Compound capable of degrading KRAS and application of compound in medicine

Abstract

The invention relates to a compound shown in a general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a co-crystal of the compound, an intermediate of the compound, and application of the compound in inhibiting or degrading Kras related diseases such as cancers. B-L-K (I)

Description

Technical Field

[0001] The present invention relates to a compound of general formula (I) or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, as well as intermediates and preparation methods thereof, and use thereof in KRAS-related diseases such as tumors or autoimmune system diseases. Background Art

[0002] RAS protein is expressed by the RAS gene (Rat Sarcoma viral oncogene). It is an intracellular guanine nucleotide binding protein and belongs to GTPase (weak hydrolysis activity). RAS protein exists in two different states: inactive GDP-bound state and active GTP-bound state. Activated RAS protein conducts signal transduction by interacting with different downstream effectors, which has an impact on cell growth, differentiation, cytoskeleton, protein transport and secretion. The activation of RAS signal transduction is regulated by guanine nucleotide exchange factor (GEF, which can cause GDP-GTP exchange) or GTPase activating protein (GAP, which can cause RAS protein to change from activated state to inactivated state). Mutant RAS protein can cause resistance to GAP, resulting in RAS protein being in a continuously activated state, causing uncontrolled cell growth and eventually developing into cancerous tissue (Molecular Cancer, 2018, 17: 33).

[0003] RAS gene mutation is a common type of gene mutation in cancer patients (Nat. Rev. Drug Discov. 2014, 13, 828-851). For example, RAS gene mutation accounts for 97.7%, 52.2%, 42.6% and 32.2% in pancreatic cancer, colorectal cancer, multiple myeloma and NSLCL, respectively. KARS gene (Kristen Rat Sarcoma viral oncogene) mutation is the most influential mutation in RAS mutation, accounting for 86% of all RAS mutations. The most common way for KRAS gene to be activated is point mutation. 95% of KRAS mutations mainly occur in codons 12 and 13 of exon 2. Common mutation forms include KRAS G12C mutation (39%), KRAS G12V (18-21%) and KRAS G12D (17-18%) mutations.

[0004] Since the discovery of KRAS mutant proteins in cancer and the observation that inhibition of these mutant proteins can inhibit tumor proliferation, KRAS mutant protein inhibitors have received widespread attention. KRAS has long been considered an "undruggable target": RAS has a high affinity for GTP / GDP (picomolar level), and the entire protein lacks other "ligand binding pockets" (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. According to organ and tissue classification, KRAS cancer is most concentrated in three types: colon cancer, pancreatic cancer, and lung adenocarcinoma. According to mutation classification, G12D accounts for the highest proportion, followed by G12V, G12C, which has been initially conquered, ranks third, G13D ranks fourth, and amplification (AMP) ranks 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. Such compounds can be recognized by the proteasome of the cell, causing the degradation of the target protein, and can effectively reduce the content of the target protein in the cell. By introducing ligands that can bind to different target proteins into PROTAC molecules, PROTAC technology can be applied to 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 object of the present invention is to provide a compound with novel structure, good efficacy, high bioavailability, greater safety, and the ability to inhibit or degrade KRAS, for treating KRAS-related diseases such as autoimmune diseases, inflammatory diseases or cancer.

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

[0009] BLK(I);

[0010] In some embodiments, the compound represented by general formula (I) is selected from the compounds represented by general formula (Ia), (Ib) or (Ic),

[0011]

[0012] In certain embodiments, L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0013] In certain embodiments, L is selected from the group consisting of -NHCH2-, -Cy1-, -Cy1-CH2-, -CH2-Cy1-, -Cy1-C≡C-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -Cy1-C(=O)-CH2-Cy2-, -Cy1-C(=O)-Cy2-, -C(=O)-Cy1-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-, -NH-Cy1-, -NH-Cy1-O-, -O-Cy1-NH-, -NH-Cy1-Cy2-, -NH-Cy1-CH2-C y2, -N(CH3)-CH2-Cy1-, -CH2-Cy1-CH2-Cy2-NH-, -Cy1-CH2-Cy2-NH-, -Cy1-CH2CH2-Cy2-, -CH2-Cy1-CH2CH2-Cy2-, -CH2-Cy1-CH2-Cy2-, -Cy 1-C(=O)NH-CH2CH2-O-CH2CH2-O-, -Cy1-C(=O)NH-CH2CH2-O-, -Cy1-C(=O)NH-, -CH2-Cy1-C(=O)-Cy2-, -Cy1-C(=O)-CH2-Cy2- or -C(=O)-Cy1-;

[0014] In certain embodiments, Ak1, Ak2, Ak3, Ak4, and Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q - or a bond, wherein the -CH2- is optionally replaced by 1 to 2 R z replace;

[0015] In certain embodiments, Ak1, Ak2, Ak3, Ak4, and Ak5 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)-;

[0016] In certain embodiments, 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: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl;

[0017] In certain embodiments, Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl;

[0018] In certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 Substituted by one of the following groups: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl,

[0020] In certain embodiments, Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following groups which are optionally substituted: When substituted, it is substituted by 1 to 4 substituents selected from deuterium, F, CF3, OH, methyl, =O, hydroxymethyl, methoxy, COOH, CN, NH2, cyclopropyl;

[0022] In certain embodiments, R L Selected from H, C 1-4 Alkyl, C 3-7 carbocyclic group, 4 to 10 membered heterocyclic group, the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z Substitution; in certain embodiments, R L Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl, the alkyl, cycloalkyl is optionally substituted by 1 to 4 R z Substitution; in certain embodiments, R L Select from H or C 1-4 alkyl;

[0023] In certain embodiments, s1, s3, s5 are each independently selected from 0, 1 or 2; in certain embodiments, s2, s4 are each independently selected from 0 or 1; in certain embodiments, s6 is selected from 0, 1, 2 or 3; in certain embodiments, s7 is selected from 1, 2 or 3;

[0024] In certain embodiments, R L is selected from H, methyl or ethyl;

[0025] In certain embodiments, q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0026] In certain embodiments, L is selected from the group shown in Table L-1, wherein the left side of the group is connected to B;

[0027] In certain embodiments, L is selected from the groups shown in Table L-1 or Table L-2, wherein the left side of the group is connected to B;

[0028] In certain embodiments, B is selected from In certain embodiments, B is selected from

[0029]

[0030]

[0031] In certain embodiments, B is selected from one of the structures shown in Table B-1;

[0032] In certain embodiments, b1 is selected from 0, 1, 2, 3 or 4;

[0033] In certain embodiments, Ring B is selected from one of the structural fragments shown in Table B-1;

[0034] In certain embodiments, X1 is selected from N or CR x1 ; In certain embodiments, X1 is selected from N or CH; In certain embodiments, X2 is selected from a bond, O, S or NR x2 In certain embodiments, X2 is selected from a bond, O, S, NH, N(CH3); In certain embodiments, X3 is selected from a bond or C 1-4 Alkylene, the alkylene group is optionally substituted by 1 to 4 R z Substitution; In certain embodiments, X3 is selected from a bond, -CH2- or -CH2CH2-;

[0035] In certain embodiments, B1 is selected from C 6-10 aryl or 5 to 10 membered heteroaryl, said B1 is optionally substituted by 1 to 4 R b1 In certain embodiments, B1 is selected from phenyl, naphthyl, pyridyl, benzopyridyl, benzopyrimidinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyrazolyl, benzopyrrolyl, and B1 is optionally substituted by 1 to 4 R b1 replace;

[0036] In certain embodiments, B2 is selected from a 6- to 12-membered nitrogen-containing heterocyclic group or NR x3 R x4 , preferably a 6- to 12-membered nitrogen-containing heterocycloalkyl, wherein B2 is optionally replaced by 1 to 4 R b2 In some embodiments, B2 is selected from a 6- to 7-membered monocyclic nitrogen-containing heterocyclic group, a 6- to 10-membered cyclic nitrogen-containing heterocyclic group, a 6- to 10-membered spirocyclic nitrogen-containing heterocyclic group, a 6- to 10-membered bridged nitrogen-containing heterocyclic group, preferably a 6- to 7-membered monocyclic nitrogen-containing heterocycloalkyl group, a 6- to 10-membered cyclic nitrogen-containing heterocycloalkyl group, a 6- to 10-membered spirocyclic nitrogen-containing heterocycloalkyl group, a 6- to 10-membered bridged nitrogen-containing heterocycloalkyl group or NR x3 R x4 , said B2 is optionally replaced by 1 to 4 R b2 Substituted; In certain embodiments, B2 is selected from or NR x3 R x4 , said B2 is optionally replaced by 1 to 4 R b2 replace;

[0038] In certain embodiments, R x3 , R x4 Each independently selected from C1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocycloalkyl, the alkyl, cycloalkyl, heterocycloalkyl optionally substituted by 1 to 4 R z Substitution; in certain embodiments, R x3 , R x4 Each independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocycloalkyl, the alkyl, cycloalkyl, heterocycloalkyl optionally substituted by 1 to 4 R z Substitution; in certain embodiments, R x3 , R x4 Each independently selected from optionally 1 to 4 R z substituted with one of the following groups: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxolanyl, oxetanyl; in certain embodiments, B3 is selected from -C 0-4 Alkylene-C 3-12 Carbocyclic or -C 0-4 Alkylene-4 to 12 membered heterocyclic group, said B3 is optionally substituted by 1 to 6 R b3 In certain embodiments, B3 is selected from C 3-6 Monocyclic carbocyclic group, C 6-12 Spirocarbocyclic group, C 6-12 Cyclic carbocyclic group, C 5-10 bridged ring carbocyclic group, 4-7 membered monocyclic heterocyclic group, 6-12 membered cyclic heterocyclic group, 6-13 membered spirocyclic heterocyclic group, 7-12 membered bridged ring heterocyclic group, -CH2-C 3-6 Carbocyclic group, -CH2-C 6-12 Spirocyclic carbocyclic group, -CH2-C 6-12 Cyclic carbocyclic group, -CH2-C 5-10 bridged ring carbocyclic group, -CH2-4-7 membered monocyclic heterocyclic group, -CH2-6-12 membered cyclic heterocyclic group, -CH2-6-13 membered spirocyclic heterocyclic group, -CH2-7-12 membered bridged ring heterocyclic group, -CH2CH2-C 3-6 Carbocyclic group, -CH2CH2-C 6-12 Spirocyclic carbocyclic group, -CH2CH2-C 6-12 Cyclic carbocyclic group, -CH2CH2-C 5-10 a bridged ring carbocyclic group, a -CH2CH2-4-7-membered monocyclic heterocyclic group, a -CH2CH2-6-12-membered cyclic heterocyclic group, a -CH2CH2-6-13-membered spirocyclic heterocyclic group, a -CH2CH2-7-12-membered bridged ring heterocyclic group, wherein B3 is optionally substituted by 1 to 6 R b3substituted; in certain embodiments, B3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, azetidinyl, azetyl, azocyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-phenyl, -CH2-pyridyl, -CH2-pyrimidinyl, -CH2-pyrazinyl, -CH2-pyridazinyl, -CH2-azetidinyl, -CH2- azocyclopentyl, -CH2-azacyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-cyclohexyl, -CH2CH2-phenyl, -CH2CH2-pyridyl, -CH2CH2-pyrimidinyl, -CH2CH2-pyrazinyl, -CH2CH2-pyridazinyl, -CH2CH2-azetidinyl, -CH2CH2-azacyclopentyl, -CH2CH2-azacyclohexyl, The B3 is optionally replaced by 1 to 6 R b3 replace;

[0039] In certain embodiments, R x2 Selected from H, D, C 1-6 Alkyl, C 3-7 Cycloalkyl, the alkyl, cycloalkyl is optionally substituted by 1 to 4 R z Substitution; in certain embodiments, R x2 Selected from H, D, C 1-4 Alkyl, C 3-6 Cycloalkyl, the alkyl, cycloalkyl is optionally substituted by 1 to 4 R z Substitution; in certain embodiments, R x2 Selected from H, D or optionally 1 to 4 R z Substituted one of the following groups: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0040] In certain embodiments, R b1 , R x1 , R b4 , R b5 Each independently selected from H, deuterium, halogen, OH, cyano, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, -OC3-6 Cycloalkyl, C 6-10 Aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkylene, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted by 1 to 4 R z replace;

[0041] In certain embodiments, R b1 , R x1 , R b4 , R b5 Each independently selected from H, deuterium, halogen, OH, cyano, NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, -CH2-C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, phenyl or 5- to 6-membered heteroaryl, wherein the alkyl, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl is optionally substituted by 1 to 4 R z replace;

[0042] In certain embodiments, R b1 Each independently selected from H, deuterium, F, Cl, Br, OH, CN, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R z substituted with one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, -CH2-ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxolyl, oxetanyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, phenyl, or a 5- to 6-membered heteroaryl;

[0043] In certain embodiments, R b4 is selected from H, deuterium, F, Cl, Br, OH, CN, CF3, CHF2, CH2F, methyl, ethyl, methoxy or cyclopropyl; in certain embodiments, R b5 is selected from F, Cl, Br, OH, CN, CF3, CHF2, CH2F, methyl, ethyl, methoxy or cyclopropyl;

[0044] In certain embodiments, R b2, R b3 Each independently selected from deuterium, halogen, OH, =O, cyano, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, C(=O)C 1-6 Alkyl, C(=O)C 2-6 Alkenyl, C(=O)C 2-6 Alkynyl, C(=O)NH2, C(=O)NH(C 1-6 alkyl), C(=O)N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, alkylthio, alkynyl, alkenyl, cycloalkyl is optionally substituted by 1 to 4 R z replace;

[0045] In certain embodiments, R b2 , R b3 Each independently selected from deuterium, halogen, OH, =O, cyano, NH2, -NH(C 1-4 Alkyl), -N(C 1-4 Alkyl)2, -C(=O)C 1-4 Alkyl, -C(=O)C 2-4 Alkenyl, -C(=O)C 2-4 Alkynyl, C(=O)NH2, C(=O)NH(C 1-4 alkyl), C(=O)N(C 1-4 Alkyl)2, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, C 2-4 Alkynyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, alkylthio, alkynyl, alkenyl, cycloalkyl is optionally substituted by 1 to 4 R z replace;

[0046] In certain embodiments, R b2 , R b3 Each independently selected from deuterium, F, Cl, Br, OH, =O, CN, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R zsubstituted by one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, -CH2-ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C(=O)NH2, C(=O)N(CH3)2, -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH=CH2, -C(=O)CH=CH2CH3;

[0047] In certain embodiments, ring K1 and ring K2 are each independently selected from phenyl, benzo 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl, 5-membered heteroaryl and 4- to 6-membered heterocyclyl, 6-membered heteroaryl and 4- to 6-membered heterocyclyl, C 10-15 tricyclic carbocyclyl, 10- to 15-membered tricyclic heterocyclyl, 12- to 19-membered tetracyclic heterocyclyl;

[0048] In certain embodiments, ring K1 is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl,

[0050] In certain embodiments, ring K1 is selected from phenyl, naphthyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,

[0051] In certain embodiments, ring K2 is selected from cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 2,3-dihydro-1H-indenyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazine, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, furanyl, thienyl, thiazolyl, 2-pyridonyl,

[0052] In certain embodiments, ring K2 is selected from phenyl, naphthyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl,

[0053] In certain embodiments, Fa is selected from N, CH or CR k1 In certain embodiments, Fb is selected from N, CH or CR k1 ;

[0054] In certain embodiments, Fc is selected from O, S, NH, N(CH3) or NR k7a In certain embodiments, Fd is selected from N, CH or CR k1 ;

[0055] In certain embodiments, Ff is selected from a bond, O, CH2, CHF, CF2, NH, N(CH3), N(R k1 )、C(R k1 )2; in certain embodiments, Fg is selected from N or C; in certain embodiments, Fh is selected from N or C; in certain embodiments, Faa is selected from a bond, O, CH2;

[0056] In certain embodiments, Fab is selected from O, CH2;

[0057] In certain embodiments, ring E is selected from phenyl or 5-6 membered heteroaryl, wherein ring E is optionally substituted by 1 to 3 R k1 replace;

[0058] In certain embodiments, each ring E is independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl, and the ring E is optionally substituted by 1 to 3 R k1 replace;

[0059] In certain embodiments, ring F1, ring F2, ring F3, and ring F4 are each independently selected from phenyl or 5-6 membered heteroaryl, and the ring F1, ring F2, ring F3, and ring F4 are optionally substituted by 1 to 2 R k1 In certain embodiments, ring F1 and ring F2 are each independently selected from phenyl, pyridyl, thiazolyl, furyl, thienyl or oxazolyl, and the ring F1 and ring F2 are optionally substituted by 1 to 2 R k1 replace;

[0060] In certain embodiments, ring F3 and ring F4 are each independently selected from phenyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, furanyl, thienyl or oxazolyl, and the ring F3 and ring F4 are optionally substituted by 1 to 2 R k1 replace;

[0061] In certain embodiments, R k5 Each independently selected from C(CH3)2, C(=O), CH2, CH2CH2, S(=O)2, In certain embodiments, R k6 are each independently selected from CO, CH, S(=O), S(=O)2, CH2 or N; in certain embodiments, Rk7 Each independently selected from C(CH3)2, CH2, O; in certain embodiments, R k8 Selected from CH2CH2,

[0062] In certain embodiments, R k7a is selected from methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, CF3, C 1-4 Alkyl, C 1-4 Alkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Substituted by a cycloalkyl substituent;

[0063] In certain embodiments, R k7a is selected from CD3, methyl, ethyl, -CH2CF3, isopropyl, -CH2-cyclopropyl, -CH(CH3)-cyclopropyl, -CH2OCH3, -CH2CH2OCH3, cyclopropyl, -CH2-vinyl, -CH2-ethynyl,

[0064] In certain embodiments, R k9 are each independently selected from a bond, C(CH3)2, C(=O), CH2, CH2CH2 or S(=O)2;

[0065] In certain embodiments, G is selected from NH, N, CR k3 or C(R k3 )2; In certain embodiments, G is selected from CH or N;

[0066] In certain embodiments, each Q is independently selected from -O-, -S-, -NR q -, -NHCO- or -NR q CO-; in certain embodiments, Q is selected from N(CH3), O, S, C(=O), NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3);

[0067] In certain embodiments, R q Selected from C 1-4 alkyl;

[0068] In certain embodiments, R k1 Each independently selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R z replace;

[0069] Alternatively, two R k1 Direct connection to form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 selected from R z replace;

[0070] In certain embodiments, R k1 , R k3 Each independently selected from F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2;

[0071] In certain embodiments, R k2 are each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-; In certain embodiments, R k2 are each independently selected from -C(=O)-, -S(=O)2- or -S(=O)-; in certain embodiments, R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl or 3 to 8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace;

[0072] Alternatively, two R k3 Direct connection to form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 selected from R z replace;

[0073] In certain embodiments, R k4 Each independently selected from H, OH, NH2, CN, CONH2, C 1-4 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 R z Substitution; in certain embodiments, R k4 Each independently selected from H, CF3 or C 1-4 alkyl; in certain embodiments, R k4 Each is independently selected from H or methyl;

[0074] 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, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0075] Alternatively, R L2 With R k1 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0076] In certain embodiments, 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, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0077] Alternatively, R L2 With R k1 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0078] In certain embodiments, n1 is each independently selected from 0, 1, 2 or 3; In certain embodiments, n1 is selected from 0, 1 or 2;

[0079] In certain embodiments, p1, p2, and p3 are each independently selected from 0, 1, 2, 3, 4, or 5;

[0080] In certain embodiments, p2 is each independently selected from 0, 1, 2 or 3;

[0081] In certain embodiments, K is selected from

[0082] In certain embodiments, Selected from In certain embodiments, Selected from In certain embodiments, K is selected from In certain embodiments, K is selected from

[0084] In certain embodiments, K is selected from one of the structural fragments shown in Table K-1;

[0085] In certain embodiments, The ring where the representative is located is an aromatic ring or a non-aromatic ring;

[0086] In certain embodiments, F jSelected from N, NH, CH, CH2, NR k1 , CR k1 , C(R k1 )2;

[0087] In certain embodiments, F6, F7, F8 are each independently selected from N, CH or CR k1 , and F6, F7, and F8 contain at most 2 Ns;

[0088] In certain embodiments, Y1 is selected from N or CH;

[0089] In certain embodiments, Y2 is selected from N, C or CH;

[0090] Optionally, when ring K2 is selected from phenyl, p1 is selected from 1, 2, 3, 4 or 5;

[0091] K is not optionally substituted

[0092] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

[0093] L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-;

[0094] Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q - or a bond, wherein the -CH2- is optionally replaced by 1 to 2 R z replace;

[0095] q is each independently selected from 0, 1, 2, 3, 4, 5 or 6;

[0096] R L Selected from H, C 1-4 Alkyl, C 3-7 carbocyclic group, 4 to 10 membered heterocyclic group, the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0097] 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: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl;

[0098] B is selected from

[0099] X1 is selected from N or CR x1 ;

[0100] X2 is selected from a bond, O, S or NR x2 ;

[0101] X3 is selected from a bond or C 1-4 Alkylene, the alkylene group is optionally substituted by 1 to 4 R z replace;

[0102] B1 is selected from C 6-10 aryl or 5 to 10 membered heteroaryl, said B1 is optionally substituted by 1 to 4 R b1 replace;

[0103] B2 is selected from a 6- to 12-membered nitrogen-containing heterocyclic group or NR x3 R x4 , preferably a 6- to 12-membered nitrogen-containing heterocycloalkyl, wherein B2 is optionally replaced by 1 to 4 R b2 replace;

[0104] R x3 , R x4 Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocycloalkyl, the alkyl, cycloalkyl, heterocycloalkyl optionally substituted by 1 to 4 R z replace;

[0105] B3 Selected from -C 0-4 Alkylene-C 3-12 Carbocyclic or -C 0-4Alkylene-4 to 12 membered heterocyclic group, said B3 is optionally substituted by 1 to 6 R b3 replace;

[0106] R x2 Selected from H, D, C 1-6 Alkyl, C 3-7 Cycloalkyl, the alkyl, cycloalkyl is optionally substituted by 1 to 4 R z replace;

[0107] R b1 , R x1 , R b4 , R b5 Each independently selected from H, deuterium, halogen, OH, cyano, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 6-10 Aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkylene, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted by 1 to 4 R z replace;

[0108] R b2 , R b3 Each independently selected from deuterium, halogen, OH, =O, cyano, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, C(=O)C 1-6 Alkyl, C(=O)C 2-6 Alkenyl, C(=O)C 2-6 Alkynyl, C(=O)NH2, C(=O)NH(C 1-6 alkyl), C(=O)N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, alkylthio, alkynyl, alkenyl, cycloalkyl is optionally substituted by 1 to 4 R z replace;

[0109] K is selected from

[0110] G is selected from NH, N, CR k3 or C(R k3 )2;

[0111] Q is independently selected from -O-, -S-, -NR q -, -NHCO- or -NR q CO-;

[0112] R q Selected from C 1-4 alkyl;

[0113] Ring K1 and Ring K2 are each independently selected from phenyl, benzo 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl, 5-membered heteroaryl and 4- to 6-membered heterocyclyl, 6-membered heteroaryl and 4- to 6-membered heterocyclyl, C 10-15 tricyclic carbocyclyl, 10- to 15-membered tricyclic heterocyclyl, 12- to 19-membered tetracyclic heterocyclyl;

[0114] R k1 Each independently selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R z replace;

[0115] R k2 are each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-;

[0116] R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl or 3 to 8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace;

[0117] Alternatively, two R k3 Direct connection to form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 selected from Rz replace;

[0118] Alternatively, two R k1 Direct connection to form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace;

[0119] R k4 Each independently selected from H, OH, NH2, CN, CONH2, C 1-4 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0120] 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, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0121] Alternatively, R L2 With R k1 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace;

[0122] n1 is independently selected from 0, 1, 2 or 3;

[0123] p1, p2, p3 are each independently selected from 0, 1, 2, 3, 4 or 5;

[0124] When ring K2 is selected from phenyl, p1 is selected from 1, 2, 3, 4 or 5;

[0125] K is not optionally substituted

[0126] As a second embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

[0127] R L is selected from H, methyl or ethyl, the methyl or ethyl group is optionally substituted by 1 to 4 R z replace;

[0128] Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl;

[0129] X1 is selected from N or CH;

[0130] X2 is selected from a bond, O, S, NH, N(CH3);

[0131] X3 is selected from a bond, -CH2- or -CH2CH2-;

[0132] B2 is selected from a 6- to 7-membered monocyclic nitrogen-containing heterocyclic group, a 6- to 10-membered fused nitrogen-containing heterocyclic group, a 6- to 10-membered spirocyclic nitrogen-containing heterocyclic group, a 6- to 10-membered bridged nitrogen-containing heterocyclic group or NR x3 R x4 ,

[0133] B3 is selected from C 3-6 Monocyclic carbocyclic group, C 6-12 Spirocarbocyclic group, C 6-12 Cyclic carbocyclic group, C 5-10 bridged ring carbocyclic group, 4-7 membered monocyclic heterocyclic group, 6-12 membered cyclic heterocyclic group, 6-13 membered spirocyclic heterocyclic group, 7-12 membered bridged ring heterocyclic group, -CH2-C 3-6 Carbocyclic group, -CH2-C 6-12 Spirocyclic carbocyclic group, -CH2-C 6-12 Cyclic carbocyclic group, -CH2-C 5-10 bridged ring carbocyclic group, -CH2-4-7 membered monocyclic heterocyclic group, -CH2-6-12 membered cyclic heterocyclic group, -CH2-6-13 membered spirocyclic heterocyclic group, -CH2-7-12 membered bridged ring heterocyclic group, -CH2CH2-C 3-6 Carbocyclic group, -CH2CH2-C 6-12Spirocyclic carbocyclic group, -CH2CH2-C 6-12 Cyclic carbocyclic group, -CH2CH2-C 5-10 a bridged ring carbocyclic group, a -CH2CH2-4-7-membered monocyclic heterocyclic group, a -CH2CH2-6-12-membered cyclic heterocyclic group, a -CH2CH2-6-13-membered spirocyclic heterocyclic group, a -CH2CH2-7-12-membered bridged ring heterocyclic group, wherein B3 is optionally substituted by 1 to 6 R b3 replace;

[0134] K is selected from

[0135] G is selected from CH or N;

[0136] Q is selected from N(CH3), O, S, C(=O), NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3);

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

[0138] F j Selected from N, NH, CH, CH2, NR k1 , CR k1 , C(R k1 )2;

[0139] Ff is selected from a bond, O, CH2, CHF, CF2, NH, N(CH3), N(R k1 )、C(R k1 )2;

[0140] F6, F7, F8 are each independently selected from N, CH or CR k1 , and F6, F7, and F8 contain at most 2 Ns;

[0141] Y1 is selected from N or CH;

[0142] Y2 is selected from N, C or CH;

[0143] R k1 Each independently selected from F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2;

[0144] R k2 Each independently selected from -C(=O)-, -S(=O)2- or -S(=O)-;

[0145] n1 is selected from 0, 1 or 2.

[0146] 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, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0147] The remaining definitions are the same as those of the first embodiment of the present invention.

[0148] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

[0149] K is selected from

[0150] Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following groups which are optionally substituted: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, methyl, =0, hydroxymethyl, methoxy, COOH, CN, NH2 or cyclopropyl.

[0152] 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)-;

[0153] B1 is selected from phenyl, naphthyl, pyridyl, benzopyridyl, benzopyrimidinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyrazolyl, benzopyrrolyl, and said B1 is optionally substituted by 1 to 4 R b1 replace;

[0154] B2 is selected from

[0155] or NR x3 R x4 , said B2 is optionally replaced by 1 to 4 R b2 replace;

[0156] R x3 , R x4 Each independently selected from optionally 1 to 4 R z substituted with one of the following groups: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxolanyl, oxehexyl;

[0157] B3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, azetidinyl, azetyl, azopentyl, azohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-phenyl, -CH2-pyridyl, -CH2-pyrimidinyl, -CH2-pyrazinyl, -CH2-pyridazinyl, -CH2-azetidinyl, -CH2-azacyclopentyl, -CH2-azacyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-cyclohexyl, -CH2CH2-phenyl, -CH2CH2-pyridyl, -CH2CH2-pyrimidinyl, -CH2CH2-pyrazinyl, -CH2CH2-pyridazinyl, -CH2CH2-azetidinyl, -CH2CH2-azacyclopentyl, -CH2CH2-azacyclohexyl, The B3 is optionally replaced by 1 to 6 R b3 replace;

[0158] R b1 Each independently selected from H, deuterium, F, Cl, Br, OH, CN, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R z substituted with one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, -CH2-ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxolyl, oxetanyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, phenyl, or a 5- to 6-membered heteroaryl;

[0159] R b4 is selected from H, deuterium, F, Cl, Br, OH, CN, CF3, CHF2, CH2F, methyl, ethyl, methoxy or cyclopropyl;

[0160] R b5 is selected from F, Cl, Br, OH, CN, CF3, CHF2, CH2F, methyl, ethyl, methoxy or cyclopropyl;

[0161] R b2 , R b3 Each independently selected from deuterium, F, Cl, Br, OH, =O, CN, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R zsubstituted by one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, -CH2-ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C(=O)NH2, C(=O)N(CH3)2, C(=O)CH3, C(=O)CH2CH3, C(=O)CH=CH2, C(=O)CH=CH2CH3;

[0162] R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

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

[0164] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

[0165] K is selected from

[0166] L is selected from -NHCH2-, -Cy1-, -Cy1-CH2-, -CH2-Cy1-, -Cy1-C≡C-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -Cy1-C(=O)-CH2-Cy2-, -Cy1-C(=O)-Cy2-, -C(=O)-C y1-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-, -NH-Cy1-, -NH-Cy1-O-, -O-Cy1-NH-, -NH-Cy1-Cy2-, -NH-Cy1-CH2-Cy2, - N(CH3)-CH2-Cy1-, -CH2-Cy1-CH2-Cy2-NH-, -Cy1-CH2-Cy2-NH-, -Cy1-CH2CH2-Cy2-, -CH2-Cy1-CH2CH2-Cy2-, -CH2-Cy1-CH2-Cy2-, -Cy1- C(=O)NH-CH2CH2-O-CH2CH2-O-, -Cy1-C(=O)NH-CH2CH2-O-, -Cy1-C(=O)NH-, -CH2-Cy1-C(=O)-Cy2-, -Cy1-C(=O)-CH2-Cy2- or -C(=O)-Cy1-;

[0167] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0168] As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

[0169] B is selected from

[0170]

[0171] b1 is selected from 0, 1, 2, 3 or 4;

[0172] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0173] As a sixth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:

[0174] B is selected from one of the structures shown in Table B-1;

[0175] L is selected from one of the structures shown in Table L-1 or Table L-2;

[0176] K is selected from one of the structural fragments shown in Table K-1;

[0177] The remaining definitions are the same as those of the first, second, third, fourth or fifth embodiment of the present invention.

[0178] The present invention relates to the following compound or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from one of the structures in Table E.

[0179] The present invention relates to a pharmaceutical composition, comprising the above-mentioned compound of the present invention or its stereoisomer, deuterated substance, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0180] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a drug for treating a disease related to KRAS activity or expression.

[0181] The present invention relates to the use of the above-mentioned compound of the present invention or its stereoisomer, deuterated product, stereoisomer, tautomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the preparation of a drug for treating, inhibiting or degrading KRAS-related diseases.

[0182] In some embodiments, the disease associated with inhibiting or degrading KRAS is cancer.

[0183] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal and a pharmaceutical excipient. The pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").

[0184] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition. In some embodiments, the mammal of the present invention includes a human.

[0185] "Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition (e.g., cancer) being treated to some extent. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3 -500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg , 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400 mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300- 400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 9 0-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40 -200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1500mg, 80-1000mg, 80-800mg;.

[0186] 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 mg, 130 mg,

[0187] 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg, 1000 mg of a compound of the present invention or a stereoisomer, deuterated substance, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0188] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated substance, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being an autoimmune disease, an inflammatory disease or a cancer.

[0189] A method for treating a disease in a mammal, the method comprising administering a drug compound of the present invention or a stereoisomer, deuterated substance, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof to a subject 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-

[0190] In some embodiments, the daily dose includes but is not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 80 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 160 mg / day, 200 mg / day, 300 mg / day, 320 mg / day, 400 mg / day, 480 mg / day, 600 mg / day, 640 mg / day, 800 mg / day, 1000 mg / day, 1500 mg / day.

[0191] The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, deuterated substance, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as its amount in the above-mentioned pharmaceutical composition.

[0192] The amount of the compound of the invention or its stereoisomer, deuterated form, stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0193] In order to accomplish the purpose of the present invention, the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TCI (Shanghai) Chemical Industry Development Co., Ltd., Anage Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.

[0194] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0195] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C. 13 C and 14C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0196] "CN" refers to cyano.

[0197] "Halogen" refers to F, Cl, Br or I.

[0198] "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".

[0199] "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.

[0200] "Alkylene" refers to substituted or unsubstituted straight-chain or 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.

[0201] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms, and the cycloalkyl radical can be a monocyclic, cyclic, bridged, and spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, adamantane, etc. The cycloalkyl radical can be monovalent, divalent, trivalent, or tetravalent.

[0202] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocyclic, cyclic, bridged and spirocyclic. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxadiazine, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazininyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,

[0203] The heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

[0204] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least 1, typically 1, 2 or 3 carbon-carbon double bonds, with a main chain including but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl and the like; alkenyl can be monovalent, divalent, trivalent or tetravalent.

[0205] "Alkynyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least 1, typically 1, 2 or 3 carbon-carbon triple bonds, with a main chain comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms on the main chain and 2 to 4 carbon atoms on the main chain. Examples of alkynyl include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, etc.; alkynyl can be monovalent, divalent, trivalent or tetravalent.

[0206] "Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0207] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, a 10-15-membered tricyclic ring, or a 12-18-membered quaternary system. The carbocyclyl can be attached to an aromatic ring or a non-aromatic ring, and the ring can be optionally a monocyclic ring, a cyclic ring, a bridged ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

[0208] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se selectively 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-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

[0210] "Spiro" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called spiro atom), and the number of ring atoms in the spiro system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 selected from N, O or S (=O) n (n is 0, 1 or 2).

[0211]

[0212] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0213] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to selected from N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:

[0215] "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

[0216] "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 0 or more double bonds. Any ring in the bridged ring system may contain 0 to 5 groups selected from heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12 or 5 to 10.

[0217] Non-limiting examples include Cubane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent or tetravalent.

[0219] "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" wherein the ring system consists of only carbon atoms.

[0220] "Carbocyclic", "cyclic carbocyclyl", "carbocyclyl" or "carbocyclyl" refers to a "cyclic" ring system consisting of only carbon atoms.

[0221] "Carbobridged ring", "bridged ring carbocyclic group", "bridged carbocyclic group" or "carbon bridged cyclic group" refers to a "bridged ring" wherein the ring system consists of only carbon atoms.

[0222] "Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a monocyclic ring system of "heterocyclyl" or "heterocycle",

[0223] "Heterocyclic ring", "heterocyclic group", "cycloheterocyclyl" or "cycloheterocyclyl" refers to a "cyclo" containing a heteroatom.

[0224] "Heterospirocycle", "heterospirocyclyl", "spiroheterocyclyl" or "spiroheterocyclyl" refers to a "spirocycle" containing a heteroatom.

[0225] "Heterobridged ring", "heterobridged ring group", "bridged ring heterocyclyl" or "bridged heterocyclyl" refers to a "bridged ring" containing a heteroatom.

[0226] "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.

[0227] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group, and contains 1 to 5 selected heteroatoms or groups containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. The atoms C, N, and S on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, n is 1, 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furanyl, thienyl, selenophenyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl, and the like. The heteroaryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include The heteroaryl groups appearing in this article have the same definition as this definition. The heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment site is located on the aromatic ring.

[0228] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, 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, silane or -NR b R c etc., where R b With R c is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R b With R c Can form a five- or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or paracyclic groups.

[0229] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is selected from any integer between 1 and 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k For example, "1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4 or 5 substituents selected from..." For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0230] The XY-membered ring (X, Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes X, X+1, X+2, X+3, X+4...Y-membered rings. The ring includes a heterocyclic ring, a carbocyclic ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocyclic ring, a heterocyclic ring, a heterospirocyclic ring or a heterobridged ring. For example, "4-7-membered heteromonocyclic ring" refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5-10-membered heterocyclic ring" refers to a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heterocyclic ring.

[0231] C x-y Carbocycles (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, fused carbocycle or bridged carbocycle) include C x , Cx+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" means C3, C4, C5 or C6 cycloalkyl;

[0232] When a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection is non-positional and there are hydrogen atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds and become a group with the corresponding valence. For example It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes

[0233] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0234] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0235] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0236] "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.

[0237] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0238] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0239] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.

[0240] General synthesis method 1:

[0241]

[0242] The compound of the general formula (D-1-2) is subjected to a nucleophilic substitution reaction, or a coupling reaction, or a reductive amination, or a condensation reaction to obtain a compound of the general formula (D-1-3); or the compound of the general formula (D-1-2) is first subjected to the removal of the protecting group, and then subjected to a nucleophilic substitution reaction, or a coupling reaction, or a reductive amination, or a condensation reaction to obtain a compound of the general formula (D-1-3);

[0243] Compound (Z-1-1) and compound (Z-1-2) of the general formula are reacted by nucleophilic substitution to obtain a compound of the general formula (Z-1-3);

[0244] The compound of the general formula (Z-1-3) and the compound (Z-1-4) are subjected to coupling reaction to obtain the compound of the general formula (Z-1-5);

[0245] The compound of the general formula (Z-1-5) is firstly subjected to the removal of the hydroxyl protecting group and oxidation to the aldehyde group, and then subjected to a nucleophilic substitution reaction with the compound of the general formula (D-1-3) (or the removal of the amino protecting group of the compound of the general formula (D-1-3)) to obtain the compound of the general formula (Z-1-6);

[0246] The compound of the general formula (Z-1-6) is freed from the protecting group to obtain the compound of the general formula (Z-1);

[0247] R D-1-1 Selected from H, or a hydroxyl protecting group;

[0248] R D-1-2 is selected from H, an amino protecting group;

[0249] R D-1-3 is selected from H, an amino protecting group;

[0250] The definitions of the remaining groups are consistent with the description. DETAILED DESCRIPTION

[0251] The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0252] The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. "Commercially available chemicals" are obtained from regular commercial sources, and suppliers include: Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Nanjing Yaoshi, WuXi AppTec, and Bailingwei Technology.

[0253] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were measured in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometer, the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS);

[0254] MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0255] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0256] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) uses a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;

[0257] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0258] The * next to a chiral atom indicates that the atom has either R or S chirality.

[0259] Preparation of compounds Aa and Ab:

[0260]

[0261] The intermediate A (2.8 g, 13.58 mmol) (synthesis method, see Bioorganic & Medicinal Chemistry Letters, 2016, 26, 5877-5882) was dissolved in dichloromethane (50 mL), and Boc2O (5.93 g, 27.17 mmol) and DMAP (3.32 g, 27.18 mmol) were added, and the reaction was carried out at room temperature for 16 h. The reaction system was washed with 0.5 mol / L hydrochloric acid (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1-1:9) to obtain a racemic mixture of Aa and Ab (3.4 g, yield: 82%).

[0262] The racemic mixture of Aa and Ab is subjected to chiral separation, and the chiral separation method is as follows:

[0263] 1. Instrument: SFC Prep 150AP; Chromatographic column: Daicel IC-H (19 mm × 250 mm).

[0264] 2. Dissolve the sample in methanol and filter it with a 0.45 μm filter to prepare a sample solution.

[0265] 3. Preparative chromatographic conditions: a. The mobile phase consists of A and B system: mobile phase A: CO2; mobile phase B: methanol / isopropanol (v / v) = 1:1; b. Isocratic elution, mobile phase B content is 20%; c. Flow rate is 40 mL / min.

[0266] Peak time: chiral isomer 1 (compound Aa): 5.7 min, chiral isomer 2 (compound Ab): 6.47 min.

[0267] According to the MicroED structure determination of compound Ab-1, compound Aa is R configuration and compound Ab is S configuration.

[0268] LCMS m / z=307.3[M+1] + .

[0269] Synthesis of intermediate A-2:

[0270]

[0271] Step 1: Preparation of Ab-1

[0272] Ab (1.4 g, 4.57 mmol) was dissolved in acetonitrile (50 mL), and NBS (0.81 g, 4.55 mmol) was added, and the reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1-1:9) to obtain Ab-1 (1.6 g, yield: 92%).

[0273] LCMS m / z=385.3[M+1] + .

[0274] The compound Ab-1 was determined to be in S configuration by MicroED structure analysis.

[0275] Step 2: Preparation of Ab-2

[0276] Ab-1 (1.6 g, 4.16 mmol), intermediate Ab-1-1 (3.46 g, 8.29 mmol), Pd(dppf)Cl2·DCM (0.34 g, 0.42 mmol) and cesium carbonate (2.70 g, 8.3 mmol) were added to a reaction bottle, 1,4-dioxane (50 mL) and water (5 mL) were added, and the reaction was carried out at 100°C for 20 h under a nitrogen atmosphere. The reaction system was cooled to room temperature, 50 mL of water and 50 mL of ethyl acetate were added, the aqueous phase was extracted with ethyl acetate (50 mL), the organic phase was washed with 30 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to obtain Ab-2 (1.4 g, yield: 56%).

[0277] Step 3: Preparation of Ab-3

[0278] Ab-2 (1.4 g, 2.35 mmol) was dissolved in THF (50 mL), 10% palladium carbon (1.25 g) was added, and the mixture was reacted at 45°C under a hydrogen atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel chromatography (MeOH:DCM (v / v) = 0:1-5:95) to obtain Ab-3 (0.85 g, yield: 87%).

[0279] LCMS m / z=418.1[M+1] + .

[0280] Step 4: Preparation of A-2

[0281] Ab-3 (620 mg, 1.49 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (3 mL) was added, and the reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the reaction was concentrated under reduced pressure to obtain a crude product A-2 (460 mg).

[0282] LCMS m / z=318.3[M+1] + .

[0283] Synthesis of intermediate A-1:

[0284]

[0285] Step 1: Preparation of Aa-1

[0286] Aa (1.8 g, 5.88 mmol) was dissolved in acetonitrile (50 mL), and NBS (1.05 g, 5.90 mmol) was added, and the reaction was carried out at room temperature for 1 h. The reaction system was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether (v / v) = 0:1-1:9) to obtain Aa-1 (1.6 g, yield: 71%).

[0287] LCMS m / z=385.3[M+1] + .

[0288] Step 2: Preparation of Aa-2

[0289] Aa-1 (0.77 g, 2.0 mmol), intermediate Ab-1-1 (1.67 g, 4.0 mmol) (synthesis method see WO2022235945), Pd (dppf) Cl2·DCM (0.16 g, 0.20 mmol) and cesium carbonate (1.30 g, 4.0 mmol) were added to a reaction flask, 1,4-dioxane (30 mL) and water (3 mL) were added, and the reaction was carried out at 100 ° C for 20 h under a nitrogen atmosphere. The reaction system was cooled to room temperature, 50 mL of water and 50 mL of ethyl acetate were added, the aqueous phase was extracted with 50 mL of ethyl acetate, the organic phase was washed with 30 mL of saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate (v / v) = 1:0-9:1) to obtain Aa-2 (0.70 g, yield: 59%).

[0290] Step 3: Preparation of Aa-3

[0291] Aa-2 (0.70 g, 1.18 mmol) was dissolved in THF (20 mL), 10% palladium carbon (0.63 g) was added, and the mixture was reacted at 45°C under a hydrogen atmosphere for 20 h. The reaction system was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel chromatography (MeOH:DCM (v / v) = 0:1-5:95) to obtain Aa-3 (0.25 g, yield: 51%).

[0292] LCMS m / z=418.1[M+1] + .

[0293] Step 4: Preparation of A-1

[0294] Aa-3 (250 mg, 0.6 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (2 mL) was added, and the reaction was carried out at room temperature for 3 h. The reaction system was concentrated under reduced pressure, 5 mL of dichloromethane and 1 mL of triethylamine were added, and the reaction was concentrated under reduced pressure to obtain a crude product A-1 (190 mg).

[0295] LCMS m / z=318.3[M+1] + .

[0296] Example 1: Synthesis of Compound 1

[0297]

[0298] Step 1: Synthesis of 1C

[0299] The raw material A-1 (0.3 g, 0.95 mmol) was dissolved in 5 mL DMAc, N-BOC-4-piperidinecarboxaldehyde (0.3 g, 1.42 mmol) was added, and then 2 drops of glacial acetic acid were added, and the reaction was allowed to react at room temperature for 1 h, and sodium triacetoxyborohydride (0.4 g, 1.9 mmol) was added to the reaction, and the reaction was continued for 2 h. Saturated sodium bicarbonate aqueous solution was added to quench, and the mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the target compound 1C (0.4 g. Yield 81%).

[0300] LCMS m / z=515.3[M+H] +

[0301] Step 2: 1D synthesis

[0302] The raw material 1C (400 mg, 0.78 mmol) was dissolved in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, the reaction was carried out at room temperature for 0.5 h, and the mixture was concentrated under reduced pressure. 20 mL of dichloromethane was added to dissolve the residue, and the pH was adjusted to about 8 with saturated sodium bicarbonate aqueous solution. The organic layer was dried and concentrated to obtain a crude product of the target compound 1D (0.24 g, yield: 80.4%).

[0303] LCMS m / z=414.2[M+H] +

[0304] Step 3: Synthesis of 1F

[0305] The raw materials 1E (0.85 g, 0.72 mmol) and 1E-1 (1.76 g, 3.44 mmol) were placed in a sealed tube, 10 mL of 1,4-dioxane and 2 mL of water were added to dissolve, and then [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium (60 mg, 0.072 mmol) and cesium carbonate (1.68 g, 5.16 mmol) were added in sequence. Under nitrogen protection, the temperature was raised to 100°C for reaction for 16 h, the solvent was removed under reduced pressure, 15 mL of water and 30 mL of ethyl acetate were added to dissolve, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, the organic phases were washed once with 10 mL of saturated brine, and then the organic phases were dried over anhydrous sodium sulfate, spin-dried, and separated and purified by column chromatography to obtain the target compound 1F (0.93 g, yield 64%).

[0306] Step 4: Synthesis of 1G

[0307] The raw material 1F (0.55 g, 0.65 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (0.2 g, 1.95 mmol) was added. Under nitrogen protection, methylsulfonyl chloride (0.15 g, 1.3 mmol) was added dropwise at 0°C. After the addition was complete, the mixture was reacted at room temperature for 2 h, and the mixture was directly concentrated under reduced pressure. The target compound 1G (0.43 g, yield 71%) was obtained by column chromatography separation and purification.

[0308] Step 5: Synthesis of 1H

[0309] The raw material 1G (0.25 g, 0.27 mmol) was dissolved in 3 mL of DMF, 1D (0.17 g, 0.41 mmol) was added, and potassium carbonate (0.11 g, 0.81 mmol) was added, and the mixture was heated to 60°C under nitrogen protection and reacted for 16 h. 15 mL of water and 30 mL of ethyl acetate were added to dissolve the mixture, and the aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, and the organic phases were washed once with 30 mL of saturated brine, and then the organic phases were dried over anhydrous sodium sulfate, spin-dried, and separated and purified by column chromatography to obtain the target compound 1H (90 mg, yield 27%).

[0310] LCMS m / z=1240.5[M+H] +

[0311] Step 6: Synthesis of 1I

[0312] The raw material 1H (90 mg, 0.073 mmol) was dissolved in 3 mL of DMF, cesium fluoride (55 mg, 0.36 mmol) was added, and the mixture was reacted at room temperature for 2 h. 30 mL of ethyl acetate was added to dilute the mixture, and the mixture was washed with water twice and once with saturated brine. The organic phase was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain the target compound 1I (65 mg, yield 82%).

[0313] LCMS m / z=1084.5[M+H] +

[0314] Step 7: Synthesis of Compound 1

[0315] The raw material 1I (65 mg, 0.060 mmol) was dissolved in 10 mL of acetonitrile, and 2 mL of 4N hydrochloric acid-dioxane solution was added. The mixture was reacted at room temperature for 20 minutes, concentrated under reduced pressure, and sent to liquid phase (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) to prepare the target compound 1 (25 mg, yield 44%).

[0316] LCMS m / z=940.5[M+H] +

[0317] 1 H NMR(400MHz,CD3OD)δ9.04(s,1H),7.89–7.81(m,1H),7.38–7.27(m,2H),7.21(d,1H),6.79(d,1H) ,6.53(d,1H),4.67–4.52(m,3H),4.41–4.34(m,1H),3.89–3.80(m,1H),3.76–3.67(m,4H),3.66–3 .58(m,1H),3.55–3.45(m,2H),3.34(s,1H),3.00–2.85(m,4H),2.84–2.53(m,8H),2.28–2.05(m,5 H),1.98–1.73(m,9H),1.72–1.59(m,1H),1.49–1.33(m,2H),0.92–0.83(m,2H),0.76–0.66(m,2H).

[0318] Referring to the preparation of compound 1, the following compound was synthesized:

[0319]

[0320]

[0321]

[0322]

[0323] Example 20: Synthesis of Compound 20

[0324]

[0325] Step 1: Synthesis of compound 20B

[0326] The raw material 20A (10 g, 30.2 mmol) (synthesis method reference WO2022132200) was dissolved in 100 mL DCM, triethylamine (19.52 g, 151 mmol) was slowly added, bromomethyl methyl ether (7.55 g, 60.36 mmol) was added under ice bath, and the reaction was carried out at room temperature under nitrogen protection for 2 days. 300 mL of ethyl acetate was added to dilute, washed with water twice, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to column chromatography to obtain product 20B (8.6 g, yield: 75.89%).

[0327] LCMS m / z=375.1[M+H]+

[0328] Step 2: Synthesis of intermediate P

[0329] Compound 20B (8 g, 21.32 mmol) and 1,1-cyclopropane dimethanol (3.27 g, 31.97 mmol) were dissolved in 100 mL DMF, cesium carbonate (20.84 g, 63.96 mmol) and triethylenediamine (0.23 g, 2.09 mmol) were slowly added, and the reaction was allowed to proceed overnight at room temperature. 600 mL of ethyl acetate was added, washed with water twice, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography to obtain intermediate P (7.8 g, yield: 82.98%). Intermediate P was separated by chiral HPLC to obtain chiral isomer P1 (2.3 g, retention time: 2.427 min) and chiral isomer P2 (2.7 g, retention time: 3.503 min). LCMS m / z=441.1[M+H] +

[0330] The chiral separation method is as follows:

[0331] 1.Instrument: SHIMADZU LC-20AP; Chromatographic column: Chiral IA column.

[0332] 2. The sample was dissolved in a mixed solvent of acetonitrile and DMSO, filtered with a 0.45 μm filter head to prepare a 10 mg / mL sample solution.

[0333] 3. Preparative chromatographic conditions: a. The mobile phase consists of A and B system: mobile phase A: n-hexane; mobile phase B: isopropanol (containing 0.1% isopropanolamine); b. Isocratic elution, mobile phase B content is 20%; c. Flow rate is 60 mL / min.

[0334] The chiral isomer P1 and the chiral isomer P2 of the intermediate P are respectively one of the structures C-1 or C-2. When P1 is the structure C-1, P2 is the structure C-2; conversely, when P1 is the structure C-2, P2 is the structure C-1.

[0335]

[0336] Step 3: Synthesis of compound 20D

[0337] The raw material 20C (1.5 g, 4.04 mmol) was dissolved in 50 mL of 1,4-dioxane, and diboric acid pinacol ester (1.54 g, 6.06 mmol), potassium acetate (1.19 g, 12.12 mmol), and Pd(DPEphos)Cl2 (0.29 g, 0.40 mmol) were added and reacted at 100°C for 12 h. The mixture was cooled to room temperature, diluted with water, extracted with EA three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the product (0.92 g, yield: 54.44%) was obtained by column chromatography.

[0338] LCMS m / z=419.2[M+H] +

[0339] Step 4: Synthesis of compound 20E

[0340] The chiral isomer P2 (0.65 g, 1.47 mmol) was dissolved in 20 mL of toluene, and 20D (0.68 g, 1.62 mmol), potassium phosphate (0.62 g, 2.94 mmol), XPhos-Pd-G3 (0.25 g, 0.29 mmol) and XPhos (0.14 g, 0.29 mmol) were added and reacted at 100°C for 12 h. The mixture was cooled to room temperature, diluted with water, extracted with EA three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the product (0.5 g, yield: 48.82%) was obtained by column chromatography.

[0341] LCMS m / z=697.2[M+H] +

[0342] Step 5: Synthesis of Compound 20F

[0343] Dissolve triphenylphosphine (0.34 g, 1.3 mmol), imidazole (0.36 g, 1.3 mmol), and iodine (0.25 g, 0.98 mmol) in 15 ml tetrahydrofuran, protect with nitrogen, and react for 30 min in the dark. Then add 20E (0.45 g, 0.65 mmol) in tetrahydrofuran (dissolved in 5 mL), and heat to 50°C to react for 2 h. Directly concentrate under reduced pressure, and the residue is subjected to column chromatography to obtain the product (0.23 g, yield: 58.19%).

[0344] LCMS m / z=807.1[M+H] +

[0345] Step 6: Synthesis of Compound 20G

[0346] Compound 20F (0.12 g, 0.15 mmol) was dissolved in 5 mL DMF, and intermediate 3B (0.099 g, 0.22 mmol) and potassium carbonate (0.062 g, 0.45 mmol) were added, and the mixture was heated to 80°C under nitrogen protection for 2 h. 30 mL of ethyl acetate was added, and the mixture was washed with water twice. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography to obtain the product (0.11 g, yield: 65.4%).

[0347] LCMS m / z=1119.4[M+H]+

[0348] Step 7: Synthesis of compound 20

[0349] 20G (0.11 g, 0.098 mmol) was dissolved in 10 mL of dichloromethane, and 3 mL of 4N HCl / Dioxane was added, and the mixture was reacted at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the residue was subjected to liquid phase to obtain the product (22 mg, yield: 18.76%).

[0350] Preparation method: Instrument: Waters 2545; Preparation chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% ammonium acetate).

[0351] LCMS m / z=975.4[M+H] +

[0352] 1 H NMR(400MHz,CD3OD)δ9.21(s,1H),7.41(dd,1H),7.10–7.02(m,1H),6.81(d,1H),6.57(d ,1H),4.55–4.41(m,3H),4.25(d,1H),3.84(dd,1H),3.74(d,1H),3.62(d,1H),3.49–3.3 9(m,1H),3.10–2.86(m,8H),2.84–2.75(m,3H),2.72–2.62(m,3H),2.24–2.02(m,6H),1. 93(s,4H),1.90–1.85(m,2H),1.83–1.71(m,7H),1.27(s,3H),0.90(t,2H),0.74(t,2H).

[0353] Example 21: Synthesis of Compound 21

[0354]

[0355] Step 1: Synthesis of compound 21B

[0356] The raw material 21A (3.0 g, 9.58 mmol) was dissolved in 50 mL of 1,4-dioxane, and diboric acid pinacol ester (4.87 g, 19.16 mmol), potassium carbonate (2.82 g, 28.74 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (0.78 g, 0.96 mmol) were added and reacted at 100°C for 12 h. The mixture was cooled to room temperature, diluted with water, extracted with EA three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography to obtain the product (2.8 g, yield: 81.1%).

[0357] LCMS m / z=361.2[M+H] +

[0358] Step 2: Synthesis of compound 21C

[0359] The chiral isomer P1 (1.0 g, 2.27 mmol) was dissolved in 20 mL of 1,4-dioxane and 4 mL of water, and 21B (1.1 g, 2.95 mmol), cesium carbonate (2.2 g, 6.84 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (0.2 g, 0.23 mmol) were added and reacted at 100°C for 12 h. The mixture was cooled to room temperature, diluted with water, extracted with EA three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography to obtain the product (1.1 g, yield: 75.8%).

[0360] LCMS m / z=639.4[M+H] +

[0361] Step 3: Synthesis of compound 21D

[0362] Dissolve triphenylphosphine (0.66 g, 2.5 mmol), imidazole (0.25 g, 3.71 mmol), and iodine (0.63 g, 2.5 mmol) in 20 ml tetrahydrofuran, protect with nitrogen, and react for 30 min in the dark. Then add 21C (0.8 g, 1.25 mmol) tetrahydrofuran solution (dissolved in 5 mL), and heat to 50°C to react for 2 h. Directly concentrate under reduced pressure, and the residue is subjected to column chromatography to obtain the product (0.63 g, yield: 67.3%).

[0363] LCMS m / z=749.4[M+H] +

[0364] Step 4: Synthesis of compound 21E

[0365] Compound 21D (0.11 g, 0.15 mmol) was dissolved in 5 mL DMF, and intermediate 3B (0.066 g, 0.15 mmol) and potassium carbonate (0.041 g, 0.3 mmol) were added, and the mixture was heated to 80°C for 2 h under nitrogen protection. The mixture was cooled to room temperature, 30 mL of ethyl acetate was added, and the mixture was washed with water twice. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product (0.0778 g, yield: 49%).

[0366] LCMS m / z=1061.6[M+H] +

[0367] Step 5: Synthesis of compound 21

[0368] Compound 21E (0.070 g, 0.066 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of 4N HCl / Dioxane was added, and the mixture was reacted at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the residue was subjected to liquid phase purification to obtain the product (0.012 g, yield: 19.5%).

[0369] Preparation method: Instrument: Waters 2545; Preparation chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% TFA).

[0370] LCMS m / z=933.7[M+H] +

[0371] 1 H NMR(400MHz,CD3OD)δ9.34(s,1H),7.71(s,1H),7.40(d,1H),6.89(d,1H),6.69(d,1H),4 .62(d,1H),4.50(q,2H),4.34(d,1H),4.09(d,1H),3.92–3.85(m,1H),3.84–3.70(m,3H), 3.68–3.62(m,1H),3.60–3.37(m,3H),3.15–2.95(m,4H),2.91–2.47(m,7H),2.37–2.15(m ,8H),2.14–2.04(m,5H),2.00–1.67(m,6H),1.40–1.25(m,4H),1.01(t,2H),0.88(t,2H).

[0372] Example 22: Synthesis of Compound 22

[0373]

[0374] Compound 22 (23 mg) was prepared by replacing 3B with intermediate 1D and referring to the synthetic route and experimental operation of compound 21. Preparation method: Instrument: Waters 2545; Preparation chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% ammonium acetate).

[0375] LCMS m / z=907.7[M+H] +

[0376] 1 H NMR(400MHz,CD3OD)δ9.31(s,1H),7.71(s,1H),7.38(d,1H),6.79(d,1H),6.54(d,1H),4.58(d,1 H),4.49(q,2H),4.31(d,1H),3.90–3.81(m,1H),3.72–3.56(m,4H),3.46–3.38(m,1H),3.07–2.90 (m,4H),2.80–2.59(m,7H),2.26–2.23(m,4H),2.19–2.08(m,3H),2.04–1.98(m,2H),1.93(s,4H) ,1.90–1.77(m,5H),1.73–1.61(m,1H),1.55–1.42(m,2H),1.29(s,3H),0.91(t,2H),0.76(t,2H).

[0377] Example 23: Synthesis of Compound 23

[0378]

[0379] Referring to the synthetic route and experimental operation of compound 20, intermediate P1 was used to replace P2 in the original route to obtain compound 23 (45 mg). 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).

[0380] 1H NMR(400MHz,CD3OD)δ9.21(s,1H),7.42(dd,1H),7.11–7.03(m,1H),6.81(d,1H),6.57(d, 1H),4.54–4.42(m,3H),4.25(d,1H),3.85(dd,1H),3.74(d,1H),3.63(d,1H),3.51–3.38( m,1H),3.09–2.85(m,8H),2.84–2.75(m,3H),2.74–2.60(m,3H),2.24–1.99(m,6H),1.96– 1.88(m,4H),1.87–1.83(m,2H),1.80–1.68(m,7H),1.27(s,3H),0.87(t,2H),0.71(t,2H).

[0381] LCMS m / z=975.6[M+H] +

[0382] Example 24: Synthesis of Compound 24

[0383]

[0384] Step 1: Synthesis of 24B

[0385] The raw material N-Boc cyclopropylamine (10 g, 63.6 mmol) was dissolved in 50 mL DMF, and the mixture was cooled to 0°C under nitrogen protection. Sodium hydride (2.3 g, 95.4 mmol) was added in batches. Stirring was continued for 30 min after the addition was completed. Methyl iodide (13.8 g, 95.4 mmol) was added dropwise. The mixture was reacted at room temperature for 3 h after the addition was completed. Water was added to quench the reaction, and the mixture was extracted twice with ethyl acetate (100 mL × 2). The organic phases were combined, washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and column chromatography was performed to obtain compound 24B (10.5 g, yield: 64.4%).

[0386] LCMS m / z=175.1[M+H] +

[0387] Step 2: Synthesis of 24C

[0388] 24B (10.5 g, 60.3 mmol) was dissolved in 100 mL of dichloromethane, and 20 mL of 4N hydrochloric acid / dioxane solution was added, reacted at room temperature for 16 h, and concentrated under reduced pressure to obtain compound 24C (4.2 g, yield: 95%). The product was not purified and used directly in the next step.

[0389] Step 3: Synthesis of compound 24D

[0390] 2.4.7-Trichloro-8-fluoropyrido[4.3-d]pyrimidine (5 g, 20 mmol) was dissolved in 100 mL of dichloromethane, and N,N-diisopropylethylamine (7.7 g, 60 mmol) was added. Then 24C (2.2 g, 30 mmol) was added and reacted at room temperature for 16 h. The mixture was concentrated under reduced pressure and column chromatography was performed to obtain compound 24D (4.1 g, yield: 72%).

[0391] In steps 4 to 8, compound 24 (20 mg) was prepared by referring to the synthetic route and experimental operation of compound 20.

[0392] Preparation method: Instrument: Waters 2545; Preparation chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% ammonium acetate).

[0393] 1 H NMR(400MHz,CD3OD)δ9.63(s,1H),7.42(dd,1H),7.12–7.03(m,1H),6.81(d,1H),6.57(d,1H ),4.45(s,2H),3.84(dd,1H),3.78–3.69(m,1H),3.59–3.52(m,1H),3.11–2.93(m,7H),2.91– 2.85(m,1H),2.84–2.74(m,3H),2.74–2.59(m,3H),2.28–2.15(m,1H),2.14–1.97(m,4H),1. 92–1.84(m,4H),1.83–1.65(m,6H),1.18–1.10(m,2H),0.91–0.80(m,4H),0.76–0.68(m,2H).

[0394] LCMS m / z=467.8[M / 2+H] +

[0395] Example 25: Synthesis of Compound 25

[0396]

[0397] Step 1: Synthesis of compound 25A

[0398] 2.4.7-Trichloro-8-fluoropyrido[4.3-d]pyrimidine (5 g, 20 mmol) was dissolved in 100 mL of dichloromethane, and N,N-diisopropylethylamine (7.7 g, 60 mmol) was added. Then, 3-acetonitrilecyclobutylamine hydrochloride (2.4 g, 30 mmol) was added and reacted at room temperature for 16 h. The mixture was concentrated under reduced pressure and compound 25A (4.1 g, yield: 72%) was obtained by column chromatography.

[0399] The second to sixth steps were carried out with reference to the synthetic route and experimental procedures of compound 21 to obtain compound 25 (15 mg).

[0400] Preparation method: Instrument: Waters 2545; Preparation chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% ammonium acetate).

[0401] 1 H NMR(400MHz,CD3OD)δ9.03(s,1H),7.66(s,1H),7.40(d,1H),6.90(d,1H),6.69(d,1H),4. 87(s,2H),5.05–4.87(m,2H),4.50(m,2H),4.14–4.00(m,2H),3.91–3.71(m,4H),3.62–3.4 9(m,2H),3.28–3.20(m,3H),3.12–2.94(m,4H),2.87–2.48(m,7H),2.38–2.28(m,1H),2.27 –2.15(m,6H),2.14–1.90(m,7H),1.81–1.68(m,1H),1.05–0.97(m,2H),0.91–0.84(m,2H).

[0402] LCMS m / z=900.3[M+H] +

[0403] Example 26: Synthesis of Compound 26

[0404]

[0405] Compound 26 (19 mg) was prepared using compound 24E as the starting material and referring to the synthetic route and experimental operation of compound 25.

[0406] Preparation method: Instrument: Waters 2545; Preparation chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% ammonium acetate).

[0407] LCMS m / z=892.8[M+H] +

[0408] 1 H NMR(400MHz,CD3OD)δ9.77(s,1H),7.71(s,1H),7.41(d,1H),6.89(d,1H),6.69(d,1H), 4.50(s,2H),4.15–4.04(m,1H),3.92–3.69(m,4H),3.67–3.45(m,4H),3.14–2.92(m,4H ),2.87–2.60(m,6H),2.59–2.47(m,1H),2.36–2.16(m,8H),2.14–1.98(m,5H),1.96–1. 88(m,1H),1.81–1.63(m,1H),1.23–1.15(m,2H),1.04–0.96(m,2H),0.95–0.80(m,4H).

[0409] Example 27: Synthesis of Compound 27

[0410]

[0411] Steps 1 to 3: Preparation of compound 27C

[0412] Compound 27C (95 mg) was prepared by using compound 25B as the raw material and referring to the synthetic route and experimental operation of compound 25.

[0413] Step 4: Preparation of compounds 27-1 and 27-2

[0414] Compound 27C (95 mg, 0.091 mmol) was dissolved in 5 ml of dichloromethane, and 1 mL of 4N hydrochloric acid dioxane solution was added. The mixture was reacted at room temperature for 15 min, and then concentrated under reduced pressure. The mixture was sent to HPLC to obtain compound 27-1 (14 mg, 16%) and compound 27-2 (16 mg, 18%).

[0415] Preparation method: Instrument: Waters 2545; Preparation chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% ammonium acetate).

[0416] Compound 27-1:

[0417] LCMS m / z=942.2[M+H] +

[0418] 1H NMR(400MHz,CD3OD)δ8.93(s,1H),7.43–7.36m,1H),7.10–7.03(m,1H),6.90(d,1H),6 .69(d,1H),5.07–4.89(m,2H),4.57–4.43(m,2H),4.16–4.00(m,2H),3.93–3.68(m,4H) ,3.61–3.47(m,2H),3.34–3.25(m,4H),3.15–2.92(m,4H),2.89–2.46(m,7H),2.38–2. 14(m,4H),2.14–1.89(m,6H),1.81–1.65(m,1H),1.05–0.96(m,2H),0.90–0.82(m,2H).

[0419] Compound 27-2:

[0420] LCMS m / z=960.2[M+H] +

[0421] 1 H NMR(400MHz,CD3OD)δ8.97(s,1H),7.39(dd,1H),7.14–7.02(m,1H),6.90(d,1H),6.69 (d,1H),4.86–4.80(m,2H),4.56–4.42(m,2H),4.16–4.06(m,2H),3.93–3.84(m,1H),3 .83–3.67(m,3H),3.62–3.49(m,2H),3.34–3.25(m,4H),3.12–2.92(m,4H),2.87–2.49 (s,7H),2.38–1.89(m,10H),1.84–1.64(m,1H),1.04–0.96(m,2H),0.91–0.79(m,2H).

[0422] Example 28: Synthesis of Compound 28

[0423]

[0424] Step 1: Synthesis of compound 28B

[0425] The raw material 28A (1.6 g, 5.03 mmol) was dissolved in 25 mL DMAc, 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (1.81 g, 7.54 mmol) was added, and glacial acetic acid (0.3 g, 5.03 mmol) was added, and the reaction was allowed to react at room temperature for 1 h, and sodium triacetoxyborohydride (2.13 g, 10.06 mmol) was added to the reaction, and the reaction was continued for 16 h. Saturated sodium bicarbonate aqueous solution was added to quench, and the mixture was extracted with ethyl acetate twice, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the target compound 28B as a light yellow solid (1.9 g. Yield 69%).

[0426] LCMS m / z=542.3[M+H] +

[0427] Step 2: Synthesis of 28C

[0428] The raw material 28B (1.9 g, 3.51 mmol) was dissolved in 10 mL of dichloromethane, and 5 mL of trifluoroacetic acid was directly added. The mixture was reacted at room temperature for 2 h, and concentrated under reduced pressure. 20 mL of dichloromethane was added to dissolve the residue, and the pH was adjusted to about 8 with saturated sodium bicarbonate aqueous solution. The organic layer was dried and concentrated to obtain the target compound 28C (1.2 g, yield: 77%).

[0429] LCMS m / z=442.4[M+H] +

[0430] The trifluoroacetic acid salt of compound 28 (31 mg) was obtained by referring to the synthetic operation of compound 26 in the next two steps.

[0431] Preparation method: Instrument: Waters 2545; Preparation chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% TFA).

[0432] LCMS m / z=893.3[M+H] +

[0433] Example 29: Synthesis of Compound 29

[0434]

[0435] Using 25D as the starting material and referring to the synthetic procedure of compound 28, the trifluoroacetic acid salt of compound 29 (36 mg) was obtained.

[0436] Preparation method: Instrument: Waters 2545; Preparation chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% TFA).

[0437] LCMS m / z=901.2[M+H] +

[0438] Example 30: Preparation of Compound 30

[0439]

[0440] Step 1: Synthesis of compound 30B

[0441] The raw material 30A (3 g, 7.17 mmol) was dissolved in 30 mL of dichloromethane, and 5 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 3 hours. After concentration under reduced pressure, the target compound 30B (2.1 g, yield 92.01%) was obtained. The product was not purified and was directly used for the next step.

[0442] LCMS m / z=319.1[M+H] +

[0443] Step 2: Synthesis of compound 30C

[0444] The raw material 30B (2.1 g, 6.60 mmol) was dissolved in 35 mL of N,N-dimethylacetamide, 2-oxo-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester (3.16 g, 13.2 mmol) was added, and then 5 drops of glacial acetic acid were added, and the mixture was reacted at room temperature for 1 hour. Sodium triacetoxyborohydride (4.2 g, 19.80 mmol) was added in batches, and the mixture was reacted at room temperature for 16 hours. Saturated sodium bicarbonate aqueous solution (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL×2), and the ethyl acetate layers were combined. The ethyl acetate layers were washed with water (60 mL×2) and saturated NaCl aqueous solution (60 mL) in turn, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain compound 30C (2.4 g, yield 67.17%).

[0445] LCMS m / z=542.2[M+H] +

[0446] Step 3: 30D synthesis

[0447] The raw material 30C (0.28 g, 0.52 mmol) was dissolved in 8 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 3 hours. After concentration under reduced pressure, the target compound 30D (0.22 g, yield 96.39%) was obtained. The product was not purified and was directly used for the next step.

[0448] LCMS m / z=442.1[M+H] +

[0449] Step 4: Synthesis of 30E

[0450] 30D (0.22 g, 0.50 mmol) was dissolved in 12 mL of N,N-dimethylformamide, and intermediate 25D (0.34 g, 0.50 mmol) and potassium carbonate (0.14 g, 1.00 mmol) were added, and the mixture was reacted at 80°C for 16 hours. After cooling to room temperature, aqueous solution (25 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (25 mL×2). The ethyl acetate layers were combined, and the ethyl acetate layers were washed with water (40 mL×2) and saturated aqueous NaCl solution (40 mL) in sequence. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column to obtain compound 30E (0.12 g, yield 24.45%).

[0451] LCMS m / z=985.1[M+H] +

[0452] Step 5: Synthesis of Compound 30-1 and Compound 30-2

[0453] 30E (0.12 g, 0.12 mmol) was dissolved in 10 mL of dichloromethane, and 2 mL of HCl-dioxane solution was slowly added dropwise at room temperature. The mixture was reacted at room temperature for 30 min. The residue was concentrated under reduced pressure and purified to obtain compound 30-1 (12 mg, yield 10.93%) and compound 30-2 (5 mg, yield 4.47%).

[0454] Preparation method: Instrument: Waters 2545; Preparation chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% ammonium acetate).

[0455] Compound 30-1:

[0456] LCMS m / z=901.3[M+1] +

[0457] 1H NMR(400MHz,CD3OD)δ9.01(s,1H),7.68(s,1H),7.39(d,1H),6.94(d,1H),6.65(d,1H),4.47(s,2H),4.10–3.99(m,1H),3.79–3.67(m,3H),3.08 –2.62(m,16H),2.21(s,3H),2.14–1.98(m,3H),1.97–1.90(m,4H),1.88 –1.82(m,2H),1.80–1.63(m,6H),0.89–0.83(m,2H),0.73–0.67(m,2H).

[0458] Compound 30-2:

[0459] LCMS m / z=919.4[M+H] +

[0460] 1 H NMR (400MHz, CD3OD) δ9.04(s,1H),7.69(s,1H),7.38(d,1H),6.93(d,1H),6.65(d,1H),4.46(s,2H),3.79–3.66(m,4H),3.08–2.62(m, 16H),2.21(s,3H),2.11–1.99(m,3H),1.98–1.87(m,4H),1.84–1.78(m,2H),1.77–1.60(m,6H),0.88–0.79(m,2H),0.79–0.62(m,2H).

[0461] Example 31: Preparation of Compound 31

[0462]

[0463] Using compound 30C as the starting material, the trifluoroacetate salt of compound 31 (7 mg) was synthesized according to the operation steps of compound 28.

[0464] LCMS m / z=893.4[M+H] +

[0465] Preparation method: Instrument: Waters 2545; Preparation chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% TFA).

[0466] Example 32: Synthesis of Compound 32

[0467]

[0468] Step 1: Synthesis of compound 32A

[0469] The raw material 24E (0.356 g, 1 mmol) and the intermediate 1 (0.67 g, 1.3 mmol) were placed in a sealed tube, 10 mL of 1,4-dioxane and 2 mL of water were added to dissolve, and then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (82 mg, 0.1 mmol) and cesium carbonate (0.65 g, 2 mmol) were added in sequence. Under nitrogen protection, the temperature was raised to 100°C for reaction for 16 h, the solvent was removed under reduced pressure, 15 mL of water and 30 mL of ethyl acetate were added to dissolve, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined, the organic phases were washed once with 10 mL of saturated brine, and then the organic phases were dried over anhydrous sodium sulfate, concentrated, and separated and purified by column chromatography to obtain the target compound 32A (0.61 g, yield 85%).

[0470] Step 2: Synthesis of 32B

[0471] The raw material 32A (0.6 g, 0.84 mmol) was dissolved in 10 mL of dichloromethane, and triethylamine (0.25 g, 2.52 mmol) was added. Under nitrogen protection, methylsulfonyl chloride (0.14 g, 1.26 mmol) was added dropwise at 0°C. After the addition was complete, the mixture was reacted at room temperature for 2 h, and the mixture was directly concentrated under reduced pressure. The target compound 32B (0.61 g, yield 91%) was obtained by column chromatography separation and purification.

[0472] Step 3: Synthesis of 32C

[0473] The raw material 28A (1 g, 3.1 mmol) was dissolved in 15 mL DMAc, N-BOC-4-piperidinecarboxaldehyde (1 g, 4.7 mmol) was added, and then 2 drops of glacial acetic acid were added, and the reaction was allowed to react at room temperature for 1 h. Sodium triacetoxyborohydride (1 g, 4.7 mmol) was added to the reaction, and the reaction was continued for 2 h. Saturated sodium bicarbonate aqueous solution was added to quench, and the mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the target compound 32C (1.2 g, yield 74%).

[0474] LCMS m / z=516.3[M+H] +

[0475] Step 4: 32D synthesis

[0476] The raw material 32C (1 g, 1.9 mmol) was dissolved in 5 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 0.5 h, concentrated under reduced pressure, and used directly in the next step.

[0477] LCMS m / z=416.3[M+H] +

[0478] Step 5: Synthesis of 32E

[0479] The raw material 32D (0.75 g, 1.81 mmol) was dissolved in 15 mL of DMAc, N-BOC-4-piperidinecarboxaldehyde (0.58 g, 2.71 mmol) was added, and then 2 drops of glacial acetic acid were added, and the reaction was allowed to react at room temperature for 1 h. Sodium triacetoxyborohydride (0.57 g, 2.71 mmol) was added to the reaction, and the reaction was continued for 2 h. Saturated sodium bicarbonate aqueous solution was added to quench, and the mixture was extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the target compound 32E (0.8 g, yield 72%).

[0480] LCMS m / z=613.4[M+H]+

[0481] Step 6: Synthesis of 32F

[0482] The raw material 32E (0.8 g, 1.3 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 0.5 h, and concentrated under reduced pressure. 20 mL of dichloromethane was added to dissolve the residue, and the pH was adjusted to about 8 with saturated aqueous sodium bicarbonate solution. The organic layer was dried and concentrated to obtain a crude product of the target compound 32F (0.6 g, yield: 90%).

[0483] LCMS m / z=513.3[M+H] +

[0484] Step 7: Synthesis of compound 32G

[0485] The raw material 32B (0.20 g, 0.25 mmol) was dissolved in 3 mL DMF, 32F (0.17 g, 0.33 mmol) was added, and potassium carbonate (0.069 g, 0.5 mmol) was added, and the mixture was heated to 60°C under nitrogen protection for 16 h. 15 mL of water and 30 mL of ethyl acetate were added to dissolve the mixture, and the aqueous phase was extracted twice with ethyl acetate, and the organic phases were combined, and the organic phases were washed once with 30 mL of saturated brine, and then dried over anhydrous sodium sulfate, spin-dried, and separated and purified by column chromatography to obtain the target compound 32G (60 mg, yield 19%).

[0486] LCMS m / z=1240.5[M+H] +

[0487] Step 8: Synthesis of compound 32

[0488] 32G (60 mg, 0.05 mmol) was dissolved in 10 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added at room temperature. The mixture was reacted at room temperature for 30 min. The residue was concentrated under reduced pressure and purified to obtain compound 32 (8 mg, yield 16%).

[0489] Preparation method: Instrument: Waters 2545; Preparation chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, mobile phase B: water (containing 0.1% NH4HCO3).

[0490] LCMS m / z=964.4[M+1] +

[0491] 1 H NMR(400MHz,CD3OD)δ9.76(s,1H),7.70(s,1H),7.40(d,1H),7.03(d,1H),6.80(d, 1H),4.48(s,2H),4.15–4.05(m,1H),4.02–3.85(m,2H),3.76–3.55(m,7H),3.44–3 .33(m,3H),3.25–2.90(m,11H),2.87–2.72(m,4H),2.37–2.20(m,5H),2.19–2.02( m,5H),1.88–1.64(m,5H),1.23–1.14(m,2H),1.04–0.96(m,2H),0.95–0.81(m,4H).

[0492] Referring to the preparation of compound 32, the following compound was synthesized:

[0493]

[0494] Example 36: Preparation of Compound 36

[0495]

[0496] Step 1: Preparation of 36B

[0497] 1-Boc-L-acridine-2-carboxylic acid 36A (15 g, 74.55 mmol) and triethylamine (7.54 g, 74.55 mmol) were dissolved in 150 mL of tetrahydrofuran. Under nitrogen atmosphere, isopropyl chloroformate (10.96 g, 89.46 mmol) was slowly added dropwise at 0°C and reacted at room temperature for 20 min. 28% ammonia water (13.65 g, 389.44 mmol) was slowly added dropwise at 0°C and the temperature was slowly restored to room temperature for 16 h. After concentrating under reduced pressure, 150 mL of petroleum ether was added to the residue, stirred at room temperature for 30 min, and filtered to obtain 36B (14.9 g, yield 99.82%).

[0498] LCMS m / z=201.2[M+H] +

[0499] Step 2: Preparation of 36C

[0500] 36B (14.9 g, 74.41 mmol) was dissolved in 50 mL of dichloromethane, and 15 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 16 h. After concentration under reduced pressure, the trifluoroacetate salt of the target compound 36C (7.4 g, yield 99.32%) was obtained. The product was directly used for the next step without purification.

[0501] LCMS m / z=101.3[M+H] +

[0502] Step 3: Preparation of 36D

[0503] 2.4.7-Trichloro-8-fluoropyrido[4.3-d]pyrimidine (10 g, 39.61 mmol) was dissolved in 100 mL of dichloromethane, diisopropylethylamine (25.60 g, 198.05 mmol) was added, and then the trifluoroacetate of 36C (4.76 g, 47.53 mmol) was added, and the mixture was reacted at room temperature for 16 h. After concentration under reduced pressure, the residue was purified by column chromatography to obtain compound 36D (4.8 g, yield: 38.33%).

[0504] LCMS m / z=316.1[M+H] +

[0505] Step 4: Preparation of 36E

[0506] 36D (4.8 g, 15.18 mmol) was dissolved in 45 mL of dichloromethane, and 1,1-cyclopropane dimethanol (2.0 g, 19.73 mmol), triethylenediamine (0.85 g, 7.59 mmol), and cesium carbonate (9.89 g, 30.36 mmol) were added in sequence, and the mixture was reacted at room temperature for 16 h. After concentration under reduced pressure, the residue was purified by column chromatography to obtain compound 36E (2.6 g, yield: 44.85%).

[0507] LCMS m / z=382.1[M+H] +

[0508] Step 5: Preparation of 36F

[0509] 36E (2.6 g, 6.81 mmol) was dissolved in 20 mL of 1,4-dioxane and 2 mL of water, and 21B (5.3 g, 10.21 mmol), potassium carbonate (1.88 g, 13.62 mmol), [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (0.56 g, 0.68 mmol) were added, and the mixture was reacted at 100°C for 16 h under a nitrogen atmosphere. The mixture was cooled to room temperature, diluted with water, extracted with EA three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography to obtain 36F (1.7 g, yield: 33.83%).

[0510] LCMS m / z=738.1[M+H] +

[0511] Step 6: Preparation of 36G

[0512] 36F (1 g, 1.36 mmol) was dissolved in 15 mL of dichloromethane, triethylamine (0.41 g, 4.08 mmol) was added, 2 mL of dichloromethane solution of methylsulfonyl chloride (0.20 g, 1.77 mmol) was slowly added dropwise at 0°C, and the temperature was slowly restored to room temperature for 2 h. 20 mL of water was added, the liquids were separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the residue was concentrated under reduced pressure and subjected to column chromatography to obtain 36G (0.9 g, yield: 81.39%).

[0513] LCMS m / z=738.1[M+H] +

[0514] Step 7: Preparation of 36I

[0515] 36H (3 g, 7.17 mmol) was dissolved in 15 mL of dichloromethane, and 4 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 3 h. After concentration under reduced pressure, the trifluoroacetate salt of the target compound 36I (2.3 g, yield 100.00%) was obtained, which was directly used for the next step without purification.

[0516] LCMS m / z=319.1[M+H] +

[0517] Step 8: Preparation of 36J

[0518] The trifluoroacetate salt of the raw material 36I (2.3 g, 7.22 mmol) was dissolved in 25 mL of N,N-dimethylacetamide, and N-BOC-4-piperidinecarboxaldehyde (2.31 g, 10.83 mmol) was added, and then 4 drops of glacial acetic acid were added, and the mixture was reacted at room temperature for 1 h, and sodium triacetoxyborohydride (4.59 g, 21.66 mmol) was added in batches, and the reaction was continued for 16 h. A saturated aqueous sodium bicarbonate solution (40 mL) was added, and the mixture was extracted twice with ethyl acetate (40 mL×2), and the organic phases were combined, and the organic phases were washed twice with water (50 mL×2) and once with a saturated aqueous solution of NaCl (40 mL), and the organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the target compound 36J (3.3 g, yield 88.59%).

[0519] LCMS m / z=516.3[M+H] +

[0520] Step 9: Preparation of 36K

[0521] 36J (3.3 g, 6.40 mmol) was dissolved in 15 mL of dichloromethane, and 4 mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 3 h. After concentration under reduced pressure, the trifluoroacetate salt of the target compound 36K (2.4 g, yield 0.25%) was obtained, which was directly used for the next step without purification.

[0522] LCMS m / z=416.1[M+H] +

[0523] Step 10: Preparation of 36L

[0524] The trifluoroacetate of the raw material 36K (2.4 g, 5.78 mmol) was dissolved in 25 mL of N,N-dimethylacetamide, and N-BOC-4-piperidinecarboxaldehyde (1.85 g, 8.67 mmol) was added, and then 4 drops of glacial acetic acid were added, and the mixture was reacted at room temperature for 1 h, and sodium triacetoxyborohydride (3.68 g, 17.34 mmol) was added in batches, and the reaction was continued for 16 h. A saturated aqueous sodium bicarbonate solution (40 mL) was added, and the mixture was extracted twice with ethyl acetate (40 mL×2), and the organic phases were combined, and the organic phases were washed twice with water (50 mL×2) and once with a saturated aqueous solution of NaCl (40 mL), and the organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated and purified by column chromatography to obtain the target compound 36L (0.95 g, yield 26.84%).

[0525] LCMS m / z=613.1[M+H] +

[0526] Step 11: Preparation of 36M

[0527] The raw material 36L (0.9 g, 1.47 mmol) was dissolved in 12 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, the reaction was carried out at room temperature for 0.5 h, and the mixture was concentrated under reduced pressure. 20 mL of dichloromethane was added to dissolve the residue, and the pH was adjusted to about 8 with saturated sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain a crude product of the target compound 36M (0.65 g, yield: 86.67%).

[0528] LCMS m / z=513.3[M+H] +

[0529] Step 11: Preparation of 36N

[0530] The raw material 36M (0.15 g, 0.29 mmol) was dissolved in 5 mL DMF, 36G (0.24 g, 0.29 mmol) was added, potassium carbonate (0.20 g, 1.45 mmol) was added, and the mixture was reacted at 80°C for 16 h under a nitrogen atmosphere. 15 mL of water was added, and the mixture was extracted twice with ethyl acetate (30 mL×2), and the organic phases were combined, and the organic phases were washed twice with water (30 mL×2) and once with a saturated aqueous solution of NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound 36N (61 mg, yield: 16.92%).

[0531] LCMS m / z=1232.1[M+H] +

[0532] Step 12: Preparation of compound 36

[0533] Compound 36N (0.061 g, 0.049 mmol) was dissolved in 5 mL of dichloromethane, and 1 mL of trifluoroacetic acid was added. The mixture was reacted at room temperature for 1 h. The mixture was concentrated under reduced pressure, and the residue was prepared by liquid phase to obtain the product (6 mg, yield: 12.24%). Preparation method: Instrument: Waters 2545; Preparation chromatographic column: Waters Xslect CSH 5μm (19mm×250mm); (Mobile phase composition: Mobile phase A: acetonitrile, Mobile phase B: water (containing 0.1% NH4HCO3).

[0534] 1H NMR(400MHz,CD3OD)δ9.08(s,1H),7.67(s,1H),7.38(d,1H),6.93(d,1H),6.64(d,1H),5.25–4.87 (m,1H),4.56–4.40(m,2H),3.76–3.65(m,3H),3.48–3.35(m,2H),3.22–3.10(m,2H),3.09–3.00(m ,1H),2.99–2.86(m,4H),2.85–2.74(m,6H),2.73–2.63(m,1H),2.62–2.30(m,7H),2.29–2.11(m,7 H),1.93–1.80(m,4H),1.78–1.55(m,3H),1.50–1.22(m,6H),0.86–0.79(m,2H),0.68–0.60(m,2H).

[0535] LCMS m / z=990.1[M+H] +

[0536] The following compound was prepared by referring to the synthesis of compound 36

[0537]

[0538] Biological test cases

[0539] Biological test 1: In vitro KRAS G12D binding assay

[0540] Add 2 μL of dilution buffer to the 384-well white plate with different concentrations of compounds. Dilute 250X Tag2-KRAS-G12D protein and 10mM GTP 50-fold and 200-fold respectively with dilution buffer, and take 4 μL of the mixture to the test plate. Dilute 500X Tag1-RAF 100-fold with dilution buffer and take 4 μL to the test plate; incubate the test plate at 25°C for 15 minutes. After the incubation, dilute anti-Tag1-Eu and anti-Tag2-XL665 100-fold and 50-fold respectively with detection buffer, take 10 μL of the mixture and add it to the test plate, incubate at 4°C for 2 hours. After the reaction, read the signal value using a multi-label analyzer, excitation: 320nm, emission: 615nm, 665nm.

[0541] The formula used is Ratio = [Signal 665] / [Signal 615] × 10 4 The signal ratio was calculated using (Equation 1), and the inhibition rate was calculated using (Equation 2), where R sample is the compound pore signal ratio, Rmin is the signal ratio of the control well without KRAS G12D protein, R max The IC was calculated by four-parameter curve fitting using GraphPad Prism software. 50 value.

[0542] Inhibition%=(1-(R sample -R min ) / (R max -R min ))×100%(Formula 2)

[0543] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good inhibitory activity on the protein interaction between KRAS G12D and RAF1.

[0544] Biological test 2: Cell proliferation inhibition experiment

[0545] ASPC-1 cell culture conditions: RPMI-1640 + 10% FBS + 1% double antibody, cultured at 37 ° C, 5% CO2 incubator. On the first day, ASPC-1 cells in the exponential growth phase were collected and plated on 96-well culture plates, 80 μL per well, with a plating density of 1000 cells / well, and cultured overnight in a 37 ° C, 5% CO2 incubator. T0 wells were plated at the same time. On the second day, 20 μL of different concentrations of compounds were added to each well, so that the final DMSO concentration in each well was 0.5%, and cultured in a 37 ° C, 5% CO2 incubator for 6 days. On the second day, the CellTiter-Glo kit was used to detect the T0 plate while adding drugs, recorded as RLU0. After the culture was completed, 25 μL of detection solution (Cell4Viability Assay, Promega) was added to each well, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the chemiluminescence readings were detected using the Nivo multi-label analyzer (PerkinElmer). The results were processed according to formula (3) to calculate the proliferation inhibition rate of each concentration of the compound, and GraphPad Prism software was used to fit the curve using four parameters to calculate the concentration GI of the compound when the proliferation inhibition rate was 50%. 50 Value. RLU compound The readings for the drug treatment groups, RLU control The values ​​are the average values ​​of the solvent control group.

[0546] Inhibition % = (1-(RLU c Compound -RLU0) / (RLU c ontrol - RLU0))×100% Formula (3)

[0547] ASPC-1 cell proliferation inhibition results

[0548] Compound No. <![CDATA[IC 50 (nM)]]> Compound 1 <50nM Compound 3 <50nM Compound 4 <50nM Compound 9 <50nM Compound 10 <50nM Compound 11 <50nM Compound 12 <50nM Compound 19 <50nM

[0549] Conclusion: The compounds of the present invention, such as the compounds in the examples, have proliferation inhibitory activity on ASPC-1 cells. Specifically, compounds 1, 3, 4, 9, 10, 11, 12, and 19 have good proliferation inhibitory activity on ASPC-1.

[0550] Biological test 3: KRAS G12D degradation detection in ASPC-1 cells

[0551] ASPC-1 is a human metastatic pancreatic cancer cell line purchased from ATCC. The culture conditions are: RPMI-1640 + 10% FBS + 1% double antibody, cultured at 37°C, 5% CO2 incubator. The cells were plated in 12-well plates, 3×105 cells / well. After plating, different concentrations of compounds were added and cultured in a 37°C, 5% CO2 incubator for 24 hours. After the culture, the cells were collected and lysed on ice for 20 minutes with RIPA lysis buffer (beyotime, Cat. P0013B), and then centrifuged at 12000 rpm and 4°C for 10 minutes. The supernatant protein samples were collected and quantified with 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 a fully automatic protein blot quantitative analyzer (Proteinsimple). The relative peak area of ​​KRAS G12D was calculated using the "Compass for SW" software when the internal reference area was 10000. The proportion of KRAS G12D relative to the solvent control group at different drug concentrations was calculated according to formula (1), where KRAS G12Dstreat is the relative peak area of ​​the drug group, and KRAS G12Dsolvent is the relative peak area of ​​the solvent control group. The data processed according to formula (4) were used to calculate DC using GraphPad Prism 8.3.0 software using a four-parameter nonlinear regression model. 50 value

[0552] KRAS G12D%=KRAS G12Dstreat / KRAS G12Dsolvent×100% (Formula 4)

[0553] KRASG12D protein degradation results

[0554] Compound No. <![CDATA[DC 50 (nM)]]> Compound 1 <20nM Compound 2 <20nM Compound 3 <20nM Compound 4 <20nM Compound 9 <20nM Compound 11 <20nM Compound 12 <20nM

[0555] Conclusion: The compounds of the present invention, such as the example compounds, have degradation activity on KRAS G12D protein in ASPC-1 cells. Specifically, compounds 1, 2, 3, 4, 9, 11, and 12 have good degradation activity on KRAS G12D protein in ASPC-1 cells.

Claims

1. A compound or a stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein: The compound is selected from the compounds represented by general formula (I), BLK (I); L is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-Cy3-Ak4-Cy4-Ak5-; Ak1, Ak2, Ak3, Ak4, Ak5 are each independently selected from -(CH2) q -、-(CH2) q -O-, -O-(CH2) q -、-(CH2) q -S-, -S-(CH2) q -、-(CH2) q -NR L -、-NR L -(CH2) q -、-(CH2) q -NR L C(=O)-、-(CH2) q -C(=O)NR L -, -C(=O)-, -C(=O)-(CH2) q -NR L -、-(C≡C) q - or a bond, wherein the -CH2- is optionally 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, the alkyl, carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R z replace; 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: 4-8 membered heteromonocyclic group, 4-12 membered heterocyclic group, 5-13 membered heterospirocyclic group, 7-12 membered heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl; B is selected from X1 is selected from N or CR x1 ; X2 is selected from a bond, O, S or NR x2 ; X3 is selected from a bond or C 1-4 Alkylene, the alkylene group is optionally substituted by 1 to 4 R z replace; B1 is selected from C 6-10 aryl or 5 to 10 membered heteroaryl, said B1 is optionally substituted by 1 to 4 R b1 replace; B2 is selected from a 6- to 12-membered nitrogen-containing heterocyclic group or NR x3 R x4 , preferably a 6- to 12-membered nitrogen-containing heterocycloalkyl, wherein B2 is optionally replaced by 1 to 4 R b2 replace; R x3 , R x4 Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, 4 to 6 membered heterocycloalkyl, the alkyl, cycloalkyl, heterocycloalkyl optionally substituted by 1 to 4 R z replace; B3 Selected from -C 0-4 Alkylene-C 3-12 Carbocyclic or -C 0-4 Alkylene-4 to 12 membered heterocyclic group, said B3 is optionally substituted by 1 to 6 R b3 replace; R x2 Selected from H, D, C 1-6 Alkyl, C 3-7 Cycloalkyl, the alkyl, cycloalkyl is optionally substituted by 1 to 4 R z replace; R b1 , R x1 , R b4 , R b5 Each independently selected from H, deuterium, halogen, OH, cyano, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, 4- to 6-membered heterocycloalkyl, -C 0-2 Alkylene-C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, C 6-10 Aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkylene, alkoxy, alkylthio, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl are optionally substituted by 1 to 4 R z replace; R b2 , R b3 Each independently selected from deuterium, halogen, OH, =O, cyano, NH2, -NH(C 1-6 Alkyl), -N(C 1-6 alkyl)2, C(=O)C 1-6 Alkyl, C(=O)C 2-6 Alkenyl, C(=O)C 2-6 Alkynyl, C(=O)NH2, C(=O)NH(C 1-6 alkyl), C(=O)N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, alkylthio, alkynyl, alkenyl, cycloalkyl is optionally substituted by 1 to 4 R z replace; K is selected from G is selected from NH, N, CR k3 or C(R k3 )2; Q is independently selected from -O-, -S-, -NR q -, -NHCO- or -NR q CO-; R q Selected from C 1-4 alkyl; Ring K1 and Ring K2 are each independently selected from phenyl, benzo 4-6 carbocyclyl, benzo 4- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, 8- to 10-membered heteroaryl, 5-membered heteroaryl and 4- to 6-membered heterocyclyl, 6-membered heteroaryl and 4- to 6-membered heterocyclyl, C 10-15 tricyclic carbocyclyl, 10- to 15-membered tricyclic heterocyclyl, 12- to 19-membered tetracyclic heterocyclyl; R k1 Each independently selected from F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, 3 to 6 membered heterocycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocycloalkyl is optionally substituted by 1 to 4 R z replace; R k2 are each independently selected from a bond, -C(=O)-, -S(=O)2-, -S(=O)- or -C(R k3 )2-; R k3 Each independently selected from H, F, Cl, Br, I, OH, =O, NH2, CN, COOH, CONH2, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-8 Cycloalkyl or 3 to 8 membered heterocyclic group, wherein the alkyl, alkoxy, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; Alternatively, two R k3 Direct connection to form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; Alternatively, two R k1 Direct connection to form C 3-8 A carbocyclic group or a 4-8 membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 groups selected from R z replace; R k4 Each independently selected from H, OH, NH2, CN, CONH2, C 1-4 Alkyl, C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by 1 to 4 R z replace; R L2 , R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, NHC 1-4 Alkyl, N(C 1-4 alkyl)2, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent; Alternatively, R L2 With R k1 Direct connection to form C 4-6 A carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or the heterocyclic group is optionally substituted by 1 to 4 R z replace; n1 is selected from 0, 1, 2 or 3; p1, p2, p3 are each independently selected from 0, 1, 2, 3, 4 or 5; When ring K2 is selected from phenyl, p1 is selected from 1, 2, 3, 4 or 5; K is not optionally substituted 2. The compound according to claim 1 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R L is selected from H, methyl or ethyl, the methyl or ethyl group is optionally substituted by 1 to 4 R z replace; Cy1, Cy2, Cy3 or Cy4 are each independently selected from a bond or optionally substituted by 1 to 4 R L2 One of the following substituted groups: 4-7 membered nitrogen-containing heteromonocyclic group, 4-12 membered nitrogen-containing heterocyclic group, 5-13 membered nitrogen-containing heterospirocyclic group, 7-12 membered nitrogen-containing heterobridged ring group, C 3-7 Monocyclic alkyl, C 4-7 Monocyclic alkenyl, C 4-12 Cycloalkyl, C 5-13 Spirocycloalkyl, C 5-12 bridged cycloalkyl, 5-10 membered heteroaryl or C 6-10 Aryl; X1 is selected from N or CH; X2 is selected from a bond, O, S, NH, N(CH3); X3 is selected from a bond, -CH2- or -CH2CH2-; B2 is selected from a 6- to 7-membered monocyclic nitrogen-containing heterocyclic group, a 6- to 10-membered fused nitrogen-containing heterocyclic group, a 6- to 10-membered spirocyclic nitrogen-containing heterocyclic group, a 6- to 10-membered bridged nitrogen-containing heterocyclic group or NR x3 R x4 , B3 is selected from C 3-6 Monocyclic carbocyclic group, C 6-12 Spirocarbocyclic group, C 6-12 Cyclic carbocyclic group, C 5-10 bridged ring carbocyclic group, 4-7 membered monocyclic heterocyclic group, 6-12 membered cyclic heterocyclic group, 6-13 membered spirocyclic heterocyclic group, 7-12 membered bridged ring heterocyclic group, -CH2-C 3-6 Carbocyclic group, -CH2-C 6-12 Spirocyclic carbocyclic group, -CH2-C 6-12 Cyclic carbocyclic group, -CH2-C 5-10 bridged ring carbocyclic group, -CH2-4-7 membered monocyclic heterocyclic group, -CH2-6-12 membered cyclic heterocyclic group, -CH2-6-13 membered spirocyclic heterocyclic group, -CH2-7-12 membered bridged ring heterocyclic group, -CH2CH2-C 3-6 Carbocyclic group, -CH2CH2-C 6-12 Spirocyclic carbocyclic group, -CH2CH2-C 6-12 Cyclic carbocyclic group, -CH2CH2-C 5-10 a bridged ring carbocyclic group, a -CH2CH2-4-7-membered monocyclic heterocyclic group, a -CH2CH2-6-12-membered cyclic heterocyclic group, a -CH2CH2-6-13-membered spirocyclic heterocyclic group, a -CH2CH2-7-12-membered bridged ring heterocyclic group, wherein B3 is optionally substituted by 1 to 6 R b3 replace; K is selected from G is selected from CH or N; Q is selected from N(CH3), O, S, C(=O), NHC(=O), C(=O)NH, N(CH3)C(=O), C(=O)N(CH3); The ring where the representative is located is an aromatic ring or a non-aromatic ring; F j Selected from N, NH, CH, CH2, NR k1 , CR k1 , C(R k1 )2; Ff is selected from a bond, O, CH2, CHF, CF2, NH, N(CH3), N(R k1 )、C(R k1 )2; F6, F7, F8 are each independently selected from N, CH or CR k1 , and F6, F7, and F8 contain at most 2 Ns; Y1 is selected from N or CH; Y2 is selected from N, C or CH; R k1 Each independently selected from F, Cl, Br, I, OH, =O, NH2, CF3, CN, COOH, CONH2, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy, wherein the methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, NH2; R k2 Each is independently selected from -C(=O)-, -S(=O)2- or -S(=O)-; n1 is selected from 0, 1 or 2. 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, COOH, CONH2, C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 1-4 Alkoxy, -SC 1-4 Alkyl, -C 0-4 Alkylene-C 3-6 Cycloalkyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, cycloalkyl is optionally substituted by 1 to 4 deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

3. The compound according to claim 2 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: K is selected from Cy1, Cy2, Cy3, and Cy4 are each independently selected from a bond or one of the following groups which are optionally substituted: When substituted, it is substituted with 1 to 4 substituents selected from deuterium, F, CF3, OH, methyl, =0, hydroxymethyl, methoxy, COOH, CN, NH2 or cyclopropyl. 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)-; B1 is selected from phenyl, naphthyl, pyridyl, benzopyridyl, benzopyrimidinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyrazolyl, benzopyrrolyl, and said B1 is optionally substituted by 1 to 4 R b1 replace; B2 is selected from or NR x3 R x4 , said B2 is optionally replaced by 1 to 4 R b2 replace; R x3 , R x4 Each independently selected from optionally 1 to 4 R z substituted with one of the following groups: methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxolanyl, oxehexyl; B3 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, azetidinyl, azetyl, azopentyl, azohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -CH2-phenyl, -CH2-pyridyl, -CH2-pyrimidinyl, -CH2-pyrazinyl, -CH2-pyridazinyl, -CH2-azetidinyl, -CH2-azacyclopentyl, -CH2-azacyclohexyl, -CH2CH2-cyclopropyl, -CH2CH2-cyclobutyl, -CH2CH2-cyclopentyl, -CH2CH2-cyclohexyl, -CH2CH2-phenyl, -CH2CH2-pyridyl, -CH2CH2-pyrimidinyl, -CH2CH2-pyrazinyl, -CH2CH2-pyridazinyl, -CH2CH2-azetidinyl, -CH2CH2-azacyclopentyl, -CH2CH2-azacyclohexyl, The B3 is optionally replaced by 1 to 6 R b3 replace; R b1 Each independently selected from H, deuterium, F, Cl, Br, OH, CN, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R z substituted with one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, -CH2-ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxolyl, oxetanyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, phenyl, or a 5- to 6-membered heteroaryl; R b4 is selected from H, deuterium, F, Cl, Br, OH, CN, CF3, CHF2, CH2F, methyl, ethyl, methoxy or cyclopropyl; R b5 is selected from F, Cl, Br, OH, CN, CF3, CHF2, CH2F, methyl, ethyl, methoxy or cyclopropyl; R b2 , R b3 Each independently selected from deuterium, F, Cl, Br, OH, =O, CN, NH2, NHCH3, N(CH3)2 or optionally substituted by 1 to 4 R z substituted by one of the following groups: methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, -CH2-ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, C(=O)NH2, C(=O)N(CH3)2, C(=O)CH3, C(=O)CH2CH3, C(=O)CH=CH2, C(=O)CH=CH2CH3; R z Each independently selected from deuterium, F, Cl, Br, I, OH, =O, CF3, SF5, CN, NH2, NO2, COOH, CONH2, N(CH3)2, NHCH3, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, wherein the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, OH, CN, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

4. The compound according to claim 3 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: K is selected from L is selected from -NHCH2-, -Cy1-, -Cy1-CH2-, -CH2-Cy1-, -Cy1-C≡C-, -Cy1-Cy2-, -Cy1-CH2-Cy2-, -Cy1-C(=O)-CH2-Cy2-, -Cy1-C(=O)-Cy2-, -C(=O)-C y1-, -Cy1-Cy2-Cy3-, -Cy1-CH2-Cy2-Cy3-, -Cy1-Cy2-CH2-Cy3-, -NH-Cy1-, -NH-Cy1-O-, -O-Cy1-NH-, -NH-Cy1-Cy2-, -NH-Cy1-CH2-Cy2, - N(CH3)-CH2-Cy1-, -CH2-Cy1-CH2-Cy2-NH-, -Cy1-CH2-Cy2-NH-, -Cy1-CH2CH2-Cy2-, -CH2-Cy1-CH2CH2-Cy2-, -CH2-Cy1-CH2-Cy2-, -Cy1- C(=O)NH-CH2CH2-O-CH2CH2-O-, -Cy1-C(=O)NH-CH2CH2-O-, -Cy1-C(=O)NH-, -CH2-Cy1-C(=O)-Cy2-, -Cy1-C(=O)-CH2-Cy2- or -C(=O)-Cy1-.

5. The compound according to claim 4 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B is selected from b1 is selected from 0, 1, 2, 3 or 4.

6. The compound according to claim 1 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B is selected from one of the structures shown in Table B-1; Table B-1 L is selected from one of the structures shown in Table L-1 or Table L-2; Table L-1L Group Table L-2 K is selected from one of the structural fragments shown in Table K-1; Table K-1 。 7. The compound according to claim 1 or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: The compound is selected from one of the structures shown in Table E; 8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of a compound according to any one of claims 1 to 7 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

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

10. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 8 for preparing a medicament for treating and inhibiting or degrading KRAS-related diseases, preferably, the disease is selected from cancer.

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