Spiro-fused ring derivative and application thereof in medicine

Abstract

The invention relates to a spiro-fused ring derivative and application thereof in medicine, in particular to a compound shown in a general formula (I) B-L-K (I) or a stereoisomer, a racemate, a tautomer, a deuterated compound, a solvate, a prodrug, a metabolite, pharmaceutically acceptable salt or eutectic crystal and an intermediate thereof. And uses thereof in inhibition or degradation of c-MYC related diseases, such as cancer.

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 cocrystals, as well as intermediates and preparation methods thereof, and uses in c-MYC related diseases such as cancer. Background Art

[0002] The MYC oncogene is a "major driver" of human cancers and is abnormally activated in a variety of hematological malignancies such as leukemia, lymphoma, and multiple myeloma, as well as various solid tumors such as pancreatic ductal adenocarcinoma (PDAC), brain cancer, non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), liver cancer, and prostate cancer. The MYC gene is one of the most studied classes of nuclear protein oncogenes, including 4 types: c-MYC, N-MYC, L-MYC, and R-MYC. The c-MYC proto-oncogene is one of the most common activated proto-oncogenes. Cancers regulated by c-MYC account for about 20% of human cancers, and hundreds of thousands of cancer patients die each year due to the influence of the c-MYC proto-oncogene. However, at the same time, the c-MYC protein is considered "undruggable" because its helix-helix topology lacks a druggable domain and its nuclear localization within cancer cells makes it difficult to directly target c-MYC with traditional small molecule inhibitors. In the field of developing drugs for treating c-MYC overexpressing tumors, great efforts have been made by humans, but no drug-like c-MYC inhibitors have been developed in the past thirty years.

[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 the 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 c-MYC PROTAC drugs for treating c-MYC related 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 c-MYC for treating c-MYC related diseases such as cancer.

[0006] The present invention provides a compound or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the compounds represented by general formula (I),

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

[0008] 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 ;

[0009] In some embodiments, Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH 2 ) q -, -(CH2 ) 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 by 1 to 2 R z substituents;

[0010] In some embodiments, 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 CH 2 -, -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 CH2 NH-, -NHCH 2 CH 2 -, -C(=O)-, -C(=O)CH 2 NH-, -CH 2 C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

[0011] In some embodiments, each -Cy- is independently selected from a bond or one of the following groups optionally substituted with 1 to 4 R L2 substituted: 4- to 8-membered hetero monocyclic group, 4- to 12-membered hetero fused ring group, 5- to 13-membered hetero spiro ring group, 7- to 12-membered hetero bridged ring group, 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;

[0012] In some embodiments, 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 substituted: 4- to 7-membered nitrogen-containing hetero monocyclic group, 4- to 12-membered nitrogen-containing hetero fused ring group, 5- to 13-membered nitrogen-containing hetero spiro ring group, 7- to 12-membered nitrogen-containing hetero bridged ring group, 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;

[0013] In some 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 substituted: phenyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, pyridazinyl group, pyrazolyl group, thiazolyl group, oxazolyl group, triazolyl group,

[0014] In some embodiments, Cy1, Cy2, Cy3, Cy4 are each independently selected from a bond or one of the following optionally substituted groups:

[0015]

[0016] When substituted, with 1 to 4 substituents selected from deuterium, F, CF 3, OH, =O, COOH, CN, NH 2 and is substituted by substituents such as hydroxymethyl, methyl, methoxy, and cyclopropyl;

[0017] In some embodiments, Cy1, Cy2, and Cy3 are each independently selected from one of the following optionally substituted groups: When substituted, it is substituted by 1 to 4 substituents selected from deuterium, F, CF 3 , OH, =O, COOH, CN, NH 2 , hydroxymethyl, methyl, methoxy, and cyclopropyl;

[0018] In some embodiments, s1, s3, and s5 are each independently selected from 0, 1, or 2;

[0019] In some embodiments, s2 and s4 are each independently selected from 0 or 1;

[0020] In some embodiments, s6 is selected from 0, 1, 2, or 3;

[0021] In some embodiments, s7 is selected from 1, 2, or 3;

[0022] In some embodiments, 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- or -Cy-;

[0023] In some embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0024] In some embodiments, L is selected from -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-Ak2-, -Ak1-Cy1-Ak2-, -CH 2 -Cy2-, -CH 2 -Cy2-CH 2 -Cy3-, -CH 2 -Cy1-Cy2-;

[0025] In some embodiments, L is selected from a bond,

[0026] In some embodiments, L 1 is selected from a bond, -Cy1-CH 2 -Cy2-, -Cy1-Cy2-, -Cy1-, -CH 2 -Cy2-, -CH 2 -Cy2-CH 2 -Cy3-, -CH 2 -Cy1-Cy2-;

[0027] In some embodiments, L 1 is selected from a bond,

[0028] In some embodiments, L 2 is selected from -Cy1-CH 2 - or -Cy1-;

[0029] In some embodiments, L 2 is selected from

[0030] 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;

[0031] Table L-1 L groups

[0032]

[0033]

[0034] In certain embodiments, R L is selected from H, C 1-4 alkyl, C 3-7 carbocyclic group, 4- to 10-membered heterocyclic group, and the alkyl, carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 R z substituents;

[0035] In certain embodiments, R L are each independently selected from H or C 1-4 alkyl;

[0036] In certain embodiments, R L is selected from H, methyl or ethyl;

[0037] In certain embodiments, q are each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0038] In certain embodiments, B is selected from

[0039] In certain embodiments, B is selected from

[0040] In certain embodiments, B is selected from

[0041] In certain embodiments, B is selected from

[0042] In certain embodiments, B is selected from

[0043] In certain embodiments, B 1 is selected from a bond, C 3-10 carbocyclic group or a 4- to 10-membered heterocyclic group, and said B 1 is optionally substituted with 1 to 4 R b1 substituents;

[0044] In certain embodiments, B 1 is selected from phenyl, benzo C 4-6 carbocyclic group, benzo 4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl group, 8- to 10-membered heteroaryl group, and said B 1 is optionally substituted with 1 to 4 R b1 substituents;

[0045] In certain embodiments, B 1 is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, and said B 1 is optionally substituted with 1 to 4 R b1 substituents;

[0046] In certain embodiments, B 1 is selected from thiazolyl or oxazolyl, and said thiazolyl or oxazolyl is optionally substituted with 1 substituent selected from deuterium, F, Cl, Br, I, OH, CF 3 , CD 3 , methyl, ethyl;

[0047] In certain embodiments, B 2 is selected from C 3-10 carbocyclic group or a 4- to 10-membered heterocyclic group, and said B 2 is optionally substituted with 1 to 4 R b2 substituents;

[0048] In certain embodiments, B 2 is selected from phenyl, benzo C 4-6A carbocyclic group, a benzo 4- to 6-membered heterocyclic group, a 5- to 6-membered heteroaryl group, an 8- to 10-membered heteroaryl group, said B 2 optionally substituted by 1 to 4 R b2 substituents;

[0049] In certain embodiments, B 2 is selected from phenyl, pyridyl, pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyridyl, thiazolophenyl, thiazolopyrimidinyl, oxazolopyridyl, oxazolophenyl, oxazolopyrimidinyl, pyrazolopyridyl, pyrazolophenyl, pyrazolopyrimidinyl, said B 2 optionally substituted by 1 to 4 R b2 substituents;

[0050] In certain embodiments, B 2 is selected from phenyl, pyridyl, pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyridyl, thiazolophenyl, thiazolopyrimidinyl, oxazolopyridyl, oxazolophenyl, oxazolopyrimidinyl, pyrazolopyridyl, pyrazolophenyl, pyrazolopyrimidinyl, said B 2 optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CF 3 , CD 3 , SF 5 , CN, NH 2 , N(CH 3 ) 2 , NHCH 3 , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl;

[0051] In certain embodiments, B 2 is selected from phenyl or pyridyl, said phenyl or pyridyl optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CF 3 , CD 3 , SF 5 , CN, NH 2 , N(CH 3 ) 2 , NHCH 3 , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH2 substituted by substituents of -cyclohexyl;

[0052] In certain embodiments, B 3 is selected from a bond, -N(R B )-, -N(R B )C(=O)-, -C(=O)N(R B );

[0053] In certain embodiments, B 3 is selected from a bond, -NH-, -NHC(=O)-, -C(=O)NH-, -N(CH 3 )-, -N(CH 3 )C(=O)-, -C(=O)N(CH 3 );

[0054] In certain embodiments, R B is selected from H or C 1-4 alkyl, and the alkyl is optionally substituted by 1 to 4 R z ;

[0055] In certain embodiments, B 4 is selected from a 5- to 6-membered heteroaryl or phenyl, and the B 4 is optionally substituted by 1 to 2 R b4 ;

[0056] In certain embodiments, z1 and z2 are each independently selected from 0, 1, 2;

[0057] In certain embodiments, z3 is selected from 0, 1, 2, 3, 4;

[0058] In certain embodiments, z1 and z2 are not both 0;

[0059] In certain embodiments, R b1 , R b2 , R b3 , R b4 , R b5 are each independently selected from H, halogen, =O, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -O-C 0-4 alkylene-C 3-10 carbocyclic group, -O-C 0-4 alkylene-4- to 10-membered heterocyclic group, -NH-C 0-4Alkylene-C 3-10 Carbocyclic group, -NH-C 0-4 Alkylene-4- to 10-membered heterocyclic group, -C 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-4- to 10-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z substituents;

[0060] In certain embodiments, R b1 , R b2 , R b5 are each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , CN or one of the following groups optionally substituted by 1 to 4 R z substituents: methyl, ethyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 R z substituents;

[0061] In certain embodiments, R b3 is selected from H, one of the following groups optionally substituted by 1 to 4 R z substituents: methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, oxetanyl, oxolanyl, oxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl;

[0062] In certain embodiments, R b3 is selected from CF 3 , CD 3 , methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl;

[0063] In certain embodiments, K is selected from In certain embodiments, is selected from

[0064] In certain embodiments, K is selected from

[0065] In certain embodiments, -L-K is selected from In certain embodiments, -L-K is selected from In certain embodiments, K is selected from one of the structural fragments shown in Table K-1;

[0066] In certain embodiments, K is selected from one of the structural fragments shown in Table K-2;

[0067] Table K-1

[0068]

[0069]

[0070]

[0071] Table K-2

[0072]

[0073]

[0074]

[0075]

[0076]

[0077]

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

[0079] In certain embodiments, each Q is independently selected from a bond, -O-, -S-, -CH 2 -, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q -;

[0080] 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(CH3 );

[0081] In certain embodiments, a nitrogen-nitrogen bond, a nitrogen-oxygen bond, or a nitrogen-sulfur bond cannot be directly formed between Q and G;

[0082] In certain embodiments, R q is selected from H or C 1-4 alkyl;

[0083] In certain embodiments, F is selected from C 3-20 carbocyclic group, C 6-20 aryl, 3- to 20-membered heterocyclic group, or 5- to 20-membered heteroaryl;

[0084] In certain embodiments, F is selected from C 3-7 monocyclic group, C 4-10 fused ring group, C 5-12 spiro ring group, C 5-10 bridged ring group, 4- to 7-membered hetero monocyclic group, 4- to 10-membered bicyclic hetero fused ring group, 8- to 15-membered tricyclic hetero fused ring group, 12- to 19-membered tetracyclic hetero fused ring group, 5- to 17-membered hetero spiro ring group, 5- to 10-membered hetero bridged ring group, C 6-14 aryl, 5- to 10-membered heteroaryl;

[0085] In certain embodiments, F is selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopenta[c]pyridyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthryl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridinone,

[0086]

[0087] In certain embodiments, R k1 are each independently selected from H, deuterium, halogen, 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 cycloalkyl, 3- to 6-membered heterocycloalkyl, and the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted with 1 to 4 R z substituents;

[0088] In certain embodiments, R k1 , R k3Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CF 3 , CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 ;

[0089] In certain embodiments, R k2 each independently selected from a bond, -C(═O)-, -S(═O) 2 -, -S(═O)- or -C(R k3 ) 2 -;

[0090] In certain embodiments, R k3 each independently selected from H, deuterium, halogen, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl or a 3- to 8-membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted with 1 to 4 substituents selected from R z ;

[0091] Alternatively, two R k3 are directly connected to form a C 3-8 carbocyclic group or a 4- to 8-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from R z ;

[0092] In certain embodiments, R L2 , R z each independently selected from deuterium, halogen, OH, ═O, CF 3 , SF 5 , CN, NH 2 , NO 2 , COOH, CONH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , COOH, CONH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -S-C 1-4 alkyl, -C 0-4 alkylene-C 3-6A cycloalkyl group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl groups 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;

[0093] 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(CH 3 ) 2 , NHCH 3 , methyl, ethyl, vinyl, ethynyl, 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, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl 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;

[0094] In certain embodiments, n1 is selected from 0, 1, 2 or 3;

[0095] In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, 3, 4 or 5;

[0096] In certain embodiments, represents that the ring where it is located is an aromatic ring or a non-aromatic ring;

[0097] In certain embodiments, Fa is selected from N, CH or CR k1 ;

[0098] In certain embodiments, Fb is selected from N, CH or CR k1 ;

[0099] In certain embodiments, Fc is selected from O, S, NH, N(CH 3 ) or NR k7a ;

[0100] In certain embodiments, Fd is selected from N, CH or CR k1 ;

[0101] In certain embodiments, Fg is selected from N or C;

[0102] In certain embodiments, Fh is selected from N or C;

[0103] In certain embodiments, Faa is selected from a bond, O, CH 2 ;

[0104] In certain embodiments, Fab is selected from O, CH 2 ;

[0105] 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 ;

[0106] In certain embodiments, H 2 is selected from a bond, O, N, NH, CH, CH 2 , CHR k1 , NR k1 , CR k1 or C(R k1 ) 2 ;

[0107] In certain embodiments, H 3 is selected from N or CH;

[0108] In certain embodiments, H 4 is selected from C, N or CH;

[0109] 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;

[0110] In certain embodiments, ring E is selected from phenyl or a 5- or 6-membered heteroaryl, and the ring E is optionally substituted with 1 to 3 Rs k1 ;

[0111] In certain embodiments, ring E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl or oxazolyl, and the ring E is optionally substituted with 1 to 3 Rs k1 ;

[0112] In certain embodiments, ring F 1 , ring F 2 , ring F 3 , ring F 4 are each independently selected from phenyl or 5-6 membered heteroaryl, and said ring F 1 , ring F 2 , ring F 3 , ring F 4 is optionally substituted with 1 to 2 R k1 ;

[0113] In certain embodiments, ring F 1 , ring F 2 are each independently selected from phenyl, pyridyl, thiazolyl, furyl, thienyl or oxazolyl, and said ring F 1 , ring F 2 is optionally substituted with 1 to 2 R k1 ;

[0114] In certain embodiments, ring F 3 , ring F 4 are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl or oxazolyl, and said ring F 3 , ring F 4 is optionally substituted with 1 to 2 R k1 ;

[0115] In certain embodiments, R k5 are each independently selected from C(CH 3 ) 2 , C(=O), CH 2 , CH 2 CH 2 , S(=O) 2 ,

[0116] In certain embodiments, R k6 are each independently selected from C(=O), CH, S(=O), S(=O) 2 , CH 2 or N;

[0117] In certain embodiments, R k7 are each independently selected from C(CH 3 ) 2 , CH 2 , O or NR k7a ;

[0118] In certain embodiments, R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl;

[0119] In certain embodiments, R k9 are each independently selected from a bond, C(CH 3 ) 2 , C(=O), CH 2 , CH 2 CH 2 or S(=O) 2 ;

[0120] In certain embodiments, p2 are each independently selected from 0, 1, 2, or 3.

[0121] As a first embodiment of the present invention, a compound represented by the foregoing general formula (I) or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0122] 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-;

[0123] 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 -, -NRL -(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, wherein the CH, -CH 2 - is optionally substituted by 1 to 2 R z ;

[0124] q is independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0125] R L is selected from H, C 1-4 alkyl, C 3-7 carbocyclic group, 4- to 10-membered heterocyclic group, wherein the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z ;

[0126] 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, 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;

[0127] B is selected from

[0128] z1, z2 are independently selected from 0, 1, 2;

[0129] z3 is selected from 0, 1, 2, 3, 4;

[0130] z1 and z2 are not both 0 at the same time;

[0131] B 1 is selected from a bond, C 3-10 a carbocyclic group or a 4- to 10-membered heterocyclic group, and the B 1 is optionally substituted by 1 to 4 Rs b1 ;

[0132] B 2 is selected from C 3-10 a carbocyclic group or a 4- to 10-membered heterocyclic group, and the B 2 is optionally substituted by 1 to 4 Rs b2 ;

[0133] B 3 is selected from a bond, -N(R B )-, -N(R B )C(=O)-, -C(=O)N(R B );

[0134] R B is selected from H or C 1-4 an alkyl group, and the alkyl group is optionally substituted by 1 to 4 Rs z ;

[0135] B 4 is selected from a 5- to 6-membered heteroaryl group or a phenyl group, and the B 4 is optionally substituted by 1 to 2 Rs b4 ;

[0136] R b1 , R b2 , R b3 , R b4 , R b5 are each independently selected from H, halogen, =O, OH, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , CN, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -O-C 0-4 alkylene-C 3-10 carbocyclic group, -O-C 0-4 alkylene-4- to 10-membered heterocyclic group, -NH-C 0-4 alkylene-C 3-10 carbocyclic group, -NH-C 0-4 alkylene-4- to 10-membered heterocyclic group, -C0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-4- to 10-membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic group, and heterocyclic group are optionally substituted by 1 to 4 R z substituents;

[0137] K is selected from

[0138] G is selected from N or CH;

[0139] Q are each independently selected from a bond, -O-, -S-, -CH 2 -, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q -;

[0140] A nitrogen-nitrogen bond, nitrogen-oxygen bond, or nitrogen-sulfur bond cannot be directly formed between Q and G;

[0141] R q is selected from H or C 1-4 alkyl;

[0142] F is selected from C 3-20 carbocyclic group, C 6-20 aryl, 3- to 20-membered heterocyclic group, or 5- to 20-membered heteroaryl;

[0143] R k1 are each independently selected from H, deuterium, halogen, 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 cycloalkyl, 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, and heterocycloalkyl are optionally substituted by 1 to 4 R z substituents;

[0144] R k2 are each independently selected from a bond, -C(=O)-, -S(=O) 2 -, -S(=O)-, or -C(R k3 ) 2 -;

[0145] R k3 are each independently selected from H, deuterium, halogen, OH, =O, NH 2 , CN, COOH, CONH 2 , C 1-4 alkyl, C1-4 Alkoxy, C 3-8 ycloalkyl or a 3- to 8-membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted with 1 to 4 substituents selected from R z ;

[0146] Alternatively, two Rs k3 are directly connected to form a C 3-8 arbocyclic group or a 4- to 8-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 substituents selected from R z ;

[0147] R L2 , R z are each independently selected from deuterium, halogen, OH, ═O, CF 3 , SF 5 , CN, NH 2 , NO 2 , COOH, CONH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , COOH, CONH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, -S-C 1-4 alkyl, -C 0-4 alkylene-C 3-6 ycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 alkyl, C 1-4 alkoxy;

[0148] n1 is selected from 0, 1, 2 or 3;

[0149] p1 or p2 is each independently selected from 0, 1, 2, 3, 4 or 5.

[0150] 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,

[0151] L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0152] 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, wherein the -CH 2 - is optionally substituted by 1 to 2 R z ;

[0153] R L are each independently selected from H or C 1-4 alkyl;

[0154] Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or one of the following groups optionally substituted by 1 to 4 R L2 : 4- to 7-membered nitrogen-containing monocyclic group, 4- to 12-membered nitrogen-containing fused ring group, 5- to 13-membered nitrogen-containing spiro ring group, 7- to 12-membered nitrogen-containing bridged ring group, 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;

[0155] F is selected from C 3-7 monocyclic group, C 4-10 fused ring group, C 5-12 spiro ring group, C 5-10 bridged ring group, 4- to 7-membered hetero monocyclic group, 4- to 10-membered bicyclic hetero fused ring group, 8- to 15-membered tricyclic hetero fused ring group, 12- to 19-membered tetracyclic hetero fused ring group, 5- to 17-membered hetero spiro ring group, 5- to 10-membered hetero bridged ring group, C 6-14 aryl, 5- to 10-membered heteroaryl;

[0156] B is selected from

[0157] B 1 phenyl, benzo-C 4-6 carbocyclic group, benzo 4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl group, 8- to 10-membered heteroaryl group, and said B 1 is optionally substituted by 1 to 4 Rs b1 ;

[0158] B 2 is selected from phenyl, benzo-C 4-6 carbocyclic group, benzo 4- to 6-membered heterocyclic group, 5- to 6-membered heteroaryl group, 8- to 10-membered heteroaryl group, and said B 2 is optionally substituted by 1 to 4 Rs b2 ;

[0159] The remaining definitions are the same as those in the first embodiment of the present invention.

[0160] 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,

[0161] R L is selected from H, methyl or ethyl;

[0162] Cy1, Cy2, Cy3, Cy4 are each independently selected from a bond or one of the following groups optionally substituted by 1 to 4 Rs L2 : phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl,

[0163]

[0164] s1, s3, s5 are each independently selected from 0, 1 or 2;

[0165] s2, s4 are each independently selected from 0 or 1;

[0166] s6 is selected from 0, 1, 2 or 3;

[0167] s7 is selected from 1, 2 or 3;

[0168] B 1 is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, and said B 1 is optionally substituted by 1 to 4 Rs b1 ;

[0169] B 2 Selected from phenyl, pyridyl, pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyridyl, thiazolophenyl, thiazolopyrimidinyl, oxazolopyridyl, oxazolophenyl, oxazolopyrimidinyl, pyrazolopyridyl, pyrazolophenyl, pyrazolopyrimidinyl, wherein the B 2 is optionally substituted by 1 to 4 Rs b2 ;

[0170] B 3 Selected from a bond, -NH-, -NHC(=O)-, -C(=O)NH-, -N(CH 3 )-, -N(CH 3 )C(=O)-, -C(=O)N(CH 3 );

[0171] R b1 , R b2 , R b5 are each independently selected from H, F, Cl, Br, I, =O, OH, NH 2 , CN or one of the following groups optionally substituted by 1 to 4 Rs z : methyl, ethyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted by 1 to 4 Rs z ;

[0172] R b3 is selected from H, or one of the following groups optionally substituted by 1 to 4 Rs z : methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, oxetanyl, oxolanyl, oxanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl;

[0173] Selected from

[0174] F is selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, 6,7-dihydro-5H-cyclopenta[c]pyridyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthryl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furyl, thienyl, thiazolyl, 2-pyridinone,

[0175] indicating that the ring where it is located is an aromatic ring or a non-aromatic ring;

[0176] Fa is selected from N, CH or CR k1 ;

[0177] Fb is selected from N, CH or CR k1 ;

[0178] Fc is selected from O, S, NH, N(CH 3 ) or NR k7a ;

[0179] Fd is selected from N, CH or CR k1 ;

[0180] Fg is selected from N or C;

[0181] Fh is selected from N or C;

[0182] Faa is selected from a bond, O, CH 2 ;

[0183] Fab is selected from O, CH 2 ;

[0184] H 1 is selected from N, NH, CH, CH 2 , CHR k1 , NR k1 , CR k1 , C(=O), C(R k1 ) 2 ;

[0185] H 2 is selected from a bond, O, N, NH, CH, CH 2 , CHR k1 , NR k1 , CR k1 or C(R k1 ) 2 ;

[0186] H 3 is selected from N or CH;

[0187] H4 Selected from C, N or CH;

[0188] H 5 , H 6 , H 7 Each independently selected from N, C, CH or CR k1 , and H 5 , H 6 , H 7 Contains at most 2 N;

[0189] Ring E is selected from phenyl or 5-6 membered heteroaryl, and the ring E is optionally substituted by 1 to 3 R k1 substituted;

[0190] Ring F 1 , Ring F 2 , Ring F 3 , Ring F 4 Each independently selected from phenyl or 5-6 membered heteroaryl, and the ring F 1 , Ring F 2 , Ring F 3 , Ring F 4 Optionally substituted by 1 to 2 R k1 substituted;

[0191] 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 );

[0192] R k1 , R k3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH 2 , CF 3 , CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, and the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH 2 ;

[0193] R k5 Each independently selected from C(CH 3 ) 2 , C(=O), CH 2 , CH 2 CH 2 , S(=O) 2 ,

[0194] R k6 Each independently selected from C(=O), CH, S(=O), S(=O) 2 , CH 2 or N;

[0195] R k7 Each independently selected from C(CH 3 ) 2 , CH 2 , O or NR k7a ;

[0196] R k7a Selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl are optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl;

[0197] R k9 Each independently selected from a bond, C(CH 3 ) 2 , C(=O), CH 2 , CH 2 CH 2 or S(=O) 2 ;

[0198] 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 , N(CH 3 ) 2 , NHCH 3 , methyl, ethyl, vinyl, ethynyl, 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, 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;

[0199] p2 are each independently selected from 0, 1, 2 or 3;

[0200] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0201] As the 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,

[0202] Ring E is each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl or oxazolyl, and the ring E is optionally substituted by 1 to 3 R k1 substituents;

[0203] Ring F 1 and ring F 2 are each independently selected from phenyl, pyridyl, thiazolyl, furyl, thienyl or oxazolyl, and the ring F 1 and ring F 2 are optionally substituted by 1 to 2 R k1 substituents;

[0204] Ring F 3 and ring F 4 are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furyl, thienyl or oxazolyl, and the ring F 3 and ring F 4 are optionally substituted by 1 to 2 R k1 substituents;

[0205] B 1 is selected from thiazolyl or oxazolyl, and the said thiazolyl or oxazolyl is optionally substituted by 1 substituent selected from deuterium, F, Cl, Br, I, OH, CF 3 , CD 3 methyl, ethyl;

[0206] B 2Selected from phenyl, pyridyl, pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyridyl, thiazolophenyl, thiazolopyrimidinyl, oxazolopyridyl, oxazolophenyl, oxazolopyrimidinyl, pyrazolopyridyl, pyrazolophenyl, pyrazolopyrimidinyl, the said B 2 Optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CF 3 , CD 3 , SF 5 , CN, NH 2 , N(CH 3 ) 2 , NHCH 3 , methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl;

[0207] R b3 Selected from CF 3 , CD 3 , methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl;

[0208] 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 CH 2 -, -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(CH3 )-, -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)-;

[0209] 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;

[0210] The remaining definitions are the same as those of the first, second, or third embodiment of the present invention.

[0211] 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,

[0212] B is selected from

[0213] L is selected from a bond, -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-Ak2-, -Ak1-Cy1-Ak2-, -CH 2 -Cy2-, -CH 2 -Cy2-CH 2 -Cy3-, -CH 2 -Cy1-Cy2-;

[0214] Cy1, Cy2, Cy3 are each independently selected from one of the following optionally substituted groups: When substituted, it is substituted by 1 to 4 substituents selected from deuterium, F, CF 3 , OH, ═O, COOH, CN, NH 2 , hydroxymethyl, methyl, methoxy, cyclopropyl;

[0215] Preferably, L is selected from a bond,

[0216] The remaining definitions are the same as those in the first, second, third or fourth embodiment of the present invention.

[0217] As a sixth embodiment of the present invention, a compound represented by the foregoing general formula (I) or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0218] -L-K is selected from

[0219] L 1 is selected from a bond, -Cy1-CH 2 -Cy2-, -Cy1-Cy2-, -Cy1-, -CH 2 -Cy2-, -CH 2 -Cy2-CH 2 -Cy3-, -CH 2 -Cy1-Cy2-;

[0220] Preferably, L 1 is selected from a bond,

[0221] L 2 is selected from -Cy1-CH 2 - or -Cy1-;

[0222] Preferably, L 2 is selected from

[0223] The remaining definitions are the same as those in the first, second, third, fourth or fifth embodiment of the present invention.

[0224] 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.

[0225] 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.

[0226] 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 medicament for treating diseases related to c-MYC activity or expression level.

[0227] 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 medicament for treating diseases related to the inhibition or degradation of c-MYC.

[0228] In some embodiments, the diseases related to the inhibition or degradation of c-MYC are cancers.

[0229] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, wherein the pharmaceutical composition or pharmaceutical preparation comprises 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").

[0230] The present invention further 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 as described above or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or a pharmaceutical composition. In some embodiments, the mammal in the present invention includes humans.

[0231] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of a compound disclosed herein that, when administered, will, to some extent, 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 the amount of a compound disclosed herein that is required to provide a clinically significant reduction in the symptoms of the disease. Examples of therapeutically effective amounts include, but are not limited to, 1 - 1500 mg, 1 - 1000 mg, 1 - 900 mg, 1 - 800 mg, 1 - 700 mg, 1 - 600 mg, 2 - 600 mg, 5 - 600 mg, 6 - 600 mg, 20 - 600 mg, 30 - 600 mg, 40 - 600 mg, 50 - 600 mg, 70 - 600 mg, 75 - 600 mg, 80 - 600 mg, 90 - 600 mg, 100 - 600 mg, 200 - 600 mg, 1 - 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, 250 - 500 mg, 300 - 500 mg, 5 - 400 mg, 10 - 400 mg, 20 - 400 mg, 25 - 400 mg, 30 - 400 mg, 40 - 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, 1 - 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, 100 - 300 mg, 125 - 300 mg, 150 - 300 mg, 200 - 300 mg, 250 - 300 mg, 1 - 200 mg, 5 - 200 mg, 10 - 200 mg, 20 - 200 mg, 30 - 200 mg, 50 - 200 mg, 60 - 200 mg, 70 - 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;

[0232] 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.

[0233] 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.

[0234] A method for treating a disease in a mammal, the method comprising administering to a subject the compound of the present invention or its stereoisomers, racemates, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals at a daily dose of 1 - 1500 mg / day, the daily dose can 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.

[0235] 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.

[0236] 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 the free base in each case.

[0237] "Formulation specification" refers to the weight of the active ingredient contained in each vial, tablet or other unit formulation.

[0238] Unless otherwise specified, the terms used in the specification and claims have the following meanings.

[0239] Carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds of the present invention all include their isotope situations, that is, carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds of the present invention are optionally further substituted by one or more of their corresponding isotopes, where the isotopes of carbon include 11 C, 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), and the isotopes of oxygen include 15 O, 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S, 35 S and 36 S, the isotopes of nitrogen include 13 N, 14 N and 15 N, the isotopes of fluorine include 17 F, 18 F and 19 F, the isotopes of chlorine include 35 Cl, 36 Cl and 37 Cl, the isotopes of bromine include 79 Br and 81 Br, the isotopes of iodine include 123 I,125 I. The isotopes of phosphorus include 31 P,[[]] 32 P.[[]]

[0240] "CN" refers to a cyano group.[[]]

[0241] "Halogen" refers to F, Cl, Br or I.[[]]

[0242] "Halogen-substituted" means substituted by F, Cl, Br or I, including but not limited to substituted by 1 to 10 substituents selected from F, Cl, Br or I, substituted by 1 to 6 substituents selected from F, Cl, Br or I, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halogen-substituted" is abbreviated as "halogenated".[[]]

[0243] "Alkyl" refers to a substituted or unsubstituted straight-chain or branched-chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups having 1 to 20 carbon atoms, alkyl groups having 1 to 8 carbon atoms, alkyl groups having 1 to 6 carbon atoms, alkyl groups 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 their various branched isomers; the alkyl group can be monovalent, divalent, trivalent or tetravalent.[[]]

[0244] "Alkylene" refers to a substituted or unsubstituted straight-chain and branched-chain divalent saturated hydrocarbon group, including -(CH 2 ) v -(where v is an integer from 1 to 10), and examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene, etc.[[]]

[0245] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 12 carbon atoms, and the cycloalkyl group 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. The cycloalkyl group can be monovalent, divalent, trivalent or tetravalent.[[]]

[0246] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of the heterocycloalkyl group can be oxidized to various oxidation states. The heterocycloalkyl group can be monocyclic, fused-ring, bridged-ring and spiro-ring. The heterocycloalkyl group can be attached to a heteroatom or a carbon atom, and non-limiting examples include epoxyethyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,[[]]

[0247] The heterocycloalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0248] "Alkenyl" 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 double bonds, and the main chain includes but is not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent or tetravalent.

[0249] "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, and the main chain includes 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms in the main chain and 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.; the alkynyl group can be monovalent, divalent, trivalent or tetravalent.

[0250] "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.

[0251] "Carbocyclic group" or "carbocycle" refers to a substituted or unsubstituted aromatic ring 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. The carbocyclic group can be attached to an aromatic ring or a non-aromatic ring, and the ring can be 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.

[0252] "Heterocyclic group" or "heterocycle" refers to a substituted or unsubstituted aromatic ring 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, S, or Se 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 the heterocyclic group can be attached to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic ring, a bridged ring, a fused ring, or a 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]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azadamantyl, oxaspiro[3.3]heptyl,

[0253] "Heterocyclic group" or "heterocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0254] "Spirocycle" or "spirocyclic group" refers to a polycyclic group in which two rings, whether substituted or unsubstituted, share a single atom (the spiro atom). The number of ring atoms in the spirocyclic system includes, but is not limited to, 5 to 20, 6 to 14, 6 to 12, or 6 to 10. One or more of the rings may contain zero or more (including, but not limited to, 1, 2, 3, or 4) double bonds, and optionally may contain 0 to 5 heteroatoms selected from N, O, or S(=O) n (where n is 0, 1, or 2). Non-limiting examples include:

[0255]

[0256] ."Spirocycle" or "spirocyclic group" can be monovalent, divalent, trivalent, or tetravalent.

[0257] "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 the other rings in the system. One or more of the 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 0 to 5 heteroatoms or heteroatom-containing groups (including, but not limited to, selected from N, S(=O) n or O, where 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:

[0258]

[0259] "Fused ring" or "fused ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0260] "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 0 to 5 heteroatoms or heteroatom-containing groups (including, but not limited to, N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include:

[0261]

[0262] Cubane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0263] "Carbospirocycle", "spirocarbocyclic group", "spirocarbonyl group", or "carbospirocyclic group" refers to a "spirocycle" in which the ring system consists only of carbon atoms.

[0264] "Carbocyclic fused ring", "fused carbocyclic group", "fused carbocyclic radical" or "carbocyclic fused ring group" refers to a "fused ring" in which the ring system consists only of carbon atoms.

[0265] "Carbocyclic bridged ring", "bridged carbocyclic group", "bridged carbocyclic radical" or "carbocyclic bridged ring group" refers to a "bridged ring" in which the ring system consists only of carbon atoms.

[0266] "Heteromonocyclic ring", "monocyclic heterocyclic group" or "heteromonocyclic group" refers to a "heterocyclic group" or "heterocyclic ring" of a monocyclic system.

[0267] "Heterocyclic fused ring", "heterocyclic fused ring group", "fused heterocyclic group" or "fused heterocyclic radical" refers to a "fused ring" containing heteroatoms.

[0268] "Heterospiro ring", "heterospiro ring group", "spiro heterocyclic group" or "spiro heterocyclic radical" refers to a "spiro ring" containing heteroatoms.

[0269] "Heterocyclic bridged ring", "heterocyclic bridged ring group", "bridged heterocyclic group" or "bridged heterocyclic radical" refers to a "bridged ring" containing heteroatoms.

[0270] "Aryl" or "aromatic ring" refers to 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 may 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 sites are located on the aryl ring.

[0271] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including, but not limited to, N, O, S(=O)n or Se(=O)n, where n is 0, 1, 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 on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1, 2). Non-limiting examples of heteroaryl include, but are not limited to, pyridyl, furyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, pyridone group, etc. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, and the ring connected to the parent structure is the aryl ring. Non-limiting examples include: The heteroaryl groups appearing in this article have the same definition as this definition. The heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment site is located on the aromatic ring.

[0272] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring group, spiro ring group, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a 、-O-(CH 2 ) m -C(=O)-R a 、-(CH 2 ) m -C(=O)-NR b R c 、-(CH 2 ) m S(=O) n R a 、-(CH 2 ) m -Alkenyl-R a , OR d or -(CH 2 ) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR b R c etc., where R b With R c is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R b With R c Can form a five- or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or paracyclic groups.

[0273] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is selected from any integer between 1 and 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R kSubstituted. 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 hetero-bridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means the hetero-bridged ring is optionally substituted by 1, 2, 3, or 4 substituents selected from H or F.

[0274] The X-Y membered ring (X and Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, where Y is any integer selected from 4 to 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, hetero-monocyclic rings, hetero-fused rings, hetero-spiro rings, or hetero-bridged rings. For example, "4-7 membered hetero-monocyclic ring" means a 4-membered, 5-membered, 6-membered, or 7-membered hetero-monocyclic ring, and "5-10 membered hetero-fused ring" means a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, or 10-membered hetero-fused ring.

[0275] C x-y The carbocyclic ring (including aryl group, cycloalkyl group, monocyclic carbocyclic ring, spirocarbocyclic ring, fused carbocyclic ring, or bridged carbocyclic ring) includes 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 The "cycloalkyl group" means C 3 、C 4 、C 5 or C 6 cycloalkyl group.

[0276] When a certain group has one or more connectable sites, any one or more of these sites of the group can be connected to other groups through 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 bonds, the number of H atoms at these sites will correspondingly decrease according to the number of connected chemical bonds to form groups with corresponding valences. For example indicates that any connectable site on the piperidyl group can be connected to other groups through 1 chemical bond, including at least these 4 connection modes. Even if an H atom is drawn on the -N-, it also includes For example indicates that the R group on the piperidyl group can be located on the C or on the N, including at least For example, the general formula fragment is When X is selected from CH 2 or NH, it means that the R group on this general formula fragment can be located on the C or on the X. When X is selected from CH 2 , the general formula fragment can be When X is selected from NH, the general formula fragment can be

[0277]

[0278] Unless otherwise specified, the solid wedge bond and the dashed wedge bond represent the absolute configuration of a stereocenter, and the solid straight bond and the dashed straight bond represent the relative configuration of a stereocenter.

[0279] When the listed linking groups do not specify their linking directions, the linking directions include linking 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.

[0280] "Optional" or "optionally" means that the subsequently described event or circumstance may but does not have to occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted by F" means that the alkyl may but does not have to be substituted by F, and the description includes the case where the alkyl is substituted by F and the case where the alkyl is not substituted by F.

[0281] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means a salt of the compound of the present invention that retains the biological effectiveness and characteristics of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0282] "Pharmaceutical composition" means a mixture formed by one or more compounds of the present invention, or their stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals and other chemical components, where "other chemical components" means a pharmaceutically acceptable carrier, excipient and / or one or more other therapeutic agents.

[0283] "Carrier" means a material that does not cause significant irritation to the organism and does not eliminate the biological activity and characteristics of the administered compound.

[0284] "Prodrug" means a compound that can be metabolically converted in vivo into a compound of the present invention with biological activity. The prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compound 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 a free amino group or carboxyl group.

[0285] "Co-crystal" refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, where both the pure states of the API and the CCF are solids at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal, including binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0286] "Animal" refers to including mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0287] "Stereoisomer" refers to an isomer generated by the different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereoisomers, and conformational isomers.

[0288] "Tautomer" refers to a functional group isomer generated by the rapid movement of a certain atom in a molecule between two positions, such as keto-enol tautomerism and amide-imidol tautomerism, etc. Detailed Description of the Invention

[0289] 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.

[0290] 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, Shanghai Yuanye Bio-Technology, Nanjing Pharmatech, WuXi AppTec, and J&K Scientific, etc.

[0291] 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);

[0292] The MS measurements are performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0293] The determination by HPLC was performed using an Agilent 1260 DAD high-pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM).

[0294] For thin-layer chromatography silica gel plates, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used. The specifications of the silica gel plates used for thin-layer chromatography (TLC) were 0.15 mm - 0.20 mm, and the specifications of the silica gel plates used for separating and purifying products by thin-layer chromatography were 0.4 mm - 0.5 mm.

[0295] For column chromatography, silica gel with 200 - 300 mesh from Yantai Huanghai was generally used as the carrier.

[0296] Example 1: Preparation of Compound 1

[0297]

[0298] First step: Preparation of 1B

[0299] Compound 1A (CAS: 1824063 - 21 - 9, synthesis reference US20190048019) (5.35 g, 26.35 mmol) and tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate (6.62 g, 27.66 mmol) were dissolved in toluene (50 mL). Ammonium acetate (2.03 g, 26.35 mmol) was added, and the temperature was raised to 110 °C and stirred for 3 h. After cooling to room temperature, the solvent was removed by reduced pressure concentration. 60 mL of ethyl acetate and 50 mL of water were added and stirred to separate the layers. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in ethanol (80 mL). Sulfur (1.27 g, 39.53 mmol) and triethylamine (5.34 g, 52.74 mmol) were successively added under stirring at room temperature, and the temperature was raised to 50 °C and stirred overnight. After cooling to room temperature, it was filtered, and the filter cake was washed with 20 mL of ethanol and dried under reduced pressure to obtain 1B (9.6 g, yield: 79%).

[0300] Second step: Preparation of 1C

[0301] Compound 1B (9.5 g, 20.81 mmol) was dissolved in THF (100 mL). Triethylamine (6.31 g, 62.40 mmol) was added, and acetyl chloride (3.27 g, 41.62 mmol) was slowly added dropwise at room temperature. After addition, stirring was continued for 1 h. The reaction was monitored by TLC until completion. 100 mL of dichloromethane and 100 mL of water were added and stirred to separate the layers. The organic layer was washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was slurried (methyl tert-butyl ether / petroleum ether (V / V) = 1 / 2) to obtain 1C (6.8 g, yield: 65%).

[0302] LCMS m / z = 498.0 [M+H] +

[0303] Step 3: Preparation of 1D

[0304] Compound 1C (1.5 g, 3.01 mmol), pyridine-4-boronic acid (0.74 g, 6.02 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.25 g, 0.31 mmol), and cesium carbonate (1.96 g, 6.02 mmol) were placed in a 100 mL single-necked flask. 1,4-dioxane (15 mL) and water (5 mL) were added, and the mixture was purged with nitrogen three times. The temperature was raised to 100 °C and stirred for 3 h. After cooling to room temperature, 30 mL of dichloromethane was added for extraction, and the organic layer was directly concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 0 / 1 - 50 / 1) to obtain 1D (1.5 g, yield: 99%).

[0305] LCMS m / z = 497.3 [M+H] +

[0306] Step 4: Preparation of 1E

[0307] Compound 1D (1.5 g, 3.02 mmol) was dissolved in DCM (10 mL), and trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 1 h. It was concentrated under reduced pressure and adjusted to pH > 8 with 1N aqueous sodium hydroxide solution. A large amount of solid precipitated, which was filtered. The filter cake was added to 20 mL of dichloromethane, 1 mL of acetic acid was added, and it was concentrated under reduced pressure to obtain 1E acetate.

[0308] LCMS m / z = 397.4 [M+H] +

[0309] Step 5: Preparation of 1G

[0310] Compound 1F (6 g, 19.93 mmol), 4-piperidone ethylene acetal (2.85 g, 19.93 mmol), L-proline (0.46 g, 3.99 mmol), copper(I) iodide (0.38 g, 1.99 mmol), and potassium carbonate (8.26 g, 59.79 mmol) were placed in a 100 mL single-necked flask. DMSO (50 mL) was added. The mixture was purged with nitrogen three times and stirred at 60 °C overnight. After cooling to room temperature, 100 mL of water was added, and it was extracted with 50 mL of ethyl acetate. The organic layer was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 - 1 / 5) to obtain 1G (2.2 g, yield: 35%).

[0311] LCMS m / z = 316.0 [M+H] +

[0312] Step 6: Preparation of 1H

[0313] Compound 1G (2.2 g, 6.96 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.19 g, 7.66 mmol), cesium carbonate (4.54 g, 13.87 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.57 g, 0.70 mmol) were placed in a 100 mL single-necked flask, 1,4-dioxane (20 mL) and water (5 mL) were added, the mixture was purged with nitrogen three times, and the temperature was raised to 100 °C and stirred overnight. After cooling to room temperature, 50 mL of dichloromethane and 50 mL of water were added and stirred to separate the layers. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate / petroleum ether (V / V) = 0 / 1 - 1 / 5) to obtain 1H (3.4 g, yield: 92%).

[0314] Step 7: Preparation of 1I

[0315] Compound 1H (3.4 g, 6.46 mmol) was dissolved in THF (20 mL), palladium on carbon (2 g, wt% = 10%) was added, the mixture was purged with hydrogen three times, and stirred overnight under a hydrogen atmosphere (balloon pressure). It was filtered, the filter cake was washed once with 20 mL of tetrahydrofuran, and the filtrates were combined and concentrated under reduced pressure to obtain compound 1I.

[0316] Step 8: Preparation of 1J

[0317] Compound 1I (1.1 g, 3.16 mmol) was dissolved in THF (6 mL), 6 mL of 3N hydrochloric acid was added, and the temperature was raised to 45 °C and stirred overnight. After cooling to room temperature, the pH was adjusted to >7 with saturated aqueous sodium bicarbonate solution, 20 mL of dichloromethane was added for extraction, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 1J.

[0318] LCMS m / z = 305.1 [M+H] +

[0319] Step 9: Preparation of Compound 1

[0320] Compound 1E acetate (0.080 g), 1J (0.068 g, 0.22 mmol) and 0.1 g of anhydrous sodium sulfate were placed in a 50 mL single-necked flask. 1,2-Dichloroethane (10 mL) and acetic acid (0.018 g, 0.30 mmol) were added. The temperature was raised to 60 °C and stirred for 16 h. Sodium triacetoxyborohydride (0.32 g, 1.51 mmol) was added and stirring was continued at 60 °C for 6 h. After cooling to room temperature, the reaction was quenched with saturated aqueous sodium bicarbonate solution. 30 mL of a dichloromethane / ethanol (V / V = 5 / 1) mixed solution was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 1 - 10 / 1) to obtain Compound 1 (30 mg, yield: 29%).

[0321] LCMS m / z = 343.1 [(M + 2H) / 2] +

[0322] Example 2: Preparation of Compound 2

[0323]

[0324] First step: Preparation of 2A

[0325] Compound 1C (0.6 g, 1.20 mmol), p-fluorophenylboronic acid (0.34 g, 2.40 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.098 g, 0.12 mmol) and cesium carbonate (1.17 g, 3.59 mmol) were placed in a 50 mL single-necked flask. 1,4-Dioxane (9 mL) and water (3 mL) were added. The flask was purged with nitrogen three times and the temperature was raised to 100 °C and stirred for 3 h. After cooling to room temperature, 30 mL of dichloromethane was added for extraction. The organic layer was directly concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0 - 50 / 1) to obtain 2A (0.33 g, yield: 53%).

[0326] LCMS m / z = 514.3 [M + H] +

[0327] Second step: Preparation of 2B

[0328] Compound 2A (0.33 g, 0.64 mmol) was dissolved in 4M HCl / 1,4-dioxane (5 mL) and stirred at room temperature for 1 h. It was concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium bicarbonate solution were added and stirred. After phase separation, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain Compound 2B (0.23 g), which was directly used in the next step.

[0329] LCMS m / z = 414.2 [M+H] +

[0330] Step 3: Preparation of Compound 2

[0331] Compound 2B (0.1 g, 0.24 mmol), 1J (0.080 g, 0.26 mmol) and 0.1 g of anhydrous sodium sulfate were placed in a 25 mL single-necked flask. 1,2-Dichloroethane (5 mL) and acetic acid (0.043 g, 0.72 mmol) were added. The temperature was raised to 60 °C and stirred for 16 h. Sodium triacetoxyborohydride (0.20 g, 0.96 mmol) was added and stirring was continued at 60 °C for 6 h. After cooling to room temperature, the reaction was quenched with saturated aqueous sodium bicarbonate solution. The mixture was extracted with a dichloromethane / ethanol (V / V = 5 / 1) mixed solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 1 - 10 / 1). The obtained crude product was further purified by preparative HPLC (instrument: Waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate salt of Compound 2 (50 mg).

[0332] LCMS m / z = 702.1 [M+H] +

[0333] Example 3: Preparation of Compound 3

[0334]

[0335] Compound 2B (0.1 g, 0.24 mmol), 3A (synthesis reference: WO2023138607) (0.077 g, 0.24 mmol) and 0.1 g of anhydrous sodium sulfate were placed in a 25 mL single-necked flask. 1,2-Dichloroethane (5 mL) and acetic acid (0.043 g, 0.72 mmol) were added. The temperature was raised to 60 °C and stirred for 16 h. Sodium triacetoxyborohydride (0.20 g, 0.96 mmol) was added and stirring was continued at 60 °C for 6 h. After cooling to room temperature, the reaction was quenched with saturated aqueous sodium bicarbonate solution. 30 mL of a dichloromethane / ethanol (V / V = 5 / 1) mixed solution was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 1 - 10 / 1). The crude product obtained was further purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate of compound 3 (30 mg).

[0336] LCMS m / z = 720.3 [M+H] +

[0337] Example 4: Preparation of Compound 4

[0338]

[0339] First step: Preparation of 4A

[0340] Compound 1C (0.2 g, 0.40 mmol), 1-methyl-1H-pyrazole-4-boronic acid (0.10 g, 0.80 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.033 g, 0.04 mmol) and cesium carbonate (0.39 g, 1.20 mmol) were placed in a 25 mL single-necked flask. 1,4-Dioxane (6 mL) and water (2 mL) were added. The flask was purged with nitrogen three times, and the temperature was raised to 100 °C and stirred for 3 h. After cooling to room temperature, 30 mL of dichloromethane was added for extraction. The organic layer was directly concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0 - 50 / 1) to obtain 4A (0.20 g).

[0341] LCMS m / z = 500.1 [M+H] +

[0342] Second step: Preparation of 4B

[0343] Compound 4A (0.2 g, 0.40 mmol) was dissolved in 4 M HCl / 1,4-dioxane (5 mL), and the reaction was stirred at room temperature for 1 h. It was concentrated under reduced pressure, ethyl acetate and saturated aqueous sodium bicarbonate were added, stirred and separated into layers. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain compound 4B (0.15 g), which was directly used for the next step.

[0344] LCMS m / z = 400.3 [M+H] +

[0345] Step 3: Preparation of Compound 4

[0346] Compound 4B (0.15 g, 0.38 mmol), 1J (0.14 g, 0.46 mmol) and 0.1 g of anhydrous sodium sulfate were placed in a 25 mL single-necked flask, chloroform (5 mL) and acetic acid (0.068 g, 1.14 mmol) were added, and the temperature was raised to 60 °C and stirred for 16 h. Sodium triacetoxyborohydride (0.32 g, 1.52 mmol) was added, and stirring was continued at 60 °C for 6 h. It was cooled to room temperature, the reaction was quenched with saturated aqueous sodium bicarbonate, extracted with a dichloromethane / ethanol (V / V = 5 / 1) mixed solution, the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 1 - 10 / 1). The obtained crude product was further purified by preparative HPLC (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate of compound 4 (85 mg).

[0347] LCMS m / z = 688.2 [M+H] +

[0348] Example 5: Preparation of Compound 5

[0349]

[0350] Step 1: Preparation of 5A

[0351] 4-Chloro-5-fluoropyrimidine (0.05 g, 0.38 mmol) and hexamethylditin (0.05 g, 0.38 mmol) were dissolved in 1,4-dioxane (5 mL). Tetrakis(triphenylphosphine)palladium (0.044 g, 0.038 mmol) was added. The mixture was purged with nitrogen three times and then heated to 100 °C and reacted overnight. After cooling to room temperature, compound 1C (0.19 g, 0.38 mmol), copper(I) iodide (0.015 g, 0.079 mmol) and tetrakis(triphenylphosphine)palladium (0.044 g, 0.038 mmol) were added. The mixture was purged with nitrogen three times and then heated to 100 °C and stirred for 3 h. After cooling to room temperature, dichloromethane was added for extraction. The organic layer was directly concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0 - 50 / 1) to obtain 5A (0.12 g, yield: 61%).

[0352] LCMS m / z = 516.7 [M+H] +

[0353] Step 2: Preparation of 5B

[0354] Compound 5A (0.12 g, 0.40 mmol) was dissolved in 4M HCl / 1,4-dioxane (4 mL). The mixture was stirred at room temperature for 1 h. After concentration under reduced pressure, ethyl acetate and saturated aqueous sodium bicarbonate were added. The mixture was stirred and separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 5B (0.08 g), which was directly used in the next step.

[0355] LCMS m / z = 416.1 [M+H] +

[0356] Step 3: Preparation of compound 5

[0357] Compound 5B (0.08 g, 0.19 mmol), 1J (0.064 g, 0.21 mmol) and 0.1 g of anhydrous sodium sulfate were placed in a 25 mL single-necked flask. Chloroform (3 mL) and acetic acid (0.034 g, 0.57 mmol) were added. The temperature was raised to 60 °C and stirred for 16 h. Sodium triacetoxyborohydride (0.16 g, 0.76 mmol) was added and stirring was continued at 60 °C for 6 h. After cooling to room temperature, the reaction was quenched with saturated aqueous sodium bicarbonate. Extraction was carried out with a dichloromethane / ethanol (V / V = 5 / 1) mixed solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 1 - 10 / 1). The crude product obtained was further purified by preparative HPLC (instrument: Waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate salt (25 mg) of the target compound 5.

[0358] LCMS m / z = 704.3 [M+H] +

[0359] Example 6: Preparation of Compound 6

[0360]

[0361] First step: Preparation of 6A

[0362] Compound 1C (0.25 g, 0.50 mmol), 2-methyl-4-pyridineboronic acid (0.14 g, 1.00 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.037 g, 0.05 mmol) and cesium carbonate (0.49 g, 1.50 mmol) were placed in a 50 mL single-necked flask. 1,4-Dioxane (6 mL) and water (1 mL) were added. The flask was purged with nitrogen three times and the temperature was raised to 100 °C and stirred for 3 h. After cooling to room temperature, extraction was carried out with 30 mL of dichloromethane. The organic layer was directly concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0 - 50 / 1) to obtain 6A (0.2 g, yield: 78%).

[0363] Second step: Preparation of 6B

[0364] Compound 6A (0.2 g, 0.39 mmol) was dissolved in DCM (6 mL). Trifluoroacetic acid (1.5 mL) was added and stirred at room temperature for 1 h. The reaction solution was directly concentrated under reduced pressure to remove trifluoroacetic acid. Water was added and the pH was adjusted to alkaline with solid potassium carbonate. A solid precipitated out. It was filtered, and the filter cake was washed twice with water, concentrated and dried to obtain the product, which was directly used for the next step.

[0365] LCMS m / z = 411.2 [M+H] +

[0366] Step 3: Preparation of Compound 6

[0367] Compound 6B (0.12 g, 0.29 mmol), 1J (0.088 g, 0.29 mmol) and 0.1 g of anhydrous sodium sulfate were placed in a 50 mL single-necked flask. 1,2-Dichloroethane (10 mL) and acetic acid (0.035 g, 0.58 mmol) were added. The temperature was raised to 60 °C and stirred for 16 h. Sodium triacetoxyborohydride (0.18 g, 0.87 mmol) was added and stirring was continued at 60 °C for 6 h. After cooling to room temperature, the reaction was quenched with saturated aqueous sodium bicarbonate solution. 30 mL of a dichloromethane / ethanol (V / V = 5 / 1) mixed solution was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 1 - 10 / 1) and then preparatively purified (instrument: waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate of Compound 6 (50 mg).

[0368] LCMS m / z = 699.3 [M+H] +

[0369] Example 7: Preparation of Compound 7

[0370]

[0371] Step 1: Preparation of 7A

[0372] Compound 1C (0.15 g, 0.3 mmol), 3,4-difluorophenylboronic acid (95 mg, 0.6 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (22 mg, 0.03 mmol) and cesium carbonate (290 mg, 0.9 mmol) were placed in a 50 mL single-necked flask. 1,4-Dioxane (9 mL) and water (3 mL) were added. The flask was purged with nitrogen three times and the temperature was raised to 100 °C and stirred for 3 h. After cooling to room temperature, 20 mL of dichloromethane was added for extraction. The organic layer was directly concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 1 / 0 - 50 / 1) to obtain 7A (100 mg, yield: 63%).

[0373] LCMS m / z = 532.4 [M+H] +

[0374] Step 2: Preparation of 7B

[0375] Dissolve compound 7A (90 mg, 0.17 mmol) in dichloromethane (2 mL), add trifluoroacetic acid (1 mL), and stir the reaction at room temperature for 1 h. Concentrate under reduced pressure, add dichloromethane and saturated aqueous sodium carbonate solution, stir and separate the layers. Wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to obtain the crude product of compound 7B, which is directly used in the next step.

[0376] Step 3: Preparation of compound 7

[0377] Place the crude product of compound 7B obtained in the previous step, 3A (55 mg, 0.17 mmol), and 0.1 g of anhydrous sodium sulfate in a 25 mL single-necked flask, add chloroform (5 mL) and acetic acid (31 mg, 0.51 mmol), heat to 60 °C and stir for 16 h. Add sodium triacetoxyborohydride (110 mg, 0.51 mmol) and continue to stir at 60 °C for 16 h. Cool to room temperature, quench the reaction with saturated aqueous sodium bicarbonate solution, extract with a dichloromethane / isopropanol (V / V = 10 / 1) mixed solution. Dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure. Purify the residue by column chromatography (dichloromethane / methanol (V / V) = 100 / 1 - 10 / 1), and further purify the obtained crude product by preparative HPLC (instrument: Waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate of compound 7 (80 mg).

[0378] LCMS m / z = 738.2 [M+H] +

[0379] Example 8: Preparation of compound 8

[0380]

[0381] Compound 4B (56 mg, 0.14 mmol), 3A (45 mg, 0.14 mmol) and 0.1 g of anhydrous sodium sulfate were placed in a 25 mL single-necked flask. Chloroform (5 mL) and acetic acid (25 mg, 0.42 mmol) were added. The temperature was raised to 60 °C and stirred for 16 h. Sodium triacetoxyborohydride (89 mg, 0.42 mmol) was added and stirring was continued at 60 °C for 16 h. After cooling to room temperature, the reaction was quenched with saturated aqueous sodium bicarbonate solution. The mixture was extracted with a dichloromethane / isopropanol (V / V = 10 / 1) mixed solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 1 - 10 / 1). The crude product obtained was further purified by preparative HPLC (instrument: Waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate salt of compound 8 (80 mg).

[0382] LCMS m / z = 706.2 [M+H] +

[0383] Example 9: Preparation of Compound 9

[0384]

[0385] Compound 5B (50 mg, 0.096 mmol), 3A (31 mg, 0.096 mmol) and 0.1 g of anhydrous sodium sulfate were placed in a 25 mL single-necked flask. Chloroform (3 mL) and acetic acid (17 mg, 0.29 mmol) were added. The temperature was raised to 60 °C and stirred for 16 h. Sodium triacetoxyborohydride (61 mg, 0.29 mmol) was added and stirring was continued at 60 °C for 16 h. After cooling to room temperature, the reaction was quenched with saturated aqueous sodium bicarbonate solution. The mixture was extracted with a dichloromethane / isopropanol (V / V = 10 / 1) mixed solution. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane / methanol (V / V) = 100 / 1 - 10 / 1). The crude product obtained was further purified by preparative HPLC (instrument: Waters 2767 preparative liquid phase; chromatographic column: SunFire@Prep C18 (19 mm × 150 mm); mobile phase composition: mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate salt of compound 9 (40 mg).

[0386] LCMS m / z = 722.3 [M+H] + 。

[0387] Biological Test Example

[0388] Test Example 1: Study on c-MYC Degradation Activity in HL60 Cells

[0389] The human promyelocytic leukemia cell line HL60 was purchased from ATCC. The complete cell culture medium was IMDM + 20% FBS + 1% antibiotic-antifungal double antibody, and the cells were cultured in an incubator at 37°C and 5% CO 2 2. Cells in the exponential growth phase were collected, and the cell suspension was adjusted to the appropriate concentration with the complete medium and plated. The cells were plated in 6-well plates at 2×10 6 cells / well. After plating, different concentrations of the compound were added, and the cells were cultured in an incubator at 37°C and 5% CO 2 for 24 hours. After the culture, the cells were collected, and RIPA lysis buffer (sigma, Cat.R0278) containing 1% protease inhibitor (Roche, 04693124001) and 1% phosphatase inhibitor (Sigma, P5726) was added. After lysing on ice for 15 minutes, the mixture was centrifuged at 12,000 rpm at 4°C for 10 minutes, and the supernatant protein sample was collected. After protein quantification using a BCA kit (Thermo Scientific, Cat.23225), the protein was diluted to 2 mg / mL, and 10 μL was loaded into each well. The expression of c-MYC (CST, Cat.18583S) and the internal reference GAPDH (abcam, Cat.ab8245) was detected by Western blot. The near-infrared fluorescence signal was detected using Odyssey Clx, and the intensity of each band was quantified using Image Studio (NIR) software for analysis. The expression level of c-MYC relative to the internal reference GAPDH was calculated in excel, and the degradation rate (DR) of the test compound at the measured concentration was calculated using the following formula: DR(%) = (1 - Protein 给药 / Protein 溶媒 ) × 100% Equation (1), where Protein 给药 is the relative expression level of c-MYC in different concentration dosing groups, and Protein 溶媒 is the relative expression level of c-MYC in the vehicle control group. The inhibition curve was plotted and relevant parameters were calculated using GraphPad Prism software, including the maximum degradation rate Dmax and DC 50 .

[0390] Table 1 Degradation Rate of c-MYC in HL60 Cells by Test Compounds at Different Concentrations

[0391] Compound Number c-MYC Degradation Rate (0.1 μM) c-MYC Degradation Rate (1 μM) Compound 1 A A Trifluoroacetate Salt of Compound 2 B A Trifluoroacetate Salt of Compound 3 B A Trifluoroacetate Salt of Compound 4 A A Trifluoroacetate Salt of Compound 5 A A Trifluoroacetate Salt of Compound 7 A A Trifluoroacetate Salt of Compound 9 A A

[0392] Note: In Table 1, A ≥ 80%, 80% > B ≥ 50%

[0393] Table 2 Results of the c-MYC degradation activity of the compounds against HL60 cells

[0394] Compound Number <![CDATA[DC 50 (μM)]]> Compound 1 A

[0395] Note: In Table 2, A < 0.1 μM

[0396] Conclusion: The compounds of the present invention, such as the compounds of the examples, have a degradation effect on the c-MYC protein of HL60 cells. Specifically, compound 1 has a good protein degradation effect on the c-MYC protein of HL60 cells.

[0397] Test Example 2: Proliferation inhibitory activity against human promyelocytic leukemia cells HL60

[0398] Human promyelocytic leukemia cells HL60 were purchased from ATCC. The complete cell culture medium was IMDM + 20% FBS + 1% antibiotic-antifungal double antibody, and the cells were cultured in an incubator at 37°C and 5% CO 2 On the first day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the corresponding concentration with the complete medium and plated so that there were 6000 cells per well, with a volume of 135 μL per well. Subsequently, 15 μL of compounds at different concentrations were added, and the cells were placed in a CO 2 incubator and continued to be incubated for 3 days. After the culture was completed, according to the operation instructions of the CellTiter-Glo kit (Promega, G7573), 50 μL of CTG solution pre-melted and equilibrated to room temperature was added to each well, and the mixture was mixed with a microplate shaker for 2 minutes. After standing at room temperature for 10 minutes, the fluorescence signal value RLU was measured with a microplate reader (EnVision). The following formula was used to calculate the inhibition rate (IR) of the tested compounds: IR (%) = (1 - (RLU compound - RLU blank control) / (RLU vehicle control - RLU blank control)) * 100%. The inhibition rates of compounds at different concentrations were calculated in Excel, and then the inhibition curve was plotted and relevant parameters were calculated using GraphPad Prism software, including the minimum inhibition rate, the maximum inhibition rate, and the IC 50 .

[0399] Table 2-1 Proliferation inhibitory activity of the compounds against HL60 cells

[0400] Compound Number <![CDATA[IC 50 (μM)]]> Compound 1 A Trifluoroacetate Salt of Compound 4 A Trifluoroacetate Salt of Compound 5 A

[0401] Note: In Table 2-1, A < 0.05 μM

[0402] Conclusion: The compounds of the present invention, such as the compounds of the examples, have good proliferation inhibitory activity against human promyelocytic leukemia cells HL60.

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, 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 z1, z2 are each independently selected from 0, 1, 2; z3 is selected from 0, 1, 2, 3, 4; z1 and z2 are not 0 at the same time; B1 is selected from a bond, C 3-10 carbocyclic group or 4 to 10 membered heterocyclic group, said B1 is optionally substituted by 1 to 4 R b1 replace; B2 is selected from C 3-10 carbocyclic group or 4 to 10 membered heterocyclic group, said B2 is optionally substituted by 1 to 4 R b2 replace; B3 is selected from a bond, -N(R B )-、-N(R B )C(=O)-、-C(=O)N(R B )-; R B Select from H or C 1-4 Alkyl, the alkyl group is optionally substituted by 1 to 4 R z replace; B4 is selected from 5- to 6-membered heteroaryl or phenyl, said B4 is optionally substituted by 1 to 2 R b4 replace; R b1 , R b2 , R b3 , R b4 , R b5 Each independently selected from H, halogen, =O, OH, NH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -OC 0-4 Alkylene-C 3-10 Carbocyclic group, -OC 0-4 Alkylene-4 to 10-membered heterocyclic group, -NH-C 0-4 Alkylene-C 3-10 Carbocyclic group, -NH-C 0-4 Alkylene-4 to 10 membered heterocyclic group, -C 0-4 Alkylene-C 3-10 Carbocyclic group, -C 0-4 Alkylene-4 to 10 membered heterocyclic group, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylene, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R z replace; K is selected from G is selected from N or CH; Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -, -C(=O)-, -NR q C(=O)-, -C(=O)NR q -; Q and G cannot directly form a nitrogen-nitrogen bond, a nitrogen-oxygen bond, or a nitrogen-sulfur bond; R q Select from H or C 1-4 alkyl; F is selected from C 3-20 Carbocyclic group, C 6-20 Aryl, 3-20 membered heterocyclyl or 5-20 membered heteroaryl; R k1 Each independently selected from H, deuterium, halogen, 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 Cycloalkyl, 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl is 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, halogen, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl or 3 to 8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups 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 groups selected from R z replace; R L2 , R z Each independently selected from deuterium, halogen, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, 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, 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; F is selected from C 3-7 Monocyclic group, C 4-10 Cyclic group, C 5-12 Spirocyclyl, C 5-10 bridged cyclyl, 4-7 membered heteromonocyclic group, 4-10 membered bicyclic heterocyclic group, 8-15 membered tricyclic heterocyclic group, 12-19 membered tetracyclic heterocyclic group, 5-17 membered heterospirocyclic group, 5-10 membered heterobridged cyclyl, C 6-14 Aryl, 5-10 membered heteroaryl; B is selected from B1 is selected from phenyl, benzo 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, said B1 is optionally substituted by 1 to 4 R b1 replace; B2 is selected from phenyl, benzo 4-6 carbocyclyl, benzo 4 to 6 membered heterocyclyl, 5 to 6 membered heteroaryl, 8 to 10 membered heteroaryl, said B2 is optionally substituted by 1 to 4 R b2 replace.

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; B1 is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, furanyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazolyl, said B1 is optionally substituted by 1 to 4 R b1 replace; B2 is selected from phenyl, pyridyl, pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyridinyl, thiazolopyridinyl, thiazolopyridinyl, oxazolophenyl, oxazolopyrimidinyl, pyrazolopyridinyl, pyrazolophenyl, pyrazolopyrimidinyl, said B2 is optionally substituted by 1 to 4 R b2 replace; B3 is selected from a bond, -NH-, -NHC(=O)-, -C(=O)NH-, -N(CH3)-, -N(CH3)C(=O)-, -C(=O)N(CH3)-; R b1 , R b2 , R b5 Each independently selected from H, F, Cl, Br, I, =O, OH, NH2, CN or optionally substituted by 1 to 4 R z substituted by one of the following groups: methyl, ethyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 R z replace; R b3 Selected from H, optionally substituted by 1 to 4 R z substituted by one of the following groups: methyl, ethyl, isopropyl, methoxy, ethoxy, vinyl, ethynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, oxetanyl, oxolanyl, oxhexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, furanyl, thienyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl; Selected from F is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthryl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazine, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl, The ring where the representative is located is an aromatic ring or a non-aromatic ring; Fa is selected from N, CH or CR k1 ; Fb is selected from N, CH or CR k1 ; Fc is selected from O, S, NH, N(CH3) or NR k7a ; Fd is selected from N, CH or CR k1 ; Fg is selected from N or C; Fh is selected from N or C; Faa is selected from a bond, O, CH2; Fab is selected from O, CH2; 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 , 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 5-6 membered heteroaryl, and the ring E is optionally substituted by 1 to 3 R k1 replace; Ring F1, ring F2, ring F3, ring F4 are each independently selected from phenyl or 5-6 membered heteroaryl, and the ring F1, ring F2, ring F3, ring F4 are optionally substituted by 1 to 2 R k1 replace; 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, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2; R k5 Each independently selected from C(CH3)2, C(=O), CH2, CH2CH2, S(=O)2, R k6 Each is independently selected from C(═O), CH, S(═O), S(═O)2, CH2 or N; R k7 Each independently selected from C(CH3)2, CH2, O or NR k7a ; R k7a is selected from H, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 substituted by a cycloalkyl substituent; R k9 are each independently selected from a bond, C(CH3)2, C(=O), CH2, CH2CH2 or S(=O)2; 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, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; p2 is independently selected from 0, 1, 2 or 3.

4. The compound according to claim 3 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: Ring E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl, and the ring E is optionally substituted by 1 to 3 R k1 replace; Ring F1 and Ring F2 are each independently selected from phenyl, pyridyl, thiazolyl, furyl, thienyl or oxazolyl, and the ring F1 and ring F2 are optionally substituted by 1 to 2 R k1 replace; Ring F3 and Ring F4 are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl, and the ring F3 and ring F4 are optionally substituted by 1 to 2 R k1 replace; B1 is selected from thiazolyl or oxazolyl, wherein the thiazolyl or oxazolyl is optionally substituted by a substituent selected from deuterium, F, Cl, Br, I, OH, CF3, CD3, methyl, ethyl; B2 is selected from phenyl, pyridyl, pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolopyridinyl, thiazolopyridinyl, thiazolopyridinyl, thiazolopyridinyl, oxazolophenyl, oxazolopyrimidinyl, pyrazolopyridinyl, pyrazolophenyl, pyrazolopyrimidinyl, and B2 is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CF3, CD3, SF5, CN, NH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl; R b3 Selected from CF3, CD3, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -CH2-cyclopropyl, -CH2-cyclobutyl; 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 with 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, and cyclopropyl.

5. The compound according to claim 4 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B is selected from L is selected from the group consisting of bonds, -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-Cy2-, -NH-Cy1-CH2-Cy2, -Cy1-Ak2-, -Ak1-Cy1-Ak2-, -CH2-Cy2-, -CH2-Cy2-CH2-Cy3-, -CH2-Cy1-Cy2-; Cy1, Cy2, and Cy3 are each independently selected from one of the following optionally substituted groups: When substituted, it is substituted by 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl; Preferably, L is selected from a bond, 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: -LK is selected from L1 is selected from a bond, -Cy1-CH2-Cy2-, -Cy1-Cy2-, -Cy1-, -CH2-Cy2-, -CH2-Cy2-CH2-Cy3-, -CH2-Cy1-Cy2-; Preferably, L1 is selected from a bond, L2 is selected from -Cy1-CH2- or -Cy1-; Preferably, L2 is selected from 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: 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 and inhibiting or degrading c-MYC-related diseases.

10. The use according to claim 9, characterized in that: The disease is selected from cancer.

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