CN118647616A - A nitrogen-containing heteroaromatic compound and its composition and pharmaceutical application - Google Patents

Abstract

The present invention relates to a compound described by general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and intermediates thereof, as well as use in BRD9-related diseases such as cancer. B-L-K(I).

Description

A nitrogen-containing heteroaromatic compound and its composition and pharmaceutical application Technical Field

The present invention relates to a compound of general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, as well as intermediates and preparation methods thereof, and uses thereof in BRD9-related diseases such as cancer diseases.

Background Art

Rhabdomyosarcoma is a malignant tumor originating from striated muscle cells or mesenchymal cells that differentiate into striated muscle cells. It is the most common soft tissue sarcoma in children. The incidence of rhabdomyosarcoma is second only to malignant fibrous histiocytoma and liposarcoma, ranking third among soft tissue sarcomas. Synovial sarcoma (SS) is a highly malignant soft tissue sarcoma, accounting for about 7-10% of soft tissue sarcomas. Synovial sarcoma is a malignant tumor of soft tissue originating from joints, synovium and tendon sheath synovium. It is prone to occur in the large joints of the limbs, and can also occur on the sarcolemma and fascia of the forearm, thigh, waist and back. The main clinical symptoms are local swelling, lumps, pain, and limited movement. Surgical treatment is the main treatment.

SWI/SNF complexes are a type of multi-subunit complex that can use the energy of ATP hydrolysis to remodel chromatin. They play an important regulatory role in DNA replication, transcription, repair, and recombination by changing the structure of nucleosomes. SWI/SNF complexes are mainly divided into three categories: BAF (canonical BRGI/BRM associated factor), PBAF (polybromo-associated BAF), and nc-BAF (non-canonical BAF). BRD9 protein is mainly present in ncBAF. All complexes contain ATPase substructures.

SMARCB1 belongs to the SWI/SNF family and is a tumor suppressor protein. Tumors with SMARCB1 inactivation are more malignant. In rhabdoid tumors, >95% of patients have SMARCB1 protein inactivation. SMARCB1 embryonic knockout mice show embryonic lethality (E3.3-5.5 days), somatic homozygous knockout mice show rapid, 100% tumorigenesis, and the tumor types are mainly lymphomas and sarcomas; somatic heterozygous deletion mice show 10-30% tumorigenesis, and the tumor types are mainly nervous system tumors and soft tissue sarcomas.

SMARCB1 mutant cells have an increased dependence on the ncBAF complex containing BRD9. By inhibiting or degrading the BRD9 protein, the activity and skeletal function of BRD9 can be removed, showing a significant effect on SMARCB1 mutant cells.

Currently, research on inhibiting or degrading BRD9 protein is still in the early stages, so it is necessary to develop a compound that can inhibit or degrade BRD9 protein for the treatment of related diseases caused by SMARCB1 mutations.

Summary of the invention

The purpose of the present invention is to provide a compound with novel structure, good efficacy, high bioavailability, greater safety, and the ability to inhibit and degrade BRD9, for the treatment of BRD9-related diseases such as cancer.

The compound of the present invention has good pharmacokinetic properties and bioavailability, oral properties and good safety.

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

B-L-K(I);

In certain embodiments, L is selected from a bond or -C _1-50 alkyl-, wherein 0 to 20 methylene units in the alkyl are optionally further replaced by -Ak-, -Cy-;

In certain embodiments, L is selected from a bond or -C _1-30 alkyl-, wherein 0 to 10 methylene units in the alkyl are optionally further replaced by -Ak-, -Cy-;

In certain embodiments, L is selected from a bond or -C _1-10 alkyl-, wherein 0 to 10 methylene units in the alkyl are optionally further replaced by -Ak-, -Cy-;

In certain embodiments, L is selected from a bond or -C _1-5 alkyl-, wherein 0 to 5 methylene units in the alkyl are optionally further replaced by -Ak-, -Cy-;

In certain embodiments, L is selected from -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2- Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Ak1-Cy2-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3- Ak4-, -Cy1- Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3 -, -Cy1-Cy2 -Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-C y2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak1-Cy2- Ak2-Cy3-Ak3- Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1 -Cy2-Ak2-、- Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1 -Ak1-Cy2-A k2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-C y2-Ak2-Ak3-;

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

In certain embodiments, each -Ak- is each independently selected from the group consisting of -( _CH2 ) _q- , -( _CH2 ) _q -O-, -O-( _CH2 ) _q- , -( _CH2 ) _q -NR ^L -, -NR ^L- ( _CH2 ) _q- , -( _CH2 ) _q -NR ^L C(=O)-, -NR ^L ( _CH2 ) _qC (=O)-, -( _CH2 ) _q -C(=O)NR ^L -, -C(=O)-( _CH2 ) _q- , -C(=O)-( _CH2 ) _q -NR ^L -, -(C≡C) _q- , -CH=CH-, -Si( ^RL ) _2- , -Si(OH)( ^RL )-, -Si(OH) _2- , -P(=O)(OR ^L )-, -P(=O)(R ^L )-, or -Si(OH)2-. )-, -S-, -S(=O)-, -S(=O) ₂ - or a bond, wherein the -CH ₂ - is optionally further substituted by 0 to 2 substituents selected from H, halogen, OH, CN, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, halogen-substituted C _1-6 alkyl, hydroxy-substituted C _1-6 alkyl, cyano-substituted C _1-6 alkyl;

In certain embodiments, Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -( _CH2 ) _q- , -( _CH2 ) _q -O-, -O-( _CH2 ) _q- , -( _CH2 ) _q -NR ^L -, -NR ^L -( _CH2 ) _q- , -( _CH2 )q-NR ^L C(＝O)-, -( _CH2 ) _q -C(＝O)NR ^L -, -C(＝O)-( _CH2 ) _q- , -C(＝O)-( _CH2 ) _q -NR ^L -, -(C≡C) _q- , or a bond, wherein the _-CH2- is optionally further substituted with 0 to 2 (e.g., 0, 1, 2) atoms selected from H, halogen, OH, CN, _NH2 , _C1-4 alkyl, _{C1-4 alkoxy, C1-4} alkyl substituted with halogen, _C1-4 alkyl substituted with hydroxyl, substituted by a C _1-4 alkyl, a cyano-substituted C _1-4 alkyl substituent;

In certain embodiments, Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -O-, _-OCH2- , _{-CH2O- ,} -OCH2CH2- _, -CH2CH2O-, -C≡C-, -C( _CH3 ) _2- , -CH2- _{, -CH2CH2- ,} -CH2CH2CH2- _{, -N} (CH3) _{- ,} -NH- _{, -CH2N} (CH3) _- , -CH2NH- _, -NHCH2- _{, -CH2CH2N} ( _CH3 ) _- , _{-CH2CH2NH- ,} -NHCH2CH2-, -C( _{=O) -} , -C(=O _{) CH2NH- , -CH2C} (=O)NH-, -C(=O)NH-, or -NHC(=O)-;

In certain embodiments, Ak1, Ak2, Ak3, and Ak4 are each independently selected from -CH ₂ -, -CH ₂ CH ₂ -, -O-, -NH-, -N(CH ₃ )-, -NHC=O-, and -C=ONH-;

In certain embodiments, each ^{of RL} is independently selected from H, C _1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl;

In certain embodiments, ^RL are each independently selected from H or _C1-6 alkyl;

In certain embodiments, ^RL are each independently selected from H or _C1-4 alkyl;

In certain embodiments, R ^L are each independently selected from H or methyl;

In certain embodiments, ^RL is selected from H;

In certain embodiments, each -Cy- is independently selected from a bond, a 4-8 membered heteromonocycle, a 4-10 membered heterocyclo, a 5-12 membered heterospirocycle, a 7-10 membered heterobridged ring, a 3-7 membered monocycloalkyl, a 4-10 membered cycloalkyl, a 5-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl, a 5-10 membered heteroaryl, or a 6-10 membered aryl, wherein the aryl, heteroaryl, cycloalkyl, heteromonocycle, heterocyclo, heterospirocycle, or heterobridged ring is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3, or 4) members selected from H, F, Cl, Br, I, OH, COOH, CN, _NH2 , =O, _C1-4 alkyl, C1-4 alkyl substituted with halogen, _C1-4 alkyl substituted with hydroxy, or _C1-4 alkyl substituted with hydroxy. The heteroaryl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring contains 1 to 4 heteroatoms selected from O, S and N. When the heteroatom is selected from S, it is optionally further substituted by 0, ₁ or 2 =0;

In certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond, a 4-7 membered nitrogen-containing heteromonocycle, a 4-10 membered nitrogen-containing heterocyclo, a 5-12 membered nitrogen-containing heterospirocycle, a 7-10 membered nitrogen-containing heterobridged ring, a 3-7 membered monocycloalkyl, a 4-10 membered cycloalkyl, a 5-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl, a 5-10 membered heteroaryl, or a 6-10 membered aryl, wherein the heteromonocycle, heterocyclo, heterobridged ring, heterospirocycle, cycloalkyl, aryl, or heteroaryl is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3, or 4) members selected from H, F, Cl, Br, I, OH, COOH, CN, _NH2 , =O, _C1-4 alkyl, C1-4 alkyl substituted with halogen, _C1-4 alkyl substituted with hydroxyl, or _C1-4 alkyl. The _heterocyclic , heterocyclic, heterobridged, heterospirocyclic or heteroaryl group contains 1 to 4 heteroatoms selected from O, S and N. When the heteroatom is selected from S, it is optionally further substituted by 0, 1 or 2 =0;

In certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azidine, piperidinyl, morpholinyl, piperazinyl, phenyl, cyclopropyl-cyclopropyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spirocyclopropyl , cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazacyclotidinyl, cyclopropylazacyclopentyl, cyclopropylazacyclohexyl, cyclopropylpiperidinyl, cyclobutylazacyclotidinyl, cyclobutylazacyclopentyl, cyclobutylazacyclohexyl, cyclobutylpiperidinyl, cyclopentylazacyclotidinyl, cyclopentylazacyclopentyl, cyclopentylazacyclohexyl, cyclopentylpiperidinyl cyclohexylazetidinyl, cyclohexylazepanyl, cyclohexylazepanyl, cyclohexylpiperidinyl, azetidinazetidinyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, azetidinazepanyl, cyclobutylspiroazetidinyl, cyclobutylspiroazepanyl, cyclobutylspiroazepanyl, cyclopentylspiroazepanyl butyl, cyclopentyl spiroazacyclopentyl, cyclopentyl spiroazacyclohexyl, cyclohexyl spiroazetidinyl, cyclohexyl spiroazacyclopentyl, cyclohexyl spiroazacyclohexyl, azetidinyl spiroazetidinyl, azetidinyl spiroazacyclopentyl, azetidinyl spiroazacyclohexyl, azetidinyl spiroazacyclopentyl, azetidinyl spiroazacyclohexyl, azetidinyl spiroazacyclopentyl, azetidinyl spiroazacyclohexyl, azetidinyl spiroazacyclopentyl, azetidinyl spiroazacyclohexyl, azetidinyl spiroazacyclohexyl, azetidinyl spiroazacyclopentyl, azetidinyl spiroazacyclohexyl, cyclobutyl spiropiperidinyl, cyclopentyl spiropiperidinyl, cyclohexyl spiropiperidinyl, azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, When substituted, it is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, NH ₂ , COOH, CN, ═O, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxy-substituted C _1-4 alkyl or C _1-4 alkoxy;

In certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, CF ₃ , methyl, =0, hydroxymethyl, COOH, CN or NH ₂ ;

In certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, CF ₃ , methyl, =0, hydroxymethyl, COOH, CN or NH ₂ ;

In certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, NH ₂ , COOH, CN, ═O, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxy-substituted C _1-4 alkyl, or C _1-4 alkoxy;

In certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally further substituted with 0 to 4 substituents selected from H, F, OH, CF ₃ , methyl, =0, hydroxymethyl, COOH, CN or NH ₂ ;

In certain embodiments, L is selected from one of the following structural fragments in Table A:

Table AL Structure fragment table

In certain embodiments, B is selected from

In certain embodiments, B is selected from b1 is selected from 0, 1, 2, 3 or 4;

In certain embodiments, B is selected from

In certain embodiments, B is selected from

In certain embodiments, b1, b2 are selected from 0, 1, 2, 3 or 4;

In certain embodiments, B is selected from

In certain embodiments, B is selected from

In certain embodiments, B is selected from one of the structural fragments of Table B:

Table BB Structural fragment table

In certain embodiments, _T1 is selected from N or CR ^b4 , _T2 is selected from N or CR ^b2 , and _T3 is selected from N or CR ^b3 ;

In certain embodiments, _T1 is selected from CR ^b4 , _T2 is selected from CR ^b2 , and _T3 is selected from CR ^b3 ;

In certain embodiments, R ^b1 is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _{2-6 alkynyl, C 1-6 heteroalkyl} , C _3-10 carbocycle, C _6-10 aromatic ring, 5-10 membered heteroaromatic ring or R ¹ , wherein the alkyl, alkenyl, alkynyl, heteroalkyl, carbocycle, heterocycle, aromatic ring or heteroaromatic ring is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _3-6 cycloalkyl or 3 to 7 membered heterocycle, wherein the heteroalkyl, heterocycle or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, N;

In certain embodiments, R ¹ is each independently selected from a 4- to 10-membered heterocycle, -(CH ₂ ) _1-4 -R ^1a , wherein the heterocycle or CH ₂ is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C _1-6 alkyl, C _1-6 alkoxy, halogen-substituted C _1-6 alkyl, cyano-substituted C _1-6 alkyl, C _3-6 cycloalkyl, or a 3- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from O, S, and N;

In certain embodiments, each R ¹ is independently selected from a 4- to 10-membered heterocycle, -(CH ₂ ) _1-2 -R ^1a , wherein the heterocycle or CH ₂ is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _3-6 cycloalkyl, or a 3- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from O, S, and N;

In certain embodiments, R ¹ is each independently selected from azetidinyl, azepentyl, azetidinyl, oxetanyl, oxolanyl, oxetanyl, morpholinyl, -(CH ₂ ) _1-2 -R ^1a , wherein the azetidinyl, azepentyl, azetidinyl, oxetanyl, oxetanyl, oxetanyl or morpholinyl is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl substituted with halogen, C _1-4 alkyl substituted with cyano, C _3-6 cycloalkyl or a 3 to 7 membered heterocycle containing 1 to 3 heteroatoms selected from O, S, and N;

In certain embodiments, R ¹ is each independently selected from azetidinyl, aziridine, azetidinyl, oxetanyl, oxolanyl, oxhexyl, morpholinyl, -CH ₂ -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -azetidinyl, -CH _{2 -oxetanyl, -CH 2} -azetidinyl, -CH ₂ -oxetanyl, -CH ₂ -azetidinyl, -CH ₂ -oxetanyl, wherein the azetidinyl, aziridine, azetidinyl, oxetanyl, oxolanyl, oxhexyl or morpholinyl is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3 or 4) moieties selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C _1-4 alkyl, C 1-4 alkoxy, C 1-4 alkyl substituted with halogen, C _1-4 alkyl substituted with cyano, C _1-4 alkyl substituted _with halogen, C _1-4 alkyl substituted with cyano, C substituted by a _3-6- membered cycloalkyl or a 3- to 7-membered heterocyclic substituent;

In certain embodiments, R ^1a is selected from C _1-6 alkoxy, C _3-10 carbocycle, 4 to 10 membered heterocycle, wherein the alkoxy, carbocycle, heterocycle is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _3-6 cycloalkyl, or 3 to 7 membered heterocycle containing 1 to 3 heteroatoms selected from O, S, N;

In certain embodiments, R ^1a is selected from C _1-4 alkoxy, C _3-10 carbocycle, 4 to 10 membered heterocycle, wherein the alkoxy, carbocycle, heterocycle is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _3-6 cycloalkyl, or 3 to 7 membered heterocycle containing 1 to 3 heteroatoms selected from O, S, N;

In certain embodiments, R ^1a is selected from methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azerol, azepine, oxetanyl, oxolanyl, oxetanyl or morpholinyl, wherein the methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azerol, azepine, oxetanyl, oxolanyl, oxetanyl or morpholinyl is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, methyl, ethyl, propyl, methoxy, ethoxy, CH ₂ F, CF ₃ ;

In certain embodiments, R ^b2 , R ^b3 , and R ^b4 are each independently selected from H, halogen, CN, OH, NH ₂ , SH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _3-10 carbocycle, 4 to 10 membered heterocycle, C _6-10 aromatic ring, or 5 to 10 membered heteroaromatic ring, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, carbocycle, heterocycle, aromatic ring, or heteroaromatic ring is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) selected from H, F, Cl, Br, I, OH, ═O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl substituted with halogen, C _1-4 alkyl substituted with cyano, C 3-10 substituted by a _3-6- membered cycloalkyl or a 3- to 7-membered heterocyclic ring, wherein the heteroalkyl, heterocyclic or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, and N, and when the heteroatom is selected from S, it is optionally further substituted by 0, 1 or 2 =O;

In certain embodiments, R ^b2 , R ^b3 , and R ^b4 are each independently selected from H, halogen, CN, OH, NH ₂ , SH, C _1-4 alkyl, C 2-4 alkenyl, C _2-4 alkynyl, C _1-4 heteroalkyl, C _3-6 carbocycle, _4- to 6-membered heterocycle, benzene ring, or 5- to 6-membered heteroaromatic ring, wherein the alkyl, alkenyl, alkynyl, carbocycle, heterocycle, benzene ring, or heteroaromatic ring is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) substituents selected from H, F, Cl, Br, I, OH, ＝O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _3-6 cycloalkyl, or 3- to 7-membered heterocycle, wherein the heteroalkyl, heterocycle, or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, or N;

In certain embodiments, R ^b2 , R ^b3 , and R ^b4 are each independently selected from H, F, Cl, Br, I, CN, OH, NH ₂ , SH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, propyl, butyl, methoxy, ethoxy, and cyclopropyl are optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl substituted with halogen, C _1-4 alkyl substituted with cyano, C _3-6 cycloalkyl, or a 3- to 7-membered heterocycle;

In certain embodiments, R ^b2 is selected from R ² ;

In certain embodiments, R ^b3 is selected from R ³ ;

In certain embodiments, R ² and R ³ are each independently selected from halogen, CN, OH, halogen-substituted C _1-4 alkyl, C _3-6 cycloalkyl;

In certain embodiments, R ² and R ³ are each independently selected from F, CF ₃ , -CHF ₂ , -CH ₂ F, CN, OH, cyclopropyl;

In certain embodiments, R ^b2 is selected from H, F, CN, OH, methyl, ethyl;

In certain embodiments, R ^b3 is selected from H, F, CN, OH, methyl, ethyl;

In certain embodiments, R ^b4 is selected from H, F, CN, OH, methyl, ethyl;

In certain embodiments, R ^b2 and R ^b3 are directly linked to form Ring B ₁ ;

In certain embodiments, ring B ₁ is selected from C _5-6 carbocycle, benzene ring, 5-6 membered heterocycle, 5-6 membered heteroaromatic ring, B ₂ is selected from C _3-10 carbocycle, 4 to 10 membered heterocycle, C _6-10 aromatic ring, 5 to 10 membered heteroaromatic ring, said ring B ₁ is optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3 or 4) R ^b6 , said B ₂ is optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3 or 4) R ^b5 , said heterocycle or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, N;

In certain embodiments, ring _B1 is selected from a _C5-6 carbocycle, a benzene ring, a 5-6 membered heterocycle, a 5-6 membered heteroaromatic ring, _B2 is selected from a benzene ring or a 5-6 membered heteroaromatic ring, the ring _B1 is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3 or 4) ^Rb6 , the _B2 is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3 or 4) ^Rb5 , the heterocycle or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, N;

In certain embodiments, ring B ₁ is selected from cyclopentene, cyclohexene, cyclohexadiene, benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, oxazole, furan, thiophene, thiazole, azocyclopentene, oxacyclopentene, azocyclohexene, azocyclohexadiene, oxacyclohexene, oxacyclohexadiene,

In certain embodiments, ^Rb5 and ^Rb6 are each independently selected from H, halogen, OH, =O, _NH2 , CN, COOH, _NHC1-6 alkyl, N( _C1-6 alkyl) ₂ , -NHC(=O) _-C1-6 alkyl, -NHC(=O) _-C3-6 carbocycle, -NHC(=O)-3 to 7 membered heterocycle, -C(=O)NH- _C3-6 carbocycle, -C(=O)NH-3 to 7 membered heterocycle, -C(=NH)NH- _C3-6 carbocycle, -C(=NH)NH- ₃ to 7 membered heterocycle, _{-SO2NH2 , -SO2NHC1-6} alkyl, _-SO2N ( _C1-6 alkyl) ₂ , _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 alkoxy, _-OC3-6 cycloalkyl, -O-3 to 7 membered heterocycle, C _3-6 cycloalkyl or 3 to 7 membered heterocycle, wherein the alkyl, alkoxy, cycloalkyl, heterocycle is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, _NH2 , CN, COOH, _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C1-4 alkoxy, halogen-substituted _C1-4 alkyl, _C1-4 alkoxy-substituted _C1-4 alkyl, _C3-6 cycloalkyl or 3 to 7 membered heterocycle, wherein the heteroalkyl, heterocycle or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, N, and when the heteroatom is selected from S, it is optionally further substituted by 0, 1 or 2 =O;

In certain embodiments, ^Rb5 and ^Rb6 are each independently selected from H, halogen, OH, =O, _NH2 , CN, COOH, _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , -NHC(=O) _-C1-4 alkyl, -NHC(=O) _-C3-6 carbocycle, -NHC(=O)-3 to 7 membered heterocycle, -C(=O)NH- _C3-6 carbocycle, -C(=O)NH-3 to 7 membered heterocycle, -C(=NH)NH- _C3-6 carbocycle, -C(=NH)NH- ₃ to 7 membered heterocycle, _-SO2NH2 , _-SO2NHC1-4 alkyl, _-SO2N ( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C1-4 heteroalkyl, _C1-4 alkoxy _{, -OC3-6} cycloalkyl, -O-3 to 7 membered heterocycle, C _3-6 cycloalkyl or 3 to 7 membered heterocycle, wherein the alkyl, alkoxy, cycloalkyl, heterocycle is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, _NH2 , CN, COOH, _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C1-4 alkoxy, halogen-substituted _C1-4 alkyl, _C1-4 alkoxy-substituted _C1-4 alkyl, _C3-6 cycloalkyl or 3 to 7 membered heterocycle, wherein the heteroalkyl, heterocycle or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, N;

In certain embodiments, R ^b5 and R ^b6 are each independently selected from H, F, Cl, I, OH, ═O, NH ₂ , CN, NHCH ₃ , N(CH ₃ ) ₂ , NHCH ₂ CH ₃ , N(CH ₂ CH ₃ ) ₂ , -NHC(═O)CH ₃ , -NHC(═O)CH ₂ CH ₃ , -NHC(═O)-piperidinyl, -C(＝O)NH-piperidinyl, -C(＝NH)NH-piperidinyl, -SO ₂ NH ₂ , methyl, ethyl, propyl, butyl, isopropyl, methoxy, ethoxy, -O-cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxolyl, oxetanyl, morpholinyl, pyrrolyl, pyrazolyl, pyrimidinyl, triazolyl, the piperidinyl, Methyl, ethyl, propyl, butyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azelanyl, azetidinyl, oxolanyl, oxhexyl, morpholinyl, pyrrolyl, pyrazolyl, pyrimidinyl, triazolyl are optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, _NH2 , CN, _NHC1-4alkyl , N( _C1-4alkyl ) ₂ , _C1-4alkyl , _C1-4alkoxy , halogen-substituted _C1-4alkyl , _C1-4alkoxy -substituted _C1-4alkyl ;

In certain embodiments, R ^b5 is selected from H, F, CN, OH, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, CF ₃ , -OCHF ₂ , -OCH ₂ F, -OCF ₃ , -CH ₂ -azetidinyl, -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ ;

In certain embodiments, R ^b6 is selected from H, F, NH ₂ , CN, NHCH ₃ , N(CH ₃ ) ₂ , NHCH ₂ CH ₃ , N(CH ₂ CH ₃ ) ₂ , -NHC(=O)CH ₃ , -NHC(=O)CH ₂ CH ₃ , -NHC(=O)-piperidinyl, -C(＝O)NH-piperidinyl, -C(＝NH)NH-piperidinyl, -SO ₂ NH ₂ , CF ₃ , -OCHF ₂ , -OCH ₂ F, -OCF ₃ , methyl, ethyl, propyl, methoxy, ethoxy, hydroxymethyl, cyclopropyl, azetidinyl, azetidinyl, azetidinyl, morpholinyl,

In certain embodiments, K is selected from

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

In certain embodiments, K is selected from

In certain embodiments, K is selected from

In certain embodiments, K is selected from one of the following structural fragments:

In certain embodiments, K is selected from K1;

In certain embodiments, K1 is selected from

In certain embodiments, K1 is selected from In certain embodiments, K1 is selected from

In certain embodiments, K1 is selected from

In certain embodiments, K1 is selected from

In certain embodiments, K1 is selected from one of the following structural fragments:

In certain embodiments, K1 is selected from

In certain embodiments, R ^k is selected from F, Cl, Br, I, OH, NH ₂ , CN, COOH, C(═O)NH ₂ , C _1-6 alkyl, or C _1-6 alkoxy, wherein the alkyl or alkoxy is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) substituents selected from H, F, Cl, Br, I, OH, ═O, NH ₂ , CN, COOH, C(═O)NH ₂ , C _1-4 alkyl, or C _1-4 alkoxy;

In certain embodiments, R ^k is selected from F, Cl, OH, NH ₂ , CN, methyl, ethyl, methoxy, or ethoxy;

In certain embodiments, E, F, and G are each independently selected from a C _3-8 carbocyclic ring, a benzene ring, a 4-7 membered heterocyclic ring, or a 5-6 membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S, and N;

In certain embodiments, E and G are each independently selected from a benzene ring or a pyridine ring;

In certain embodiments, each F is independently selected from phenyl, pyridonyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl;

In certain embodiments, each Q is independently selected from a bond, -O-, -S-, -CH ₂ -, -NR ^q -;

In certain embodiments, each Q is independently selected from a bond, -O-, -CH ₂ -, -NH-, -NHCH ₃ -;

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

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

In certain embodiments, R ^k1 is each independently selected from H, F, Cl, Br, I, OH, ＝O, NH ₂ , CN, COOH, C(＝O)NH ₂ , C _1-6 alkyl, or C _1-6 alkoxy, wherein the alkyl or alkoxy is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) substituents selected from H, F, Cl, Br, I, OH, ＝O, NH ₂ , CN, COOH, C(＝O)NH ₂ , C _1-4 alkyl, or C _1-4 alkoxy;

In certain embodiments, R ^k1 is each independently selected from H, F, Cl, Br, I, OH, ＝O, NH ₂ , CN, COOH, C(＝O)NH ₂ , C _1-4 alkyl, or C _1-4 alkoxy, wherein the alkyl or alkoxy is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) substituents selected from H, F, Cl, Br, I, OH, ＝O, NH ₂ , CN, COOH, C(＝O)NH ₂ , C _1-4 alkyl, or C _1-4 alkoxy;

In certain embodiments, each R ^k1 is independently selected from H, F, Cl, OH, NH ₂ , CN, methyl, ethyl, methoxy, or ethoxy;

In certain embodiments, R ^k3 is each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C(=O)NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl, or 3-8 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocyclyl is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C(=O)NH ₂ , C _1-4 alkyl, or C _1-4 alkoxy, wherein the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;

or two R ^k3 and the carbon atom or ring skeleton directly connected to the two together form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring, wherein the carbocyclic ring or the heterocyclic ring is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, ＝O, NH ₂ , CN, COOH, C(＝O)NH ₂ , C _1-4 alkyl or C _1-4 alkoxy, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S and N;

In certain embodiments, R ^k3 is each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C(=O)NH ₂ , C _1-4 alkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, or 3-6 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocyclyl is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C(=O)NH ₂ , C _1-4 alkyl, or C _1-4 alkoxy, wherein the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;

In certain embodiments, R ^k3 is each independently selected from H, F, OH, methyl;

In certain embodiments, R ^k4 is each independently selected from H, OH, NH ₂ , CN, C(═O)NH ₂ , C _1-6 alkyl, C _3-8 cycloalkyl, or 3-8 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) substituents selected from H, F, Cl, Br, I, OH, ═O, NH ₂ , CN, COOH, C(═O)NH ₂ , C _1-4 alkyl, or C _1-4 alkoxy, wherein the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;

In certain embodiments, R ^k4 is each independently selected from H, OH, NH ₂ , CN, C(═O)NH ₂ , C _1-4 alkyl, C _3-6 cycloalkyl, or 3-6 membered heterocyclyl, wherein the alkyl, cycloalkyl, or heterocyclyl is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) substituents selected from H, F, Cl, Br, I, OH, ═O, NH ₂ , CN, COOH, C(═O)NH ₂ , C _1-4 alkyl, or C _1-4 alkoxy, wherein the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;

In certain embodiments, R ^k4 is each independently selected from H or methyl;

In certain embodiments, each R ^k5 is independently selected from C(＝O), CH ₂ or

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

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

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

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

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

In certain embodiments, p3 is selected from 1 or 2;

In certain embodiments, the compound represented by general formula (I) is selected from one of the structures represented by (II), (III) or (IV):

B _X1 -L-K1(II)

_Bx2 -L-K2(III)

The definitions of the various groups are the same as in the above embodiment;

The condition is that when B is selected from When R ^b6 is not H, halogen, C _1-6 alkyl, C _1-6 alkoxy, or halogen-substituted C _1-6 alkyl, and K is selected from K1;

The condition is that when B is selected from When K is selected from

The condition is that when B is selected from When K is selected from

The condition is that when B is selected from When K is selected from At least one of R ^b2 and R ^b3 is selected from halogen, CN, OH, substituted C _1-6 alkyl, C _3-10 carbocycle or 4 to 10 membered heterocycle.

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

L is selected from a bond or -C _1-50 hydrocarbon group-, wherein 0 to 20 methylene units in the hydrocarbon group are optionally further replaced by -Ak-, -Cy-;

Each -Ak- is independently selected from -( _CH2 ) _q- , -( _CH2 ) _q -O-, -O-( _CH2 ) _q- , -( _CH2 ) _q -NR ^L -, -NR ^L- ( _CH2 ) _q- , -( _CH2 ) _q -NR ^L C(=O)-, -NR ^L ( _CH2 ) _qC (=O)-, -( _CH2 ) _q -C(=O)NR ^L -, -C(=O)-( _CH2 ) _q- , -C(=O)-( _CH2 ) _q -NR ^L -, -(C≡C) _q- , -CH=CH-, -Si( ^RL ) _2- , -Si(OH)( ^RL )-, -Si(OH) _2- , -P(=O)(OR ^L )-, -P(=O)(R ^L) -, )-, -S-, -S(=O)-, -S(=O) ₂ - or a bond, wherein the -CH ₂ - is optionally further substituted by 0 to 2 (e.g. 0, 1, 2) substituents selected from H, halogen, OH, CN, NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, halogen-substituted C _1-6 alkyl, hydroxy-substituted C _1-6 alkyl, cyano-substituted C _1-6 alkyl;

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

R ^L are each independently selected from H, C _1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl;

Each -Cy- is independently selected from a bond, a 4-8 membered heteromonocycle, a 4-10 membered heterocyclic ring, a 5-12 membered heterospirocycle, a 7-10 membered heterobridged ring, a 3-7 membered monocycloalkyl, a 4-10 membered cyclic ring, a 5-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl, a 5-10 membered heteroaryl, or a 6-10 membered aryl, wherein the aryl, heteroaryl, cycloalkyl, heteromonocycle, heterocyclic ring, heterospirocycle, or heterobridged ring is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3, or 4) members selected from H, F, Cl, Br, I, OH, COOH, CN, _NH2 , =O, _C1-4 alkyl, C1-4 alkyl substituted with halogen, _C1-4 alkyl substituted with hydroxy, or _C1-4 alkyl substituted with hydroxyl. The heteroaryl, heteromonocyclic, heterocyclic, heterospirocyclic or heterobridged ring contains 1 to 4 heteroatoms selected from O, S and N. When the heteroatom is selected from S, it is optionally further substituted by 0, ₁ or 2 =0;

B is selected from

Or B is selected from

_T1 is selected from N or CR ^b4 , _T2 is selected from N or CR ^b2 , and _T3 is selected from N or CR ^b3 ;

R ^b1 is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _3-10 carbocycle, C _6-10 aromatic ring, 5- to 10-membered heteroaromatic ring or R ¹ , wherein the alkyl, alkenyl, alkynyl, heteroalkyl, carbocycle, heterocycle, aromatic ring or heteroaromatic ring is optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, ＝O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _3-6 cycloalkyl or 3 to 7-membered heterocycle, wherein the heteroalkyl, heterocycle or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, N;

R ¹ is independently selected from a 4- to 10-membered heterocycle, -(CH ₂ ) _1-4 -R ^1a , wherein the heterocycle or CH ₂ is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C _1-6 alkyl, C _1-6 alkoxy, halogen-substituted C _1-6 alkyl, cyano-substituted C _1-6 alkyl, C _3-6 cycloalkyl or a 3- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from O, S and N;

R ^1a is selected from C _1-6 alkoxy, C _3-10 carbocycle, 4 to 10 membered heterocycle, wherein the alkoxy, carbocycle, heterocycle is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _3-6 cycloalkyl, or 3 to 7 membered heterocycle containing 1 to 3 heteroatoms selected from O, S, N;

R ^b2 , R ^b3 , and R ^b4 are each independently selected from H, halogen, CN, OH, NH ₂ , SH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _3-10 carbocycle, 4 to 10 membered heterocycle, C _6-10 aromatic ring, 5 to 10 membered heteroaromatic ring, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, carbocycle, heterocycle, aromatic ring, or heteroaromatic ring is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3, or 4) selected from H, F, Cl, Br, I, OH, ═O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl substituted by halogen, C _1-4 alkyl substituted by cyano, C 3-10 substituted by a _3-6- membered cycloalkyl or a 3- to 7-membered heterocyclic ring, wherein the heteroalkyl, heterocyclic or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, and N, and when the heteroatom is selected from S, it is optionally further substituted by 0, 1 or 2 =O;

Alternatively, R ^b2 and R ^b3 are directly linked to form ring B ₁ ;

Ring _B1 is selected from _C5-6 carbocycle, benzene ring, 5-6 membered heterocycle, 5-6 membered heteroaromatic ring, _B2 is selected from _C3-10 carbocycle, 4 to 10 membered heterocycle, _C6-10 aromatic ring, 5 to 10 membered heteroaromatic ring, said ring _B1 is optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3 or 4) ^Rb6 , said _B2 is optionally further substituted by 0 to 4 (e.g. 0, 1, 2, 3 or 4) ^Rb5 , said heterocycle or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S and N;

^Rb5 and ^Rb6 are each independently selected from H, halogen, OH, =O, _NH2 , CN, COOH, _NHC1-6 alkyl, N( _C1-6 alkyl) ₂ , -NHC(=O) _-C1-6 alkyl, -NHC(=O) _-C3-6 carbocycle, -NHC(=O)-3 to 7 membered heterocycle, -C(=O)NH- _C3-6 carbocycle, -C(=O)NH-3 to 7 membered heterocycle, -C(=NH)NH- _C3-6 carbocycle, -C(=NH)NH- ₃ to 7 membered heterocycle, _-SO2NH2 , _-SO2NHC1-6 alkyl, _-SO2N ( _C1-6 alkyl) ₂ , _C1-6 alkyl, _C1-6 heteroalkyl, _C1-6 alkoxy, _-OC3-6 cycloalkyl, -O-3 to 7 membered _heterocycle , C _3-6 cycloalkyl or 3 to 7 membered heterocycle, wherein the alkyl, alkoxy, cycloalkyl, heterocycle is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, _NH2 , CN, COOH, _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C1-4 alkoxy, halogen-substituted _C1-4 alkyl, _C1-4 alkoxy-substituted _C1-4 alkyl, _C3-6 cycloalkyl or 3 to 7 membered heterocycle, wherein the heteroalkyl, heterocycle or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, N, and when the heteroatom is selected from S, it is optionally further substituted by 0, 1 or 2 =O;

K is selected from

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

E, F, and G are each independently selected from a C _3-8 carbocyclic ring, a benzene ring, a 4-7-membered heterocyclic ring, or a 5-6-membered heteroaromatic ring, wherein the heterocyclic ring or heteroaromatic ring contains 1 to 4 heteroatoms selected from O, S, and N;

Q is each independently selected from a bond, -O-, -S-, -CH ₂ -, -NR ^q -;

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

R ^k1 is each independently selected from H, F, Cl, Br, I, OH, ＝O, NH ₂ , CN, COOH, C(＝O)NH ₂ , C _1-6 alkyl or C _1-6 alkoxy, wherein the alkyl or alkoxy is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, ＝O, NH ₂ , CN, COOH, C(＝O)NH ₂ , C _1-4 alkyl or C _1-4 alkoxy;

R ^k3 is each independently selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C(=O)NH ₂ , C _1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C(=O)NH ₂ , C _1-4 alkyl or C _1-4 alkoxy, wherein the heterocyclyl contains 1 to 4 heteroatoms selected from O, S, and N;

or two R ^k3 and the carbon atom or ring skeleton directly connected to the two together form a 3-8 membered carbocyclic ring or a 3-8 membered heterocyclic ring, wherein the carbocyclic ring or the heterocyclic ring is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, ＝O, NH ₂ , CN, COOH, C(＝O)NH ₂ , C _1-4 alkyl or C _1-4 alkoxy, and the heterocyclic ring contains 1 to 4 heteroatoms selected from O, S and N;

R ^k4 is each independently selected from H, OH, NH ₂ , CN, C(═O)NH ₂ , C _1-6 alkyl, C _3-8 cycloalkyl or 3-8 membered heterocyclyl, wherein the alkyl, cycloalkyl or heterocyclyl is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, ═O, NH ₂ , CN, COOH, C(═O)NH ₂ , C _1-4 alkyl or C _1-4 alkoxy, wherein the heterocyclyl contains 1 to 4 heteroatoms selected from O, S and N;

R ^k5 is each independently selected from C(＝O), CH ₂ or

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

b1 is selected from 0, 1, 2, 3 or 4.

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

B is selected from

Or B is selected from

R ¹ is independently selected from a 4- to 10-membered heterocycle, -(CH ₂ ) _1-2 -R ^1a , wherein the heterocycle or CH ₂ is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _3-6 cycloalkyl or a 3- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from O, S and N;

R ^1a is selected from C _1-4 alkoxy, C _3-10 carbocycle, 4 to 10 membered heterocycle, wherein the alkoxy, carbocycle, heterocycle is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _3-6 cycloalkyl, or 3 to 7 membered heterocycle containing 1 to 3 heteroatoms selected from O, S, N;

R ^b2 , R ^b3 , and R ^b4 are each independently selected from H, halogen, CN, OH, NH ₂ , SH, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _3-10 carbocycle, 4 to 10 membered heterocycle, C _6-10 aromatic ring, 5 to 10 membered heteroaromatic ring, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, carbocycle, heterocycle, aromatic ring, or heteroaromatic ring is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3, or 4) selected from H, F, Cl, Br, I, OH, ═O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl substituted by halogen, C _1-4 alkyl substituted by cyano, C 3-10 substituted by a _3-6- membered cycloalkyl or a 3- to 7-membered heterocyclic ring, wherein the heteroalkyl, heterocyclic or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, and N, and when the heteroatom is selected from S, it is optionally further substituted by 0, 1 or 2 =O;

b1, b2 are selected from 0, 1, 2, 3 or 4;

The condition is that when B is selected from When R ^b6 is not H, halogen, C _1-6 alkyl, C _1-6 alkoxy, or halogen-substituted C _1-6 alkyl, and K is selected from K1;

K1 is selected from

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

R ^k is selected from F, Cl, Br, I, OH, NH ₂ , CN, COOH, C(═O)NH ₂ , C _1-6 alkyl or C _1-6 alkoxy, wherein the alkyl or alkoxy is optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, ═O, NH ₂ , CN, COOH, C(═O)NH ₂ , C _1-4 alkyl or C _1-4 alkoxy;

The condition is that when B is selected from When K is selected from

The condition is that when B is selected from When K is selected from

The condition is that when B is selected from When K is selected from and at least one of R ^b2 and R ^b3 is selected from halogen, CN, OH, substituted C _1-6 alkyl, C _3-10 carbocycle or 4 to 10 membered heterocycle;

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

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

L is selected from -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, - Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2- , -Cy1-Ak1-Cy2-Ak2-Ak3-, -Ak1-Cy2-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2- Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy 1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, - Cy1-Cy2-Cy3-Ak3-,-Cy1-Ak1-Cy2-Cy3-Ak3-,- Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, - Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy 4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4- , -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-, -Cy1-Ak 1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3- Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Ak1-Ak2-Ak 3-Ak4-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2- Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak 3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-, - Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;

Ak1, Ak2, Ak3, Ak4 and Ak5 are each independently selected from -( _CH2 ) _q- , -( _CH2 ) _q -O-, -O-( _CH2 ) _q- , -( _CH2 ) _q -NR ^L -, -NR ^L -( _CH2 ) _q- , -( _CH2 )q-NR ^L C(＝O)-, -( _CH2 ) _q -C(＝O)NR ^L -, -C(＝O)-( _CH2 ) _q- , -C(＝O)-( _CH2 ) _q -NR ^L -, -(C≡C) _q- or a bond, wherein the _-CH2- is optionally further substituted with 0 to 2 (e.g. 0, 1, 2) atoms selected from H, halogen, OH, CN, _NH2 , _C1-4 alkyl, C1-4 alkoxy, _C1-4 alkyl substituted with halogen, _C1-4 alkyl substituted with hydroxyl, substituted by a C _1-4 alkyl, a cyano-substituted C _1-4 alkyl substituent;

Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond, a 4-7 membered nitrogen-containing heteromonocycle, a 4-10 membered nitrogen-containing heterocyclo, a 5-12 membered nitrogen-containing heterospirocycle, a 7-10 membered nitrogen-containing heterobridged ring, a 3-7 membered monocycloalkyl, a 4-10 membered cycloalkyl, a 5-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl, a 5-10 membered heteroaryl, or a 6-10 membered aryl, wherein the heteromonocycle, heterocyclo, heterobridged ring, heterospirocycle, cycloalkyl, aryl, or heteroaryl is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3, or 4) members selected from H, F, Cl, Br, I, OH, COOH, CN, _NH2 , =O, _C1-4 alkyl, _C1-4 alkyl substituted with halogen, C1-4 alkyl substituted with hydroxy, or _C1-4 alkyl The _heterocyclic , heterocyclic, heterobridged, heterospirocyclic or heteroaryl group contains 1 to 4 heteroatoms selected from O, S and N. When the heteroatom is selected from S, it is optionally further substituted by 0, 1 or 2 =0;

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

R ^L are each independently selected from H or C _1-6 alkyl;

R ^b2 , R ^b3 , and R ^b4 are each independently selected from H, halogen, CN, OH, NH ₂ , SH, C _1-4 alkyl, C _2-4 alkenyl, C _2-6 alkynyl, C _1-4 heteroalkyl, C _3-8 carbocycle, 4 to 10 membered heterocycle, C _6-10 aromatic ring, or 5 to 10 membered heteroaromatic ring, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, carbocycle, heterocycle, aromatic ring, or heteroaromatic ring is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) selected from H, F, Cl, Br, I, OH, ═O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkyl substituted with halogen, C _1-4 alkyl substituted with cyano, C 3-8 substituted by a _3-6- membered cycloalkyl or a 3- to 7-membered heterocyclic ring, wherein the heteroalkyl, heterocyclic or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, and N, and when the heteroatom is selected from S, it is optionally further substituted by 0, 1 or 2 =O;

^Rb5 and ^Rb6 are each independently selected from H, halogen, OH, =O, _NH2 , CN, COOH, _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , -NHC(=O) _-C1-4 alkyl, -NHC(=O) _-C3-6 carbocycle, -NHC(=O)-3 to 7 membered heterocycle, -C(=O)NH- _C3-6 carbocycle, -C(=O)NH-3 to 7 _membered heterocycle, -C(=NH)NH- _C3-6 carbocycle, -C(=NH)NH- ₃ to 7 membered heterocycle, _-SO2NH2 , _-SO2NHC1-4 alkyl, _-SO2N ( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C1-4 heteroalkyl, _C1-4 alkoxy, _-OC3-6 cycloalkyl, -O-3 to 7 membered heterocycle, C _3-6 cycloalkyl or 3 to 7 membered heterocycle, wherein the alkyl, alkoxy, cycloalkyl, heterocycle is optionally further substituted by 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, _NH2 , CN, COOH, _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C1-4 alkoxy, halogen-substituted _C1-4 alkyl, _C1-4 alkoxy-substituted _C1-4 alkyl, _C3-6 cycloalkyl or 3 to 7 membered heterocycle, wherein the heteroalkyl, heterocycle or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, N;

The remaining radicals are defined the same as in the first or second embodiment of the present invention.

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

Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, aziridine, azidine, piperidinyl, morpholinyl, piperazinyl, phenyl, cyclopropylcyclopropyl, cyclopropylcyclobutyl, cyclopropylcyclopentyl, cyclopropylcyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentylcyclohexyl, cyclohexylcyclohexyl, cyclopropylspirocyclopropyl, cyclopropylspirocyclobutyl, cyclopropylspirocyclopentyl, cyclopropylspirocyclohexyl, cyclobutylspirocyclobutyl cyclohexyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclopropylazetidinyl, cyclopropylazetidinyl, cyclopropylazetidinyl, cyclopropylazetidinyl, cyclopropylazetidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclobutylazetidinyl, cyclopentyl ... yl, cyclopentylpiperidinyl, cyclohexylazetidinyl, cyclohexylazacyclopentyl, cyclohexylazacyclohexyl, cyclohexylpiperidinyl, azetidinylazetidinyl, azetidinylazepentyl, azetidinylazetidinyl, azetidinylpiperidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylpiperidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylazetidinyl, azetidinylpiperidinyl, azetidinylazetidinyl Azetidinyl, Azacyclohexyl and Azacyclopentyl, Azacyclohexyl and Azacyclohexyl, Azacyclohexyl and Piperidinyl, Cyclobutyl Spiroazetidinyl, Cyclobutyl Spiroazetyl, Cyclobutyl Spiroazetyl, Cyclobutyl Spiroazetyl, Cyclopentyl Spiroazetyl, Cyclopentyl Spiroazetyl, Cyclopentyl Spiroazetyl, Cyclohexyl Spiroazetyl, Cyclohexyl Spiroazetyl, Cyclohexyl Spiroazetyl, Azetidinyl Spiroazetyl, Azetidine cyclobutyl spiropiperidinyl, cyclopentyl spiropiperidinyl, cyclohexyl spiropiperidinyl, azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, When substituted, it is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, NH ₂ , COOH, CN, ═O, C _1-4 alkyl, halogen-substituted C _1-4 alkyl, hydroxy-substituted C _1-4 alkyl or C _1-4 alkoxy;

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

R ¹ is each independently selected from azetidinyl, aziridine, azetidinyl, oxadiazine, oxadiazine, oxadiazine, morpholinyl, -(CH ₂ ) _1-2 -R ^1a , wherein the azetidinyl, aziridine, azetidinyl, oxadiazine, oxadiazine, oxadiazine or morpholinyl is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _3-6 cycloalkyl or a 3 to 7 membered heterocycle containing 1 to 3 heteroatoms selected from O, S and N;

R ^1a is selected from methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azerol, azepinyl, oxetanyl, oxolanyl, oxetanyl or morpholinyl, wherein the methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azerol, azepinyl, oxetanyl, oxolanyl, oxetanyl or morpholinyl is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _3-6 cycloalkyl or 3 to 7 membered heterocycle;

R ^b2 , R ^b3 , and R ^b4 are each independently selected from H, F, Cl, Br, I, CN, OH, NH ₂ , SH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, and cyclopropyl, wherein the methyl, ethyl, propyl, butyl, methoxy, ethoxy, and cyclopropyl are optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3, or 4) substituents selected from H, F, Cl, Br, I, OH, ＝O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _3-6 cycloalkyl, or 3- to 7-membered heterocycle;

Ring _B1 is selected from cyclopentene, cyclohexene, cyclohexadiene, benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, oxazole, furan, thiophene, thiazole, azocyclopentene, oxacyclopentene, azocyclohexene, azocyclohexadiene, oxacyclohexene, oxacyclohexadiene,

R ^b5 and R ^b6 are each independently selected from H, F, Cl, I, OH, ═O, NH ₂ , CN, NHCH ₃ , N(CH ₃ ) ₂ , NHCH ₂ CH ₃ , N(CH ₂ CH ₃ ) ₂ , -NHC(═O)CH ₃ , -NHC(═O)CH ₂ CH ₃ , -NHC(═O)-piperidinyl, -C(＝O)NH-piperidinyl, -C(＝NH)NH-piperidinyl, -SO ₂ NH ₂ , methyl, ethyl, propyl, butyl, isopropyl, methoxy, ethoxy, -O-cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxolyl, oxetanyl, morpholinyl, pyrrolyl, pyrazolyl, pyrimidinyl, triazolyl, the piperidinyl, methyl, ethyl, propyl, butyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azelanyl, azetidinyl, oxolanyl, oxhexyl, morpholinyl, pyrrolyl, pyrazolyl, pyrimidinyl, triazolyl are optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, _NH2 , CN, _NHC1-4alkyl , N( _C1-4alkyl ) ₂ , _C1-4alkyl , _C1-4alkoxy , halogen-substituted _C1-4alkyl , _C1-4alkoxy -substituted _C1-4alkyl ;

K is selected from

K1 is selected from

Or K1 is selected from

F is independently selected from phenyl, pyridone, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl;

R ^k is selected from F, Cl, OH, NH ₂ , CN, methyl, ethyl, methoxy or ethoxy;

R ^k1 are each independently selected from H, F, Cl, OH, NH ₂ , CN, methyl, ethyl, methoxy or ethoxy;

R ^k3 are each independently selected from H, F, OH, methyl;

R ^k4 are each independently selected from H or methyl;

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

p3 is selected from 1 or 2;

b1, b2 are selected from 0, 1, 2, 3 or 4;

The remaining radicals are defined the same as in the first, second or third embodiment of the present invention.

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

Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -O-, _{-OCH2- ,} -CH2O- _{, -OCH2CH2-, -CH2CH2O-, -C≡C-} , -C( _CH3 ) _2- , -CH2- _{, -CH2CH2- ,} -CH2CH2CH2-, _-N (CH3) _{-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N ( CH3 ) - , -CH2CH2NH- , -NHCH2CH2- , -C(= O )} -, -C(=O ₎ CH2NH- _, -CH2C(=O)NH- _, -C(=O)NH-, or -NHC(=O)-;

Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, CF ₃ , methyl, =0, hydroxymethyl, COOH, CN or NH ₂ ;

Or Cy1, Cy2, Cy3, Cy4 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, OH, _CF3 , methyl, =0, hydroxymethyl, COOH, CN or _NH2 ;

B is selected from

Or B is selected from R ^1a is selected from methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azerol, azepinyl, oxetanyl, oxolyl, oxetanyl or morpholinyl, wherein the methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azerol, azepinyl, oxetanyl, oxolyl, oxetanyl or morpholinyl is optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, =O, NH ₂ , CN, COOH, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, CF ₃ , -OCHF ₂ , -OCH ₂ F, -OCF ₃ ;

R ² and R ³ are each independently selected from F, CF ₃ , -CHF ₂ , -CH ₂ F, CN, OH, and cyclopropyl;

R ^b2 is selected from H, F, CN, OH, methyl, ethyl;

R ^b3 is selected from H, F, CN, OH, methyl, ethyl;

R ^b4 is selected from H, F, CN, OH, methyl, ethyl;

R ^b5 is selected from H, F, CN, OH, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, CF ₃ , -OCHF ₂ , -OCH ₂ F, -OCF ₃ , -CH ₂ -azetidine, -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ ;

R ^b6 is selected from H, F, NH ₂ , CN, NHCH ₃ , N(CH ₃ ) ₂ , NHCH ₂ CH ₃ , N(CH ₂ CH ₃ ) ₂ , -NHC(=O)CH ₃ , -NHC(=O)CH ₂ CH ₃ , -NHC(=O)-piperidinyl, -C(=O)NH-piperidinyl, -C(=NH)NH-piperidinyl, -SO ₂ NH ₂ , CF ₃ , -OCHF ₂ , -OCH ₂ F, -OCF ₃ , methyl, ethyl, propyl, methoxy, ethoxy, hydroxymethyl, cyclopropyl, azetidinyl, azetidinyl, azetidinyl, morpholinyl,

K is selected from

K1 is selected from

Or K1 is selected from

The remaining radicals are defined the same as in the first, second, third or fourth embodiment of the present invention.

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

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

Cy1, Cy2, Cy3, and Cy4 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, CF ₃ , methyl, =0, hydroxymethyl, COOH, CN or NH ₂ ;

Or Cy1, Cy2, Cy3, Cy4 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, it is optionally further substituted with 0 to 4 (e.g., 0, 1, 2, 3 or 4) substituents selected from H, F, OH, _CF3 , methyl, =0, hydroxymethyl, COOH, CN or _NH2 ;

Ak1, Ak2, Ak3, Ak4 are each independently selected from -CH ₂ -, -CH ₂ CH ₂ -, O, NH, N(CH ₃ ), -NHC(=O)- or -C(=O)NH-;

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

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

L is selected from one of the structural fragments in Table A;

B is selected from one of the structural fragments in Table B;

K1 is selected from one of the following structural fragments:

Or K1 is selected from

K is selected from one of the following structural fragments;

The remaining radicals are defined the same as in the first, second, third, fourth, fifth or sixth embodiment of the present invention.

As an eighth embodiment of the present invention, a compound or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compounds represented by the following general formula (II) and (III),

B _X1 -L-K1(II)

_Bx2 -L-K2(III)

B _x1 is selected from

B _x2 is selected from

K1 is selected from

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

R ^k is selected from F, Cl, Br, I, OH, NH ₂ , CN, COOH, C(═O)NH ₂ , C _1-6 alkyl or C _1-6 alkoxy, wherein the alkyl or alkoxy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, OH, ═O, NH ₂ , CN, COOH, C(═O)NH ₂ , C _1-4 alkyl or C _1-4 alkoxy;

K2 is selected from

^R2 and ^R3 are each independently selected from halogen, CN, OH, _NH2 , SH, halogen-substituted _C1-6 alkyl, _C2-6 alkenyl, _{C2-6 alkynyl, C1-6 heteroalkyl} , _C3-10 carbocyclic ring, 4-10 membered heterocyclic ring, _C6-10 aromatic ring, 5-10 membered heteroaromatic ring, wherein the alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally further substituted by 0 to 4 members selected from H, F, Cl, Br, I, OH, =O, _NH2 , CN, COOH, _C1-4 alkyl, _C1-4 alkoxy, halogen-substituted _C1-4 alkyl, cyano-substituted _C1-4 alkyl, C substituted by a _3-6- membered cycloalkyl or a 3- to 7-membered heterocyclic ring, wherein the heteroalkyl, heterocyclic or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, and N, and when the heteroatom is selected from S, it is optionally further substituted by 0, 1 or 2 =O;

^R6 is selected from _NHC1-6 alkyl, N( _C1-6 alkyl) ₂ , -NHC(=O) _-C1-6 alkyl, -NHC(=O) _-C3-6 carbocycle, -NHC(=O)-3 to 7 membered heterocycle, -C(=O)NH- _C3-6 carbocycle, -C(=O)NH-3 to 7 membered heterocycle, -C(=NH)NH- _C3-6 carbocycle, -C(=NH)NH-3 to 7 membered heterocycle, _-SO2NH2 , _-SO2NHC1-6 alkyl, _-SO2N ( _C1-6 alkyl) ₂ , _-OC3-6 cycloalkyl, -O-3 to 7 membered heterocycle, _C3-6 cycloalkyl or 3 to 7 membered heterocycle, wherein the alkyl, cycloalkyl or heterocycle is optionally further substituted by 0 to 4 members selected _from H, F, Cl, Br _, I, OH, =O, _NH2 , CN, COOH, NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy-substituted C _1-4 alkyl, C _3-6 cycloalkyl or a 3 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S and N, and when the heteroatom is selected from S, it is optionally substituted with 0, 1 or 2 =0;

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

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

R ² and R ³ are each independently selected from F, Cl, Br, I, CN, OH, NH ₂ , SH, halogen-substituted C _1-4 alkyl, C _3-6 cycloalkyl, 4 to 7 membered heterocycle, wherein the alkyl, cycloalkyl, heterocycle is optionally further substituted by 0 to 4 substituents selected from H, F, Cl, Br, I, OH, ＝O, NH ₂ , CN, COOH, C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, cyano-substituted C _1-4 alkyl, C _3-6 cycloalkyl, or 3 to 7 membered heterocycle, wherein the heterocycle contains 1 to 3 heteroatoms selected from O, S, and N, and when the heteroatom is selected from S, it is optionally further substituted by 0, 1 or 2 ＝O;

^R6 is selected from _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , -NHC(=O) _-C1-4 alkyl, -NHC(=O) _-C3-6 carbocycle, -NHC(=O)-3 to 7 membered heterocycle, -C(=O)NH- _C3-6 carbocycle, -C(=O)NH-3 to 7 membered heterocycle, -C(=NH)NH- _C3-6 carbocycle, -C(=NH)NH-3 to 7 membered heterocycle, _-SO2NH2 , _-SO2NHC1-6 alkyl, _-SO2N ( _C1-6 alkyl) ₂ , _-OC3-6 cycloalkyl, -O-3 to 7 membered heterocycle, _C3-6 cycloalkyl or 3 to 7 membered heterocycle, wherein the alkyl, cycloalkyl or heterocycle is optionally further substituted by 0 to 4 members selected _from H, F, Cl, Br _, I, OH, =O, _NH2 , CN, COOH, NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy-substituted C _1-4 alkyl, C _3-6 cycloalkyl or a 3 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S and N, and when the heteroatom is selected from S, it is optionally further substituted by 0, 1 or 2 =0;

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

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

^R6 is selected from _NHCH3 , N( _CH3 ) ₂ , _{NHCH2CH3 ,} N( _{CH2CH3 ) 2} , -NHC(=O) _CH3 , -NHC(=O) _{CH2CH3 ,} -NHC(=O)-piperidinyl, -C(＝O)NH-piperidinyl, -C(＝NH)NH-piperidinyl, -SO ₂ NH ₂ , -O-cyclopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxolyl, oxetanyl, morpholinyl, pyrrolyl, pyrazolyl, pyrimidinyl, triazolyl, the piperidinyl, Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, aziridine, azetidinyl, oxetanyl, oxolanyl, oxetanyl, morpholinyl, pyrrolyl, pyrazolyl, pyrimidinyl, triazolyl are optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) substituents selected from H, F, Cl, Br, I, OH, ═O, NH ₂ , CN, NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _1-4 alkoxy, halogen-substituted C _1-4 alkyl, C _1-4 alkoxy-substituted C _1-4 alkyl;

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

As an eleventh embodiment of the present invention, a compound or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compound represented by the following general formula (IV),

B is selected from

The remaining radicals are defined the same as in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth or tenth embodiment of the present invention.

The present invention relates to the following compound or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table C below:

Table C

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

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

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

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

"Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition being treated (e.g., inhibiting or degrading BRD9-related diseases such as cancer) to some extent. In some embodiments, the result is a reduction and/or alleviation of the signs, symptoms or causes of the disease, or any other desired changes in the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg, 4-500 mg, 5-500 mg, 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, 150-500 mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300 mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300m g, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg , 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1500mg, 80-1000mg, 80-800mg.

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

A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a disease related to the inhibition or degradation of BRD9 (such as cancer).

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

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

The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a drug for treating a disease related to BRD9 activity or expression.

The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of drugs for treating and inhibiting or degrading BRD9-related diseases.

The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the disease is selected from cancer.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

"Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The N and S selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, the heterocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the heterocyclic group can be connected to a bridged ring or a spiro ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl 1.1.1]dodecyl, 1. ... "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

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

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

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

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

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

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

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

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

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

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

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

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

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

“Substituted C _1-6 alkyl” refers to an alkyl group in which hydrogen is replaced by one or more (including but not limited to 2, 3, 4 or 5) substituents, and the substituents include but are not limited to F, Cl, Br, I, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic group, bridged ring group, spirocyclic group, cyclocyclic group, 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 ^Ra , -(CH ₂ ) _m -alkenyl-R ^a , OR ^d or -(CH ₂ ) _m -alkynyl-R ^a (wherein m and n are 0, 1 or 2) or -NR ^b R ^c and the like, wherein R ^b and R ^{R and} R are independently selected from H, hydroxyl, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and R and ^R can form a five- or six-membered cycloalkyl or heterocyclyl. ^R and ^R are independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or cyclized ring.

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

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

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

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

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

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

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

"Excipient" refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.

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

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

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

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

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

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

Synthesis method:

The compound of the general formula (Z-1) and the compound of the general formula (Z-2) are subjected to coupling reaction to obtain the compound of the general formula (Z-3);

The compound of the general formula (Z-3) and the compound of the general formula (Z-4) are subjected to a reductive amination reaction to obtain the compound of the general formula (Z-5);

^RX and ^RY are each independently selected from boric acid, boron ester, alkyl-substituted tin, alkyl-substituted zinc, chlorine, bromine, iodine, OTf, etc.;

^RZ is selected from H.

DETAILED DESCRIPTION

The technical solution of the present invention is described in detail below in conjunction with embodiments, but the protection scope of the present invention includes but is not limited to this.

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

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

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

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF ₂₅₄ or Qingdao GF ₂₅₄ silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

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

Chemical experiments were carried out at room temperature unless otherwise specified.

Wavy lines in structural formula It means that the configuration is a single configuration of R or S.

DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; DCE: 1,2-dichloroethane; DMA: N,N-dimethylacetamide; THF: tetrahydrofuran.

RuPhos: CAS#787618-22-8; RuPhos Pd G3: CAS#1445085-77-7.

Preparation of intermediate A-6:

Step 1: Synthesis of A-2

Dissolve tert-butyl piperazine-1-carboxylate (82 g, 0.44 mol) in 500 mL DMF, add cesium carbonate (215 g, 0.66 mol), stir at room temperature for 20 min, add A-1 (70 g, 0.44 mol), and react at 50°C overnight under nitrogen protection. Add 1.5 L of ice water to quench the reaction, filter, wash the filter cake twice with 500 mL of water, and dry to obtain A-2 (135 g, yield: 95%).

LCMS m/z = 326.1 [M+H] ⁺ .

Step 2: Synthesis of A-3

Under nitrogen protection, A-2 (83.0 g, 0.255 mol) was dissolved in 400 mL of acetonitrile, stirred in an ice bath for 20 minutes, 200 mL of hydrochloric acid/1,4-dioxane solution was added, reacted at room temperature for 1 hour, and concentrated under reduced pressure to obtain the hydrochloride of A-3 (72 g crude product).

LCMS m/z = 226.1 [M+H] ⁺ .

Steps 3 and 4: Synthesis of A-5

The hydrochloride of A-3 (72 g crude product) was added to 800 mL toluene, and sodium acetate (52 g, 0.64 mol) and acetic acid (60 mL) were added in sequence under nitrogen protection, and stirred at room temperature for 20 min. 3,3-difluoro-4-oxopiperidine-1-carboxylic acid tert-butyl ester (66 g, 0.28 mol) was added, and the mixture was reacted at 100°C for 6 h, cooled to room temperature, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain A-4.

Under nitrogen protection, A-4 was dissolved in 200 mL of ultra-dry methanol and 200 mL of ultra-dry DCE, sodium cyanoborohydride (41.4 g, 1.275 mol) was added, and the mixture was reacted at room temperature overnight. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography to obtain A-5 (65 g, Three-step yield: 57%).

LCMS m/z = 445.2 [M+H] ⁺ .

Step 5: Synthesis of A-6

A-5 (55 g, 0.124 mol) was dissolved in 1000 mL of ethyl acetate, 10% Pd/C (5.5 g) was added, and the gas was replaced with hydrogen three times and then reacted at room temperature overnight. Filtered through celite, the filtrate was concentrated to obtain A-6 (50.5 g, yield: 97.7%).

LCMS m/z = 415.2 [M+H] ⁺ .

After SFC preparation, separation and purification of A-6, isomer A-6-P1 (23.15 g, SFC preparation retention time is 0.946 min; chiral HPLC retention time is 20.460 min; [α] ²⁰ _D ＝+31.1 ^° ) and isomer A-6-P2 (19.94 g, SFC preparation retention time is 1.883 min, chiral HPLC retention time is 17.221 min; [α] ²⁰ _D ＝-27.1 ^° ) were obtained (A-6-P1 and A-6-P2 are one of the structures of compounds A-6-a and A-6-b, and A-6-P1 and A-6-P2 are corresponding isomers of each other).

SFC chiral preparation method:

Instrument: Waters 150 SFC; Preparative column model: Chiralpak IC-3 Column (250×30 mm, I.D 50 mm, 10 um particle size);

Mobile phase: A is CO ₂ ; B is isopropanol and acetonitrile solution containing 0.1% ammonia water;

Elution conditions: 35% B isocratic elution; flow rate: 200 mL/min; column pressure: 100 bar; column temperature: 25°C; detection wavelength: 220 nm; post-treatment: after preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain A-6-P1 and A-6-P2.

Chiral analysis HPLC conditions:

Instrument: Shimadzu LC-20A; Chiral column: CHIRALCEL OD-H, 4.6×250mm, 5μm;

Mobile phase: n-hexane (containing 0.1% diethylamine)-isopropanol (70:30);

Flow rate: 1 mL/min; column temperature: 35°C; detection wavelength: 210 nm; injection volume: 10 μL; running time: 30 min.

Optical rotation measurement method: instrument model: Anton Paar MCP 4100; measuring tube length: 1dm; detection solvent: methanol; sample amount: A-6-P1: 100.66mg; A-6-P2: 104.50mg; sample concentration: A-6-P1: 3.8024mg/ml; A-6-P2: 3.8024mg/ml.

Preparation of intermediates A-7-P1 and A-7-P2:

A-6-P2 (2.62 g, 6.33 mmol) and 3-bromopiperidine-2,6-dione (3.65 g, 19 mmol) were placed in a sealed tube, 20 mL of DMF and sodium bicarbonate (3.19 g, 37.98 mmol) were added, and the mixture was reacted overnight at 90°C. 100 mL of ethyl acetate was added, and the organic phase was washed three times with 50 mL of water and once with 50 mL of saturated brine. The organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain A-7 (2.5 g, yield: 75%).

LCMS m/z = 526.2 [M+H] ⁺ .

A-7 was separated and purified by SFC preparation to obtain isomer A-7-P1 (1.02 g, SFC preparation retention time was 2.256 min; chiral HPLC retention time was 36.312 min) and isomer A-7-P2 (0.92 g, SFC preparation retention time was 2.476 min, chiral HPLC retention time was 62.314 min).

A-7-P1： ¹ H NMR (400MHz, CD ₃ OD) δ6.89(t,1H),6.56–6.42(m,2H),4.30–4.08(m,3H),3.15–2.62(m,13H ),2.37–2.23(m,1H),2.01–1.77(m,3H),1.46(s,9H).

SFC chiral preparation method:

Instrument: Waters 150SFC; Preparative column model: Chiralcel AD Column (250×30 mm, I.D 30 mm, 10 um particle size);

Mobile phase: A is CO ₂ ; B is isopropanol; elution conditions: 30% B isocratic elution; flow rate: 100 mL/min; column pressure: 100 bar; column temperature: 25° C.; detection wavelength: 220 nm;

Post-treatment: After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compounds A-7-P1 and A-7-P2.

Chiral HPLC analysis method:

Instrument: Shimadzu LC-20A; Chiral column: CHIRAL PAKAD-H, 4.6×250mm, 5μm;

Mobile phase: n-hexane (containing 0.1% diethylamine)-anhydrous ethanol (50:50); flow rate: 0.7 mL/min; column temperature: 35°C; detection wavelength: 210 nm; injection volume: 50 μL; running time: 90 min.

Preparation of intermediate B-1:

A-6-P1 (3.00 g, 7.25 mmol) and 3-bromopiperidine-2,6-dione (4.18 g, 21.8 mmol) were placed in a sealed tube, 20 mL of DMF and sodium bicarbonate (3.65 g, 43.49 mmol) were added, and the mixture was reacted overnight at 90°C. 100 mL of ethyl acetate was added for dilution, the organic phase was washed three times with 50 mL of water, and once with 50 mL of saturated brine, the organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain B-1 (2.7 g, yield: 71%).

LCMS m/z = 526.2 [M+H] ⁺ .

Preparation of intermediate C-6

Step 1: Synthesis of C-2

C-1 (20 g, 64.95 mmol) was added to 250 mL of ultra-dry dimethyl sulfoxide, ethyl 2-bromo-2,2-difluoroacetate (10 mL, 77.94 mmol) and copper powder (16.51 g, 259.8 mmol), and stirred at 60 ° C for 18 h under nitrogen protection. Cooled to room temperature, saturated ammonium chloride solution was added dropwise to quench the reaction, extracted three times with 300 mL of ethyl acetate, the organic phases were combined, and washed three times with 100 mL of saturated brine. After the organic phase was dried, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain C-2 (7.77 g, 39.34%).

Step 2: Synthesis of C-3

C-2 (7.77 g, 25.55 mmol) was added to 100 mL of methanol, and anhydrous cobalt chloride (19.9 g, 153.3 mmol) was added in an ice bath, and stirred for 5 min under nitrogen protection, and sodium borohydride (5.80 g, 153.3 mmol) was slowly added in batches, and stirred at 0°C for 3 h. Saturated ammonium chloride solution was added dropwise to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was extracted three times with 100 mL of ethyl acetate, and the organic phases were combined and washed once with 100 mL of saturated brine. After the organic phase was dried, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain C-3 (3.2 g, 48%).

Step 3: Synthesis of C-4

C-3 (246 mg, 0.94 mmol) was placed in a sealed tube and dissolved in 10 mL of ultra-dry THF. Under nitrogen protection, a THF solution of borane dimethyl sulfide (2.5 mL, 4.7 mmol, 2 mol/L) was added dropwise. The mixture was stirred in an ice bath for 30 min and reacted at 70°C overnight. The mixture was cooled to room temperature, 2N HCl was added dropwise to adjust the pH value of the system to about 1-2, and the reaction was carried out at 70°C for 2 h. The mixture was cooled to room temperature, the pH was adjusted to alkaline with saturated sodium bicarbonate, the aqueous phase was extracted three times with 80 mL of ethyl acetate, the organic phases were combined, and the mixture was washed once with 100 mL of saturated brine. The organic phase was dried, filtered, and concentrated under reduced pressure to obtain C-4 (310 mg crude product).

LCMS m/z = 248.1 [M+H] ⁺ .

Step 4: Synthesis of C-5

Under nitrogen protection, C-4 (310 mg crude product) was dissolved in 15 mL ultra-dry THF, and di-tert-butyl dicarbonate (0.22 mL, 0.94 mmol) and DIPEA (0.32 mL, 1.88 mmol) were added in sequence, and the mixture was kept at room temperature overnight. 20 mL of water was added to quench the reaction, and the mixture was extracted three times with 50 mL of ethyl acetate. The organic phases were combined and washed once with 100 mL of saturated brine. The organic phases were dried and concentrated under reduced pressure, and compound C-5 (238 mg, two-step yield: 73%) was obtained by column chromatography.

¹ H NMR (400MHz, CDCl ₃ ) δ7.82(s,1H),7.54(d,1H),7.08(d,1H),4.61(s,2H),4.00(t,2H),1.49(s, 9H).

Step 5: Synthesis of C-6

Under nitrogen protection, C-5 (238 mg, 0.684 mmol), bipyralidin (261 g, 1.03 mmol), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (50 mg, 0.1 mmol) and potassium acetate (201 g, 2.05 mmol) were placed in a sealed tube, 15 mL of ultra-dry 1,4-dioxane was added, and the mixture was reacted at 100°C for 3 h. The mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain C-6 (270 mg, yield: 99%).

LCMS m/z = 396.2 [M+H] ⁺ .

Example 1: Preparation of Compound 1

Step 1: Synthesis of 1b

1a (1.0 g, 4.95 mmol) was dissolved in 30 mL of ultra-dry DMF, and ice-bathed for 10 min under nitrogen protection. Sodium hydride (238 mg, 60%, 5.94 mmol) was added. After ice-bathed for 15 min, (bromomethyl)cyclopropane (0.72 mL, 7.41 mmol) in 5 mL of ultra-dry THF was slowly added dropwise, and reacted at room temperature for 5 h. The reaction solution was poured into 30 mL of ice water to quench the reaction, and 100 mL of ethyl acetate was added. The organic phase was separated, and the organic phase was washed twice with 50 mL of water and once with 30 mL of saturated brine. The organic phase was dried and concentrated under reduced pressure. The residue was subjected to column chromatography (PE: EA = 2:1) to obtain the product 1b (0.73 g, yield: 57%).

LCMS m/z = 256.1 [M+H] ⁺ .

Step 2: Synthesis of 1c

Under nitrogen protection, 1b (730 mg, 2.85 mmol), (4-formyl-3,5-dimethoxyphenyl)boronic acid (598 mg, 2.85 mmol), Pd(dppf)Cl _2. DCM (233 mg, 0.29 mmol) and cesium carbonate (1.86 g, 5.71 mmol) were placed in a sealed tube, 20 mL of 1,4-dioxane and 2.0 mL of water were added, and the mixture was reacted at 100°C for 3 h. The reaction was cooled to room temperature, diluted with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 1c (820 mg, yield 84%).

LCMS m/z = 342.2 [M+H] ⁺ .

Step 3: Synthesis of Compound 1

1d (0.23 g, 0.54 mmol) was dissolved in 5 mL of ultra-dry methanol and 5 mL of ultra-dry DCE, and sodium acetate (0.145 g, 1.72 mmol), acetic acid (34 uL, 0.59 mmol) and dried powder were added in sequence under nitrogen protection. Molecular sieves (0.24 g), stirred at room temperature for 15 min. 1c (0.2 g, 0.59 mmol) was added, reacted at 70°C for 2 h, cooled to room temperature, sodium cyanoborohydride (0.185 g, 2.92 mmol) was added, and the mixture was allowed to react at room temperature overnight. The molecular sieves were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 1 (60 mg, yield: 13.5%).

LCMS m/z = 751.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ7.46(s,1H),6.93–6.84(m,1H),6.56(s,2H),6.55–6.43(m,2H),4.22(dd,1H) ,3.89(d,2H),3.86–3.79(m,8H),3.17–3.04(m,2H),3.00–2.89(m,8H),2.84–2.62(m,3H),2.42–2.20(m, 3H),2.18(s,3H),2.15(s,3H),2.02–1.79(m,3H),1.38–1.26(m,1H),0.60–0.52(m,2H),0.46–0.39(m, 2H).

Example 2: Preparation of Compound 2

The reaction conditions and operations were similar to those of the synthesis of compound 1, to obtain compound 2 (15 mg).

LCMS m/z = 755.4 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ7.40(s,1H),6.91(t,1H),6.58(s,2H),6.57–6.47(m,2H),4.28–4.19(m,3H) ,3.91–3.80(m,8H),3.75–3.69(m,2H),3.35(s,3H),3.18–3.07(m,2H),3.00–2.96(m,8H),2.88–2.65(m, 3H),2.44–2.23(m,3H),2.19(m,3H),2.18(m,3H),2.03–1.81(m,3H).

Example 3: Preparation of Compound 3

Referring to the third step reaction of compound 1, compound 3 (25 mg) was obtained by reacting 3a+1d.

LCMS m/z = 789.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.08(s,1H),7.42(s,1H),6.89(t,1H),6.74(s,2H),6.56–6.43(m,2H),6.21 (s,1H),4.22(dd,1H),4.11–4.02(m,4H),3.90–3.80(m,8H),3.57(s,3H),3.17–3.06(m,2H),2.99–2.88 (m,8H),2.85–2.64(m,3H),2.47–2.23(m,5H),1.98–1.81(m,3H).

Example 4: Preparation of Compound 4

Step 1: Synthesis of 4B

Under nitrogen protection, 4A (40.0 mg, 0.18 mmol), (4-formyl-3,5-dimethoxyphenyl)boronic acid (41.58 mg, 0.2 mmol), Pd(dppf)Cl ₂ (13.17 mg, 0.018 mmol) and cesium carbonate (117.3 mg, 0.36 mmol) were placed in a 10 mL sealed tube, 1,4-dioxane (1 mL) was added, and the mixture was stirred at 100°C for 2 h. After cooling to room temperature, the solvent was removed under reduced pressure, 100 mL of water was added, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 4B (50.0 mg, yield: 91.0%).

LCMS m/z = 306.1 [M+H] ⁺ .

Step 2: Synthesis of compound 4

4B (50.0 mg, 0.16 mmol) was added to 1 mL of ultra-dry DMA, and 1d (74.88 mg, 0.18 mmol), AcOH (1.92 mg, 0.032 mmol) and Molecular sieve 5 mg, react at 30 ° C for 1 h, cool to room temperature, add sodium triacetoxyborohydride (101.73 mg, 0.48 mmol), react at room temperature for 5 h, add ethyl acetate 200 mL and 100 mL saturated NaHCO ₃ aqueous solution for extraction and separation, the aqueous phase is extracted with ethyl acetate (100 mL × 1), the ethyl acetate layers are combined, and the ethyl acetate layers are washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is separated and purified by preparative TLC to obtain compound 4 (60.0 mg, yield: 52.47%).

¹ H NMR (400MHz, CD ₃ OD) δ7.45(s,1H),6.94–6.87(m,1H),6.63(s,2H),6.58–6.48(m,2H),4.24(dd,1H) ,3.87(s,6H),3.83(s,2H),3.66(s,3H),3.17–3.04(m,2H),3.00–2.90(m,8H),2.88–2.64(m,3H),2.40 –2.19(m,3H),2.17(d,3H),1.98–1.80(m,3H).

LCMS m/z = 715.3 [M+H] ⁺ .

Example 5: Preparation of Compound 5

The reaction conditions and operations were similar to those of the synthesis of compound 4, to obtain compound 5 (30.0 mg).

¹ H NMR (400MHz, CD ₃ OD) δ8.22(s,1H),8.13(s,1H),7.02–6.71(m,4H),6.58–6.44(m,2H),4.24(dd,1H) ,3.93(s,6H),3.83(s,2H),3.72(s,3H),3.17–3.05(m,2H),3.01–2.89(m,8H),2.88–2.63(m,3H),2.42 –2.17(m,3H),2.09–1.80(m,3H).

LCMS m/z = 733.3 [M+H] ⁺ .

Example 6: Preparation of Compound 6

Step 1: Synthesis of 6B

6A (2.0 g, 9.35 mmol) was dissolved in 20 mL of ultra-dry DMF, and ice-bathed for 10 min under nitrogen protection. Sodium hydride (440 mg, 60%, 18.50 mmol) was added, and ice-bathed for 15 min. A solution of iodomethane (0.64 mL, 10.29 mmol) in 5 mL of ultra-dry DMF was slowly added dropwise, and the reaction was carried out at room temperature for 3 h. 30 mL of water was added to quench the reaction, 100 mL of ethyl acetate was added, and the liquid was separated. The organic phase was washed twice with 50 mL of water and once with 30 mL of saturated brine, and the organic phase was dried and concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 6B (1.353 g, yield: 63%).

LCMS m/z = 228.0 [M+H] ⁺ .

Step 2: Synthesis of 6C

Under nitrogen protection, 6B (300 mg, 1.32 mmol), (4-formyl-3,5-dimethoxyphenyl)boronic acid (330 mg, 1.58 mmol), Pd(dppf)Cl _2. DCM (CAS: 95464-05-4) (110 mg, 0.13 mmol) and cesium carbonate (860 mg, 2.64 mmol) were placed in a sealed tube, 3 mL of 1,4-dioxane and 1 mL of water were added, and the mixture was reacted at 100°C for 3 h. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 6C (358 mg, yield 87%).

LCMS m/z = 314.1 [M+H] ⁺ .

Step 3: Synthesis of compound 6

Under nitrogen protection, 1d (150 mg, 0.35 mmol) and 6C (100 mg, 0.32 mmol) were dissolved in 4 mL DMF, acetic acid (37 uL, 0.64 mmol) was added, and the mixture was reacted at 40°C for 2 h, and sodium triacetoxyborohydride (140 mg, 0.66 mmol) was added, and the reaction was continued at this temperature for 5 h. The mixture was diluted with water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 6 (21 mg, yield: 9%).

LCMS m/z = 723.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ7.90(s,1H),7.83(d,1H),7.06(d,1H),7.04(s,2H),6.92–6.81(m,1H),6.56 –6.32(m,2H),4.21(dd,1H),3.91(s,6H),3.83(s,2H),3.74(s,3H),3.17–3.04(m,2H),2.98–2.87(m ,8H),2.85–2.60(m,3H),2.41–2.18(m,3H),2.03–1.79(m,3H).

Example 7: Preparation of Compound 7

The reaction conditions and operations were similar to those of the synthesis of compound 6, to obtain compound 7 (32 mg).

¹ H NMR (400MHz, CD ₃ OD) δ8.30(d,1H),8.22(d,1H),6.91–6.84(m,1H),6.81(s,2H),6.54–6.44(m,2H) ,4.21(dd,1H),3.91(s,6H),3.80(s,2H),3.70(s,3H),3.15–3.02(m,2H),2.98–2.87(m,8H),2.85–2.60 (m,3H),2.38–2.17(m,3H),1.97–1.78(m,3H).

LCMS m/z = 751.2 [M+H] ⁺ .

Example 8: Preparation of Compound 8

Step 1: Synthesis of 8b

8a (0.50 g, 3.24 mmol) was dissolved in 5 mL of acetic acid, potassium bromide (1.54 g, 12.96 mmol) was added, and hydrogen peroxide (36%) (1.80 ml, 58.75 mmol) was added dropwise, and the mixture was reacted at room temperature for 4 h. The reaction solution was poured into 30 mL of ice water to quench the reaction, and the pH was adjusted to 7 with saturated sodium bicarbonate solution, and 100 mL of ethyl acetate was added, and the organic phase was separated, and the organic phase was washed twice with 50 mL of water and once with 30 mL of saturated brine, and the organic phase was dried and concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 8b (0.325 g, yield: 43.04%).

Step 2: Synthesis of 8c

Under nitrogen protection, 8b (300 mg, 1.29 mmol), (4-formyl-3,5-dimethoxyphenyl)boronic acid (410 mg, 1.94 mmol), Pd(dppf)Cl _2. DCM (160 mg, 0.19 mmol) and cesium carbonate (1.05 g, 3.23 mmol) were placed in a sealed tube, 20 mL of 1,4-dioxane and 2.0 mL of water were added, and the mixture was reacted at 100°C for 3 h. The mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 8c (300 mg, yield 73.06%).

LCMS m/z = 319.1 [M+H] ⁺ .

Step 3: Synthesis of Compound 8

1d (0.13 g, 0.31 mmol) was dissolved in 5 mL DMAc, 8c (0.10 g, 0.31 mmol) and acetic acid (0.038 mL, 0.31 mmol) were added, and the mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (0.20 g, 0.93 mmol) was added, and the mixture was allowed to stand overnight at room temperature, and saturated sodium bicarbonate solution was added to quench the mixture, and the mixture was extracted with ethyl acetate (30 ml × 3). The combined organic phase was washed with saturated brine and concentrated under reduced pressure. The residue was purified by column chromatography and then prepared to obtain trifluoroacetate of compound 8 (10 mg, yield: 4.43%).

1. Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm).

2. The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution.

3. Preparative chromatographic conditions: a. Composition of mobile phases A and B; mobile phase A: acetonitrile; mobile phase B: water (containing 1% TFA); b. Gradient elution, mobile phase A content from 10% to 55%; c. Flow rate 12 mL/min; d. Elution time 15 min.

LCMS m/z = 728.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ6.94(t,1H),8.22(d,1H),6.54(s,2H),6.52–6.41(m,2H),4.36 (s,2H),4.17 (dd,1H),3.81(s,6H),3.79–3.70(m,1H),3.58–3.49(m,1H),3.45–3.31(m,4H),3.27(s,3H),3.17–3.11 (m,1H),3.11–3.04(m,4H),3.03–2.96(m,4H),2.76–2.57(m,2H),2.23–2.06(m,6H),1.91–1.78(m,1H) .

Example 9: Preparation of Compound 9

Step 1: Synthesis of 9b

9a (5.0 g, 28.23 mmol) was dissolved in 50 mL of water, potassium hydride (4.75 g, 84.69 mmol) was added, and the mixture was reacted in an ice bath for 15 min, and then at 120°C for 2 h. The reaction solution was poured into 30 mL of ice water, and the pH was adjusted to about 4 with 1N dilute hydrochloric acid. The solid was collected by filtration to obtain 9b (3.8 g, yield: 84.88%).

LCMS m/z = 159.3 [M+H] ⁺ .

Step 2: Synthesis of 9c

9b (2.0 g, 12.61 mmol) was dissolved in 50 mL of ultra-dry THF, and ice-bathed for 10 min under nitrogen protection. Sodium hydride (910 mg, 60%, 37.83 mmol) was added, and reacted in an ice-bath for 15 min. Then, a solution of iodomethane (1.18 mL, 18.91 mmol) in 5 mL of ultra-dry THF was slowly added dropwise, and reacted at room temperature for 12 h. The reaction was quenched by pouring into 30 mL of ice water, and the solid was collected by filtration to obtain 9c (1.7 g, yield: 78.1%).

LCMS m/z = 173.2 [M+H] ⁺ .

Step 3: Synthesis of 9d

Under nitrogen protection, 9c (1.5 g, 8.69 mmol), (4-formyl-3,5-dimethoxyphenyl)boronic acid (2.19 g, 10.43 mmol), Pd(dppf)Cl _2. DCM (710 mg, 0.87 mmol) and cesium carbonate (8.49 g, 26.07 mmol) were placed in a flask, 40 mL of 1,4-dioxane and 10.0 mL of water were added, and the mixture was reacted at 90°C for 2 h. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 9d (1.4 g, yield 53.29%).

LCMS m/z = 303.3 [M+H] ⁺ .

Step 4: Synthesis of compound 9

9d (0.3 g, 0.99 mmol) was dissolved in 5 mL of ultra-dry methanol and 5 mL of ultra-dry DCE, and sodium acetate (0.44 g, 3.27 mmol), acetic acid (65 mg, 1.09 mmol) and dried powder were added in sequence under nitrogen protection. Molecular sieves (0.35 g) were added and stirred at room temperature for 15 minutes. 1d (0.46 g, 1.09 mmol) was added and the reaction was continued at 70°C for 2 hours. The mixture was cooled to room temperature and sodium cyanoborohydride (0.63 g, 2.97 mmol) was added. The mixture was allowed to stand overnight at room temperature. The molecular sieves were filtered off and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain compound 9 (200 mg, yield: 28.38%).

¹ H NMR(400MHz, DMSO-d ₆ )δ10.76(br.s,1H),6.81(t,1H),6.68(s,2H),6.53–6.46(m,1H), 6.44–6.37(m ,1H),6.77(d,1H),4.29–4.18(m,1H),3.79(s,6H),3.71–3.62(m,5H),3.02–2.89(m,2H),2.87–2.65(m ,10H),2.61–2.53(m,1H),2.34–2.20(m,1H),2.18–2.03(m,8H),1.91–1.67(m,3H).

LCMS m/z = 712.3 [M+H] ⁺ .

Compound 10: Preparation of Compound 10

Step 1: Synthesis of 10B

10A (1.0 g, 3.66 mmol) and 3-fluoroazetidine (0.41 g, 5.49 mmol) were dissolved in 15 mL DMSO, and sodium bicarbonate (0.92 g, 10.98 mmol) and DIPEA (1.42 g, 10.98 mmol) were added, and the mixture was reacted at 80°C for 12 h. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 10B (645 mg, yield: 56.46%).

LCMS m/z = 312.0 [M+H] ⁺ .

Step 2: 10D synthesis

Under nitrogen protection, 10B (0.6 g, 1.92 mmol), 10C (0.6 g, 2.88 mmol), Pd(dppf)Cl _2. DCM (160 mg, 0.19 mmol) and cesium carbonate (1.88 g, 5.76 mmol) were placed in a flask, and 40 mL of 1,4-dioxane and 10.0 mL of water were added. The reaction was carried out at 90 ° C for 2 h. The reaction was cooled to room temperature, diluted with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 10D (0.32 g, yield 41.94%).

LCMS m/z = 398.2 [M+H] ⁺ .

Step 3: Synthesis of compound 10

10D (0.13 g, 0.38 mmol) and 1d (0.13 g, 0.38 mmol) were dissolved in 5 mL of DMF, and acetic acid (20 mg, 0.33 mmol) was added successively under nitrogen protection. The mixture was stirred at room temperature for 60 min, and sodium triacetoxyborohydride (0.21 g, 0.99 mmol) was added. The mixture was stirred at room temperature overnight, and the pH was adjusted to about 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 10 (25 mg, yield: 12.39%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.75(s,1H),9.05(s,1H),7.65(s,1H),6.81(t,1H),6.75(s,2H),6.50( dd,1H),6.41(dd,1H),6.32(s,1H),5.78(d,1H),5.61–5.40(m,1H),4.41–4.29(m,2H),4.28–4. 19(m,1H),4.16–4.02(m,2H),3.82(s,6H),3.71–3.61(m,2H),3.49(s,3H),3.03–2.90(m,2H),2.87– 2.67(m,10H),2.61–2.53(m,1H),2.31–2.02(m,3H),1.90–1.69(m,3H).

LCMS m/z = 807.3 [M+H] ⁺ .

Example 11: Preparation of Compound 11

Step 1: Synthesis of 11b

11a (2.0 g, 8.84 mmol) was dissolved in 20 mL DMF, cesium carbonate (4.3 g, 13.26 mmol) was added, and the mixture was stirred at room temperature for 15 min. 3,4-difluoronitrobenzene (1.4 g, 8.84 mmol) was added, and the mixture was reacted at 50°C overnight under nitrogen protection. 100 mL of ethyl acetate was added for dilution, and the organic phase was washed three times with 50 mL of water and once with 500 mL of saturated brine. The organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain 11b (3.4 g, yield: 99%).

LCMS m/z = 366.2 [M+H] ⁺ .

Step 2: Synthesis of 11c

11b (3.4 g, 9.3 mmol) was dissolved in 40 mL of ethyl acetate, 10% Pd/C (0.3 g) was added, and the gas was replaced with hydrogen three times and reacted at room temperature for 2 h. Pd-carbon was filtered off with Celite pad, and the filtrate was concentrated to obtain 11c (3.0 g, yield: 96%).

LCMS m/z = 336.2 [M+H] ⁺ .

Step 3: Synthesis of 11d

11c (3.0 g, 8.94 mmol) and 3-bromopiperidine-2,6-dione (5.15 g, 26.83 mmol) were placed in a sealed tube, 15 mL of DMF and sodium bicarbonate (4.51 g, 53.7 mmol) were added, and the mixture was reacted overnight at 90°C. 100 mL of ethyl acetate was added for dilution, the organic phase was washed three times with 50 mL of water, and once with 50 mL of saturated brine, the organic phase was dried and concentrated, and the residue was purified by column chromatography to obtain 11d (3.7 g, yield: 92.6%).

LCMS m/z = 447.2 [M+H] ⁺ .

Step 4: Synthesis of 11e

Under nitrogen protection, 11e (1.05 g, 2.35 mmol) was dissolved in 10 mL of acetonitrile, and 10 mL of hydrochloric acid/1,4-dioxane solution was added. The mixture was reacted at room temperature for 2 h and concentrated under reduced pressure to obtain the trifluoroacetate salt of 11e (800 mg crude product).

LCMS m/z = 347.2 [M+H] ⁺ .

Step 5: Synthesis of compound 11

11e (0.15 g, 0.43 mmol) was dissolved in 15 mL of ultra-dry methanol and 15 mL of ultra-dry DCE. Sodium acetate (0.116 g), acetic acid (27 uL) and dried powder were added in sequence under nitrogen protection. Molecular sieves (0.11 g), stirred at room temperature for 15 minutes. 2,6-dimethoxy-4-(1-methyl-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin-3-yl)benzaldehyde (163 mg, 0.477 mmol) was added, reacted at 70°C for 2 hours, cooled to room temperature, sodium triacetoxyborohydride (0.497 g, 2.35 mmol) was added, and the mixture was allowed to stand at room temperature overnight. The molecular sieves were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 11 (45 mg, yield: 15%).

¹ H NMR (400MHz, CD ₃ OD) δ8.32(d,1H),8.25(d,1H),6.83(s,2H),6.57–6.33(m,3H),4.17(dd,1H),3.93 (s,6H),3.77–3.67(m,5H),3.60–3.52(m,4H),2.87–2.67(m,2H),2.67–2.49(m,4H),2.42–2.26(m,1H) ,2.14–1.79(m,5H).

LCMS m/z = 672.3 [M+H] ⁺ .

Example 12: Preparation of Compound 12

Step 1: Synthesis of 12B

3,4-Difluoronitrobenzene (1.0 g, 6.25 mmol), N-BOC-4,4-bipiperidine (1.68 g, 6.25 mmol), and cesium carbonate (3.05 g, 9.38 mmol) were dissolved in 10 mL of DMF, and reacted at 50 °C under nitrogen for 16 h. Cesium carbonate was filtered, and the filtrate was poured into 100 mL of water, filtered, and the filter cake was dried to obtain 12B (1.2 g, yield: 47.12%).

LCMS m/z = 352.2 [M+H] ⁺ .

Step 2: Synthesis of 12C

12B (1.2 g, 2.94 mmol) was dissolved in 30 ml of ethyl acetate, 0.5 g of palladium carbon was added, hydrogen was replaced twice, and the mixture was stirred at room temperature for 3 h. Filtered through celite pad, the filtrate was concentrated to obtain 12C (1.0 g, yield 90.10%).

LCMS m/z = 378.3 [M+H] ⁺ .

Step 3: Synthesis of compound 12D

12C (1.0 g, 2.65 mmol) and 3-bromopiperidine-2,6-dione (1.53 g, 7.95 mmol) were dissolved in 10 mL of DMF, sodium bicarbonate (1.34 g, 15.90 mmol) was added, and the mixture was reacted overnight at 90° C. The mixture was concentrated under reduced pressure and subjected to column chromatography to obtain 12D (0.89 g, yield 68.74%).

LCMS m/z = 489.2 [M+H] ⁺ .

Step 4: Synthesis of 12E

12D (0.89 g, 1.82 mmol) was dissolved in 10 mL of acetonitrile, 5 mL of 4N hydrogen chloride/dioxane solution was added, and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to obtain the hydrochloride of 12E (0.65 g, yield 91.93%).

LCMS m/z = 389.3 [M+H] ⁺ .

Step 5: Synthesis of compound 12

12E (0.12 g, 0.31 mmol) was dissolved in 5 mL of dichloroethane and 5 mL of methanol, and sodium acetate (0.064 g, 0.78 mmol), acetic acid (0.047 g, 0.78 mmol) and Molecular sieve 200mg. Stir at room temperature for 10min, add 3a (0.10g, 0.26mmol), react at 70℃ for 4h, cool to room temperature, add sodium triacetoxyborohydride (0.17g, 0.80mmol), react at room temperature overnight. Add 50mL of ethyl acetate and 50mL of saturated _NaHCO3 aqueous solution for extraction and separation, extract the aqueous phase with ethyl acetate (50mL×1), combine the ethyl acetate layers, wash the ethyl acetate layers with saturated brine (50mL×1), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and obtain a crude product by column chromatography of the residue. The liquid phase is used to prepare the trifluoroacetate salt of compound 12 (0.020g, yield 10.1%).

1. Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm).

2. The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution.

3. Preparation of chromatographic conditions: a. Composition of mobile phase A, B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 1% TFA).

b. Gradient elution, mobile phase A content from 10 to 55%; c. Flow rate 12 mL/min; d. Elution time 15 min.

LCMS m/z = 752.4 [M+H] ⁺ .

Embodiment 13:

Step 1: Synthesis of 13B

13A (1.6 g, 10.72 mmol) was dissolved in 25 mL of acetonitrile, and N-bromosuccinimide (2.1 g, 11.79 mmol) was added. The mixture was stirred at room temperature for 1 h, and 13B (1.81 g, yield 74%) was obtained by column chromatography.

LCMS m/z = 228.1 [M+H] ⁺ .

Step 2: Synthesis of 13C

Under nitrogen protection, 13B (0.456 g, 2.0 mmol), 4-formyl-3,5-dimethoxyphenylboronic acid (0.63 g, 3.0 mmol), Pd(dppf)Cl _2. DCM (0.16 g, 0.2 mmol) and cesium carbonate (1.95 g, 6.0 mmol) were added to 1,4-dioxane (10 mL) and water (2 mL) and stirred at 100°C for 3 h. After cooling to room temperature, the solvent was removed under reduced pressure, 30 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column to obtain 13C (0.43 g, yield 68.61%).

LCMS m/z = 314.2 [M+H] ⁺ .

Step 3: Synthesis of compound 13

1d (0.10 g, 0.24 mmol) was dissolved in 5 mL of dichloroethane and 5 mL of methanol, and sodium acetate (0.098 g, 0.72 mmol), acetic acid (0.043 g, 0.72 mmol) and Molecular sieve 200mg, stirred at room temperature for 10min, added 13C (0.075g, 0.24mmol), reacted at 70℃ for 4h. Cooled to room temperature, added sodium triacetoxyborohydride (0.15g, 0.72mmol), reacted at room temperature overnight. Added ethyl acetate 50mL and saturated NaHCO ₃ aqueous solution 50mL for extraction and separation, the aqueous phase was extracted with ethyl acetate (50mL×1), the ethyl acetate layer was combined, the ethyl acetate layer was washed with saturated brine (50mL×1), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to column chromatography to obtain compound 13 (0.060g, yield 34.59%).

LCMS m/z = 723.2 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ7.65(s,1H),6.90(t,1H),6.68(s,2H),6.57–6.45(m,2H),4.23(dd,1H),3.88 (s,6H),3.82(s,2H),3.67(s,3H),3.16–3.00(m,4H),2.99–2.85(m,10H),2.85–2.62(m,3H),2.41–2.19 (m,3H),2.18–2.07(m,2H),2.02–1.80(m,3H).

Example 14: Preparation of Compound 14

Step 1: Synthesis of 14B

14A (1.50 g, 6.64 mmol) and N-tert-butyloxycarbonyl-4-piperidone (1.98 g, 9.94 mmol) were dissolved in 10 mL DMF, 0.1 mL glacial acetic acid and anhydrous magnesium sulfate were added, and the mixture was reacted at room temperature for 2 h, sodium triacetoxyborohydride (4.22 g, 19.92 mmol) was added, and the reaction was continued for 2 h. Saturated aqueous sodium bicarbonate solution was added to quench the mixture, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel chromatography to obtain 14B (1.6 g, yield 58.99%).

LCMS m/z = 409.2 [M+H] ⁺ .

Step 2: Synthesis of 14C

14B (1.5 g, 3.68 mmol) was dissolved in 30 mL of ethyl acetate, 0.5 g of palladium carbon was added, hydrogen was replaced twice, and the mixture was stirred at room temperature for 3 h. Filtered through celite pad, the filtrate was concentrated to obtain 14C (1.3 g, yield 93.34%).

LCMS m/z=379.2 [M+H].

Step 3: 14D synthesis

14C (1.0 g, 2.65 mmol) and 3-bromopiperidine-2,6-dione (1.53 g, 7.95 mmol) were dissolved in 10 mL DMF, sodium bicarbonate (1.34 g, 15.90 mmol) was added, and the mixture was reacted at 90° C. overnight. The mixture was concentrated under reduced pressure and subjected to column chromatography to obtain 14D (0.89 g, yield 68.6%).

LCMS m/z = 490.3 [M+H] ⁺ .

Step 4: Synthesis of 14E

14D (0.85 g, 1.74 mmol) was dissolved in 10 mL of acetonitrile, 5 mL of 4N hydrogen chloride/dioxane solution was added, and the mixture was stirred at room temperature for 2 h. 14E (0.65 g, yield 95.92%) was obtained by concentration under reduced pressure.

LCMS m/z = 390.3 [M+H] ⁺ .

Step 5: Synthesis of compound 14

14E (0.12 g, 0.31 mmol) was dissolved in 5 mL of dichloroethane and 5 mL of methanol, and sodium acetate (0.064 g, 0.78 mmol), acetic acid (0.047 g, 0.78 mmol) and Molecular sieve 200mg. Stir at room temperature for 10min, add 3a (0.10g, 0.26mmol), react at 70℃ for 4h, cool to room temperature, add sodium triacetoxyborohydride (0.17g, 0.80mmol), react at room temperature overnight. Add 50mL of ethyl acetate and 50mL of saturated _NaHCO3 aqueous solution for extraction and separation, extract the aqueous phase with ethyl acetate (50mL×1), combine the ethyl acetate layers, wash the ethyl acetate layers with saturated brine (50mL×1), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and obtain a crude product by column chromatography of the residue. The liquid phase is used to prepare the trifluoroacetate salt of compound 14 (0.040g, yield 20.43%).

Preparation conditions:

1. Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm).

2. The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution.

3. Preparation of chromatographic conditions: a. Composition of mobile phase A, B: Mobile phase A: acetonitrile; Mobile phase B: water (containing 1% TFA).

b. Gradient elution, mobile phase A content from 10 to 55%; c. Flow rate 12 mL/min; d. Elution time 15 min.

LCMS m/z = 753.3 [M+H] ⁺ .

Example 15: Preparation of Compound 15

Step 1: Synthesis of 15A

10A (0.7 g, 2.56 mmol) and 15a (0.71 g, 7.68 mmol) were dissolved in 5 mL of NMP, and DIPEA (0.85 mL, 5.12 mmol) and cesium carbonate (2.5 g, 7.68 mmol) were added, and the mixture was reacted at 120° C. for 2 h in a microwave oven. The reaction mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. After concentration under reduced pressure, the residue was purified by column chromatography to obtain 15A (697 mg, yield: 82.47%).

LCMS m/z = 330.0 [M+H] ⁺ .

Step 2: Synthesis of 15B

Under nitrogen protection, 15A (0.654 g, 1.98 mmol), 10C (0.83 g, 3.96 mmol), Pd(dppf)Cl _2. DCM (160 mg, 0.20 mmol) and cesium carbonate (1.29 g, 3.96 mmol) were placed in a flask, 6 mL of 1,4-dioxane and 1.5 mL of water were added, and the mixture was reacted at 100°C for 3 h. The reaction was cooled to room temperature, diluted with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 15B (0.59 g, yield 71.73%).

LCMS m/z = 416.2 [M+H] ⁺ .

Step 3: Synthesis of compound 15

15B (0.10 g, 0.24 mmol) and 1d (92 mg, 0.22 mmol) were dissolved in 3 mL DMF, and acetic acid (0.1 mL, 1.75 mmol) and molecular sieves were added in sequence under nitrogen protection, and stirred at 50°C for 60 min. Sodium triacetoxyborohydride (0.10 g, 0.47 mmol) was added and the mixture was allowed to stand at room temperature overnight. The mixture was diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain trifluoroacetate of compound 15 (22 mg, yield: 11.11%).

Preparative HPLC conditions:

Apparatus: Waters 2767 preparative liquid phase;

Chromatographic column: SunFire@Prep C18 (19 mm×250 mm); mobile phase: A: acetonitrile; B: water (containing 1% TFA).

Elution conditions: gradient elution with mobile phase A content from 10% to 55%; flow rate: 12 mL/min; elution time: 15 min.

¹ H NMR (400MHz, CD ₃ OD) δ9.20(s,1H),7.54(s,1H),7.11(t,1H),6.90(s,2H),6.66–6.54(m,2H),6.44 (s,1H),4.54–4.39(m,6H),4.31(dd,1H),3.99(s,6H),3.91–3.80(m,1H),3.73–3.64(m,1H),3.62(s ,3H),3.59–3.38(m,2H),3.29–3.13(m,9H),2.88–2.68(m,2H),2.35–2.19(m,3H),2.04–1.91(m,1H).

LCMS m/z = 825.3 [M+H] ⁺ .

Example 16: Preparation of Compound 16

9d (0.1 g, 0.33 mmol) and 11e (0.11 g, 0.33 mmol) were dissolved in 5 mL of DMF, and acetic acid (60 mg, 1.0 mmol) was added in sequence under nitrogen protection. The mixture was stirred at room temperature for 60 min, and sodium triacetoxyborohydride (0.21 g, 0.99 mmol) was added. The mixture was stirred at room temperature overnight, and the pH was adjusted to about 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 16 (5 mg, yield: 2.39%).

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.73(s,1H),6.65(s,2H),6.52–6.43(m,1H),6.42–6.30(m,2H),5.49(d,1H ),4.22–4.12(m,1H),3.78(s,6H),3.68(s,3H),3.53–3.39(m,6H),2.78–2.65(m,1H),2.61–2.52(m,1H ),2.43–2.25(m,4H),2.15–2.03(m,7H),1.88–1.74(m,1H),1.72–1.58(m,4H).

LCMS m/z = 633.3 [M+H] ⁺ .

Example 17: Preparation of Compound 17

Step 1: Synthesis of 17B

17A (0.5 g, 1.83 mmol) and 3-methylazetidine (0.26 g, 3.66 mmol) were dissolved in 10 mL of acetonitrile, sodium bicarbonate (0.46 g, 5.48 mmol) was added, and stirred at 80°C for 2 h. After concentration under reduced pressure, 17B (320 mg, yield: 56.74%) was obtained by separation and purification by column chromatography.

LCMS m/z = 308.2 [M+H] ⁺ .

Step 2: Synthesis of 17C

17B (300 mg, 0.97 mmol), (4-formyl-3,5-dimethoxyphenyl)boronic acid (0.24 g, 1.16 mmol), Pd(dppf)Cl _2. DCM (0.12 g, 0.15 mmol) and cesium carbonate (0.79 g, 2.42 mmol) were placed in a sealed tube, 13 mL of 1,4-dioxane and 3 mL of water were added, and the mixture was reacted at 100°C for 3 h under nitrogen protection. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 17C (250 mg, yield 65.51%).

LCMS m/z = 394.2 [M+H] ⁺ .

Step 3: Synthesis of compound 17

1d (110 mg, 0.25 mmol) and 17C (100 mg, 0.25 mmol) were dissolved in 3 mL DMF, and AcOH (0.014 mL, 0.25 mmol) and Molecular sieve 20 mg, react at 50°C for 2 h, add sodium triacetoxyborohydride (160 mg, 0.75 mmol), and continue to react for 5 h. Cool to room temperature, dilute the reaction with 100 mL of water, extract three times with 100 mL of ethyl acetate, combine the ethyl acetate layers, wash the ethyl acetate layers with saturated brine (100 mL×1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated and purified by column chromatography to obtain compound 17 (40 mg, yield: 19.93%).

LCMS m/z = 803.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.10(s,1H),7.43(s,1H),6.90(t,1H),6.75(s,2H),6.57–6.47(m,2H),6.23 (s,1H),4.27–4.14(m,3H),3.89(s,6H),3.84(s,2H),3.62(dd,2H),3.59(s,3H),3.18–3.07(m,2H ),2.96(s,8H),2.89–2.69(m,4H),2.41–2.25(m,3H),2.01–1.84(m,3H),1.31(d, 3H).

Example 18: Preparation of Compound 18

Step 1: Synthesis of 18B

17A (0.5 g, 1.83 mmol) and 3-methoxyazetidine (0.32 g, 3.68 mmol) were dissolved in 10 mL of acetonitrile, sodium bicarbonate (0.46 g, 5.48 mmol) was added, stirred at 80 °C for 2 h, concentrated under reduced pressure, and the residue was separated and purified by column chromatography to obtain 18B (350 mg, yield: 59.00%).

LCMS m/z = 324.1 [M+H] ⁺ .

Step 2: Synthesis of 18C

18B (300 mg, 0.93 mmol), (4-formyl-3,5-dimethoxyphenyl)boronic acid (0.24 g, 1.16 mmol), Pd(dppf)Cl _2. DCM (0.12 g, 0.15 mmol) and cesium carbonate (0.79 g, 2.42 mmol) were placed in a sealed tube, 12 mL of 1,4-dioxane and 3 mL of water were added, and the mixture was reacted at 100°C for 3 h under nitrogen protection. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 18C (250 mg, yield 65.65%).

LCMS m/z = 410.2 [M+H] ⁺ .

Step 3: Synthesis of compound 18

1d (85 mg, 0.20 mmol) and 18C (80 mg, 0.20 mmol) were dissolved in 3 mL DMF, and AcOH (0.012 mL, 0.20 mmol) and Molecular sieve 20 mg, react at room temperature for 2 h, add sodium triacetoxyborohydride (130 mg, 0.60 mmol), react at room temperature for 2 h. Cool to room temperature, dilute the reaction with 20 mL of water, extract three times with 15 mL of ethyl acetate, combine the ethyl acetate layers, wash the ethyl acetate layers with saturated brine (30 mL × 1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated and purified by column chromatography to obtain compound 18 (14 mg, yield: 8.55%).

¹ H NMR (400MHz, CD ₃ OD) δ9.12(s,1H),7.46(s,1H),6.91(t,1H),6.76(s,2H),6.58–6.46(m,2H),6.28 (s,1H),4.42–4.35(m,1H),4.28–4.21(m,3H),3.92–3.87(m,8H),3.85(s,2H),3.60(s,3H),3.35(s ,3H),3.17–3.09(m,2H),2.96(s,8H),2.85–2.67(m,3H),2.44–2.24(m,3H),2.04–1.82(m,3H).

LCMS m/z=410.2[(M+2H)/2] ⁺ .

Example 19: Synthesis of Compound 19

Referring to the preparation method of compound 20, the trifluoroacetate salt of compound 19 (25 mg) was prepared by the reaction of 19A+1d. The crude product was separated and purified by preparative HPLC.

1. Instrument: Waters 2767 preparative liquid phase; Chromatographic column: SunFire@Prep C18 (19mm×250mm).

2. The sample was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution.

3. Preparation of chromatographic conditions: a. Composition of mobile phase A, B: mobile phase A: acetonitrile; mobile phase B: water (containing 1% TFA); b. Gradient elution, mobile phase A content from 10% to 55%; c. Flow rate 12 mL/min; d. Elution time 15 min.

¹ H NMR (400MHz, CD ₃ OD) δ9.14(s,1H),7.40(s,1H),6.92–6.86(m,1H),6.76(s,2H),6.56–6.45(m,3H) ,4.22(dd,1H),3.86(s,6H),3.83(s,2H),3.57(s,3H),3.14–3.07(m,8H),2.94(s,8H),2.79–2.68(m ,3H),2.35–2.25(m,3H),1.99–1.87(m,3H).

LCMS m/z = 777.2 [M+H] ⁺ .

Example 20: Synthesis of Compound 20

Step 1: Synthesis of 20B

20A (800 mg, 3.51 mmol), (4-formyl-3,5-dimethoxyphenyl)boronic acid (1.25 g, 5.96 mmol), Pd(dppf)Cl _2. DCM (290 mg, 0.35 mmol) and cesium carbonate (2.29 g, 7.03 mmol) were placed in a sealed tube, 13 mL of 1,4-dioxane and 3 mL of water were added, and the mixture was reacted at 100°C for 3 h under nitrogen protection. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 20B (114 mg, yield 10%).

LCMS m/z = 314.0 [M+H] ⁺ .

Step 2: Synthesis of compound 20

1d (140 mg, 0.33 mmol) and 20B (103 mg, 0.33 mmol) were dissolved in 3 mL DMF, and AcOH (0.38 mL, 6.6 mmol) and Molecular sieve 50 mg, react at 50 ° C for 2 h, add sodium triacetoxyborohydride (140 mg, 6.6 mmol), continue to react for 5 h, cool to room temperature, dilute the reaction with 100 mL of water, extract three times with 100 mL of ethyl acetate, combine the ethyl acetate layers, wash the ethyl acetate layers with saturated brine (100 mL×1), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is separated and purified by reverse phase column chromatography (mobile phase A: acetonitrile, mobile phase B: 0.5% NH ₄ HCO ₃ aqueous solution, gradient elution from 10% of A to 70% of B solution) to obtain compound 20 (12 mg, yield: 5%).

LCMS m/z = 723.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ8.22(d,1H),7.94(d,1H),6.94–6.84(m,4H),6.56–6.45(m,2H),4.22(dd,1H) ,3.89(s,6H),3.83(s,2H),3.53(s,3H),3.14–3.07(m,2H),2.94(s,8H),2.82–2.68(m,3H),2.36–2.22 (m,3H),1.99–1.84(m,3H).

Example 21: Synthesis of Compound 21

Referring to the legal method of compound 22, compound 21 (150.0 mg) was prepared.

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.74(s,1H),9.07(s,1H),7.63(s,1H),6.85–6.78(m,1H),6.75(s,2H), 6.63(s,1H),6.50(dd,1H),6.41(d,1H),5.77(d,1H),4.28–4.20(m,1H),3.81(s,6H) ,3.71–3.62(m,6H),3.53–3.47(m,7H),2.95(d,3H),2.81(s,8H),2.74–2.64(m,2H),2.60–2.53(m,1H) ,2.36–2.20(m,2H),2.14–1.98(m,2H),1.88–1.78(m,1H).

LCMS m/z = 819.3 [M+H] ⁺ .

Example 22: Synthesis of Compound 22

1d (100.0 mg, 0.24 mmol) was added to 2 mL DMF, and 22A (104.9 mg, 0.29 mmol), AcOH (2.9 mg, 0.05 mmol) and Molecular sieve 200 mg, react at 40 ° C for 1 h, cool to room temperature, add sodium triacetoxyborohydride (101.7 mg, 0.48 mmol), react at room temperature for 5 h. Add ethyl acetate 200 mL and 100 mL saturated NaHCO ₃ aqueous solution for extraction and separation, extract the aqueous phase with ethyl acetate (100 mL × 1), combine the ethyl acetate layers, wash the ethyl acetate layers with saturated brine (100 mL × 1), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and separate and purify by preparative HPLC to obtain the trifluoroacetate salt of compound 22 (8.0 mg, yield: 4.3%).

Preparative HPLC method:

Instrument: SHIMADZU LC-20AP; Chromatographic column: Phenomenex C18 (150 mm × 25 mm, I.D, 10 um particle size);

Mobile phase: A is 0.1% TFA in water; B is acetonitrile; Gradient: 12% to 27% B in A solution gradient elution for 10 minutes; Flow rate: 25 mL/min; Column temperature: room temperature; Detection wavelength: 210 nm;

LCMS m/z = 774.6 [M+H] ⁺ .

¹ H NMR(400MHz,D ₂ O)δ9.36(s,1H),7.87(s,1H),7.48(s,1H),7.22(t,1H),6.81(s,2H),6.70–6.55 (m,2H),4.58–4.47(m,2H),4.40(dd,1H),3.97–3.83(m,7H),3.80–3.71(m,1H),3.67(s,3H),3.63–3.36 (m,6H),3.35–3.15(m,5H),2.90–2.73(m,2H),2.42–2.18(m,4H),2.13–1.98(m, 1H),1.35–1.25(m,2H),1.08–0.99(m,2H).

Example 23: Synthesis of Compound 23

Step 1: Synthesis of 23B

Under nitrogen protection, 23A (1.0 g, 5.09 mmol), 1-methyl-1H-pyrazol-4-ylboronic acid (1.28 g, 10.18 mmol), palladium acetate (110.0 mg, 0.51 mmol), tricyclohexylphosphine (290.0 mg, 1.02 mmol) and potassium phosphate (3.24 g, 15.27 mmol) were added to a sealed tube in sequence, and toluene (10 mL) was added, and stirred at 100°C for 2 h. After cooling to room temperature, the solvent was removed under reduced pressure, 100 mL of water was added, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 23B (1.0 g, yield: 81.09%).

LCMS m/z = 241.1 [M+H] ⁺ .

Step 2: Synthesis of 23C

Under nitrogen protection, 23B (500.0 mg, 2.08 mmol) and NBS (444.2 mg, 2.50 mmol) were added to DMF (10 mL) and reacted at 90°C for 2 h. After cooling to room temperature, the solvent was removed under reduced pressure, 100 mL of water was added, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 23C (350.0 mg, yield: 52.72%).

LCMS m/z = 319.0 [M+H] ⁺ .

Step 3: 23D synthesis

Under nitrogen protection, 23C (300.0 mg, 0.94 mmol), (4-formyl-3,5-dimethoxyphenyl)boronic acid (236.9 mg, 1.13 mmol), Pd(dppf)Cl _2. DCM (68.8 mg, 0.09 mmol) and cesium carbonate (612.5 mg, 1.88 mmol) were placed in a sealed tube, 1,4-dioxane (2 mL) was added, and the mixture was stirred at 100°C for 2 h. After cooling to room temperature, the solvent was removed under reduced pressure, 100 mL of water was added, and the mixture was extracted with ethyl acetate (80 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 23D (200.0 mg, yield: 52.61%).

LCMS m/z = 405.2 [M+H] ⁺ .

Step 4: Synthesis of compound 23

1d (100.0 mg, 0.24 mmol) was added to 2 mL DMF, and 23D (116.5 mg, 0.29 mmol), AcOH (2.9 mg, 0.05 mmol) and Molecular sieve 200 mg, react at 40 ° C for 1 h. Cool to room temperature, add sodium triacetoxyborohydride (66.1 mg, 0.31 mmol), and react at room temperature for 5 h. Add ethyl acetate 200 mL and saturated NaHCO ₃ aqueous solution 100 mL for extraction and separation, the aqueous phase is extracted with ethyl acetate (100 mL × 1), the ethyl acetate layer is combined, the ethyl acetate layer is washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue is separated and purified by preparative HPLC to obtain the trifluoroacetate salt of compound 23 (20.0 mg, yield: 10.2%).

Preparative HPLC method:

Instrument: SHIMADZU LC-20AP; Chromatographic column: Phenomenex C18 (150mm×25mm, I.D, 10um particle size);

Mobile phase: A is 0.1% TFA in water; B is acetonitrile; Gradient: 5% to 35% B in A solution gradient elution for 10 minutes; Flow rate: 25 mL/min; Column temperature: room temperature; Detection wavelength: 210 nm;

LCMS m/z = 814.3 [M+H] ⁺ .

¹ H NMR (400MHz, D ₂ O) δ9.19(s,1H),7.98(s,1H),7.79(s,1H),7.65(s,1H),7.48(s,1H),7.23(t ,1H),6.75(s,2H),6.69–6.54(m,2H),4.58–4.47(m,2H),4.39(dd,1H),3.97–3.70(m,11H),3.69–3.18(m ,14H),2.88–2.73(m,2H),2.43–2.20(m,3H),2.13–1.98(m,1H).

Compound 24: Synthesis of Compound 24

Step 1: Synthesis of 24A

Methyl 4-bromo-2-fluorophenyl acetate (6.00 g, 24.29 mmol) and N-Boc-piperazine (8.25 g, 36.44 mmol) were dissolved in 40 mL of 1,4-dioxane, and RuPhos (1.13 g, 2.43 mmol), RuPhos Pd G3 (2.03 g, 2.43 mmol) and cesium carbonate (19.79 g, 60.72 mmol) were added in sequence under nitrogen protection, and reacted at 100°C for 16 h. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with dichloromethane 3 times. The organic phase was collected, concentrated under reduced pressure, and flash column chromatography was performed to obtain 24A (8.76 g, yield: 92%).

LCMS m/z = 353.1 [M+H] ⁺ .

Step 2: Synthesis of 24B

24A (6.50 g, 18.44 mmol) and acrylonitrile (1.47 g, 27.66 mmol) were dissolved in 50 mL of toluene, and benzyltrimethylammonium hydroxide (1.54 g, 3.69 mmol) was added. The mixture was reacted at room temperature for 16 h, and 500 mL of ethyl acetate was added to dilute the reaction solution. The reaction solution was washed with water three times, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 24B (3.95 g, yield: 53%).

LCMS m/z = 406.2 [M+H] ⁺ .

Step 3: Synthesis of compound 24C

24B (2.00 g, 4.93 mmol) was dissolved in 20 mL of toluene, and acetaldehyde oxime (0.87 g, 14.79 mmol) and indium chloride (III) tetrahydrate (0.72 g, 2.46 mmol) were added, and the mixture was reacted at 130°C for 2 h. The mixture was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography to obtain 24C (1.0 g, yield: 48%).

LCMS m/z = 424.2 [M+H] ⁺ .

Step 4: 24D synthesis

24C (1.00 g, 2.36 mmol) was dissolved in 9.5 mL of acetonitrile, and benzyltrimethylammonium hydroxide (1.97 g, 4.72 mmol) was added, and the mixture was reacted at 60°C for 1 h. The mixture was cooled to room temperature, and 50 mL of ethyl acetate was added to dilute the reaction solution, which was washed with water 3 times, washed with saturated sodium chloride once, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 24D (0.3 g, yield: 32%).

LCMS m/z = 392.1 [M+H] ⁺ .

Step 5: Synthesis of 24E

24D (250 mg, 0.64 mmol) was dissolved in 2 mL of dichloromethane, and 2 mL of hydrochloric acid solution (1 M in Diox) was added, and the mixture was reacted at room temperature for 3 h. The mixture was concentrated under reduced pressure to obtain the hydrochloride salt of crude 24E (190 mg).

LCMS m/z = 292.2 [M+H] ⁺ .

Step 6: Synthesis of 24F

24E (190 mg, 0.64 mmol) and tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (210 mg, 0.90 mmol) were dissolved in toluene (4 mL) and acetonitrile (2 mL). Acetic acid (77 mg, 1.28 mmol) and sodium acetate (130 mg, 1.60 mmol) were added in sequence under nitrogen protection. molecular sieves, stirred at room temperature for 15 minutes, reacted at 135°C for 5 hours, filtered through diatomaceous earth, and concentrated under reduced pressure to obtain 24F.

LCMS m/z = 509.2 [M+H] ⁺ .

Step 7: Synthesis of 24G

24F (330 mg, 0.64 mmol) was dissolved in 6 ml DCE, and acetic acid (77 mg, 1.28 mmol) and sodium cyanoborohydride (200 mg, 3.20 mmol) were added respectively, and the mixture was reacted at room temperature for 12 h. 40 mL of water and 50 mL of ethyl acetate were added and extracted three times respectively, and the ethyl acetate layer was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography to obtain 24G (0.24 g, yield 70%).

LCMS m/z = 511.2 [M+H] ⁺ .

Step 8: Synthesis of 24H

24G (240 mg, 0.46 mmol) was dissolved in 3 mL of dichloromethane, and 3 mL of hydrochloric acid dioxane solution was added, and the mixture was reacted at room temperature for 3 h. The mixture was concentrated under reduced pressure to obtain the trifluoroacetate salt of crude 24H (230 mg).

LCMS m/z = 411.2 [M+H] ⁺ .

Step 9: Synthesis of compound 24

24G (30 mg, 0.08 mmol) was dissolved in 1 mL of ultra-dry DMA, and 3A (33 mg, 0.46 mmol) and 0.1 mL of tetraisopropyl titanate were added in sequence. After reacting at 70°C for 5 h, the mixture was cooled to room temperature, and sodium triacetoxyborohydride (83 mg, 1.38 mmol) was added. The mixture was reacted at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was separated and purified by preparative HPLC to obtain compound 24 (3 mg, yield 5%).

Preparation method:

Instrument model: SHIMADZU LC-20AP; Chromatographic column model: Phenomenex C18;

Mobile phase: A is 10 mM NH ₄ HCO ₃ aqueous solution; B is acetonitrile; elution conditions: gradient elution of A solution from 25% to 55% B for 10 minutes; flow rate: 25 mL/min; column temperature: 45°C; detection wavelength: 210 & 254 nm;

¹ H NMR (400MHz, CD ₃ OD) δ9.08(s,1H),7.41(s,1H),7.09(t,1H),6.85–6.58(m,4H),6.21(s,1H),4.12 –4.02(m,4H),3.94–3.78(m,9H),3.57(s,3H),3.17–3.08(m,6H),2.95–2.91(m,4H),2.79–2.60(m,3H) ,2.47–2.18(m,5H),2.15–1.77(m,3H).

LCMS m/z = 774.3 [M+H] ⁺ .

Example 25: Synthesis of Compound 25

Step 1: Dissolve A-7-P1 (0.2 g, 0.38 mmol) in 8 mL of acetonitrile, add 4N hydrochloric acid/dioxane solution (3 mL), react at room temperature for 1 h, and concentrate under reduced pressure to obtain the hydrochloride of 25A (200 mg, crude product).

LCMS m/z = 426.1 [M+H] ⁺ .

Step 2: Dissolve the hydrochloride of 25A (200 mg, crude product) and 3a (214 mg, 0.56 mmol) in 6 mL DMF, add acetic acid (0.1 mL) and molecular sieves (50 mg), and stir at 50 ° C for 60 min. Add sodium triacetoxyborohydride (198 mg, 0.94 mmol) and react at room temperature overnight. Dilute with water, extract with ethyl acetate, and wash the organic layer three times with saturated brine. Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified by reverse phase column to obtain compound 25 (108 mg, two-step yield: 36%, chiral HPLC retention time: 7.795 min).

Reversed Phase Chromatography Method:

Instrument: Isolera One; Column model: C18 spherical 20-35μM 100A 40g.

Mobile phase: A is 0.1% ammonium bicarbonate aqueous solution; B is acetonitrile; elution conditions: 5%-50% B gradient elution.

Flow rate: 60mL/min; column pressure: 3.0bar; detection wavelength: 210nm&254nm.

Chiral HPLC analysis method:

Instrument: CAS-CD-HPLC-E (SHIMADZU LC-20AD); Chiral column: Chiralpak IE-3 50x 4.6mm I.D., 3um;

Mobile phase: A is n-hexane (0.05% IPAm), B is ethanol and acetonitrile (0.05% IPAm); gradient washing: 50% B in A.

Flow rate: 1 mL/min; column temperature: 35°C; detection wavelength: 220 nm; injection volume: 2 μL; running time: 15 min.

LCMS m/z = 789.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.08(s,1H),7.41(s,1H),6.92–6.84(m,1H),6.73(s,2H),6.55–6.45(m,2H) ,6.21(s,1H),4.21(dd,1H),4.06(t,4H),3.86(s,6H),3.82(s,2H),3.56(s,3H),3.15–3.05(m,2H ),2.99–2.87(m,8H),2.82–2.65(m,3H),2.46–2.23(m,5H),1.97–1.82(m,3H).

Example 26: Synthesis of Compound 26

Step 1: Dissolve A-7-P2 (0.08 g, 0.15 mmol) in 6 mL of acetonitrile, add 4N hydrochloric acid-dioxane solution (6 mL), react at room temperature for 0.5 h, and concentrate under reduced pressure to obtain the hydrochloride of 26A (63 mg, crude product).

LCMS m/z = 426.1 [M+H] ⁺ .

Step 2: Dissolve the hydrochloride of 26A (63 mg, 0.15 mmol, crude product) and 3a (63 mg, 0.17 mmol) in 6 mL DMF, add acetic acid (0.1 mL) and molecular sieves (50 mg), and stir at 50°C for 60 min. Add sodium triacetoxyborohydride (64 mg, 0.30 mmol) and react at room temperature overnight. Dilute with water, extract with ethyl acetate, and wash the organic layer three times with saturated brine. Dry the organic layer with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The residue is purified by reverse phase column to obtain compound 26 (108 mg, two-step yield: 59%; chiral HPLC retention time: 13.158 min).

Reversed Phase Chromatography Method:

Instrument: Isolera One; Column model: C18 spherical 20-35μM 100A 40g.

Mobile phase: A is 0.1% ammonium bicarbonate aqueous solution; B is acetonitrile; elution conditions: 5%-50% B gradient elution.

Flow rate: 60mL/min; column pressure: 3.0bar; detection wavelength: 210nm&254nm.

Chiral HPLC analysis method:

Instrument: CAS-CD-HPLC-E (SHIMADZU LC-20AD); Chiral column: Chiralpak IE-3 50x 4.6mm I.D., 3um;

Mobile phase: A is n-hexane (0.05% IPAm), B is ethanol and acetonitrile (0.05% IPAm); gradient washing: 50% B in A.

Flow rate: 1 mL/min; column temperature: 35°C; detection wavelength: 220 nm; injection volume: 2 μL; running time: 15 min.

LCMS m/z = 789.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.08(s,1H),7.41(s,1H),6.88(t,1H),6.70(s,2H),6.55–6.44(m,2H),6.21 (s,1H),4.21(dd,1H),4.06(t,4H),3.86(s,6H),3.82(s,2H),3.56(s,3H),3.16–3.04(m,2H), 2.99–2.87(m,8H),2.85–2.62(m,3H),2.47–2.19(m,5H),2.00–1.80(m,3H).

Example 27: Synthesis of Compound 27

The hydrochloride of 25A (160 mg, crude product) and 13C (140 mg, 0.45 mmol) were dissolved in 6 mL of DMF, and acetic acid (0.1 mL) and molecular sieves (50 mg) were added, and stirred at 50°C for 1 h. Sodium triacetoxyborohydride (160 mg, 0.76 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The mixture was diluted with water, extracted with ethyl acetate, and the organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column to obtain compound 27 (120 mg, two-step yield: 43%; chiral HPLC retention time: 3.831 min).

Reversed Phase Chromatography Method:

Instrument: Isolera One; Column model: C18 spherical 20-35μM 100A 40g.

Mobile phase: A is 0.1% ammonium bicarbonate aqueous solution; B is acetonitrile; elution conditions: 5%-50% B gradient elution.

Flow rate: 60mL/min; column pressure: 3.0bar; detection wavelength: 210nm&254nm.

Chiral HPLC analysis method:

Instrument: CAS-CD-HPLC-E (SHIMADZU LC-20AD); Chiral column: Chiralpak IE-3 50x 4.6mm I.D., 3um;

Mobile phase: A is n-hexane (0.05% IPAm), B is ethanol and acetonitrile (0.05% IPAm); gradient washing: 50% B in A.

Flow rate: 1 mL/min; column temperature: 35°C; detection wavelength: 220 nm; injection volume: 3 μL; running time: 15 min.

LCMS m/z = 723.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ7.63(s,1H),6.87(t,1H),6.65(s,2H),6.55–6.42(m,2H),4.20(dd,1H),3.86 (s,6H),3.79(s,2H),3.64(s,3H),3.14–2.97(m,4H),2.95–2.82(m,10H),2.82–2.59(m,3H),2.38–2.16 (m,3H),2.15–2.05(m,2H),2.00–1.73(m,3H).

Example 28: Synthesis of Compound 28

The hydrochloride of 26A (160 mg, crude product) and 13C (141 mg, 0.45 mmol) were dissolved in 6 mL of DMF, and acetic acid (0.1 mL) and molecular sieves (50 mg) were added, and stirred at 50°C for 1 h. Sodium triacetoxyborohydride (159 mg, 0.75 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The mixture was diluted with water, extracted with ethyl acetate, and the organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column to obtain compound 28 (50 mg, two-step yield: 23%; chiral HPLC retention time: 6.287 min).

Reversed Phase Chromatography Method:

Instrument: Isolera One; Column model: C18 spherical 20-35μM 100A 40g.

Mobile phase: A is 0.1% ammonium bicarbonate aqueous solution; B is acetonitrile; elution conditions: 5%-50% B gradient elution; flow rate: 60mL/min; column pressure: 3.0bar; detection wavelength: 210nm&254nm.

Chiral HPLC analysis method:

Instrument: CAS-CD-HPLC-E (SHIMADZU LC-20AD).

Chiral column: Chiralpak IE-3 50x 4.6mm I.D., 3um;

Mobile phase: A is n-hexane (0.05% IPAm), B is ethanol and acetonitrile (0.05% IPAm); gradient washing: 50% B in A.

Flow rate: 1 mL/min; column temperature: 35°C; detection wavelength: 220 nm; injection volume: 3 μL; running time: 15 min.

LCMS m/z = 723.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ7.66(s,1H),6.91(t,1H),6.68(s,2H),6.58–6.47(m,2H),4.24(dd,1H),3.88 (s,6H),3.82(s,2H),3.67(s,3H),3.16–3.00(m,4H),3.00–2.92(m,8H),2.92–2.85(m,2H),2.85–2.63 (m,3H),2.41–2.20(m,3H),2.18–2.07(m,2H),2.03–1.81(m,3H).

Example 29: Synthesis of Compound 29

The hydrochloride of 25A (200 mg, crude) and 22A (206 mg, 0.56 mmol) were dissolved in 6 mL of DMF, acetic acid (0.1 mL) and molecular sieves (50 mg) were added, and the mixture was stirred at 50 °C for 60 min. Sodium triacetoxyborohydride (198 mg, 0.94 mmol) was added, and the mixture was reacted at room temperature overnight. The mixture was diluted with water, extracted with ethyl acetate, and the organic layer was washed three times with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column to obtain compound 29 (39 mg, two-step yield: 13%; chiral retention time: 4.487 min).

LCMS m/z = 774.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.38(s,1H),7.64(s,1H),7.39(s,1H),6.91(t,1H),6.76(s,2H),6.58–6.47 (m,2H),4.24(dd,1H),3.90(s,6H),3.87(s,2H),3.67(s,3H),3.19–3.08(m,2H),3.01–2.91(m,8H ),2.88–2.67(m,3H),2.45–2.25(m,3H),2.23–2.12(m,1H),2.07–1.85(m,3H),1.36–1.29(m,2H),1.09–1.06 (m,2H).

Reversed Phase Chromatography Method:

Instrument: Isolera One; Column model: C18 spherical 20-35μM 100A 40g.

Mobile phase: A is 0.1% ammonium bicarbonate aqueous solution; B is acetonitrile; elution conditions: 5%-50% B gradient elution.

Flow rate: 60mL/min; column pressure: 3.0bar; detection wavelength: 210nm&254nm.

Chiral HPLC analysis method:

Instrument: CAS-CD-HPLC-E (SHIMADZU LC-20AD); Chiral column: Chiralpak IE-3 50x 4.6mm I.D., 3um;

Mobile phase: A is n-hexane (0.05% IPAm), B is ethanol and acetonitrile (0.05% IPAm); gradient washing: 50% B in A.

Flow rate: 1 mL/min; column temperature: 35°C; detection wavelength: 220 nm; injection volume: 3 μL; running time: 15 min.

Example 30: Synthesis of Compound 30

The hydrochloride of 26A (95.0 mg, crude product) and 22A (93.2 mg, 0.26 mmol) were dissolved in 2 mL of DMF, and acetic acid (2.6 mg, 0.04 mmol) and molecular sieves (50 mg) were added, and stirred at 50°C for 60 min. Sodium triacetoxyborohydride (93.3 mg, 0.44 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The mixture was diluted with water, extracted with ethyl acetate, and the organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column to obtain compound 30 (10 mg, two-step yield: 5.86%; chiral HPLC retention time: 7.579 min).

Reversed Phase Chromatography Method:

Instrument: Isolera One; Column model: C18 spherical 20-35μM 100A 40g.

Mobile phase: A is 0.1% ammonium bicarbonate aqueous solution; B is acetonitrile; elution conditions: 5%-50% B gradient elution.

Flow rate: 60mL/min; column pressure: 3.0bar; detection wavelength: 210nm&254nm.

Chiral HPLC analysis method:

Instrument: CAS-CD-HPLC-E (SHIMADZU LC-20AD); Chiral column: Chiralpak IE-3 50x 4.6mm I.D., 3um;

Mobile phase: A is n-hexane (0.05% IPAm), B is ethanol and acetonitrile (0.05% IPAm); gradient washing: 50% B in A.

Flow rate: 1 mL/min; column temperature: 35°C; detection wavelength: 220 nm; injection volume: 3 μL; running time: 15 min.

LCMS m/z = 774.3 [M+H] ⁺ .

Compound 30 was further separated and purified by preparative HPLC (instrument: SHIMADZU LC-20AP; chromatographic column model: Phenomenex C18; mobile phase: A is 0.1% TFA aqueous solution; B is acetonitrile; elution conditions: 1%-30% B gradient elution; flow rate: 25 mL/min, detection wavelength: 210 nm) to obtain the trifluoroacetate salt of compound 30.

¹ H NMR(400MHz,D ₂ O)δ9.36(s,1H),7.87(s,1H),7.48(s,1H),7.22(t,1H),6.81(s,2H),6.70–6.57 (m,2H),4.58–4.47(m,2H),4.40(dd,1H),3.98–3.83(m,7H),3.81–3.72(m,1H),3.67(s,3H),3.64–3.14 (m,11H),2.89–2.74(m,2H),2.41–2.21(m,4H),2.13–1.98(m,1H),1.35–1.25(m,2H),1.07–1.00(m,2H) .

Example 31: Synthesis of Compound 31

Referring to the synthesis method of compound 25, compound 31 (140 mg, chiral HPLC retention time: 7.970 min) was obtained by reacting the hydrochloride salt of 25A with 18C.

Chiral HPLC analysis method:

Instrument: CAS-CD-HPLC-E (SHIMADZU LC-20AD); Chiral column: Chiralpak IE-3 50x 4.6mm I.D., 3um;

Mobile phase: A is n-hexane (0.05% IPAm), B is ethanol and acetonitrile (0.05% IPAm); gradient washing: 50% B in A.

Flow rate: 1 mL/min; column temperature: 35°C; detection wavelength: 220 nm; injection volume: 2 μL; running time: 15 min.

LCMS m/z = 819.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.12(s,1H),7.45(s,1H),6.90(t,1H),6.76(s,2H),6.59–6.46(m,2H),6.27 (s,1H),4.43–4.34(m,1H),4.31–4.19(m,3H),3.96–3.80(m,10H),3.59(s,3H),3.34(s,3H),3.19–3.05 (m,2H),3.02–2.90(m,8H),2.88–2.64(m,3H),2.44–2.22(m,3H),2.06–1.81(m,3H).

Example 32: Synthesis of Compound 32

Referring to the synthesis method of compound 26, compound 32 (30 mg, chiral HPLC retention time: 13.745 min) was obtained by reacting the hydrochloride salt of 26A with 18C.

Chiral HPLC analysis method:

Instrument: CAS-CD-HPLC-E (SHIMADZU LC-20AD); Chiral column: Chiralpak IE-3 50x 4.6mm I.D., 3um;

Mobile phase: A is n-hexane (0.05% IPAm), B is ethanol and acetonitrile (0.05% IPAm); gradient wash: 50% B in A; flow rate: 1 mL/min; column temperature: 35°C; detection wavelength: 220 nm; injection volume: 2 μL; running time: 15 min.

LCMS m/z = 819.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.12(s,1H),7.46(s,1H),6.91(t,1H),6.76(s,2H),6.58–6.48(m,2H),6.28 (s,1H),4.42–4.35(m,1H),4.30–4.21(m,3H),3.94–3.83(m,10H),3.60(s,3H),3.35(s,3H),3.22–3.10 (m,2H),3.05–2.90(m,8H),2.88–2.67(m,3H),2.49–2.25(m,3H),2.06–1.83(m,3H).

Example 33: Synthesis of Compound 33

The hydrochloride of 25A (2 g, crude product) and 15B (2.15 g, 5.17 mmol) were dissolved in 20 mL of DMF, acetic acid (1.3 mL) and molecular sieves (300 mg) were added, stirred at 50°C for 60 min, sodium triacetoxyborohydride (1.99 g, 9.4 mmol) was added, and the reaction was allowed to react overnight at room temperature. The mixture was diluted with water, extracted with ethyl acetate, and the organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column to obtain compound 33 (1.13 g, two-step yield: 36%).

The reverse phase chromatography method was the same as that of compound 25.

LCMS m/z = 825.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.19(s,1H),7.51(s,1H),6.90(t,1H),6.76(s,2H),6.58–6.47(m,2H),6.45 (s,1H),4.51–4.37(m,4H),4.22(dd,1H),3.89(s,6H),3.84(s,2H),3.61(s,3H),3.18–3.07(m,2H ),3.02–2.90(m,8H),2.88–2.65(m,3H),2.44–2.23(m 3H),2.03–1.82(m,3H).

Example 34: Synthesis of Compound 34

The hydrochloride of 26A (80 mg, crude product) and 15B (87 mg, 0.21 mmol) were dissolved in 6 mL of DMF, and acetic acid (0.1 mL) and molecular sieves (50 mg) were added, and stirred at 50°C for 60 min. Sodium triacetoxyborohydride (81 mg, 0.38 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. The mixture was diluted with water, extracted with ethyl acetate, and the organic layer was washed three times with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase column to obtain compound 34 (30 mg, two-step yield: 19%).

The reverse phase chromatography method was the same as that of compound 26.

LCMS m/z = 825.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.19(s,1H),7.51(s,1H),6.91(t,1H),6.76(s,2H),6.58–6.47(m,2H),6.45 (s,1H),4.49–4.38(m,4H),4.24(dd,1H),3.89(s,6H),3.84(s,2H),3.62(s,3H),3.19–3.08(m,2H ),3.01–2.91(m,8H),2.87–2.67(m,3H),2.45–2.24(m 3H),2.06–1.81(m,3H).

Example 35: Synthesis of Compound 35

Referring to the synthesis method of compound 25, compound 35 (500 mg) was obtained by reacting the hydrochloride of 25A with 19A.

LCMS m/z = 777.2 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.15(s,1H),7.42(s,1H),6.91(t,1H),6.78(s,2H),6.58–6.45(m,3H),4.24 (dd,1H),3.89(d,6H),3.85(s,2H),3.59(s,3H),3.18–3.07(m,8H),3.02–2.96(m,8H),2.87–2.68(m ,3H),2.44–2.23(m,3H),2.03–1.82(m,3H).

Example 36: Synthesis of Compound 36

Referring to the synthesis method of compound 26, compound 36 (23 mg) was obtained by reacting the hydrochloride of 26A with 19A.

LCMS m/z = 777.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.16(s,1H),7.42(s,1H),6.91(t,1H),6.78(s,2H),6.58–6.46(m,3H),4.24 (dd,1H),3.89(s,6H),3.85(s,2H),3.59(s,3H),3.17–3.08(m,8H),2.99–2.93(m,8H),2.83–2.68(m ,3H),2.44–2.22(m,3H),2.00–1.82(m,3H).

Example 37: Synthesis of Compound 37

Referring to the synthesis method of compound 25, compound 37 (1.2 g) was obtained by reacting the hydrochloride of 25A with 10D.

LCMS m/z = 807.3 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ )δ10.74(s,1H),9.05(s,1H),7.64(s,1H),6.81(t,1H),6.75(s,2H),6.50(dd,1H),6.41(dd,1H),6.32(s,1H),5.78(d,1H),5.60–5.40(m,1H),4.41 –4.20(m,3H),4.16–4.02(m,2H),3.82(s,6H),3.65(s,2H),3.49(s,3H),3.03–2.91(m,2H),2.87–2.66(m,10H),2.59–2.52(m,1H),2.35–2.03(m,3 H),1.90–1.69(m,3H).

Example 38: Synthesis of Compound 38

Referring to the synthesis method of compound 26, compound 38 (30 mg) was obtained by reacting the hydrochloride of 26A with 10D.

LCMS m/z = 807.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.12(s,1H),7.45(s,1H),6.89(t,1H),6.74(s,2H),6.56–6.44(m,2H),6.31 (s,1H),5.56–5.34(m,1H),4.42–4.29(m,2H),4.22(dd,1H),4.18–4.05(m,2H),3.87(s,6H),3.83(s ,2H),3.58(s,3H),3.16–3.06(m,2H),3.00–2.88(s,8H),2.85–2.66(m,3H),2.42–2.22(m,3H),2.02–1.80 (m,3H).

Example 39: Synthesis of Compound 39

Referring to the synthesis method of compound 25, compound 39 (1.0 g) was obtained by reacting the hydrochloride of 25A with 17C.

LCMS m/z = 803.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.07(s,1H),7.41(s,1H),6.88(t,1H),6.73(s,2H),6.56–6.44(m,2H),6.21 (s,1H),4.25–4.13(m,3H),3.87(s,6H),3.82(s,2H),3.64–3.58(m,2H),3.56(s,3H),3.16–3.04(m ,2H),2.99–2.93(m,8H),2.88–2.64(m,4H),2.42–2.21(m,3H),2.01–1.78(m,3H),1.29(d,3H).

Example 40: Synthesis of Compound 40

Referring to the synthesis method of compound 26, compound 40 (0.15 g) was obtained by reacting the hydrochloride of 26A with 17C.

LCMS m/z = 803.2 [M+H] ⁺ .

Example 41: Synthesis of Compound 41

Referring to the synthesis method of compound 25, compound 41 (400.0 mg) was obtained by reacting the hydrochloride of 25A with 23D.

LCMS m/z = 814.8 [M+H] ⁺ .

¹ H NMR (400MHz, CDCl ₃ ) δ9.62(s,1H),8.07(s,1H),8.00(s,1H),7.89(s,1H),7.53(s,1H),7.25(s, 1H),6.91–6.82(m,1H),6.59(s,2H),6.45–6.36(m,2H),4.03–3.93(m,4H),3.90(s,2H),3.85(s,6H) ,3.66(s,3H),3.31–3.14(m,2H),3.08–2.91(m,8H),2.90–2.82(m,1H),2.80–2.48(m, 3H),2.45–2.19(m,2H),2.07–1.80(m,3H).

Example 42: Synthesis of Compound 42

Referring to the synthesis method of compound 25, compound 42 (1.4 g) was obtained by reacting the hydrochloride of 25A with 23D.

LCMS m/z = 819.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.16(s,1H),7.43(s,1H),6.87(t,1H),6.74(s,2H),6.63(s,1H),6.55–6.46 (m,2H),4.21(dd,1H),3.86(s,6H),3.82(s,2H),3.78–3.73(m,4H),3.58(s,3H),3.56–3.52(m,4H ),3.15–3.04(m,2H),2.98–2.88(m,8H),2.85–2.63(m,3H),2.42–2.22(m,3H),2.01–1.81(m,3H).

Example 43: Synthesis of Compound 43

Step 1: Synthesis of 43B

Under nitrogen protection, 43A (272 mg, 1.35 mmol), cyclopropylboronic acid (230 mg, 2.7 mmol), palladium acetate (30 mg, 0.14 mmol), tricyclohexylphosphine (76 mg, 0.27 mmol) and potassium phosphate (570 mg, 2.7 mmol) were added to a 15 mL sealed tube, 1,4-dioxane (4 mL) and water (1 mL) were added, and stirred at 100°C for 3 h. After cooling to room temperature, 50 mL of water was added to dilute, and then extracted with ethyl acetate (40 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 43B (100 mg, yield: 45.45%).

LCMS m/z = 164.2 [M+H] ⁺ .

Step 2: Synthesis of 43C

43B (100 mg, 0.61 mmol) was dissolved in 2 mL of acetic acid, and NBS (110 mg, 0.64 mmol) was added. The mixture was protected by nitrogen and reacted at room temperature for 3 h. The mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined and washed twice with saturated sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 43C (58 mg, yield: 39.27%).

LCMS m/z = 242.1 [M+H] ⁺ .

Step 3: 43D synthesis

Under nitrogen protection, 43C (56 mg, 0.23 mmol), (4-formyl-3,5-dimethoxyphenyl)boronic acid (82 mg, 0.39 mmol), Pd(dppf)Cl _2. DCM (19 mg, 0.023 mmol) and cesium carbonate (150 mg, 0.46 mmol) were placed in a 15 mL sealed tube, 1,4-dioxane (1.5 mL) and water (0.5 mL) were added, and stirred at 100°C for 2 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 43D (34 mg, yield: 45.16%).

LCMS m/z = 328.1 [M+H] ⁺ .

Step 4: Synthesis of 43E

1d (66 mg, 0.15 mmol), 43D (34 mg, 0.10 mmol) were dissolved in 2 mL DMF, AcOH (0.1 mL) and Molecular sieve 30 mg, react at 50°C for 1 h, cool to room temperature, add sodium triacetoxyborohydride (42 mg, 0.2 mmol), stir at room temperature overnight. Dilute with water, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate and purify the residue by preparative HPLC to obtain trifluoroacetate of compound 43 (17 mg, yield: 23.10%).

Preparative HPLC method:

Instrument: SHIMADZU LC-20AP; Chromatographic column: Phenomenex C18 (150 mm × 25 mm, I.D, 10 um particle size);

Mobile phase: A is 0.1% TFA in water; B is acetonitrile; Elution conditions: mobile phase A content from 5% to 35%, gradient elution for 10 minutes;

Flow rate: 25 mL/min; column temperature: room temperature; detection wavelength: 210 nm;

LCMS m/z = 737.7 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ7.47(s,1H),6.93–6.84(m,1H),6.64(s,2H),6.55–6.43(m,2H),4.21(dd,1H) ,3.84(s,6H),3.81(s,2H),3.60(s,3H),3.11–3.02(m,2H),2.93(s,8H),2.84–2.66(m,3H),2.34–2.18 (m,6H),1.99–1.82(m,4H),0.82–0.73(m,2H),0.24–0.14(m,2H).

Example 44: Synthesis of Compound 44-1 and Compound 44-2

Step 1: Synthesis of 44A

Dissolve B-1 (1.0 g, 1.9 mmol) in 15 mL of acetonitrile, add 4N hydrochloric acid/dioxane solution (5 mL), stir and react at room temperature for 1 h, and concentrate under reduced pressure to obtain the hydrochloride of 44A (1.3 g, crude product).

LCMS m/z = 426.1 [M+H] ⁺ .

Step 2: Synthesis of compounds 44-1 and 44-2

44A (500 mg, 1.21 mmol, crude) and 13C (0.44 g, 1.40 mmol) were dissolved in 15 mL DMF, acetic acid (0.5 mL) was added, stirred at 25°C for 60 minutes, NaBH(OAc) ₃ (0.74 mg, 3.52 mmol) was added, and the reaction was allowed to react at room temperature overnight. The mixture was diluted with water, and pH was adjusted to 8 with saturated sodium bicarbonate, extracted with ethyl acetate (10 mL×3), the organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase column to obtain compound 44 (610 mg, 72%), which was then separated by SFC to obtain compound 44-1 (254.1 mg, retention time: 1.408 min) and compound 44-2 (190.2 mg, retention time: 2.006 min).

SFC chiral preparation method:

Instrument: Waters 150 SFC; Preparative column model: Chiralpak AS Column (250×30 mm, I.D 30 mm, 10 um particle size).

Mobile phase: A is CO ₂ ; B is ethanol and acetonitrile solution containing 0.1% ammonia water; elution condition: 45% B isocratic elution.

Flow rate: 120 mL/min; column pressure: 100 bar; column temperature: 25°C; detection wavelength: 220 nm.

Post-treatment: After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compounds 44-1 and 44-2.

Chiral analysis conditions:

Instrument: Shimadzu LC-30AD; Chiral column: Chiralpak AS-3 50×4.6mm I.D., 3μm.

Mobile phase: A is CO ₂ ; B is ethanol and acetonitrile (0.05% diethylamine); flow rate: 3 mL/min.

Column temperature: 35°C; detection wavelength: 220nm.

Compound 44-1:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.74(s,1H),7.75(s,1H),6.81(t,1H),6.66(s,2H),6.55–6.36(m,2H), 5.77(d,1H),4.29–4.19(m,1H),3.81(s,6H),3.65–3.55(m,2H),3.50(s,3H),3.02–2.87(m,4H),2.86– 2.65(m,12H),2.62–2.53(m,1H),2.34–1.92(m,5H),1.90–1.66(m,3H).

LCMS m/z = 723.4 [M+H] ⁺ .

Compound 44-2:

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.74(s,1H),7.75(s,1H),6.81(t,1H),6.66(s,2H),6.53–6.37(m,2H), 5.77(d,1H),4.28–4.18(m,1H),3.81(s,6H),3.66–3.57(m,2H),3.50(s,3H),3.01–2.87(m,4H),2.86– 2.65(m,12H),2.61–2.52(m,1H),2.34–1.93(m,5H),1.90–1.67(m,3H).

LCMS m/z = 723.4 [M+H] ⁺ .

Example 45: Synthesis of Compound 45

Step 1: Synthesis of 45a

1-Cbz-4-piperidone (1.5 g, 6.42 mmol), N-tert-butyloxycarbonyl-1,2-ethylenediamine (1.0 g, 6.42 mmol), acetic acid (0.81 g, 13.48 mmol) were dissolved in 20 mL of dichloromethane, stirred at room temperature for 30 min, sodium triacetoxyborohydride (1.77 g, 8.35 mmol) was added, and stirred at room temperature for 1.5 h. A small amount of saturated sodium bicarbonate was added to adjust the pH of the filtrate to 7-8, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain 45a (2.1 g, yield: 86.65%).

LCMS m/z = 378.3 [M+H] ⁺ .

Step 2: Synthesis of 45b

45a (2.1 g, 5.56 mmol) was dissolved in 30 mL of dichloromethane, DIPEA (2.16 g, 16.68 mmol) was added, chloroacetyl chloride (0.75 g, 6.67 mmol) was added dropwise at 0°C, and stirred at room temperature overnight. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain 45b (1.1 g, yield 43.58%).

LCMS m/z=354.2[M+H-100] ⁺ .

Step 3: Synthesis of 45c

45b (2.0 g, 4.41 mmol) was dissolved in 20 mL DMF, potassium tert-butoxide (1.1 g, 9.7 mmol) was added, and the mixture was reacted at 70°C overnight. The mixture was cooled to room temperature, 50 mL of ethyl acetate was added, and the mixture was washed with water twice, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 45c (1.54 g, yield: 83.64%).

LCMS m/z=362.2[M+H-56] ⁺ .

Step 4: Synthesis of 45d

45c (1.54 g, 3.69 mmol) was dissolved in 10 mL of methanol, 0.15 g of 10% palladium carbon was added, hydrogen was replaced three times, and the mixture was reacted at room temperature for 2 h. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 45d (1.0 g, yield 95.64%).

LCMS m/z = 284.3 [M+H] ⁺ .

Step 5: Synthesis of 45e

45d (1.1 g, 3.88 mmol) was dissolved in 10 mL DMF, 3,4-difluoronitrobenzene (0.62 g, 3.88 mmol) and cesium carbonate (2.53 g, 7.77 mmol) were added, and the mixture was reacted at 50°C for 16 h under nitrogen protection. The mixture was cooled to room temperature, 150 ml of ethyl acetate was added, and the mixture was washed with water (50 mL × 3), washed once with 50 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 45e (1.35 g, yield 82.36%).

LCMS m/z = 423.1 [M+H] ⁺ .

Step 6: Synthesis of 45f

45e (1.3 g, 3.08 mmol) was dissolved in 20 mL of ethyl acetate, 0.13 g of 10% palladium carbon was added, hydrogen was replaced three times, and the reaction was carried out at room temperature for 2 h. The palladium carbon was filtered and the filtrate was concentrated under reduced pressure to obtain 45f (1.15 g, yield 95.14%).

LCMS m/z = 393.3 [M+H] ⁺ .

Step 7: Synthesis of 45g

45f (0.8 g, 2.04 mmol) was dissolved in 10 mL DMF, 3-bromopiperidine-2,6-dione (1.18 g, 6.12 mmol) and sodium bicarbonate (1.03 g, 12.24 mmol) were added, and the mixture was reacted at 90° C. overnight. The mixture was concentrated under reduced pressure and purified by column chromatography to obtain the product 45g (0.45 g, yield 43.8%).

LCMS m/z = 504.8 [M+H] ⁺ .

Step 8: 45h Synthesis

Dissolve 45g (0.45g, 0.89mmol) in 10mL acetonitrile, add 3mL 4N hydrochloric acid dioxane solution, react at room temperature for 30min, concentrate under reduced pressure to remove the solvent, add 20mL 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 45g (0.35g, yield 97.47%).

LCMS m/z = 404.1 [M+H] ⁺ .

Step 9: Synthesis of compound 45

45h (0.20 g, 0.50 mmol) and 13C (0.16 g, 0.50 mmol) were dissolved in 10 mL of chloroform, acetic acid (0.06 g, 1 mmol) was added dropwise, and the mixture was stirred at 50°C for 2 h under nitrogen protection, cooled to room temperature, and sodium triacetoxyborohydride (0.21 g, 1 mmol) was added, and the mixture was reacted at room temperature for 18 h. The mixture was quenched with saturated sodium bicarbonate solution, extracted with DCM (30 mL×3), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain compound 45 (82 mg, yield: 23.4%).

LCMS m/z = 701.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ7.65(s,1H),6.93(t,1H),6.69(s,2H),6.57–6.45(m,2H),4.50–4.37(m,1H) ,4.23(dd,1H),3.89(s,6H),3.78(s,2H),3.66(s,3H),3.40–3.25(m,4H),3.22(s,2H),3.07–2.97(m ,2H),2.94–2.66(m,8H),2.37–2.26(m,1H),2.18–2.06(m,2H),2.04–1.88(m,3H),1.74–1.63(m,2H).

Example 46: Synthesis of Compound 46

45h (0.15 g, 0.37 mmol) and 22A (0.13 g, 0.37 mmol) were dissolved in 10 mL of chloroform, acetic acid (0.044 g, 0.74 mmol) was added dropwise, stirred at 50°C for 2 h under nitrogen protection, cooled to room temperature, sodium triacetoxyborohydride (0.16 g, 0.74 mmol) was added, and reacted at room temperature for 18 h. The mixture was quenched with saturated sodium bicarbonate solution, extracted with DCM (30 mL×3), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain compound 46 (0.11 g, yield: 39.54%).

LCMS m/z = 752.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ10.76(s,1H),9.27(s,1H),7.79(s,1H),7.43(s,1H),6.85(t,1H),6.76( s,2H),6.56–6.36(m,2H),5.80(d,1H),4.36–4.21(m,2H),3.84(s,6H),3.63(s,2H), 3.55(s,3H),3.26–3.11(m,4H),3.04(s,2H),2.79–2.54(m,6H),2.31–2.22(m,1H),2.13–2.03(m,1H), 1.92–1.75(m,3H),1.60–1.49(m,2H),1.05–0.90(m,4H).

Example 47: Synthesis of Compounds 47-1 and 47-2

44A (978 mg, 2.3 mmol, crude) and 22A (1.0 g, 2.76 mmol) were dissolved in 30 mL DMF, acetic acid (1 mL) was added, stirred at 25°C for 1 h, NaBH(OAc) ₃ (1.46 g, 6.9 mmol) was added, and the mixture was reacted at room temperature overnight. The mixture was diluted with water, and pH was adjusted to 8 with saturated sodium bicarbonate, extracted with ethyl acetate (10 mL×3), and the organic layer was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase column to obtain compound 47 (630 mg, 75%), which was then separated to obtain compound 47-1 (P1: 250 mg, retention time: 1.259 min) and compound 47-2 (P2: 275 mg, retention time: 1.621 min).

SFC chiral preparation method:

Instrument: Waters 150SFC; Preparative column model: Chiralpak AS Column (250×30 mm, I.D 30 mm, 10 um particle size).

Mobile phase: A is CO ₂ ; B is ethanol and acetonitrile solution containing 0.1% ammonia water; elution condition: 45% B isocratic elution.

Flow rate: 120 mL/min; column pressure: 100 bar; column temperature: 25°C; detection wavelength: 220 nm.

Post-treatment: After preparative separation, the components with the same retention time were combined and concentrated under reduced pressure to obtain compounds 47-1 and 47-2.

Chiral analysis conditions:

Instrument: Shimadzu LC-30AD; Chiral column: Chiralpak AS-3 50×4.6mm I.D., 3μm.

Mobile phase: A is CO ₂ ; B is ethanol and acetonitrile (0.05% diethylamine) Flow rate: 3 mL/min; Column temperature: 35°C;

Detection wavelength: 220nm.

Compound 47-1:

¹ H NMR (400MHz, CD ₃ OD) δ9.38(s,1H),7.64(s,1H),7.40(s,1H),6.95–6.87(m,1H),6.76(s,2H),6.58 –6.47(m,2H),4.24(dd,1H),3.92–3.83(m,8H),3.68(s,3H),3.20–3.09(m,2H),3.02–2.92(m,8H),2.89 –2.67(m,3H),2.47–2.26(m,3H),2.21–2.12(m,1H),2.07–1.84(m,3H),1.13–1.04(m,4H).

LCMS m/z = 774.4 [M+H] ⁺ .

Compound 47-2:

¹ H NMR (400MHz, CD ₃ OD) δ9.38(s,1H),7.64(s,1H),7.39(s,1H),6.95–6.87(m,1H),6.76(s,2H),6.58 –6.46(m,2H),4.24(dd,1H),3.93–3.85(m,8H),3.67(s,3H),3.21–3.11(m,2H),3.02–2.91(m,8H),2.88 –2.66(m,3H),2.47–2.25(m,3H),2.22–2.10(m,1H),2.06–1.83(m,3H),1.12–1.03(m,4H).

LCMS m/z = 774.4 [M+H] ⁺ .

Example 48: Synthesis of Compound 48

Step 1: Synthesis of 48D

Under nitrogen protection, 48C (6.6 g, 21.3 mmol) was dissolved in 20 mL of ethanol, and DIPEA (18.2 mL, 106.5 mmol) and methyl acrylate (3.86 mL, 42.6 mmol) were added, and the reaction was allowed to proceed overnight at room temperature. The solvent was removed under reduced pressure, and the mixture was diluted with 50 mL of water, extracted three times with 100 mL of ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. After reduced pressure concentration, the residue was purified by column chromatography to obtain 48D (6.5 g, yield: 77%).

LCMS m/z = 396.2 [M+H] ⁺ .

Step 2: Synthesis of 48E

Under nitrogen protection, 48D (6.5 g, 16.46 mmol) was dissolved in 100 mL of ultra-dry THF, and bromonitrile (3.5 g, 32.92 mmol) and sodium bicarbonate (2.71 g, 82.3 mmol) were added in sequence, and the mixture was kept at 35°C overnight. The reaction mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 48E (6.2 g, yield: 90%).

LCMS m/z = 421.2 [M+H] ⁺ .

Step 3: Synthesis of 48F

48E (7.21 g, 17.2 mmol) was dissolved in 80 mL of toluene, and acetaldehyde oxime (3.1 mL, 51.6 mmol) and indium trichloride tetrahydrate (1.14 g, 5.16 mmol) were added under nitrogen protection, and the reaction was refluxed overnight. The reaction was cooled to room temperature, the solvent was removed under reduced pressure, diluted with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, and filtered, and the residue was concentrated under reduced pressure and purified by column chromatography to obtain 48F (3.0 g, yield: 43%).

LCMS m/z = 407.2 [M+H] ⁺ .

Step 4: Synthesis of 48G

Under nitrogen protection, 48F (0.91 g, 2.24 mmol) was dissolved in 15 mL of acetonitrile, and 5 mL of 1,4-dioxane hydrochloride solution was added. The mixture was reacted at room temperature for 1 h, and the solvent was removed by concentration under reduced pressure to obtain 48G (0.69 g, crude product).

LCMS m/z = 307.2 [M+H] ⁺ .

Step 5: Synthesis of 48H

48G (0.69 g, crude product) was dissolved in 30 mL toluene and 15 mL acetonitrile, and sodium acetate (0.46 g, 5.6 mmol), acetic acid (1 mL) and dried powder were added in sequence under nitrogen protection. Molecular sieves (1.0 g) were added, stirred at room temperature for 15 min, tert-butyl 3,3-difluoro-4-oxopiperidine-1-carboxylate (0.74 g, 3.14 mmol) was added, and the mixture was reacted at 100°C for 12 h. The mixture was cooled to room temperature, the molecular sieves were filtered out by padding with celite, and the filtrate was concentrated under reduced pressure to obtain 48H (1.2 g crude product).

LCMS m/z = 524.2 [M+H] ⁺ .

Step 6: Synthesis of 48I

Under nitrogen protection, 48H (1.2 g crude product) was dissolved in 30 mL ultra-dry methanol and 30 mL ultra-dry DCE, and acetic acid (1 mL) and sodium cyanoborohydride (0.42 g, 6.72 mmol) were added, and the mixture was allowed to stand at room temperature overnight. The mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 48I (1.15 g, three-step yield: 97%).

LCMS m/z = 526.2 [M+H] ⁺ .

Step 7: Synthesis of 48J

Under nitrogen protection, 48I (1.15 g, 2.19 mmol) was dissolved in 15 mL of acetonitrile, and 5 mL of 1,4-dioxane hydrochloric acid solution was added. The mixture was reacted at room temperature for 1 h and concentrated under reduced pressure to obtain 48J (1.3 g, crude product).

LCMS m/z = 426.2 [M+H] ⁺ .

Step 8: Synthesis of Compound 48

48J (400 mg, 0.94 mmol) and 13C (355 mg, 1.13 mmol) were dissolved in 15 mL of chloroform, and acetic acid (110 mg, 1.88 mmol) and dried powder were added under nitrogen protection. Molecular sieves (100 mg) were added and reacted at room temperature for 30 min. Sodium triacetoxyborohydride (300 mg, 1.41 mmol) was added and reacted at room temperature overnight. The molecular sieves were filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 48 (110 mg, yield: 16%).

LCMS m/z = 723.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ7.63(s,1H),7.07–6.95(m,3H),6.66(s,2H),4.51(s,2H),3.86(s,6H),3.80 (s,2H),3.64(s,3H),3.38–3.33(m,2H),3.13–2.98(m,8H),2.97–2.91(m,4H),2.90–2.83(m,2H),2.76 –2.63(m,1H),2.63–2.57(m,2H),2.38–2.17(m,2H),2.16–2.05(m,2H),2.00–1.88(m,1H),1.86–1.78(m, 1H).

Example 49: Synthesis of Compound 49

Step 1: Synthesis of 49B

49A (2.5 g, 11.36 mmol) was dissolved in 30 mL of ethanol and 10 mL of water, and iron powder (3.18 g, 22.72 mmol) and ammonium chloride (6.08 g, 0.11 mol) were added in sequence under nitrogen protection, and the mixture was reacted at 75°C for 3 h. Filtered through diatomaceous earth, the filtrate was decompressed and 100 mL of ethyl acetate was added to dissolve it, and the organic phase was washed once with 50 mL of water and 50 mL of saturated brine, respectively, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed to obtain 49B (2.25 g, yield: 99%).

LCMS m/z = 190.1 [M+H] ⁺ .

Step 2: Synthesis of 49C

49B (2.25 g, 11.84 mmol) and 3-bromopiperidine-2,6-dione (6.82 g, 35.5 mmol) were placed in a sealed tube, 10 mL of DMF and sodium bicarbonate (5.97 g, 71.04 mmol) were added, and the mixture was reacted overnight at 90°C. 100 mL of ethyl acetate was added to dilute the mixture, and the organic phase was washed three times with 50 mL of water and once with 50 mL of saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was slurried to obtain 49C (0.76 g, yield: 21%).

LCMS m/z = 301.1 [M+H] ⁺ .

Step 3: Synthesis of 49D

Under nitrogen protection, 49C (0.7 g, 2.3 mmol), C-6 (0.91 g, 2.3 mmol), RuPhos Pd G3 (193 mg, 0.23 mmol), X-PHOS (219 mg, 0.46 mmol) and potassium phosphate (975 mg, 4.6 mmol) were placed in a sealed tube, 15 mL of 1,4-dioxane and 4 mL of water were added, and the mixture was reacted at 60°C for 2 h. The reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain 49D (789 mg, yield: 74%).

LCMS m/z = 490.2 [M+H] ⁺ .

Step 4: Synthesis of 49E

Under nitrogen protection, 49D (789 mg, 1.61 mmol) was dissolved in 10 mL of acetonitrile, 5 mL of hydrochloric acid/1,4-dioxane solution was added, the mixture was reacted at room temperature for 1 h, and the mixture was concentrated under reduced pressure to obtain 49E (933 mg crude product).

LCMS m/z = 390.1 [M+H] ⁺ .

Step 5: Synthesis of compound 49

49E (260 mg, 0.67 mmol) and 13C (210 mg, 0.67 mmol) were dissolved in 15 mL of chloroform, and acetic acid (80 mg, 1.34 mmol) and dried powder were added under nitrogen protection. Molecular sieves (50 mg), stirred at room temperature for 15 min, reacted at 70°C for 1 h, cooled to room temperature, added sodium triacetoxyborohydride (212 mg, 1.0 mmol), and allowed to stand at room temperature overnight. Filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 49 (35 mg, yield: 7.6%).

LCMS m/z = 687.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ7.73–7.64(m,2H),7.57–7.51(m,1H),7.30–7.19(m,2H),6.71(s,2H),6.67–6.54( m,2H),4.38(dd,1H),3.99(s,2H),3.92(s,6H),3.78(s,2H),3.67(s,3H),3.24–3.11(m,2H),3.07 –3.00(m,2H),2.93–2.69(m,4H),2.42–2.30(m,1H),2.18–2.07(m,2H),2.06–1.93(m,1H).

Example 50: Synthesis of Compound 50

Referring to the preparation method of compound 49, 22A+49E was reacted to obtain compound 50 (29 mg)

LCMS m/z = 738.2 [M+H] ⁺ .

¹ H NMR (400 MHz, CD ₃ OD)δ9.37(s,1H),7.71(s,1H),7.65(s,1H),7.54(d,1H),7.40(s,1H),7.29–7.22(m,2H),6.79(s,2H),6.69–6.53(m,2H),4.38(dd,1H),4.03(s,2H) ,3.93(s,6H),3.82(s,2H),3.66(s,3H),3.27–3.17(m,2H),2.92–2.70(m,2H),2.41–2.32(m,1H),2.21–2.11(m,1H),2.06–2.93(m,1H),1.11–1. 03(m,4H).

Example 52: Synthesis of Compound 52

48J (450 mg, 1.06 mmol) and 22A (384 mg, 1.06 mmol) were dissolved in 15 mL of chloroform, and acetic acid (110 mg, 1.88 mmol) and dried powder were added under nitrogen protection. Molecular sieves (100 mg) were added and stirred at room temperature for 30 min. Sodium triacetoxyborohydride (330 mg, 1.59 mmol) was added and the mixture was allowed to stand overnight at room temperature. The molecular sieves were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain compound 52 (10 mg, yield: 1.2%).

LCMS m/z = 774.3 [M+H] ⁺ .

¹ H NMR (400MHz, CD ₃ OD) δ9.37(s,1H),7.75(s,1H),7.43(s,1H),7.10–6.97(m,3H),6.88(s,2H),4.57 –4.46(m,4H),3.97(s,6H),3.90–3.79(m,1H),3.72–3.64(m,4H),3.60–3.45(m,1H),3.40–3.33(m,2H) ,3.33–3.20(m,2H),3.12–3.00(m,8H),2.65–2.57(m,2H),2.36–2.15(m,3H), 1.19–1.05(m,4H).

Control compound 1 (WO2021178920 Example 172): Control compound 2 (WO2021178920 Example 176), control compound 3 (WO2021178920 Example 184).

Biological test example 1:

Study on the degradation activity of BRD9 protein in Yamato-SS cells

Human synovial sarcoma cell line Yamato-SS was purchased from Riken, culture conditions: 80% DMEM + 20% FBS, cultured at 37°C, 5% CO ₂ incubator. On the first day, Yamato-SS cells in the exponential growth phase were collected and plated on 12-well plates with a density of 3×10 ⁵ cells/well, and cultured overnight in a 37°C, 5% CO ₂ incubator. On the second day, different concentrations of compounds were added and cultured in a 37°C, 5% CO ₂ incubator for 24 hours. After the culture, the cells were collected, lysed on ice for 15 minutes with RIPA lysis buffer (beyotime, Cat. P0013B), centrifuged at 12000 rpm and 4°C for 10 minutes, and the supernatant protein samples were collected. After protein quantification using a BCA kit (Beyotime, Cat. P0009), the protein was diluted to 1 mg/mL, and the expression of BRD9 (CST, Cat. 58906) and the internal reference β-actin (CST, Cat. 3700S) was detected using an automatic protein blotting quantitative analyzer (Proteinsimple). The expression of BRD9 relative to the internal reference was calculated using COmpass software, and the DC ₅₀ value was calculated using GraphPad Prism 8.0 software according to formula (1). Protein _{administration} is the relative expression of BRD9 in different dose administration groups, and Protein _solvent is the relative expression of BRD9 in the solvent control group.

Protein % = Protein _{administration} /Protein _solvent × 100% Formula (1)

The test results are shown in Table 1:

Table 1

*:A: degradation rate ≥50%;

**: A: DC ₅₀ ≤10nM;

NC: not detected;

Conclusion: The compounds of the present invention have a good degradation effect on BRD9 protein in Yamato-SS cells.

Biological test example 2:

Study on the degradation activity of BRD7 protein in Yamato-SS cells

Human synovial sarcoma cell line Yamato-SS was purchased from Riken, culture conditions: 80% DMEM + 20% FBS, cultured at 37°C, 5% CO ₂ incubator. On the first day, Yamato-SS cells in the exponential growth phase were collected and plated on 12-well plates with a density of 3×10 ⁵ cells/well, and cultured overnight in a 37°C, 5% CO ₂ incubator. On the second day, different concentrations of compounds were added and cultured in a 37°C, 5% CO ₂ incubator for 24 hours. After the culture, the cells were collected, lysed on ice for 15 minutes with RIPA lysis buffer (beyotime, Cat. P0013B), centrifuged at 12000 rpm, 4°C for 10 minutes, and the supernatant protein samples were collected. After protein quantification using a BCA kit (Beyotime, Cat. P0009), the protein was diluted to 1 mg/mL, and the expression of BRD7 (CST, Cat. 15125S) and the internal reference β-actin (CST, Cat. 3700S) was detected using a fully automatic protein blot quantitative analyzer (Proteinsimple). The expression of BRD7 relative to the internal reference was calculated using Compass software, and the DC ₅₀ value was calculated using GraphPad Prism 8.0 software according to formula (2). Protein _{administration} is the relative expression of BRD7 in different dose administration groups, and Protein _solvent is the relative expression of BRD7 in the solvent control group.

Protein % = Protein _{administration} /Protein _solvent × 100% Formula (2)

Conclusion: The compounds of the present invention have no obvious degradation effect on BRD7 protein in Yamato-SS cells.

Biological test example 3:

Yamato-SS cell proliferation inhibition assay

Human synovial sarcoma cell line Yamato-SS was purchased from Riken, culture conditions: 80% DMEM + 20% FBS, cultured at 37°C, 5% CO ₂ incubator. On the first day, Yamato-SS cells in the exponential growth phase were collected and plated on a transparent bottom black 96-well culture plate with a density of 500 cells/well, and cultured overnight in a 37°C, 5% CO ₂ incubator. On the second day, different concentrations of compounds were added and cultured in an incubator at 37°C and 5% _CO2. After the compounds were incubated for 7 days, the original culture medium was removed and 50 μL of trypsin (Gibco) was added to digest the cells. After the cells were completely digested, 150 μL of complete culture medium was added to terminate the digestion and mix the cells. 40 μL of cells were taken to a new 96-well culture plate, 160 μL of complete culture medium was added, and 40 μL of cells were taken to a new 96-well culture plate after mixing again. 140 μL of complete culture medium and 20 μL of compounds containing different concentrations were added to keep the final DMSO concentration of each well at 0.1%. The cells were cultured in an incubator at 37°C and 5% _CO2 for 7 days. After the culture was completed, 50 μL of cell viability detection reagent (Promega, G7573) was added, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the chemiluminescence reading was detected by an enzyme reader. The results were processed according to formula (3), and the inhibition rate of each concentration of the compound was calculated. The inhibition curve was plotted and the _IC50 value was calculated using GraphPad Prism software. Where RLU _compound is the reading of the drug-treated group, RLU _{solvent control} is the reading of the solvent control group, and RLU _{blank control} is the average of the medium control readings.

Inhibition% = (1 - (RLU _compound - RLU _{blank control} ) / (RLU _{solvent control} - RLU _{blank control} )) × 100% Formula (3)

Table 2

A:IC ₅₀ ≤100nM

Conclusion: The compounds of the present invention have a good inhibitory effect on Yamato-SS cells. For example, the trifluoroacetate of compound 15, compound 18, the trifluoroacetate of compound 22, the trifluoroacetate of compound 23, compound 25, compound 27 and compound 31 have _IC50 of 8.6nM, 8.4nM, 5.2nM, 4.6nM, 9.0nM, 2.4nM and 1.7nM, respectively.

Biological Test Example 4:

ASKA-SS cell proliferation inhibition experiment

Human synovial sarcoma cell line ASKA-SS was purchased from Riken, and the culture conditions were: 80% DMEM + 20% FBS, cultured at 37°C, 5% CO ₂ incubator. On the first day, ASKA-SS cells in the exponential growth phase were collected and plated on a transparent bottom black 96-well culture plate with a density of 3000 cells/well, and cultured overnight in a 37°C, 5% CO ₂ incubator. On the second day, different concentrations of compounds were added and cultured in a 37°C, 5% CO ₂ incubator. After the compound was incubated for 7 days, the original culture medium was aspirated, 180 μL of complete culture medium was added, and 20 μL of compounds with different concentrations were added, keeping the final DMSO concentration of each well at 0.1%, and continued to be cultured in a 37°C, 5% CO ₂ incubator for 7 days. After the culture was completed, 50 μL of cell viability detection reagent (Promega, G7573) was added, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the chemiluminescence reading was detected by an enzyme reader. The results were processed according to formula (4), the inhibition rate of each concentration of the compound was calculated, and the inhibition curve was plotted and the IC ₅₀ value was calculated using GraphPad Prism software. RLU _compound is the reading of the drug treatment group, RLU _{solvent control} is the reading of the solvent control group, and RLU _{blank control} is the average of the medium control readings.

Inhibition% = (1-(RLU _compound -RLU _{blank control} )/(RLU _{solvent control} -RLU _{blank control} )) × 100% Formula (4)

Table 3

Conclusion: The compounds of the present invention have a good inhibitory effect on ASKA-SS cells.

Biological Test Example 5:

CYP450 enzyme inhibition testing

The purpose of this study was to evaluate the effects of the test substances on the activities of five isoenzymes of human liver microsomal cytochrome P450 (CYP) (CYP1A2, CYP2C9, CYP2D6, and CYP3A4) using an in vitro test system. Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH). After the reaction, the metabolites produced by the specific substrates were quantitatively detected by treating the samples and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine the changes in CYP enzyme activity, calculate IC ₅₀ values, and evaluate the inhibitory potential of the test substances on each CYP enzyme subtype CYP1A2, CYP2C9, CYP2D6, and CYP3A4-M (with midazolam as substrate).

Experimental results: Under the test conditions, when the incubation concentration is 0-50 or 0-100 μM, the IC ₅₀ values of the inhibitory effects of each test compound on CYP enzymes are shown in Table 4 below:

Table 4

Conclusion: The inhibitory effect of the compounds of the present invention on CYP3A4-M is weaker than that of the reference compound 1, and it is inferred that the risk of drug interaction caused by CYP3A4-M metabolism is lower. The compounds of the present invention have no obvious inhibitory effect on each subtype of CYP enzyme.

Biological Test Example 6:

6.1 Pharmacokinetic test in rats

Experimental animals: Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

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

Table 5. Dosing Information

Note: Intravenous: 10% DMA + 10% Solutol + 80% (saline) or 5% DMA + 5% Solutol + 90% (saline); Oral administration solvent: 5% DMSO + 5% Solutol + 30% PEG400 + 60% (20% SBE-CD); (DMSO: dimethyl sulfoxide; DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; PEG400: polyethylene glycol 400; SBE-β-CD: sulfobutyl-β-cyclodextrin;)

Before and after drug administration, 0.10 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

Table 6 Pharmacokinetic parameters of test compounds in rat plasma

Conclusion: The compound of the present invention has good oral absorption performance in rats.

6.2 Pharmacokinetic test in mice

Experimental animals: Male BALB/C mice, 20-25 g, 6 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

Experimental design: On the day of the experiment, 6 BALB/C mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration, and fed 4 hours after administration.

Table 7 Dosage information

Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastrically administered solvent: 5% DMSO + 5% Solutol + 30% PEG 400 + 60% (20% SBE-β-CD); (DMA: dimethylacetamide; DMSO: dimethyl sulfoxide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; PEG400: polyethylene glycol 400; SBE-β-CD: sulfobutyl-β-cyclodextrin;)

Before and after drug administration, 0.06 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 7, and 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

Table 8-1 Pharmacokinetic parameters of test compounds in mouse plasma

Table 8-2 Pharmacokinetic parameters of test compounds in mouse plasma

Conclusion: The compounds of the present invention have good oral absorption properties in mice.

6.3 Pharmacokinetics in Beagle Dogs

Experimental animals: Male beagle dogs, about 8-11 kg, 5-6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

Test method: On the test day, 5-6 beagle dogs/compound were randomly divided into groups according to body weight. The dogs were fasted but not watered for 12-14 hours one day before administration, and food was given 4 hours after administration.

Table 9 Dosage information

Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; intragastrically administered solvent: 5% DMSO + 5% Solutol + 30% PEG 400 + 60% (20% SBE-β-CD)

Before and after administration, 1 ml of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm, 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group in groups G1 and G2 were all: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h, 48, 72 h. The blood collection time points for the intravenous group and the gavage group in groups G3 and G4 were all: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

Table 10 Pharmacokinetic parameters of test compounds in beagle dog plasma

Conclusion: The compounds of the present invention have good oral absorption properties in beagle dogs.

Test Example 7: MOLM-13 Cell Proliferation Inhibition Experiment

MOLM-13 cells: human acute myeloid leukemia cell line, purchased from AddexBio, culture conditions: RPMI 1640 + 10% FBS, cultured at 37 ° C, 5% CO ₂ incubator. Cells in the exponential growth phase were collected and plated at a density of 2500 per well on a transparent bottom black 96-well plate. On the second day, different concentrations of the test compound were added, and after incubation for 7 days in a 37 ° C, 5% CO ₂ incubator, the cells in the solvent control wells were counted and the ratio was calculated. The number of new solvent control plates was 2500 per well, and the whole plate was transferred in proportion, and new culture medium containing the corresponding compound concentration was added, and incubated in a 37 ° C, 5% CO ₂ incubator for 7 days. After the incubation, 75 μL of cell viability detection reagent (Promega, G7573) was added, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the chemiluminescence reading was detected by an enzyme reader. The results were processed according to formula (5) to calculate the inhibition rate (IR) of each concentration of the compound, and then GraphPad Prism software was used to draw inhibition curves and calculate related parameters, including the maximum inhibition rate and IC ₅₀ .

IR (%) = (1 - (RLU _compound - RLU _{blank control} ) / (RLU _{solvent control} - RLU _{blank control} )) × 100% Formula (5)

Table 11

Conclusion: The compounds of the present invention have a good inhibitory effect on MOLM-13 cells

Test Example 8: MV4-11 cell proliferation inhibition experiment

MV4-11 cells: human myelomonocytic leukemia cell line, purchased from ATCC, culture conditions: RPMI 1640 + 10% FBS, cultured at 37 ° C, 5% CO ₂ incubator. Cells in the exponential growth phase were collected and plated at a density of 2500 cells/well in a transparent bottom black 96-well plate. On the second day, different concentrations of the test compound were added, and after incubation in a 37 ° C, 5% CO ₂ incubator for 7 days, the cells in the solvent control wells were counted and the ratio was calculated. The number of new solvent control plates was 2500/well, and the whole plate was transferred according to the proportion, and new culture medium containing the corresponding compound concentration was added, and incubated in a 37 ° C, 5% CO ₂ incubator for another 7 days. After the incubation, 75 μL of cell viability detection reagent (Promega, G7573) was added, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the chemiluminescence reading was detected by an enzyme reader. The results were processed according to formula (6) to calculate the inhibition rate (IR) of each concentration of the compound, and then GraphPad Prism software was used to draw inhibition curves and calculate related parameters, including the maximum inhibition rate and IC ₅₀ .

IR (%) = (1 - (RLU _compound - RLU _{blank control} ) / (RLU _{solvent control} - RLU _{blank control} )) × 100% Formula (6)

Table 12

Conclusion: The compounds of the present invention have a good inhibitory effect on MV4-11 cells

Test Example 9: Liver microsome stability test

In this study, monkey liver microsomes were used as an in vitro model to evaluate the metabolic stability of the test substances.

At 37°C, 1 μM of the test compound was incubated with microsomal proteins and coenzyme NADPH. After a certain period of time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing the internal standard was added to terminate the reaction. The LC-MS/MS method was used to detect the concentration of the test compound in the sample. The T1/2 was calculated based on the ln value of the drug residual rate in the incubation system and the incubation time, and the liver microsomal intrinsic clearance CLint(mic) and liver intrinsic clearance CLint(Liver) were further calculated.

Table 13

Conclusion: The compounds of the present invention have good stability in monkey liver microsomes.

Claims (13)

1. A compound or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal thereof, wherein the compound is selected from compounds shown in a general formula (I),

   B-L-K(I)；

   L is selected from a bond or a-C _1-50 hydrocarbyl-, of which 0 to 20 methylene units are optionally further replaced by-Ak-, -Cy-;

   each-Ak-is independently selected from -(CH₂)_q-、-(CH₂)_q-O-、-O-(CH₂)_q-、-(CH₂)_q-NR^L-、-NR^L-(CH₂)_q-、-(CH₂)_q-NR^LC(＝O)-、-NR^L(CH₂)_qC(＝O)-、-(CH₂)_q-C(＝O)NR^L-、-C(＝O)-(CH₂)_q-、-C(＝O)-(CH₂)_q-NR^L-、-(C≡C)_q-、-CH＝CH-、-Si(R^L)₂-、-Si(OH)(R^L)-、-Si(OH)₂-、-P(＝O)(OR^L)-、-P(＝O)(R^L)-、-S-、-S(＝O)-、-S(＝O)₂- or a bond, said-CH ₂ -is optionally further substituted with 0 to 2 substituents selected from H, halogen, OH, CN, NH ₂、C_1-6 alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkyl, hydroxy substituted C _1-6 alkyl or cyano substituted C _1-6 alkyl;

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

   R ^L is independently selected from H, C _1-6 alkyl, 3-7 membered heterocyclyl, 3-7 membered cycloalkyl, phenyl or 5-6 membered heteroaryl;

   each-Cy-is independently selected from the group consisting of a bond, 4-8 membered heteromonocyclic ring, 4-10 membered heteromonocyclic ring, 5-12 membered heterospiro ring, 7-10 membered heterobridged ring, 3-7 membered monocycloalkyl, 4-10 membered cycloalkyl, 5-12 membered spirocycloalkyl, 7-10 membered bridged cycloalkyl, 5-10 membered heteroaryl, or 6-10 membered aryl, said aryl, heteroaryl, cycloalkyl, heteromonocyclic ring, heterospiro ring, or heterobridged ring optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, COOH, CN, NH ₂、＝O、C_1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxy substituted C _1-4 alkyl, or C _1-4 alkoxy, said heteroaryl, heteromonocyclic ring, heterospiro, or heterobridged ring containing 1 to 4 heteroatoms selected from O, S or N, optionally further substituted with 0, 1, or 2 = O when the heteroatoms are selected from S;

   B is selected from

   Or B is selected from

   T ₁ is selected from N or CR ^b4,T₂ is selected from N or CR ^b2,T₃ is selected from N or CR ^b3;

   R ^b1 is selected from H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _3-10 carbocycle, C _6-10 aryl ring, 5 to 10 membered heteroaryl ring, or R ¹, said alkyl, alkenyl, alkynyl, heteroalkyl, carbocycle, heterocycle, aryl ring, or heteroaryl ring optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C_1-4 alkyl, C _1-4 alkoxy, halo substituted C _1-4 alkyl, cyano substituted C _1-4 alkyl, C _3-6 cycloalkyl, or 3 to 7 membered heterocycle, said heteroalkyl, heterocycle, or heteroaryl ring containing 1 to 3 heteroatoms selected from O, S or N;

   R ¹ is each independently selected from a4 to 10 membered heterocycle, - (CH ₂)_1-4-R^1a), said heterocycle or CH ₂ optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C_1-6 alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkyl, cyano substituted C _1-6 alkyl, C _3-6 cycloalkyl or a 3 to 7 membered heterocycle, said heterocycle containing 1 to 3 heteroatoms selected from O, S or N;

   R ^1a is selected from C _1-6 alkoxy, C _3-10 carbocycle, or a4 to 10 membered heterocycle, said alkoxy, carbocycle, or heterocycle optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C_1-4 alkyl, C _1-4 alkoxy, halogen substituted C _1-4 alkyl, cyano substituted C _1-4 alkyl, C _3-6 cycloalkyl, or a 3 to 7 membered heterocycle, said heterocycle containing 1 to 3 heteroatoms selected from O, S or N;

   r ^b2、R^b3、R^b4 is each independently selected from H, halogen, CN, OH, NH ₂、SH、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _3-10 carbocycle, 4 to 10 membered heterocycle, C _6-10 aryl ring, or 5 to 10 membered heteroaryl ring, said alkyl, alkenyl, alkynyl, heteroalkyl, carbocycle, heterocycle, aryl ring, or heteroaryl ring optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C_1-4 alkyl, C _1-4 alkoxy, halogen substituted C _1-4 alkyl, cyano substituted C _1-4 alkyl, C _3-6 cycloalkyl, or 3 to 7 membered heterocycle, said heteroalkyl, heterocycle, or heteroaryl ring containing 1 to 3 heteroatoms selected from O, S or N, optionally further substituted with 0,1, or 2=o when the heteroatom is selected from S;

   Alternatively, R ^b2、R^b3 is directly linked to form ring B ₁;

   Ring B ₁ is selected from a C _5-6 carbocyclic ring, a benzene ring, a 5-6 membered heterocyclic ring, or a 5-6 membered heteroaromatic ring, B ₂ is selected from a C _3-10 carbocyclic ring, a 4-to 10-membered heterocyclic ring, a C _6-10 aromatic ring, or a 5-to 10-membered heteroaromatic ring, said ring B ₁ is optionally further substituted with 0 to 4R ^b6, said B ₂ is optionally further substituted with 0 to 4R ^b5, said heterocyclic or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S or N;

   R ^b5、R^b6 is independently selected from H, halogen, OH, = O, NH ₂、CN、COOH、NHC_1-6 alkyl, N (C _1-6 alkyl) ₂、-NHC(＝O)-C_1-6 alkyl, -NHC (=o) -C _3-6 carbocycle, -NHC (=o) -3 to 7 membered heterocycle, -C (=o) NH-C _3-6 carbocycle, -C (=o) NH-3 to 7 membered heterocycle, -C (=nh) NH-C _3-6 carbocycle, -C (=nh) NH-3 to 7 membered heterocycle, -SO ₂NH₂、-SO₂NHC_1-6 alkyl, -SO ₂N(C_1-6 alkyl) ₂、C_1-6 alkyl, C _1-6 heteroalkyl, C _1-6 alkoxy, -O-C _3-6 cycloalkyl, -O-3 to 7 membered heterocycle, C _3-6 cycloalkyl or 3 to 7 membered heterocycle, said alkyl, alkoxy, cycloalkyl or heterocycle optionally being further substituted with 0 to 4 groups selected from H, F, cl, Br, I, OH, = O, NH ₂、CN、COOH、NHC_1-4 alkyl, N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _1-4 alkoxy, Halogen substituted C _1-4 alkyl, C _1-4 alkoxy substituted C _1-4 alkyl, C _3-6 cycloalkyl or a substituent of a 3 to 7 membered heterocycle, The heteroalkyl, heterocyclic or heteroaromatic ring contains from 1 to 3 heteroatoms selected from O, S or N, optionally further substituted with 0, 1 or 2 = O when the heteroatoms are selected from S;

   K is selected from

   Represents a ring selected from aromatic or non-aromatic rings;

   E. F, G is each independently selected from a C _3-8 carbocycle, a benzene ring, a 4-7 membered heterocycle, or a 5-6 membered heteroaryl containing 1 to 4 heteroatoms selected from O, S or N;

   Each Q is independently selected from a bond, -O-, -S-, -CH ₂ -, or-NR ^q -;

   R ^q is selected from H or C _1-4 alkyl;

   R ^k1 is each independently selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C(＝O)NH₂、C_1-6 alkyl or C _1-6 alkoxy, said alkyl or alkoxy optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C(＝O)NH₂、C_1-4 alkyl or C _1-4 alkoxy;

   R ^k3 is each independently selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C(＝O)NH₂、C_1-6 alkyl, C _1-6 alkoxy, C _3-8 cycloalkyl or a 3-8 membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C(＝O)NH₂、C_1-4 alkyl or C _1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;

   Or two R ^k3 together with the carbon atom or ring backbone directly attached to both form a 3-8 membered carbocycle or 3-8 membered heterocycle optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C(＝O)NH₂、C_1-4 alkyl or C _1-4 alkoxy, said heterocycle containing 1 to 4 heteroatoms selected from O, S or N;

   R ^k4 is each independently selected from H, OH, NH ₂、CN、C(＝O)NH₂、C_1-6 alkyl, C _3-8 cycloalkyl or a 3-8 membered heterocyclyl, said alkyl, cycloalkyl or heterocyclyl being optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C(＝O)NH₂、C_1-4 alkyl or C _1-4 alkoxy, said heterocyclyl containing 1 to 4 heteroatoms selected from O, S or N;

   R ^k5 are each independently selected from C (=O), CH ₂ or

   P1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;

   b1 is selected from 0, 1, 2, 3 or 4.
2. The compound of claim 1, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,

   B is selected from

   Or B is selected from

   R ¹ is each independently selected from a4 to 10 membered heterocycle or- (CH ₂)_1-2-R^1a), said heterocycle or CH ₂ optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C_1-4 alkyl, C _1-4 alkoxy, halogen substituted C _1-4 alkyl, cyano substituted C _1-4 alkyl, C _3-6 cycloalkyl or a 3 to 7 membered heterocycle, said heterocycle containing 1 to 3 heteroatoms selected from O, S or N;

   r ^1a is selected from C _1-4 alkoxy, C _3-10 carbocycle, or a4 to 10 membered heterocycle, said alkoxy, carbocycle, or heterocycle optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C_1-4 alkyl, C _1-4 alkoxy, halogen substituted C _1-4 alkyl, cyano substituted C _1-4 alkyl, C _3-6 cycloalkyl, or a 3 to 7 membered heterocycle, said heterocycle containing 1 to 3 heteroatoms selected from O, S or N;

   r ^b2、R^b3、R^b4 is each independently selected from H, halogen, CN, OH, NH ₂、SH、C_1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 heteroalkyl, C _3-10 carbocycle, 4 to 10 membered heterocycle, C _6-10 aryl ring, or 5 to 10 membered heteroaryl ring, said alkyl, alkenyl, alkynyl, heteroalkyl, carbocycle, heterocycle, aryl ring, or heteroaryl ring optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C_1-4 alkyl, C _1-4 alkoxy, halogen substituted C _1-4 alkyl, cyano substituted C _1-4 alkyl, C _3-6 cycloalkyl, or 3 to 7 membered heterocycle, said heteroalkyl, heterocycle, or heteroaryl ring containing 1 to 3 heteroatoms selected from O, S or N, optionally further substituted with 0,1, or 2=o when the heteroatom is selected from S;

   b1, b2 are selected from 0, 1, 2, 3 or 4;

   With the proviso that when B is selected from When R ^b6 is not H, halogen, C _1-6 alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkyl, and K is selected from K1;

   K1 is selected from

   P3 is selected from 1, 2, 3 or 4;

   R ^k is selected from F, cl, br, I, OH, NH ₂、CN、COOH、C(＝O)NH₂、C_1-6 alkyl or C _1-6 alkoxy, said alkyl or alkoxy optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C(＝O)NH₂、C_1-4 alkyl or C _1-4 alkoxy;

   With the proviso that when B is selected from When K is selected from

   With the proviso that when B is selected from When K is selected from

   With the proviso that when B is selected fromWhen K is selected from And at least one of R ^b2 and R ^b3 is selected from halogen, CN, OH, substituted C _1-6 alkyl, C _3-10 carbocycle, or 4 to 10 membered heterocycle.
3. The compound of claim 2, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,

   L is -Cy1-、-Cy1-Ak1-、-Cy1-Ak1-Ak2-、-Cy1-Ak1-Ak2-Ak3-、-Cy1-Ak1-Ak2-Ak3-Ak4-、-Cy1-Cy2-、-Cy1-Ak1-Cy2-、-Cy1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-、-Cy1-Ak1-Cy2-Ak2-Ak3-、-Ak1-Cy2-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Cy2-Ak2-Ak3-、-Cy1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-、-Cy1-Ak1-Ak2-Cy3-、-Cy1-Ak1-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-、-Cy1-Ak1-Cy2-Cy3-、-Cy1-Cy2-Ak2-Cy3-、-Cy1-Cy2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Cy3-Ak3-、-Cy1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Ak1-Cy2-Ak2-Cy3-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-、-Cy1-Cy2-Cy3-Ak3-Ak4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-、-Cy1-Ak1-Cy2-Cy3-Cy4-、-Cy1-Cy2-Ak2-Cy3-Cy4-、-Cy1-Cy2-Cy3-Ak3-Cy4-、-Cy1-Cy2-Cy3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-、-Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-、-Ak1-Cy2-Ak2-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-、-Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5-、-Ak1-Cy2-Ak2-Ak3-Ak4- or-Ak 1-Cy2-Ak2-Ak3-;

   Ak1, ak2, ak3, ak4, ak5 are each independently selected from -(CH₂)_q-、-(CH₂)_q-O-、-O-(CH₂)_q-、-(CH₂)_q-NR^L-、-NR^L-(CH₂)_q-、-(CH₂)q-NR^LC(＝O)-、-(CH₂)_q-C(＝O)NR^L-、-C(＝O)-(CH₂)_q-、-C(＝O)-(CH₂)_q-NR^L-、-(C≡C)_q- or a bond, said-CH ₂ -is optionally further substituted with 0 to 2 substituents selected from H, halogen, OH, CN, NH ₂、C_1-4 alkyl, C _1-4 alkoxy, halogen substituted C _1-4 alkyl, hydroxy substituted C _1-4 alkyl or cyano substituted C _1-4 alkyl;

   Cy1, cy2, cy3, cy4 are each independently selected from the group consisting of a bond, a 4-7 membered nitrogen containing heteromonocyclic ring, a 4-10 membered nitrogen containing heteromonocyclic ring, a 5-12 membered nitrogen containing heterospiro ring, a 7-10 membered nitrogen containing heterobridged ring, a 3-7 membered monocyclic alkyl, a 4-10 membered fused cycloalkyl, a 5-12 membered spirocycloalkyl, a 7-10 membered bridged cycloalkyl, a 5-10 membered heteroaryl or a 6-10 membered aryl, said heteromonocyclic ring, heterobridged ring, heterospiro ring, cycloalkyl, aryl or heteroaryl being optionally further substituted with 0 to 4 substituents selected from the group consisting of H, F, cl, br, I, OH, COOH, CN, NH ₂、＝O、C_1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxy substituted C _1-4 alkyl or C _1-4 alkoxy, said heteromonocyclic ring, heterobicyclic ring, heterobridged ring, heterospiro ring or heteroaryl containing 1 to 4 heteroatoms selected from O, S or N, when the heteroatoms are selected from S, optionally being further substituted with 0, 1 or 2 = O;

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

   R ^L is independently selected from H or C _1-6 alkyl;

   R ^b2、R^b3、R^b4 is each independently selected from H, halogen, CN, OH, NH ₂、SH、C_1-4 alkyl, C _2-4 alkenyl, C _2-6 alkynyl, C _1-4 heteroalkyl, C _3-8 carbocycle, 4 to 10 membered heterocycle, C _6-10 aryl ring, or 5 to 10 membered heteroaryl ring, said alkyl, alkenyl, alkynyl, heteroalkyl, carbocycle, heterocycle, aryl ring, or heteroaryl ring optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C_1-4 alkyl, C _1-4 alkoxy, halogen substituted C _1-4 alkyl, cyano substituted C _1-4 alkyl, C _3-6 cycloalkyl, or 3 to 7 membered heterocycle, said heteroalkyl, heterocycle, or heteroaryl ring containing 1 to 3 heteroatoms selected from O, S or N, optionally further substituted with 0,1, or 2=o when the heteroatom is selected from S;

   r ^b5、R^b6 is independently selected from H, halogen, OH, = O, NH ₂、CN、COOH、NHC_1-4 alkyl, N (C _1-4 alkyl) ₂、-NHC(＝O)-C_1-4 alkyl, -NHC (=o) -C _3-6 carbocycle, -NHC (=o) -3 to 7 membered heterocycle, -C (=o) NH-C _3-6 carbocycle, -C (=o) NH-3 to 7 membered heterocycle, -C (=nh) NH-C _3-6 carbocycle, -C (=nh) NH-3 to 7 membered heterocycle, -SO ₂NH₂、-SO₂NHC_1-4 alkyl, -SO ₂N(C_1-4 alkyl) ₂、C_1-4 alkyl, C _1-4 heteroalkyl, C _1-4 alkoxy, -O-C _3-6 cycloalkyl, -O-3 to 7 membered heterocycle, C _3-6 cycloalkyl or 3 to 7 membered heterocycle, said alkyl, alkoxy, cycloalkyl or heterocycle optionally being further substituted with 0 to 4 groups selected from H, F, cl, Br, I, OH, = O, NH ₂、CN、COOH、NHC_1-4 alkyl, N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _1-4 alkoxy, Halogen substituted C _1-4 alkyl, C _1-4 alkoxy substituted C _1-4 alkyl, C _3-6 cycloalkyl or a substituent of a 3 to 7 membered heterocycle, The heteroalkyl, heterocyclic or heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S or N.
4. The compound of claim 3, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,

   Cy1, cy2, cy3, cy4 are each independently selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclohexenyl, piperidinyl, morpholinyl, piperazinyl, phenyl, cyclopropyl-and-cyclopropyl, cyclopropyl-and-cyclobutyl, cyclobutyl-and-cyclopentyl, cyclobutyl-and-cyclohexyl, cyclopentyl-and-cyclopentyl, cyclopentyl-and-cyclohexyl, cyclohexyl-and-cyclohexyl, cyclopropyl-and-spirocyclopropyl-and-spirobutyl, cyclopropyl-and-spirocyclopentyl, cyclopropyl-and-spirocyclohexyl, cyclobutyl-and-spirobutyl, cyclobutyl-and-spirocyclopentyl, cyclobutyl-and-spirocyclohexyl, cyclopentyl-and-spirocyclopentyl, cyclopentyl-and-spirocyclohexyl, cyclohexyl-and-spirocyclohexyl, cyclopropyl-and-spirocyclobutyl, cyclopropyl-and-azacyclohexyl, cyclopropyl-and-piperidinyl, cyclobutyl-and-azacyclobutyl cyclobutyl azetidinyl, cyclopentyl piperidyl cyclohexyl azetidinyl, azetidinyl, a cyclohexylazetidinyl group, a cyclohexyl-piperidyl, azetidino-azetidinyl, cyclobutyl spiroazetidinyl, cyclopentyl spiroazetidinyl cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, cyclopentyl cyclopentyl spiroazetidinyl, cyclohexyl spiroazetidinyl, and cyclohexyl spiroazacyclopentyl an azacyclopentyl spiroazacyclopentyl group, an azacyclopentyl spiroazacyclohexyl group, an azacyclohexyl spiroazacyclobutyl group, an azacyclohexyl spiroazacyclopentyl group, an azacyclohexyl spiroazacyclohexyl group cyclobutyl spiropiperidinyl, cyclopentyl spiropiperidinyl, cyclohexyl spiropiperidinyl azetidinyl spiropiperidinyl, azetidinyl spiropiperidinyl, When substituted, optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, NH ₂、COOH、CN、＝O、C_1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxy substituted C _1-4 alkyl or C _1-4 alkoxy;

   Or Cy1, cy2, cy3, cy4 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, NH ₂、COOH、CN、＝O、C_1-4 alkyl, halogen substituted C _1-4 alkyl, hydroxy substituted C _1-4 alkyl or C _1-4 alkoxy;

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

   R ¹ is each independently selected from the group consisting of azetidinyl, oxetanyl, morpholinyl, or- (CH ₂)_1-2-R^1a), said azetidinyl, oxetanyl, oxolanyl, or morpholinyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C_1-4 alkyl, C _1-4 alkoxy, halogen substituted C _1-4 alkyl, cyano substituted C _1-4 alkyl, C _3-6 cycloalkyl, or 3 to 7 membered heterocycle containing 1 to 3 heteroatoms selected from O, S or N;

   R ^1a is selected from methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxolanyl, oxetanyl or morpholinyl, said methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl or morpholinyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C_1-4 alkyl, C _1-4 alkoxy, halogen substituted C _1-4 alkyl, cyano substituted C _1-4 alkyl, C _3-6 cycloalkyl or 3 to 7 membered heterocycle;

   R ^b2、R^b3、R^b4 are each independently selected from H, F, cl, br, I, CN, OH, NH ₂, SH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, or cyclopropyl, said methyl, ethyl, propyl, butyl, methoxy, ethoxy, or cyclopropyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、COOH、C_1-4 alkyl, C _1-4 alkoxy, halogen substituted C _1-4 alkyl, cyano substituted C _1-4 alkyl, C _3-6 cycloalkyl, or3 to 7 membered heterocycle;

   The ring B ₁ is selected from cyclopentene, cyclohexene, cyclohexadiene, benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, triazine, pyrrole, pyrazole, imidazole, triazole, oxazole, furan, thiophene, thiazole, azapentene, oxapentene, azacyclohexene, azadiene, oxacyclohexene, oxadiene,

   R ^b5、R^b6 is independently selected from H、F、Cl、I、OH、＝O、NH₂、CN、NHCH₃、N(CH₃)₂、NHCH₂CH₃、N(CH₂CH₃)₂、-NHC(＝O)CH₃、-NHC(＝O)CH₂CH₃、-NHC(＝O)- piperidinyl,-C (=o) NH-piperidinyl,-C (=nh) NH-piperidinyl,-SO ₂NH₂, methyl, ethyl, propyl, butyl, isopropyl, methoxy, ethoxy, -O-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxycyclohexyl, morpholinyl, pyrrolyl, pyrazolyl, pyrimidinyl or triazolyl, said piperidinyl,Methyl, ethyl, propyl, butyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, morpholinyl, pyrrolyl, pyrazolyl, pyrimidinyl or triazolyl optionally further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂、CN、NHC_1-4 alkyl, N (C _1-4 alkyl) ₂、C_1-4 alkyl, C _1-4 alkoxy, halogen substituted C _1-4 alkyl or C _1-4 alkoxy substituted C _1-4 alkyl;

   K is selected from

   K1 is selected from

   Or K1 is selected from

   F is each independently selected from phenyl, pyridonyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl or thiazolyl;

   R ^k is selected from F, cl, OH, NH ₂, CN, methyl, ethyl, methoxy or ethoxy;

   Each R ^k1 is independently selected from H, F, cl, OH, NH ₂, CN, methyl, ethyl, methoxy or ethoxy;

   Each R ^k3 is independently selected from H, F, OH or methyl;

   Each R ^k4 is independently selected from H or methyl;

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

   p3 is selected from 1 or 2;

   b1, b2 are selected from 0, 1, 2, 3 or 4.
5. The compound of claim 4, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,

   Ak1, ak2, ak3, ak4, ak5 are each independently selected from -O-、-OCH₂-、-CH₂O-、-OCH₂CH₂-、-CH₂CH₂O-、-C≡C-、-C(CH₃)₂-、-CH₂-、-CH₂CH₂-、-CH₂CH₂CH₂-、-N(CH₃)-、-NH-、-CH₂N(CH₃)-、-CH₂NH-、-NHCH₂-、-CH₂CH₂N(CH₃)-、-CH₂CH₂NH-、-NHCH₂CH₂-、-C(＝O)-、-C(＝O)CH₂NH-、-CH₂C(＝O)NH-、-C(＝O)NH- or-NHC (=O) -;

   Cy1, cy2, cy3, cy4 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, optionally further substituted with 0 to 4 substituents selected from H, F, CF ₃, methyl, =o, hydroxymethyl, COOH, CN, or NH ₂;

   Or Cy1, cy2, cy3, cy4 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, optionally further substituted with 0 to 4 substituents selected from H, F, OH, CF ₃, methyl, =o, hydroxymethyl, COOH, CN, or NH ₂;

   B is selected from

   Or B is selected from

   R ^1a is selected from methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, or morpholinyl, said methoxy, ethoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, oxacyclohexyl, or morpholinyl optionally being further substituted with 0 to 4 substituents selected from H, F, cl, br, I, OH, = O, NH ₂, CN, COOH, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, CF ₃、-OCHF₂、-OCH₂ F, or-OCF ₃;

   R ²、R³ are each independently selected from F, CF ₃、-CHF₂、-CH₂ F, CN, OH or cyclopropyl;

   R ^b2 is selected from H, F, CN, OH, methyl or ethyl;

   R ^b3 is selected from H, F, CN, OH, methyl or ethyl;

   R ^b4 is selected from H, F, CN, OH, methyl or ethyl;

   R ^b5 is selected from H, F, CN, OH, methyl, ethyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, CF ₃、-OCHF₂、-OCH₂F、-OCF₃、-CH₂ -azetidine, -CH ₂NHCH₃, or-CH ₂N(CH₃)₂;

   R ^b6 is selected from H、F、NH₂、CN、NHCH₃、N(CH₃)₂、NHCH₂CH₃、N(CH₂CH₃)₂、-NHC(＝O)CH₃、-NHC(＝O)CH₂CH₃、-NHC(＝O)- piperidinyl, -C (=o) NH-piperidinyl, -C (=nh) NH-piperidinyl,-SO ₂NH₂、CF₃、-OCHF₂、-OCH₂F、-OCF₃, methyl, ethyl, propyl, methoxy, ethoxy, hydroxymethyl, cyclopropyl, azetidinyl, morpholinyl,

   K is selected from

   K1 is selected from

   Or K1 is selected from
6. The compound of claim 5, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,

   L is -Ak1-Ak2-Cy3-、-Ak1-Ak2-Cy3-Ak3-、-Ak1-Ak2-Cy3-Ak3-Ak4-、-Ak1-Ak2-Cy3-Cy4-、-Ak1-Cy2-、-Ak1-Cy2-Cy3-、-Ak1-Cy2-Ak2-Cy3-、-Ak1-Cy2-Cy3-Ak3-Cy4-、-Ak1-Cy2-Cy3-Cy4-Ak4-、-Ak1-Cy2-Ak2-、-Ak1-Cy2-Cy3-Ak3- or-Ak 1-Cy2-Ak2-Ak3-;

   Cy1, cy2, cy3, cy4 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, optionally further substituted with 0 to 4 substituents selected from H, F, CF ₃, methyl, =o, hydroxymethyl, COOH, CN, or NH ₂;

   Or Cy1, cy2, cy3, cy4 are each independently selected from one of the following substituted or unsubstituted groups: When substituted, optionally further substituted with 0 to 4 substituents selected from H, F, OH, CF ₃, methyl, =o, hydroxymethyl, COOH, CN, or NH ₂;

   Ak1, ak2, ak3, ak4 are each independently selected from-CH ₂-、-CH₂CH₂-、O、NH、N(CH₃, -NHC (=O) -or-C (=O) NH-.
7. The compound of claim 6, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,

   L is selected from one of the structural fragments shown in Table A;

   Or L is selected from

   Or L is selected from

   B is selected from one of the following structural fragments:

   or B is selected from one of the following structural fragments:

   K is selected from one of the following structural fragments:

   K1 is selected from one of the following structural fragments:

   Or K1 is selected from
8. The compound of claim 1, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the structures of table C.
9. A pharmaceutical composition comprising a compound according to any one of claims 1-8 or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, and a pharmaceutically acceptable carrier, preferably comprising 1-1500mg of a compound according to any one of claims 1-8 or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof.
10. Use of a compound according to any one of claims 1-8, or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment of a disease associated with BRD9 activity or expression level.
11. Use of a compound according to any one of claims 1-8, or a stereoisomer, a deuterate, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or co-crystal thereof, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the treatment and inhibition or degradation of BRD 9-associated diseases.
12. The use according to claim 10 or 11, wherein the disease is selected from cancer.
13. A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1-8, or a stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, preferably 1-1500mg, said disease preferably being associated with BRD9 activity or expression.