylspirocyclohexyl, Azacyclopentylspirocyclohexyl, Azacyclohexylspirocyclohexyl, Azacyclobutyl and cyclopropyl, Azacyclopentyl and cyclopropyl, Azacyclohexyl and cyclopropyl, Azacyclobutyl and cyclobutyl, Azacyclopentyl and cyclobutyl, Azacyclohexyl cyclobutyl, cyclopentyl aza-butyl, cyclopentyl aza-pentyl, cyclopentyl aza-hexyl, cyclopentyl aza-butyl, cyclohexyl aza-pentyl, cyclohexyl aza-hexyl, cyclohexyl aza-hexyl, 3-cyclohexanobicyclo[3.2.1]octyl, 8-cyclohexanobicyclo[3.2.1]octyl, 2-cyclohexanobicyclo[3.2.1]octyl Cyclo[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 Z ₁ is optionally substituted with 1 to 4 R ^z1a or optionally substituted with 1 substituent selected from -OP(=O)(OH) ₂ or -CH ₂ OP(=O)(OH) ₂ ;

In some embodiments, _Z is selected from , , , , , , , , , , , , said Z ₁ is optionally substituted by 1 to 4 R ^z1a or optionally substituted by 1 substituent selected from -OP(=O)(OH) ₂ or -CH ₂ OP(=O)(OH) ₂ ;

In some embodiments, R ^k2 and R ^z2 are each independently selected from C _6-10 aryl or 5- to 10-membered heteroaryl, said R ^k2 is optionally substituted with 1 to 4 R ^k2a , and said R ^z2 is optionally substituted with 1 to 4 R ^z2a ;

In some embodiments, R ^k2 and R ^z2 are each independently selected from phenyl, benzo C _4-6 carbocyclic group, benzo 5-6 membered heterocyclic group, 5-6 membered heteroaryl group, 9-10 membered heteroaryl group, said R ^k2 is optionally substituted with 1 to 4 R ^k2a , and said R ^z2 is optionally substituted with 1 to 4 R ^z2a ;

In some embodiments, R ^k2 and R ^z2 are each independently selected from phenyl, pyridine, , , , , , , , , , , , , , , the R ^k2 is optionally replaced by 1 to 4 R ^k2a , and the R ^z2 is optionally replaced by 1 to 4 R ^z2a ;

In some embodiments, R ^z1a , R ^k2a , and R ^z2a are each independently selected from halogen, cyano, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -(CH ₂ ) _q -C _3-10 carbocycle, -(CH ₂ ) _q -4 to 10 membered heterocycle, wherein the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle is optionally substituted with 1 to 4 members selected from halogen, OH, cyano, NH ₂ , C 1-6 alkyl, C _1-6 alkyl substituted with halogen, C _1-6 alkyl substituted with hydroxyl, C 1-6 alkyl substituted with cyano, C _2-6 alkynyl, C _1-6 alkoxy, C _3-10 carbocycle, and -(CH ₂ ) q -4 to 10 membered heterocycle. substituted by a substituent of a _3-10- membered carbocyclic group or a 4- to 10-membered heterocyclic group;

In some embodiments, R ^z1a , R ^k2a , and R ^z2a are each independently selected from halogen, cyano, OH, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -(CH ₂ ) _q -C _3-6 carbocycle, -(CH ₂ ) _q -4 to 7 membered heterocycle, wherein the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle is optionally substituted with 1 to 4 members selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, C _1-4 alkyl substituted with halogen, C _1-4 alkyl substituted with hydroxyl, C _1-4 alkyl substituted with cyano, C _2-4 alkynyl, C _1-4 alkoxy, C substituted by a substituent of a _3-6- membered carbonyl or 4- to 7-membered heterocyclic group;

In some embodiments, R ^z1a , R ^k2a , R ^z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF ₃ , methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and the methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl are optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , CF ₃ , hydroxymethyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

In some embodiments, R ^z1a , R ^k2a , and R ^z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF ₃ , methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, , ;

In some embodiments, ^Rz3 is selected from -OH, _-CH2OH , -OP(=O)(OH) ₂ , _-CH2OP (=O ₎ (OH) ₂ , -OP(=O)(OH)( _OC1-6alkyl ), -CH2OP(=O)(OH)( _OC1-6alkyl ), -OP(=O)( _OC1-6alkyl ) ₂ , _-CH2OP (=O)( _OC1-6alkyl ) ₂ ;

In some embodiments, R ^z3 is selected from -OH, -CH ₂ OH, -OP(=O)(OH) ₂ , -CH ₂ OP(=O)(OH) ₂ ;

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

In some embodiments, q is independently selected from 0, 1, 2;

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

In some implementations, Selected from , ;

casually,

1) When B selects When B is replaced by 1 to 8 R ^b ;

or 2) when B is selected from unsubstituted , and Z ₁ is selected from a 4- to 7-membered monocyclic heterocyclic group linked to an alkylene group via a nitrogen atom, Z ₁ is substituted by 1 to 4 R ^z1a ;

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

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

Ring A, Ring C, and Ring D are each independently selected from C _6-10 aryl or 5- to 10-membered heteroaryl, the Ring A is optionally substituted by 1 to 4 ^Ra , the Ring C is optionally substituted by 1 to 4 ^Rc , and the Ring D is optionally substituted by 1 to 4 ^Rd ;

B is selected from -B ₁ -, -N(R ⁿ )-B ₁ -, -B ₁ -N(R ⁿ )-;

B ₁ is selected from a 4- to 12-membered heterocyclic group, wherein the heterocyclic group is optionally substituted with 1 to 10 R ^b ;

X is selected from -N(R ^x )S(=O) ₂ -, -S(=O) ₂ N(R ^x )-, , , , , the left side is connected to ring C;

K is selected from a 5-membered heteroaryl group, wherein K is substituted by 1 to 3 R ^k1 and 1 R ^k2 ;

^Rx is selected from H, _C1-6 alkyl or _C3-6 cycloalkyl;

^Rn is selected from H, _C1-6 alkyl, _-C1-4 alkylene- _C3-6 cycloalkyl, wherein the alkyl, alkylene or cycloalkyl is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-6 alkyl, halogen-substituted _C1-6 alkyl, hydroxyl-substituted _C1-6 alkyl, cyano-substituted _C1-6 alkyl, and _C1-6 alkoxy;

^Ra , ^Rb , and ^Rc are each independently selected from deuterium, halogen, cyano, OH, =O, _C1-6 alkyl, _C2-6 alkenyl, _C2-6 alkynyl, _C1-6 alkoxy, -( _CH2 ) _q - _C3-10 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 with 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-6 alkyl, _C1-6 alkyl substituted with halogen, _C1-6 alkyl substituted with hydroxy, _C1-6 alkyl substituted with cyano, _C2-6 alkynyl, _C1-6 alkoxy, _C3-10 carbocyclic ring or 4 to 10 membered heterocyclic ring;

Or any R ^b and R ^c are directly linked to form a 4- to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R ^a1 ;

Or any R ^b and ^Ra are directly linked to form a 4- to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 ^Ra1 ;

R ^a1 is each independently substituted with a substituent selected from halogen, OH, cyano, NH ₂ , =O, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-10 carbocyclic group or 4-10 membered heterocyclic group, wherein said alkyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, halogen-substituted C _1-6 alkyl, hydroxyl-substituted C _1-6 alkyl, cyano-substituted C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-10 carbocyclic group or 4-10 membered heterocyclic group;

R ^d and R ^k1 are each independently selected from deuterium, CD ₃ , halogen, cyano, OH, NO ₂ , 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, -(CH ₂ ) _q -C _3-10 carbocycle, -(CH ₂ ) _q -4 to 10 membered heterocycle, -S(=O) ₂ R ¹ , -S(=O) ₂ NR ¹ R ² , -C(=O)NR ¹ R ² , C(=O)NR ¹ S(=O) ₂ R ³ , -C(=O)R ¹ , wherein -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic optionally substituted with 1 to 4 substituents selected from deuterium, CD ₃ , halogen, OH, cyano, NH ₂ , 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 carbocyclic or 4-10 membered heterocyclic;

R ¹ , R ² , and R ³ are each independently selected from H, C _1-6 alkyl, C _3-10 carbocyclic group, or 4- to 10-membered heterocyclic group, wherein the alkyl, carbocyclic group, or heterocyclic group is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, halogen-substituted C _1-6 alkyl, hydroxyl-substituted C _1-6 alkyl, cyano-substituted C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-10 carbocyclic group, or 4- to 10-membered heterocyclic group;

Z is selected from -CH(R ^z1 )CH ₂ -SR ^z2 or -CH(R ^z1 )CH ₂ -Se-R ^z2 ;

R ^z1 is selected from -C _1-4 alkylene- _{Z 1} -R ^z3 ;

Z ₁ is selected from a 4- to 12- _membered heterocyclic group, and is optionally substituted with 1 to 4 R ^z1a or optionally substituted with 1 substituent selected from -OP(=O)(OH) ₂ or -CH ₂ OP(=O)(OH) ₂ ;

R ^k2 and R ^z2 are each independently selected from C _6-10 aryl or 5- to 10-membered heteroaryl, said R ^k2 is optionally substituted by 1 to 4 R ^k2a , and said R ^z2 is optionally substituted by 1 to 4 R ^z2a ;

R ^z1a , R ^k2a , R ^z2a are each independently selected from halogen, cyano, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -(CH ₂ ) _q -C _3-10 carbocyclic ring, -(CH ₂ ) _q -4 to 10 membered heterocyclic ring, wherein the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, C _1-6 alkyl substituted with halogen, C _1-6 alkyl substituted with hydroxy, C _1-6 alkyl substituted with cyano, C _2-6 alkynyl, C _1-6 alkoxy, C _3-10 carbocyclic ring or 4 to 10 membered heterocyclic ring;

R ^z3 is selected from -OH, -CH ₂ OH, -OP(=O)(OH) ₂ , -CH ₂ OP(=O)(OH) ₂ , -OP(=O)(OH)(OC _1-6 alkyl), -CH ₂ OP(=O)(OH)(OC _1-6 alkyl), -OP(=O)(OC _1-6 alkyl) ₂ , -CH ₂ OP(=O)(OC _1-6 alkyl) ₂ ;

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

The condition is,

1) When B selects When B is replaced by 1 to 8 R ^b ;

or 2) when B is selected from unsubstituted , and Z ₁ is selected from a 4- to 7-membered monocyclic heterocyclic group connected to an alkylene group through a nitrogen atom, Z ₁ is substituted by 1 to 4 R ^z1a ;

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

As a second 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,

Ring A, Ring C, and Ring D are each independently selected from phenyl, benzo _C4-6 carbocyclic group, benzo 5- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl group, and 9- to 10-membered heteroaryl group, wherein Ring A is optionally substituted with 1 to 4 ^Ra , Ring C is optionally substituted with 1 to 4 ^Rc , and Ring ^D is optionally substituted with 1 to 4 Rd;

_B1 is selected from a 4- to 7-membered nitrogen-containing monocyclic heterocyclic group, a 5- to 10-membered nitrogen-containing bicyclic heterocyclic group, a 5- to 11-membered nitrogen-containing spirocyclic heterocyclic group, and a 5- to 11-membered nitrogen-containing bridged heterocyclic group, and _B1 is optionally substituted by 1 to 8 ^Rb ;

^Rn is selected from H, _C1-4 alkyl;

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

^Ra , ^Rb , and ^Rc are each independently selected from deuterium, halogen, cyano, OH, =O, _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, -( _CH2 ) _q - _C3-6 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 with 1 to 4 substituents selected from halogen, OH, cyano, NH2, _C1-6 alkyl, halogen-substituted _C1-4 alkyl, _{hydroxy-substituted C1-4 alkyl, cyano-substituted C1-4 alkyl, C2-4 alkynyl, C1-4 alkoxy, C3-6 carbocyclic ring or 4 to} 7-membered heterocyclic ring;

Or any R ^b and R ^c are directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted with 1 to 4 R ^a1 ;

Or any R ^b and R ^a are directly connected to form a 4- to 7-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted by 1 to 4 R ^a1 ;

R ^a1 is each independently selected from halogen, OH, cyano, NH ₂ , =O, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 carbocyclic group or 4-7 membered heterocyclic group, wherein said alkyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 carbocyclic group or 4-7 membered heterocyclic group;

R ^d and R ^k1 are each independently selected from deuterium, CD ₃ , halogen, cyano, OH, NO ₂ , 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, -(CH ₂ ) _q -C _3-6 carbocycle, -(CH ₂ ) _q -4 to 7 membered heterocycle, -S(=O) ₂ R ¹ , -S(=O) ₂ NR ¹ R ² , -C(=O)NR ¹ R ² , C(=O)NR ¹ S(=O) ₂ R ³ , -C(=O)R ¹ , wherein -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic optionally substituted with 1 to 4 substituents selected from deuterium, CD ₃ , halogen, OH, cyano, NH ₂ , 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 carbocyclic or 4-7 membered heterocyclic;

R ¹ , R ² , and R ³ are each independently selected from H, C _1-4 alkyl, C _3-6 carbocyclic ring, or 4- to 7-membered heterocyclic ring, wherein the alkyl, carbocyclic ring, or heterocyclic ring is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 carbocyclic ring, or 4- to 7-membered heterocyclic ring;

_Z1 is selected from a 4- to 7-membered nitrogen-containing monocyclic heterocyclic group, a 5- to 10-membered nitrogen-containing cycloheterocyclic group, a 5- to 11-membered nitrogen-containing spirocyclic heterocyclic group, and a 5- to 11-membered nitrogen-containing bridged heterocyclic group, and said _Z1 is optionally substituted with 1 to 4 ^Rz1a or optionally substituted with 1 substituent selected from -OP(=O)(OH) ₂ or _-CH2OP (=O)(OH) ₂ ;

R ^k2 and R ^z2 are each independently selected from phenyl, benzo C _4-6 carbocyclic group, benzo 5-6 membered heterocyclic group, 5-6 membered heteroaryl group, 9-10 membered heteroaryl group, said R ^k2 is optionally substituted by 1 to 4 R ^k2a , and said R ^z2 is optionally substituted by 1 to 4 R ^z2a ;

R ^z1a , R ^k2a , R ^z2a are each independently selected from halogen, cyano, OH, C _1-4 alkyl, C 2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -(CH ₂ ) _q -C _3-6 carbocyclic ring, -(CH ₂ ) _q -4 to ₇ -membered heterocyclic ring, wherein the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, C _1-4 alkyl substituted with halogen, C _1-4 alkyl substituted with hydroxy, C _1-4 alkyl substituted with cyano, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 carbocyclic ring or 4 to 7-membered heterocyclic ring;

R ^z3 is selected from -OH, -CH ₂ OH, -OP(=O)(OH) ₂ , -CH ₂ OP(=O)(OH) ₂ ;

q is independently selected from 0, 1, 2;

The rest of the group definitions are the same as in the first implementation.

As a third 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,

_B1 is selected from azidocyclobutyl, azidocyclopentyl, azidocyclohexyl, azidocyclohexenyl, azidocycloheptyl, azidocyclobutyl spirocyclopropyl, azidocyclopentyl spirocyclopropyl, azidocyclohexyl spirocyclopropyl, azidocyclobutyl spirocyclobutyl, azidocyclopentyl spirocyclobutyl, azidocyclohexyl spirocyclobutyl, azidocyclobutyl spirocyclopentyl, azidocyclohexyl spirocyclobutyl, azidocyclobutyl spirocyclopentyl, azidocyclohexyl spirocyclopentyl ...hexyl spirocyclopentyl, azidocyclobutyl spirocyclopentyl, azidocyclohexyl spirocyclopentyl, azidocyclohexyl spirocyclopentyl, azidocyclobutyl spirocyclopentyl, azidocyclopentyl spirocyclopentyl, azidocyclopentyl spirocyclopentyl, azidocyclopentyl spirocyclopentyl, azidocyclopentyl spirocyclopentyl, azidocyclopentyl spirocyclopentyl, azidocyclopentyl spirocyclopentyl, azidocyclopentyl spirocyclopentyl, azidocyclopentyl cyclopentyl, spirocyclopentyl, cyclohexyl, spirocyclopentyl, cyclobutyl, spirocyclohexyl, cyclopentyl, spirocyclohexyl, cyclohexyl, cyclobutyl, spiroazacyclobutyl, cyclopentyl, spiroazacyclobutyl, cyclohexyl, spiroazacyclobutyl, cyclopentyl, spiroazacyclobutyl, cyclohexyl, spiroazacyclobutyl, cyclobutyl, spiroazacyclopentyl, cyclopentyl, cyclobutyl Pentylspiroazacyclopentyl, azacyclohexylspiroazacyclopentyl, azacyclobutylspiroazacyclohexyl, azacyclopentylspiroazacyclohexyl, azacyclohexylspiroazacyclohexyl, piperazinespirocyclopropyl, piperazinespirocyclobutyl, piperazinespirocyclopentyl, piperazinespirocyclohexyl, piperazinespiroazacyclopropyl, piperazinespirocyclobutyl , piperazine spiroazacyclopentyl, piperazine spiroazacyclohexyl, azacyclobutyl and cyclopropyl, azacyclopentyl and cyclopropyl, azacyclohexyl and cyclopropyl, azacyclobutyl and cyclobutyl, azacyclopentyl and cyclobutyl, azacyclohexyl and cyclobutyl, azacyclobutyl and cyclopentyl, azacyclopentyl and cyclopentyl, azacyclohexyl and cyclobutyl azacyclopentyl, azacyclobutyl and azacyclohexyl, azacyclopentyl and azacyclohexyl, azacyclohexyl and azacyclohexyl, azacyclobutyl and azacyclobutyl, azacyclopentyl and azacyclobutyl, azacyclohexyl and azacyclobutyl, azacyclobutyl and azacyclopentyl, azacyclopentyl and azacyclopentyl, azacyclohexyl and azacyclobutyl, azacyclobutyl and azacyclopentyl, azacyclopentyl and azacyclopentyl, azacyclohexyl and azacyclohexyl Azacyclopentyl, Azacyclobutyl and Azacyclohexyl, Azacyclopentyl and Azacyclohexyl, Azacyclohexyl and Azacyclohexyl, Piperazinylcyclopropyl, Piperazinylcyclobutyl, Piperazinylcyclopentyl, Piperazinylcyclohexyl, Piperazinylspirocyclopropyl, Piperazinylcyclobutyl, Piperazinylcyclopentyl, Piperazinylcyclohexyl, Piperazinylspirocyclopropyl, Piperazinylcyclobutyl, Piperazinylcyclopentyl, Piperazinylcyclo hexyl, 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, said B ₁ is optionally substituted by 1 to 8 R ^b ;

_Z1 is selected from azidocyclobutyl, azidocyclopentyl, azidocyclohexyl, azidocyclohexenyl, azidocycloheptyl, azidocyclobutyl spirocyclopropyl, azidocyclopentyl spirocyclopropyl, azidocyclohexyl spirocyclopropyl, azidocyclobutyl spirocyclobutyl, azidocyclopentyl spirocyclobutyl, azidocyclohexyl spirocyclobutyl, azidocyclobutyl spirocyclopentyl, Azacyclopentylspirocyclopentyl, Azacyclohexylspirocyclopentyl, Azacyclobutylspirocyclohexyl, Azacyclopentylspirocyclohexyl, Azacyclohexylspirocyclohexyl, Azacyclobutyl and cyclopropyl, Azacyclopentyl and cyclopropyl, Azacyclohexyl and cyclopropyl, Azacyclobutyl and cyclobutyl, Azacyclopentyl and cyclobutyl, Azacyclohexyl cyclobutyl, cyclopentyl aza-butyl, cyclopentyl aza-pentyl, cyclopentyl aza-hexyl, cyclopentyl aza-butyl, cyclohexyl aza-pentyl, cyclohexyl aza-hexyl, cyclohexyl aza-hexyl, 3-cyclohexanobicyclo[3.2.1]octyl, 8-cyclohexanobicyclo[3.2.1]octyl, 2-cyclohexanobicyclo[3.2.1]octyl Cyclo[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 Z ₁ is optionally substituted with 1 to 4 R ^z1a or optionally substituted with 1 substituent selected from -OP(=O)(OH) ₂ or -CH ₂ OP(=O)(OH) ₂ ;

^Ra , ^Rb , and ^Rc are each independently selected from deuterium, halogen, cyano, OH, =O, _C1-4 alkyl, _C2-4 alkynyl, _C1-4 alkoxy, or _C3-6 cycloalkyl, wherein the alkyl, alkynyl, alkoxy, or cycloalkyl is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-4 alkyl, halogen-substituted _C1-4 alkyl, hydroxyl-substituted _C1-4 alkyl, cyano-substituted _C1-4 alkyl, _C2-4 alkynyl, _C1-4 alkoxy, or _C3-6 cycloalkyl;

R ^a1 is independently selected from halogen, OH, cyano, NH ₂ , =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 with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

R ^d and R ^k1 are each independently selected from deuterium, CD ₃ , halogen, cyano, OH, NO ₂ , 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, -CH ₂ -C _3-6 cycloalkyl, -S(=O) ₂ NH ₂ , -C(=O)NH ₂ , -S(=O) ₂ C _1-4 alkyl, -S(=O) ₂ -C _3-6 cycloalkyl, -S(=O) ₂ NHC _1-4 alkyl, -C(=O)C _1-4 alkyl, -C(=O)-C _3-6 cycloalkyl, -C(=O)NHC _1-4 alkyl, wherein the -CH ₂ -, alkyl, alkynyl, alkoxy, alkylthio, cycloalkyl optionally substituted with 1 to 4 substituents selected from deuterium, CD ₃ , halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

The remaining group definitions are the same as those of the first and second embodiments of the present invention.

As a fourth 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,

B is selected from -B ₁ -, -N(CH ₃ )-B ₁ -, -B ₁ -N(CH ₃ )-;

B _1Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , said B ₁ is optionally substituted with 1 to 8 R ^b ;

Ring A selected from , , , , , , , , , , , , , , , , , , , the ring A is optionally substituted with 1 to 4 ^Ra ;

Ring C and Ring D are independently selected from , , , , , , , , , , , , , , , , , , , , the ring C is optionally substituted by 1 to 4 R ^c , and the ring D is optionally substituted by 1 to 4 R ^d ;

or Selected from , , , , , , , , , , , , , the left side is connected to ring A;

or Selected from , , , , , , , , , , , , , the left side is connected to ring C;

^Ra , ^Rb , and ^Rc are each independently selected from deuterium, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-4 alkyl, _C2-4 alkynyl, _C1-4 alkoxy, and _C3-6 cycloalkyl;

R ^a1 is each independently selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

R ^d is independently selected from F, Cl, Br, I, cyano, OH, NO ₂ , COOH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, -S(=O) ₂ NH ₂ , -C(=O)NH ₂ , -S(=O) ₂ -methyl, -S(=O) ₂ -ethyl, -S(=O) ₂ NH-methyl, -S(=O) ₂ NH-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 with 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-4 alkyl, _C2-4 alkynyl, _C1-4 alkoxy, _C3-6 cycloalkyl;

R ^z1 is selected from -CH ₂ CH ₂ -Z ₁ -R ^z3 ;

Z ₁ selected from , , , , , , , , , , , , said Z ₁ is optionally substituted by 1 to 4 R ^z1a or optionally substituted by 1 substituent selected from -OP(=O)(OH) ₂ or -CH ₂ OP(=O)(OH) ₂ ;

R ^z3 is selected from -OH, -CH ₂ OH, -OP(=O)(OH) ₂ , -CH ₂ OP(=O)(OH) ₂ ;

K Selected from ;

R ^k1a is selected from COOH, S(=O) ₂ NH ₂ , -C(=O)NH ₂ , -S(=O) ₂ -methyl, -S(=O) ₂ -ethyl, -S(=O) ₂ NH-methyl, -S(=O) ₂ NH-ethyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, wherein the methyl or ethyl group is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , CF ₃ , hydroxymethyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

R ^k1b is selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , CF ₃ , hydroxymethyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

R ^k1c is selected from deuterium, CD ₃ , H, methyl, ethyl, propyl, isopropyl, butyl and cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, butyl and cyclopropyl are optionally substituted with 1 to 4 substituents selected from deuterium, CD ₃ , halogen, OH, cyano, NH ₂ , CF ₃ , hydroxymethyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy and C _3-6 cycloalkyl;

R ^k2 and R ^z2 are each independently selected from phenyl, pyridine, , , , , , , , , , , , , , , the R ^k2 is optionally replaced by 1 to 4 R ^k2a , and the R ^z2 is optionally replaced by 1 to 4 R ^z2a ;

R ^z1a , R ^k2a , R ^z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF ₃ , methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl are optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , CF ₃ , hydroxymethyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl;

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

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

As a fifth 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,

R ^k1a is selected from COOH;

R ^k1c is selected from methyl, ethyl, propyl, isopropyl, , , , , -CH ₂ -CF ₃ , -CH ₂ -cyclopropyl, cyclopropyl;

R ^k1b is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH ₂ -cyclopropyl;

R ^z1a , R ^k2a , and R ^z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF ₃ , methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, , ;

Selected from , ;

The remaining group definitions are the same as in any one of the first, second, third or fourth embodiments of the present invention.

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), (II-a);

B is selected from -B ₁ -, -N(CH ₃ )-B ₁ -, -B ₁ -N(CH ₃ )-;

B _1Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , said B ₁ is optionally substituted with 1 to 8 R ^b ;

R ^{and b} are independently selected from deuterium and F;

or Selected from ;

Z ₁ selected from , , , , , , , , , , , , said Z ₁ is optionally substituted by 1 to 4 F;

R ^k1c is selected from methyl, ethyl, propyl, isopropyl, , , , , -CH ₂ -CF ₃ , -CH ₂ -cyclopropyl, cyclopropyl;

R ^k2a is selected from F, Cl, methyl, ethyl, cyclopropyl;

^Rz3 is selected from -OH, _-CH2OH , -OP(=O)(OH) ₂ , _-CH2OP (=O)(OH) ₂ .

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 the general formula (I) is selected from the compounds represented by the general formula (III-a) or (III-b), (III-a), (III-b);

R ^k1c is selected from methyl, ethyl, propyl, isopropyl, , , , , -CH ₂ -CF ₃ , -CH ₂ -cyclopropyl, cyclopropyl;

Z ₁ selected from , , , , , , , , , , , said Z ₁ is optionally substituted by 1 to 4 F;

R ^k2a is selected from F, Cl, methyl, ethyl, cyclopropyl;

R ^z3 is selected from -OH, -OP(=O)(OH) ₂ .

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

Table E-1 .

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 compound or its stereoisomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals.

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

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

The "effective amount" or "therapeutically effective amount" described in this application refers to administering 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., inhibiting Bcl-2 or Bcl-xL related diseases such as tumors or eye diseases) to some extent. In some embodiments, the result is to reduce and/or alleviate 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, 200-600 mg, 1-500 mg, 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, 25-40 0mg, 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 -200mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.

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.

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, preferably 1-1500 mg, wherein the disease preferably inhibits Bcl-2 or Bcl-xL-related diseases (such as tumors or eye diseases).

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 a divided dose, 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, the daily dose includes but is not limited to 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day, 200 mg/day, 300 mg/day, 320 mg/day, 400 mg/day, 480 mg/day, 600 mg/day, 640 mg/day, 800 mg/day, 1000 mg/day.

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

The present invention relates to the use of any of the above-mentioned compounds or stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof in the preparation of drugs for treating diseases associated with Bcl-2 or Bcl-xL activity or expression, preferably, the diseases are selected from tumors or eye diseases.

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 an eye disease associated with retinal lesions.

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

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

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

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

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

"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 isomers thereof; the alkyl groups appearing herein are defined in accordance with this definition. Alkyl groups may be monovalent, divalent, trivalent, or tetravalent.

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

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

"Heteroalkylene" refers to a substituted or unsubstituted alkylene 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 )v-, v is an integer from 1 to 5, each X is independently selected from a bond, N, O or S, and at least one X is selected from N, O or S.

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

"Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S. The N and S optionally substituted in the heterocycloalkyl ring can be oxidized to various oxidation states. The heterocycloalkyl group may be attached to a heteroatom or a carbon atom, may be attached to an aromatic ring or a non-aromatic ring, may be attached to a bridged ring or a spiro ring, and non-limiting examples include oxadiazine, cyclopropyl, cyclobutyl, cyclobutyl, tetrahydrofuranyl, tetrahydro- 2H -pyranyl, dioxolane, dioxahexane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. The heterocycloalkyl group may be monovalent, divalent, trivalent, or tetravalent.

"Alkenyl" refers to a substituted or unsubstituted straight or branched unsaturated alkyl radical having at least one, typically one, two or three carbon-carbon double bonds, with the main chain including but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl 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-1-butenyl, 2-methyl-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; the alkenyl groups used herein have the same meaning as in this definition. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.

"Alkynyl" refers to a substituted or unsubstituted straight or branched unsaturated hydrocarbon radical 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, or 2 to 4 carbon atoms in the main chain. Examples of alkynyl radicals include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- Methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; alkynyl can be monovalent, divalent, trivalent, or tetravalent.

"Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

"Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, the aromatic or non-aromatic ring may be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, the carbocyclyl may be attached to the aromatic ring or the non-aromatic ring, the aromatic or non-aromatic ring may 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, naphthyl ring, , , or "Carbocyclyl" or "carbocycle" may be monovalent, divalent, trivalent or tetravalent.

"Heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which may be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The N and S optionally substituted in the heterocyclic ring may be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, the heterocyclic group can be attached to an aromatic ring or a non-aromatic ring, the heterocyclic group can be attached to a bridge ring or a spiro ring, and non-limiting examples include ethylene oxide, cyclopropyl azopropane, cyclobutyl azopropane, 1,3-dioxolane, 1,4-dioxolanyl, Pentyl, 1,3-dioxane, azacycloheptyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, oxazinyl, imidazolyl, piperidinyl, fluorenyl, thiofluorenyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl 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]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantanyl, oxaspiro[3.3]heptanyl, , , , , , , , , , , , , or "Heterocyclic group" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

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

"Cyclic" or "Cyclic 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 cyclic system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to selected from N, S(=O) _n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: , , , "Cyclo" or "cycloalkyl" may be monovalent, divalent, trivalent or tetravalent.

"Bridged ring" or "bridged cyclic 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 groups selected from heteroatoms or heteroatoms (including but not limited to N, S(=O) _n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12 or 5 to 10. Non-limiting examples include , , , , , cubane, and adamantane. "Bridging ring" or "bridged ring group" may be monovalent, divalent, trivalent, or tetravalent.

"Carbospirocycle", "spirocarbocyclic group", "spirocarbocyclic group" or "carbospirocyclic group" refers to a "spirocycle" whose ring system consists of only carbon atoms. "Carbospirocycle", "spirocarbocyclic group", "spirocarbocyclic group" or "carbospirocyclic group" appearing in this article have the same definition as spirocycle.

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

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

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

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

"Heterospirocycle", "heterospirocycloyl", "spiroheterocycloyl" or "heterospirocycloyl" refers to a "spirocycle" containing a hetero atom. The heterospirocycle, "heterospirocycloyl", "spiroheterocycloyl" or "heterospirocycloyl" appearing in this article has the same definition as spirocycle.

"Hetero-bridged ring", "hetero-bridged cycloalkyl", "bridged-cyclohetero-cycloalkyl" or "hetero-bridged cycloalkyl" refer to a "bridged ring" containing a hetero atom. The hetero-bridged ring, "hetero-bridged cycloalkyl", "bridged-cyclohetero-cycloalkyl" or "hetero-bridged cycloalkyl" mentioned herein have the same definition as that of the bridged ring.

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

"Heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or a group 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 heteroaryl 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, oxazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbon ring or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include and The heteroaryl groups appearing herein have the same definition as in this definition. The heteroaryl groups may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment point is located on the heteroaryl ring.

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

"5- and 6-membered heteroaromatic ring" refers to a 5- and 6-membered fused heteroaromatic ring, at least one of the two 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 group, 6-membered heteroaromatic ring and 5-membered heteroaromatic ring.

“Substituted” or “substituted” means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, alkyl, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridging, spirocyclic, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, ‒(CH ₂ ) _m ‒C(=O)‒R ^a , ‒O‒(CH ₂ ) _m ‒C(=O)‒R ^a , ‒(CH ₂ ) _m ‒C(=O)‒NR ^b R ^c , ‒(CH ₂ ) _m S(=O) _n R ^a , ‒(CH ₂ ) _m ‒alkenyl ‒R ^a , OR ^d or ‒(CH ₂ ) _m ‒alkynyl ‒R ^a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or ‒NR ^b R ^c , wherein R ^b and R ^c are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, alternatively, R ^b and R ^c can form a five- or six-membered cycloalkyl or heterocyclic group, and R ^a and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridging, spiro or cycloalkyl.

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

"Replaced by 1 to X substituents selected from..." means substituted by 1, 2, 3 .... X substituents selected from...", X is any integer selected from 1 to 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.

X-Y membered rings (3≤X＜Y, Y is any integer between 4 and 12) include X, X+1, X+2, X+3, X+4….Y membered rings. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heteroparacyclic rings, heterospirocyclic rings or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to heteromonocyclic rings with 4, 5, 6 or 7 members, and "5-10 membered heteroparacyclic ring" refers to heteroparacyclic rings with 5, 6, 7, 8, 9 or 10 members.

"Optional" or "optionally" or "arbitrarily" means that the subsequently described event or circumstance may but need not occur, and the description includes instances 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 instances where alkyl is substituted with F and instances where alkyl is not substituted with F.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to 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 reacted with a non-toxic inorganic base or organic base, and the free base is reacted with a non-toxic inorganic acid or organic acid to form a salt.

"Drug composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated products, 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.

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

"Preparation specification" refers to the weight of the main drug contained in each tube, tablet or other unit preparation. "Prodrug" refers to the 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 individual, the prodrug is cleaved to form a free amino or carboxyl group.

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

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

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

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

" _IC50 " 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.

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

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

For MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));

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

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

Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh as the carrier;

In order to accomplish the purpose of the present invention, the compounds used in the reactions described herein are prepared starting from commercially available chemicals and/or compounds described in chemical literature according to organic synthesis techniques known to those skilled in the art. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLennan 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.

THF: tetrahydrofuran; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; HATU: CAS 148893-10-1.

Example 1: Synthesis of Compound 1

Step 1: Synthesis of 1a

Dissolve tert-butyl 2-oxo-7-azaspiro[3.5]nonane-7-carboxylate (5.0 g, 20.89 mmol) in 30 mL methanol, and add sodium borohydride (1.19 g, 31.34 mmol) in batches at 0°C under nitrogen protection. Continue the reaction for 1 hour. Add 20 mL of water, extract twice with 30 mL of ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 1a (4.5 g, yield: 89.26%).

LCMS m/z = 186.1 [M-55] ⁺

Step 2: Synthesis of 1b

1a (4.0 g, 16.57 mmol) was dissolved in 50 mL tetrahydrofuran, and sodium hydroxide (1.0 g, 41.42 mmol) was added in portions at 0°C under nitrogen protection. The mixture was stirred for 30 minutes, and then benzyl bromide (5.67 g, 33.14 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was quenched by adding water, and the mixture was extracted twice with 50 mL ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and subjected to column chromatography to obtain 1b (4.6 g, yield: 83.76%).

LCMS m/z = 332.2 [M+H] ⁺

Step 3: Synthesis of 1c

Dissolve 1b (1.8 g, 5.43 mmol) in 20 mL of acetonitrile, add 4 mL of 4 N dioxane hydrochloride solution, and react at room temperature for 2 hours. Concentrate under reduced pressure, add 5 mL of sodium bicarbonate aqueous solution to adjust the pH to about 8, extract with dichloromethane 5 times, combine the organic phases, and concentrate under reduced pressure to obtain 1c (1.0 g, yield: 79.61%).

LCMS m/z = 232.2 [M+H] ⁺

Step 4: 1D synthesis

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, which was subjected to column chromatography to obtain 1d (1.45 g, yield: 64.52%).

LCMS m/z = 511.3 [M+H] ⁺

Step 5: Synthesis of 1e

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. The product was extracted twice with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1e (40 mg, yield: 12.74%).

LCMS m/z = 321.4[M+H] ⁺

Step 6: Synthesis of Compound 1

Intermediate B (33 mg, 0.04 mmol) was dissolved in 2 mL 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 twice with water (20 mL×2), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and column chromatography was performed to obtain the product, which was then subjected to reverse phase column chromatography to obtain the trifluoroacetic acid salt of compound 1 (10 mg, yield: 22.33%).

LCMS m/z = 560.3[M/2+H] ⁺

Example 3: Synthesis of Compound 3

Step 1: Synthesis of 3a

(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, and 5 mL of trifluoroacetic acid was added, and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain 3a (0.54 g, yield: 99.4%).

LCMS m/z = 120.2[M+H] ⁺

Step 2: Synthesis of 3b

Intermediate A (0.45 g, 1.52 mmol) was dissolved in 20 mL of dichloromethane, and 3a (0.18 g, 1.52 mmol) was added. Under nitrogen protection, the mixture was cooled in an ice-water bath, and triethylamine (0.62 g, 6.08 mmol) was added. The mixture was stirred at 0°C for 30 minutes, and sodium triacetoxyborohydride (0.48 g, 2.28 mmol) was added. The mixture was stirred at room temperature overnight. 30 mL of purified water was added, and the mixture 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. 3b (0.5 g, yield: 82.54%) was obtained by column chromatography.

LCMS m/z =399.3 [M+H] ⁺

Step 3: Synthesis of compound 3c

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 give 3c (0.070 g, yield: 93.83%).

LCMS m/z =299.2 [M+H] ⁺

Step 4: Synthesis of compound 3

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 twice with water (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 trifluoroacetic acid salt of compound 3 (22 mg, yield: 54.17%) was obtained by reverse phase column chromatography.

LCMS m/z = 549.6[M/2+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.28 (d, 1H), 8.19 (s, 1H), 8.00 (dd, 1H), 7.93 (d, 1H), 7.86 (d, 1H), 7.83 – 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).

Example 4: Synthesis of Compound 4

Step 1: Synthesis of 4a

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

LCMS m/z = 120.2[M+H] ⁺

Step 2: Synthesis of compound 4b

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, which was subjected to column chromatography to obtain 4b (0.5 g, yield: 82.54%).

LCMS m/z =399.3 [M+H] ⁺

Step 3: Synthesis of compound 4c

4b (0.1 g, 0.25 mmol) was dissolved in 2 mL of dichloromethane, and 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 compound 4c (0.070 g, yield: 93.83%).

LCMS m/z =299.2 [M+H] ⁺

Step 4: Synthesis of compound 4

Intermediate B (50 mg, 0.061 mmol) was dissolved in 2 mL N,N-dimethylformamide, 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, washed twice with water (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 trifluoroacetic acid salt of compound 4 (20 mg, yield: 29.87%) was obtained by reverse phase column chromatography.

LCMS m/z = 549.8[M/2+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.26 (s, 1H), 8.18 (s, 1H), 7.98 (dd, 1H), 7.91 (d, 1H), 7.84 (d, 1H), 7.81 – 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).

Example 5: Synthesis of Compound 5

Step 1: Synthesis of 5B

5A (1.0 g, 1.91 mmol), 5A-1 (530 mg, 2.29 mmol), cuprous iodide (36 mg, 0.19 mmol), [(2,6-dimethylphenyl)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 sealed at 130°C for 12 hours. Water was added, extracted with ethyl acetate, 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 5B (651 mg, 50.48%).

Step 2: Synthesis of 5C

Dissolve 5B (610 mg, 0.90 mmol) in 10 mL of ethanol and 2 mL of water, add iron powder (250 mg, 4.5 mmol) and ammonium chloride (240 mg, 4.5 mmol), and react at 90°C for 12 hours. Cool to room temperature, filter, concentrate under reduced pressure, and purify by column chromatography to obtain 5C (435 mg, 74.9%).

LCMS m/z = 645.2 [M+H] ⁺

Step 3: 5D Synthesis

Dissolve 5C-1 (350 mg, 1.06 mmol) in 5 mL of dichloromethane, add pyridine (170 mg, 2.13 mmol) at 0°C, stir for 1 minute, slowly add 5C (460 mg, 0.71 mmol), and stir at room temperature for 2 hours. Add water, extract with ethyl acetate, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography to obtain 5D (410 mg, 61.73%).

LCMS m/z =935.4 [M+H] ⁺

Step 4: Synthesis of 5F

Dissolve 5D (80 mg, 0.086 mmol) and 5E (48 mg, 0.13 mmol) in 3 mL N,N-dimethylformamide, slowly add N,N-diisopropylethylamine (33 mg, 0.26 mmol), and stir at room temperature for 2 hours. Add water, extract with ethyl acetate, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography to obtain 5F (75 mg, 67.81%).

LCMS m/z = 1285.4 [M+H] ⁺

Step 5: Synthesis of Compound 5

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 the reaction was carried out at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by column analysis to obtain compound 5 (20 mg, 31.19%).

LCMS m/z = 1105.3 [M+H] ⁺

Example 7: Synthesis of Compound 7

Step 1: Synthesis of 7B

7A (5.0 g, 22.19 mmol) was dissolved in 30 mL of methanol. Under nitrogen protection, sodium borohydride (1.26 g, 33.29 mmol) was added in batches at 0°C and reacted at 0°C for 1 hour. 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%).

Ms m/z (ESI): 228.3 [M+H] ⁺

Step 2: Synthesis of 7C

Dissolve 7B (1.8 g, 7.92 mmol) in 20 mL of acetonitrile, add 4 mL of 4 N dioxane hydrochloride solution, and react at room temperature for 2 hours. Concentrate under reduced pressure, add 5 ml of sodium bicarbonate aqueous solution to adjust pH to about 8, extract with dichloromethane 5 times, combine the organic phases, and concentrate under reduced pressure to obtain 7C (1.0 g, yield: 99.28%).

Ms m/z (ESI): 128.2 [M+H] ⁺

Step 3: 7D Synthesis

Dissolve (R)-(4-oxo-1-(phenylthio)butan-2-yl)carbamic acid tert-butyl ester (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 was purified by column chromatography to obtain 7D (1.45 g, yield: 81.05%).

Ms m/z (ESI): 407.3 [M+H] ⁺

Step 4: Synthesis of 7E

7D (1 g, 2.46 mmol) was dissolved in 10 mL of DCM, and 3 mL of 4 N dioxane hydrochloride 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%).

Step 5: Synthesis of compound 7

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 twice with water (20 mL × 2), washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the product was obtained by column chromatography, and then the trifluoroacetic acid salt of compound 7 (10 mg, yield: 14.83%) was obtained by reverse phase column chromatography.

Ms m/z (ESI):1105.4[M+H] ⁺

Example 8: Synthesis of Compound 8

Step 1: Synthesis of compound 8B

Compound 8A (0.4 g, 1.82 mmol) was dissolved in 20 mL of acetonitrile, and 2 mL of 4 N dioxane hydrochloride solution was added. The mixture was stirred and 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 8. 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%).

Ms m/z (ESI): 120.1 [M+H] ⁺

Step 2: Synthesis of compound 8C

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 for overnight reaction. 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%).

Ms m/z (ESI):343.2 [M+H-56] ⁺

Step 3: Synthesis of compound 8D

Dissolve 8C (1 g, 2.51 mmol) in 10 mL of dichloromethane, add 3 mL of 4 N dioxane hydrochloride solution, and react at room temperature for 2 h. Remove the solvent by concentration under reduced pressure to obtain the hydrochloride of 8D, which is directly used for the next step without purification (500 mg, yield: 66.75%).

Step 4: Synthesis of compound 8

Intermediate B (50 mg, 0.061 mmol) was dissolved in 2 mL 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 twice with water (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%).

Ms m/z (ESI):1097.4[M+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.27 (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).

Example 9: Synthesis of Compound 9

Step 1: Synthesis of compound 9B

Compound 9A (0.7 g, 3.06 mmol) was dissolved in 10 mL of acetonitrile, and 3 mL of 4 N dioxane hydrochloride solution was added. 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. 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%).

Ms m/z (ESI): 128.2 [M+H] ⁺

Step 2: Synthesis of compound 9C

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%).

Ms m/z (ESI):351.2 [M+H-56] ⁺

Step 3: Synthesis of compound 9D

Compound 9C (0.3 g, 0.74 mmol) was dissolved in 8 mL of dichloromethane, and 3 mL of 4 N dioxane hydrochloride solution was added. 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%).

Ms m/z (ESI):306.2 [M+H] ⁺

Step 4: Synthesis of compound 9

Intermediate B (50 mg, 0.061 mmol) was dissolved in 3 mL 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 twice with water (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 9 (21 mg, yield: 31.13%).

Ms m/z (ESI):1105.4[M+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.25 (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), 7.41 – 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).

Example 10: Synthesis of Compound 10

Step 1: Synthesis of compound 10B

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 the mixture was extracted twice with ethyl acetate (15 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was chromatographed on a silica gel column to obtain 10B (0.75 g, yield: 73.99%).

Ms m/z (ESI): 242.3 [M+H] ⁺

Step 2: Synthesis of compound 10C

Compound 10B (0.75 g, 3.11 mmol) was dissolved in 8 mL of acetonitrile, and 3 mL of 4 N dioxane hydrochloride solution was added. 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. 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%).

Ms m/z (ESI): 142.2 [M+H] ⁺

Step 3: Synthesis of compound 10D

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 bottle, and the mixture was stirred at room temperature overnight. 30 mL of water was added to dilute, and the liquid 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%).

Ms m/z (ESI):365.3[M+H-56] ⁺

Step 4: Synthesis of compound 10E

Compound 10D (0.31 g, 0.76 mmol) was dissolved in 8 mL of dichloromethane, and 3 mL of 4 N dioxane hydrochloride solution was added. 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%).

Ms m/z (ESI):321.4 [M+H] ⁺

Step 5: Synthesis of compound 10

Intermediate B (50 mg, 0.061 mmol) was dissolved in 3 mL 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 twice with water (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%).

Ms m/z (ESI):1119.4[M+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.30 – 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).

Example 11: Synthesis of Compound 11

Step 1: Synthesis of compound 11B

(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, and then 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 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%).

Step 2: Synthesis of compound 11C

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 for 12 h. The reaction solution was cooled to room temperature, saturated ammonium chloride solution was added to quench the reaction, and ethyl acetate (10 mL × 5) was used for extraction 5 times. 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%).

Step 3: Synthesis of compound 11D

Compound 11C (0.6 g, 0.85 mmol) was dissolved in 20 mL of methanol, and 100 mg of 10% palladium-carbon was added. 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%).

Ms m/z (ESI): 583.8[M+H] ⁺

Step 4: Synthesis of compound 11E

3-(Trifluoromethylsulfonyl)-4-fluorobenzenesulfonyl chloride (300 mg, 0.51 mmol) was dissolved in 10 mL of dichloromethane. 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. After the addition, the reaction was continued for 1 h. 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%).

Ms m/z (ESI): 873.1[M+H] ⁺

Step 5: Synthesis of compound 11

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 twice with water (20 mL×2), and once with 30 mL of saturated salt water. 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%).

Ms m/z (ESI): 1151.3 [M+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.34 – 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).

Example 12: Synthesis of Compound 12

Step 1: Synthesis of compound 12a

The raw material N-tert-butyloxycarbonyl-nortropine (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. The reaction was quenched by adding 20 mL of water, and ethyl acetate (15 mL×2) was added for extraction twice, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 12a (0.95 g, yield: 94.13%).

Ms m/z (ESI): 172.2 [M+H-56] ⁺

Step 2: Synthesis of compound 12b

Compound 12a (0.95 g, 4.18 mmol) was dissolved in 10 mL of acetonitrile, and 3 mL of 4 N dioxane hydrochloride solution was added, and the mixture was reacted at room temperature for 2 h. Compound 12b was obtained by concentration under reduced pressure as a white solid (0.5 g, yield: 94.05%).

Ms m/z (ESI): 128.2 [M+H] ⁺

Step 3: Synthesis of compound 12c

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 a nitrogen atmosphere, triethylamine (0.68 g, 6.76 mmol) was added at 0°C, and the mixture was 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 stirred overnight at room temperature. 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 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 as a colorless oil (0.4 g, yield: 58.21%).

Ms m/z (ESI):407.5 [M+H] ⁺

Step 4: Synthesis of compound 12d

Compound 12c (40 mg, 0.098 mmol) was dissolved in 5 mL of acetonitrile, and 1 mL of 4 N dioxane hydrochloride solution was added. The mixture was reacted at room temperature for 2 h. The hydrochloride of compound 12d (28 mg, yield: 93.23%) was obtained by concentration under reduced pressure.

Ms m/z (ESI):307.3 [M+H] ⁺

Step 5: Synthesis of compound 12

Intermediate B (50 mg, 0.061 mmol) was dissolved in 2 mL 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 twice with water (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 trifluoroacetic acid salt of compound 12 (25 mg, yield: 37.06%).

Ms m/z (ESI): 553.5[M/2+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.27 (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).

Example 13: Synthesis of Compound 13

Step 1: Synthesis of compound 13a

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, and 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%).

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

Step 2: Synthesis of compound 13b

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 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 13b (0.4 g, yield: 66.03%).

Ms m/z (ESI):399.3 [M+H] ⁺

Step 3: Synthesis of compound 13c

Compound 13b (0.1 g, 0.25 mmol) was dissolved in 2 mL of dichloromethane, and 2 mL of dioxane hydrochloride was added, and 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%).

Ms m/z (ESI):299.2 [M+H] ⁺

Step 4: Synthesis of compound 13

Intermediate B (50 mg, 0.061 mmol) was dissolved in 2 mL 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 twice with water (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 trifluoroacetic acid salt of compound 13 (23 mg, yield: 34.35%).

Ms m/z (ESI): 549.3[M/2+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.24 (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).

Example 14: Synthesis of Compound 14

Step 1: Synthesis of compound 14a

The raw material (S)-1,1,1-trifluoroisopropylamine hydrochloride (1.5 g, 10.00 mmol) was dissolved in 10 mL of methanol, and triethylamine was added to adjust the pH to about 7. Then 11A (1.0 g, 2.00 mmol) and acetic acid (1.32 g, 22 mmol) were added, and the mixture was sealed and reacted at 100°C overnight. 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%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.30 (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).

Step 2: Synthesis of compound 14b

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-dimethylphenylcarbamoylcarbamic acid (0.20 g, 1.04 mmol), and potassium carbonate (0.43 g, 3.12 mmol). The mixture was heated to 130 °C under a nitrogen atmosphere for 12 h. 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, dried over anhydrous magnesium sulfate, and the crude product was purified by silica gel column chromatography to obtain 14b (0.12 g, yield: 17.77%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.14 (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).

Step 3: Synthesis of compound 14c

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

Ms m/z (ESI): 583.8[M+H] ⁺

Step 4: Synthesis of compound 14d

3-(Trifluoromethylsulfonyl)-4-fluorobenzenesulfonyl chloride (20 mg, 0.061 mmol) was dissolved in 20 mL of dichloromethane. Pyridine (20 mg, 0.26 mmol) was added at 0°C under a nitrogen atmosphere, and then a dichloromethane solution of compound 14c (30 mg, 0.051 mmol) was added in 10 mL. After the addition was complete, the reaction was continued for 1 h. The residue was directly concentrated under reduced pressure and chromatographed on a silica gel column to obtain 14d (27 mg, yield: 60.62%).

Ms m/z (ESI): 873.1[M+H] ⁺

Step 5: Synthesis of compound 14

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 twice with water (20 mL×2), and once with 20 mL of saturated salt water, 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 14 (12 mg, yield: 18.28%)

Ms m/z (ESI): 549.8[M/2+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.25 (s, 1H), 7.97 (d, 1H), 7.88 – 7.72 (m, 3H), 7.60 – 7.29 (m, 13H), 7.26 – 7.15 (m, 1H), 6.76 – 6.69 (m, 1H), 5.23 (d,1H), 4.90 (dd, 1H), 4.56 – 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).

Example 15: Synthesis of Compound 15

The raw material 14d (50 mg, 0.057 mmol) was dissolved in 2 mL 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 twice with water (20 mL×2), and once with 10 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 15 (12 mg, yield: 18.15%)

Ms m/z (ESI): 580.3[M/2+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.20 (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 – 4.63 (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).

Example 17: Synthesis of Compound 17

Step 1: Synthesis of compound 17a

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%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.27 – 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).

Step 2: Synthesis of compound 17b

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, dried over anhydrous magnesium sulfate, and the crude product was purified by silica gel column chromatography to obtain 17b (0.63 g, yield: 51.27%).

Step 3: Synthesis of compound 17c

Dissolve the raw material 17b (0.63 g, 0.93 mmol) in 20 mL of methanol, add 50 mg of 10% palladium carbon, and react at room temperature for 1 h under hydrogen atmosphere. Filter and directly concentrate the filtrate to obtain compound 17c. Gray solid (0.42 g, yield: 81.36%)

Ms m/z (ESI): 555.2[M+H] ⁺

Step 4: Synthesis of compound 17d

The raw material 3-(trifluoromethylsulfonyl)-4-fluorobenzenesulfonyl chloride (0.3 g, 0.91 mmol) was dissolved in 20 mL of dichloromethane. Under nitrogen atmosphere, pyridine (0.3 g, 3.8 mmol) was added at 0°C, and then 17c (0.42 g, 0.76 mmol) in dichloromethane (10 mL) 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. Yellow solid (0.27 g, yield: 42.03%).

Ms m/z (ESI): 845.7[M+H] ⁺

Step 4: Synthesis of compound 17

The raw material 17d (50 mg, 0.059 mmol) was dissolved in 2 mL 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 twice with water (20 mL×2), and once with 10 mL of saturated salt water, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography and reverse column chromatography to obtain compound 17 (14 mg, yield: 20.97%)

Ms m/z (ESI): 566.3[M/2+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.20 (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), 4.17 – 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).

Compound 18: Synthesis of Compound 18

The raw material 17d (50 mg, 0.059 mmol) was dissolved in 2 mL 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 twice with water (20 mL×2), and once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography and reverse column chromatography to obtain compound 18 (13 mg, yield: 19.61%).

Ms m/z (ESI): 1123.5[M+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.24 – 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, 9 (m, 2H), 3.61 – 3.35 (m, 4H), 3.27 – 3.18 (m, 2H), 2.96 – 2.89 (m, 3H), 2.67 – 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).

Example 19: Preparation of Compound 19

The raw material 11E (50 mg, 0.057 mmol) was dissolved in 2 ml DMF, 7E (26 mg, 0.086 mmol) and DIPEA (22 mg, 0.17 mmol) were added, and the mixture was stirred at room temperature for 2 h. 30 ml ethyl acetate was added, and the mixture was washed twice with water (20 mL × 2), and once with 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 19 (14 mg, 21.18%).

Ms m/z (ESI): 1159.3[M+H] ⁺

Example 20: Preparation of Compound 20

Step 1: Preparation of compound 20B

20A (5.0 g, 46.24 mmol) was placed in a sealed tube, dissolved with 100 mL 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 salt water. The organic phase was dried and vortexed, and the residue was purified by column chromatography to obtain compound 20B (3.0 g, yield: 36.5%).

LCMS m/z = 356.2[M+H] ⁺

Step 2: Preparation of compound 20C

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 under nitrogen protection for 20 min. Then 60% sodium hydroxide (375 mg, 9.3 mmol) was added. After the addition, the system was automatically heated to room temperature 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 vortexed. The residue was purified by column chromatography to obtain compound 20C (2.8 g, yield: 99%).

LCMS m/z = 336.2[M+H] ⁺

Step 3: Preparation of compound 20D

Under nitrogen protection, the 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 was then automatically heated to room temperature 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 reaction.

LCMS m/z = 236.1[M+H] ⁺

Step 4: Preparation of 20E

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 with anhydrous sodium sulfate, and purified by column chromatography to obtain compound 20E (320 mg, 29.15%).

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

Step 5: Preparation of 20F

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 mixture was filtered through diatomaceous earth, and the filtrate was collected and concentrated under reduced pressure to obtain compound 20F (200 mg, 81.59%).

LCMS m/z = 557.2 [M+H] ⁺

Step 3: 20G preparation

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. 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 with anhydrous sodium sulfate, and purified by column chromatography to obtain product 20G (180 mg, 59.01%).

LCMS m/z =847.1 [M+H] ⁺

Step 4: Preparation of compound 20

Dissolve 20G (80 mg, 0.094 mmol) in 5 ml DMF, add 10E (45.19 mg, 0.14 mmol) and DIPEA (36.45 mg, 0.28 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 the crude product by silica gel column chromatography and reverse column chromatography to obtain compound 20 (15 mg, 13.9%).

Ms m/z (ESI): 1147.3[M+H] ⁺

Example 21: Preparation of Compound 21

Step 1: Preparation of 21C

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-methylthiazolium bromide (0.77 g, 3.06 mmol) were added in sequence. Nitrogen was introduced, and the system was heated to 75°C and stirred for 6 hours. The reaction system was cooled to room temperature, concentrated, and diluted with ethyl acetate. The organic phase was washed, dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was subjected to column chromatography to obtain product 21C (1.8 g, yield: 58.2%).

Step 2: Preparation of 21D

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, 3.56 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%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.23 (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).

Step 3: Preparation of 21E

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-boronic acid pinacol ester (0.48 g, 1.54 mmol), cesium carbonate (0.67 g, 2.06 mmol), and Pd(dppf)Cl ₂ 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 product 21E (0.55 g, yield 78%).

Step 4: Preparation of 21F

The raw material 21E (0.55 g, 0.80 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of 4 N 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%).

LCMS m/z =585.3 [M+H] ⁺

Step 5: Preparation of 21G

The hydrochloride of the raw material 21F (0.45 g, 0.77 mmol) was dissolved in 5 mL DMF, and p-fluoronitrobenzene (0.16 g, 1.16 mmol) and potassium carbonate (0.21 g, 0.54 mmol) were added in sequence. The mixture was heated to 50°C and reacted 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 salt water. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography to obtain 21G (0.53 g, yield: 97%).

Step 6: 21H preparation

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. The filtrate was concentrated to obtain 21H (0.31 g, yield: 70%), which was directly used in the next step.

Ms m/z (ESI): 588.3[M+H] ⁺

Step 7: Preparation of 21I

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 under nitrogen protection. Pyridine (0.21 g, 2.65 mmol) was added, and 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 product 21I (0.15 g, yield: 32%).

Ms m/z (ESI): 878.1[M+H] ⁺

Step 8: Preparation of compound 21

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 twice with water (20 mL × 2), and 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 the compound (23 mg, yield: 27.5%).

Ms m/z (ESI): 1178.4[M+H] ⁺

Example 22: Synthesis of Compound 22

Step 1: Synthesis of 22A

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)ferrocene dichloropalladium (II) (138 mg, 0.19 mmol), and 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, and the mixture was 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%).

Step 2: Synthesis of 22B

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

LCMS m/z = 525.3 [M+H] ⁺

Step 3: Synthesis of 22C

Dissolve the hydrochloride of 22B (524 mg, 1.00 mmol) in 15 mL of N,N-dimethylformamide, potassium carbonate (276 mg, 2.00 mmol), and p-fluoronitrobenzene (211 mg, 1.50 mmol), heat to 80°C and stir for 2 hours. Add water to dilute, extract with ethyl acetate (25 mL×3), dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure, and purify the residue by column chromatography to obtain 22C (350 mg, 56.86%).

LCMS m/z = 646.4 [M+H] ⁺

Step 4: Synthesis of 22D

Dissolve 22C (350 mg, 0.54 mmol) in 10 mL of methanol, add 10% Pd/C (350 mg), replace with hydrogen, and stir at room temperature for 2 hours. After filtration, concentrate under reduced pressure to obtain 22D (200 mg, 69.93%).

LCMS m/z = 528.3 [M+H] ⁺

Step 5: Synthesis of Compound 22E

Dissolve 5C-1 (105 mg, 0.318 mmol) in 5 mL of dichloromethane, add pyridine (51 mg, 0.639 mmol) at 0°C, stir for 1 minute, slowly add 22D (121 mg, 0.23 mmol), and stir at room temperature for 2 hours. Add water to dilute, extract with ethyl acetate (25 mL×3), wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure, and purify the residue by column chromatography to obtain 22E (80 mg, 42.64%).

LCMS m/z = 818.2 [M+H] ⁺

Step 6: Synthesis of compound 22

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%).

LCMS m/z = 1118.4 [M+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.23 – 8.11 (m, 1H), 7.94 (dd, 1H), 7.72 – 7.62 (m, 2H), 7.57 (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).

Example 23: Preparation of Compound 23

Step 1: Preparation of compound 23C

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. The reaction was quenched by adding water, extracted with EA (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%).

Ms m/z (ESI): 566.1[M+H] ⁺

Step 2: Preparation of compound 23D

Under nitrogen protection, the 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. 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 reaction.

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

Step 3: Preparation of compound 23E

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 DMF, and then cesium carbonate (0.83 g, 2.56 mmol) was added. The temperature was raised to 80 °C for 12 h, and the reaction was quenched by adding water. The reaction was 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%).

LCMS m/z = 587.2[M+H] ⁺

Step 4: Preparation of compound 23F

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 for reaction for 3 hours, cooled to room temperature, and silica gel was directly added to stir the sample. The product was concentrated under reduced pressure and purified by column chromatography to obtain compound 23F (200 mg, 70.9%).

LCMS m/z = 557.3 [M+H] ⁺

Step 5: Preparation of Compound 23G

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. 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 23G (180 mg, 59.01%).

LCMS m/z =847.3 [M+H] ⁺

Step 6: Preparation of compound 23H

Dissolve 23G (180 mg, 0.21 mmol) in 5 ml DMF, add intermediate B (71 mg, 0.25 mmol), 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%).

LCMS m/z = 1107.2 [M+H] ⁺

Step 7: Preparation of compound 23

Dissolve 23H (100 mg, 0.09 mmol) in 10 mL of methanol and 2 mL of water, add sodium hydroxide (18 mg, 0.45 mmol), and stir at room temperature for 12 hours. Adjust pH to about 4 with dilute hydrochloric acid, dilute with water, extract with ethyl acetate (25 mL×2), wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure, and purify the crude product by silica gel column chromatography and reverse column chromatography (mobile phase A: 0.5% NH ₄ HCO ₃ 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%).

LCMS m/z = 1080.2 [M+H] ⁺

Example 24: Synthesis of Compound 24

22E (60 mg, 0.076 mmol) and intermediate 24A (21 mg, 0.076 mmol) were dissolved in 3 mL DMF, DIPEA (49 mg, 0.38 mmol) was slowly added, and the mixture was 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 phase column chromatography (mobile phase A: 0.5% NH ₄ HCO ₃ 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%).

LCMS m/z (ESI): 540.0[M/2+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.29 (s, 1H), 8.08 – 7.98 (m, 1H), 7.80 – 7.71 (m, 2H), 7.70 – 7.62 (m, 1H), 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).

Example 25: Synthesis of Compound 25

Step 1: Synthesis of 25A

Dissolve deuterated isopropylamine hydrochloride (0.65 g, 10.00 mmol) in 10 mL of methanol, add triethylamine to adjust the pH to about 7, add 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), and react in a pressure bottle at 100°C overnight. The reaction solution was concentrated, and the residue was purified by column chromatography to obtain 25A (0.3 g, yield: 28.36%).

Step 2: Synthesis of 25B

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)Cl ₂ (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, 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 25B (0.30 g, 77.91%).

Step 2: Synthesis of 25C

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

LCMS m/z = 531.7 [M+H] ⁺

Step 3: Synthesis of 25D

Dissolve the hydrochloride of 25C (0.155 g, 0.29 mmol) 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 stir at 50°C for 2 hours. Add water for dilution, extract with ethyl acetate (25 mL×3), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure, and purify the residue by column chromatography to obtain 25D (0.145 g, 76.66%).

Step 4: Synthesis of 25E

25D (145 mg, 0.22 mmol) was dissolved in 10 mL of methanol, 10% Pd/C (50 mg) was added, the atmosphere was replaced with hydrogen, 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%).

LCMS m/z = 534.6 [M+H] ⁺

Step 5: Synthesis of compound 25F

Dissolve 5C-1 (98 mg, 0.30 mmol) in 5 mL of dichloromethane, add pyridine (48 mg, 0.60 mmol) at 0°C, stir for 1 minute, slowly add 25E (108 mg, 0.20 mmol), stir at room temperature for 2 hours. Add water to dilute, extract with ethyl acetate (25 mL×3), wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure, and purify the residue by column chromatography to obtain 25F (70 mg, 42.46%).

LCMS m/z = 818.2 [M+H] ⁺

Step 6: Synthesis of compound 25

25F (38 mg, 0.046 mmol) and intermediate 24A (39 mg, 0.14 mmol) were dissolved in 3 mL 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, and the crude product was purified by silica gel column chromatography and reverse column chromatography (mobile phase A: 0.5% NH ₄ HCO ₃ 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%).

LC-Ms m/z (ESI): 542.8[M/2+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.28 (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 – 4.52 (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).

Example 26: Synthesis of Compound 26

Step 1: Synthesis of 26A

The raw materials N-Boc-piperazine- d ₈ (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, and the mixture was washed with water 3 times (20 mL×3) and once with 30 mL of salt water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed to obtain product 26A (0.78 g, yield: 80.04%).

Step 2: Synthesis of 26B

The raw material 26A (0.57 g, 1.81 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of 4 N dioxane hydrochloride solution was added. The mixture was stirred at room temperature for 2 h, concentrated under reduced pressure, and the residue was dissolved in 30 mL of dichloromethane. 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 product 26 B (0.36 g, yield: 92.39%).

Step 3: Synthesis of 26C

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-dimethylphenylcarbamoylcarbamic 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. The mixture was extracted with ethyl acetate (10 mL×5), and the organic phases were combined, washed, dried over anhydrous magnesium sulfate, and the crude product was purified by silica gel column chromatography to obtain 26C (0.2 g, yield: 26.46%).

Step 4: Synthesis of 26D

Dissolve 26C (0.20 g, 0.30 mmol) in 10 mL methanol, add 50 mg 10% palladium carbon, react at room temperature for 1 h in a hydrogen atmosphere, filter, and directly concentrate the filtrate to obtain 26D (0.112 mg, yield: 69.51%)

LC-Ms m/z (ESI): 537.8[M+H] ⁺

Step 5: Synthesis of 26E

3-(Trifluoromethylsulfonyl)-4-fluorobenzenesulfonyl chloride (78 mg, 0.24 mmol) was dissolved in 20 mL of dichloromethane. Pyridine (79 mg, 1.0 mmol) was added at 0°C under nitrogen atmosphere, followed by 10 mL of dichloromethane solution of 26D (110 mg, 0.20 mmol). 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%).

Step 6: Synthesis of compound 26

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 twice with water (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 phase column chromatography (mobile phase A: 0.5% NH ₄ HCO ₃ 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%).

LC-Ms m/z (ESI): 544.3[M/2+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.33 – 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, 3H), 3.73 – 3.61 (m, 1H), 3.59 – 3.39 (m, 3H), 3.37 – 3.16 (m, 3H), 3.04 (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).

Example 27: Synthesis of Compound 27

Step 1: Synthesis of compound 27B

Dissolve 27A (5 g, 49.43 mmol) in 50 mL THF and 5 mL water, slowly add sodium carbonate (15.72 g, 148.23 mmol), slowly add 9-fluorenylmethyl chloroformate (15.35 g, 59.34 mmol) in an ice bath, warm to room temperature and stir for 2 hours. Add water to dilute, extract with ethyl acetate (25 mL×3), dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure, and purify the residue by column chromatography to obtain 27B (11.2 g, 70.06%).

LCMS m/z = 324.2 [M+H] ⁺

Step 2: Synthesis of compound 27C

Dissolve 27B (5 g, 15.47 mmol) in 15 mL pyridine, slowly add carbon tetrabromide (10.26 g, 30.94 mmol), replace nitrogen three times, stir for 30 minutes, slowly add trimethoxyphosphine (4.03 g, 32.49 mmol) in an ice bath, warm to room temperature and stir for 2 hours. Add water to dilute, extract with ethyl acetate (25 mL×3), dry with anhydrous sodium sulfate, filter and concentrate under reduced pressure, and purify the residue by column chromatography to obtain 27C (4.5 g, 67.43%).

LCMS m/z = 432.2 [M+H] ⁺

Step 3: Synthesis of compound 27D

Dissolve 27C (4.5 g, 1.61 mmol) in 50 mL THF and 5 mL water, add lithium hydroxide (4.5 g, 1.61 mmol), react at room temperature for 12 h, collect the filtrate by filtration, and concentrate under reduced pressure to obtain crude 27D (0.78 g), which was directly used for the next step without further purification.

LCMS m/z = 210.1[M+H] ⁺

Step 4: Synthesis of compound 27E

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 the mixture was stirred for 30 minutes under nitrogen protection. Sodium triacetoxyborohydride (0.72 g, 3.40 mmol) was added, and the mixture was stirred at room temperature overnight. 30 mL of purified water was added, and the mixture 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, which was subjected to column chromatography to obtain 27E (0.61 g, yield: 73.88%).

LCMS m/z =489.3 [M+H] ⁺

Step 5: Synthesis of compound 27F

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. The reaction was carried out at room temperature for 2 h, and the solvent was removed to obtain crude 27F (0.21 g), which was directly used in the next reaction without further purification.

LCMS m/z =361.2 [M+H] ⁺

Step 6: Synthesis of compound 27

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 the mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and acetonitrile was added to precipitate the solid, which was collected by filtration and purified by preparative HPLC to obtain the trifluoroacetic acid salt of compound 27 (80 mg, yield: 22.27%).

HPLC preparation method: Instrument: SHIMADZU LC-20AP; Preparation column: C18; Mobile phase: A is 0.1% TFA aqueous solution; B is acetonitrile;

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

LCMS m/z = 1158.2 [M+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.34 – 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).

Example 28: Preparation of Compound 28

Step 1: Preparation of 28B

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 formed a yellow color, 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, 1 N 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 1 N dilute hydrochloric acid, dried with Na ₂ SO ₄ , filtered, concentrated, and column chromatography was performed to obtain 28B (0.6 g, yield: 83%).

LCMS m/z = 350.2 [M+H] ⁺

Step 2: Preparation of 28C

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 the crude product 28C (89 mg), which was directly used in the next reaction without further purification.

LCMS m/z = 250.2 [M+H] ⁺

Step 3: Preparation of 28D

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 4Å molecular sieve (50 mg) were added respectively, stirred at room temperature for 15 min, and 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.

LCMS m/z = 529.2 [M+H] ⁺

Step 4: Preparation of 28E

Under nitrogen protection, the 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, concentrated, and the residue was dissolved in 10 mL of dichloromethane and concentrated again. After repeating the process twice, the crude product 28E (210 mg) was obtained, which was directly used in the next reaction.

LCMS m/z = 401.2 [M+H] ⁺

Step 5: Preparation of compound 28

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, concentrated under reduced pressure, and purified by preparative HPLC to obtain the trifluoroacetic acid salt of compound 28 (20 mg, yield: 8.5%).

HPLC preparation method:

Instrument: SHIMADZU LC-20AP;

Preparation column: C18;

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

Extraction method: 48% to 68% of B solution A, gradient extraction for 15 minutes;

Flow rate: 25mL/min;

Column temperature: room temperature;

Detection wavelength: 220 nm;

LCMS m/z = 1199.3[M+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.37 – 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).

Example 29: Preparation of Compound 29

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 reaction was carried out at room temperature overnight, and the excess solvent was removed under reduced pressure. The trifluoroacetic acid salt of compound 29 (97 mg, yield: 8.5%) was obtained by preparative HPLC separation and purification.

HPLC preparation method: Instrument: SHIMADZU LC-20AP; Preparation column: C18; Mobile phase: A is 0.1% TFA aqueous solution; B is acetonitrile; Flushing method: 25% to 60% of B in A solution, gradient elution for 15 minutes; Flow rate: 25 mL/min; Column temperature: room temperature; Detection wavelength: 220 nm;

LCMS m/z = 1167.3[M+H] ⁺

¹ H NMR (400 MHz, CF ₃ COOD) δ 8.33 – 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).

According to the synthesis method of the above embodiment, the following compound was prepared: MS m/z (ESI): 1171.3 [M+H] ⁺ MS m/z (ESI): 1156.3 [M+H] ⁺ MS m/z (ESI): 1185.4 [M+H] ⁺ MS m/z (ESI): 1191.3 [M+H] ⁺ MS m/z (ESI): 1196.3 [M+H] ⁺ MS m/z (ESI): 1205.4 [M+H] ⁺ MS m/z (ESI): 1199.4 [M+H] ⁺ MS m/z (ESI): 1204.4 [M+H] ⁺

Biological test examples

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

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

The test compounds were diluted 3-fold in a 384-well plate with DMSO (Sigma, D4540), and the final starting concentration of the test compounds was 10,000 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, and centrifuged at 1000 rpm for 1 min. Transfer 5 μL of 1× MAb-Anti-His-Tb (Cisbio, 61HISTLA) reagent to a 384 reaction plate, centrifuge at 1000 rpm for 1 min, and incubate at 25°C for 60 min. After the reaction, use a BMG enzyme labeler to read the HTRF (Homogeneous Time-Resolved Fluorescence) signal. The signal intensity is used to characterize the activity of the enzyme. Calculate IC ₅₀ using the GraphPad nonlinear fitting formula (Formula 1):

Y = Bottom + (Top-Bottom)/(1+10^((LogIC ₅₀ -X) × HillSlope) Formula (1)

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

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

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

Y = Bottom + (Top-Bottom)/(1+10^((LogIC ₅₀ -X) × HillSlope) Formula (2)

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

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

Table 1 TR-FRET IC ₅₀ of the compounds' affinity for Bcl-xL target Compound No. Bcl-xL Target Affinity TR-FRET IC ₅₀ (nM) Compound No. Bcl-xL Target Affinity TR-FRET IC ₅₀ (nM) Trifluoroacetate of compound 1 A Compound 11 A Trifluoroacetate of compound 3 A Trifluoroacetate of compound 12 A Trifluoroacetate of compound 4 A Trifluoroacetate of compound 13 A Compound 5 A Compound 14 A Trifluoroacetate of compound 7 A Compound 15 A Compound 8 A Compound 17 A Compound 9 A Compound 18 A Compound 10 A Compound 22 A Compound 26 A

Note: A ≤ 20 nM

Table 2 TR-FRET IC ₅₀ of the compounds' affinity for Bcl-xL/Bcl-2 targets Compound No. Bcl-xL Target Affinity TR-FRET IC ₅₀ (nM) Bcl-2 Target Affinity TR-FRET IC ₅₀ (nM) Target selective Bcl-2: Bcl-xL Compound 21 4.5 1393 309.6 Compound 22 5.1 4557 893.5 Compound 24 4.4 1732 393.6 Compound 25 4.2 5071 1207.4 Trifluoroacetate salt of compound 27 3.1 1645 530.6 Trifluoroacetate of compound 28 3.4 1006 296 Control compound 1 3.5 118 39.3 Comparative compound 2 trifluoroacetate 2.6 259 99.6

Conclusion: The compounds of the present invention, such as the compounds of the examples, have a higher 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 trifluoroacetic acid 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 trifluoroacetic acid 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.

Structure of reference compound 1: .

Control compound 2: .

2. Anti-aging test

Experimental methods: 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 ^cm2 dishes. After the cells adhered to the wall, the cells were treated with 200nM mitomycin C (MMC, manufacturer: Absin, Cat. No.: 47029279) for 48h to construct a cell aging 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 in 384-well plates at a density of 5000 cells/well (MMC) and 1000 cells/well (DMSO) for 5 days. The prepared compounds of different concentrations were then added for 48 hours, followed by SA-β-gal staining. The staining steps are as follows:

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

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

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

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

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);

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 hour;

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

Data processing: The cell percentage of SA-β-gal+ 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 solvent control was calculated according to formula (1). GraphPad Prism software was used to draw the dose-effect curve and the _IC50 value was calculated using the four-parameter analysis method.

Cpd% = (SA% drug administration/SA% solvent control)*100%   Formula (1)

Table 3 IC ₅₀ of compounds against SA-β-gal stained WI-38 senescent cells Compound No. IC ₅₀ (nM) for SA-β-gal stained WI-38 senescent cells Compound 22 30 nM Control compound 1 100 nM

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

Senescent Cell Selective Killing Assay Protocol

Experimental methods: 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 ^cm2 dishes. After the cells adhered to the wall, the cells were treated with 200 nM mitomycin C (MMC, manufacturer: Absin, Cat. No.: 47029279) for 48 h 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 in 384-well plates at a density of 5000 cells/well (MMC-treated) and 1000 cells/well (DMSO-treated). The prepared compounds of different concentrations were added for co-culture. Seven days after 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 No.: 18002030) as a surrogate indicator of cell activity to determine the selective killing effect of the compound on senescent cells.

The CTG test steps are as follows:

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

b) Add the reagent to the test plate at a 1:1 ratio and shake to mix. Detect on the Evision instrument.

Data processing: The luminescence readings were calculated using GraphPad Prism 8.0 software according to equations (1) and (2) to calculate the _IC50 value and maximum inhibition rate of the compound in inhibiting cell proliferation. _Tdrug is the signal reading after 7 days of compound culture, and _Tvehicle is the cell signal reading after 7 days of vehicle control culture.

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

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

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

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

3. CYP450 enzyme inhibition test

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 co-cultured 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 samples were treated and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS), the changes in CYP enzyme activity were determined, and the IC ₅₀ values were calculated to evaluate the inhibitory potential of the test substances on each CYP enzyme subtype CYP2C9 and CYP2D6.

Table 4 CYP450 enzyme inhibition test results of compounds Compound No. CYP2C9 IC ₅₀ (µM) CYP2D6 IC ₅₀ (µM) Compound 22 >30 >30 Compound 24 25.2 34.7 Compound 26 14.8 28.3 Control compound 1 4.62 8.04

Conclusion: The compounds of the present invention, such as the compounds of the examples, especially compounds 22, 24, and 26, have weaker inhibition on CYP2C9 and CYP2D6 than the control compound 1, and the risk of drug interaction caused by CYP2C9 and CYP2D6 metabolism is lower. The compounds of the present invention have no significant inhibitory effect on any subtype of CYP enzyme.

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

MOLT-4 cells are human acute lymphoblastic leukemia cell lines. They were purchased from ATCC and cultured in RPMI-1640 + 10% FBS + 1% double-antibody at 37 °C, 5% CO ₂ incubator. Cells were plated in 96-well plates at 5×10 ³ cells/well. After plating, different concentrations of compounds were added and cultured for 72 hours in a 37 °C, 5% CO ₂ incubator. After the culture was completed, cell viability detection reagent (Promega, G7573) was added, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the luminescent signal was detected using a multifunctional enzyme marker (BMG, PHERAstar FSX). The luminescence readings were calculated using GraphPad Prism 8.0 software according to formula (1) and formula (2) to calculate the IC ₅₀ value and maximum inhibition rate of the compound's inhibition of cell proliferation. Where _Tdrug is the cell signal reading after 72 hours of compound culture, and _Tsolvent is the cell signal reading after 72 hours of solvent control culture. Growth % = _Tdrug / _Tsolvent ×100 Formula (1)

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

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

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

NCI-H446 cells (human small cell lung cancer cell line) were purchased from ATCC, cultured in RPMI-1640 + 10% FBS + 1% dual antibody, cultured at 37 °C, 5% CO ₂ incubator. Cells were plated in 96-well plates with a seeding density of 1×10 ³ cells/well. On the second day, different concentrations of compounds were added to the well plates (compound initial concentration 10 μM, 5-fold dilution, 9 concentration gradients), and cultured for 72 h in a 37 °C, 5% CO ₂ incubator. After the incubation, add the cell viability assay reagent (Promega, G7573), mix for 2 minutes, incubate at room temperature for 10 minutes, and use a multifunctional enzyme marker (BMG, PHERAstar FSX) to detect the luminescence signal. The luminescence readings were used to calculate the IC ₅₀ value and the maximum inhibition rate of the compound's inhibition of cell proliferation according to formula (1) and formula (2), respectively. Where _Tdrug is the cell signal reading after 72 hours of compound incubation, and _Tsolvent is the cell signal reading after 72 hours of solvent control incubation. Growth % = ( _Tdrug / _Tsolvent × 100)% Formula (1)

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

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

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

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% CO ₂ incubator. Cells were plated in 96-well plates with a seeding density of 1.2×10 ⁴ cells/well. 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 cultured for 72 hours in a 37 °C, 5% CO ₂ incubator. After the incubation, add the cell viability assay reagent (Promega, G7573), mix for 2 minutes, incubate at room temperature for 10 minutes, and use a multifunctional enzyme marker (BMG, PHERAstar FSX) to detect the luminescence signal. The luminescence readings were used to calculate the IC ₅₀ value and the maximum inhibition rate of the compound's inhibition of cell proliferation according to formula (1) and formula (2), respectively. Where _Tdrug is the cell signal reading after 72 hours of compound incubation, and _Tsolvent is the cell signal reading after 72 hours of solvent control incubation. Growth % = ( _Tdrug / _Tsolvent × 100)% Formula (1)

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

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

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 test compound 27 and its corresponding original drug compound 24 at the same time.

7. Mouse pharmacokinetic test

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

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 drug administration and fed 4 hours after drug administration.

Table 5. Medication Information quantity Medication Information male Test compound Dosage (mg/kg) Dosage concentration (mg/mL) Dosage volume (mL/kg) Collect samples How to give medicine 3-6 Test compound 2 0.4 5 Plasma Venous

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

Before and after drug administration, 0.06 mL of blood was collected from the eye sockets under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm, 4 ^o C for 10 min to collect plasma. The blood sampling 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 ^o 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.

Conclusion: The compounds of the present invention, especially the compounds of the examples, have good exposure in mice via 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.

8. Pharmacokinetics test in rats

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.

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

Table 6. Medication Information Group quantity Medication Information male Test compound Dosage (mg/kg) Dosage concentration (mg/mL) Dosage volume (mL/kg) Collect samples How to give medicine G1 3-6 Test compound 2.5 0.5 5 Plasma Venous

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: physiological saline)

Before and after drug administration, 0.15 ml of blood was collected from the eye sockets under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000rpm, 4 ^o C for 10 minutes to collect plasma. The blood sampling time points for the intravenous group and the gavage group were: 0, 5, 15, 30min, 1, 2, 4, 6, 8, 24 h. Before analysis and detection, all samples were stored at -80 ^o 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.

Conclusion: The compounds of the present invention, especially the compounds of the examples, have good exposure in rats via 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.

9. Beagle dog pharmacokinetic test

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

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

Table 7. Medication Information Group quantity Medication Information male Test compound Dosage (mg/kg) Dosage concentration (mg/mL) Dosage volume (mL/kg) Collect samples How to give medicine G1 3-6 Test compound 1 1 1 Plasma Venous

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: physiological saline)

Before and after drug administration, 1 ml of blood was collected from the cervical vein or limb vein and placed in an EDTAK2 centrifuge tube. Centrifuge at 5000rpm, 4℃ for 10min, and collect plasma. The blood sampling time points for the intravenous group and the gavage group were: 0, 5, 15, 30min, 1, 2, 4, 6, 8, 10, 12, 24, 48, 72 h. Before analysis and detection, all samples were stored at -80℃ 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.

Conclusion: The compounds of the present invention, especially the compounds of the examples, have good exposure in beagle dogs via 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.

10. Monkey pharmacokinetic test

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

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

Table 8. Medication Information Group quantity Medication Information male Test compound Dosage (mg/kg) Dosage concentration (mg/mL) Dosage volume (mL/kg) Collect samples How to give medicine G1 3 Test compound 1 0.5 2 Plasma Venous

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: physiological saline)

Before and after drug administration, 1.0 mL of blood was collected from the limb veins and placed in EDTAK2 centrifuge tubes. Centrifuge at 5000 rpm, 4 ^o C for 10 min, and collect plasma. The blood sampling 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 detection, all samples were stored at -80 ^o 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.

Conclusion: The compounds of the present invention, especially the compounds of the examples, have good exposure in monkeys via 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.

11. Liver microsome stability test

This experiment uses liver microsomes from five species, including humans, dogs, rats, and mice, as in vitro models to evaluate the metabolic stability of the test substances.

At 37°C, 1 µM of the test substance was co-cultured with microsomal proteins and coenzyme NADPH. After a certain period of time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing an internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS/MS. T _1/2 was calculated using the ln value of the drug residue rate in the culture system and the culture time. The hepatic microsomal intrinsic clearance CL _int(mic) and the hepatic intrinsic clearance CL _int(Liver) were further calculated.

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

without

without

without

Claims (12)

A compound or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the compound being selected from the compounds represented by the general formula (I), wherein (I) Ring A, Ring C and Ring D are each independently selected from C _6-10 aryl or 5- to 10-membered heteroaryl, Ring A is optionally substituted by 1 to 4 ^Ra , Ring C is optionally substituted by 1 to 4 ^Rc , and Ring D is optionally substituted by 1 to 4 ^Rd ; B is selected from _-B1- , -N( ^Rn ) _-B1- , and _-B1 -N( ^Rn )-; _B1 is selected from 4- to 12-membered heterocyclic groups, and the heterocyclic groups are optionally substituted by 1 to 10 ^Rb ; X is selected from -N( ^Rx )S(=O) _2- , -S(=O) _2N ( ^Rx )-, , , , , the left side is connected to the ring C; K is selected from a 5-membered heteroaryl group, and the K is substituted by 1 to 3 R ^k1 and 1 R ^k2 ; R ^x is selected from H, C _1-6 alkyl or C _3-6 cycloalkyl; R ⁿ is selected from H, C _1-6 alkyl, -C _1-4 alkylene-C _3-6 cycloalkyl, and the alkyl, alkylene or cycloalkyl is optionally substituted by 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, halogen-substituted C _1-6 alkyl, hydroxyl-substituted C _1-6 alkyl, cyano-substituted C _1-6 alkyl, C _1-6 alkoxy; ^Ra , R ^b , and R ^c are each independently selected from deuterium, halogen, cyano, OH, =O, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C wherein _{the -CH 2 -} , alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted _by 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , _{C 1-6} alkyl, halogen-substituted C _1-6 alkyl, hydroxyl-substituted C _1-6 alkyl, _cyano -substituted C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-10 carbocyclic ring or 4 to 10-membered heterocyclic ring; or any R b and R c are directly linked to form a 4 to _{7 -} membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R a1; or any R ^b and R ^c are directly linked to form ^a 4 to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 R ^a1 ; ^a are directly connected to form a 4- to 7-membered heterocyclic ring, and the heterocyclic ring is optionally substituted by 1 to 4 ^Ra1 ; ^Ra1 is independently substituted by a substituent selected from halogen, OH, cyano, _NH2 , =O, _C1-6 alkyl, _C2-6 alkynyl, _C1-6 alkoxy, _C3-10 carbocyclic group or 4- to 10-membered heterocyclic group, and the alkyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-6 alkyl, halogen-substituted _C1-6 alkyl, hydroxyl-substituted _C1-6 alkyl, cyano-substituted _C1-6 alkyl, _C2-6 alkynyl, _C1-6 alkoxy, _C3-10 carbocyclic group or 4- to 10-membered heterocyclic group; R ^d and R ^k1 are each independently selected from deuterium, halogen, cyano, OH, NO ₂ , COOH, CD ₃ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, -OC _3-6 cycloalkyl, -(CH ₂ ) _q -C _3-10 carbocycle, -(CH ₂ ) _q -4 to 10 membered heterocycle, -S(=O) ₂ R ¹ , -S(=O) ₂ NR ¹ R ² , -C(=O)NR ¹ R ² , C(=O)NR ¹ S(=O) ₂ R ³ , -C(=O)R ¹ , wherein -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, carbocyclic or heterocyclic optionally substituted by 1 to 4 substituents selected from deuterium, CD ₃ , halogen, OH, cyano, NH ₂ , C _1-6 alkyl, halogen-substituted C _1-6 alkyl, hydroxyl-substituted C _1-6 alkyl, cyano-substituted C _1-6 alkyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-10 carbocyclic or 4 to 10 membered heterocyclic; R ¹ , R ² , R ³ are each independently selected from H, C _1-6 alkyl, C _3-10 carbocyclic or 4 to 10 membered heterocyclic, and the alkyl, carbocyclic or heterocyclic is optionally substituted by 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C wherein the substituent is selected from -CH _{(Rz1 )} CH2 _{- SRz2} or -CH( _Rz1 ) _CH2 -Se- ^{Rz2 ;} Rz1 is selected from _{-C1-4alkylene} - _{Z1 -} ^Rz3 ; ^Z1 is selected from 4 to 12-membered heterocyclic groups, wherein _Z1 is optionally substituted by ₁ to 4 ^Rz1a or optionally substituted by ₁ substituent selected from -OP(= ^O )(OH) ₂ or _-CH2OP ( _{=O)(OH)2 ;} ^Rk2 and ^Rz2 are ^each independently selected from C _6-10 membered aryl or 5-10 membered heteroaryl, said R ^k2 is optionally substituted by 1 to 4 R ^k2a , said R ^z2 is optionally substituted by 1 to 4 R ^z2a ; R ^z1a , R ^k2a , R ^z2a are each independently selected from halogen, cyano, OH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, -(CH ₂ ) _q -C _3-10 carbocycle, -(CH ₂ ) _q -4 to 10 membered heterocycle, said -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle is optionally substituted by 1 to 4 members selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, C _1-6 alkyl substituted by halogen, C 1-6 alkyl substituted by hydroxyl, C _1-6 alkyl substituted by cyano R ^z3 is selected from -OH, -CH ₂ OH, -OP(=O)(OH _{) 2} , -CH 2 OP(=O)(OH) 2 _, -OP(=O)(OH)(OC _1-6 alkyl), -CH ₂ OP(=O)(OH)(OC _1-6 alkyl ₎ , -OP(=O)(OC _1-6 alkyl) ₂ , -CH ₂ OP(= _O )(OC _1-6 alkyl) ₂ ; q is each independently selected from 0, 1 _{, 2} , 3 or 4; provided that, 1) when B is selected from When B is substituted by 1 to 8 R ^b ; or 2) when B is selected from unsubstituted , and when Z ₁ is selected from a 4- to 7-membered monocyclic heterocyclic group connected to an alkylene group via a nitrogen atom, Z ₁ is substituted by 1 to 4 R ^z1a ; the compound of the general formula (I) is optionally substituted by 1 to 20 deuteriums. The compound as described in claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein Ring A, Ring C and Ring D are each independently selected from phenyl, benzo _C4-6 carbocyclic group, benzo 5-6 membered heterocyclic group, 5-6 membered heteroaryl group, 9-10 membered heteroaryl group, Ring A is optionally substituted with 1 to 4 ^Ra , Ring C is optionally substituted with 1 to 4 ^Rc , and Ring D is optionally substituted with 1 to 4 ^Rd ; B ₁ is selected from a 4- to 7-membered nitrogen-containing monocyclic heterocyclic group, a 5- to 10-membered nitrogen-containing cycloheterocyclic group, a 5- to 11-membered nitrogen-containing spirocyclic heterocyclic group, and a 5- to 11-membered nitrogen-containing bridged heterocyclic group, wherein B ₁ is optionally substituted by 1 to 8 R ^b ; R ⁿ is selected from H and C _1-4 alkyl; X is selected from -NHS(=O) ₂ -, and the left side is connected to the ring C; ^Ra , R ^b , and R ^c are 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, -(CH ₂ ) _q -C _3-6 carbon ring, -(CH ₂ ) _q -4 to 7-membered heterocyclic ring, wherein the -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring optionally substituted by 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 carbocyclic ring or 4 to 7 membered ^heterocyclic ring; or any R ^b and R ^c are directly connected to form ^a 4 to 7 membered heterocyclic ring, and the ^heterocyclic ring is optionally substituted by 1 to 4 R ^a1 ; R ^a1 is independently selected from halogen, OH, cyano, NH ₂ , =O, C wherein R d and R k1 are each independently selected from deuterium, CD ₃ , halogen, cyano, OH, NO 2 , COOH, C _1-4 alkyl, C _{2-4 alkenyl, C 2-4} alkynyl, C _1-4 alkoxy, C _3-6 carbocyclic group or 4 to 7 membered heterocyclic group; wherein the alkyl, alkynyl, alkoxy, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkyl substituted with halogen, C _1-4 alkyl substituted with hydroxyl, C _1-4 alkyl substituted with cyano, C _{2-4 alkynyl, C 1-4} alkoxy, C _3-6 carbocyclic group or 4 to 7 membered heterocyclic group; and R ^d and R ^k1 are each independently selected from deuterium, CD ₃ , halogen, cyano, OH, NO ₂ , COOH, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C ^-C (=O) _R1 , wherein the -CH2-, _{alkyl ,} alkenyl ^, _{alkynyl ,} ^alkoxy _, ^alkylthio , ^cycloalkyl , carbocycle or ^heterocycle is optionally substituted with _{1 to 4 groups selected from deuterium, CD3, halogen, OH, cyano, NH2, C1-4} ^alkyl _{, C1-4 alkyl substituted with} ^halogen _{, C1-4 alkyl} substituted with hydroxyl, R ¹ , R ² , and R ³ are each independently selected from _{H, C 1-4 alkyl} , C _3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring, and the alkyl, carbocyclic ring or heterocyclic ring is optionally substituted with 1 _to 4 substituents selected from halogen, OH, cyano, NH 2 , C _1-4 alkyl, C _1-4 alkyl substituted with halogen, C 1-4 alkyl substituted with hydroxy, C 1-4 alkyl substituted with cyano, C 2-4 alkynyl, C _1-4 alkoxy, C _3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring; R 1 , R 2 , and R 3 are each independently selected from H, C _1-4 alkyl, C 3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring, and the alkyl, carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, C 1-4 alkyl substituted with halogen, C _1-4 alkyl substituted with hydroxy, C _1-4 alkyl substituted with cyano, C _2-4 alkynyl, C 1-4 alkoxy, C _3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring; ₁ is selected from a 4-7 membered nitrogen-containing heteromonocyclic ring, a 5-10 membered nitrogen-containing cycloheterocyclic ring, a 5-11 membered nitrogen-containing spirocyclic ring, and a 5-11 membered nitrogen-containing bridged ring heterocyclic ring, and the Z ₁ is optionally substituted by 1 to 4 R ^z1a or optionally substituted by 1 substituent selected from -OP(=O)(OH) ₂ or -CH ₂ OP(=O)(OH) ₂ ; R ^k2 and R ^z2 are each independently selected from phenyl, benzo C _4-6 carbocyclic ring, benzo 5-6 membered heterocyclic ring, 5-6 membered heteroaryl, and 9-10 membered heteroaryl, and the R ^k2 is optionally substituted by 1 to 4 R ^k2a , and the R ^z2 is optionally substituted by 1 to 4 R ^z2a ; R ^z1a , R ^k2a , R ^z2a are each independently selected _from halogen, cyano, OH, C _1-4 alkyl, C 2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, -(CH ₂ ) _q -C _3-6 carbocyclic ring, -(CH ₂ ) _q -4 to 7 membered heterocyclic ring, wherein said -CH ₂ -, alkyl, alkenyl, alkynyl, alkoxy, carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-6 alkyl, C _1-4 alkyl substituted with halogen, C _1-4 alkyl substituted with hydroxy, C _1-4 alkyl substituted with cyano, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring; R ^z3 is selected from -OH, -CH ₂ OH, -OP(=O)(OH) ₂ , -CH ₂ OP(=O)(OH) ₂ ; q is independently selected from 0, 1, and 2. The compound as claimed in claim 2 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, _B1 is selected from azidobutyl, azidocyclopentyl, azidocyclohexyl, azidocyclohexenyl, azidocycloheptyl, azidocyclobutylspiropropyl, azidocyclopentylspiropropyl, azidocyclohexylspiropropyl, azidocyclobutylspirobutyl, azidocyclopentylspirobutyl, azidocyclohexylspirobutyl, azidocyclobutylspirocyclopentylspirobutyl, azidocyclohexylspirocyclo ...propyl, azidocyclopentylspirocyclopentylspiropropyl, azidocyclohexylspirocyclobutyl, azidocyclobutylspirocyclopentylspiropropyl, azidocyclopentylspirocyclopentylspirobutyl, azidocyclohexylspirocyclobutyl, azidocyclobutylspirocyclopentylspiropropyl, azidocyclopentylspirocyclopentylspiropropyl, azidocyclopentylspirocyclopentylspirobutyl, azidocyclohexylspirocyclobutyl, azidocyclobutylspirocyclopentylspiropropyl, azidocyclopentylspirocyclopentylspiropropyl, azidocyclopentylspirocyclopentylspiropropyl, azidocyclopentylspirocyclopentylspirobutyl, azidocyclohexylspirocyclobutyl, cyclopentyl, spirocyclopentyl, cyclohexyl, spirocyclopentyl, cyclobutyl, spirocyclohexyl, cyclopentyl, spirocyclohexyl, cyclohexyl, cyclobutyl, spiroazacyclobutyl, cyclopentyl, spiroazacyclobutyl, cyclohexyl, spiroazacyclobutyl, cyclopentyl, spiroazacyclobutyl, cyclohexyl, spiroazacyclobutyl, cyclobutyl, spiroazacyclopentyl, cyclopentyl, cyclobutyl Pentylspiroazacyclopentyl, azacyclohexylspiroazacyclopentyl, azacyclobutylspiroazacyclohexyl, azacyclopentylspiroazacyclohexyl, azacyclohexylspiroazacyclohexyl, piperazinespirocyclopropyl, piperazinespirocyclobutyl, piperazinespirocyclopentyl, piperazinespirocyclohexyl, piperazinespiroazacyclopropyl, piperazinespirocyclobutyl , piperazine spiroazacyclopentyl, piperazine spiroazacyclohexyl, azacyclobutyl and cyclopropyl, azacyclopentyl and cyclopropyl, azacyclohexyl and cyclopropyl, azacyclobutyl and cyclobutyl, azacyclopentyl and cyclobutyl, azacyclohexyl and cyclobutyl, azacyclobutyl and cyclopentyl, azacyclopentyl and cyclopentyl, azacyclohexyl and cyclobutyl azacyclopentyl, azacyclobutyl and azacyclohexyl, azacyclopentyl and azacyclohexyl, azacyclohexyl and azacyclohexyl, azacyclobutyl and azacyclobutyl, azacyclopentyl and azacyclobutyl, azacyclohexyl and azacyclobutyl, azacyclobutyl and azacyclopentyl, azacyclopentyl and azacyclopentyl, azacyclohexyl and azacyclobutyl, azacyclobutyl and azacyclopentyl, azacyclopentyl and azacyclopentyl, azacyclohexyl and azacyclohexyl Azacyclopentyl, Azacyclobutyl and Azacyclohexyl, Azacyclopentyl and Azacyclohexyl, Azacyclohexyl and Azacyclohexyl, Piperazinylcyclopropyl, Piperazinylcyclobutyl, Piperazinylcyclopentyl, Piperazinylcyclohexyl, Piperazinylspirocyclopropyl, Piperazinylcyclobutyl, Piperazinylcyclopentyl, Piperazinylcyclohexyl, Piperazinylspirocyclopropyl, Piperazinylcyclobutyl, Piperazinylcyclopentyl, Piperazinylcyclo hexyl, 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, said B ₁ is optionally substituted by 1 to 8 R ^b ; Z ₁ is selected from the group consisting of azidocyclobutyl, azidocyclopentyl, azidocyclohexyl, azidocyclohexenyl, azidocycloheptyl, azidocyclobutyl spirocyclopropyl, azidocyclopentyl spirocyclopropyl, azidocyclohexyl spirocyclopropyl, azidocyclobutyl spirocyclobutyl, azidocyclopentyl spirocyclobutyl, azidocyclohexyl spirocyclobutyl, azidocyclobutyl spirocyclopentyl, Azacyclopentylspirocyclopentyl, Azacyclohexylspirocyclopentyl, Azacyclobutylspirocyclohexyl, Azacyclopentylspirocyclohexyl, Azacyclohexylspirocyclohexyl, Azacyclobutyl and cyclopropyl, Azacyclopentyl and cyclopropyl, Azacyclohexyl and cyclopropyl, Azacyclobutyl and cyclobutyl, Azacyclopentyl and cyclobutyl, Azacyclohexyl cyclobutyl, cyclopentyl aza-butyl, cyclopentyl aza-pentyl, cyclopentyl aza-hexyl, cyclopentyl aza-butyl, cyclohexyl aza-pentyl, cyclohexyl aza-hexyl, 3-cyclohexanobicyclo[3.2.1]octyl, 8-cyclohexanobicyclo[3.2.1]octyl, 2-cyclohexanobicyclo[3.2.1]octyl cyclo[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-oxabicyclo[3.3.1]nonyl, 7-azabicyclo[3.3.1]nonyl, wherein Z ₁ is optionally substituted with 1 to 4 R ^z1a or is optionally substituted with 1 substituent selected from -OP(=O)(OH) ₂ or -CH ₂ OP(=O)(OH) ₂ ; ^Ra , ^Rb , and ^Rc are 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 with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, or C _3-6 cycloalkyl; ^Ra1 is each independently selected from halogen, OH, cyano, NH _{R 2} , =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 with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxyl-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl; R ^d and R ^k1 are each independently selected from deuterium, CD ₃ , halogen, cyano, OH, NO ₂ , 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, -CH ₂ -C _3-6 cycloalkyl, -S(=O) ₂ NH ₂ , -C(=O)NH ₂ , -S(=O) ₂ C _1-4 alkyl, -S(=O) ₂ -C _3-6 cycloalkyl, -S(=O) ₂ NHC _1-4 alkyl, -C(=O)C _1-4 alkyl, -C(=O)-C _3-6 cycloalkyl, -C(=O)NHC _1-4 alkyl, wherein -CH ₂ -, alkyl, alkynyl, alkoxy, alkylthio, cycloalkyl are optionally substituted with 1 to 4 groups selected from deuterium, CD ₃ , halogen, OH, cyano, NH ₂ , C _1-4 alkyl, C _1-4 alkyl substituted with halogen, C _1-4 alkyl substituted with hydroxyl, C _1-4 alkyl substituted with cyano, C _2-4 alkynyl, C _1-4 alkoxy, C The substituent is substituted by a _3-6 cycloalkyl group. The compound as claimed in claim 3 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein B is selected from -B ₁ -, -N(CH ₃ )-B ₁ -, -B ₁ -N(CH ₃ )-; B ₁ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , said B ₁ is optionally substituted with 1 to 8 R ^b ; 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 by 1 to 4 R ^c , and the ring D is optionally substituted by 1 to 4 R ^d ; or Selected from , , , , , , , , , , , , , the left side is connected to ring A; or Selected from , , , , , , , , , , , , , the left side is connected to the ring C; ^Ra , ^Rb , and ^Rc are each independently selected from deuterium, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propargyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and the methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propargyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl are optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-4 alkyl, _C2-4 alkynyl, _C1-4 alkoxy, and _C3-6 cycloalkyl; R ^a1 is independently selected from F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propargyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propargyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, _NH2 , _C1-4 alkyl, _C2-4 alkynyl, _C1-4 alkoxy, _C3-6 cycloalkyl; ^{Rd is} 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) ₂ NH ₂ , -C(=O)NH ₂ , -S(=O) ₂ -methyl, -S(=O) ₂ -ethyl, -S(=O) ₂ NH-methyl, -S(=O) ₂ NH-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 with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , C _1-4 alkyl, C _{2-4 alkynyl, C 1-4 alkoxy} , C _3-6 cycloalkyl; R ^z1 is selected from -CH ₂ CH ₂ -Z ₁ -R ^z3 ; Z ₁ is selected from , , , , , , , , , , , , said Z ₁ is optionally substituted by 1 to 4 R ^z1a or optionally substituted by 1 substituent selected from -OP(=O)(OH) ₂ or -CH ₂ OP(=O)(OH) ₂ ; R ^z3 is selected from -OH, -CH ₂ OH, -OP(=O)(OH) ₂ , -CH ₂ OP(=O)(OH) ₂ ; K is selected from ; R ^k1a is selected from COOH, S(=O) ₂ NH ₂ , -C(=O)NH ₂ , -S(=O) ₂ -methyl, -S(=O) ₂ -ethyl, -S(=O) ₂ NH-methyl, -S(=O) ₂ NH-ethyl, -C(=O)-methyl, -C(=O)-ethyl, -C(=O)NH-methyl, -C(=O)NH-ethyl, wherein the methyl or ethyl group is optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , CF ₃ , hydroxymethyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl; R ^k1b is selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propargyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propargyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl are optionally substituted with 1 to 4 substituents selected from halogen, OH, cyano, NH ₂ , CF ₃ , hydroxymethyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl; R ^k1c is selected from deuterium, CD ₃ , H, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, CD ₃ , halogen, OH, cyano, NH ₂ , CF ₃ , hydroxymethyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C _3-6 cycloalkyl; R ^k2 , R ^z2 are each independently selected from phenyl, pyridine, , , , , , , , , , , , , , , said R ^k2 is optionally substituted by 1 to 4 R ^k2a , said R ^z2 is optionally substituted by 1 to 4 R ^z2a ; R ^z1a , R ^k2a , R ^z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF ₃ , methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl; said methyl, ethyl, propyl, isopropyl, butyl, t-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl are optionally substituted by 1 to 4 halogens, OH, cyano, NH ₂ , CF ₃ , hydroxymethyl, C _1-4 alkyl, C _2-4 alkynyl, C _1-4 alkoxy, C substituted by a substituent of a _3-6 cycloalkyl group; p1, p2, p3 are each independently 0, 1, 2 or 3. The compound as claimed in claim 4 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein R ^k1a is selected from COOH; R ^k1c is selected from methyl, ethyl, propyl, isopropyl, , , , , -CH ₂ -CF ₃ , -CH ₂ -cyclopropyl, cyclopropyl; R ^k1b is selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, -CH ₂ -cyclopropyl; R ^z1a , R ^k2a , R ^z2a are each independently selected from F, Cl, Br, I, cyano, OH, CF ₃ , methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, , ; Selected from , . The compound as described in 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 compounds represented by general formula (II-a), (II-a); B is selected from -B ₁ -, -N(CH ₃ )-B ₁ -, -B ₁ -N(CH ₃ )-; B ₁ is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , said B ₁ is optionally substituted by 1 to 8 R ^b ; R ^b are each independently selected from deuterium, F; or Selected from ; Z ₁ selected from , , , , , , , , , , , , said Z ₁ is optionally substituted by 1 to 4 F; R ^k1c is selected from methyl, ethyl, propyl, isopropyl, , , , , -CH ₂ -CF ₃ , -CH ₂ -cyclopropyl, cyclopropyl; R ^k2a is selected from F, Cl, methyl, ethyl, cyclopropyl; R ^z3 is selected from -OH, -CH ₂ OH, -OP(=O)(OH) ₂ , -CH ₂ OP(=O)(OH) ₂ . The compound as claimed in 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 compounds represented by general formula (III-a) or (III-b), (III-a), (III-b); R ^k1c is selected from methyl, ethyl, propyl, isopropyl, , , , , -CH ₂ -CF ₃ , -CH ₂ -cyclopropyl, cyclopropyl; Z ₁ is selected from , , , , , , , , , , , said Z ₁ is optionally substituted by 1 to 4 F; R ^k2a is selected from F, Cl, methyl, ethyl, cyclopropyl; R ^z3 is selected from -OH, -OP(=O)(OH) ₂ . A compound as described in claim 1 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from one of the structures shown in Table E-1. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 8 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of the compound as described in any one of claims 1 to 8 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof. Use of a compound as described in any one of claims 1 to 8 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof or the composition as described in claim 9 for preparing a drug for treating a disease associated with the activity or expression of Bcl-2 or Bcl-xL. The use as described in 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 the composition according to claim 9, the therapeutically effective amount being preferably 1-1500 mg, and the disease being preferably a disease related to Bcl-2 or Bcl-xL activity or expression.