Halogenated pyrimidine derivative and application thereof in medicine

Abstract

The invention relates to a halogenated pyrimidine derivative and application thereof in medicine, in particular to a compound shown in a general formula (I) or a stereoisomer, a tautomer, a deuterated compound, a solvate, a prodrug, a metabolite, pharmaceutically acceptable salt or eutectic of the compound, an intermediate of the compound and application of the compound to inhibition or degradation of EGFR (epidermal growth factor receptor) related diseases such as cancer. And B-L-K (I).

Description

Technical Field

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

[0002] Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase that can act as a receptor for EGF family members to trigger the EGFR signaling pathway in human epithelial cells, thereby regulating cell proliferation, invasion, metastasis, apoptosis and angiogenesis (Nat. Rev. Cancer, 2007, 7, 169-181; Expert Opin. Ther. Targets, 2012, 16, 15-31.). Overexpression, mutation or amplification of the EGFR gene in the human body causes abnormal increase in EGFR activity, which can lead to the occurrence of many malignant tumors such as esophageal cancer, glioblastoma, anal cancer, head and neck epithelial cancer, breast cancer, lung cancer, especially non-small cell lung cancer (NSCLC) (Cells, 2019, 8, 350-361.).

[0003] PROTAC (proteolysis targeting chimera) molecules are bifunctional compounds that can simultaneously bind to targeted proteins and E3 ubiquitin ligases. Such compounds can be recognized by the proteasome of the cell, causing degradation of the targeted protein, and can effectively reduce the content of the targeted protein in the cell. By introducing ligands that can bind to different targeted proteins in PROTAC molecules, PROTAC technology can be applied to the treatment of various diseases. This technology has also received widespread attention in recent years (ACS Chem.Biol.2017,12,892-898; Drug Discovery Today Technol.2019,31,15-27.).

[0004] The development of new PROTAC drugs that bind to EGFR protein and E3 ubiquitin ligase for the treatment of diseases related to EGFR protein will be full of application prospects. Summary of the invention

[0005] The object of the present invention is to provide a compound with novel structure, good efficacy, high bioavailability, greater safety, and the ability to inhibit or degrade EGFR, for treating EGFR-related diseases such as cancer.

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

[0007] BLK(I);

[0008] In some embodiments, the compound represented by general formula (I) is selected from general formula (Ia) or general formula (Ib)

[0009] B-L1-K1(Ia)BL-K2(Ib)

[0010] In some embodiments, L1 is selected from -Cy1-, -Cy1-CH 2 -、-Cy1-Cy2-CH 2 -, -Cy1-Cy2-, preferably -Cy1-, -Cy1-CH 2 -;

[0011] 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-, -Cy-;

[0012] In some embodiments, L is selected from a bond or -C 1-20 Hydrocarbyl-, wherein 1 to 10 methylene units in the hydrocarbyl are optionally replaced by -Ak-, -Cy-;

[0013] 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)NRL -, -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 bond, the CH, -CH 2 - optionally substituted by 1 to 2 selected from deuterium, halogen, =O, OH, CN, C 1-4 Alkyl or C 3-6 Substituted by a cycloalkyl substituent;

[0014] In some embodiments, q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0015] In some embodiments, R L Selected from H, C 1-4 Alkyl, C 3-7 Carbocyclyl, 4- to 10-membered heterocyclyl;

[0016] In some embodiments, 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;

[0017] In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, or Ak9;

[0018] In some embodiments, Ak is selected from Ak1, Ak2, Ak3, Ak4, or Ak5;

[0019] In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3, Cy4 or Cy5;

[0020] In some embodiments, -Cy- is selected from Cy1, Cy2, Cy3 or Cy4;

[0021] In some embodiments, L is selected from -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Cy5-Ak5-, -Cy1-Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-Cy4-Ak4-Ak5-, -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, 5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak1-Ak2-Ak 3-Ak4-Ak5-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Ak5-Cy4-, -Cy1 -Cy2-Cy3-Cy4-Ak1-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Cy3-Cy4-Ak2-A k3-Ak4-Ak5-, -Cy1-Cy2-Ak1-Cy3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy 3-Ak1-Cy4-Ak2-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Cy2-Cy3-Cy4-Ak3-Ak4- Ak5-, -Cy1-Cy2-Ak1-Ak2-Cy3-Cy4-Ak3-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1- Ak2-Cy4-Ak3-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Cy2-Cy3-Cy4-Ak4-Ak5-, - Cy1-Cy2-Ak1-Ak2-Ak3-Cy3-Cy4-Ak4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3 -Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Cy2-Cy3-Cy4-Ak5-, -Cy1-Cy2 -Ak1-Ak2-Ak3-Ak4-Cy3-Cy4-Ak5-, -Cy1-Cy2-Cy3-Ak1-Ak2-Ak3-Ak4-Cy 4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Cy1-Cy2-Cy3-Cy4-, -Ak1-Cy1-Cy2-Cy 3-Cy4-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Cy1-Cy2-Cy3-Cy4-Ak3-Ak4-Ak5-,-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Cy4-Ak5-、-Ak1-Cy1-Ak2-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Cy1-Cy2-Ak2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Cy1-Cy2-Cy3-Ak2-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Cy1-Ak3-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Ak3-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Cy1-Ak4-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Ak4-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Cy1-Cy2-Cy3-Ak4-Ak5-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Ak5-Cy2-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Ak5-Cy3-Cy4-、-Ak1-Ak2-Ak3-Ak4-Cy1-Cy2-Cy3-Ak5-Cy4-、-Ak1-、-Ak1-Ak2-、-Ak1-Ak2-Ak3-、-Ak1-Ak2-Ak3-Ak4-、-Ak1-Ak2-Ak3-Ak4-Ak5-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-、-Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-Ak7-Ak8-Ak9-;、

[0022] In certain embodiments, L is selected from a bond, -Ak1-, -Ak1-Ak2-, -Ak1-Ak2-Ak3-, -Ak1-Ak2-Ak3-Ak4-, -Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Ak2-Ak3-Ak4-Ak5-Ak6-, -Cy1-, -Cy1-Ak1-, -Cy1-Ak1-Ak2-, -Cy1-Ak1-Ak2-Ak3-, -Cy1-Ak1-Ak2-Ak3-Ak4-, -Cy1-Cy2-, -Cy1-Ak1-Cy2-, -Cy1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-, -Cy1-Ak1-Cy2-Ak2-Ak3-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Cy2-Ak2-Ak3-, -Cy1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-, -Cy1-Ak1-Ak2-Cy3-, -Cy1-Ak1-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-, -Cy1-Ak1-Cy2-Cy3-, -Cy1-Cy2-Ak2-Cy3-, -Cy1-Cy2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Cy3-Ak3-, -Cy1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Ak1-Cy2-Ak2-Cy3-, -Cy1-Ak1-Cy2-Ak2-Cy3-Ak3-, -Cy1-Cy2-Cy3-Ak3-Ak4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-, -Cy1-Ak1-Cy2-Cy3-Cy4-, -Cy1-Cy2-Ak2-Cy3-Cy4-, -Cy1-Cy2-Cy3-Ak3-Cy4-, -Cy1-Cy2-Cy3-Cy4-Ak4-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Cy4-, -Cy1-Ak1-Cy2-Ak2-Cy3-Cy4-, -Ak1-Cy2-, -Ak1-Cy2-Cy3-, -Ak1-Ak2-Cy3-, -Ak1-Ak2-Cy3-Cy4-, -Ak1-Cy2-Ak2-Cy3-, -Ak1-Cy2-Cy3-Ak3-Cy4-, -Ak1-Cy2-Cy3-Cy4-Ak4-Cy5-, -Ak1-Cy2-Ak2-, -Cy1-Cy2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Cy2-Ak2-Cy3-Ak3-Ak4-Ak5-, -Cy1-Ak1-Cy2-Ak2-Ak3-Ak4-Ak5--Cy1-Cy2-Cy3-Cy4-Ak4-Ak5-, -Cy1-Ak1-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy 2-Ak2-Ak3-Ak4-Ak5-, -Ak1-Cy2-Ak2-Ak3-Ak4-, -Ak1-Cy2-Ak2-Ak3-;,

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

[0024] In certain embodiments, L is selected from -Cy1-, -Cy1-CH 2 -、-Cy1-Cy2-、-Cy1-CH 2 -Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH 2 -Cy2-Cy3-, -Cy1-Cy2-CH 2 -Cy3-, preferably -Cy1-, -Cy1-CH 2 -、-Cy1-Cy2-CH 2 -, -Cy1-Cy2-;

[0025] In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 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 bond, the -CH 2- optionally substituted by 1 to 2 selected from deuterium, halogen, =O, OH, CN, C 1-4 Alkyl or C 3-6 substituted by a cycloalkyl substituent;

[0026] In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 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 -、-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 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)-, preferably O, NH or -CH 2 -;

[0027] In certain embodiments, Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from O, NH, or -CH 2 -;

[0028] In certain embodiments, R L Select from H or C 1-4 alkyl;

[0029] In certain embodiments, R L is selected from H, methyl or ethyl;

[0030] In certain embodiments, Cy1, Cy2, Cy3, Cy4 or Cy5 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 7-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl;

[0031] In certain embodiments, Cy5 is defined the same as Cy1;

[0032] In certain embodiments, 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,

[0033] s1, s3, s5 are each independently selected from 0, 1 or 2, s2, s4 are each independently selected from 0 or 1, s6 is selected from 0, 1, 2 or 3, s7 is selected from 1, 2 or 3;

[0034] In certain embodiments, Cy1, Cy2, Cy3, Cy4, and Cy5 are each independently selected from a bond or one of the following groups which are optionally substituted:

[0035]

[0036] When substituted, it is replaced by 1 to 4 atoms selected from deuterium, F, CF 3 , OH, =O, COOH, CN, NH 2 , hydroxymethyl, methyl, methoxy, cyclopropyl;

[0037] Cy1, Cy2, and Cy3 are each independently selected from one of the following optionally substituted groups:

[0038] When substituted, it is replaced by 1 to 4 atoms selected from deuterium, F, CF 3 , OH, =O, COOH, CN, NH 2, hydroxymethyl, methyl, methoxy, cyclopropyl;

[0039] In some embodiments, L or L1 are each independently selected from

[0040] In some embodiments, L is selected from L1, K is selected from K1;

[0041] In some embodiments, B is selected from In some embodiments, B is selected from

[0042] is a single bond or a double bond;

[0043] In some embodiments, B is selected from one of the structural fragments shown in Table B-1;

[0044] Table B-1

[0045]

[0046]

[0047] In some embodiments, B 1 Select from N or CR B1 ;

[0048] In some embodiments, B 2 Select from N or CR B2 ;

[0049] In some embodiments, B 3 Select from N or CR B3 , preferably N or CH; in some embodiments, B 4 Select from N or CR B4 , preferably CH;

[0050] In some embodiments, B 1 , B 2 , B 3 , B 4 At most 2 of them are selected from N;

[0051] In some embodiments, R b1 Selected from -P(=O)R b1a R b1b 、-NR b1c S(=O) 2 R b1d 、-NR b1c S(=O)(=NH)R b1d ;

[0052] In some embodiments, R b1a , R b1b , R b1d Each independently selected from C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0053] Or, R b1a With R b1b directly connected to form a 4- to 6-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0054] In some embodiments, R b1a , R b1b , R b1d Each is independently selected from methyl, ethyl, propyl, isopropyl or cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl or cyclopropyl is optionally substituted by 1 to 4 deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0055] Or, R b1a With R b1b directly connected to form a 5-membered heterocyclic group containing 0 or 1 double bonds, wherein the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0056] In some embodiments, R b1c Selected from H, C 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0057] Or, R b1c With R B1directly connected to form a 4- to 7-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0058] In some embodiments, R b1c is selected from H, methyl, ethyl, propyl, isopropyl or cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl or cyclopropyl is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0059] Or, R b1c With R B1 directly connected to form a 5-membered or 6-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0060] In some embodiments, R B1 , R B2 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-4 Alkylene-C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, -OC 3-6 Cycloalkyl, -O-4 to 6 membered heterocyclic group, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclic group, heteroaryl group are optionally substituted by 1 to 4 deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, halogen substituted C 3-6 substituted by a cycloalkyl substituent;

[0061] or R B1 With R B2 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group (preferably a phenyl group or a pyridyl group), wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2 , CN, C 1-4Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, halogen substituted C 3-6 Substituted by a cycloalkyl substituent;

[0062] In some embodiments, R B1 Selected from H, F, Cl, Br, CN, CF 3 , methyl or cyclopropyl;

[0063] R B2 Each is independently selected from H, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl is optionally substituted by 1 to 4 deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen-substituted C 1-4 Alkyl, halogen substituted C 3-6 Substituted by a cycloalkyl substituent;

[0064] or R B1 With R B2 Direct connection to form C 6 A carbocyclic group or a 5- to 6-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, halogen substituted C 3-6 Substituted by a cycloalkyl substituent;

[0065] In some embodiments, R b2 is selected from halogen, preferably F, Cl or Br;

[0066] In some embodiments, R b3 Selected from H, deuterium, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -O-4 to 6 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0067] In some embodiments, R b3 is selected from H, deuterium, methoxy, ethoxy, -O-cyclopropyl, wherein the methoxy, ethoxy or cyclopropyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0068] In some embodiments, R b4 Selected from H, deuterium, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl are optionally substituted by 1 to 4 deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, deuterated C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, halogen substituted C 3-6 Substituted by a cycloalkyl substituent;

[0069] In some embodiments, R b4 is selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, ethynyl, phenyl, pyrazolyl or imidazolyl, wherein the methyl, ethyl, ethynyl, phenyl, pyrazolyl or imidazolyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, deuterated C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, halogen substituted C 3-6 Substituted by a cycloalkyl substituent;

[0070] In some embodiments, R b5 , R B3 , R B4 are each independently selected from H, deuterium, halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy or -C 0-4 Alkylene-C3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy or cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0071] In some embodiments, R b5 Selected from H, deuterium, F, Cl, Br, CN, CF 3 , methyl, ethyl;

[0072] In some embodiments, R B2 is selected from cyclopropyl or phenyl, wherein the cyclopropyl or phenyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, CN, CF 3 , methyl or methoxy substituents;

[0073] In some embodiments, R by Selected from deuterium, F, Cl, Br, CN, CF 3 , CHF 2 , CH 2 F, methyl, methoxy or cyclopropyl;

[0074] In some embodiments, R b3 Selected from methoxy, ethoxy, -OCF 3 or-OCD 3 ;

[0075] In some embodiments, R b4 Selected from methyl, ethyl or

[0076] In some embodiments, R b4a Selected from methyl, ethyl, CF 3 , CHF 2 , CH 2 F.CD 3 , CHD 2 , CH 2 D;

[0077] K is selected from K1 or K2;

[0078] In some embodiments, K1 is selected from Best

[0079] Best More preferably, one of the structural fragments shown in Table K-1;

[0080] In some embodiments, K1 is selected from

[0081] In some embodiments, K2 is selected from Best

[0082] Best More preferably, one of the structural fragments shown in Table K-2;

[0083] The ring where the representative is located is an aromatic ring or a non-aromatic ring;

[0084] In some embodiments, F 1 Selected from N, NH, CH, CH 2 NR k1 , CR k1 , C(R k1 ) 2 ;

[0085] In some embodiments, F 2 Selected from a bond, N, NH, CH, CH 2 , CHR k1 NR k1 , CR k1 or C(R k1 ) 2 ;

[0086] In some embodiments, F 3 、F 4 、F 5 、F 6 、F 7 、F 8 Each independently selected from N, C, CH or CR k1 , and F 3 、F 4 、F 5 Contains at most 2 N, and F 6 、F 7 、F 8 Contains at most 2 Ns;

[0087] G is selected from CH or N;

[0088] Y 1 Selected from N or CH, preferably N;

[0089] Y 2 Selected from N, C or CH, preferably N;

[0090] In some embodiments, each Q is independently selected from a bond, -O-, -S-, -CH 2 -、-NR q -、-CO-、-NRq CO-、-CONR q -;

[0091] In some embodiments, each Q is independently 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 ); preferably, Q is selected from a bond, NH, N(CH 3 ), O, S, NHC(=O), C(=O)NH, N(CH 3 )C(=O), C(=O)N(CH 3 ); preferably, Q is selected from a bond or NH;

[0092] Q and G cannot directly form a nitrogen-nitrogen bond or a nitrogen-oxygen bond;

[0093] In some embodiments, R q Select from H or C 1-4 alkyl;

[0094] In some embodiments, R q Selected from H or methyl;

[0095] In some embodiments, R k1 Each independently selected from deuterium, halogen, OH, 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, 4 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 groups 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, -SC 1-4 Alkyl, -C 0-4 Alkylene-C3-6 Cycloalkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, halogen substituted C 3-6 Substituted by a cycloalkyl substituent;

[0096] Preferably, R k1 Each independently selected from deuterium, halogen, OH, NH 2 、CN、COOH、CONH 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 deuterium, halogen, OH, CF 3 、CN、NH 2 , C 1-4 substituted by an alkyl substituent;

[0097] Preferably, R k1 Each independently selected from deuterium, F, Cl, Br, I, OH, NH 2 、CN、COOH、CONH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, NH 2 substituted by a substituent;

[0098] In some embodiments, R L2 , R k2 Each independently selected from deuterium, halogen, OH, CN, =O, CF 3 , SF 5 、NO 2 NH 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, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, -C 0-4 Alkylene-4 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl group is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4Alkyl, C 1-4 substituted by an alkoxy substituent;

[0099] In some embodiments, R L2 , R k2 Each independently selected from deuterium, halogen, OH, CN, NH 2 , =O, C 1-4 Alkyl, -CH 2 -C 3-6 Cycloalkyl, C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 Preferably, R L2 , R k2 Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH 2 , =O, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl 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;

[0100] In some embodiments, b1 is selected from 0, 1 or 2;

[0101] In some embodiments, p1 is each independently selected from 0, 1 or 2;

[0102] In some embodiments, p2 is each independently selected from 0, 1, 2 or 3;

[0103] In some embodiments, p3 and p4 are each independently selected from 0 or 1;

[0104] In some embodiments, m1 is selected from 0, 1, 2 or 3;

[0105] Table K-1

[0106]

[0107]

[0108] Table K-2

[0109]

[0110]

[0111] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

[0112] L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0113] Ak1, Ak2, Ak3, Ak4, and 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 bond, the -CH 2 - optionally substituted by 1 to 2 selected from deuterium, halogen, =O, OH, CN, C 1-4 Alkyl or C 3-6 substituted by a cycloalkyl substituent;

[0114] q is selected from 0, 1, 2 or 3;

[0115] R L Each independently selected from H or C 1-4 alkyl;

[0116] Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2One of the following substituted groups: 4-7 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;

[0117] B is selected from

[0118] B 1 Select from N or CR B1 ;

[0119] B 2 Select from N or CR B2 ;

[0120] B 3 Select from N or CR B3 ;

[0121] B 4 Select from N or CR B4 ;

[0122] B 1 , B 2 , B 3 , B 4 At most 2 of them are selected from N;

[0123] R b1 Selected from -P(=O)R b1a R b1b 、-NR b1c S(=O) 2 R b1d 、-NR b1c S(=O)(=NH)R b1d ;

[0124] R b1a , R b1b , R b1d Each independently selected from C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0125] Or, R b1a With R b1bdirectly connected to form a 4- to 6-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0126] R b1c Selected from H, C 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0127] Or, R b1c With R B1 directly connected to form a 4- to 7-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0128] R B1 , R B2 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-4 Alkylene-C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, -OC 3-6 Cycloalkyl, -O-4 to 6 membered heterocyclic group, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclic group, heteroaryl group are optionally substituted by 1 to 4 deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, halogen substituted C 3-6 substituted by a cycloalkyl substituent;

[0129] or R B1 With R B2 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, halogen substituted C 3-6 Substituted by a cycloalkyl substituent;

[0130] R b2 is selected from halogen;

[0131] R b3 Selected from H, deuterium, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -O-4 to 6 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0132] R b4 Selected from H, deuterium, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl are optionally substituted by 1 to 4 deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, deuterated C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, halogen substituted C 3-6 Substituted by a cycloalkyl substituent;

[0133] R b5 , R B3 , R B4 are each independently selected from H, deuterium, halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy or -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy or cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0134] K is selected from K1 or K2;

[0135] K1 is selected from

[0136] K2 is selected from

[0137] The ring where the representative is located is an aromatic ring or a non-aromatic ring;

[0138] F 1 Selected from N, NH, CH, CH 2 NR k1 , CR k1 , C(R k1 ) 2 ;

[0139] F 2 Selected from a bond, N, NH, CH, CH 2 , CHR k1 NR k1 , CR k1 or C(R k1 ) 2 ;

[0140] F 3 、F 4 、F 5 、F 6 、F 7 、F 8 Each independently selected from N, C, CH or CR k1 , and F 3 、F 4 、F 5 Contains at most 2 N, and F 6 、F 7 、F 8 Contains at most 2 Ns;

[0141] G is selected from CH or N;

[0142] Y 1 is selected from N or CH;

[0143] Y 2 is selected from N, C or CH;

[0144] Q is independently selected from a bond, -O-, -S-, -CH 2 -、-NR q -、-CO-、-NR q CO-、-CONR q -;

[0145] Q and G cannot directly form a nitrogen-nitrogen bond or a nitrogen-oxygen bond;

[0146] R q Select from H or C 1-4 alkyl;

[0147] R k1 Each independently selected from deuterium, halogen, OH, 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, 4 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 groups 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, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, halogen substituted C 3-6 substituted by a cycloalkyl substituent;

[0148] R L2 , R k2 Each independently selected from deuterium, halogen, OH, CN, =O, CF 3 , SF 5 、NO 2 NH 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, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, -C0-4 Alkylene-4 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl group 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;

[0149] b1 is selected from 0, 1 or 2;

[0150] p1 is independently selected from 0, 1 or 2;

[0151] p2 is each independently selected from 0, 1, 2 or 3;

[0152] p3 and p4 are each independently selected from 0 or 1.

[0153] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound represented by general formula (I) is selected from general formula (Ia) or general formula (Ib),

[0154] B-L1-K1(Ia)BL-K2(Ib)

[0155] L1 is selected from -Cy1-, -Cy1-CH 2 -、-Cy1-Cy2-CH 2 -, -Cy1-Cy2-, preferably -Cy1-, -Cy1-CH 2 -;

[0156] R L is selected from H, methyl or ethyl;

[0157] 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,

[0158]

[0159] s1, s3, s5 are each independently selected from 0, 1 or 2;

[0160] s2 and s4 are each independently selected from 0 or 1;

[0161] s6 is selected from 0, 1, 2 or 3;

[0162] s7 is selected from 1, 2 or 3;

[0163] The remaining definitions are the same as those of the first embodiment of the present invention.

[0164] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound represented by general formula (I) is selected from general formula (Ia) or general formula (Ib),

[0165] B 3 is selected from N or CH;

[0166] B 4 Selected from CH;

[0167] R b1a , R b1b , R b1d Each is independently selected from methyl, ethyl, propyl, isopropyl or cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl or cyclopropyl is optionally substituted by 1 to 4 deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0168] Or, R b1a With R b1b directly connected to form a 5-membered heterocyclic group containing 0 or 1 double bonds, wherein the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0169] R b1c is selected from H, methyl, ethyl, propyl, isopropyl or cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl or cyclopropyl is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0170] Or, R b1c With R B1 directly connected to form a 5-membered or 6-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0171] R B1 Selected from H, F, Cl, Br, CN, CF 3 , methyl or cyclopropyl;

[0172] R B2 Each is independently selected from H, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furanyl, pyrrolyl is optionally substituted by 1 to 4 deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen-substituted C 1-4 Alkyl, halogen substituted C 3-6 Substituted by a cycloalkyl substituent;

[0173] or R B1 With R B2 Direct connection to form C 6 A carbocyclic group or a 5- to 6-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, halogen substituted C 3-6 Substituted by a cycloalkyl substituent;

[0174] R b2 is selected from F, Cl or Br;

[0175] R b3 is selected from H, deuterium, methoxy, ethoxy, -O-cyclopropyl, wherein the methoxy, ethoxy or cyclopropyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0176] R b4 is selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, ethynyl, phenyl, pyrazolyl or imidazolyl, wherein the methyl, ethyl, ethynyl, phenyl, pyrazolyl or imidazolyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH 2 , CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, deuterated C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, halogen substituted C 3-6 Substituted by a cycloalkyl substituent;

[0177] R b5 Selected from H, deuterium, F, Cl, Br, CN, CF 3 , methyl, ethyl;

[0178] K1 is selected from

[0179] K2 is selected from

[0180] Preferably, K2 is selected from

[0181] 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 );

[0182] Preferably, Q is selected from a bond, NH, N(CH 3 ), O, S, NHC(=O), C(=O)NH, N(CH 3 )C(=O), C(=O)N(CH 3 );

[0183] Preferably, Q is selected from a bond or NH;

[0184] R k1 Each independently selected from deuterium, halogen, OH, NH 2 、CN、COOH、CONH 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 deuterium, halogen, OH, CF 3 、CN、NH 2 , C 1-4 substituted by an alkyl substituent;

[0185] Preferably, R k1 Each independently selected from deuterium, F, Cl, Br, I, OH, NH 2 、CN、COOH、CONH 2 , methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, NH 2substituted by a substituent;

[0186] R L2 , R k2 Each independently selected from deuterium, halogen, OH, CN, NH 2 , =O, C 1-4 Alkyl, -CH 2 -C 3-6 Cycloalkyl, C 3-6 Cycloalkyl, wherein the alkyl or 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;

[0187] Preferably, R L2 , R k2 Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH 2 , =O, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, wherein the methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl 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;

[0188] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0189] As a fourth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound represented by general formula (I) is selected from general formula (Ia) or general formula (Ib)

[0190] B is selected from

[0191] R B2 is selected from cyclopropyl or phenyl, wherein the cyclopropyl or phenyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, CN, CF 3 , methyl or methoxy substituents;

[0192] R by Selected from deuterium, F, Cl, Br, CN, CF 3 , CHF 2 , CH 2F, methyl, methoxy or cyclopropyl;

[0193] R b3 Selected from methoxy, ethoxy, -OCF 3 or-OCD 3 ;

[0194] R b4 Selected from methyl, ethyl or

[0195] R b4a Selected from methyl, ethyl, CF 3 , CHF 2 , CH 2 F.CD 3 , CHD 2 , CH 2 D;

[0196] is a single bond or a double bond;

[0197] Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following groups which are optionally substituted:

[0198]

[0199] When substituted, it is replaced by 1 to 4 atoms selected from deuterium, F, CF 3 , OH, =O, COOH, CN, NH 2 , hydroxymethyl, methyl, methoxy, cyclopropyl;

[0200] m1 is selected from 0, 1, 2 or 3;

[0201] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0202] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound represented by general formula (I) is selected from general formula (Ia) or general formula (Ib),

[0203] B is selected from one of the structural fragments shown in Table B-1;

[0204] L is selected from -Cy1-, -Cy1-CH 2 -、-Cy1-Cy2-、-Cy1-CH 2 -Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH 2-Cy2-Cy3-, -Cy1-Cy2-CH 2 -Cy3-, preferably -Cy1-, -Cy1-CH 2 -、-Cy1-Cy2-CH 2 -, -Cy1-Cy2-;

[0205] Cy1, Cy2, and Cy3 are each independently selected from one of the following optionally substituted groups:

[0206] When substituted, it is replaced by 1 to 4 atoms selected from deuterium, F, CF 3 , OH, =O, COOH, CN, NH 2 , hydroxymethyl, methyl, methoxy, cyclopropyl;

[0207] Preferably, L or L1 are each independently selected from

[0208] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0209] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, the compound represented by general formula (I) is selected from general formula (Ia) or general formula (Ib),

[0210] K1 is selected from one of the structural fragments shown in Table K-1;

[0211] K2 is selected from one of the structural fragments shown in Table K-2;

[0212] The remaining definitions are the same as those of the first, second, third, fourth or fifth embodiment of the present invention.

[0213] The present invention relates to the following compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table E below.

[0214] The present invention relates to a pharmaceutical composition, comprising the above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0215] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals in the preparation of drugs for treating diseases related to EGFR activity or expression.

[0216] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of drugs for treating and inhibiting or degrading EGFR-related diseases.

[0217] In some embodiments, the disease associated with inhibition or degradation of EGFR is cancer, such as lung cancer.

[0218] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, tautomer, deuterated substance, 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 "preparation specification").

[0219] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition. In some embodiments, the mammal of the present invention includes a human.

[0220] "Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition (e.g., cancer) being treated to some extent. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3 -500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg , 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400 mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300- 400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 9 0-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40 -200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1500mg, 80-1000mg, 80-800mg;.

[0221] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1500 mg, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 1 25 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg, 1000 mg of a compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0222] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being cancer such as lung cancer.

[0223] A method for treating a disease in a mammal, the method comprising administering to a subject a drug compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1500 mg / day, the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 2 5-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day, 1500 mg / day.

[0224] The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as its amount in the above-mentioned pharmaceutical composition.

[0225] The amount of the compound of the invention or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0226] In order to accomplish the purpose of the present invention, the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Anage Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

[0227] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0228] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, isotopes of chlorine include 35 Cl and 37 Isotopes of Cl and bromine include 79Br and 81 Br.

[0229] "CN" refers to cyano.

[0230] "Halogen" refers to F, Cl, Br or I.

[0231] "Halogen substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen substituted" is abbreviated as "halo".

[0232] "Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0233] "Alkylene" refers to substituted or unsubstituted straight or branched divalent saturated hydrocarbon groups, including -(CH 2 ) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0234] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms, and the cycloalkyl radical can be a monocyclic, cyclic, bridged, and spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, adamantane, etc. The cycloalkyl radical can be monovalent, divalent, trivalent, or tetravalent.

[0235] "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, including 1 to 3 heteroatoms selected from N, O or S, and the C, N, S on the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocyclic, cyclic, bridged and spirocyclic. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxadiazole, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazininyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,

[0236] The heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

[0237] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least 1, typically 1, 2 or 3 carbon-carbon double bonds, with a main chain including but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl 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 and the like; alkenyl can be monovalent, divalent, trivalent or tetravalent.

[0238] "Alkynyl" refers to a substituted or unsubstituted straight chain and branched unsaturated hydrocarbon group having at least 1, typically 1, 2 or 3 carbon-carbon triple bonds, with a main chain comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms on the main chain and 2 to 4 carbon atoms on 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 and the like; alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0239] "Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0240] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, a 10-15-membered tricyclic ring, or a 12-18-membered quaternary system. The carbocyclyl can be attached to an aromatic ring or a non-aromatic ring, and the ring can be optionally a monocyclic ring, a cyclic ring, a bridged ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

[0241] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, and can be connected to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

[0242] "Spiro" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called spiro atom), and the number of ring atoms in the spiro ring system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 selected from N, O, S (=O) n OrSe(=O) n (n is 0, 1 or 2).

[0243]

[0244] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0245] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to selected from N, S(=O) n 、Se(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:

[0246]

[0247] "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0248] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, which may contain 0 or more double bonds, and any ring in the bridged ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, S(=O)n, Se(=O) n or O, wherein n is 0, 1, 2). The number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10. Non-limiting examples include cubane, adamantane,

[0249]

[0250] A "bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0251] "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0252] "Carbocyclic", "cyclic carbocyclyl", "carbocyclyl" or "carbocyclyl" refers to a "cyclic" ring system consisting of only carbon atoms.

[0253] "Carbobridged ring", "bridged ring carbocyclic group", "bridged carbocyclic group" or "carbon bridged cyclic group" refers to a "bridged ring" wherein the ring system consists of only carbon atoms.

[0254] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle",

[0255] "Heterocyclic ring", "heterocyclic group", "cyclic heterocyclic group" or "cyclic heterocyclic group" refers to a "cyclic ring" containing a heteroatom.

[0256] "Heterospirocycle", "heterospirocyclyl", "spiroheterocyclyl" or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0257] "Heterobridged ring", "heterobridged ring group", "bridged ring heterocyclyl" or "bridged heterocyclyl" refers to a "bridged ring" containing a heteroatom.

[0258] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0259] "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, Se(=O) n , n is 0, 1, 2), the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. The atoms C, N, S, Se on the ring are optionally oxidized (i.e. C(=O), NO, S(=O)n, Se(=O)n, n is 1, 2), non-limiting examples of heteroaryl include but are not limited to pyridyl, furanyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is an 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.

[0260] "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.

[0261] "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 k For example, "1 to 5 substituents selected from ..." means substituted by 1, 2, 3, 4 or 5 substituents selected from ..." For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0262] The XY-membered ring (X, Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes X, X+1, X+2, X+3, X+4...Y-membered rings. The ring includes a heterocyclic ring, a carbocyclic ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocyclic ring, a heterocyclic ring, a heterospirocyclic ring or a heterobridged ring. For example, "4-7-membered heteromonocyclic ring" refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5-10-membered heterocyclic ring" refers to a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heterocyclic ring.

[0263] Cx-y Carbocycles (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, fused carbocycle or bridged carbocycle) include C x , C x+1 , C x+2 , C x+3 , C x+4 …C y A ring of 1-membered ring (x is an integer, and 3≤x<y, y is selected from any integer between 4 and 20), for example. 3-6 "Cycloalkyl" refers to C 3 , C 4 , C 5 or C 6 Cycloalkyl;

[0264] When a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection is non-positional and there are hydrogen atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds and become a group with the corresponding valence. For example It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes

[0265] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0266] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0267] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0268] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0269] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0270] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0271] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, optical isomers, enantiomers, diastereomers and conformational isomers.

[0272] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.

[0273] “IC 50 ” is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of the process such as an enzyme, receptor, cell, etc.) by half.

[0274] Synthesis method 1:

[0275]

[0276] R D1 , R D2 Selected from H or an amine protecting group;

[0277] R D3 is selected from amine protecting groups;

[0278] R D4 Selected from halogen or OTf, OTs, OMs, preferably selected from F, Br, I, OTf;

[0279] R D5 Selected from halogen or OTf, OTs, OMs, preferably from Cl, Br, OTf;

[0280] The definitions of the remaining groups are consistent with the specification;

[0281] The compound of the general formula (D1-1) or the compound of the general formula (D1-2) is subjected to a nucleophilic substitution reaction, or a reductive amination reaction, or a condensation reaction to obtain the compound of the general formula (D1-3); or the compound of the general formula (D1-1) or the compound of the general formula (D1-2) is first subjected to the removal of the amino protecting group, and then subjected to a nucleophilic substitution reaction, or a reductive amination reaction, or a condensation reaction to obtain the compound of the general formula (D1-3);

[0282] The compound of the general formula (D1-3) is firstly deprotected, and then reacted with the compound of the general formula (D1-4) through a nucleophilic substitution reaction or a coupling reaction to obtain the compound of the general formula (D1-5);

[0283] The compound of the general formula (D1-5) is subjected to a reduction reaction to obtain a compound of the general formula (D1-6);

[0284] The compound of the general formula (D1-6) and the compound of the general formula (D1-7) are reacted by a nucleophilic substitution reaction or a coupling reaction to obtain the compound of the general formula (I). DETAILED DESCRIPTION

[0285] The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0286] 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 suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology.

[0287] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were measured in 10 -6 The units of (ppm) are given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 nuclear magnetic spectrometer, and the solvent used was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), the internal standard was tetramethylsilane (TMS);

[0288] MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0289] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0290] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

[0291] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0292] Example 1: Preparation of Compound 1

[0293]

[0294] Step 1: Preparation of 1A

[0295] 2-Nitro-4-bromo-5-fluoroanisole (CAS: 1352244-77-9) (17.37 g, 69.46 mmol) and 4-hydroxymethylpiperidine (8.00 g, 69.46 mmol) were dissolved in DMSO (100 mL), potassium carbonate (28.80 g, 208.38 mmol) was added, and the temperature was raised to 100°C for reaction for 3 h after the addition. The reaction solution was cooled to room temperature, ethyl acetate (200 mL) was added to dilute the reaction solution, washed with water 3 times, washed with saturated sodium chloride once, dried over anhydrous sodium sulfate, and the organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) to obtain 1A (22.00 g, yield: 91%).

[0296] Step 2: Preparation of 1B

[0297] 1A (22.00 g, 63.73 mmol) and 1-methyl-1H-pyrazole-4-boronic acid (12.84 g, 101.97 mmol) were added to a 1L single-mouth bottle, dissolved in 480 mL of dioxane and 80 mL of water, and then [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (5.20 g, 6.37 mmol) and potassium carbonate (17.62 g, 127.46 mmol) were added thereto, nitrogen was replaced three times, and the temperature was raised to 90°C for reaction for 5 h. The temperature was lowered to room temperature, the reaction solution was diluted with 500 mL of ethyl acetate, washed with water three times, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and flash column chromatography (mobile phase: dichloromethane / methanol (V / V) = 15 / 1) was performed to obtain 1B (16.00 g, yield: 72%).

[0298] LCMS m / z=347.1[M+H] +

[0299] Step 3: Preparation of 1C

[0300] 1B (6.50 g, 18.77 mmol) was dissolved in tetrahydrofuran (180 mL), and then zinc powder (12.28 g, 187.7 mmol) and an aqueous solution (30 mL) of ammonium chloride (10.04 g, 187.7 mmol) were added. After the addition, the mixture was reacted at room temperature for 10 min, 5 mL of ammonia water was added, and the mixture was extracted with dichloromethane for 3 times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1C (5.90 g, yield: 99%).

[0301] LCMS m / z=317.2[M+H] +

[0302] Step 4: 1D preparation

[0303] 1C (3.3 g, 10.43 mmol) and 1J (CAS: 2640178-41-0, synthesis reference patent: WO2022228547) (5.0 g, 12.52 mmol) were dissolved in 50 mL of isopropanol, p-toluenesulfonic acid (5.95 g, 31.29 mmol) was added, and the mixture was stirred at 85°C overnight. The solvent was removed by concentration under reduced pressure, 100 mL of ethyl acetate and 30 mL of water were added, and the organic layer was washed once with 20 mL of saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 1 / 1) to obtain 1D (3.5 g, yield: 49%).

[0304] LCMS m / z=680.2[M+H] +

[0305] Step 5: Preparation of 1E

[0306] 1D (1.5 g, 2.2 mmol) was dissolved in 15 mL DMSO, triethylamine (6 mL, 44 mmol) was added, and then pyridine sulfur trioxide (3.5 g, 22 mmol) was added. After the addition was completed, the mixture was stirred at room temperature for 15 min. 20 mL of water and 50 mL of ethyl acetate were added for extraction. The organic phase was washed with 20 mL of saturated brine, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 1 / 20) to obtain 1E (0.5 g, yield: 33%).

[0307] LCMS m / z=678.2[M+H] +

[0308] Step 6: Preparation of 1F

[0309] 2-Bromo-1,3-difluoro-5-iodobenzene (3.00 g, 9.39 mmol) and N-Boc-piperazine (1.75 g, 9.39 mmol) were added to a 500 mL single-necked bottle and dissolved in 30 mL of dioxane. Then, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (0.27 g, 0.47 mmol), tris(dibenzyl-BASE acetone)dipalladium (0.43 g, 0.47 mmol) and cesium carbonate (4.59 g, 14.09 mmol) were added thereto. The atmosphere was replaced with nitrogen three times and the temperature was raised to 90 °C for reaction for 16 h. The reaction solution was cooled to room temperature, diluted with 200 mL of ethyl acetate, the organic phase was washed three times with water and once with saturated sodium chloride, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 4 / 1) to obtain 1F (3.04 g, yield: 85%).

[0310] LCMS m / z=321.0[M-55] +

[0311] Step 7: Preparation of 1G

[0312] 1F (3.50 g, 9.28 mmol) and 2,6-di(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (4.65 g, 11.14 mmol) were dissolved in 1,4-dioxane (60 mL) solution, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.76 g, 0.93 mmol) and cesium carbonate (9.07 g, 27.84 mmol) aqueous solution (6 mL) were added, and stirred at 80°C for 16 h under nitrogen protection. The reaction solution was diluted with 300 mL of ethyl acetate, then washed once with water and once with saturated sodium chloride. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and flash column chromatography (mobile phase: dichloromethane / methanol (V / V=20 / 1)) was performed to obtain 1G (1.34 g, yield: 24%).

[0313] Step 8: Preparation of 1H

[0314] 1G (3.80 g, 6.47 mmol) was dissolved in tetrahydrofuran (60 mL), palladium carbon (3.80 g) was added, and stirred at room temperature for 16 h under hydrogen. The reaction solution was directly filtered through diatomaceous earth to remove palladium carbon, and the filter cake was washed with 200 mL of dichloromethane. The organic phases were combined and concentrated under reduced pressure to obtain 1H (2.63 g, yield: 99%).

[0315] LCMS m / z=354.1[M-55] +

[0316] Step 9: 1I preparation

[0317] 1H (1.30 g, 3.18 mmol) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (30 mL) was added dropwise at room temperature, and stirred at room temperature for 1 h. The reaction solution was directly concentrated under reduced pressure to remove trifluoroacetic acid, and then 100 mL of dichloromethane / methanol (V / V=10 / 1) was added for redissolution, and sodium hydroxide aqueous solution was adjusted to alkalinity, and the organic phase was separated and extracted. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 1I (0.98 g, yield: 99%).

[0318] LCMS m / z=310.2[M+H] +

[0319] Step 10: Preparation of Compound 1

[0320] 1I (23 mg, 0.074 mmol) and 1E (50 mg, 0.074 mmol) were dissolved in 20 mL of dichloromethane, and acetic acid (8.89 mg, 0.15 mmol) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 30 min, and then sodium triacetyl borohydride (31.4 mg, 0.15 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours. 20 mL of saturated sodium bicarbonate aqueous solution and 20 mL of dichloromethane were added for extraction. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 1 / 20) to obtain compound 1 (30 mg, yield: 42%).

[0321] LCMS m / z=486.3[(M+2H) / 2] +

[0322] Example 2: Preparation of Compound 2

[0323]

[0324] Step 1: Preparation of 2A

[0325] 1C (3.0 g, 9.48 mmol) and 2C (CAS: 2640178-43-2, synthesis reference patent: WO2022228547) (4.05 g, 11.38 mmol) were dissolved in 50 mL of isopropanol, p-toluenesulfonic acid (5.41 g, 28.44 mmol) was added, and the mixture was stirred at 85°C overnight. The solvent was removed by concentration under reduced pressure, 100 mL of ethyl acetate and 30 mL of water were added, and the organic layer was washed once with 20 mL of saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 1 / 1) to obtain 2A (3.6 g, yield: 60%).

[0326] LCMS m / z=636.2[M+H] +

[0327] Step 2: Preparation of 2B

[0328] 2A (1.0 g, 1.57 mmol) was dissolved in 15 mL DMSO, triethylamine (4 mL, 31.4 mmol) was added, and then pyridine sulfur trioxide (2.5 g, 15.7 mmol) was added. After the addition was completed, the mixture was stirred at room temperature for 15 min. 20 mL of water and 50 mL of ethyl acetate were added for extraction. The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 1 / 20) to obtain 2B (0.45 g, yield: 45%).

[0329] Step 3: Preparation of Compound 2

[0330] 2B (90 mg, 0.14 mmol) and 1I (43.3 mg, 0.14 mmol) were dissolved in 20 mL of dichloromethane, and acetic acid (16.8 mg, 0.28 mmol) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 30 min, and then sodium triacetyl borohydride (59.34 mg, 0.28 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours. 20 mL of saturated sodium bicarbonate solution and 20 mL of dichloromethane were added for extraction. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 1 / 20) to obtain compound 2 (60 mg, yield: 46%).

[0331] LCMS m / z=927.3[M+H] +

[0332] Example 3: Preparation of Compound 3

[0333]

[0334] Step 1: 3A preparation

[0335] 1C (3.00 g, 9.48 mmol) and compound (4-((5-bromo-2-chloropyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)dimethylphosphine oxide (CAS: 2638535-64-3, synthesis reference patent WO2022228547) (4.14 g, 9.48 mmol) were dissolved in isopropanol (60 mL), and p-toluenesulfonic acid hydrate (5.41 g, 28.44 mmol) was added. After the addition, the temperature was raised to 85 ° C and stirred for 16 hours. The reaction solution was cooled to room temperature, and saturated sodium bicarbonate aqueous solution was added to precipitate a yellow solid. After vacuum filtration, the solid was washed with water three times, and then 100 mL of dichloromethane / methanol (V / V=10 / 1) was added for redissolution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and flash column chromatography (mobile phase: dichloromethane / methanol (V / V=15 / 1)) was performed to obtain 3A (3.86 g, yield: 56%).

[0336] LCMS m / z=716.2[M+H] +

[0337] Step 2: 3B preparation

[0338] 3A (2.00 g, 2.79 mmol) was dissolved in DMSO (50 mL), triethylamine (5.65 g, 55.80 mmol) was added dropwise at room temperature, and sulfur trioxide pyridine (4.44 g, 27.90 mmol) was added, and stirred at room temperature for 0.5 h. 500 mL of ethyl acetate was added to dilute the reaction solution, washed with water 3 times, and washed once with a saturated sodium chloride aqueous solution, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and flash column chromatography (mobile phase: dichloromethane / methanol (V / V=15 / 1)) was performed to obtain 3B (1.44 g, yield: 72%).

[0339] LCMS m / z=357.7[(M+2H) / 2] +

[0340] Step 3: Preparation of Compound 3

[0341] 3B (0.21 g, 0.29 mmol) and 1I (0.09 g, 0.29 mmol) were dissolved in dichloromethane (20 mL), glacial acetic acid (0.035 g, 0.58 mmol) was added dropwise at room temperature, sodium triacetoxyborohydride (0.12 g, 0.58 mmol) was added, and the mixture was stirred at room temperature for 16 h. Sodium bicarbonate aqueous solution was added to adjust the mixture to alkalinity, and the mixture was extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V=15 / 1)) to obtain a crude product, which was further purified by preparative purification to obtain compound 3 (0.13 g, yield: 43%).

[0342] LCMS m / z=1007.3[M+H] +

[0343] Example 4: Preparation of Compound 4

[0344]

[0345] Step 1: 4A preparation

[0346] 1C (3.00 g, 9.48 mmol) and compound (4-((2,5-dichloropyrimidin-4-yl)amino)-[1,1'-biphenyl]-3-yl)dimethylphosphine oxide (CAS: 2638536-74-8, synthesis reference patent WO2022228547) (3.72 g, 9.48 mmol) were dissolved in isopropanol (60 mL), and p-toluenesulfonic acid hydrate (5.41 g, 28.44 mmol) was added. After the addition, the temperature was raised to 85 ° C and stirred for 16 hours. The reaction solution was cooled to room temperature, and saturated sodium bicarbonate aqueous solution was added to precipitate a yellow solid. After vacuum filtration, the solid was washed with water three times, and then 100 mL of dichloromethane / methanol (V / V=10 / 1) was added for redissolution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and flash column chromatography (mobile phase: dichloromethane / methanol (V / V=15 / 1)) was performed to obtain 4A (4.16 g, yield: 65%).

[0347] LCMS m / z=672.2[M+H] +

[0348] Step 2: 4B preparation

[0349] 4A (2.00 g, 2.98 mmol) was dissolved in DMSO (50 mL), triethylamine (6.03 g, 59.60 mmol) was added dropwise at room temperature, and then sulfur trioxide pyridine (4.74 g, 29.80 mmol) was added, and stirred at room temperature for 0.5 h. 500 mL of ethyl acetate was added to dilute the reaction solution, washed with water 3 times, and washed with saturated sodium chloride once, the organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and flash column chromatography (mobile phase: dichloromethane / methanol (V / V=15 / 1)) was performed to obtain 4B (1.54 g, yield: 77%).

[0350] LCMS m / z=670.3[M+H] +

[0351] Step 3: Preparation of Compound 4

[0352] 4B (0.20 g, 0.30 mmol) and 1I (0.093 g, 0.30 mmol) were dissolved in dichloromethane (20 mL), glacial acetic acid (0.036 g, 0.60 mmol) was added dropwise at room temperature, sodium triacetoxyborohydride (0.13 g, 0.60 mmol) was added, and the mixture was stirred at room temperature for 16 h. Sodium bicarbonate aqueous solution was added to adjust the mixture to alkalinity, and dichloromethane was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V=15 / 1)) to obtain a crude product, which was further purified by preparative purification to obtain compound 4 (0.17 g, yield: 57%).

[0353] LCMS m / z=482.3[(M+2H) / 2] +

[0354] Example 5: Preparation of Compound 5

[0355]

[0356] Step 1: Preparation of 5B

[0357] 5A (1.28 g, 3.49 mmol), cesium carbonate (2.27 g, 6.97 mmol), palladium acetate (0.16 g, 0.71 mmol), XANT PHOS (0.20 g, 0.35 mmol), 5A-1 (0.89 g, 4.91 mmol) were added to a dioxane solution (40 mL), and reacted at 105 ° C for 3 h under a nitrogen atmosphere. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (80×3 mL). The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 1 / 3) to obtain 5B (1.30 g, yield: 80%).

[0358] LCMS m / z=468.4[M+H] +

[0359] Step 2: Preparation of 5C

[0360] 5B (1.30 g, 2.78 mmol) was added to methanol (10 mL), palladium carbon (1.33 g, wt% = 10%), ammonium acetate (1.32 g, 17.13 mmol), and the mixture was reacted at room temperature for 12 h under a hydrogen atmosphere. The mixture was filtered through celite, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 1 / 1) to obtain 5C (0.76 g, yield: 90%).

[0361] LCMS m / z=304.4[M+1] +

[0362] Step 3: Preparation of 5E

[0363] 5C (0.76 g, 2.50 mmol), 5D (0.75 g, 7.50 mmol) and N,N-diisopropylethylamine (0.97 g, 7.50 mmol) were added to ethanol (50 mL) in sequence, and the temperature was raised to 100°C for reaction for 36 h. The mixture was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (V / V) = 1 / 20) to obtain 5E (0.70 g, yield: 69%).

[0364] LCMS m / z=404.2[M+H] +

[0365] Step 4: Preparation of 5F

[0366] 5E (700 mg, 1.73 mmol) and N,N-diisopropylethylamine (671 mg, 5.19 mmol) were added to tetrahydrofuran (20 mL), and then triphosgene (565 mg, 1.90 mmol) was slowly added and reacted at room temperature for 1 h. Ammonia water (5 mL) was added, and the temperature was raised to 50 ° C and the reaction was continued for 2 h. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50×2 mL). The organic phase was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (V / V) = 1 / 20) to obtain 5F (700 mg, yield: 90%).

[0367] Step 5: 5G preparation

[0368] 5F (0.70 g, 1.57 mmol) was added to acetonitrile (30 mL), and then 40% benzyltrimethylammonium hydroxide methanol solution (2 mL) was added and the temperature was raised to 60°C for 2 h. Silica gel was added and the mixture was concentrated under reduced pressure. The residue was separated and purified by column chromatography (mobile phase: methanol / dichloromethane (V / V) = 1 / 20) to obtain 5G (530 mg, yield: 84%).

[0369] LCMS m / z=401.4[M+H] +

[0370] Step 6: Preparation of 5H

[0371] 5G (50 mg, 0.12 mmol) was dissolved in dichloromethane (3 mL), trifluoroacetic acid (2 mL) was added, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to remove trifluoroacetic acid, and 5 mL of dichloromethane and 0.2 mL of triethylamine were added, and the mixture was concentrated under reduced pressure to obtain 5H.

[0372] LCMS m / z=301.2[M+H] +

[0373] Step 7: Preparation of compound 5

[0374] 5H (130 mg, 0.44 mmol) and 1E (300 mg, 0.44 mmol) were dissolved in 40 mL of dichloromethane, and acetic acid (52.8 mg, 0.88 mmol) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 30 min, and then sodium triacetyl borohydride (187 mg, 0.88 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours. 20 mL of saturated sodium bicarbonate solution and 30 mL of dichloromethane were added for extraction. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 1 / 20) to obtain compound 5 (130 mg, yield: 31%).

[0375] LCMS m / z=481.7[(M+2H) / 2] +

[0376] Example 6: Preparation of Compound 6

[0377]

[0378] 2B (300 mg, 0.47 mmol) and 5H (140 mg, 0.47 mmol) were dissolved in 40 mL of dichloromethane, and acetic acid (54 mg, 0.94 mmol) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 30 min, and then sodium triacetyl borohydride (199 mg, 0.94 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours. 20 mL of saturated sodium bicarbonate solution and 30 mL of dichloromethane were added for extraction. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 1 / 20) to obtain compound 6 (120 mg, yield: 28%).

[0379] LCMS m / z=459.8[(M+2H) / 2] +

[0380] Example 7: Preparation of Compound 7

[0381]

[0382] Step 1: Preparation of Compound 7

[0383] 3B (0.48 g, 0.67 mmol) and 5H (0.20 g, 0.67 mmol) were dissolved in dichloromethane (20 mL), glacial acetic acid (0.08 g, 1.34 mmol) was added dropwise at room temperature, sodium triacetoxyborohydride (0.28 g, 1.34 mmol) was added, and the mixture was stirred at room temperature for 16 h. Sodium bicarbonate aqueous solution was added to adjust the mixture to alkalinity, and the mixture was extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V=15 / 1)) to obtain a crude product, which was then purified by preparative liquid phase (mobile phase: 0.1% TFA water / acetonitrile) to obtain trifluoroacetate (0.085 g) of compound 7.

[0384] LCMS m / z=499.8[(M+2H) / 2] +

[0385] Example 8: Preparation of Compound 8

[0386]

[0387] Step 1: Preparation of Compound 8

[0388] 4B (0.45 g, 0.67 mmol) and 5H (0.20 g, 0.67 mmol) were dissolved in dichloromethane (20 mL), glacial acetic acid (0.08 g, 1.34 mmol) was added dropwise at room temperature, sodium triacetoxyborohydride (0.28 g, 1.34 mmol) was added, and the mixture was stirred at room temperature for 16 h. Sodium bicarbonate aqueous solution was added to adjust the mixture to alkalinity, and the mixture was extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V=15 / 1)) to obtain a crude product, which was then purified by preparative liquid phase (mobile phase: 0.1% TFA water / acetonitrile) to obtain trifluoroacetate salt of compound 8 (0.135 g).

[0389] LCMS m / z=954.4[M+H] +

[0390] Example 9: Preparation of Compound 9

[0391]

[0392] Step 1: Preparation of compounds 9B-1 and 9B-2

[0393] 9A (2.8 g, 13.58 mmol) (synthesis method, see Bioorganic & Medicinal Chemistry Letters, 2016, 26, 5877-5882) was dissolved in dichloromethane (50 mL), and Boc 2O (5.93 g, 27.17 mmol), DMAP (3.32 g, 27.18 mmol) was added, and the reaction was carried out at room temperature for 16 h. The reaction system was washed with 0.5 mol / L hydrochloric acid (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1-1:9) to obtain the racemate of 9B (3.4 g, yield: 82%).

[0394] The racemate of 9B was subjected to chiral separation, and the chiral separation method was as follows:

[0395] 1. Instrument: SFC Prep 150AP; Chromatographic column: Daicel IC-H (19 mm × 250 mm).

[0396] 2. Dissolve the sample in methanol and filter it with a 0.45 μm filter to prepare a sample solution.

[0397] 3. Preparation of chromatographic conditions: a. The mobile phase consists of A and B system: Mobile phase A: CO 2 ; Mobile phase B: methanol / isopropanol (v / v) = 1:1; b. Isogradient elution, mobile phase B content is 20%; c. Flow rate is 40 mL / min.

[0398] Peak time: chiral isomer 1 (compound 9B-1): 5.7 min, chiral isomer 2 (compound 9B-2): 6.47 min.

[0399] According to MicroED structural determination, compound 9B-1 is of R configuration and compound 9B-2 is of S configuration.

[0400] LCMS m / z=307.3[M+1] +

[0401] Step 2: Preparation of 9C

[0402] 9B-1 (0.45 g, 1.47 mmol) and NBS (0.31 g, 1.74 mmol) were added to acetonitrile (10 mL) and reacted at room temperature for 1 h. The mixture was directly concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: petroleum ether / ethyl acetate (V / V) = 0-50%) to obtain 9C (0.50 g, yield: 88%).

[0403] LCMS m / z=329.1[M-55] +

[0404] Step 3: Preparation of 9D

[0405] Add 9C (0.5g, 1.30mmol), 9K (2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine, 1.36g, 3.26mmol), Pd(dppf)Cl 2 DCM (0.11 g, 0.13 mmol) and cesium carbonate (1.27 g, 3.90 mmol) were added to dioxane (15 mL) and water (3 mL), and reacted at 100°C overnight under a nitrogen atmosphere. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 0-60%) to obtain 9D (0.34 g, yield: 44%).

[0406] Step 4: Preparation of 9E

[0407] 9D (0.34 g, 0.57 mmol) and palladium carbon (10%, 0.49 g) were added to THF (10 mL) and reacted at 35°C overnight under a hydrogen atmosphere. The filtrate was filtered through celite and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V) = 0-10%) to obtain 9E (0.22 g, yield: 92%).

[0408] LCMS m / z=418.2[M+H] +

[0409] Step 5: Preparation of 9F

[0410] 9E (0.22 g, 0.53 mmol) was dissolved in 3 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, and a mixed solvent of dichloromethane / methanol (10:1) (30 mL×5) and a saturated sodium bicarbonate solution (30 mL) were added, and the mixture was stirred to separate layers. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 9F (160 mg, yield 95%).

[0411] Step 6: Preparation of compound 9

[0412] 9F (41 mg, 0.13 mmol) and 1E (90 mg, 0.13 mmol) were dissolved in 10 mL of dichloromethane, and acetic acid (16 mg, 0.26 mmol) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 30 min, and then sodium triacetyl borohydride (55 mg, 0.26 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours. 10 mL of saturated sodium bicarbonate solution and 20 mL of dichloromethane were added for extraction. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 1 / 20) to obtain compound 9 (60 mg, yield: 47%).

[0413] LCMS m / z=979.3[M+H] +

[0414] Example 10: Preparation of Compound 10

[0415]

[0416] 2B (90 mg, 0.14 mmol) and 9F (45 mg, 0.14 mmol) were dissolved in 10 mL of dichloromethane, and acetic acid (17 mg, 0.28 mmol) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 30 min, and then sodium triacetyl borohydride (60 mg, 0.28 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours. 10 mL of saturated sodium bicarbonate solution and 20 mL of dichloromethane were added for extraction. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 1 / 20) to obtain compound 9 (80 mg, yield: 61%).

[0417] LCMS m / z=935.3[M+H] +

[0418] Example 11: Preparation of Compound 11

[0419]

[0420] Step 1: Preparation of 11A

[0421] 9B-2 (1.145 g, 3.74 mmol) and NBS (0.73 g, 4.11 mmol) were added to acetonitrile (30 mL) and reacted at room temperature for 1 h. The reaction solution was diluted with 200 mL of ethyl acetate, washed with water 3 times, and washed with saturated sodium bicarbonate aqueous solution once. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 5 / 1) to obtain 11A (1.30 g, yield: 90%).

[0422] LCMS m / z=329.0[M-55]+

[0423] Step 2: Preparation of 11B

[0424] 11A (1.30 g, 3.37 mmol), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.11 g, 5.05 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.28 g, 0.34 mmol) and cesium carbonate (3.29 g, 10.12 mmol) were added to dioxane (50 mL) and water (5 mL) and reacted at 80 °C overnight under nitrogen atmosphere. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (mobile phase: ethyl acetate / petroleum ether (V / V) = 3 / 1) to obtain 11B (1.75 g, yield: 87%).

[0425] Step 3: Preparation of 11C

[0426] 11B (1.75 g, 2.94 mmol) and palladium carbon (10%, 1.75 g) were added to THF (20 mL) and reacted overnight at 25° C. under a hydrogen atmosphere. The palladium carbon was removed by filtration through celite, the filter cake was washed with 200 mL of dichloromethane, and concentrated under reduced pressure to obtain 11C (1.20 g, yield: 97%).

[0427] LCMS m / z=362.1[M-55] +

[0428] Step 4: Preparation of 11D

[0429] 11C (0.50 g, 1.20 mmol) was dissolved in 15 mL of dichloromethane, and 15 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure, and a mixed solvent of dichloromethane / methanol (10:1) (30 mL×5) and a saturated sodium bicarbonate solution (30 mL) were added, and the mixture was stirred and separated into layers. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 11D (0.38 g, yield 99%).

[0430] LCMS m / z=318.2[M+H] +

[0431] Step 5: Preparation of compound 11

[0432] 1E (0.15 g, 0.22 mmol) and 11D (0.07 g, 0.22 mmol) were dissolved in dichloromethane (20 mL), glacial acetic acid (0.026 g, 0.44 mmol) was added dropwise at room temperature, sodium triacetoxyborohydride (0.093 g, 0.44 mmol) was added, and the mixture was stirred at room temperature for 16 h. Sodium bicarbonate aqueous solution was added to adjust the mixture to alkalinity, and the mixture was extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V=15 / 1)) to obtain a crude product, which was further purified by preparative purification to obtain compound 11 (0.03 g, yield: 13%).

[0433] LCMS m / z=979.3[M+H] +

[0434] Example 12: Preparation of Compound 12

[0435]

[0436] Step 1: Preparation of compound 12

[0437] 2B (0.11 g, 0.27 mmol) and 11D (0.085 g, 0.27 mmol) were dissolved in dichloromethane (20 mL), glacial acetic acid (0.032 g, 0.54 mmol) was added dropwise at room temperature, sodium triacetoxyborohydride (0.114 g, 0.54 mmol) was added, and the mixture was stirred at room temperature for 16 h. Sodium bicarbonate aqueous solution was added to adjust the mixture to alkalinity, and the mixture was extracted with dichloromethane three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V=15 / 1)) to obtain a crude product, which was further purified by preparative purification to obtain compound 12 (0.14 g, yield: 55%).

[0438] LCMS m / z=935.4[M+H] +

[0439] Example 13: Preparation of Compound 13

[0440]

[0441] 3B (150 mg, 0.21 mmol) and 9F (67 mg, 0.21 mmol) were dissolved in 10 mL of dichloromethane, and acetic acid (25 mg, 0.42 mmol) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 30 min, and then sodium triacetyl borohydride (89 mg, 0.42 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours. 10 mL of saturated sodium bicarbonate solution and 20 mL of dichloromethane were added for extraction. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 1 / 20) to obtain compound 13 (150 mg, yield: 70%).

[0442] LCMS m / z=508.2[(M+2H) / 2] +

[0443] Example 14: Preparation of Compound 14

[0444]

[0445] 4B (150 mg, 0.22 mmol) and 9F (70 mg, 0.22 mmol) were dissolved in 10 mL of dichloromethane, and acetic acid (26 mg, 0.44 mmol) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 30 min, and then sodium triacetyl borohydride (93 mg, 0.44 mmol) was slowly added. The mixture was stirred at room temperature for 2 hours. 10 mL of saturated sodium bicarbonate solution and 20 mL of dichloromethane were added for extraction. The organic phase was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase: methanol / dichloromethane (V / V) = 1 / 20) to obtain compound 14 (140 mg, yield: 66%).

[0446] LCMS m / z=486.2[(M+2H) / 2] +

[0447] Example 15: Preparation of Compound 15

[0448]

[0449] Step 1: Preparation of Compound 15

[0450] 3B (0.20 g, 0.28 mmol) and 11D (0.089 g, 0.28 mmol) were dissolved in dichloromethane (20 mL), glacial acetic acid (0.033 g, 0.56 mmol) was added dropwise at room temperature, sodium triacetoxyborohydride (0.119 g, 0.56 mmol) was added, and the mixture was stirred at room temperature for 16 h. Sodium bicarbonate aqueous solution was added to adjust the mixture to alkalinity, and dichloromethane was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V=15 / 1)) to obtain a crude product, which was further purified by preparative purification to obtain compound 15 (0.11 g, yield: 37%).

[0451] LCMS m / z=1015.2[M+H] +

[0452] Example 16: Preparation of Compound 16

[0453]

[0454] Step 1: Preparation of compound 16

[0455] 4B (0.15 g, 0.22 mmol) and 11D (0.07 g, 0.22 mmol) were dissolved in dichloromethane (20 mL), glacial acetic acid (0.026 g, 0.44 mmol) was added dropwise at room temperature, sodium triacetoxyborohydride (0.093 g, 0.44 mmol) was added, and the mixture was stirred at room temperature for 16 h. Sodium bicarbonate aqueous solution was added to adjust the mixture to alkalinity, and dichloromethane was extracted three times. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: dichloromethane / methanol (V / V=15 / 1)) to obtain a crude product, which was further purified by preparative purification to obtain compound 16 (0.11 g, yield: 51%).

[0456] LCMS m / z=971.3[M+H] +

[0457] Biological test cases

[0458] Test Example 1: Proliferation Inhibitory Activity of NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) Cells

[0459] NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells were purchased from ATCC and cultured in RPMI1640 + 10% FBS and DMEM + 10% FBS, respectively. The cells were incubated at 37°C with 5% CO 2Incubate in an incubator. On the first day, collect NCI-H1975 (EGFR-L858R-T790M) and A431 (EGFR-WT) cells in the exponential growth phase, and count the live cells using an automatic cell analyzer (countstar). Adjust the cell suspension with culture medium and plate a 96-well cell culture plate, with 1000 NCI-H1975 (EGFR-L858R-T790M) cells per well and 3000 A431 cells per well. On the second day, remove the culture medium, add 90 μL of fresh culture medium and 10 μL of different concentrations of compounds to each well, and the final concentration of DMSO in each well is 0.1%. Incubate at 37°C, 5% CO 2 After 72 hours of drug treatment, 50 μL of CTG solution (promega, G7572) pre-melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes before measuring the fluorescence signal value with an enzyme reader (PHERAstar FSX).

[0460] The cell viability was calculated using the formula V sample / V vehicle control x100% calculation. Where V sample is the reading of the drug-treated group, V vehicle control The origin9.2 software was used to draw the S-shaped dose-survival rate curve and calculate the IC 50 value.

[0461] Table 1 Results of the proliferation inhibition activity of the test compounds on NCI-H1975 (EGFR-L858R-T790M) cells

[0462] Compound No. <![CDATA[IC 50 (μM)]]> Compound 1 A Compound 2 A Compound 3 A Compound 4 A Compound 5 A Trifluoroacetate salt of compound 7 A Compound 9 A Compound 10 A Compound 11 A Compound 12 A Compound 13 A Compound 14 A Compound 15 A Compound 16 A

[0463] Note: A in Table 1 < 0.2 μM

[0464] Table 2 Results of the proliferation inhibition activity of the test compounds on A431 (EGFR-WT) cells

[0465] Compound No. <![CDATA[IC 50 (μM)]]> Compound 2 C Compound 3 C Compound 4 C Compound 9 C Compound 10 C Compound 13 C Compound 14 C Compound 15 C Compound 16 C

[0466] Note: 10μM≤C in Table 2

[0467] Conclusion: The compounds of the present invention have good proliferation inhibitory activity against NCI-H1975 (EGFR-L858R-T790M) cells; poor proliferation inhibitory activity against A431 (EGFR-WT) cells, and have good selectivity.

Claims

1. A compound or a stereoisomer, 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 -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 substituted by 1 to 2 groups selected from deuterium, halogen, =O, OH, CN, C 1-4 Alkyl or C 3-6 substituted by a cycloalkyl substituent; q is selected from 0, 1, 2 or 3; 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 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 B1 is selected from N or CR B1 ; B2 is selected from N or CR B2 ; B3 is selected from N or CR B3 ; B4 is selected from N or CR B4 ; At most 2 of B1, B2, B3, and B4 are selected from N; R b1 Selected from -P(=O)R b1a R b1b 、-NR b1c S(=O)2R b1d 、-NR b1c S(=O)(=NH)R b1d ; R b1a , R b1b , R b1d Each independently selected from C 1-4 Alkyl or C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; Or, R b1a With R b1b Directly connected to form a 4- to 6-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R b1c Selected from H, C 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; Or, R b1c With R B1 directly connected to form a 4- to 7-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R B1 , R B2 are each independently selected from H, halogen, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -C 0-4 Alkylene-C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, -OC 3-6 Cycloalkyl, -O-4 to 6 membered heterocyclic group, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclic group, heteroaryl group are optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, halogen substituted C 3-6 substituted by a cycloalkyl substituent; or R B1 With R B2 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, halogen substituted C 3-6 substituted by a cycloalkyl substituent; R b2 is selected from halogen; R b3 Selected from H, deuterium, -OC 1-4 Alkyl, -OC 3-6 Cycloalkyl, -O-4 to 6 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R b4 Selected from H, deuterium, halogen, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl, wherein the alkylene, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heteroaryl are optionally substituted by 1 to 4 deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, deuterated C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, halogen substituted C 3-6 substituted by a cycloalkyl substituent; R b5 , R B3 , R B4 are each independently selected from H, deuterium, halogen, CN, C 1-4 Alkyl, C 1-4 Alkoxy or -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy or cycloalkyl is optionally substituted by 1 to 4 deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; K is selected from K1 or K2; K1 is selected from K2 is selected from The ring where the representative is located is an aromatic ring or a non-aromatic ring; F1 is selected from N, NH, CH, CH2, NR k1 , CR k1 , C(R k1 )2; F2 is selected from a bond, N, NH, CH, CH2, CHR k1 NR k1 , CR k1 or C(R k1 )2; F3, F4, F5, F6, F7, F8 are each independently selected from N, C, CH or CR k1 , and F3, F4, and F5 contain at most 2 Ns, and F6, F7, and F8 contain at most 2 Ns; G is selected from CH or N; Y1 is selected from N or CH; Y2 is selected from N, C or CH; Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR q -; Q and G cannot directly form a nitrogen-nitrogen bond or a nitrogen-oxygen bond; R q Select from H or C 1-4 alkyl; R k1 Each independently selected from deuterium, halogen, OH, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 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, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, halogen substituted C 3-6 substituted by a cycloalkyl substituent; R L2 , R k2 Each independently selected from deuterium, halogen, OH, CN, =O, CF3, SF5, NO2, NH2, 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, -C 0-4 Alkylene-4 to 6 membered heterocyclic group, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl group 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; b1 is selected from 0, 1 or 2; p1 is independently selected from 0, 1 or 2; p2 is each independently selected from 0, 1, 2 or 3; p3 and p4 are each independently selected from 0 or 1.

2. The compound according to claim 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) is selected from general formula (Ia) or general formula (Ib) B-L1-K1(Ia)BL-K2(Ib) L1 is selected from -Cy1-, -Cy1-CH2-, -Cy1-Cy2-CH2-, -Cy1-Cy2-, preferably -Cy1-, -Cy1-CH2-; 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.

3. The compound according to claim 2 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B3 is selected from N or CH; B4 is selected from CH; R b1a , R b1b , R b1d Each is independently selected from methyl, ethyl, propyl, isopropyl or cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl or cyclopropyl is optionally substituted by 1 to 4 deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; Or, R b1a With R b1b directly connected to form a 5-membered heterocyclic group containing 0 or 1 double bonds, wherein the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R b1c is selected from H, methyl, ethyl, propyl, isopropyl or cyclopropyl, wherein the methyl, ethyl, propyl, isopropyl or cyclopropyl is optionally substituted by 1 to 4 deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; Or, R b1c With R B1 directly connected to form a 5-membered or 6-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R B1 is selected from H, F, Cl, Br, CN, CF3, methyl or cyclopropyl; R B2 Each is independently selected from H, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furyl, pyrrolyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, furyl, pyrrolyl is optionally substituted by 1 to 4 deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen-substituted C 1-4 Alkyl, halogen substituted C 3-6 substituted by a cycloalkyl substituent; or R B1 With R B2 Directly connected to form a C6 carbocyclic group or a 5- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, halogen-substituted C 1-4 Alkyl, cyano substituted C 1-4 Alkyl, halogen substituted C 3-6 substituted by a cycloalkyl substituent; R b2 is selected from F, Cl or Br; R b3 is selected from H, deuterium, methoxy, ethoxy, -O-cyclopropyl, wherein the methoxy, ethoxy or cyclopropyl is optionally substituted by 1 to 4 groups selected from deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; R b4 is selected from H, deuterium, F, Cl, Br, CN, methyl, ethyl, ethynyl, phenyl, pyrazolyl or imidazolyl, wherein the methyl, ethyl, ethynyl, phenyl, pyrazolyl or imidazolyl is optionally substituted by 1 to 4 deuterium, halogen, OH, NH2, CN, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, deuterated C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, halogen substituted C 3-6 substituted by a cycloalkyl substituent; R b5 Selected from H, deuterium, F, Cl, Br, CN, CF3, methyl, ethyl; K1 is selected from K2 is selected from Preferably, K2 is selected from 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); Preferably, Q is selected from a bond, NH, N(CH3), O, S, NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3); Preferably, Q is selected from a bond or NH; R k1 Each independently selected from deuterium, halogen, OH, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 4 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl are optionally substituted by 1 to 4 deuterium, halogen, OH, CF3, CN, NH2, C 1-4 substituted by an alkyl substituent; Preferably, R k1 Each independently selected from deuterium, F, Cl, Br, I, OH, NH2, 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 L2 , R k2 Each independently selected from deuterium, halogen, OH, CN, NH2, =O, C 1-4 Alkyl, -CH2-C 3-6 Cycloalkyl, C 3-6 Cycloalkyl, wherein the alkyl or 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; Preferably, R L2 , R k2 Each independently selected from deuterium, F, Cl, Br, I, OH, CN, NH2, =O, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, 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; 4. The compound according to claim 3 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B is selected from R B2 is selected from cyclopropyl or phenyl, wherein the cyclopropyl or phenyl is optionally substituted by 1 to 4 substituents selected from deuterium, F, Cl, Br, CN, CF3, methyl or methoxy; R by is selected from deuterium, F, Cl, Br, CN, CF3, CHF2, CH2F, methyl, methoxy or cyclopropyl; R b3 Selected from methoxy, ethoxy, -OCF3 or -OCD3; R b4 Selected from methyl, ethyl or R b4a Selected from methyl, ethyl, CF3, CHF2, CH2F, CD3, CHD2, CH2D; is a single bond or a double bond; Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following groups which are optionally substituted: When substituted, it is substituted by 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl; m1 is selected from 0, 1, 2 or 3.

5. The compound according to claim 4 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B is selected from one of the structural fragments shown in Table B-1; L is selected from -Cy1-, -Cy1-CH2-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-, preferably -Cy1-, -Cy1-CH2-, -Cy1-Cy2-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 or L1 are each independently selected from 6. The compound according to claim 1 or 5, or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: K1 is selected from one of the structural fragments shown in Table K-1; K2 is selected from one of the structural fragments shown in Table K-2.

7. The compound according to claim 1 or its stereoisomer, 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, 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, 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, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition according to claim 8 in the preparation of a drug for treating a disease associated with EGFR activity or expression.

10. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 8 in the preparation of a drug for treating diseases related to the inhibition or degradation of EGFR, preferably cancer such as lung cancer.

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