Benzo five-membered heterocyclic derivative and application thereof in medicine

Abstract

The invention relates to a benzo five-membered heterocyclic derivative and application thereof in medicine, a compound shown in a general formula (I) or a stereoisomer, a racemate, a tautomer, a deuterated compound, a solvate, a prodrug, a metabolite, pharmaceutically acceptable salt or eutectic of the compound, an intermediate of the compound, and application of the compound in inhibiting or degrading Bcl6 related diseases such as cancers. And B-L-K (I).

Description

Technical Field

[0001] The present invention relates to a compound of general formula (I) or its stereoisomers, racemates, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and intermediates and preparation methods thereof, as well as uses in Bcl6-related diseases such as tumors or autoimmune diseases. Background Art

[0002] Bcl6 is a transcriptional repressor that can regulate the development and function of germinal center B cells. High expression of Bcl6 protein caused by various influencing factors such as exon mutations, regulatory pathway mutations, somatic Bcl6 translocations, and promoter mutations can enable the rapid proliferation of germinal center B cells, thereby promoting the generation of B-cell lymphoma. At the same time, Bcl6 can inhibit both cell cycle checkpoints and genes related to differentiation and DNA damage response. Preclinical studies have shown that the deletion of Bcl6 in lymphoma cells will cause the arrest of tumor development. Therefore, Bcl6 is a suitable target with potential for treating various lymphomas.

[0003] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to a target protein and an E3 ubiquitin ligase. Such compounds can be recognized by the cell's proteasome, causing the degradation of the target protein and effectively reducing the content of the target protein in the cell. By introducing ligands that can bind different target proteins into PROTAC molecules, it becomes possible to apply PROTAC technology to the treatment of various diseases, and this technology has received extensive attention in recent years.

[0004] Therefore, it is necessary to develop novel PROTAC drugs targeting Bcl6 protein for the treatment of Bcl6-related tumor diseases. Summary of the Invention

[0005] The object of the present invention is to provide a compound with a novel structure, good drug efficacy, high bioavailability, greater safety, and capable of inhibiting or degrading Bcl6 for the treatment of Bcl6-related diseases such as autoimmune diseases, inflammatory diseases or cancers.

[0006] The present invention provides a compound or its stereoisomers, racemates, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, wherein the compound is selected from the compounds represented by general formula (I),

[0007] B-L-K (I);

[0008] In some embodiments, L is selected from a bond or -C 1-50Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl are optionally replaced by -Ak- or -Cy-; in some embodiments, L is selected from a bond or -C 1-20 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl are optionally replaced by -Ak- or -Cy-;

[0009] In some embodiments, each -Ak- is independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -S-, -S-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -NR L (CH 2 ) q C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) 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, and the CH, -CH 2 - is optionally substituted by 1 to 2 R z substituents;

[0010] In some embodiments, q is independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0011] In some embodiments, R L is selected from H, C1-4 alkyl, C 3-7 carbocyclic group, 4- to 10-membered heterocyclic group, and the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z substituents;

[0012] In some embodiments, each -Cy- is independently selected from a bond or one of the following groups optionally substituted by 1 to 4 R L2 : 4- to 8-membered heteromonocyclic group, 4- to 12-membered hetero-fused ring group, 5- to 13-membered heterospiro ring group, 7- to 12-membered heterobridged ring group, 10- to 16-membered heterotricyclic ring, C 3-7 monocyclic alkyl, C 4-7 monocyclic alkenyl, C 4-12 fused ring alkyl, C 5-13 spiroalkyl, C 5-12 bridged ring alkyl, 5- to 10-membered heteroaryl or C 6-10 aryl;

[0013] In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8 or Ak9; in some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4 or Ak5;

[0014] In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3, Cy4 or Cy5; in some embodiments, -Cy- is selected from Cy1, Cy2, Cy3 or Cy4;

[0015] In some embodiments, L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2-Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5--Ak1 - Ak2 - Ak3 - Cy1 - Cy2 - Cy3 - Cy4 - Ak4 - Ak5 -, -Ak1 - Ak2 - Ak3 - Ak4 - Cy1 - Cy2 - Cy3 - Cy4 - Ak5 -, -Ak1 - Cy1 - Ak2 - Ak3 - Ak4 - Ak5 - Cy2 - Cy3 - Cy4 -, -Ak1 - Cy1 - Cy2 - Ak2 - Ak3 - Ak4 - Ak5 - Cy3 - Cy4 -, -Ak1 - Cy1 - Cy2 - Cy3 - Ak2 - Ak3 - Ak4 - Ak5 - Cy4 -, -Ak1 - Ak2 - Cy1 - Ak3 - Ak4 - Ak5 - Cy2 - Cy3 - Cy4 -, -Ak1 - Ak2 - Cy1 - Cy2 - Ak3 - Ak4 - Ak5 - Cy3 - Cy4 -, -Ak1 - Ak2 - Cy1 - Cy2 - Cy3 - Ak3 - Ak4 - Ak5 - Cy4 -, -Ak1 - Ak2 - Ak3 - Cy1 - Ak4 - Ak5 - Cy2 - Cy3 - Cy4 -, -Ak1 - Ak2 - Ak3 - Cy1 - Cy2 - Ak4 - Ak5 - Cy3 - Cy4 -, -Ak1 - Ak2 - Ak3 - Cy1 - Cy2 - Cy3 - Ak4 - Ak5 - Cy4 -, -Ak1 - Ak2 - Ak3 - Ak4 - Cy1 - Ak5 - Cy2 - Cy3 - Cy4 -, -Ak1 - Ak2 - Ak3 - Ak4 - Cy1 - Cy2 - Ak5 - Cy3 - Cy4 -, -Ak1 - Ak2 - Ak3 - Ak4 - Cy1 - Cy2 - Cy3 - Ak5 - Cy4 -, -Ak1 -, -Ak1 - Ak2 -, -Ak1 - Ak2 - Ak3 -, -Ak1 - Ak2 - Ak3 - Ak4 -, -Ak1 - Ak2 - Ak3 - Ak4 - Ak5 -, -Ak1 - Ak2 - Ak3 - Ak4 - Ak5 - Ak6 -, -Ak1 - Ak2 - Ak3 - Ak4 - Ak5 - Ak6 - Ak7 -, -Ak1 - Ak2 - Ak3 - Ak4 - Ak5 - Ak6 - Ak7 - Ak8 -, -Ak1 - Ak2 - Ak3 - Ak4 - Ak5 - Ak6 - Ak7 - Ak8 - Ak9 -; In certain embodiments, L is selected from a bond, -Ak1 -, -Ak1 - Ak2 -, -Ak1 - Ak2 - Ak3 -, -Ak1 - Ak2 - Ak3 - Ak4 -, -Ak1 - Ak2 - Ak3 - Ak4 - Ak5 -, -Ak1 - Ak2 - Ak3 - Ak4 - Ak5 - Ak6 -, -Cy1 -, -Cy1 - Ak1 -, -Cy1 - 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 --Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3, -Cy1-Cy2-Ak2-Ak3-Ak4, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4, -Cy1-Ak1-Ak2-Cy3, -Cy1-Ak1-Ak2-Cy3-Ak3, -Cy1-Cy2-Cy3, -Cy1-Ak1-Cy2-Cy3, -Cy1-Cy2-Ak2-Cy3, -Cy1-Cy2-Cy3-Ak3, -Cy1-Ak1-Cy2-Cy3-Ak3, -Cy1-Cy2-Ak2-Cy3-Ak3, -Cy1-Ak1-Cy2-Ak2-Cy3, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3, -Cy1-Cy2-Cy3-Ak3-Ak4, -Cy1-Cy2-Cy3-Ak3-Cy4, -Cy1-Cy2-Cy3-Cy4, -Cy1-Ak1-Cy2-Cy3-Cy4, -Cy1-Cy2-Ak2-Cy3-Cy4, -Cy1-Cy2-Cy3-Ak3-Cy4, -Cy1-Cy2-Cy3-Cy4-Ak4, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4, -Ak1-Cy2, -Ak1-Cy2-Cy3, -Ak1-Ak2-Cy3, -Ak1-Ak2-Cy3-Cy4, -Ak1-Cy2-Ak2-Cy3, -Ak1-Cy2-Cy3-Ak3-Cy4, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5, -Ak1-Cy2-Ak2, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5, -Cy1-Cy2-Cy3-Cy4-Ak4-Ak5, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5, -Ak1-Cy2-Ak2-Ak3-Ak4-Ak5, -Ak1-Cy2-Ak2-Ak3-Ak4, -Ak1-Cy2-Ak2-Ak3; In certain embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; In certain embodiments, L is selected from a bond or -NHCH, 2 -, -Cy1-, -Cy1-CH 2 -, -Cy1-C≡C-, -Cy1-Cy2-, -Cy1-CH 2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH 2 -Cy2-Cy3-, -Cy1-Cy2-CH 2 -Cy3-, -NH-Cy1-, -NH-Cy1-Cy2-, -NH-Cy1-CH 2 -Cy2, -Cy1-Ak1;

[0016] In certain embodiments, each of Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 is independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -S-, -S-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q - or a bond, wherein the -CH 2 - is optionally substituted with 1 to 2 R z ; in certain embodiments, each of Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 is independently selected from a bond, -O-, -S-, -OCH 2 -, -CH 2 O-, -OCH 2 CH 2 -, -CH 2 CH 2 O-, -C≡C-, -C(CH 3 ) 2 -, -CH 2 -, -CH 2 CH 2 -, -CH 2CH 2 CH 2 -, -N(CH 3 )-, -NH-, -CH 2 N(CH 3 )-, -CH 2 NH-, -NHCH 2 -, -CH 2 CH 2 N(CH 3 )-, -CH 2 CH 2 NH-, -NHCH 2 CH 2 -, -C(=O)-, -C(=O)CH 2 NH-, -CH 2 C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

[0017] In certain embodiments, R L is selected from H or C 1-4 alkyl; in certain embodiments, R L is selected from H, methyl or ethyl;

[0018] In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 are each independently selected from a bond or one of the following groups optionally substituted with 1 to 4 R L2 substituents: 4-7 membered nitrogen-containing monocyclic group, 4-12 membered nitrogen-containing fused ring group, 5-13 membered nitrogen-containing spiro ring group, 7-12 membered nitrogen-containing bridged ring group, 10-16 membered heterotricyclic ring, C 3-7 monocyclic alkyl, C 4-7 monocyclic alkenyl, C 4-12 fused ring alkyl, C 5-13 spiroalkyl, C 7-12 bridged ring alkyl, 5-10 membered heteroaryl or C 6-10 aryl;

[0019] In certain embodiments, Cy5 is defined the same as Cy1;

[0020] In certain embodiments, Cy1, Cy2, Cy3, Cy4 are each independently selected from a bond or one of the following groups optionally substituted with 1 to 4 R L2 substituents: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, s1, s3, s5 are each independently selected from 0, 1 or 2, s2, s4 are each independently selected from 0 or 1, s6 is selected from 0, 1, 2 or 3, s7 is selected from 1, 2 or 3;

[0021] In certain embodiments, each of Cy1, Cy2, Cy3, Cy4, Cy5 is independently selected from a bond or one of the following optionally substituted groups:

[0022]

[0023] When substituted, it is substituted by 1 to 4 substituents selected from deuterium, F, CF 3 , OH, methyl, =O, hydroxymethyl, methoxy, COOH, CN or NH 2 , cyclopropyl;

[0024] In certain embodiments, B is selected from

[0025] In certain embodiments, B 1 is selected from -C(R b1 ) 2 -, -O-, -S-, -NR b1 -;

[0026] In certain embodiments, W is selected from O or S;

[0027] In certain embodiments, R b1 , R b3 or R b4 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 carbocyclic group, 3- to 8-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z ; in certain embodiments, R b1 , R b3 or R b4 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 3- to 6-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R zis substituted; in certain embodiments, R b1 , R b3 or R b4 is independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 or is optionally substituted by 1 to 4 R z substituted methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; in certain embodiments, R b3 or R b4 is independently selected from H, deuterium, F, Cl, Br, I, methyl;

[0028] In certain embodiments, R b2 is selected from H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 carbocyclic group, 3- to 8-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z ; in certain embodiments, R b2 is selected from H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 3- to 6-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z ; in certain embodiments, R b2 is selected from H, deuterium or is optionally substituted by 1 to 4 R z substituted methyl, ethyl, propyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; in certain embodiments, R b2 is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, CD 3 ,

[0029] In certain embodiments, R b2 is directly connected to R b3 to form a 4- to 8-membered heterocyclic group, and the heterocyclic group is optionally substituted by 1 to 4 selected from R z ; in certain embodiments, R b2 is directly connected to R b3 to form a 4- to 6-membered heterocyclic group, and the heterocyclic group is optionally substituted by 1 to 4 selected from R z ;

[0030] In certain embodiments, selected from

[0031] In certain embodiments, b3 is selected from 0, 1, 2, or 3;

[0032] In certain embodiments, K is selected from In certain embodiments, K is selected from

[0033] In certain embodiments, selected from

[0034] In certain embodiments, G is selected from N or CH;

[0035] In certain embodiments, each Q is independently selected from a bond, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q -; in certain embodiments, a nitrogen-nitrogen bond, a nitrogen-oxygen bond, or a nitrogen-sulfur bond cannot be directly formed between Q and G; in certain embodiments, each Q is independently selected from a bond, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q -; in certain embodiments, Q is selected from a bond, CH 2 , NH, N(CH 3 ), O, S, C(=O), NHC(=O), C(=O)NH, N(CH 3 ), C(=O)N(CH 3 ); in certain embodiments, Q is selected from a bond, NH, C(=O)NH;

[0036] In certain embodiments, Rq is selected from H or C 1-4 alkyl; in certain embodiments, R q is selected from H or methyl;

[0037] In certain embodiments, each F is independently selected from C 13-20 carbocyclic group, a 13- to 20-membered heterocyclic group, In certain embodiments, each F is independently selected from a 13- to 15-membered tricyclic hetero-fused ring group, In certain embodiments, F is selected from The ring to which it is attached is an aromatic or non-aromatic ring;

[0038] In certain embodiments, ring E is selected from phenyl or a 5- or 6-membered heteroaryl; in certain embodiments, ring E is selected from phenyl or a 6-membered heteroaryl; in certain embodiments, ring E is selected from phenyl or pyridyl; in certain embodiments, ring E is selected from phenyl;

[0039] In certain embodiments, H 1 is selected from N, NH, CH, CH 2 , CHR k1 , NR k1 , CR k1 , C(=O), C(R k1 ) 2 ; in certain embodiments, H 1 is selected from N, NH, CH, CH 2 , CHR k1 , NR k1 , CR k1 , C(=O);

[0040] In certain embodiments, H 2 is selected from a bond, O, N, NH, CH, CH 2 , CHR k1 , NR k1 , C(=O), CR k1 or C(R k1 ) 2 ; in certain embodiments, H 2 is selected from a bond, O, N, NH, CH, CH 2 , CHR k1 , NR k1 , CR k1 , C(=O);

[0041] In certain embodiments, H 3 is selected from N or CH;

[0042] In certain embodiments, H 4 is selected from C, N or CH; in certain embodiments, H 4 is selected from N;

[0043] In certain embodiments, H 5 , H 6 , H 7 are each independently selected from N, C, CH or CR k1 , and H 5 , H 6 , H 7 contain at most 2 Ns; in certain embodiments, H 6 is selected from N or CRk1 ; In certain embodiments, H 5 or H 7 is independently selected from CH;

[0044] In certain embodiments, R k1 is independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 carbocyclic group, 3- to 8-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted with 1 to 4 R z ; In certain embodiments, R k1 is independently selected from F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 or R k5 ; In certain embodiments, R k1 is independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 3- to 6-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted with 1 to 4 R z ;

[0045] In certain embodiments, R k1 , R k3 are independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CF 3 , CN, COOH, CONH 2 or the following groups optionally substituted with 1 to 4 R z : methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl; In certain embodiments, R k1 are independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CF 3 , CN, COOH, CONH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, CD3 , In certain embodiments, R k1 are each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CF 3 , CN, COOH, CONH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0046] In certain embodiments, R k2 are each independently selected from a bond, -C(═O)-, -S(═O) 2 -, -S(═O)- or -C(R k3 ) 2 -; in certain embodiments, R k2 are each independently selected from -C(═O)-;

[0047] In certain embodiments, R k3 are each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 3-8 carbocyclic group, 3- to 8-membered heterocyclic group, said alkyl, alkoxy, carbocyclic group, heterocyclic group optionally being substituted with 1 to 4 substituents selected from R z ; in certain embodiments, R k3 are each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 3- to 6-membered heterocyclic group, said alkyl, alkoxy, carbocyclic group, heterocyclic group optionally being substituted with 1 to 4 substituents selected from R z ;

[0048] In certain embodiments, R k3 are each independently selected from H, deuterium;

[0049] In certain embodiments, R k4 are each independently selected from O, S, -NR k5 -, -CHR k5 - or -C(R k5 ) 2 -; in certain embodiments, R k4 are each independently selected from O, S, -NR k5 - or -CHR k5-;

[0050] In certain embodiments, R k5 is independently selected from H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 carbocyclic group, 3- to 8-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, and heterocyclic group are optionally substituted with 1 to 4 R z substituents; in certain embodiments, R k5 is independently selected from H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 3- to 6-membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, and heterocyclic group are optionally substituted with 1 to 4 R z substituents; in certain embodiments, R k5 is independently selected from H, deuterium, or the following groups optionally substituted with 1 to 4 R z substituents: methyl, ethyl, isopropyl, cyclopropyl; in certain embodiments, R k5 is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, CD 3 ,

[0051] In certain embodiments, two R k1 are directly connected to form a C 3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from R z substituents; in certain embodiments, two R k1 are directly connected to form a C 3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from R z substituents;

[0052] In certain embodiments, two R k3 are directly connected to form a C 3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from R z substituents; in certain embodiments, two R k3 are directly connected to form a C 3-6 carbocyclic group or a 4- to 6-membered heterocyclic group, and the carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from R z substituents;

[0053] In certain embodiments, RL2 and R z are each independently selected from deuterium, F, Cl, Br, I, OH, ═O, CF 3 , SF 5 , CN, NH 2 , NO 2 , COOH, CONH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -S-C 1-6 alkyl, -C 0-4 alkylene-C 3-6 cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy; in certain embodiments, R L2 , R z are each independently selected from deuterium, F, Cl, Br, I, OH, ═O, CF 3 , SF 5 , CN, NH 2 , NO 2 , COOH, CONH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -S-C 1-4 alkyl, -C 0-2 alkylene-C 3-6 cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy; in certain embodiments, R L2 , R z are each independently selected from deuterium, F, Cl, Br, I, OH, ═O, CF 3 , SF 5 , CN, NH 2 , NO 2 , COOH, CONH 2 , N(CH3 ) 2 、NHCH 3 、 methyl, ethyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy;

[0054] In certain embodiments, n1 is selected from 0, 1, 2 or 3;

[0055] 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, 2 or 3;

[0056] In certain embodiments, L is selected from a bond or the groups shown in Table L-1, wherein the left side of the group is connected to B;

[0057] In certain embodiments, B is selected from one of the structural fragments shown in B-1;

[0058] In certain embodiments, K is selected from one of the structural fragments shown in Table K-1; in certain embodiments, K is selected from one of the structural fragments shown in Table K-2; in certain embodiments, K is selected from one of the structural fragments shown in Table K-1 or K-2;

[0059] Optionally, when F is selected from , R b2 is directly connected to R b3 to form a 4- to 8-membered heterocyclic group, and the heterocyclic group is optionally substituted by 1 to 4 substituents selected from R z ;

[0060] As a first embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0061] L is selected from a bond or -C 1-50 hydrocarbyl-, and 1 to 20 methylene units in the hydrocarbyl are optionally replaced by -Ak- or -Cy-;

[0062] Each -Ak- is independently selected from -(CH2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -S-, -S-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -NR L (CH 2 ) q C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) 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, where the CH, -CH 2 - is optionally substituted by 1 to 2 R z substituents;

[0063] q is independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0064] R L is selected from H, C 1-4 alkyl, C 3-7 carbocyclic group, 4- to 10-membered heterocyclic group, where the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z substituents;

[0065] Each -Cy- is independently selected from a bond or is optionally substituted by 1 to 4 R L2One of the following substituted groups: a 4- to 8-membered hetero monocyclic group, a 4- to 12-membered hetero fused ring group, a 5- to 13-membered hetero spiro ring group, a 7- to 12-membered hetero bridged ring group, a 10- to 16-membered hetero tricyclic ring, C 3-7 monocyclic alkyl group, C 4-7 monocyclic alkenyl group, C 4-12 fused ring alkyl group, C 5-13 spiro alkyl group, C 5-12 bridged ring alkyl group, a 5- to 10-membered heteroaryl group or C 6-10 aryl group;

[0066] B is selected from

[0067] B 1 selected from -C(R b1 ) 2 -, -O-, -S-, -NR b1 -;

[0068] W is selected from O or S;

[0069] R b1 , R b3 or R b4 each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, C 3-8 carbocyclic group, a 3- to 8-membered heterocyclic group, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z substituents;

[0070] R b2 is selected from H, deuterium, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkoxy group, C 3-8 carbocyclic group, a 3- to 8-membered heterocyclic group, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z substituents;

[0071] Optionally, R b2 is directly connected to R b3 to form a 4- to 8-membered heterocyclic group, and the heterocyclic group is optionally substituted by 1 to 4 selected from R z substituents;

[0072] b3 is selected from 0, 1, 2 or 3;

[0073] K is selected from

[0074] G is selected from N or CH;

[0075] Q is independently selected from a bond, -O-, -S-, -CH 2 -, -NR q -, -CO-, -NR q CO-, -CONR q -;

[0076] A nitrogen-nitrogen bond, a nitrogen-oxygen bond, or a nitrogen-sulfur bond cannot be directly formed between Q and G;

[0077] R q is selected from H or C 1-4 alkyl;

[0078] F is independently selected from C 13-20 carbocyclic group, 13-20 membered heterocyclic group,

[0079] provided that when F is selected from then R b2 and R b3 are directly connected to form a 4-8 membered heterocyclic group, and the heterocyclic group is optionally substituted with 1 to 4 R z substituents;

[0080] Ring E is selected from phenyl or 5-6 membered heteroaryl;

[0081] R k1 is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 carbocyclic group, 3 to 8 membered heterocyclic group, and the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, and heterocyclic group are optionally substituted with 1 to 4 R z substituents;

[0082] R k2 is independently selected from a bond, -C(=O)-, -S(=O) 2 -, -S(=O)- or -C(R k3 ) 2 -;

[0083] R k3 is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C1-6 alkyl, C 1-6 alkoxy, C 3-8 carbocyclic group, 3- to 8-membered heterocyclic group, the said alkyl, alkoxy, carbocyclic group, heterocyclic group being optionally substituted by 1 to 4 substituents selected from R z substituents;

[0084] R k4 each independently selected from O, S, -NR k5 -, -CHR k5 -, or -C(R k5 ) 2 -;

[0085] R k5 each independently selected from H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 3-8 carbocyclic group, 3- to 8-membered heterocyclic group, the said alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group being optionally substituted by 1 to 4 R z substituents;

[0086] Alternatively, two R k1 are directly connected to form a C 3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, the said carbocyclic group or heterocyclic group being optionally substituted by 1 to 4 substituents selected from R z substituents;

[0087] Alternatively, two R k3 are directly connected to form a C 3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, the said carbocyclic group or heterocyclic group being optionally substituted by 1 to 4 substituents selected from R z substituents;

[0088] R L2 、R z each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF 3 、SF 5 、CN、NH 2 、NO 2 、COOH、CONH 2 、NHC 1-6 alkyl, N(C 1-6 alkyl) 2 、C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -S-C 1-6 alkyl, -C 0-4 alkylene-C 3-6Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy;

[0089] n1 is selected from 0, 1, 2 or 3;

[0090] p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5.

[0091] As a second embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomers, racemates, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, wherein,

[0092] L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0093] Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH 2 ) q -, -(CH 2 ) q -O-, -O-(CH 2 ) q -, -(CH 2 ) q -S-, -S-(CH 2 ) q -, -(CH 2 ) q -NR L -, -NR L -(CH 2 ) q -, -(CH 2 ) q -NR L C(=O)-, -(CH 2 ) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH 2 ) q -NR L -, -(C≡C) q - or a bond, and the -CH 2 - is optionally substituted by 1 to 2 R z ;

[0094] R L are each independently selected from H or C 1-4 alkyl;

[0095] Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or one of the following groups optionally substituted with 1 to 4 R L2 : a 4- to 7-membered nitrogen-containing monocyclic group, a 4- to 12-membered nitrogen-containing fused ring group, a 5- to 13-membered nitrogen-containing spiro ring group, a 7- to 12-membered nitrogen-containing bridged ring group, a 10- to 16-membered hetero tricyclic ring, C 3-7 monocyclic alkyl group, C 4-7 monocyclic alkenyl group, C 4-12 fused ring alkyl group, C 5-13 spiroalkyl group, C 5-12 bridged ring alkyl group, 5- to 10-membered heteroaryl group or C 6-10 aryl group;

[0096] R b1 、R b3 or R b4 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH 2 、CN, COOH, CONH 2 、C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, C 3-6 carbocyclic group, 3- to 6-membered heterocyclic group, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, carbocyclic group, heterocyclic group are optionally substituted with 1 to 4 R z ;

[0097] R b2 is selected from H, deuterium, C 1-4 alkyl group, C 2-4 alkenyl group, C 2-4 alkynyl group, C 1-4 alkoxy group, C 3-6 carbocyclic group, 3- to 6-membered heterocyclic group, and the alkyl group, alkenyl group, alkynyl group, alkoxy group, carbocyclic group, heterocyclic group are optionally substituted with 1 to 4 R z ;

[0098] Optionally, R b2 is directly connected to R b3 to form a 4- to 6-membered heterocyclic group, and the heterocyclic group is optionally substituted with 1 to 4 selected from R z ;

[0099] F are each independently selected from a 13- to 15-membered tricyclic fused heterocyclic group,

[0100] Ring E is selected from a phenyl group or a 6-membered heteroaryl group;

[0101] R k1 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH 2, CN, COOH, CONH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 3- to 6-membered heterocyclic group, the said alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z substituents;

[0102] R k3 each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 3- to 6-membered heterocyclic group, the said alkyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 selected from R z substituents;

[0103] R k5 each independently selected from H, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 3-6 carbocyclic group, 3- to 6-membered heterocyclic group, the said alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z substituents;

[0104] R L2 , R z each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF 3 , SF 5 , CN, NH 2 , NO 2 , COOH, CONH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -S-C 1-4 alkyl, -C 0-2 alkylene-C 3-6 cycloalkyl, the said alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl are optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C1-4 substituted by a substituent of an alkoxy group;

[0105] The remaining definitions are the same as those in the first embodiment of the present invention.

[0106] As the third embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0107] R L is selected from H, methyl or ethyl;

[0108] Cy1, Cy2, Cy3, Cy4 are each independently selected from a bond or one of the following groups optionally substituted by 1 to 4 R L2 substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl,

[0109] s1, s3, s5 are each independently selected from 0, 1 or 2;

[0110] s2, s4 are each independently selected from 0 or 1;

[0111] s6 is selected from 0, 1, 2 or 3;

[0112] s7 is selected from 1, 2 or 3;

[0113] is selected from

[0114] F is selected from

[0115] represents that the ring where it is located is an aromatic ring or a non-aromatic ring;

[0116] H 1 is selected from N, NH, CH, CH 2 , CHR k1 , NR k1 , CR k1 , C(=O), C(R k1 ) 2 ;

[0117] H 2 is selected from a bond, O, N, NH, CH, CH 2 , CHR k1 , NR k1 , C(=O), CR k1 or C(R k1 ) 2 ;

[0118] H 3 is selected from N or CH;

[0119] H 4 is selected from C, N or CH;

[0120] H 5 、H 6 、H 7 are each independently selected from N, C, CH or CR k1 and H 5 、H 6 、H 7 contain at most 2 Ns;

[0121] Ring E is selected from phenyl or pyridyl;

[0122] Q is selected from a bond, CH 2 、NH、N(CH 3 )、O、S、C(=O)、NHC(=O)、C(=O)NH、N(CH 3 )C(=O)、C(=O)N(CH 3 );

[0123] R k1 、R k3 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH 2 、CF 3 、CN, COOH, CONH 2 or the following groups optionally substituted by 1 to 4 Rs z : methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0124] R k5 are each independently selected from H, deuterium or the following groups optionally substituted by 1 to 4 Rs z : methyl, ethyl, isopropyl, cyclopropyl;

[0125] R b1 、R b3 or R b4 are each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH 2 、CN, COOH, CONH 2 or the following groups optionally substituted by 1 to 4 Rs z : methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0126] R b2 is selected from H, deuterium or optionally substituted by 1 to 4 Rs zSubstituted methyl, ethyl, propyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0127] R L2 , R z are each independently selected from deuterium, F, Cl, Br, I, OH, ═O, CF 3 , SF 5 , CN, NH 2 , NO 2 , COOH, CONH 2 , N(CH 3 ) 2 , NHCH 3 , methyl, ethyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, and the methyl, ethyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy;

[0128] p1 or p2 is each independently selected from 0, 1, 2 or 3;

[0129] The remaining definitions are the same as in the first or second embodiment of the present invention.

[0130] As a fourth embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0131] Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from a bond, -O-, -S-, -OCH 2 -, -CH 2 O-, -OCH 2 CH 2 -, -CH 2 CH 2 O-, -C≡C-, -C(CH 3 ) 2 -, -CH 2 -, -C(CH 3 ) 2 -, -CH 2 CH2 -, -CH 2 CH 2 CH 2 -, -N(CH 3 )-, -NH-, -CH 2 N(CH 3 )-, -CH 2 NH-, -NHCH 2 -, -CH 2 CH 2 N(CH 3 )-, -CH 2 CH 2 NH-, -NHCH 2 CH 2 -, -C(=O)-, -C(=O)CH 2 NH-, -CH 2 C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

[0132] Cy1, Cy2, Cy3, Cy4 are each independently selected from a bond or one of the following optionally substituted groups: When substituted, it is substituted by 1 to 4 substituents selected from deuterium, F, CF 3 , OH, =O, COOH, CN, NH 2 , hydroxymethyl, methyl, methoxy, cyclopropyl;

[0133] K is selected from

[0134] H 1 selected from N, NH, CH, CH 2 , CHR k1 , NR k1 , CR k1 , C(=O);

[0135] H 2 selected from a bond, O, N, NH, CH, CH 2 , CHR k1 , NR k1 , CR k1 , C(=O);

[0136] H 6 selected from N or CHR k1 ;

[0137] R k4 selected from O, S, -CHR k5 -, -NR k5 -;

[0138] The remaining definitions are the same as those in the first, second, or third embodiment of the present invention.

[0139] As the fifth embodiment of the present invention, the compound represented by the foregoing general formula (I), or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0140] R b2 is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, CD 3 ,

[0141] R b3 or R b4 each independently is selected from H, deuterium, F, Cl, Br, I, methyl;

[0142] Or is selected from

[0143] L is selected from a bond or -NHCH 2 -, -Cy1-, -Cy1-CH 2 -, -Cy1-C≡C-, -Cy1-Cy2-, -Cy1-CH 2 -Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH 2 -Cy2-Cy3-, -Cy1-Cy2-CH 2 -Cy3-, -NH-Cy1-, -NH-Cy1-O-, -O-Cy1-NH-, -NH-Cy1-Cy2-, -NH-Cy1-CH 2 -Cy2, -Cy1-Ak2-, -Ak1-Cy1-Ak2-;

[0144] R k1 each independently is selected from H, deuterium, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0145] R k5 is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, CD 3 ,

[0146] The remaining definitions are the same as those in the first, second, third, or fourth embodiment of the present invention.

[0147] As a sixth embodiment of the present invention, the compound represented by the foregoing general formula (I) or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0148] B is selected from one of the structural fragments shown in Table B-1;

[0149] L is selected from a bond or one of the structural fragments shown in Table L-1;

[0150] K is selected from one of the structural fragments shown in Table K-1 or Table K-2.

[0151] The present invention relates to a compound as described below or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E below.

[0152] The present invention relates to a pharmaceutical composition comprising the compound of the present invention as described above or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0153] The present invention relates to the use of the compound of the present invention as described above or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a drug for treating a disease related to Bcl6 activity or expression level.

[0154] The present invention relates to the use of the compound of the present invention as described above or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a drug for treating a disease related to the inhibition or degradation of Bcl6.

[0155] In some embodiments, the disease related to the inhibition or degradation of Bcl6 is cancer.

[0156] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, and the pharmaceutical composition or pharmaceutical preparation contains a therapeutically effective amount of the compound of the present invention as described above or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal and a pharmaceutical excipient. The pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as the "preparation specification").

[0157] The present invention also provides a method for treating a disease in a mammal, which comprises administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal or pharmaceutical composition. In some embodiments, the mammal in the present invention includes a human.

[0158] As used herein, "effective amount" or "therapeutically effective amount" means an amount of a compound disclosed herein that, to some extent, will alleviate one or more symptoms of a disease or disorder being treated (such as cancer). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic use is an amount of a compound disclosed herein that is required to provide a clinically significant reduction in the symptoms of the disease.Examples of a therapeutically effective amount 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 - 500 mg, 10 - 500 mg, 20 - 500 mg, 25 - 500 mg, 30 - 500 mg, 40 - 500 mg, 50 - 500 mg, 60 - 500 mg, 70 - 500 mg, 75 - 500 mg, 80 - 500 mg, 90 - 500 mg, 100 - 500 mg, 125 - 500 mg, 150 - 500 mg, 200 - 500 mg, 250 - 500 mg, 300 - 500 mg, 400 - 500 mg, 5 - 400 mg, 10 - 400 mg, 20 - 400 mg, 25 - 400 mg, 30 - 400 mg, 40 - 400 mg, 50 - 400 mg, 60 - 400 mg, 70 - 400 mg, 75 - 400 mg, 80 - 400 mg, 90 - 400 mg, 100 - 400 mg, 125 - 400 mg, 150 - 400 mg, 200 - 400 mg, 250 - 400 mg, 300 - 400 mg, 1 - 300 mg, 2 - 300 mg, 5 - 300 mg, 10 - 300 mg, 20 - 300 mg, 25 - 300 mg, 30 - 300 mg, 40 - 300 mg, 50 - 300 mg, 60 - 300 mg, 70 - 300 mg, 75 - 300 mg, 80 - 300 mg, 90 - 300 mg, 100 - 300 mg, 125 - 300 mg, 150 - 300 mg, 200 - 300 mg, 250 - 300 mg, 1 - 200 mg, 2 - 200 mg, 5 - 200 mg, 10 - 200 mg, 20 - 200 mg, 25 - 200 mg, 30 - 200 mg, 40 - 200 mg, 50 - 200 mg, 60 - 200 mg, 70 - 200 mg, 75 - 200 mg, 80 - 200 mg, 90 - 200 mg, 100 - 200 mg, 125 - 200 mg, 150 - 200 mg, 80 - 1500 mg, 80 - 1000 mg, 80 - 800 mg;.

[0159] In some embodiments, the pharmaceutical composition comprises, 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, 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 the compound of the present invention or its stereoisomers, racemates, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals.

[0160] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomers, racemates, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, the therapeutically effective amount being preferably 1 - 1500 mg, and the disease being preferably an autoimmune disease, an inflammatory disease or cancer.

[0161] A method for treating a disease in a mammal, the method comprising administering to a subject a daily dose of 1 - 1500 mg / day of the compound of the present invention or its stereoisomers, racemates, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, the daily dose may be a single dose or divided doses. In some embodiments, the daily dose comprises, but is not limited to, 10 - 1500 mg / day, 10 - 1000 mg / day, 10 - 800 mg / day, 25 - 800 mg / day, 50 - 800 mg / day, 100 - 800 mg / day, 200 - 800 mg / day, 25 - 400 mg / day, 50 - 400 mg / day, 100 - 400 mg / day, 200 - 400 mg / day. In some embodiments, the daily dose comprises, 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.

[0162] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form. The kit contains the compound of the present invention or its stereoisomers, racemates, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and the amount of the compound of the present invention or its stereoisomers, racemates, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals is the same as that in the above-mentioned pharmaceutical composition.

[0163] In the present invention, the amount of the compound of the present invention or its stereoisomers, racemates, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals is converted in the form of free base in each case.

[0164] To achieve the object of the present invention, according to the organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in chemical literature, the compounds used in the reactions described herein are prepared. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai Macklin Biochemical Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Energy Chemical, Shanghai Titan Technology Co., Ltd., Kelong Chemical Industry, J&K Scientific Ltd., etc.

[0165] Unless otherwise specified, the terms used in the specification and claims have the following meanings.

[0166] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotope situations, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention may optionally be further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called superheavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, the isotopes of nitrogen include 14 N and 15 N, the isotopes of fluorine include 17 F and 19 F, the isotopes of chlorine include 35 Cl and 37Cl, and the isotopes of bromine include 79 Br and 81 Br.

[0167] "CN" refers to a cyano group.

[0168] "Halogen" refers to F, Cl, Br, or I.

[0169] "Halogen-substituted" means substituted with F, Cl, Br, or I, including but not limited to being substituted with 1 to 10 substituents selected from F, Cl, Br, or I, substituted with 1 to 6 substituents selected from F, Cl, Br, or I, substituted with 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is abbreviated as "halogenated".

[0170] "Alkyl" refers to a substituted or unsubstituted straight-chain or branched-chain saturated aliphatic hydrocarbon group, including but not limited to an alkyl group having 1 to 20 carbon atoms, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched isomers thereof; the alkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0171] "Heteroalkyl" means that one or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms in a substituted or unsubstituted alkyl group are replaced by heteroatoms (including but not limited to N, O, or S). Non-limiting examples include -X-(CH 2 )v-X-(CH 2 )v-X-(CH 2 )v-H (v is an integer from 1 to 5, X is independently selected from a bond or a heteroatom, the heteroatom includes but not limited to N, O, or S, and at least one X is selected from a heteroatom, and N or S in the heteroatom can be oxidized to various oxidation states). The heteroalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0172] "Alkylene" refers to a substituted or unsubstituted straight-chain and branched-chain divalent saturated hydrocarbon group, including -(CH 2 ) v - (v is an integer from 1 to 10), and examples of the alkylene group include but not limited to methylene, ethylene, propylene, and butylene, etc.

[0173] "Heteroalkylene" means that one or more (including but not limited to 2, 3, 4, 5, or 6) carbon atoms in a substituted or unsubstituted alkylene group are replaced by heteroatoms (including but not limited to N, O, or S). Non-limiting examples include -X-(CH 2 )v-X-(CH 2 )v-X-(CH 2)v−, where v is an integer from 1 to 5, and each X is independently selected from a bond, N, O, or S, and at least one X is selected from N, O, or S.

[0174] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 12 carbon atoms. Cycloalkyl can be monocyclic, fused-ring, bridged-ring, and spiro-ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-fused cyclobutyl, cyclobutyl-spiro cyclobutyl, adamantane, etc. Cycloalkyl can be monovalent, divalent, trivalent, or tetravalent.

[0175] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to groups having 3 to 12 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, or S, and the C, N, and S on the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be monocyclic, fused-ring, bridged-ring, and spiro-ring. Heterocycloalkyl can be attached to a heteroatom or a carbon atom. Non-limiting examples include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,

[0176] Heterocycloalkyl can be monovalent, divalent, trivalent, or tetravalent.

[0177] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched-chain unsaturated hydrocarbon group having at least 1, usually 1, 2, or 3 carbon-carbon double bonds, and the main chain includes but not limited to 2 to 10, 2 to 6, or 2 to 4 carbon atoms. Examples of alkenyl include but not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene, and 1,4-hexadiene, etc.; alkenyl can be monovalent, divalent, trivalent, or tetravalent.

[0178] "Alkynyl" refers to a substituted or unsubstituted straight-chain or branched-chain unsaturated hydrocarbon group having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, with the main chain including 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms in the main chain, having 2 to 4 carbon atoms in the main chain. Examples of alkynyl include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0179] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropoxy and cyclobutoxy.

[0180] "Carbocyclic group" or "carbocycle" refers to a substituted or unsubstituted aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered tetracyclic system. The carbocyclic group can be attached to an aromatic ring or a non-aromatic ring, and the ring is optionally a monocyclic ring, a fused ring, a bridged ring or a spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclic group" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

[0181] "Heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered tetracyclic system, and contains one or more (including but not limited to 2, 3, 4, or 5) heteroatoms selected from N, O, S, or Se. The optionally substituted C, N, or S in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic or non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused, or spiro ring. Non-limiting examples include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxanyl, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiolyl, dihydrofuryl, dihydropyranyl, dithiolanyl, tetrahydrofuryl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuryl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl, benzofuryl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octanyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecanyl, azadamantyl, oxaspiro[3.3]heptanyl,

[0182] The "heterocyclic group" or "heterocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0183] "Spiro ring" or "spiro group" refers to a polycyclic group in which substituted or unsubstituted rings share one atom (called the spiro atom). The number of ring atoms in the spiro ring system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, or 6 to 10, and one or more of the rings can contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds, and optionally can contain 0 to 5 heteroatoms selected from N, O, S(=O) n or Se(=O) n (n is 0, 1, or 2).

[0184]

[0185] The "spiro ring" or "spiro group" can be monovalent, divalent, trivalent, or tetravalent.

[0186] "Fused ring" or "fused ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, where one or more rings may contain zero or more (including but not limited to 1, 2, 3, or 4) double bonds, and may be substituted or unsubstituted. Each ring in the fused ring system may contain from 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to selected from N, S(=O) n , Se(=O) n or O, and n is 0, 1, or 2). The number of ring atoms in the fused ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include:

[0187]

[0188] "Fused ring" or "fused ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0189] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two non-directly connected atoms, which may contain zero or more double bonds. Any ring in the bridged ring system may contain from 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O)n, Se(=O) n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include cubane, adamantane,

[0190]

[0191] "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0192] "Carbospirocycle", "spirocarbocyclic group", "spirocarbonyl group" or "carbospiro group" refers to a "spirocycle" whose ring system consists only of carbon atoms.

[0193] "Carbofused ring", "fused carbocyclic group", "carbo-fused ring group" or "carbofused group" refers to a "fused ring" whose ring system consists only of carbon atoms.

[0194] "Carbobridged ring", "bridged carbocyclic group", "bridged carbonyl group" or "carbobridged group" refers to a "bridged ring" whose ring system consists only of carbon atoms.

[0195] "Heteromonocycle", "monocyclic heterocyclic group" or "heteromonocyclic group" refers to a "heterocyclic group" or "heterocycle" of a monocyclic system,

[0196] "Heterofused ring", "heterofused ring group", "fused heterocyclic group" or "hetero-fused group" refers to a "fused ring" containing heteroatoms.

[0197] "Spiroheterocycle", "spiroheterocyclic group", "heterospirocyclic group" or "heterospiro group" means a "spirocycle" containing a heteroatom.

[0198] "Bridged heterocycle", "bridged heterocyclic group", "heterobicyclic group" or "heterobridge group" means a "bridged ring" containing a heteroatom.

[0199] "Aryl" or "aromatic ring" means a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or fused ring, and the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12 or 6 to 10 carbon atoms. The aryl ring can be fused to a saturated or unsaturated carbocyclic ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection site is on the aryl ring.

[0200] "Heteroaryl" or "heteroaromatic ring" means a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O, S(=O)n, Se(=O) n , n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes, but is not limited to, 5 to 15, 5 to 10 or 5 to 6. The atoms C, N, S, Se on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, n is 1, 2). Non-limiting examples of heteroaryl include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, pyridone group, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include The heteroaryl appearing in this article has the same definition as this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the connection site is on the aromatic ring.

[0201] "Substituted" or "substitution" means being substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, and the substituents include but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, mercaptan, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic group, bridged ring group, spiro ring group, fused ring group, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a -O-(CH 2) m -C(=O)-R a 、-(CH 2 ) m -C(=O)-NR b R c 、-(CH 2 ) m S(=O) n R a 、-(CH 2 ) m -alkenyl-R a 、OR d or -(CH 2 ) m -alkynyl-R a (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c and other groups, where R b and R c are independently selected from including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R b and R c can form a five- or six-membered cycloalkyl or heterocyclic group, R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic group, carbonyl, ester group, bridged ring group, spiro ring group or fused ring group.

[0202] "Substituted by 1 to X substituents selected from..." means substituted by 1, 2, 3... X substituents selected from..., and X is any integer between 1 and 10. For example, "substituted by 1 to 4 R k " means substituted by 1, 2, 3 or 4 R k ". For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4 or 5 substituents selected from.... For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0203] An X-Y membered ring (X, Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, X and Y are any integers between 4 and 20) includes X, X + 1, X + 2, X + 3, X + 4... Y membered rings. The ring includes heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterofused rings, heterospiro rings or heterobridged rings. For example, "a 4-7 membered heteromonocyclic ring" means a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "a 5-10 membered heterofused ring" means a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heterofused ring.

[0204] Cx-y Carbocyclic rings (including aryl, cycloalkyl, monocyclic carbocyclic, spirocarbocyclic, fused carbocyclic or bridged carbocyclic rings) include C x , C x+1 , C x+2 , C x+3 , C x+4 … C y -membered rings (x is an integer, and 3 ≤ x < y, where y is any integer selected from 4 to 20), for example. Such as C 3-6 "Cycloalkyl" means C 3 , C 4 , C 5 or C 6 cycloalkyl;

[0205] When a group has one or more connectable sites, any one or more of these sites of the group can be connected to other groups by chemical bonds. When the connection mode of the chemical bond is non-specific and there are hydrogen atoms at the connectable sites, then when connecting the chemical bond, the number of H atoms at this site will correspondingly decrease according to the number of connected chemical bonds to form a group with the corresponding valence. For example indicates that any connectable site on this piperidyl group can be connected to other groups by 1 chemical bond, including at least these 4 connection modes. Even if an H atom is drawn on -N, it also includes For example indicates that the R group on this piperidyl group can be located on C or on N, including at least

[0206] When the listed connecting groups do not specify their connection directions, their connection directions include connecting in the directions of the reading orders from left to right and from right to left. For example, for A-L-B, when L is selected from -M-W-, it includes A-M-W-B and A-W-M-B.

[0207] "Optional" or "optionally" means that the subsequent described event or circumstance can but does not have to occur, and this description includes the occasions where the event or circumstance occurs or does not occur. For example: "Optionally F-substituted alkyl" means that the alkyl can but does not have to be substituted by F, and the description includes the situation where the alkyl is substituted by F and the situation where the alkyl is not substituted by F.

[0208] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means a salt obtained by reacting the free acid or free base of the compound of the present invention while maintaining the biological effectiveness and characteristics of the free acid or free base, and the free acid reacts with a non-toxic inorganic base or organic base, and the free base reacts with a non-toxic inorganic acid or organic acid.

[0209] "Pharmaceutical composition" refers to a mixture formed by one or more compounds described in the present invention, or their stereoisomers, racemates, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals and other chemical components. Among them, "other chemical components" refer to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0210] "Dosage form specification" refers to the weight of the active ingredient contained in each vial, tablet or other unit dosage form.

[0211] "Carrier" refers to a material that does not cause obvious irritation to organisms and does not eliminate the biological activity and characteristics of the administered compound.

[0212] "Prodrug" refers to a compound of the present invention that can be metabolically converted in vivo into a biologically active compound. The prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the compounds of the present invention, and this modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0213] "Cocrystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, where the pure states of API and CCF are both solids at room temperature, and there is a fixed stoichiometric ratio between the components. Cocrystals are a type of multi-component crystal, including binary cocrystals formed between two neutral solids, as well as multi-component cocrystals formed between neutral solids and salts or solvates.

[0214] "Animal" refers to including mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.

[0215] "Stereoisomer" refers to an isomer produced by the different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers and conformational isomers.

[0216] "Tautomer" refers to a functional group isomer produced by the rapid movement of a certain atom in a molecule between two positions, such as keto-enol tautomerism and amide-imidol tautomerism, etc.

[0217] "IC 50 " is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a certain component in this process, such as an enzyme, receptor, cell, etc.) by half. Detailed Description of the Invention

[0218] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to this.

[0219] Synthesis Method 1:

[0220]

[0221] The general formula compound (Z-1) and the general formula compound (Z-2) react through a coupling or nucleophilic substitution reaction to obtain the general formula compound (Z-3);

[0222] The general formula compound (Z-3) is deprotected to obtain the general formula compound (Z-4);

[0223] The general formula compound (Z-4) and the general formula compound (Z-5) react through a coupling or nucleophilic substitution reaction to obtain the general formula compound (I-a);

[0224] R m1 、R m3 are each independently selected from groups such as F, Cl, Br, I, OTf, etc.;

[0225] R m2 is selected from protecting groups such as Ts, Boc, Cbz, Fmoc, SEM, MOM, TBS, THP, Trt, etc.;

[0226] The definitions of the remaining groups are the same as those of the compound of general formula (I).

[0227] Synthesis Method 2:

[0228]

[0229] The general formula compound (Z-6) and the general formula compound (Z-5) react through a coupling or nucleophilic substitution reaction to obtain the general formula compound (I-b). R m3 is selected from groups such as F, Cl, Br, I, OTf, etc.;

[0230] The definitions of the remaining groups are the same as those of the compound of general formula (I).

[0231] Synthesis Method 3:

[0232]

[0233] The general formula compound (Z-5) and the general formula compound (Z-7) react through a coupling or nucleophilic substitution reaction to obtain the general formula compound (Z-8);

[0234] The general formula compound (Z-8) is oxidized or undergoes a nucleophilic substitution reaction to obtain the general formula compound (Z-9);

[0235] The general formula compound (Z-9) and the general formula compound (Z-6) react through reductive amination or a nucleophilic substitution reaction to obtain the general formula compound (I-c). R m3 is selected from groups such as F, Cl, Br, I, OTf, etc.;

[0236] R m4 selected from groups such as CHO, Br, I, OTf, OMs, OTs;

[0237] The definitions of the remaining groups are the same as those of the compounds of general formula (I).

[0238] The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and the suppliers include: Titan Technology, Energy Chemical, Shanghai Dermachem, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, Nanjing Pharmatech, WuXi AppTec, and J&K Scientific, etc.

[0239] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The NMR shift (δ) is given in units of 10 -6 (ppm). The NMR measurements are performed using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic resonance spectrometers, and the solvents for the measurements are deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethylsilane (TMS);

[0240] The MS measurements are performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0241] The HPLC measurements are performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0242] The silica gel plates for thin-layer chromatography use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of the silica gel plates used for thin-layer chromatography (TLC) are 0.15 mm - 0.20 mm, and the specifications of the silica gel plates used for separating and purifying products by thin-layer chromatography are 0.4 mm - 0.5 mm;

[0243] Column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200 - 300 as the carrier.

[0244] Example 1: Preparation of Compound 1 Trifluoroacetate

[0245]

[0246] First step: Preparation of 1b

[0247] Add 1a (2.0 g, 11.35 mmol) (the synthesis method is shown in WO2023212147), 2,4,5-trichloropyrimidine (2.08 g, 11.34 mmol) and 20 mL of DMF to a reaction flask, and react at room temperature for 3 h. Pour the reaction solution into 100 mL of ice water, filter, wash the filter cake with 20 mL of water, and dry the filter cake under reduced pressure to obtain the crude product 1b (3.0 g).

[0248] LCMS m / z = 323.1 [M+1] +

[0249] Step 2: Preparation of compound 1 trifluoroacetate

[0250] Dissolve 1A (0.20 g, 0.48 mmol) (the synthesis method is shown in WO2023232133) in 3 mL of dichloromethane, add 1.5 mL of trifluoroacetic acid, and stir at room temperature for 2 h. Concentrate the reaction system under reduced pressure, dissolve the residue in 5 mL of DMSO, add N,N-diisopropylethylamine (0.62 g, 4.80 mmol) and the above crude product 1b (0.16 g), and react at 100 °C for 16 h. Cool the reaction system to room temperature, and pass the reaction solution through Pre-HPLC (instrument and preparation column: use Waters 2767 preparative liquid phase, the preparation column model is SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: Filter the DMSO solution of the crude product with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile is eluted from 10% to 50% (elution time 15 min) in a gradient, and lyophilize to obtain the trifluoroacetate of compound 1 (140 mg).

[0251] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.76 (s, 1H), 9.15 (s, 1H), 8.12 (s, 1H), 7.64–7.54 (m, 1H), 7.47 (dd, 1H), 7.03 (d, 1H), 6.82 (d, 1H), 6.70 (d, 1H), 4.46–4.29 (m, 2H), 3.94–3.79 (m, 2H), 3.77–3.65 (m, 2H), 3.59 (s, 2H), 3.15–2.95 (m, 2H), 2.84–2.58 (m, 5H), 2.55–2.46 (m, 1H), 2.19–2.05 (m, 1H), 1.99–1.87 (m, 2H), 1.72–1.58 (m, 1H), 1.17 (t, 3H).

[0252] LCMS m / z = 604.2 [M+1]+

[0253] Example 2: Preparation of Compound 2 Trifluoroacetate

[0254]

[0255] Compound 2 Trifluoroacetate was obtained by using Compound 2a (for the synthesis method, see WO2023232133) and 1b as raw materials and referring to the synthesis method of Example 1.

[0256] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.76 (s, 1H), 9.05 (s, 1H), 8.12 (s, 1H), 7.64–7.54 (m, 1H), 7.46 (dd, 1H), 7.02 (d, 1H), 6.82 (d, 1H), 6.69 (d, 1H), 4.45–4.32 (m, 2H), 3.98–3.79 (m, 2H), 3.77–3.65 (m, 2H), 3.59 (s, 2H), 3.13–2.95 (m, 2H), 2.85–2.57 (m, 5H), 2.55–2.43 (m, 1H), 2.20–2.05 (m, 1H), 1.99–1.85 (m, 2H), 1.72–1.58 (m, 1H), 1.17 (t, 3H).

[0257] LCMS m / z = 604.3 [M+1] +

[0258] Example 3: Preparation of Compound 3

[0259]

[0260] First step: Preparation of 3b

[0261] 3a (6.29 g, 16.33 mmol) (synthesis method WO2023232133), 3A (4.14 g, 22.84 mmol), cesium carbonate (10.63 g, 32.63 mmol), palladium acetate (0.73 g, 3.25 mmol) and XantPhos (0.94 g, 1.62 mmol) were added to a 1,4-dioxane solution (100 mL), and the reaction was carried out at 105 °C for 16 h under a nitrogen atmosphere. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and the filter cake was washed with 50 mL of dichloromethane. The filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:5) to obtain 3b (6.94 g, yield: 88%).

[0262] LCMS m / z = 486.2 [M+1]+

[0263] Step 2: Preparation of 3c

[0264] Dissolve 3b (6.94 g, 14.30 mmol) in 200 mL of methanol, add 10% palladium on carbon (6.92 g) and ammonium acetate (6.79 g, 88.09 mmol), and react at room temperature for 12 h under a hydrogen balloon atmosphere. Filter the reaction system through diatomaceous earth, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (ethyl acetate / petroleum ether (v / v) = 1:1) to obtain 3c (4.15 g, yield: 90%).

[0265] LCMS m / z = 322.2 [M+1] +

[0266] Step 3: Preparation of 3d

[0267] Add 3c (4.15 g, 12.92 mmol), 3B (3.88 g, 38.75 mmol) and N,N-diisopropylethylamine (5.01 g, 38.76 mmol) to ethanol (60 mL) in sequence, and react at 100 °C for 72 h. Cool the reaction system to room temperature, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane (v / v) = 1:20) to obtain 3d (3.91 g, yield: 72%).

[0268] LCMS m / z = 422.3 [M+1] +

[0269] Step 4: Preparation of 3e

[0270] Add 3d (0.50 g, 1.19 mmol) and N,N-diisopropylethylamine (0.46 g, 3.56 mmol) to tetrahydrofuran (20 mL), slowly add triphosgene (0.39 g, 1.31 mmol), after reacting at room temperature for 1 h, add ammonia water (5 mL), and react at 50 °C for 2 h. Cool the reaction system to room temperature, add 100 mL of ethyl acetate, wash the organic phase with water (50 mL × 3) and 50 mL of saturated sodium chloride aqueous solution respectively, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (methanol / dichloromethane (v / v) = 1:15) to obtain 3e (0.46 g, yield: 83%).

[0271] LCMS m / z = 465.3 [M+1] +

[0272] Step 5: Preparation of 3f

[0273] 3e (0.46 g, 0.99 mmol) was added to acetonitrile (10 mL), 40% benzyltrimethylammonium hydroxide methanol solution (1.2 mL) was added, and the reaction was carried out at 60 °C for 2 h. The reaction system was cooled to room temperature, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (methanol / dichloromethane (v / v) = 1:15) to obtain 3f (0.21 g, yield: 51%).

[0274] Step 6: Preparation of Compound 3

[0275] 3f (0.15 g, 0.36 mmol) was dissolved in 3 mL of dichloromethane, 1.5 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 2 h. The reaction system was concentrated under reduced pressure, the residue was dissolved in 5 mL of DMSO, N,N-diisopropylethylamine (0.47 g, 3.64 mmol) and the above crude 1b (0.12 g) were added, and the reaction was carried out at 100 °C for 16 h. The reaction system was cooled to room temperature, and the reaction solution was passed through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid phase was used, and the preparative column model was Waters Xbridge prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 5 mmol / L ammonium acetate) / acetonitrile. Gradient elution method: Acetonitrile was eluted from 20% to 67.5% (elution time 19 min) by gradient, and the product was freeze-dried to obtain Compound 3 (10 mg, yield: 5%).

[0276] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 8.70 (s, 1H), 8.03 (s, 1H), 7.65–7.58 (m, 1H), 7.47 (dd, 1H), 7.00 (d, 1H), 6.95 (d, 1H), 6.78 (d, 1H), 4.54–4.36 (m, 2H), 3.95–3.83 (m, 1H), 3.71 (q, 2H), 3.64–3.54 (m, 4H), 3.07–2.96 (m, 2H), 2.81–2.61 (m, 6H), 2.02–1.89 (m, 1H), 1.72–1.59 (m, 1H), 1.17 (t, 3H).

[0277] LCMS m / z = 605.4 [M+1] +

[0278] Example 4: Preparation of Compound 4

[0279]

[0280] Compound 4 was obtained using compound 4a (synthesis method: WO2023232133) as the raw material and referring to the synthesis method of Example 3.

[0281] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 8.72 (s, 1H), 8.04 (s, 1H), 7.62 (s, 1H), 7.52–7.44 (m, 1H), 7.04–6.91 (m, 2H), 6.79 (d, 1H), 4.54–4.37 (m, 2H), 3.96–3.84 (m, 1H), 3.71 (q, 2H), 3.66–3.54 (m, 4H), 3.09–2.96 (m, 2H), 2.83–2.60 (m, 6H), 2.03–1.90 (m, 1H), 1.74–1.59 (m, 1H), 1.17 (t, 3H).

[0282] LCMS m / z = 605.4 [M+1] +

[0283] Example 5: Preparation of Compound 5 Trifluoroacetate

[0284]

[0285] Dissolve 5a (0.077 g, 0.15 mmol) (synthesis method referring to WO2023232133) in 3 mL of dichloromethane, add 1.5 mL of trifluoroacetic acid, and stir at room temperature for 2 h. Concentrate the reaction system under reduced pressure, dissolve the residue in 5 mL of DMSO, add N,N-diisopropylethylamine (0.20 g, 1.51 mmol) and the above crude product 1b (0.048 g), and react at 100 °C for 16 h. Cool the reaction system to room temperature, and pass the reaction solution through Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid phase, preparative column model is SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: Filter the DMSO solution of the crude product through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile is eluted from 10% to 50% in a gradient (elution time 15 min), and lyophilize to obtain compound 5 trifluoroacetate (36 mg).

[0286] 1 H NMR (400 MHz, DMSO-d 6)δ10.78(s,1H),8.87(s,1H),8.05(s,1H),7.57–7.52(m,1H),7.48(dd,1H),6.98(d,1H),6.88(d,1H),6.79(d,1H),4.51–4.36(m,2H),4.13–4.01(m,1H),3.92–3.84(m,1H),3.74–3.65(m,3H),3.64–3.56(m,2H),3.54(s,2H),3.38–3.29(m,1H),3.15–2.98(m,4H),2.96–2.79(m,3H),2.79–2.58(m,3H),2.23–2.06(m,2H),2.04–1.89(m,2H),1.87–1.70(m,2H),1.69–1.55(m,1H),1.21–1.07(m,5H).

[0287] LCMS m / z=701.3[M+1] +

[0288] Example 6: Preparation of Compound 6 Trifluoroacetate

[0289]

[0290] Compound 6 trifluoroacetate was obtained by using Compound 6a (synthesis method WO2023232133) and 1b as raw materials with reference to the synthesis method of Example 5.

[0291] 1 H NMR(400MHz,DMSO-d 6 )δ10.78(s,1H),8.87(s,1H),8.05(s,1H),7.58–7.50(m,1H),7.48(dd,1H),6.98(d,1H),6.88(d,1H),6.79(d,1H),4.52–4.34(m,2H),4.13–4.00(m,1H),3.95–3.82(m,1H),3.75–3.64(m,3H),3.64–3.55(m,2H),3.54(s,2H),3.38–3.28(m,1H),3.15–2.95(m,4H),2.95–2.79(m,3H),2.79–2.55(m,3H),2.21–2.04(m,2H),2.04–1.87(m,2H),1.87–1.70(m,2H),1.69–1.55(m,1H),1.21–1.05(m,5H).

[0292] LCMS m / z = 351.2 [M / 2 + 1] +

[0293] Example 7: Preparation of Compound 7 Trifluoroacetate

[0294]

[0295] First Step: Preparation of 7a

[0296] Add 3f (0.20 g, 0.48 mmol), 1 mL of trifluoroacetic acid and 3 mL of dichloromethane to a reaction flask, and react at room temperature for 3 h. Concentrate the reaction solution under reduced pressure, adjust the pH to 7 with triethylamine, concentrate under reduced pressure, add 10 mL of dichloromethane to the residue, successively add 7A (0.10 g, 0.48 mmol), 0.3 mL of acetic acid and sodium triacetoxyborohydride (0.20 g, 0.95 mmol), and react at room temperature for 16 h. Add 15 mL of dichloromethane and 15 mL of saturated sodium bicarbonate aqueous solution to the reaction solution, extract the aqueous phase with dichloromethane (15 mL × 3), combine the organic phases, wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate (v / v) = 1:4) to obtain 7a (0.21 g, yield: 85%).

[0297] Second Step: Preparation of Compound 7 Trifluoroacetate

[0298] Dissolve 7a (0.105 g, 0.20 mmol) in 3 mL of dichloromethane, add 1.5 mL of trifluoroacetic acid, and stir at room temperature for 2 h. Concentrate the reaction system under reduced pressure, dissolve the residue in 5 mL of DMSO, add N,N-diisopropylethylamine (0.26 g, 2.01 mmol) and the above crude product 1b (0.065 g), and react at 100 °C for 16 h. Cool the reaction system to room temperature, and pass the reaction solution through Pre-HPLC (instrument and preparation column: Waters 2767 preparative liquid phase is used, and the preparation column model is SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: Filter the DMSO solution of the crude product with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile is eluted from 10% to 50% in a gradient (elution time 15 min), and lyophilize to obtain the trifluoroacetate of Compound 7 (50 mg).

[0299] 1 H NMR (400 MHz, DMSO-d 6)δ10.35(s,1H),8.91(s,1H),8.06(s,1H),7.59–7.52(m,1H),7.48(dd,1H),7.06–6.95(m,2H),6.89(d,1H),4.54–4.36(m,2H),4.13–4.06(m,1H),3.74–3.65(m,2H),3.65–3.56(m,4H),3.54(s,2H),3.42–3.32(m,1H),3.18–2.98(m,4H),2.97–2.81(m,3H),2.79–2.61(m,4H),2.23–2.09(m,1H),2.06–1.94(m,1H),1.88–1.70(m,2H),1.70–1.55(m,1H),1.22–1.08(m,5H).

[0300] LCMS m / z=702.3[M+1] +

[0301] Example 8: Preparation of Compound 8 Trifluoroacetate

[0302]

[0303] Compound 8 trifluoroacetate was obtained from Compound 4f as the raw material with reference to the synthesis method of Example 7.

[0304] 1 H NMR(400MHz,DMSO-d 6 )δ10.36(s,1H),8.87(s,1H),8.05(s,1H),7.59–7.50(m,1H),7.48(dd,1H),7.06–6.95(m,2H),6.90(d,1H),4.54–4.36(m,2H),4.15–4.05(m,1H),3.74–3.66(m,2H),3.66–3.55(m,4H),3.55(s,2H),3.42–3.32(m,1H),3.18–2.98(m,4H),2.97–2.81(m,3H),2.79–2.61(m,4H),2.23–2.09(m,1H),2.06–1.94(m,1H),1.88–1.70(m,2H),1.70–1.55(m,1H),1.22–1.08(m,5H).

[0305] LCMS m / z=702.3[M+1] +

[0306] Example 10: Preparation of Compound 10 Trifluoroacetate

[0307]

[0308] Step 1: Preparation of 10b

[0309] Dissolve 10a (9.0 g, 42.6 mmol) in 50 mL of ultra-dry THF and 50 mL of DMSO. Add 60% sodium hydride (5.1 g, 127.8 mmol) at 0 °C. After stirring at 0 °C for 30 min, add 10A (12.3 g, 64.0 mmol) and potassium iodide (5.7 g, 34.1 mmol). React at room temperature for 16 h. Add 200 mL of ethyl acetate and 400 mL of water to the reaction solution at 0 °C. Extract the aqueous phase with ethyl acetate (200 mL × 3). Combine the organic phases, dry the organic phases with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1 - 0:1) to obtain 10b (11.0 g, yield: 80%).

[0310] LCMS m / z = 322.0 [M+1] +

[0311] Step 2: Preparation of 10c

[0312] Dissolve 10b (2.0 g, 6.2 mmol) and 10B (1.9 g, 9.3 mmol) in 40 mL of ultra-dry 1,4-dioxane. Add XPhos Pd G3 (1.1 g, 1.24 mmol). Replace nitrogen three times, and then add a THF solution of 1 mol / L LiHMDS (5.8 mL, 5.8 mmol) under a nitrogen atmosphere. React at 80 °C for 2 h. Cool the reaction solution to room temperature, add 50 mL of ethyl acetate and 50 mL of saturated ammonium chloride aqueous solution at 0 °C. Extract the aqueous phase with ethyl acetate (50 mL × 3). Combine the organic phases, dry the organic phases with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1 - 0:1) to obtain 10c (600 mg, yield: 22%).

[0313] LCMS m / z = 442.3 [M+1] +

[0314] Step 3: Preparation of 10d hydrochloride

[0315] Dissolve 10c (600 mg, 1.36 mmol) in 3 mL of dichloromethane. Add 7 mL of 4 mol / L hydrochloric acid 1,4-dioxane solution. React at room temperature for 3 h. Concentrate the reaction system under reduced pressure to obtain the crude product of 10d hydrochloride (750 mg).

[0316] LCMS m / z = 342.2 [M+1] +

[0317] Step 4: Preparation of Compound 10 Trifluoroacetate

[0318] Dissolve the above crude 10d hydrochloride (150 mg) in 5 mL of DMSO, add DIPEA (170 mg, 1.31 mmol), stir at room temperature for 10 min, then add the above crude 1b (100 mg), and react at 100 °C for 16 h. Cool the reaction solution to room temperature and pass through Pre-HPLC (instrument and preparation column: use SHIMADZU LC-20AP preparative liquid phase, the preparation column model is C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: Filter the DMSO solution of the crude product with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile is eluted from 10% to 31% in a gradient (elution time 16 min), and freeze-dry to obtain Compound 10 trifluoroacetate (42 mg).

[0319] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.06 (s, 1H), 8.81 (s, 1H), 8.05 (s, 1H), 7.67–7.58 (m, 1H), 7.58–7.52 (m, 1H), 7.51–7.43 (m, 1H), 7.39–7.21 (m, 1H), 6.99 (d, 1H), 5.80–5.67 (m, 1H), 4.55–4.41 (m, 2H), 3.81–3.72 (m, 1H), 3.67 (q, 2H), 3.54 (s, 2H), 2.99–2.88 (m, 2H), 2.87–2.79 (m, 1H), 2.78–2.64 (m, 2H), 2.51–2.45 (m, 3H), 2.29–2.18 (m, 1H), 2.00–1.86 (m, 2H), 1.57–1.38 (m, 2H), 1.14 (t, 3H).

[0320] LCMS m / z = 628.3 [M+1] +

[0321] Example 11: Preparation of Compound 11

[0322]

[0323] Step 1: Preparation of 11b

[0324] Dissolve 11a (synthetic method reference: WO2023019166) (4.0 g, 7.7 mmol) and 10B (2.3 g, 11.6 mmol) in 100 mL of 1,4-dioxane, add XPhos Pd G3 (1.3 g, 1.5 mmol) and cesium carbonate (7.6 g, 23.2 mmol), displace nitrogen three times, and react at 90 °C for 16 h under a nitrogen atmosphere. Cool the reaction solution to room temperature, add 100 mL of ethyl acetate and 150 mL of water, extract the aqueous phase with ethyl acetate (50 mL × 2), combine the organic phases, dry the organic phases with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1 - 2:1) to obtain 11b (3.0 g, yield: 61%).

[0325] LCMS m / z = 636.3 [M+1] +

[0326] Step 2: Preparation of 11c

[0327] Dissolve 11b (3.0 g, 4.72 mmol) in 20 mL of ethanol and 20 mL of tetrahydrofuran, add 10% palladium on carbon (1.5 g), and react at 40 °C for 16 h under a hydrogen balloon atmosphere. Cool the reaction solution to room temperature, filter, and concentrate the filtrate under reduced pressure to obtain the crude product 11c (2.0 g).

[0328] LCMS m / z = 458.3 [M+1] +

[0329] Step 3: Preparation of 11d hydrochloride

[0330] Dissolve the above crude product 11c (2.0 g) in 5 mL of dichloromethane, add 30 mL of 4 mol / L hydrochloric acid 1,4-dioxane solution, and react at room temperature for 3 h. Concentrate the reaction system under reduced pressure to obtain the crude product 11d hydrochloride (2.2 g).

[0331] LCMS m / z = 358.3 [M+1] +

[0332] Step 4: Preparation of Compound 11

[0333] The above crude 11d hydrochloride (150 mg) was dissolved in 5 mL of DMSO, and DIPEA (190 mg, 1.47 mmol) was added. After stirring at room temperature for 10 min, the above crude 1b (100 mg) was added, and the reaction was carried out at 90 °C for 16 h. The reaction solution was passed through Pre-HPLC (instrument and preparative column: SHIMADZU LC-20AP preparative liquid phase was used, and the preparative column model was C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: 10 mmol / L ammonium bicarbonate aqueous solution / acetonitrile. Gradient elution method: Acetonitrile was gradient eluted from 35% to 45% (elution time 15 min), and the product was freeze-dried to obtain compound 11 (12 mg, three-step yield calculated from compound 11b: 5%).

[0334] 1 H NMR(400MHz,DMSO-d 6 )δ11.01(s,1H),8.60(s,1H),8.00(s,1H),7.57–7.47(m,2H),6.98(d,1H),6.79(d,1H),6.50–6.42(m,1H),6.36–6.27(m,1H),5.23(dd,1H),5.15(d,1H),4.35(d,2H),3.67(q,2H),3.59–3.45(m,3H),3.29–3.22(m,3H),3.14–3.01(m,2H),2.96–2.81(m,1H),2.73–2.55(m,2H),2.04–1.88(m,3H),1.35–1.19(m,2H),1.13(t,3H).

[0335] LCMS m / z=644.3[M+1] +

[0336] Example 12: Preparation of Compound 12 Trifluoroacetate

[0337]

[0338] First step: Preparation of 12a

[0339] 1A (300 mg, 0.72 mmol) was dissolved in 3 mL of dichloromethane, and 3 mL of trifluoroacetic acid was added. The reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of methanol were added, the pH was adjusted to 7 with potassium bicarbonate, stirred at room temperature for 10 min, filtered, and the filtrate was concentrated under reduced pressure to obtain crude 12a (900 mg).

[0340] LCMS m / z = 318.2 [M+1] +

[0341] Step 2: Preparation of 12b

[0342] Dissolve the above crude 12a (900 mg) and 12A (360 mg, 1.42 mmol) in 10 mL of dichloromethane, add 1 mL of glacial acetic acid, react at room temperature for 2 h, then add sodium triacetoxyborohydride (300 mg, 1.42 mmol) in portions, and react at room temperature for 3 h. Add 20 mL of saturated sodium bicarbonate aqueous solution to the reaction system, extract the aqueous phase with dichloromethane (30 mL × 3), combine the organic phases, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1 - 0:1) to obtain crude 12b (500 mg).

[0343] LCMS m / z = 555.2 [M+1] +

[0344] Step 3: Preparation of 12c

[0345] Dissolve the above crude 12b (500 mg) in 3 mL of dichloromethane, add 3 mL of trifluoroacetic acid, and react at room temperature for 3 h. Concentrate the reaction system under reduced pressure, add 5 mL of dichloromethane and 1 mL of methanol, adjust the pH to 7 with potassium bicarbonate, stir at room temperature for 10 min, then filter, and concentrate the filtrate under reduced pressure to obtain crude 12c (2.0 g).

[0346] LCMS m / z = 455.2 [M+1] +

[0347] Step 4: Preparation of Compound 12 Trifluoroacetate

[0348] Dissolve the above crude 12c (2.0 g) in 7 mL of DMSO, add DIPEA (345 mg, 2.67 mmol), react at room temperature for 10 min, then add the above crude 1b (288 mg), and react at 90 °C for 16 h. Cool the reaction solution to room temperature, and pass through Pre-HPLC (instrument and preparative column: use SHIMADZU LC-20AP preparative liquid phase, the preparative column model is C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: Filter the DMSO solution of the crude product with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile is eluted from 13% to 33% in a gradient (elution time 15 min), and lyophilize to obtain Compound 12 trifluoroacetate (150 mg).

[0349] 11H NMR (400 MHz, DMSO-d 6 ) δ 10.84–10.70 (m, 1H), 8.85 (s, 1H), 8.02 (s, 1H), 7.58–7.52 (m, 1H), 7.51–7.44 (m, 1H), 6.99 (d, 1H), 6.87 (d, 1H), 6.78 (d, 1H), 4.13–4.01 (m, 1H), 3.90–3.80 (m, 1H), 3.70 (q, 2H), 3.64–3.56 (m, 2H), 3.56–3.41 (m, 6H), 3.30–3.16 (m, 3H), 3.12–2.94 (m, 2H), 2.90–2.80 (m, 1H), 2.79–2.59 (m, 4H), 2.55–2.51 (m, 1H), 2.19–2.02 (m, 3H), 2.02–1.88 (m, 2H), 1.68–1.55 (m, 5H), 1.53–1.41 (m, 2H), 1.16 (t, 3H).

[0350] LCMS m / z = 741.3 [M+1] +

[0351] Example 14: Preparation of Compound 14 Trifluoroacetate

[0352]

[0353] First Step: Preparation of 14a

[0354] Under a nitrogen atmosphere, 3a (7.00 g, 18.17 mmol) and 70 mL of tetrahydrofuran were added to a reaction flask. A 2.5 mol / L n-butyllithium hexane solution (14.50 mL, 36.25 mmol) was slowly added dropwise at -78 °C. After stirring at -78 °C for 1.5 h, carbon dioxide was displaced three times, and the reaction was carried out under a carbon dioxide balloon atmosphere while controlling the system temperature below -40 °C for 0.5 h. The reaction system was restored to room temperature, 20 mL of ethyl acetate was added, the pH was adjusted to 2 with 1 mol / L hydrochloric acid, and extraction was carried out with ethyl acetate (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 10:1 - 2:1) to obtain 14a (2.4 g, yield: 38%).

[0355] Second Step: Preparation of 14b

[0356] Dissolve 14a (400 mg, 1.14 mmol) in 3 mL of dichloromethane, add 3 mL of trifluoroacetic acid, and react at room temperature for 3 h. Concentrate the reaction system under reduced pressure, add 5 mL of dichloromethane and 1 mL of methanol, adjust the pH to 7 with potassium bicarbonate, stir at room temperature for 10 min, then filter. Concentrate the filtrate under reduced pressure to obtain crude product 14b (1.0 g).

[0357] LCMS m / z=251.1[M+1] +

[0358] Step 3: Preparation of 14c

[0359] Dissolve the above crude product 14b (1.0 g) and 12A (578 mg, 2.28 mmol) in 10 mL of dichloromethane, add 1 mL of glacial acetic acid, and react at room temperature for 2 h. Then add sodium triacetoxyborohydride (483 mg, 2.28 mmol) portionwise and react at room temperature for 3 h. Add 20 mL of saturated aqueous sodium bicarbonate to the reaction system, extract the aqueous phase with dichloromethane (30 mL×3), combine the organic phases, dry the organic phases over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:1 - 0:1) to obtain 14c (470 mg, two-step yield calculated from 14a: 85%).

[0360] LCMS m / z=488.2[M+1] +

[0361] Step 4: Preparation of 14d

[0362] Dissolve 14c (468 mg, 0.96 mmol) in 3 mL of dichloromethane, add 3 mL of trifluoroacetic acid, and react at room temperature for 3 h. Concentrate the reaction system under reduced pressure, add 5 mL of dichloromethane and 1 mL of methanol, adjust the pH to 7 with potassium bicarbonate, stir at room temperature for 10 min, then filter. Concentrate the filtrate under reduced pressure to obtain crude product 14d (1.5 g).

[0363] LCMS m / z=388.2[M+1] +

[0364] Step 5: Preparation of 14e

[0365] Dissolve the above crude product 14d (1.5 g) in 7 mL of DMSO, add DIPEA (376 mg, 2.91 mmol), stir at room temperature for 10 min, then add the above crude product 1b (314 mg), and react at 90 °C for 16 h. Cool the reaction system to room temperature, concentrate under reduced pressure, and purify the crude product by reverse phase column chromatography (acetonitrile / H 2O (containing 0.05% formic acid) (v / v) = 2:3 - 3:2), and freeze-dried to obtain 14e (200 mg, two-step yield calculated from 14c: 31%).

[0366] LCMS m / z = 674.3 [M+1] +

[0367] Step 6: Preparation of Compound 14 Trifluoroacetate

[0368] Dissolve 14e (200 mg, 0.3 mmol) in 6 mL of DMF, and add EDCI (115 mg, 0.6 mmol), HOBt (81 mg, 0.6 mmol), (S)-3-aminopiperidine-2,6-dione hydrochloride (74 mg, 0.45 mmol), and N-methylmorpholine (91 mg, 0.9 mmol) respectively, and react at room temperature for 16 h. Add 2 mL of water to the reaction system, filter, dissolve the filter cake with 10 mL of a mixed solvent of dichloromethane / methanol (v / v) = 10:1, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and subject the crude product to Pre-HPLC (instrument and preparative column: use SHIMADZU LC-20AP preparative liquid phase, preparative column model is C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: Filter the DMSO solution of the crude product through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: Water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile is gradient eluted from 13% to 33% (elution time 15 min), and the obtained sample solution is then subjected to Pre-HPLC preparation, mobile phase system: Water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile is fixed at 25% for elution (elution time 15 min), and freeze-dried to obtain the trifluoroacetate of compound 14 (100 mg).

[0369] 1 H NMR (400 MHz, DMSO-d 6)δ10.83(s,1H),8.86–8.72(m,1H),8.07–7.97(m,2H),7.60–7.53(m,1H),7.51–7.44(m,1H),7.42(d,1H),6.98(d,1H),6.84(d,1H),4.78–4.67(m,1H),4.24–4.16(m,1H),3.69(q,2H),3.65–3.57(m,2H),3.56–3.45(m,6H),3.44–3.36(m,1H),3.30–3.19(m,2H),3.16–2.98(m,2H),2.93–2.83(m,1H),2.82–2.68(m,4H),2.57–2.52(m,1H),2.18–1.95(m,5H),1.69–1.54(m,5H),1.54–1.43(m,2H),1.16(t,3H).

[0370] LCMS m / z=784.3[M+1] +

[0371] Example 15: Preparation of Compound 15 Trifluoroacetate

[0372]

[0373] Compound 15 trifluoroacetate was obtained from Compound 4a as the raw material with reference to the synthesis method of Example 14.

[0374] 1 H NMR(400MHz,DMSO-d 6 )δ10.83(s,1H),8.77(s,1H),8.07–7.98(m,2H),7.59–7.54(m,1H),7.51–7.44(m,1H),7.41(d,1H),6.98(d,1H),6.84(d,1H),4.77–4.67(m,1H),4.25–4.16(m,1H),3.69(q,2H),3.65–3.57(m,2H),3.56–3.45(m,6H),3.44–3.35(m,1H),3.30–3.17(m,2H),3.16–2.98(m,2H),2.92–2.69(m,5H),2.56–2.51(m,1H),2.14–1.96(m,5H),1.68–1.52(m,5H),1.51–1.41(m,2H),1.16(t,3H).

[0375] LCMS m / z=784.2[M+1] +

[0376] Example 16: Preparation of Compound 16 Trifluoroacetate

[0377]

[0378] Compound 16 trifluoroacetate was obtained using Compound 14b and 16A as starting materials with reference to the synthesis method of Example 14.

[0379] 1 H NMR(400MHz,DMSO-d 6 )δ10.83(s,1H),8.77(s,1H),8.06–7.99(m,2H),7.59–7.53(m,1H),7.51–7.38(m,2H),6.98(d,1H),6.87(d,1H),4.78–4.67(m,1H),4.31–4.21(m,1H),3.76–3.65(m,3H),3.64–3.58(m,2H),3.58–3.45(m,6H),3.44–3.35(m,1H),3.16–3.04(m,1H),2.96–2.85(m,1H),2.83–2.64(m,4H),2.56–2.52(m,1H),2.29–2.17(m,2H),2.14–1.95(m,5H),1.70–1.59(m,1H),1.59–1.46(m,4H),1.15(t,3H).

[0380] LCMS m / z=770.2[M+1] +

[0381] Example 18: Preparation of Compound 18 Trifluoroacetate

[0382]

[0383] First step: Preparation of 18b Trifluoroacetate

[0384] Dissolve 18a(243mg,0.45mmol)(synthesis method refers to WO2023232133) in 2mL of dichloromethane, add 2mL of trifluoroacetic acid, and react at room temperature for 3h. Concentrate the reaction system under reduced pressure to obtain the crude product of 18b trifluoroacetate(300mg).

[0385] Second step: Preparation of 18d

[0386] Add 18c (28.0 g, 161.65 mmol) and 300 mL of trifluoroacetic acid to a reaction flask, and add potassium nitrate (16.34 g, 161.65 mmol) portionwise at 0 °C. React at room temperature for 0.5 h. Pour the reaction solution into 3 L of water, extract the aqueous phase with ethyl acetate (1 L × 3), combine the organic phases, wash the organic phase with 500 mL of saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0 - 4:1) to obtain 18d (25.0 g, yield: 71%).

[0387] LCMS m / z = 219.1 [M+1] +

[0388] Step 3: Preparation of 18e

[0389] Add 18d (25.0 g, 114.57 mmol), 300 mL of methanol, 300 mL of dichloromethane, and 10% palladium on carbon (5.0 g) to a reaction flask, displace hydrogen three times, and react at room temperature for 48 h under a hydrogen atmosphere. Filter the reaction system, concentrate the filtrate under reduced pressure, slurry the crude product with 50 mL of ethyl acetate, filter, collect the filter cake, and dry the filter cake under reduced pressure to obtain the crude product 18e (8.0 g).

[0390] Step 4: Preparation of 18f

[0391] Add the above crude product 18e (8.0 g), 2,4,5-trichloropyrimidine (7.8 g, 42.50 mmol), triethylamine (8.60 g, 85.00 mmol), and 100 mL of DMF to a reaction flask, and react at room temperature for 4 h. Pour the reaction solution into 500 mL of water, filter, collect the filter cake, and dry the filter cake under reduced pressure at 60 °C to obtain the crude product 18f (10.0 g).

[0392] LCMS m / z = 335.0 [M+1] +

[0393] Step 5: Preparation of Compound 18 Trifluoroacetate

[0394] To a reaction flask were added the above-mentioned crude product 18f (0.15 g), the above-mentioned crude product 18b trifluoroacetate (300 mg), N,N-diisopropylethylamine (0.28 g, 2.20 mmol) and 5 mL of DMSO, and the reaction was carried out at 100 °C for 12 h under a nitrogen atmosphere. The reaction solution was cooled to room temperature and passed through Pre-HPLC (instrument and preparative column: using SHIMADZU LC-20AP preparative liquid phase, the preparative column model is C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: The DMSO solution of the crude product was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile was eluted from 15% to 38% (elution time 15 min) in a gradient, and the trifluoroacetate of compound 18 (0.10 g) was obtained by lyophilization.

[0395] 1 H NMR(400MHz,DMSO-d 6 )δ10.82–10.72(m,1H),8.75(s,1H),8.01(s,1H),7.36–7.27(m,2H),6.88(d,1H),6.80(d,1H),4.18–4.09(m,1H),3.90–3.81(m,1H),3.80–3.71(m,1H),3.67–3.42(m,10H),3.30–3.19(m,1H),3.03–2.85(m,2H),2.80–2.59(m,6H),2.57–2.51(m,1H),2.27–2.17(m,2H),2.16–2.10(m,1H),2.10–1.98(m,3H),1.98–1.87(m,3H),1.70–1.49(m,5H).

[0396] LCMS m / z=739.3[M+1] +

[0397] Example 19: Preparation of Compound 19 Trifluoroacetate

[0398]

[0399] Compound 19 trifluoroacetate was obtained by using compound 19a (synthesis method referring to WO2023232133) and 18f as raw materials and referring to the synthesis method of Example 18.

[0400] 1 H NMR(400MHz,DMSO-d 6)δ 10.81–10.75 (m, 1H), 8.80 (s, 1H), 8.02 (s, 1H), 7.36–7.27 (m, 2H), 6.87 (d, 1H), 6.80 (d, 1H), 4.18–4.07 (m, 1H), 3.93–3.81 (m, 1H), 3.80–3.70 (m, 1H), 3.67–3.42 (m, 10H), 3.33–3.18 (m, 1H), 3.03–2.83 (m, 2H), 2.80–2.58 (m, 6H), 2.58–2.51 (m, 1H), 2.27–2.16 (m, 2H), 2.16–2.10 (m, 1H), 2.10–1.98 (m, 3H), 1.98–1.86 (m, 3H), 1.71–1.47 (m, 5H).

[0401] LCMS m / z = 739.2 [M+1] +

[0402] Example 30: Preparation of Compound 30 Trifluoroacetate

[0403]

[0404] Compound 30 trifluoroacetate was obtained by using compound 30a hydrochloride (for the synthesis method, refer to WO2023212147) and 18f as raw materials and referring to the synthesis method of Example 29.

[0405] 1 H NMR (400 MHz, DMSO-d 6 )δ 10.81 (s, 1H), 9.04 (s, 1H), 8.08 (s, 1H), 7.42–7.25 (m, 3H), 6.63–6.48 (m, 2H), 4.33–4.26 (m, 2H), 4.23–4.16 (m, 1H), 3.83 (s, 3H), 3.71–3.62 (m, 1H), 3.62–3.55 (m, 2H), 3.51 (s, 2H), 3.22–3.10 (m, 2H), 2.72–2.66 (m, 2H), 2.64–2.47 (m, 2H), 2.30–2.21 (m, 1H), 2.19–2.11 (m, 1H), 2.07–1.97 (m, 2H), 1.96–1.86 (m, 2H), 1.44–1.29 (m, 2H).

[0406] LCMS m / z = 640.3 [M+1] +

[0407] Example 31: Preparation of Compound 31 Trifluoroacetate

[0408]

[0409] Step 1: Preparation of 31a

[0410] Add 2a (0.40 g, 0.96 mmol), 1 mL of trifluoroacetic acid and 3 mL of dichloromethane into a reaction flask, and react at room temperature for 3 h. Concentrate the reaction solution under reduced pressure, adjust the pH to 7 with triethylamine, concentrate under reduced pressure, add 20 mL of tetrahydrofuran to the residue, add 16A (0.28 g, 1.15 mmol) and 0.5 mL of glacial acetic acid, react at room temperature for 1 h, then add sodium triacetoxyborohydride (0.41 g, 1.92 mmol), and react at room temperature for 16 h. Add 30 mL of dichloromethane and 30 mL of saturated sodium bicarbonate aqueous solution to the reaction solution, extract the aqueous phase with dichloromethane (15 mL × 3), combine the organic phases, wash the organic phase with 15 mL of saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (dichloromethane:methanol (v / v) = 20:1) to obtain 31a (0.50 g, yield: 96%).

[0411] LCMS m / z = 541.4 [M+1] +

[0412] Step 2: Preparation of Compound 31 Trifluoroacetate

[0413] Dissolve 31a (0.25 g, 0.46 mmol) in 6 mL of dichloromethane, add 2 mL of trifluoroacetic acid, and react at room temperature for 3 h. Concentrate the reaction system under reduced pressure, dissolve the residue in 5 mL of DMSO, add N,N-diisopropylethylamine (0.30 g, 2.30 mmol) and the above crude product 1b (0.15 g), and react at 100 °C for 16 h. Cool the reaction system to room temperature, and pass the reaction solution through Pre-HPLC (instrument and preparative column: use Waters 2767 preparative liquid phase, the preparative column model is SunFire@Prep C18, 5 μm, inner diameter × length = 19 mm × 250 mm). Preparation method: Filter the DMSO solution of the crude product through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: water (containing 0.1% TFA) / acetonitrile. Gradient elution method: Acetonitrile is eluted from 10% to 50% in a gradient (elution time 15 min), and lyophilize to obtain the trifluoroacetate of Compound 31 (78 mg).

[0414] 1 H NMR(400MHz,DMSO-d 6)δ10.79(s,1H),9.14–9.00(m,1H),8.08(s,1H),7.54(s,1H),7.47(d,1H),7.00(d,1H),6.88(d,1H),6.80(d,1H),4.18–4.10(m,1H),3.89–3.82(m,1H),3.80–3.66(m,3H),3.64–3.45(m,8H),3.32–3.23(m,1H),3.06–2.95(m,1H),2.94–2.83(m,1H),2.80–2.59(m,4H),2.57–2.52(m,1H),2.29–1.91(m,7H),1.70–1.47(m,5H),1.16(t,3H).

[0415] LCMS m / z=727.3[M+1] +

[0416] Example 35: Preparation of Compound 35 Trifluoroacetate

[0417]

[0418] First step: Preparation of 35a

[0419] Dissolve 15a (0.30 g, 0.86 mmol) in 6 mL of dichloromethane, add 2 mL of trifluoroacetic acid, and react at room temperature for 3 h. Concentrate the reaction system under reduced pressure, dissolve the residue in 8 mL of DMF and 8 mL of 1,4-dioxane, add N,N-diisopropylethylamine (0.55 g, 4.30 mmol) and the above crude product 1b (0.28 g), and react at 100 °C for 16 h. Cool the reaction solution to room temperature, adjust the pH to 4 with 2 mol / L hydrochloric acid, concentrate under reduced pressure, and purify the crude product by silica gel column chromatography (dichloromethane:methanol (v / v) = 8:1) to obtain 35a (0.30 g, yield: 65%).

[0420] LCMS m / z=537.2[M+1] +

[0421] Second step: Preparation of Compound 35 Trifluoroacetate

[0422] Compound 35 trifluoroacetate was obtained using compound 35a and (S)-3-aminopiperidine-2,6-dione hydrochloride as raw materials with reference to the synthesis method of Example 14.

[0423] 1 H NMR(400MHz,DMSO-d 6)δ 10.82 (s, 1H), 9.10 (s, 1H), 8.11 (s, 1H), 7.96 (t, 1H), 7.60 (d, 1H), 7.47 (dd, 1H), 7.39 (d, 1H), 7.02 (d, 1H), 6.72 (d, 1H), 4.78–4.68 (m, 1H), 4.43–4.32 (m, 2H), 4.01–3.93 (m, 1H), 3.72 (q, 2H), 3.59 (s, 2H), 3.28–3.08 (m, 2H), 2.97–2.87 (m, 1H), 2.89–2.66 (m, 4H), 2.57–2.52 (m, 1H), 2.18–1.91 (m, 3H), 1.73–1.57 (m, 1H), 1.18 (t, 3H).

[0424] LCMS m / z = 647.4 [M+1] +

[0425] The following compound was synthesized by referring to the synthesis methods of other examples:

[0426]

[0427]

[0428]

[0429]

[0430] Biological test examples

[0431] 1. SU-DHL-6 cell proliferation experiment

[0432] Lymphoma SU-DHL-6 cells purchased from ATCC were placed in RPMI-1640 complete medium (containing 15% fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin) and cultured at 37 °C and 5% CO 2 conditions. Cells in the logarithmic growth phase were collected, and the cell suspension was adjusted to an appropriate density with the medium. 3000 cells / well were added to a 96-well culture plate, and then different concentrations of the test compound were added. At 37 °C and 5% CO 2Continue the culture under the conditions. After 5 days, mix the cells with a pipette, transfer 1 / 10 of the cells to a new 96-well culture plate, add the medium containing the drug, and continue to incubate for 5 days. After the incubation is completed, according to the operation instructions of the CellTiter-Glo kit (Promega, G7573), add 75 μL of CTG solution balanced to room temperature to each well, mix well with a microplate shaker for 2 minutes, place it at room temperature for 10 minutes, and then measure the fluorescence signal value with a BMG multi-functional microplate reader (PHERAstar FSX). Calculate the cell proliferation inhibition rate according to formula (1), where RLU compound is the reading of the drug treatment group, and RLU control is the average value of the solvent control group, and RLU blank is the average value of the cell-free wells. Use GraphPad Prism software to analyze the data and calculate the IC 50 value.

[0433] Inhibition rate % = [1 – (RLU compound – RLU blank ) / (RLU control – RLU blank )] × 100% (Formula 1)

[0434] Conclusion: The compound of the present invention has a certain inhibitory effect on the proliferation of SU-DHL-6 cells.

[0435] 2. Bcl-6 protein degradation experiment of Farage cells

[0436] The Farage cells purchased from ATCC are placed in RPMI-1640 complete medium (containing 10% fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin), and cultured at 37 °C and 5% CO 2Cultivate under the conditions. Collect the cells in the logarithmic growth phase, adjust the cell suspension to an appropriate density with the medium, and add it to a 6-well cell culture plate at a volume of 1 mL / well. Prepare the test compound to a concentration twice the final concentration, add 1 mL of the compound at different concentrations to the dosing wells, and add the medium containing 0.2% DMSO to the control wells. Incubate at 37 °C for 24 hours. Collect the cells in a 1.5 mL centrifuge tube, add 25 μL of RIPA lysis buffer (containing 1X protease inhibitor mixture), lyse on ice for 15 minutes, then centrifuge at 12,000 rpm at 4 °C for 10 minutes. Collect the supernatant and measure the protein content by the BCA method. Dilute the test protein sample to 0.8 mg / mL, and detect Bcl6 using a fully automatic protein expression quantitative analyzer (ProteinSimple). The internal reference protein is β-actin (the antibodies are all from CST). Use the software (Compass for SW) of the fully automatic protein expression quantitative analyzer to process the raw data, calculate the peak area and the Bcl6 expression rate relative to the control group. Use the four-parameter nonlinear fitting model in Graphpad 8.3.0 software to calculate the DC 50 value.

[0437] Conclusion: The compound of the present invention has a good degradation effect on Bcl-6 protein.

[0438] 3. Experiment on the degradation of Bcl-6 protein in OCI-LY1 cells

[0439] OCI-LY1 cells purchased from DSMZ are placed in IMDM complete medium (containing 10% fetal bovine serum, 100 U / mL penicillin, 100 μg / mL streptomycin and 50 μM mercaptoethanol), and cultured at 37 °C, 5% CO 2Cultivate under the conditions. Collect the cells in the logarithmic growth phase, adjust the cell suspension to an appropriate density with the medium, and add it to a 6-well cell culture plate at a volume of 1 mL / well. Prepare the test compound to twice the final concentration, add 1 mL of the compound at different concentrations to the dosing wells, and add the medium containing 0.2% DMSO to the control wells. Incubate at 37 °C for 24 hours. Collect the cells in a 1.5 mL centrifuge tube, add 25 μL of RIPA lysis buffer (containing 1X protease inhibitor mixture), lyse on ice for 15 minutes, then centrifuge at 12,000 rpm at 4 °C for 10 minutes, collect the supernatant, and determine the protein content by the BCA method. Dilute the test protein sample to 0.8 mg / mL, and detect Bcl6 using an automated protein expression quantitative analyzer (ProteinSimple). The internal reference protein is β-actin (the antibodies are all from CST). Use the software (Compass for SW) of the automated protein expression quantitative analyzer to process the raw data, calculate the peak area and the expression rate of Bcl6 relative to the control group. Use the four-parameter nonlinear fitting model in Graphpad 8.3.0 software to calculate the DC 50 value.

[0440] The results of the degradation rate of the compound of the present invention on Bcl-6 in OCI-LY1 cells at a concentration of 10 nM are shown in Table 1.

[0441] Table 1 Degradation rate of Bcl6 in OCI-LY1 cells at 10 nM

[0442]

[0443]

[0444] Conclusion: The compound of the present invention, such as the compound of the example, has a good degradation effect on the Bcl-6 protein in OCI-LY1 cells.

[0445] 4. Mouse pharmacokinetic test

[0446] 4.1 Test animals: Male ICR mice, 25 - 30 g, 6 mice / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0447] 4.2 Test design: On the test day, 6 ICR mice were randomly grouped according to body weight. Fast for 12 - 14 h without water restriction 1 day before dosing, and give food 4 h after dosing.

[0448] Table 2 Dosing information for mouse pharmacokinetic test

[0449]

[0450] Note: Solvent for intravenous administration: 10% DMA + 10% Solutol + 80% NS; Solvent for gavage administration: PO: 5% DMSO + 5% Solutol + 30% PEG 400 + 60% (20% SBE-β-CD)

[0451] Before and after administration, 0.03 mL of blood was collected from the orbit under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm at 4 °C for 10 min to collect plasma. The blood sampling time points for both the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 7, 24 h. Before analysis and detection, all samples were stored at -80 °C, and the samples were quantitatively analyzed by LC-MS / MS.

[0452] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good oral absorption in mice.

[0453] 5. Pharmacokinetics Test in Rats

[0454] Experimental purpose: In this experiment, the test substance was administered to SD rats by single-dose intravenous and gavage methods to determine the concentration of the test substance in rat plasma and evaluate the pharmacokinetic characteristics of the test substance in rats.

[0455] Test animals: Male SD rats, 200 - 220 g, 6 - 8 weeks old, 6 rats / compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0456] Test method: On the day of the experiment, 6 SD rats were randomly grouped according to body weight. Fast for 12 - 14 h without water deprivation 1 day before administration, and give food 4 h after administration.

[0457] Table 3 Administration Information for Pharmacokinetics Test in Rats

[0458]

[0459] *The dose is calculated as the free base.

[0460] Sampling: Before and after administration, 0.1 mL of blood was collected from the orbit under isoflurane anesthesia and placed in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm at 4 °C for 10 min to collect plasma.

[0461] Plasma collection time points for the IV&PO group: 0, 5 min, 15 min, 30 min, 1, 2, 4, 7, 24 h.

[0462] Before analysis and detection, all samples were stored at -60 °C. The samples were quantitatively analyzed by LC-MS / MS.

[0463] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good oral absorption in rats.

[0464] 6. Beagle Dog Pharmacokinetics Test

[0465] Test Animals: Male Beagle dogs, about 8 - 10 kg, 6 dogs per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

[0466] Test Method: On the test day, 6 Beagle dogs were randomly grouped according to body weight. They were fasted but allowed water for 14 - 18 h one day before dosing, and fed 4 h after dosing.

[0467] Table 4 Administration Information for Beagle Dog Pharmacokinetics Test

[0468]

[0469] Note: Solvent for intravenous administration: 5% DMA + 5% Solutol + 90% Saline;

[0470] Solvent for oral (gavage) administration: 5% DMSO + 5% Solutol + 30% PEG400 + 60% (20% SBE - CD);

[0471] *Dose is calculated based on the free base.

[0472] 1 ml of blood was taken from the jugular vein or limb veins before and after dosing and placed in an EDTAK2 centrifuge tube. Centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood sampling time points for both the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h. Before analysis and detection, all samples were stored at -80°C, and the samples were quantitatively analyzed by LC - MS / MS.

[0473] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in dogs.

[0474] 7. Monkey Pharmacokinetics Test

[0475] Test Animals: Male cynomolgus monkeys, 3 - 5 kg, 3 - 6 years old, 4 monkeys per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0476] Test Method: On the test day, 4 monkeys were randomly grouped according to body weight. They were fasted but allowed water for 14 - 18 h one day before dosing, and fed 4 h after dosing.

[0477] Table 5 Administration Information for Monkey Pharmacokinetics Test

[0478]

[0479] Note: Solvent for intravenous administration: 5% DMA + 5% Solutol + 90% Saline;

[0480] Oral (gavage) administration solvent: 5% DMSO + 5% Solutol + 30% PEG400 + 60% (20% SBE-CD);

[0481] *Dosage is calculated based on the free base.

[0482] Collect 1.0 mL of blood from the jugular vein before and after administration, and place it in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm at 4°C for 10 min to collect plasma. The blood sampling time points for both the intravenous group and the gavage group are: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h. Before analysis and detection, all samples are stored at -60°C, and LC-MS / MS is used for quantitative analysis of the samples.

[0483] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption in monkeys.

[0484] 8. hERG potassium channel function test

[0485] Experimental platform: Electrophysiological manual patch clamp system

[0486] Cell line: Chinese Hamster Ovary (CHO) cell line stably expressing hERG potassium channel

[0487] Experimental method: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channel are used to record hERG potassium channel current by whole-cell patch clamp technique at room temperature. The glass microelectrode is pulled from a glass electrode blank (BF150-86-10, Sutter) by a puller, and the tip resistance after perfusion with electrode internal solution is about 2 - 5 MΩ. Insert the glass microelectrode into the amplifier probe and connect it to the patch clamp amplifier. The clamping voltage and data recording are controlled and recorded by pClamp 10 software through a computer, with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining the whole-cell recording, the cell is clamped at -80 mV, and a 2 s depolarizing voltage is applied from -80 mV to +20 mV to induce hERG potassium current (I hERG ) and then repolarized to -50 mV, and after 1 s, it returns to -80 mV. This voltage stimulation is given every 10 s. After determining that the hERG potassium current is stable (at least 1 minute), the drug administration process is started. Each test concentration of the compound is given for at least 1 minute, and at least 2 cells are tested for each concentration (n≥2).

[0488] Data processing: Data analysis and processing are performed using pClamp 10, GraphPad Prism 5, and Excel software. The inhibition degree of different compound concentrations on hERG potassium current (peak value of hERG tail current induced at -50 mV) is calculated using the following formula:

[0489] Inhibition% = [1–(I / Io)]×100%

[0490] Among them, Inhibition% represents the inhibition percentage of the compound on the hERG potassium current, and I and Io represent the amplitudes of the hERG potassium current after and before adding the drug, respectively.

[0491] Compound IC 50 Calculated by fitting using GraphPad Prism 5 software through the following equation:

[0492] Y = Bottom+(Top - Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0493] Among them, X is the Log value of the test concentration of the test article, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0494] Conclusion: The compounds of the present invention, such as the compounds of the examples, have no obvious inhibitory effect on the hERG potassium channel current.

[0495] 9. Liver microsome stability test

[0496] In this experiment, liver microsomes of five species, namely human, dog, rat and mouse, were used as an in vitro model to evaluate the metabolic stability of the test article.

[0497] At 37 °C, 1 μM of the test article was incubated with microsomal protein and coenzyme NADPH. At a certain reaction time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing an internal standard was added to terminate the reaction. The concentration of the test article in the sample was detected by LC-MS / MS method. The T was obtained from the ln value of the remaining rate of the drug in the incubation system and the incubation time 1 / 2 , and the intrinsic clearance rate of liver microsomes CL int(mic) and the intrinsic clearance rate of the liver CL int(Liver) .

[0498] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good liver microsome stability.

[0499] 10. CYP450 enzyme inhibition test

[0500] The purpose of this study was to evaluate the effects of the test substance on the activities of five isozymes of cytochrome P450 (CYP) in human liver microsomes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) using an in vitro test system. The specific probe substrates of CYP450 isozymes were incubated with human liver microsomes and different concentrations of the test substance, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction ended, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS) to determine the changes in CYP enzyme activity and calculate the IC 50 value to evaluate the inhibitory potential of the test substance on each CYP enzyme subtype.

[0501] Conclusion: The compounds of the present invention, such as the compounds of the examples, have no obvious inhibitory effect on the five isozymes of cytochrome P450 in human liver microsomes.

[0502] 11. Caco2 Permeability Test

[0503] The experiment used a monolayer of Caco-2 cells and was incubated in triplicate in a 96-well Transwell plate. The transport buffer solution (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing the compound of the present invention (2 μM) or the control compounds digoxin (10 μM), nadolol (2 μM), and metoprolol (2 μM) was added to the dosing wells on the apical or basolateral side. The transport buffer solution containing DMSO was added to the corresponding receiving wells. After incubation at 37 ± 1 °C for 2 hours, the cell plate was removed and appropriate amounts of samples were taken from the apical and bottom ends to a new 96-well plate. Subsequently, acetonitrile containing an internal standard was added to precipitate the protein. The samples were analyzed by LC MS / MS and the concentrations of the compound of the present invention and the control compounds were determined. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical side to the basolateral side and from the basolateral side to the apical side of the monolayer cells, and thus the efflux ratio was calculated. The integrity of the monolayer cells after 2 hours of incubation was evaluated by the leakage of fluorescein yellow.

[0504] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good Caco2 permeability.

Claims

1. A compound or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: The compound is selected from the compounds represented by general formula (I), BLK(I); L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl are optionally replaced by -Ak-, -Cy-; Each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-NR L (CH2) q C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L )2-、-Si(OH)(R L )-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, wherein the CH, -CH2- is optionally substituted by 1 to 2 R z replace; q is each independently selected from 0, 1, 2, 3, 4, 5 or 6; R L Selected from H, C 1-4 Alkyl, C 3-7 carbocyclic group, 4 to 10 membered heterocyclic group, the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace; Each -Cy- is independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, 10-16 membered heterotricyclic group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl; B is selected from B1 is selected from -C(R b1 )2-、-O-、-S-、-NR b1 -; W is selected from O or S; R b1 , R b3 or R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace; R b2 Selected from H, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace; Alternatively, R b2 With R b3 Directly connected to form a 4-8 membered heterocyclic group, the heterocyclic group is optionally substituted by 1 to 4 selected from R z replace; b3 is selected from 0, 1, 2 or 3; K is selected from G is selected from N or CH; Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR q -; Q and G cannot directly form a nitrogen-nitrogen bond, a nitrogen-oxygen bond, or a nitrogen-S bond; R q Select from H or C 1-4 alkyl; F are each independently selected from C 13-20 Carbocyclic group, 13-20 membered heterocyclic group, The condition is that when F is selected from When R b2 With R b3 Directly connected to form a 4-8 membered heterocyclic group, the heterocyclic group is optionally substituted by 1 to 4 selected from R z replace; Ring E is selected from phenyl or 5-6 membered heteroaryl; R k1 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace; R k2 are each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-; R k3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 selected from R z replace; R k4 Each independently selected from O, S, -NR k5 -、-CHR k5 -or-C(R k5 )2-; R k5 are each independently selected from H, deuterium, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace; Alternatively, two R k1 Direct connection to form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 selected from R z replace; Alternatively, two R k3 Direct connection to form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 selected from R z replace; R L2 , R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; n1 is selected from 0, 1, 2 or 3; p1 and p2 are each independently selected from 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q - or a bond, wherein the -CH2- is optionally replaced by 1 to 2 R z replace; R L Each independently selected from H or C 1-4 alkyl; Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, 10-16 membered heterotricyclic group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl; R b1 , R b3 or R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace; R b2 Selected from H, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace; Alternatively, R b2 With R b3 Directly connected to form a 4-6 membered heterocyclic group, the heterocyclic group is optionally substituted by 1 to 4 selected from R z replace; F is each independently selected from a 13-15 membered tricyclic heterocyclic group, Ring E is selected from phenyl or 6-membered heteroaryl; R k1 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace; R k3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 selected from R z replace; R k5 are each independently selected from H, deuterium, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace; R L2 , R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

3. The compound according to claim 2 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R L is selected from H, methyl or ethyl; Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 Substituted by one of the following groups: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, s1, s3, s5 are each independently selected from 0, 1 or 2; s2 and s4 are each independently selected from 0 or 1; s6 is selected from 0, 1, 2 or 3; s7 is selected from 1, 2 or 3; Selected from F is selected from The ring where the representative is located is an aromatic ring or a non-aromatic ring; H1 is selected from N, NH, CH, CH2, CHR k1 NR k1 , CR k1 , C(=O), C(R k1 )2; H2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 NR k1 , C(=O), CR k1 or C(R k1 )2; H3 is selected from N or CH; H4 is selected from C, N or CH; H5, H6, H7 are each independently selected from N, C, CH or CR k1 , and H5, H6, and H7 contain at most 2 Ns; Ring E is selected from phenyl or pyridyl; Q is selected from a bond, CH2, NH, N(CH3), O, S, C(=O), NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3); R k1 , R k3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2 or optionally substituted by 1 to 4 R z Substituted groups as follows: methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl; R k5 are each independently selected from H, deuterium or optionally substituted by 1 to 4 R z Substituted groups: methyl, ethyl, isopropyl, cyclopropyl; R b1 , R b3 or R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2 or optionally substituted by 1 to 4 R z Substituted methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R b2 Selected from H, deuterium or optionally 1 to 4 R z substituted methyl, ethyl, propyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R L2 , R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; p1 and p2 are each independently selected from 0, 1, 2 or 3.

4. The compound according to claim 1 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -C(CH3)2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH- or -NHC(=O)-; Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following groups which are optionally substituted: When substituted, it is substituted by 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl; K is selected from H1 is selected from N, NH, CH, CH2, CHR k1 NR k1 , CR k1 , C(=O); H2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 NR k1 , CR k1 , C(=O); H6 is selected from N or CHR k1 ; R k4 Selected from O, S, -CHR k5 -、-NR k5 -.

5. The compound according to claim 4 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R b2 is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, CD3, R b3 or R b4 Each is independently selected from H, deuterium, F, Cl, Br, I, methyl; or Selected from L is selected from a bond or -NHCH2-, -Cy1-, -Cy1-CH2-, -Cy1-C≡C-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-, -NH-Cy1-, -NH-Cy1-O-, -O-Cy1-NH-, -NH-Cy1-Cy2-, -NH-Cy1-CH2-Cy2, -Cy1-Ak2-, -Ak1-Cy1-Ak2-; R k1 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl; R k5 is selected from H, deuterium, methyl, ethyl, isopropyl, cyclopropyl, CD3, 6. The compound according to claim 1 or 5, or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B is selected from one of the structural fragments shown in Table B-1, Table B-1 L is selected from a bond or one of the structural fragments shown in Table L-1, Table L-1 K is selected from one of the structural fragments shown in Table K-1 or Table K-2, Table K-1 Table K-2 7. The compound according to claim 1, or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures shown in Table E, 8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of a compound according to any one of claims 1 to 7 or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

9. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating a disease associated with Bcl6 activity or expression.

10. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 8 in the preparation of a drug for treating a disease associated with the inhibition or degradation of Bcl-6, wherein the disease is preferably selected from cancer.

Images