Benzopyrimidine derivative and application thereof in medicine

Abstract

The invention relates to a benzopyrimidine derivative and application thereof in medicine, in particular to a compound shown in a general formula (I) or a stereoisomer, a racemate, a tautomer, a deuterated compound, a solvate, a prodrug, a metabolite, pharmaceutically acceptable salt or eutectic of the compound, an intermediate of the compound and application of the compound to inhibition or degradation of KRAS related diseases such as cancers. And B-L-K (I).

Description

Technical Field

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

[0002] RAS proteins, expressed by the RAS gene (Rat Sarcoma viral oncogene), are intracellular guanine nucleotide-binding proteins and GTPases (with weak hydrolytic activity). RAS proteins exist in two distinct states: an inactive GDP-bound state and an active GTP-bound state. Activated RAS proteins interact with various downstream effectors to transmit signals, influencing cell growth, differentiation, the cytoskeleton, protein trafficking, and secretion. Activation of RAS signaling is regulated by guanine nucleotide exchange factors (GEFs, which induce GDP-GTP exchange) or GTPase-activating proteins (GAPs, which convert RAS proteins from an activated state to an inactive state). Mutant RAS proteins can become resistant to GAPs, resulting in a persistently activated RAS protein state, leading to uncontrolled cell growth and, ultimately, the development of cancerous tissue (Molecular Cancer, 2018, 17:33).

[0003] RAS gene mutations are common in cancer patients (Nat. Rev. Drug Discov. 2014, 13, 828-851). For example, RAS mutations account for 97.7% of pancreatic cancer, 52.2% of colorectal cancer, 42.6% of multiple myeloma, and 32.2% of non-small cell lung cancer (NSLC), respectively. KRAS (Kristen Rat Sarcoma viral oncogene) mutations are the most common RAS mutations, accounting for 86% of all RAS mutations. KRAS gene activation is most commonly achieved through point mutations, with 95% of KRAS mutations occurring at codons 12 and 13 of exon 2. Common mutations include KRAS G12C (39%), KRAS G12V (18-21%), and KRAS G12D (17-18%).

[0004] Since the discovery of KRAS mutants in cancer and the observation that their inhibition can suppress tumor growth, inhibitors of KRAS mutants have garnered widespread attention. KRAS has long been considered an undruggable target: RAS has a very high affinity for GTP / GDP (picomolar levels) and lacks a ligand-binding pocket (Clin. Cancer Res. 2015, 21, 1810–1818). KRAS G12D accounts for 36% of pancreatic cancer patients, 12% of colon cancer patients, 4% of NSCLC adenocarcinoma patients, and 6% of endometrial cancer patients. By organ and tissue classification, KRAS cancers are most prevalent in colon, pancreatic, and lung adenocarcinomas. By mutation type, G12D is the most common, followed by G12V. G12C, which has been initially investigated, ranks third, G13D fourth, and amplification (AMP) fifth. G12D and G12V account for a high proportion in colon cancer and pancreatic cancer, and G12C accounts for a high proportion in lung adenocarcinoma.

[0005] PROTAC (proteolysis targeting chimera) molecules are a class of bifunctional compounds that can simultaneously bind to target proteins and E3 ubiquitin ligases. These compounds can be recognized by the cell's proteasome, causing degradation of the target protein and effectively reducing the target protein's content in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology has become possible for the treatment of various diseases. This technology has also received widespread attention in recent years.

[0006] Therefore, it is necessary to develop a compound that can inhibit or degrade KRAS protein for the treatment of diseases caused by KRAS mutations. Summary of the Invention

[0007] The purpose of the present invention is to provide a compound with novel structure, good efficacy, high bioavailability, greater safety, and the ability to inhibit or degrade KRAS, for the treatment of KRAS-related diseases such as autoimmune diseases, inflammatory diseases or cancer.

[0008] The present invention provides a compound or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the compound represented by general formula (I),

[0009] BLK(I);

[0010] In some embodiments, L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl group are optionally replaced by -Ak- or -Cy-;

[0011] In some embodiments, L is selected from a bond or -C 1-20 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl group are optionally replaced by -Ak- or -Cy-;

[0012] In some embodiments, each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-NR L (CH2) q C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L )2-、-Si(OH)(R L )-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, wherein the CH, -CH2- is optionally replaced by 1 to 2 R z replace;

[0013] In some embodiments, q is each independently selected from 0, 1, 2, 3, 4, 5, or 6;

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

[0015] In some embodiments, R L Selected from H, C 1-4 Alkyl, C 3-7 Carbocyclic group, 4 to 10 membered heterocyclic group, said alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0016] In some embodiments, each -Cy- is independently selected from a bond or optionally substituted by 1 to 4 R L2One of the following substituted groups: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, 10-16 membered heterotricyclic group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, 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-Ak-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 -Ak1-Cy1-Ak2-, -Ak1-Cy1-Ak2-Cy2-, -Ak1-Cy1-Ak2-Cy2-Ak3-, -Ak1-Cy1--Cy2-, -Cy1-Ak2-Cy2-, -Cy1-Ak2-Cy2-Cy3-, -Ak1-Cy1-Cy2-Ak3-;

[0025] In certain embodiments, L is selected from -O-CH2-Cy1-C(=O)-, -O-CH2-Cy1-C(=O)-Cy2-, -O-CH2-Cy1-C(=O)-Cy2-CH2-, -O-CH2-Cy1-CH2-, -O-CH2-Cy1-Cy2-, -Cy1-O-Cy2-, -Cy1-O-Cy2-, -Cy1-O-Cy2-Cy3-, -O-CH2-Cy1-Cy2-CH2-, -O-CH2-Cy1-CH2-Cy2-CH2-;

[0026] In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, and Ak9 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 bond, wherein the -CH2- is optionally replaced by 1 to 2 Rz replace;

[0027] In certain embodiments, Ak1, Ak2, Ak3, Ak4, Ak5, Ak6, Ak7, Ak8, Ak9 are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH-, or -NHC(=O)-;

[0028] In certain embodiments, Ak1, Ak2, and Ak3 are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH-, or -NHC(=O)-;

[0029] In certain embodiments, R L Selected from H or C 1-4 alkyl;

[0030] In certain embodiments, R L Selected from H, methyl or ethyl;

[0031] 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, 10-16 membered heterotricyclic group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 7-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl;

[0032] In certain embodiments, Cy5 is defined the same as Cy1;

[0033] In certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl,

[0034] s1, s3, and 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, and s7 is selected from 1, 2, or 3;

[0035] In certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following optionally substituted groups:

[0036]

[0037] When substituted, it is substituted by 1 to 4 substituents selected from deuterium, F, CF3, OH, methyl, =O, hydroxymethyl, methoxy, COOH, CN or NH2, cyclopropyl;

[0038] In certain embodiments, Cy1, Cy2, and Cy3 are each independently selected from the group consisting of:

[0039] In certain embodiments, B is selected from

[0040] In certain embodiments, B is selected from

[0041] In certain embodiments, B is selected from one of the structural fragments shown in Table B-1;

[0042] In certain embodiments, X is selected from CH or N;

[0043] In certain embodiments, Ring B1 is selected from C 3-10 Carbocyclic group or 4-10 membered heterocyclic group, wherein the ring B1 is optionally substituted by 1 to 4 R b1 replace;

[0044] In certain embodiments, Ring B1 is selected from C 3-6 A carbocyclic group or a 4-6 membered heterocyclic group, wherein the ring B1 is optionally substituted by 1 to 4 R b1 replace;

[0045] In certain embodiments, Ring B1 is selected from C 3-6 Cycloalkyl or 4-6 membered heterocycloalkyl, the ring B1 is optionally substituted by 1 to 4 R b1 replace;

[0046] In certain embodiments, ring B1 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, oxetanyl, and the ring B1 is optionally substituted by 1 to 4 R b1 replace;

[0047] In certain embodiments, Ring B1 is selected from

[0048] In certain embodiments, B4 is selected from C 6-10 aryl or 5 to 10 membered heteroaryl, said B4 is optionally substituted by 1 to 4 R b4 replace;

[0049] B4 is selected from The B4 is optionally replaced by 1 to 4 R b4 replace;

[0050] In certain embodiments, B4 is selected from

[0051] In certain embodiments, R b1 、R b3 or R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace;

[0052] In certain embodiments, R b1 、R b3 or R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace;

[0053] In certain embodiments, R b1 、R b3 or R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2 or optionally substituted by 1 to 4 R z substituted methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0054] In certain embodiments, R b1 、R b3 or R b4 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, NH2, COOH, CONH2, methyl, ethyl, cyclopropyl, methoxy, CF3, CHF2;

[0055] In certain embodiments, R b2 Selected from H, deuterium, C 1-6 Alkyl, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace;

[0056] In certain embodiments, R b2 Selected from H, deuterium, C 1-4 Alkyl, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace;

[0057] In certain embodiments, R b2 Selected from H, deuterium or optionally 1 to 4 R z substituted methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0058] In certain embodiments, R b2 Selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, CD3,

[0059] In certain embodiments, m is selected from 0, 1 or 2;

[0060] In certain embodiments, K is selected from

[0061] In certain embodiments, K is selected from

[0062] In certain embodiments, G is selected from N or CH;

[0063] In certain embodiments, each Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR q -;

[0064] In certain embodiments, Q and G cannot directly form a nitrogen-nitrogen bond, a nitrogen-oxygen bond, or a nitrogen-sulfur bond;

[0065] In certain embodiments, each Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR q -;

[0066] In certain embodiments, 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);

[0067] In certain embodiments, Q is selected from a bond, NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3);

[0068] In certain embodiments, Q is selected from a bond, NH, C(=O)NH;

[0069] In certain embodiments, R q Selected from H or C 1-4 alkyl;

[0070] In certain embodiments, R q Selected from H or methyl;

[0071] In certain embodiments, each F is independently selected from 5-6 membered heteroaryl, C 13-20 Carbocyclic group, 13-20 membered heterocyclic group,

[0072] In certain embodiments, each F is independently selected from a 6-membered heteroaryl, a 13-15 membered tricyclic heterocyclyl,

[0073] In certain embodiments, F is selected from Pyridyl, pyrimidinyl, The ring where the representative is located is an aromatic ring or a non-aromatic ring;

[0074] In certain embodiments, F is selected from Pyridyl, pyrimidinyl, The ring where the representative is located is an aromatic ring or a non-aromatic ring;

[0075] In certain embodiments, ring E is selected from phenyl or 5-6 membered heteroaryl;

[0076] In certain embodiments, ring E is selected from phenyl or 6-membered heteroaryl;

[0077] In certain embodiments, Ring E is selected from phenyl or pyridinyl;

[0078] In certain embodiments, ring E is selected from phenyl;

[0079] In certain embodiments, H1 is selected from N, NH, CH, CH2, CHR k1 NR k1 , CR k1 、C(=O)、C(R k1 )2;

[0080] In certain embodiments, H1 is selected from N, NH, CH, CH2, CHR k1 NR k1 , CR k1 , C(=O);

[0081] In certain embodiments, H2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 NR k1 、C(=O)、CR k1 or C(R k1 )2;

[0082] In certain embodiments, H2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 NR k1 , CR k1 , C(=O);

[0083] In certain embodiments, H3 is selected from N or CH;

[0084] In certain embodiments, H4 is selected from C, N, or CH;

[0085] In certain embodiments, H4 is selected from N;

[0086] In certain embodiments, H5, H6, and H7 are each independently selected from N, CH, or CR. k1 , and H5, H6, and H7 contain at most 2 Ns;

[0087] In certain embodiments, H5 or H6 is selected from N or CRk1 ;

[0088] In certain embodiments, R k1 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace;

[0089] In certain embodiments, R k1 Each independently selected from F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 or R k5 ;

[0090] In certain embodiments, R k1 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace;

[0091] In certain embodiments, R k1 、R k3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2 or optionally substituted by 1 to 4 R z Substituted groups such as: methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0092] In certain embodiments, R k1 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl, CD3,

[0093] In certain embodiments, R k1Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0094] In certain embodiments, R k2 Each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-;

[0095] In certain embodiments, R k2 are each independently selected from -C(=O)-;

[0096] In certain embodiments, R k3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 groups selected from R z replace;

[0097] In certain embodiments, R k3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 groups selected from R z replace;

[0098] In certain embodiments, R k3 are each independently selected from H, deuterium;

[0099] In certain embodiments, both R k1 Direct connection to form C 3-8 Carbocyclic or 4-8 membered heterocyclic, said carbocyclic or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace;

[0100] In certain embodiments, both R k1 Direct connection to form C 3-6 Carbocyclic or 4-6 membered heterocyclic, said carbocyclic or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace;

[0101] In certain embodiments, both R k3 Direct connection to form C3-8 Carbocyclic or 4-8 membered heterocyclic, said carbocyclic or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace;

[0102] In certain embodiments, in certain embodiments, both R k3 Direct connection to form C 3-6 Carbocyclic or 4-6 membered heterocyclic, said carbocyclic or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace;

[0103] In certain embodiments, R L2 、R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, -C 0-4 Alkylene-C 4-10 Heterocycloalkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl 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;

[0104] In certain embodiments, R L2 、R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-2 Alkylene-C 4-6 Heterocycloalkyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C1-4 substituted by an alkoxy substituent;

[0105] In certain embodiments, R L2 、R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0106] In certain embodiments, n1 is selected from 0, 1, 2 or 3;

[0107] In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2, 3, 4, or 5;

[0108] In certain embodiments, p1 or p2 are each independently selected from 0, 1, 2 or 3;

[0109] In certain embodiments, L is selected from a bond or a group shown in Table L-1, wherein the left side of the group is connected to B;

[0110] Table L-1L Group

[0111]

[0112]

[0113] In certain embodiments, B is selected from one of the structural fragments shown in B-1;

[0114] Table B-1

[0115]

[0116]

[0117] In certain embodiments, K is selected from one of the structural fragments shown in Table K-1;

[0118] In certain embodiments, K is selected from one of the structural fragments shown in Table K-2;

[0119] In certain embodiments, K is selected from one of the structural fragments shown in Table K-1 or K-2;

[0120] Table K-1

[0121]

[0122]

[0123] Table K-2

[0124]

[0125]

[0126]

[0127]

[0128] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0129] L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl group are optionally replaced by -Ak- or -Cy-;

[0130] Each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-NR L (CH2) q C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L )2-、-Si(OH)(R L)-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, wherein the CH, -CH2- is optionally replaced by 1 to 2 R z replace;

[0131] q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0132] R L Selected from H, C 1-4 Alkyl, C 3-7 Carbocyclic group, 4 to 10 membered heterocyclic group, said alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0133] Each -Cy- is independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, 10-16 membered heterotricyclic group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl;

[0134] B is selected from

[0135] X is selected from CH or N;

[0136] Ring B1 is selected from C 3-10 Carbocyclic group or 4-10 membered heterocyclic group, wherein the ring B1 is optionally substituted by 1 to 4 R b1 replace;

[0137] B4 is selected from C 6-10 aryl or 5 to 10 membered heteroaryl, said B4 is optionally substituted by 1 to 4 R b4 replace;

[0138] R b1 、R b3 or R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace;

[0139] R b2 Selected from H, deuterium, C 1-6 Alkyl, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace;

[0140] m is selected from 0, 1 or 2;

[0141] K is selected from

[0142] G is selected from N or CH;

[0143] Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR q -;

[0144] Q and G cannot directly form nitrogen-nitrogen bonds, nitrogen-oxygen bonds, or nitrogen-sulfur bonds;

[0145] R q Selected from H or C 1-4 alkyl;

[0146] F are each independently selected from 5-6 membered heteroaryl, C 13-20 Carbocyclic group, 13-20 membered heterocyclic group,

[0147] Ring E is selected from phenyl or 5-6 membered heteroaryl;

[0148] R k1 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace;

[0149] R k2 Each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-;

[0150] Rk3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 groups selected from R z replace;

[0151] Alternatively, two R k1 Direct connection to form C 3-8 Carbocyclic or 4-8 membered heterocyclic, said carbocyclic or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace;

[0152] Alternatively, two R k3 Direct connection to form C 3-8 Carbocyclic or 4-8 membered heterocyclic, said carbocyclic or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace;

[0153] R L2 、R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, -C 0-4 Alkylene-C 4-10 Heterocycloalkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl 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;

[0154] n1 is selected from 0, 1, 2 or 3;

[0155] p1 and p2 are each independently selected from 0, 1, 2, 3, 4 or 5.

[0156] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0157] L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0158] 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 bond, wherein the -CH2- is optionally replaced by 1 to 2 R z replace;

[0159] R L Each independently selected from H or C 1-4 alkyl;

[0160] Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, 10-16 membered heterotricyclic group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl;

[0161] Ring B1 is selected from C 3-6 A carbocyclic group or a 4-6 membered heterocyclic group, wherein the ring B1 is optionally substituted by 1 to 4 R b1 replace;

[0162] B4 is selected from The B4 is optionally replaced by 1 to 4 R b4 replace;

[0163] R b1 、R b3 or R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace;

[0164] R b2 Selected from H, deuterium, C 1-4 Alkyl, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace;

[0165] F is independently selected from 6-membered heteroaryl, 13-15-membered tricyclic heterocyclic group,

[0166] Ring E is selected from phenyl or 6-membered heteroaryl;

[0167] R k1 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace;

[0168] R k3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 groups selected from R z replace;

[0169] R L2 、R zEach independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-2 Alkylene-C 4-6 Heterocycloalkyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl 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;

[0170] The remaining definitions are the same as those of the first embodiment of the present invention.

[0171] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0172] R L Selected from H, methyl or ethyl;

[0173] Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl,

[0174] s1, s3, and s5 are each independently selected from 0, 1, or 2;

[0175] s2 and s4 are each independently selected from 0 or 1;

[0176] s6 is selected from 0, 1, 2 or 3;

[0177] s7 is selected from 1, 2 or 3;

[0178] F is selected from pyridyl, pyrimidinyl;

[0179] The ring where the representative is located is an aromatic ring or a non-aromatic ring;

[0180] H1 is selected from N, NH, CH, CH2, CHR k1 NR k1 , CR k1 、C(=O)、C(R k1 )2;

[0181] H2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 NR k1 、C(=O)、CR k1 or C(R k1 )2;

[0182] H3 is selected from N or CH;

[0183] H4 is selected from C, N or CH;

[0184] H5, H6, and H7 are each independently selected from N, CH, or CR k1 , and H5, H6, and H7 contain at most 2 Ns;

[0185] Ring E is selected from phenyl or pyridyl;

[0186] 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);

[0187] R k1 、R k3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2 or optionally substituted by 1 to 4 R z Substituted groups such as: methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0188] R b1 、R b3 or R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2 or optionally substituted by 1 to 4 R z substituted methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0189] R b2 Selected from H, deuterium or optionally 1 to 4 R z substituted methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0190] R L2 、R zEach independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0191] p1 or p2 are each independently selected from 0, 1, 2 or 3;

[0192] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0193] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0194] Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -C(CH3)2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

[0195] Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl;

[0196] K is selected from

[0197] Q is selected from a bond, NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3);

[0198] G is selected from CH or N;

[0199] H1 is selected from N, NH, CH, CH2, CHR k1 NR k1 , CR k1 , C(=O);

[0200] H2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 NR k1 , CR k1 , C(=O);

[0201] H5 or H6 is selected from N or CR k1 ;

[0202] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0203] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

[0204] R b2 Selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, CD3,

[0205] R b1 、R b3 or R b4 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, NH2, COOH, CONH2, methyl, ethyl, cyclopropyl, methoxy, CF3, CHF2;

[0206] L is selected from -O-CH2-Cy1-C(=O)-, -O-CH2-Cy1-C(=O)-Cy2-, -O-CH2-Cy1-C(=O)-Cy2-CH2-, -O-CH2-Cy1-CH2-, - O-CH2-Cy1-Cy2-, -Cy1-O-Cy2-, -Cy1-O-Cy2-Cy3-, -O-CH2-Cy1-Cy2-CH2-, -O-CH2-Cy1-CH2-Cy2-CH2-;

[0207] R k1Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[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, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein,

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

[0211] L is selected from a bond or one of the structural fragments shown in Table L-1;

[0212] K is selected from one of the structural fragments shown in Table K-1 or Table K-2.

[0213] As a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound represented by general formula (I) is selected from the compound represented by general formula (II-1) or general formula (II-2),

[0214]

[0215] R b1 、R b2 、R b3 、R b4 、R k1 The definitions of Cy2, Ak3, and G are the same as those of any one of the first, second, third, fourth, or fifth types of the present invention.

[0216] As an eighth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

[0217] G is selected from CH or N;

[0218] R b2 Selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, CD3,

[0219] R b1 、R b3 or R b4Each is independently selected from H, deuterium, F, Cl, Br, I, CN, NH2, COOH, CONH2, methyl, ethyl, cyclopropyl, methoxy, CF3, CHF2;

[0220] R k1 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, cyclopropyl;

[0221] Cy2 is each independently selected from a bond or one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl;

[0222] Ak3 is selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -C(CH3)2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH- or -NHC(=O)-;

[0223] Cy2 is preferably a bond,

[0224] Ak3 is preferably a bond or CH2;

[0225] -Cy2-AK3- is preferably a bond or

[0226] The present invention relates to the following compound or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table E.

[0227] The present invention relates to a pharmaceutical composition comprising the above-mentioned compound of the present invention or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0228] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a drug for treating diseases related to KRAS activity or expression.

[0229] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a drug for treating, inhibiting or degrading KRAS-related diseases.

[0230] In some embodiments, the disease associated with inhibition or degradation of KRAS is cancer.

[0231] The present invention relates to a pharmaceutical composition or pharmaceutical preparation comprising a therapeutically effective amount of a compound of the present invention, or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof, and a pharmaceutically acceptable excipient. The pharmaceutical composition may be in the form of a unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as the "drug strength").

[0232] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention, or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, cocrystal, or pharmaceutical composition thereof. In some embodiments, the mammal of the present invention comprises a human.

[0233] As used herein, an "effective amount" or "therapeutically effective amount" refers to administering a sufficient amount of a compound disclosed herein to alleviate, to some extent, one or more symptoms of the disease or condition being treated (e.g., cancer). In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired 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;.

[0234] 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, 125 or 1000 mg of a compound of the present invention or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0235] A method for treating a disease in a mammal, comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the therapeutically effective amount is preferably 1-1500 mg, and the disease is preferably cancer.

[0236] A method for treating a disease in a mammal, comprising administering to a subject a compound of the present invention or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or cocrystal thereof at a daily dose of 1-1500 mg / day. The daily dose may be a single dose or divided doses. In some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-1000 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day. , 25-400 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.

[0237] The present invention relates to a kit, which may include a composition in single-dose or multi-dose form, wherein the kit contains a compound of the present invention or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as the amount in the above-mentioned pharmaceutical composition.

[0238] The amount of the compound of the invention or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0239] To accomplish the purposes 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 Macklin Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., Tokyo Chemical Industry Development Co., Ltd., Anage Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, J&K Technology Co., Ltd., etc.

[0240] General synthesis method 1:

[0241]

[0242] Compound Z-1 of the general formula is prepared through coupling, reductive amination or nucleophilic substitution to obtain compound Z-2 of the general formula;

[0243] After removing the amino protecting group from the compound of general formula Z-2, the compound of general formula Z-3 is prepared;

[0244] Referring to the synthesis method of patent WO2024034593, compound Z-4 of the general formula can be prepared;

[0245] The general formula compound Z-4 is reacted with the general formula compound Z-3 through condensation reaction to prepare the general formula compound Z.

[0246] Rm1 is selected from amino protecting groups such as Boc, Cbz, and SEM.

[0247] Ring M is selected from 4-10 membered nitrogen-containing heterocyclic groups.

[0248] The remaining definitions are as above.

[0249] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0250] 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 isotopes of carbon include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl, bromine include 79 Br and 81 Br.

[0251] "CN" refers to cyano.

[0252] "Halogen" refers to F, Cl, Br or I.

[0253] "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".

[0254] "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.

[0255] "Heteroalkyl" refers to a substituted or unsubstituted alkyl group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X-(CH2)vX-(CH2)vX-(CH2)vH (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom, including but not limited to N, O or S, and at least one X is selected from a heteroatom, and the N or S in the heteroatom can be oxidized to various oxidation states). The heteroalkyl group can be monovalent, divalent, trivalent or tetravalent.

[0256] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0257] "Heteroalkylene" refers to a substituted or unsubstituted alkylene group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S). Non-limiting examples include -X-(CH2)vX-(CH2)vX-(CH2)v-, where v is an integer from 1 to 5, each X is independently selected from a bond, N, O or S, and at least one X is selected from N, O or S.

[0258] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, and adamantane. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0259] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon radical containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, comprising 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 ring. Heterocycloalkyl can be connected to a heteroatom or carbon atom, and non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl, The heterocycloalkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0260] "Alkenyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-methyl-4-butenyl, 2-methyl-5-butenyl, 2-methyl-6-butenyl, 2-methyl-7-butenyl, 2-methyl-8-butenyl, 2-methyl-9-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3 ... -methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent or tetravalent.

[0261] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, and 2 to 4 carbon atoms in the backbone. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-pentynyl, 14-pentynyl, 15-pentynyl, 16-pentynyl, 17-pentynyl, 18-pentynyl, 19-pentynyl, 20-pentynyl, 21-pentynyl, 22-pentynyl, 23-pentynyl, 24-pentynyl, 25-pentynyl, 26-pentynyl, 27-pentynyl, 28-pentynyl, 29-pentynyl, 30-pentynyl, 31-pentynyl, 32-pentynyl, 33-pentynyl, 34-pentynyl, 35-pentynyl, 36-pentynyl, 37-pentynyl, 38-pentynyl, 39-pentynyl, 40-pentynyl, 41-pentynyl, 42-pentynyl, 43-pentynyl, 44-pentynyl, 45-pentynyl, 46-pentynyl, 47-pentynyl, 48-pentyn Alkynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, and the like; an alkynyl group may be monovalent, divalent, trivalent, or tetravalent.

[0262] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0263] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocycle, a 4-12 membered bicycle, a 10-15 membered tricycle, or a 12-18 membered quaternary system. The carbocyclyl can be attached to the aromatic or non-aromatic ring, and the ring can be optionally a monocycle, a cyclic ring, a bridged ring, or a spirocycle. 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, a benzene ring, a naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent, or tetravalent.

[0264] "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 one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S optionally substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached to an aromatic 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-dioxolane, 1,4-dioxolane, 1,3-dioxane, azepanyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithiazyl, 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]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl,

[0265] "Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.

[0266] "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted rings share one atom (called a spiro atom), and the number of ring atoms in the spirocycle 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 atoms selected from N, O, S (=O) n OrSe(=O) n (n is 0, 1 or 2).

[0267]

[0268] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0269] "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 N, S(=O) n 、Se(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the cyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:

[0270]

[0271] "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0272] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in the bridged ring system may contain zero to five 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,

[0273]

[0274] A "bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent, or tetravalent.

[0275] "Carbospirocycle," "spirocarbocyclyl," "spirocarbocyclyl," or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0276] "Carbocyclyl," "carbocyclyl," "carbocyclyl," or "carbocyclyl" refers to a "carbocyclyl" ring system consisting of only carbon atoms.

[0277] "Carbobridged ring," "bridged carbocyclic group," "bridged carbocyclic group," or "carbon-bridged cyclic group" refers to a "bridged ring" in which the ring system consists of only carbon atoms.

[0278] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle".

[0279] "Heterocyclo", "heterocycloalkyl", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

[0280] "Heterospirocycle," "heterospirocyclyl," "spiroheterocyclyl," or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0281] "Heterobridged ring", "heterobridged cyclic group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing a heteroatom.

[0282] "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.

[0283] "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, and Se on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, n is 1, 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring. Non-limiting examples include When heteroaryl appears in this document, its definition is consistent with this definition. Heteroaryl can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment point is located on the ring with aromaticity.

[0284] "Substituted" or "substituted" refers to substitution 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, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2), m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c etc., where R b With R c R is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, b With R c Can form five or six-membered cycloalkyl or heterocyclic group, R a With R dEach is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or paracyclic group.

[0285] "1 to X substituents selected from ... substituted" 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 Substitution. For example, "substituted by 1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4, or 5 substituents selected from..." For example, "a 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.

[0286] XY-membered rings (X and Y are integers, and 3≤X<Y, X<Y≤20 are selected from any integer between 4 and 20) include rings with X, X+1, X+2, X+3, X+4, ..., Y members. Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7-membered heteromonocyclic ring" refers to a 4-, 5-, 6-, or 7-membered heteromonocyclic ring, and "5-10-membered heterocyclic ring" refers to a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclic ring.

[0287] C x-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 C3, C4, C5 or C6 cycloalkyl;

[0288] When a group has one or more bondable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are hydrogen atoms at the bondable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected, and the group will become a group with the corresponding valence. For example Indicates that any linkable site on the piperidinyl group can be connected to other groups through a 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

[0289] 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 the reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0290] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs and instances where it does not. For example, "alkyl optionally substituted with F" means that the alkyl group may but need not be substituted with F, and the description includes instances where the alkyl group is substituted with F and instances where the alkyl group is not substituted with F.

[0291] "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, or the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0292] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, racemates, 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.

[0293] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0294] "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.

[0295] "Prodrugs" refer to compounds of the present invention that can be converted into biologically active compounds through in vivo metabolism. Prodrugs of the present invention are prepared by modifying amino or carboxyl groups in compounds of the present invention. These modifications can be removed by conventional manipulation or in vivo to yield the parent compound. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.

[0296] A "cocrystal" is a crystal formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) bound together by hydrogen bonds or other non-covalent bonds. Both the API and CCF are solid in their pure form at room temperature, and the components exist in a fixed stoichiometric ratio. A cocrystal is a multi-component crystal, encompassing both binary cocrystals formed between two neutral solids and multi-component cocrystals formed between a neutral solid and a salt or solvate.

[0297] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0298] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0299] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomers and amide-imino alcohol isomers. DETAILED DESCRIPTION

[0300] The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0301] The * next to a chemical bond indicates a single configuration with either R or S axial chirality.

[0302] Synthesis of intermediate 1B

[0303]

[0304] Step 1: Synthesis of compound 1B

[0305] Compound 1A (19 g, 23.37 mmol) was dissolved in 300 mL of DCM, and m-chloroperbenzoic acid (12.1 g, 70.11 mmol) was slowly added under ice-bath conditions. The mixture was stirred for 2 hours under nitrogen protection. Sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution were added under ice-bath conditions, and the mixture was stirred at room temperature for 30 minutes. The reaction was extracted with EA, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the target compound 1B (18 g, 91.15%). Chiral SFC detection revealed that the isomers in compound 1B were 1B-P1:1B-P2 = 1:3. SFC separation yielded 1B-P1 (3.2 g, yield: 16%; chiral SFC retention time: 1.971 min) and 1B-P2 (10.4 g, yield: 52.7%; chiral SFC retention time: 2.107 min). When the structure of 1B-P1 was 1B-A, the structure of 1B-P2 was 1B-B; conversely, when the structure of 1B-P1 was 1B-B, the structure of 1B-P2 was 1B-A.

[0306] Chiral SFC analysis method: Instrument: SHIMADZU LC-30AD SFC; Column: Chiral IK column; Mobile phase: A: CO2; B: 0.05% diethylamine in methanol; Elution conditions: Gradient elution from 5% to 40% B; Flow rate: 3 mL / min; Column pressure: 100 bar; Column temperature: 35°C; Detection wavelength: 220 nm.

[0307] SFC preparative separation method: Instrument: Waters 150Prep-SFC; Chromatographic column: Chiral IK column; Mobile phase: A is CO2; B is a methanol solution with 0.05% ammonia; Elution conditions: 30% B isocratic elution; Flow rate: 100 mL / min; Column pressure: 100 bar; Column temperature: room temperature; Detection wavelength: 220 nm. Sample preparation: The sample was prepared as a 20 mg / mL acetonitrile solution; The injection volume was 5 mL each time; After separation, the same separated liquid was collected and concentrated under reduced pressure to obtain 1B-P1 and 1B-P2.

[0308] Compound 1B-P1:

[0309] LCMS m / z=845.2[M+H] +

[0310] 1 H NMR(400MHz, CDCl3)δ7.36(d,1H),7.31–7.18(m,11H),7.14–7.06(m,6H),6.99–6.90(m,3H),6.83–6.74(m,2H),5.85(q,1H),3.59–3.42 (m,2H),2.08(d,3H),1.80(s,9H),1.56–1.46(m,1H),1.43(t,3H),1.37(d,3H),0.89–0.75(m,2H),0.63–0.53(m,1H),0.48–0.38(m,1H).

[0311] Compound 1B-P2:

[0312] LCMS m / z=845.3[M+H] +

[0313] 1H NMR (400MHz, CDCl3) δ7.41–7.35(m,2H),7.30–7.21(m,10H),7.20–7.10(m,9H),6.94–6.89(m,2H),5.90(q,1H),3.44(q,2H) ,1.83–1.74(m,12H),1.62–1.50(m,1H),1.39(t,3H),1.11(d,3H),0.89–0.73(m,2H),0.71–0.61(m,1H),0.56–0.46(m,1H).

[0314] Example 1: Synthesis of Compound 1

[0315]

[0316] Step 1: Synthesis of compound 1C

[0317] Compound 1B-P2 (10.24 g, 12.12 mmol) and (S)-2-methoxypropanol (1.31 g, 14.54 mmol) were dissolved in 200 mL of THF, and potassium tert-butoxide (1.9 g, 16.97 mmol) was slowly added under ice bath. The mixture was stirred for 2 hours under nitrogen protection, and saturated aqueous ammonium chloride was added to quench the mixture under ice bath. The mixture was extracted with ethyl acetate (200 mL × 3), washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 1C (10 g, 98.12%), which was directly used in the next step without purification.

[0318] Step 2: Synthesis of Compound 1D

[0319] Compound 1C (10 g, 11.89 mmol) and sodium bicarbonate (12.99 g, 154.57 mmol) were dissolved in 100 mL of THF and 100 mL of methanol. 10% palladium on carbon (5 g) was slowly added at room temperature. The mixture was stirred under a hydrogen atmosphere for 12 hours, filtered through celite, and the filtrate was collected and purified by column chromatography to obtain the target compound 1D (7.5 g, 85.6%).

[0320] Step 3: Synthesis of Compound 1E

[0321] Compound 1D (7.5 g, 10.18 mmol) was dissolved in 150 mL of DMF. DIPEA (6.58 g, 50.9 mmol), tert-butyl p-chloromethylbenzoate (3.46 g, 15.27 mmol), and cesium carbonate (14.93 g, 45.81 mmol) were added sequentially at room temperature. The mixture was stirred under a nitrogen atmosphere for 4 hours. Water was added to the reaction solution, and the reaction solution was extracted with EA. The mixture was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The mixture was purified by column chromatography to obtain the target compound 1E (8.1 g, 85.84%).

[0322] Step 4: Synthesis of Compound 1F

[0323] Compound 1E (1.1 g, 1.19 mmol) was dissolved in 20 mL of THF, and p-toluenesulfonic acid (184.4 mg, 1.07 mmol) and 3,4-dihydro-pyran (0.85 g, 10.12 mmol) were added sequentially at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours. Water was added to the reaction solution, and the reaction solution was extracted with EA. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the target compound 1F (750 mg, 88.68%).

[0324] LCMS m / z=713.3[M+H] +

[0325] Step 5: Synthesis of Compound 1G

[0326] Compound 1F (750 mg, 1.05 mmol) was dissolved in 10 mL of THF. PyBOP (1.37 g, 2.63 mmol) and cesium carbonate (0.43 g, 1.31 mmol) were added sequentially at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. 3-Acetonitrile cyclobutylamine hydrochloride (0.15 g, 1.26 mmol), DIPEA (0.5 mL), and cesium carbonate (0.43 g, 1.31 mmol) were added at room temperature. The mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the reaction mixture was extracted with EA. The mixture was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The mixture was purified by column chromatography to obtain the target compound 1G (720 mg, 88.08%).

[0327] LCMS m / z=777.5[M+H] +

[0328] Step 6: Synthesis of compound 1H

[0329] Compound 1G (80 mg, 0.43 mmol) was dissolved in 2 mL of DCM, and 1 mL of TFA was slowly added at room temperature. The mixture was stirred for 4 hours, and the organic solvent was dried to obtain crude compound 1H (58 mg), which was directly used for the next step without purification.

[0330] LCMS m / z=637.4[M+H] +

[0331] Step 7: Synthesis of compound 1

[0332] Compound 1H (58 mg, 0.091 mmol) was dissolved in 5 mL of DMF. HATU (0.042 g, 0.11 mmol), DIPEA (0.059 g, 0.45 mmol), and 1K (0.045 g, 0.11 mmol) were added sequentially at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. Water was then added to the reaction solution, and the mixture was extracted with EA. The mixture was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated. The mixture was purified by preparative HPLC to obtain the title compound 1 (11 mg, 11.69%). Preparation method: Instrument: Waters 2545; Preparative column: Waters Xslect CSH 5 μm (19 mm × 250 mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate).

[0333] LCMS m / z=1033.2[M+H] +

[0334] 1 H NMR (400MHz, CD3OD) δ7.48(s,1H),7.29–7.22(m,2H),7.14–7.08(m,2H),6.87–6.76(m,3H),6.58–6.54(m,1H),5. 30(d,1H),4.95–4.84(m,3H),4.84–4.74(m,4H),4.64–4.51(m,1H),4.42–4.35(m,2H),4.00–3.90(m,1H),3.87–3. 74(m,2H),3.72–3.57(m,2H),3.40(s,3H),3.10–2.95(m,3H),2.95–2.58(m,7H),2.31–2.24(m,2H),2.24–2.07(m ,3H),2.06–2.00(m,3H),1.98–1.85(m,4H),1.83–1.64(m,2H),1.49–1.40(m,1H),1.23(d,3H),0.75–0.55(m,4H).

[0335] Example 2: Synthesis of Compound 2

[0336]

[0337] Compound 2 was synthesized by referring to the corresponding steps in Example 1 to obtain the title compound (15 mg, 14.21%). Preparation method: Instrument: Waters 2545; Preparative chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate)).

[0338] LCMS m / z=1034.2[M+H] +

[0339] 1 H NMR (400MHz, CD3OD) δ7.48(s,1H),7.29–7.22(m,2H),7.11(d,2H),6.93(d,1H),6.84(d,2H),6.64(d,1H),5.30(d,1H),4. 94–4.84(m,3H),4.84–4.74(m,4H),4.63–4.52(m,1H),4.42–4.35(m,2H),4.01–3.90(m,1H),3.84–3.74(m,1H),3.74–3.67 (m,3H),3.67–3.56(m,1H),3.40(s,3H),3.11–2.96(m,3H),2.95–2.75(m,6H),2.73–2.63(m,1H),2.32–2.24(m,2H),2.22 –2.11(m,1H),2.06–2.00(m,3H),1.99–1.84(m,4H),1.82–1.64(m,2H),1.49–1.39(m,1H),1.23(d,3H),0.75–0.55(m,4H).

[0340] Example 3: Synthesis of Compound 3

[0341]

[0342] Compound 3 was synthesized by referring to the corresponding steps in Example 1 to obtain the title compound (14 mg, 14.63%). Preparation method: Instrument: Waters 2545; Preparative chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate)).

[0343] LCMS m / z=937.1[M+H] +

[0344] 1H NMR(400MHz,CD3OD)δ7.48(s,1H),7.30–7.23(m,2H),7.18(d,2H),6.96(d,1H),6.87(d,2H),6.7 8–6.62(m,1H),5.36–5.25(m,1H),4.96–4.86(m,3H),4.82–4.74(m,2H),4.71–4.49(m,1H),4.43–

[0345] 4.35(m,2H),4.01–3.56(m,6H),3.40(s,3H),3.16–2.96(m,2H),2.91–2.59(m,6H),2. 09–1.99(m,3H),1.90–1.54(m,2H),1.51–1.39(m,1H),1.23(d,3H),0.75–0.55(m,4H).

[0346] Example 4: Synthesis of Compound 4

[0347]

[0348] Compound 4 was synthesized by referring to the corresponding steps in Example 1 to obtain the title compound (14 mg, 14.63%). Preparation method: Instrument: Waters 2545; Preparative chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate)).

[0349] LCMS m / z=936.1[M+H] +

[0350] 1 H NMR(400MHz,CD3OD)δ7.48(s,1H),7.31–7.23(m,2H),7.17(d,2H),691–6.80(m,3H),6.69–6.5 6(m,1H),5.35–5.27(m,1H),4.95–4.87(m,3H),4.80–4.71(m,2H),4.69–4.57(m,1H),4.42–4. 35(m,2H),4.01–3.69(m,5H),3.40(s,3H),3.10–2.92(m,2H),2.87–2.57(m,6H),2.28–2.16(m ,1H),2.14–2.20(m,4H),1.87–1.54(m,2H),1.49–1.39(m,1H),1.23(d,3H),0.74–0.56(m,4H).

[0351] Example 5: Synthesis of Compound 5

[0352]

[0353] Compound 5 was synthesized by referring to the corresponding steps in Example 1 to obtain the title compound (14 mg, 14.63%). Preparation method: Instrument: Waters 2545; Preparative chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate)).

[0354] LCMS m / z=937.1[M+H] +

[0355] 1 H NMR(400MHz,CD3OD)δ7.47(s,1H),7.32–7.22(m,2H),7.17(d,2H),6.96(d,1H),6.87(d,2H),6.8 0–6.62(m,1H),5.36–5.25(m,1H),4.97–4.87(m,3H),4.82–4.73(m,2H),4.69–4.50(m,1H),4.45–

[0356] 4.34(m,2H),4.02–3.56(m,6H),3.40(s,3H),3.15–2.98(m,2H),2.93–2.57(m,6H),2. 10–2.02(m,3H),1.91–1.53(m,2H),1.51–1.39(m,1H),1.23(d,3H),0.75–0.55(m,4H).

[0357] Example 6: Synthesis of Compound 6

[0358]

[0359] Compound 6 was synthesized by referring to the corresponding steps in Example 1 to obtain the title compound (14 mg, 14.63%). Preparation method: Instrument: Waters 2545; Preparative chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate)).

[0360] LCMS m / z=936.1[M+H] +

[0361] 1H NMR (400MHz, CD3OD) δ7.47(s,1H),7.31–7.23(m,2H),7.17(d,2H),6.89–6.79(m,3H),6.70–6. 53(m,1H),5.36–5.25(m,1H),4.97–4.86(m,3H),4.82–4.73(m,2H),4.69–4.48(m,1H),4.45–4. 32(m,2H),4.01–3.55(m,5H),3.40(s,3H),3.11–2.92(m,2H),2.87–2.56(m,6H),2.29–2.15(m ,1H),2.14–1.97(m,4H),1.87–1.54(m,2H),1.49–1.39(m,1H),1.23(d,3H),0.75–0.56(m,4H).

[0362] Example 7: Synthesis of Compound 7

[0363]

[0364] Compound 7 was synthesized by referring to the corresponding steps in Example 1 to obtain the title compound (15 mg, 14.21%). Preparation method: Instrument: Waters 2545; Preparative chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate)).

[0365] LCMS m / z=1033.2[M+H] +

[0366] 1H NMR (400MHz, CD3OD) δ7.48(s,1H),7.28–7.20(m,2H),7.11(d,2H),6.88–6.76(m,3H),6.56(m,1H),5.37–6. 25(m,1H),4.95–4.87(m,3H),4.85–4.74(m,4H),4.65–4.52(m,1H),4.43–4.35(m,2H),4.00–3.90(m,1H),3 .87–3.74(m,2H),3.72–3.54(m,2H),3.40(s,3H),3.10–2.96(m,3H),2.94–2.58(m,7H),2.31–2.07(m,5H), 2.06–1.99(m,3H),1.96–1.84(m,4H),1.83–1.53(m,2H),1.51–1.40(m,1H),1.23(d,3H),0.75–0.54(m,4H).

[0367] Example 8: Synthesis of Compound 8

[0368]

[0369] The synthesis method of compound 8 was similar to that of Example 1 to obtain the title compound (15 mg, 14.21%). Preparation method: Instrument: Waters 2545; Preparative chromatographic column: Waters Xslect CSH 5 μm (19 mm × 250 mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% ammonium acetate)).

[0370] LCMS m / z=1034.2[M+H] +

[0371] 1H NMR (400MHz, CD3OD) δ7.48(s,1H),7.29–7.22(m,2H),7.11(d,2H),6.93(d,1H),6.84(d,2H),6.64(d,1H),5.30(d,1H),4. 95–4.84(m,3H),4.84–4.74(m,4H),4.63–4.51(m,1H),4.42–4.36(m,2H),4.00–3.90(m,1H),3.83–3.75(m,1H),3.74–3.67 (m,3H),3.67–3.58(m,1H),3.40(s,3H),3.11–2.90(m,5H),2.89–2.75(m,4H),2.72–2.63(m,1H),2.32–2.24(m,2H),2.22 –2.11(m,1H),2.07–2.01(m,3H),1.99–1.84(m,4H),1.81–1.64(m,2H),1.49–1.40(m,1H),1.23(d,3H),0.76–0.55(m,4H).

[0372] Example 9: Synthesis of Compound 9

[0373]

[0374] Step 1: Synthesis of compound 9B

[0375] Compound 9A (1.5 g, 4.99 mmol) and (S)-tert-butyl 2-methylpiperazine-1-carboxylate (1.2 g, 5.99 mmol) were dissolved in 15 mL of N,N-dimethylacetamide, and 0.5 mL of acetic acid was added. The mixture was stirred at room temperature for 1 hour, and sodium triacetylborohydride (2.12 g, 9.98 mmol) was slowly added. The reaction was allowed to react at room temperature overnight. Saturated aqueous sodium bicarbonate solution was added to adjust the pH to about 8. The mixture was concentrated, diluted with water, extracted with EA, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain the target compound 9B (1.5 g, 61.97%).

[0376] LCMS m / z=485.2[M+H] +

[0377] Step 2: Synthesis of compound 9C

[0378] Compound 9B (400 mg, 0.83 mmol) was dissolved in 10 mL of 4% sodium hydroxide in methanol solution, stirred at room temperature for 2 hours, extracted with dichloromethane, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain compound 9C (250 mg, 20.92%).

[0379] LCMS m / z=345.2[M+H] +

[0380] Step 3: Synthesis of compound 9D

[0381] Compound 9C (250 mg, 0.73 mmol) and sodium hydride (58.3 mg, 1.46 mmol) were dissolved in 10 mL of THF and stirred at 0°C for 30 minutes. 3-Bromopiperidine-2,6-dione (0.21 g, 1.09 mmol) was slowly added at 0°C. The mixture was concentrated, and the residue was purified by column chromatography to obtain compound 9D (0.21 g, 63.51%).

[0382] LCMS m / z=456.2[M+H] +

[0383] Step 4: Synthesis of compound 9E

[0384] Compound 9D (210 mg, 0.46 mmol) was dissolved in 6 mL of DCM, and 2 mL of TFA was slowly added at room temperature. The mixture was stirred for 2 hours, and the reaction solution was directly concentrated to obtain trifluoroacetate salt of compound 9E (150 mg, 87.4%), which was directly carried out to the next step.

[0385] Step 5: Synthesis of compound 9

[0386] Compound 1H (60 mg, 0.094 mmol) was dissolved in 5 mL of DMF. HATU (0.043 g, 0.11 mmol), DIPEA (0.049 g, 0.38 mmol), and 9E (0.045 g, 0.11 mmol) were added sequentially at room temperature. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours. Water was then added to the reaction solution, and the mixture was extracted with EA. The mixture was washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Purification by preparative HPLC afforded the trifluoroacetic acid salt of the title compound 9 (19 mg, 20.7%). Preparation method: Instrument: Waters 2545; Preparative column: Waters Xslect CSH 5 μm (19 mm × 250 mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% trifluoroacetic acid).

[0387] LCMS m / z=974.1[M+H] +

[0388] 1H NMR(400MHz,CD3OD)δ7.91(s,1H),7.68–7.60(m,1H),7.58–7.51(m,2H),7.31(s,1H),7.24–7.12(m,3H),6. 76(d,2H),5.69(dd,1H),5.18–4.96(m,4H),4.94–4.85(m,2H),4.69–4.49(m,4H),4.49–4.38(m,2H),4.13–4 .02(m,1H),3.87–3.77(m,1H),3.50–3.34(m,5H),3.23–3.02(m,2H),2.99–2.77(m,3H),2.57(s,3H),2.43– 2.32(m,1H),2.11–2.04(m,3H),1.54–1.44(m,1H),1.43–1.33(m,3H),1.32–1.24(m,4H),0.81–0.64(m,4H).

[0389] Biological test cases

[0390] 1. SW620 cell proliferation inhibition test

[0391] Human colon cancer cells SW620 were cultured in RPMI-1640 complete medium supplemented with 10% FBS and 1% antibiotic-antimycotic double antibody at 37°C in a 5% CO2 incubator. On the first day, cells in the exponential growth phase were harvested and the cell suspension was adjusted to the appropriate concentration using complete medium for plating, resulting in 500 cells per well in a 90 μL volume per well. Subsequently, 10 μL of compound at varying concentrations was added, and the cells were incubated in a CO2 incubator for an additional 6 days. Following the incubation period, 50 μL of pre-thawed and room temperature CTG solution was added to each well according to the instructions of the CellTiter-Glo kit (Promega, G7573). The cells were mixed using a microplate shaker for 2 minutes and then incubated at room temperature for 10 minutes before measuring the fluorescence signal (RLU) using a microplate reader (BMG). The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1 – (RLU compound – RLU blank control) / (RLU vehicle control – RLU blank control)) * 100%. The inhibition rate of the compound at different concentrations was calculated in Excel, and then the inhibition curve was plotted and relevant parameters, including minimum inhibition rate, maximum inhibition rate, and IC, were calculated using GraphPad Prism software. 50 .

[0392] Table 1 SW620 cell proliferation inhibition test results:

[0393] Compound number <![CDATA[IC 50 (nM)]]> Compound 1 <100nM Compound 4 <100nM Trifluoroacetate salt of compound 9 <100nM

[0394] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity against SW620 cells.

[0395] 2. Detection of KRAS G12D degradation in ASPC-1 cells

[0396] ASPC-1 is a human metastatic pancreatic cancer cell line purchased from ATCC. Culture conditions include RPMI-1640 with 10% FBS and 1% double-antibody in a 37°C, 5% CO2 incubator. Cells were plated in 12-well plates at 3×105 cells / well. Following plating, various concentrations of compounds were added and cultured for 24 hours at 37°C, 5% CO2. After the incubation period, cells were harvested and lysed on ice for 20 minutes using RIPA lysis buffer (beyotime, Cat. P0013B). The cells were then centrifuged at 12,000 rpm and 4°C for 10 minutes. The supernatant protein samples were collected and quantified using a BCA kit (Beyotime, Cat. P0009). The protein was diluted to 1 mg / mL and the expression of KRAS G12D (CST, Cat. 14429S) and the internal reference β-actin (CST, Cat. 4970S) was detected using an automated Western blot quantitative analyzer (Proteinsimple). The relative peak area of ​​KRAS G12D was calculated using "Compass for SW" software, assuming the internal reference area was 10,000. The proportion of KRAS G12D relative to the vehicle control group at different drug concentrations was calculated according to formula (1), where KRAS G12D treat represents the relative peak area of ​​the drug group and KRAS G12D solvent represents the relative peak area of ​​the vehicle control group. The DC50 value was calculated using a four-parameter nonlinear regression model using GraphPad Prism 8.3.0 software after the data were processed according to formula (3).

[0397] KRAS G12D%=KRAS G12Dstreat / KRAS G12Dsolvent×100% Formula 3

[0398] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good degradation activity on KRAS G12D protein in ASPC-1 cells.

[0399] 3. Pharmacokinetic test in rats

[0400] 1.1 Experimental Animals: Male SD rats, approximately 220 g, 6 to 8 weeks old, 6 rats per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0401] 1.2 Experimental Design: On the day of the experiment, SD rats (6 per compound) were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0402] Dosing Information

[0403]

[0404] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; oral administration solvent: 5% DMSO + 5% HS-15 + 10% PEG400 + 80% containing 20% ​​SBE-β-CD (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; DMSO: dimethyl sulfoxide; HS-15: polyethylene glycol-15-hydroxystearate; PEG400: polyethylene glycol 400; SBE-β-CD: sulfobutyl ether-β-cyclodextrin)

[0405] Before and after drug administration, 0.15 ml of blood was collected intraorbitally under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0406] Conclusion: The compound of the present invention has good oral absorption effect in rats.

[0407] 4. Pharmacokinetic test in mice

[0408] 1.1 Experimental Animals: Male ICR mice, 20-25 g, 6 mice per compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

[0409] 1.2 Experimental Design: On the day of the experiment, ICR mice (6 mice / compound) were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0410] Dosing Information

[0411]

[0412] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; Oral administration solvent: 5% DMSO + 5% HS-15 + 10% PEG400 + 80% containing 20% ​​SBE-β-CD

[0413] (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; DMSO: dimethyl sulfoxide; HS-15: polyethylene glycol-15-hydroxystearate; PEG400: polyethylene glycol 400; SBE-β-CD: sulfobutyl ether-β-cyclodextrin)

[0414] Before and after drug administration, 0.06 mL of blood was collected via the orbital cavity under isoflurane anesthesia. The blood was placed in an EDTAK2 centrifuge tube and centrifuged at 5000 rpm at 4°C for 10 minutes to collect plasma. Blood was collected from both the intravenous and oral gavage groups at 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0415] Test results

[0416]

[0417] Conclusion: The compounds of the present invention have good oral absorption effect in mice. For example, compound 1 has a lower clearance rate and a better oral exposure.

[0418] 5. Beagle dog pharmacokinetic test

[0419] Experimental animals: Male beagle dogs, weighing approximately 8-11 kg, 3 per compound, purchased from Beijing Masi Biotechnology Co., Ltd.

[0420] Test method: On the day of the test, beagle dogs (3 per compound) were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours before administration and fed 4 hours after administration.

[0421] Dosing Information

[0422]

[0423] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; oral administration solvent: 5% DMSO + 5% HS-15 + 10% PEG400 + 80% containing 20% ​​SBE-β-CD (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; DMSO: dimethyl sulfoxide; HS-15: polyethylene glycol-15-hydroxystearate; PEG400: polyethylene glycol 400; SBE-β-CD: sulfobutyl ether-β-cyclodextrin)

[0424] Before and after dosing, 1 ml of blood was collected from the jugular vein or limb vein into an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. For both the intravenous and oral administration groups, blood was collected at the following time points: 0, 5, 15, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0425] Conclusion: The compound of the present invention has good oral absorption effect in beagle dogs.

[0426] 6. Monkey pharmacokinetic test

[0427] Experimental animals: Male cynomolgus monkeys, 3-5 kg, 3-6 years old, 6 per compound, purchased from Suzhou Xishan Biotechnology Co., Ltd.

[0428] Test method: On the day of the test, monkeys (6 per compound) were randomly divided into groups according to body weight. They were fasted but not watered for 14-18 hours before administration and fed 4 hours after administration.

[0429] Dosing Information

[0430]

[0431] Note: Intravenous administration solvent: 5% DMA + 5% Solutol + 90% Saline; oral administration solvent: 5% DMSO + 5% HS-15 + 10% PEG400 + 80% containing 20% ​​SBE-β-CD (DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: normal saline; DMSO: dimethyl sulfoxide; HS-15: polyethylene glycol-15-hydroxystearate; PEG400: polyethylene glycol 400; SBE-β-CD: sulfobutyl ether-β-cyclodextrin)

[0432] *Dosage is based on the free base.

[0433] Before and after dosing, 1.0 mL of blood was collected from a limb vein and placed in an EDTAK2 centrifuge tube. The samples were centrifuged at 5000 rpm at 4°C for 10 minutes, and plasma was collected. Blood was collected from both the intravenous and oral administration groups at the following time points: 0, 5 minutes, 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, 10, 12, and 24 hours. All samples were stored at -80°C prior to analysis and quantitative analysis was performed using LC-MS / MS.

[0434] Conclusion: The compound of the present invention has good oral absorption effect in monkeys.

[0435] 7. hERG potassium channel effect test

[0436] Experimental platform: electrophysiology manual patch clamp system

[0437] Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel

[0438] Experimental methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. Glass microelectrodes were pulled from glass electrode blanks (BF150-86-10, Sutter) using a puller. The tip resistance after perfusing the electrode liquid was about 2-5 MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by a computer using pClamp 10 software, with a sampling frequency of 10 kHz and a filter frequency of 2 kHz. After obtaining the whole-cell recording, the cell was clamped at -80 mV to induce the hERG potassium current (I hERG ) was administered with a 2-second depolarization step from -80 mV to +20 mV, followed by repolarization to -50 mV for 1 second before returning to -80 mV. This voltage stimulus was administered every 10 seconds, and administration began after confirming that the hERG potassium current was stable (for at least 1 minute). Compounds were administered for at least 1 minute at each test concentration, and at least two cells (n ≥ 2) were tested for each concentration.

[0439] Data processing: Data analysis was performed using pClamp 10, GraphPad Prism 5, and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50 mV) by different compound concentrations was calculated using the following formula:

[0440] Inhibition%=[1–(I / Io)]×100%

[0441] Wherein, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current before and after drug addition, respectively.

[0442] Compound IC 50 Calculated using GraphPad Prism 5 software by fitting the following equation:

[0443] Y=Bottom+(Top-Bottom) / (1+10^((LogIC50-X)*HillSlope))

[0444] Where X is the Log value of the test sample concentration, Y is the inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum inhibition percentages, respectively.

[0445] Conclusion: The compounds of the present invention have no obvious herg inhibitory activity. For example, the IC50 values ​​of compounds 1 and 4 are both greater than 40 μM.

[0446] 8. Liver microsome stability test

[0447] In this study, liver microsomes from five species, including humans, dogs, rats, and mice, were used as in vitro models to evaluate the metabolic stability of the test substances.

[0448] At 37°C, 1 μM of the test substance was incubated with microsomal proteins and coenzyme NADPH. The reaction was terminated by adding ice-cold acetonitrile containing an internal standard after a certain time (5, 10, 20, 30, 60 min). The concentration of the test substance in the sample was detected by LC-MS / MS. The T value was calculated based on the ln value of the drug residual rate in the incubation system and the incubation time. 1 / 2 , and further calculated the liver microsomal intrinsic clearance CL int(mic) and hepatic intrinsic clearance CL int(Liver) .

[0449] Conclusion: The compounds of the present invention have good liver microsomal stability in multiple species.

[0450] 9. CYP450 enzyme inhibition test

[0451] The purpose of this study was to evaluate the effects of test substances on the activities of five isoenzymes of cytochrome P450 (CYP) in human liver microsomes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) using an in vitro test system. Specific probe substrates for the CYP450 isoenzymes were incubated with human liver microsomes and varying concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and the IC values ​​were calculated. 50 The inhibitory potential of the test substance on each CYP enzyme isoform was evaluated.

[0452] Experimental results: Under the test conditions, when the incubation concentrations were 0.03, 0.1, 0.3, 1, 3, 10, and 30 μM, the IC values ​​of each test compound for CYP enzyme inhibition were 50 The values ​​are shown in the table below:

[0453]

[0454] Conclusion: The compounds of the present invention have no significant inhibitory activity against any CYP subtype.

[0455] 10. Caco2 permeability test

[0456] The experiment used Caco-2 cell monolayers in 96-well Transwell plates, incubated in triplicate. Transport buffer (HBSS, 10 mM HEPES, pH 7.4 ± 0.05) containing the compound of the invention (2 μM) or the control compounds digoxin (10 μM), nadolol (2 μM), and metoprolol (2 μM) was added to the apical or basolateral wells of the cell monolayer. Transport buffer containing DMSO was added to the corresponding receiving wells. After incubation at 37 ± 1°C for 2 hours, the cell plate was removed and appropriate samples were taken from the apical and basolateral wells to a new 96-well plate. Proteins were then precipitated by adding acetonitrile containing an internal standard. Samples were analyzed using LC-MS / MS to determine the concentrations of the compound of the invention and the control compound. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical to basolateral side of the cell monolayer and from the basolateral to apical side, thereby calculating the efflux rate. The integrity of the cell monolayer after 2 hours of incubation was assessed by leakage of Lucifer Yellow.

[0457] Conclusion: The compound of the present invention has good permeability.

Claims

1. A compound or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: The compound is selected from the compounds represented by general formula (I), BLK(I); L is selected from a bond or -C 1-50 Hydrocarbyl-, wherein 1 to 20 methylene units in the hydrocarbyl group are optionally replaced by -Ak- or -Cy-; Each -Ak- is independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-NR L (CH2) q C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q -、-CH=CH-、-Si(R L )2-、-Si(OH)(R L )-、-Si(OH)2-、-P(=O)(OR L )-、-P(=O)(R L )-, -S-, -S(=O)-, -S(=O)2- or a bond, wherein the CH, -CH2- is optionally replaced by 1 to 2 R z replace; q is each independently selected from 0, 1, 2, 3, 4, 5 or 6; R L Selected from H, C 1-4 Alkyl, C 3-7 Carbocyclic group, 4 to 10 membered heterocyclic group, said alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace; Each -Cy- is independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, 10-16 membered heterotricyclic group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; B is selected from X is selected from CH or N; Ring B1 is selected from C 3-10 Carbocyclic group or 4-10 membered heterocyclic group, wherein the ring B1 is optionally substituted by 1 to 4 R b1 replace; B4 is selected from C 6-10 aryl or 5 to 10 membered heteroaryl, said B4 is optionally substituted by 1 to 4 R b4 replace; R b1 、R b3 or R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace; R b2 Selected from H, deuterium, C 1-6 Alkyl, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace; m is selected from 0, 1 or 2; K is selected from G is selected from N or CH; Q is independently selected from a bond, -O-, -S-, -CH2-, -NR q -、-CO-、-NR q CO-、-CONR q -; Q and G cannot directly form nitrogen-nitrogen bonds, nitrogen-oxygen bonds, or nitrogen-sulfur bonds; R q Selected from H or C 1-4 alkyl; F are each independently selected from 5-6 membered heteroaryl, C 13-20 Carbocyclic group, 13-20 membered heterocyclic group, Ring E is selected from phenyl or 5-6 membered heteroaryl; R k1 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace; R k2 Each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-; R k3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Carbocyclic group, 3 to 8 membered heterocyclic group, the alkyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 groups selected from R z replace; Alternatively, two R k1 Direct connection to form C 3-8 Carbocyclic or 4-8 membered heterocyclic, said carbocyclic or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; Alternatively, two R k3 Direct connection to form C 3-8 Carbocyclic or 4-8 membered heterocyclic, said carbocyclic or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; R L2 、R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, -C 0-4 Alkylene-C 4-10 Heterocycloalkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; n1 is selected from 0, 1, 2 or 3; p1 and p2 are each independently selected from 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1 or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q - or bond, wherein the -CH2- is optionally replaced by 1 to 2 R z replace; R L Each independently selected from H or C 1-4 alkyl; Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, 10-16 membered heterotricyclic group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spiroalkyl, C 5-12 Bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 aryl; Ring B1 is selected from C 3-6 Carbocyclic group or 4-6 membered heterocyclic group, wherein the ring B1 is optionally substituted by 1 to 4 R b1 replace; B4 is selected from The B4 is optionally replaced by 1 to 4 R b4 replace; R b1 、R b3 or R b4 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace; R b2 Selected from H, deuterium, C 1-4 Alkyl, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace; F is independently selected from 6-membered heteroaryl, 13-15-membered tricyclic heterocyclic group, Ring E is selected from phenyl or 6-membered heteroaryl; R k1 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R z replace; R k3 Each independently selected from H, deuterium, F, Cl, Br, I, OH, ═O, NH 2 , CN, COOH, CONH 2 , C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocyclic group, 3 to 6 membered heterocyclic group, the alkyl, alkoxy, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 groups selected from R z replace; R L2 、R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-2 Alkylene-C 4-6 Heterocycloalkyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl 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.

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

4. The compound according to claim 1 or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from a bond, -O-, -S-, -OCH2-, -CH2O-, -OCH2CH2-, -CH2CH2O-, -C≡C-, -C(CH3)2-, -CH2-, -C(CH3)2-, -CH2CH2-, -CH2CH2CH2-, -N(CH3)-, -NH-, -CH2N(CH3)-, -CH2NH-, -NHCH2-, -CH2CH2N(CH3)-, -CH2CH2NH-, -NHCH2CH2-, -C(=O)-, -C(=O)CH2NH-, -CH2C(=O)NH-, -C(=O)NH- or -NHC(=O)-; Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following optionally substituted groups: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, =O, COOH, CN, NH2, hydroxymethyl, methyl, methoxy, cyclopropyl; K is selected from Q is selected from a bond, NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3); G is selected from CH or N; H1 is selected from N, NH, CH, CH2, CHR k1 NR k1 , CR k1 , C(=O); H2 is selected from a bond, O, N, NH, CH, CH2, CHR k1 NR k1 , CR k1 , C(=O); H5 or H6 is selected from N or CR k1 .

5. The compound according to claim 4, or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R b2 Selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, CD3, R b1 、R b3 or R b4 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, NH2, COOH, CONH2, methyl, ethyl, cyclopropyl, methoxy, CF3, CHF2; L is selected from -O-CH2-Cy1-C(=O)-, -O-CH2-Cy1-C(=O)-Cy2-, -O-CH2-Cy1-C(=O)-Cy2-CH2-, -O-CH2-Cy1-CH2-, - O-CH2-Cy1-Cy2-, -Cy1-O-Cy2-, -Cy1-O-Cy2-Cy3-, -O-CH2-Cy1-Cy2-CH2-, -O-CH2-Cy1-CH2-Cy2-CH2-; R k1 Each is independently selected from H, deuterium, F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy, isopropoxy, and cyclopropyl.

6. The compound according to claim 1 or 5, or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: B is selected from one of the structural fragments shown in Table B-1; L is selected from a bond or one of the structural fragments shown in Table L-1; K is selected from one of the structural fragments shown in Table K-1 or Table K-2.

7. The compound according to claim 1 or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: The compound of general formula (I) is selected from the compound of general formula (II-1) or general formula (II-2), R b1 、R b2 、R b3 、R b4 、R k1 The definitions of Cy2, Ak3, and G are the same as those in any one of claims 1-5.

8. The compound according to claim 1, or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from one of the structures shown in Table E, Table E 9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of the compound according to any one of claims 1 to 8 or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

10. Use of the compound of any one of claims 1 to 8, or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition of claim 9, in the preparation of a medicament for treating a disease associated with the inhibition or degradation of KRAS, preferably cancer.

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