WO2025002430A1 - Five-membered heteroaryl derivatives and medical use thereof - Google Patents

Abstract

Compounds represented by general formula (I), or stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, and pharmaceutically acceptable salts or eutectic crystals thereof, an intermediate thereof, and the use thereof in diseases related to KRAS inhibition or degradation such as cancers.

Description

A 5-membered heteroaryl derivative and its application in medicine Technical Field

The present invention relates to a compound of general formula (I) or a stereoisomer, tautomer, deuterated substance, 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.

Background Art

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 inactive 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).

RAS gene mutation is a common gene mutation type 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 among RAS mutations, 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.

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 categories: 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.

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

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 mutant or amplified KRAS, for the treatment of diseases related thereto such as cancer.

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

In some embodiments, the compound represented by general formula (I) is selected from (Ib), (Ie)

In some embodiments, Selected from

In some embodiments, U, V, W are each independently selected from N or CR ^b7 ;

In some embodiments, any two of U, V, and W are selected from N, and the other one is selected from CR ^b7 ;

In some embodiments, Z is selected from O, S or Se;

In some embodiments, Ring B ₄ is selected from 5-membered heteroaryl, said Ring B ₄ being optionally substituted with 1 to 4 R ^b4 ;

In some embodiments, Ring B ₄ is selected from oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, and said Ring B ₄ is optionally substituted with 1 R ^b4 ;

In some embodiments, R ^b1 is selected from CN or ethynyl;

In some embodiments, R ^b2 , R ^b4 , and R ^b7 are each independently selected from H, deuterium, halogen, CN, OH, COOH, CONH ₂ , NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C 2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-6 carbocyclyl, 4 to 7 membered heterocyclyl, -C _1-2 alkylene- _{C 3-6 carbocyclyl} , -C _1-2 alkylene-4 to 7 membered heterocyclyl, and the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclyl, and heterocyclyl are optionally substituted with 1 to 4 R ^z ;

In some embodiments, R ^b2 , R ^b4 , and R ^b7 are each independently selected from H, deuterium, halogen, CN, OH, COOH, CONH ₂ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C 2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkylthio, C _3-6 cycloalkyl, phenyl, 5 to ₆ membered heteroaryl, 4 to 7 membered heterocycloalkyl, -C _1-2 alkylene-C _3-6 cycloalkyl, -C _1-2 alkylene-4 to 7-membered heterocycloalkyl, -C _1-2 alkylene-phenyl, -C _1-2 alkylene-5 to 6-membered heteroaryl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl are optionally substituted by 1 to 4 R ^z ;

In some embodiments, R ^b2 and R ^b4 are each independently selected from deuterium, F, Cl, Br, I, CN, OH, or one of the following groups optionally substituted with 1 to 4 R ^z : methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl;

In some embodiments, ^Rb7 is selected from H, deuterium, F, Cl, Br, I, _CN , OH, CONH2, _NH2 , _NHCH3 , N( _CH3 ) ₂ , or one of the following groups optionally substituted with 1 to 4 ^Rz : methyl, ethyl, propyl, isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, -CH2-cyclopropyl, _-CH2 -cyclobutyl, _-CH2 -cyclopentyl, _-CH2 -cyclohexyl, _-CH2 -phenyl, _-CH2 -pyridinyl, _-CH2 -azetidinyl, _{-CH2 -} pyrrolidinyl, -CH2- ₂ -piperidinyl, -CH ₂ -piperazinyl, -CH ₂ -morpholinyl, -CH ₂ -oxetanyl, -CH ₂ -tetrahydrofuranyl, -CH ₂ -oxhexyl;

In some embodiments, R ^b3 is selected from H, deuterium, halogen, CN, OH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 carbocyclyl, 4 to 7 membered heterocyclyl, -C _1-2 alkylene-C _3-6 carbocyclyl, -C _1-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclyl, heterocyclyl is optionally substituted with 1 to 4 R ^z ;

Alternatively, R ^b3 and any R ^b4 are directly linked to form a C _4-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R ^z ;

In some embodiments, R ^b3 is selected from H, deuterium, halogen, CN, OH, NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, wherein the alkyl, alkylene, alkenyl, alkynyl is optionally substituted with 1 to 4 R ^z ;

In some embodiments, R ^b3 is selected from H, methyl, ethyl, propyl, isopropyl, wherein the methyl, ethyl, propyl, isopropyl is optionally substituted with 1 to 4 R ^z ;

In some embodiments, R ^b3 is selected from H, methyl, ethyl, propyl or isopropyl;

In some embodiments, R ^b3 and any R ^b4 are directly linked to form a C _4-6 carbocyclyl or a 4- to 7-membered heterocyclyl, wherein the carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R ^z ;

In some embodiments, R ^b3 and R ^b4 are directly linked to form a C _5-6 carbocyclyl, which is optionally substituted with 1 to 4 R ^z ;

In some embodiments, ^R is selected from H, deuterium, halogen, CN, or one of the following groups optionally substituted: C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _3-12 carbocyclyl, 4 to 12 membered heterocyclyl, -OC _3-12 carbocyclyl, -O-4 to 12 membered heterocyclyl, -NH-C _3-12 carbocyclyl, -NH-4 to 12 membered heterocyclyl, -OC _1-4 alkylene-C _3-12 carbocyclyl, -OC _1-4 alkylene-4 to 12 membered heterocyclyl, -NHC _1-4 alkylene-C _3-12 carbocyclyl, -NHC _1-4 alkylene-4 to 12 membered heterocyclyl, when substituted, optionally substituted by 1 to 4 groups selected from or substituted by a substituent of R ^b5e ;

In some embodiments, ^Rb5 is selected from H, deuterium, halogen, OH, CN, or one of the following groups which are optionally substituted: _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, _C3-7 monocyclic cycloalkyl, _C4-7 monocyclic cycloalkenyl, C4-12 bicyclic cycloalkyl, _C5-12 spirocyclic cycloalkyl, _C5-12 bridged ring cycloalkyl, _C6-10 aryl, _4-7 membered monocyclic heterocycloalkyl, 4-7 membered monocyclic heterocycloalkenyl, 6-12 membered bicyclic heterocycloalkyl, cycloheterocycloalkyl, 6-12 membered spirocyclic heterocycloalkyl, 6-12 membered bridged heterocycloalkyl, 5-10 membered heteroaryl, -OC _3-7 monocyclic cycloalkyl, -OC _4-7 monocyclic cycloalkenyl, -OC _4-12 bicyclic cycloalkyl, -OC _5-12 spirocyclic cycloalkyl, -OC _5-12 bridged cycloalkyl, -OC _6-10 aryl, -O-4-7 membered monocyclic heterocycloalkyl, -O-4-7 membered monocyclic heterocycloalkenyl, -O-6-12 membered bicyclic heterocycloalkyl, -O-6-12 membered spirocyclic heterocycloalkyl, -O-6-12 membered bridged heterocycloalkyl, -O-5-10 membered heteroaryl, -NH-C _3-7 monocyclic cycloalkyl, -NH-C _4-7 monocyclic cycloalkenyl, -NH-C _4-12 bicyclic cycloalkyl, -NH-C _5-12 spirocyclic cycloalkyl, -NH-C _-NH -5-12 membered heteroaryl, -NH-C _5-12 membered bridged ring cycloalkyl, -NH-C 6-10 aryl, -NH-4-7 membered monocyclic heterocycloalkyl, -NH-4-7 membered monocyclic heterocycloalkenyl, -NH-6-12 membered bicyclic heterocycloalkyl, -NH-6-12 membered spirocyclic heterocycloalkyl, -NH-6-12 membered bridged ring heterocycloalkyl, -NH-5-10 membered heteroaryl, -OC _1-4 alkylene-C _3-7 monocyclic cycloalkyl, -OC _1-4 alkylene-C _4-7 monocyclic cycloalkenyl, -OC _1-4 alkylene-C _4-12 bicyclic cycloalkyl, -OC _1-4 alkylene-C _5-12 spirocyclic cycloalkyl, -OC _1-4 alkylene-C _5-12 bridged ring cycloalkyl, -OC _1-4 alkylene-C _6-10 aryl, -OC _1-4 alkylene-4-7 membered monocyclic heterocycloalkyl, -OC -OC _1-4 alkylene-4-7 membered monocyclic heterocycloalkenyl, -OC _1-4 alkylene-6-12 membered bicyclic heterocycloalkyl, -OC _{1-4 alkylene-6-12 membered spirocyclic heterocycloalkyl, -OC 1-4 alkylene} -6-12 membered bridged heterocycloalkyl, -OC _1-4 alkylene-5-10 membered heteroaryl, -NHC _1-4 alkylene-C _3-7 monocyclic cycloalkyl, -NHC _1-4 alkylene-C _4-7 monocyclic cycloalkenyl, -NHC _1-4 alkylene-C _4-12 bicyclic cycloalkyl, -NHC _{1-4 alkylene-C 5-12 spirocyclic cycloalkyl, -NHC 1-4 alkylene-C 5-12 bridged cycloalkyl} , -NHC _1-4 alkylene-C _6-10 aryl, -NHC _1-4 alkylene-4-7 membered monocyclic heterocycloalkyl, -NHC _1-4 alkylene-4-7 membered monocyclic heterocycloalkenyl, -NHC _1-4 alkylene-6-12 membered cyclic heterocycloalkyl, -NHC _{1-4 alkylene-6-12 membered spirocyclic heterocycloalkyl, -NHC 1-4 alkylene} -6-12 membered bridged heterocycloalkyl, -NHC _1-4 alkylene-5-10 membered heteroaryl, when substituted, optionally with 1 to 4 selected from R is substituted by a substituent of ^b5e ;

In some embodiments, ^Rb5 is selected from H, deuterium, halogen, OH, CN, or one of the following groups which are optionally substituted: _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, 4-7 membered monocyclic heterocycloalkyl, 4-7 membered monocyclic heterocycloalkenyl, 6-12 membered paracyclic heterocycloalkyl, 6-12 membered spirocyclic heterocycloalkyl, 6-9 membered bridged heterocycloalkyl, phenyl, 5 to 6 membered heteroaryl, 8-10 membered paracyclic heterocycloalkyl, -O-4-7 membered monocyclic heterocycloalkyl, -O-5-6 membered heteroaryl, -O-phenyl, -NH-4-7 membered monocyclic heterocycloalkyl, -NH- _5-6 membered heteroaryl, -NH-phenyl, _-OCH2-4-7 membered monocyclic heterocycloalkyl, _-OCH2-5-6 membered heteroaryl, -OCH2-phenyl, _-NHCH2-4-7 membered monocyclic heterocycloalkyl, _-NHCH2 -5-6 membered heteroaryl, -NHCH ₂ -phenyl, when substituted, optionally substituted by 1 to 4 groups selected from or substituted by a substituent of R ^b5e ;

In some embodiments, R ^b5 is selected from H, deuterium, F, Cl, Br, I, OH, CN, or one of the following groups which are optionally substituted: methyl, ethyl, vinyl, ethynyl, propynyl, methoxy, ethoxy, oxetanyl, tetrahydrofuranyl, oxhexacyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 1,4 _- diazepanyl, -CH ₂ -oxetanyl, -CH ₂ -tetrahydrofuranyl, -CH ₂ -oxetanyl, -CH ₂ -azetidinyl, -CH 2 -pyrrolidinyl, -CH ₂ -piperidinyl, -CH ₂ -piperazinyl, -CH ₂ -morpholinyl, -O-oxetanyl, -O-tetrahydrofuranyl, -O-oxahexyl, -O-azetidinyl, -O-pyrrolidinyl, -O-piperidinyl, -O-piperazinyl, -O-morpholinyl, -NH-oxetanyl, -NH-tetrahydrofuranyl, -NH-oxetanyl, -NH-azetidinyl, -NH-pyrrolidinyl, _-NH -piperidinyl, -NH-piperazinyl, -NH-morpholinyl, -NH-pyridinyl, -NH-pyrimidinyl, _-NH -pyrazinyl, -NH-pyridazinyl, -OCH 2 -oxetanyl, -OCH 2 -tetrahydrofuranyl, -OCH ₂ -oxetanyl, -OCH ₂ -azetidinyl, -OCH _{2 -pyrrolidinyl, -OCH 2 -piperidinyl} , -OCH ₂ -piperazinyl, -OCH ₂ -morpholinyl, -NHCH ₂ -oxetanyl, -NHCH ₂ -tetrahydrofuranyl, -NHCH ₂ -oxetanyl, -NHCH ₂ -azetidinyl, -NHCH ₂ -pyrrolidinyl, -NHCH ₂ -piperidinyl, -NHCH ₂ -piperazinyl, -NHCH ₂ -morpholinyl, -O-phenyl, -O-pyridinyl, -O-pyrimidinyl, -NH-phenyl, -NH-pyridinyl, _-NH -pyrimidinyl, -OCH ₂ -phenyl, -OCH ₂ -pyridinyl, -OCH 2 -pyrimidinyl, -NHCH ₂ -phenyl, -NHCH ₂ -pyridinyl, -NHCH ₂ -pyrimidinyl,

Phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, when substituted, optionally substituted by 1 to 4 selected from or substituted by a substituent of R ^b5e ;

In some embodiments, Y ₁ is selected from C _1-4 alkylene, C(═O), S(═O) ₂ , -NR ^y1 -, -C(═O)NR ^y1 -, -S(═O) ₂ NR ^y1 -, -NR ^y1 C(═O)-, -OC(═O)NR ^y1 -, -NR ^y1 C(═O)O-, -NR ^y1 S(═O) ₂ -, -C(═O)O-, -OC(═O)-, and the alkylene is optionally substituted with 1 to 4 R ^z ;

In some embodiments, Y ₁ is selected from -CH ₂ -, C(=O), S(=O) ₂ , -C(=O)O-, -OC(=O)-, -NH-, -C(=O)NH-, -C(=O)N(CH ₃ )-, -S(=O) ₂ NH-, -NHC(=O)-, -N(CH ₃ )C(=O)-, -NHS(=O) ₂ -, -OC(=O)NH-, -NHC(=O)O-;

In some embodiments, ^Rb5a , ^Rb5b , ^Rb5c , and ^Rb5d are each independently selected from H, deuterium, halogen, CN, OH, _NH2 , _NHC1-6 alkyl, N( _C1-6 alkyl) ₂ , -C(=O) _NH2 , -C(=O) _NHC1-6 alkyl, -C(=O)N( _C1-6 alkyl) ₂ , -COOH, -C(=O) _OC1-6 alkyl, _C1-6 alkyl, _C1-6 alkoxy, _C3-6 carbocyclyl, ₄ to 7 membered heterocyclyl, -C1-2 alkylene- _OC1-6 alkyl, _-C1-2 alkylene- _C3-6 carbocyclyl, -C1-2 alkylene-4 to 7 membered heterocyclyl, _-C1-2 alkylene _{- NHC1-6} alkyl, _-C1-2 alkylene-N(C1-6 alkyl)2 _1-6 alkyl) ₂ , wherein the alkyl, alkylene, alkoxy, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R ^z ;

Alternatively, R ^b5a and R ^b5b are directly linked to form a C _4-8 carbocyclic group or a 4- to 8-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R ^z ;

In some embodiments, ^Rb5a , ^Rb5b , ^Rb5c , and ^Rb5d are each independently selected from H, deuterium, halogen, CN, OH, _NH2 , _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , -C(=O) _NH2 , -C(=O) _NHC1-4 alkyl, -C(=O)N( _C1-4 alkyl) ₂ , -COOH, -C(=O) _OC1-4 alkyl, _C1-4 alkyl, _C1-4 alkoxy, _C3-6 carbocyclyl, ₄ to 7 membered heterocyclyl, _-C1-2 alkylene- _OC1-4 alkyl, -C1-2 alkylene- _C3-6 carbocyclyl, _-C1-2 alkylene-4 to 7 membered heterocyclyl, _-C1-2 alkylene- _NHC1-4 alkyl, _-C1-2 alkylene-N(C1-4 alkyl)2 _1-4 alkyl) ₂ , wherein the alkyl, alkylene, alkoxy, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R ^z ;

Alternatively, R ^b5a and R ^b5b are directly linked to form a C _4-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R ^z ;

In some embodiments, R ^b5a , R ^b5b , R ^b5c , and R ^b5d are each independently selected from H, deuterium, F, Cl, Br, I, CN, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , -C(═O)NH ₂ , -C(═O)NHCH ₃ , -C(═O)N(CH ₃ ) ₂ , -COOH, -C(═O)OCH ₃ , -C(═O)OCH ₂ CH ₃ , or one of the following groups optionally substituted with 1 to 4 R ^z : methyl, ethyl, isopropyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, phenyl, pyridinyl, pyrazolyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, -CH ₂ OCH ₃ , -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -azetidinyl, -CH ₂ -pyrrolidinyl, -CH ₂ -piperidinyl, -CH ₂ -piperazinyl, -CH ₂ -morpholinyl, -CH ₂ N(CH ₃ ) ₂ ;

Alternatively, R ^b5a and R ^b5b are directly linked to form a cyclobutenyl, cyclopentenyl, cyclohexenyl or azacyclohexenyl group, wherein the cyclobutenyl, cyclopentenyl, cyclohexenyl or azacyclohexenyl group is optionally substituted by 1 to 4 R ^z ;

In some embodiments, R ^y1 is selected from H, C _1-6 alkyl, -C _0-4 alkylene-C _3-6 carbocyclyl, wherein the alkyl, alkylene or carbocyclyl is optionally substituted with 1 to 4 R ^z ;

In some embodiments, R ^y1 is selected from H, C _1-4 alkyl;

In some embodiments, R ^y1 is selected from H or methyl;

In some embodiments, R ^b6 is selected from H, C _3-12 carbocyclyl, 4 to 12 membered heterocyclyl, -OC _1-4 alkylene-C _3-12 carbocyclyl, -OC _1-4 alkylene-4 to 12 membered heterocyclyl, -5 to 6 membered heteroaryl-C (= O) NH-C _3-12 carbocyclyl, -5 to 6 membered heteroaryl-NHC (= O) -4 to 12 membered heterocyclyl, wherein the alkylene, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R ^b6a ;

In some embodiments, R ^b6 is selected from H, C _3-6 carbocyclyl, 4 to 7 membered heterocyclyl, -OC _1-4 alkylene-C _3-6 carbocyclyl, -OC _1-4 alkylene-4 to 7 membered heterocyclyl, -5 to 6 membered heteroaryl-C (= O) NH-C _3-6 carbocyclyl, -5 to 6 membered heteroaryl-NHC (= O) -4 to 7 membered heterocyclyl, wherein the alkylene, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R ^b6a ;

In some embodiments, R ^b6 is selected from H, C _3-6 carbocyclyl, 4 to 7 membered heterocyclyl, -OC _1-2 alkylene-C _3-6 carbocyclyl, -OC _1-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkylene, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 R ^b6a ;

In some embodiments, R ^b6 is selected from one of the following groups optionally substituted with ₁ to ₄ R ^6a : azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, _1,4 -diazepanyl, oxetanyl, tetrahydrofuranyl, oxahenyl, -OCH 2 -cyclopropyl, -OCH ₂ -cyclobutyl, -OCH 2 -cyclopentyl, -OCH 2 -azetidinyl, -OCH ₂ -pyrrolidinyl, -OCH _{2 -piperidinyl, -OCH 2 -piperazinyl} ,

In some embodiments, R ^b5e , R ^b6a are each independently selected from deuterium, halogen, CN, OH, ＝O, COOH, CONH ₂ , NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , -Y ₁ -C _1-6 alkyl, -Y ₁ -C _0-4 alkylene-C _3-6 carbocyclyl, -Y ₁ -C _0-4 alkylene-4 to 7 membered heterocyclyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-6 carbocyclyl, 4 to _{7 membered heterocyclyl, -C 1-2 alkylene-C 3-6 carbocyclyl, -C 1-2 alkylene-4 to 7 membered heterocyclyl, -C 1-2 alkylene - NHC 1-6} alkyl, -C _1-2 alkylene-N(C _1-6 alkyl) ₂ , wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R ^z ;

In some embodiments, R ^b5e , R ^b6a are each independently selected from deuterium, halogen, CN, OH, ═O, COOH, CONH ₂ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , -Y ₁ -C _1-4 alkyl, -Y ₁ -C _0-2 alkylene-C _3-6 carbocyclyl, -Y ₁ -C _0-2 alkylene-4 to 7 membered heterocyclyl, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _1-4 alkoxy, C _1-4 alkylthio, C _3-6 carbocyclyl, 4 to 7 membered heterocyclyl, -C _1-2 alkylene-C 3-6 carbocyclyl, _{-C 1-2 alkylene} -4 to 7 membered heterocyclyl, -C _1-2 alkylene-NHC _1-4 alkyl, -C _1-2 alkylene-N(C _1-4 alkyl) ₂ , the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, heterocyclic group are any Select to be replaced by 1 to 4 R ^z ;

In some embodiments, each R ^b5e is independently selected from deuterium, F, Cl, Br, I, CN, OH, ═O, COOH, CONH ₂ , -Y ₁ -CH ₃ , -Y ₁ -CH ₂ CH ₃ , -Y ₁ -oxetanyl, -Y ₁ -tetrahydrofuranyl, -Y ₁ -oxacyclohexyl, -Y ₁ -azetidinyl, -Y ₁ -pyrrolidinyl, -Y ₁ -piperidinyl, -Y ₁ -piperazinyl, -Y 1 -morpholinyl, -Y ₁ -CH ₂ -phenyl, -Y ₁ -CH ₂ -pyridinyl, _{-Y 1} -C(CH ₃ ) ₄ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, isopropyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, phenyl, thienyl, furanyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, -CH ₂ -cyclopropyl, -CH ₂ -cyclobutyl, -CH ₂ -cyclopentyl, -CH 2 -cyclohexyl, -CH ₂ -azetidinyl, -CH ₂ -pyrrolidinyl, -CH ₂ -piperidinyl, _{-CH 2} -piperazinyl, -CH ₂ -morpholinyl, -CH ₂ -oxetanyl, -CH ₂ -tetrahydrofuranyl, -CH ₂ -oxacyclohexyl, -CH ₂ -phenyl, -CH ₂ -thienyl, -CH ₂ -furanyl, -CH ₂ -thiazolyl, -CH ₂ -oxazolyl, -CH ₂ -imidazolyl, -CH ₂ -pyrazolyl, -CH ₂ -pyrrolyl, -CH ₂ -triazolyl, -CH ₂ -pyridinyl, wherein the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, isopropyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, oxacyclohexyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, phenyl, thienyl, furanyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl is optionally substituted with 1 to 4 substituents selected from the group consisting of deuterium, F, Cl, Br, I, CN, OH, _NH2 , _NHCH3 , N( _CH3 ) ₂ , methyl, ethyl, methoxy, ethoxy;

In some embodiments, R ^6a is each independently selected from deuterium, F, Cl, Br, I, CN, OH, CONH ₂ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH ₂ , CF ₃ , CD ₃ , methyl or ethyl;

In some embodiments, R ^b8 is selected from NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , NHC _3-6 carbocyclyl, N(C _1-6 alkyl)C _3-6 carbocyclyl, wherein the alkyl or carbocyclyl is optionally substituted with 1 to 4 R ^z ;

In some embodiments, R ^b8 is selected from NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , NHC _3-6 cycloalkyl, N(C _1-4 alkyl)C _3-6 cycloalkyl, said alkyl or cycloalkyl being optionally substituted with 1 to 4 R ^z ;

In some embodiments, R ^b8 is selected from NH ₂ , NHCH ₃ , -NH-cyclopropyl or -NHCH ₂ -cyclopropyl;

R ^b5 and R ^b6 are not H at the same time;

In some embodiments, R ^b5 is selected from

In some embodiments, when the compound is selected from (Ib), Selected from

In some embodiments, R ^b5 is selected from H, deuterium, F, Cl, Br, I, CN, one of the following groups optionally substituted: oxetanyl, tetrahydrofuranyl, oxacyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, 1,4-diazepanyl, Phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, when substituted, optionally substituted by 1 to 4 selected from or substituted by a substituent of R ^b5e ;

In some embodiments, each R ^b5e is independently selected from deuterium, F, Cl, Br, I, CN, OH, ═O, COOH, CONH ₂ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , —CONHCH ₃ , —CONHCH ₂ CH ₃ , —CONHCH ₂ CH ₂ OCH ₃ , -COOCH ₃ , -COOCH ₂ CH ₃ , CF ₃ , methyl, ethyl, methoxy, ethoxy, -CH ₂ CN, ethynyl, Phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl,

In some embodiments, R ^b5 is selected from H or pyrazolyl, which is optionally substituted with R ^b5e ;

In some embodiments, R ^b5 is selected from

In some embodiments, Selected from

In some embodiments, Selected from

In some embodiments, R ^b6 is selected from

In some embodiments, R ^b6 is selected from

In some embodiments, R ^b7 is selected from H, F, CF ₃ , methyl, methoxy;

In some embodiments, Selected from

In some embodiments, Selected from

In some embodiments, Selected from

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

U, V, and W are each independently selected from N or CR ^b7 ;

Z is selected from O or Se;

Ring B ₄ is selected from 5-membered heteroaryl, and said ring B ₄ is optionally substituted by 1 to 4 R ^b4 ;

R ^b1 is selected from CN or ethynyl;

R ^b2 , R ^b4 , and R ^b7 are each independently selected from H, deuterium, halogen, CN, OH, COOH, CONH ₂ , NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-6 carbocyclyl, 4- to 7-membered heterocyclyl, -C _1-2 alkylene- _{C 3-6 carbocyclyl} , -C _1-2 alkylene-4- to 7-membered heterocyclyl, and the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclyl, and heterocyclyl are optionally substituted by 1 to 4 R ^z ;

R ^b3 is selected from H, deuterium, halogen, CN, OH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, wherein the alkyl and alkylene groups are optionally substituted with 1 to 4 R ^z ;

Alternatively, R ^b3 and any R ^b4 are directly linked to form a C _4-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R ^z ;

R ^b5 is selected from H, deuterium, halogen, CN or one of the following groups which are optionally substituted: C _1-6 alkyl, C _1-6 alkoxy, C _3-12 carbocyclyl, 4 to 12 membered heterocyclyl, when substituted, optionally substituted with 1 to 4 selected from R ^b5e ;

R ^b6 is selected from H, C _3-12 carbocyclyl, 4 to 12-membered heterocyclyl, -OC _1-4 alkylene-C _3-12 carbocyclyl, -OC _1-4 alkylene-4 to 12-membered heterocyclyl, wherein the alkylene, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R ^b6a ;

R ^b5e , R ^b6a are each independently selected from deuterium, halogen, CN, OH, ═O, COOH, CONH ₂ , NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , -Y ₁ -C _1-6 alkyl, -Y ₁ -C _0-4 alkylene-C _3-6 carbocyclyl, -Y ₁ -C _0-4 alkylene-4 to 7-membered heterocyclyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-6 carbocyclyl, 4 to 7-membered heterocyclyl, -C _1-2 alkylene-C _3-6 carbocyclyl, -C _1-2 alkylene-4 to 7-membered heterocyclyl, -C _1-2 alkylene-NHC _1-6 alkyl, -C _1-2 alkylene-N(C _1-6 alkyl) ₂ , the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R ^z ;

Y ₁ is selected from C(=O), S(=O) ₂ , -NR ^y1 -, -C(=O)NR ^y1 -, -S(=O) ₂ NR ^y1 -, -NR ^y1 C(=O )-,-OC(＝O)NR ^y1 -,-NR ^y1 C(＝O)O-,-NR ^y1 S(＝O) ₂ -, -C(=O)O-, -OC(=O)-;

R ^y1 is selected from H, C _1-6 alkyl, -C _0-4 alkylene-C _3-6 carbocyclyl, wherein the alkyl, alkylene or carbocyclyl is optionally substituted by 1 to 4 R ^z ;

R ^b8 is selected from NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , NHC _3-6 carbocyclyl, N(C _1-6 alkyl)C _3-6 carbocyclyl, wherein the alkyl or carbocyclyl is optionally substituted by 1 to 4 R ^z ;

R ^b5 and R ^b6 are not H at the same time;

^{Rz is} each independently selected from deuterium, F, Cl, Br, I, OH, =O, _SF5 , CN, _NO2 , COOH, _CONH2 , _NH2 , _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, _-SC1-4 alkyl, -C0-4 alkylene- _C3-6 carbocyclyl, _-C0-4 alkylene- ₄ to 7 membered heterocyclyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl, _C1-4 alkoxy;

b1 is selected from 0, 1 or 2;

b2 is selected from 0, 1, 2, 3, 4 or 5.

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

R ^b2 , R ^b4 , and R ^b7 are each independently selected from H, deuterium, halogen, CN, OH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, and C _3-6 cycloalkyl, wherein the alkyl, alkoxy, alkylthio, and cycloalkyl are optionally substituted by 1 to 4 R ^z ;

R ^b3 is selected from H;

Alternatively, R ^b3 and any R ^b4 are directly linked to form a C _4-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R ^z ;

R ^b5 is selected from H, deuterium, halogen, OH, CN or one of the following groups which are optionally substituted: C _6-10 aryl, 5-10 membered heteroaryl, 4-12 membered heterocyclyl, when substituted, optionally substituted with 1 to 4 R ^b5e ;

R ^b6 is selected from H, C _3-6 carbocyclyl, 4 to 7 membered heterocyclyl, -OC _1-4 alkylene-C _3-6 carbocyclyl, -OC _1-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkylene, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R ^b6a ;

R ^b5e , R ^b6a are each independently selected from deuterium, halogen, CN, OH, ＝O, COOH, CONH ₂ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , -Y ₁ -C _1-4 alkyl, -Y ₁ -C _0-2 alkylene-C _3-6 carbocyclyl, -Y ₁ -C _0-2 alkylene-4 to 7 membered heterocyclyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclyl, heterocyclyl is optionally substituted by 1 to 4 R ^z ;

R ^b8 is selected from NH ₂ ;

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

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

R ^b5 is selected from H, one of the following groups which are optionally substituted: phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered monocyclic heterocycloalkyl, 6- to 12-membered cycloheterocycloalkyl, 6- to 12-membered spirocyclic heterocycloalkyl, 6- to 12-membered bridged heterocycloalkyl, and when substituted, is optionally substituted with 1 to 4 R ^b5e ;

R ^b6 is selected from H, C _3-6 carbocyclyl, 4 to 7 membered heterocyclyl, -OC _1-2 alkylene-C _3-6 carbocyclyl, -OC _1-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R ^b6a ;

^{Rz is} 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 with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl, _C1-4 alkoxy;

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

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

The compound represented by the general formula (I) is selected from (Ib)

Any two of U, V, and W are selected from N, and the other one is selected from CR ^b7 ;

Ring B ₄ is selected from oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, and the ring B ₄ is optionally substituted by 1 R ^b4 ;

R ^b3 is selected from H;

R ^b2 and R ^b4 are each independently selected from deuterium, F, Cl, Br, I, CN, OH or one of the following groups optionally substituted with 1 to 4 R ^z : methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

Alternatively, R ^b3 and R ^b4 are directly linked to form a C _5-6 carbocyclic group, wherein the carbocyclic group is optionally substituted by 1 to 4 R ^z ;

R ^b5 is selected from H or one of the following groups which are optionally substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, when substituted, optionally substituted with 1 to 4 selected from R ^b5e ;

R ^b5e are each independently selected from deuterium, F, Cl, Br, I, CN, OH, =O, COOH, CONH ₂ , -Y ₁ -CH ₃ , -Y ₁ -CH ₂ CH ₃ , -Y ₁ -oxetanyl, -Y ₁ -tetrahydrofuranyl, -Y 1 -oxetanyl, -Y _{1 -azetidinyl, -Y 1 -pyrrolidinyl} , -Y ₁ -piperidinyl, -Y ₁ -piperazinyl, -Y _{1 -morpholinyl} , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, azetidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, I, CN, OH, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , methyl, ethyl, methoxy, ethoxy;

Y ₁ is selected from -C(=O)NH-, -C(=O)N(CH ₃ )-, -NHC(=O)-, -N(CH ₃ )C(=O)-;

R ^b6 is selected from one of the following groups optionally substituted with 1 to 4 R ^6a : azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 1,4-diazepanyl, oxetanyl, tetrahydrofuranyl, oxhexyl, -OCH ₂ -cyclopropyl, -OCH ₂ -cyclobutyl, -OCH ₂ -cyclopentyl, -OCH 2 -azetidinyl, -OCH ₂ -pyrrolidinyl, -OCH ₂ -piperidinyl _{, -OCH 2 -piperazinyl} ;

R ^6a are each independently selected from deuterium, F, Cl, Br, I, CN, OH, CONH ₂ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH ₂ , CF ₃ , CD ₃ , methyl or ethyl;

R ^b7 is selected from H, deuterium, F, Cl, Br, I, CN, OH, CONH ₂ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ or one of the following groups optionally substituted with 1 to 4 R ^z : methyl, ethyl, propyl, isopropyl;

Preferably, Selected from

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

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

Selected from

R ^b5 is selected from H or one of the following groups which are optionally substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, thienyl, when substituted, optionally substituted with 1 to 4 R ^b5e ;

R ^b5e are each independently selected from deuterium, F, Cl, Br, I, CN, OH, ═O, COOH, CONH ₂ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , —CONHCH ₃ , —CONHCH ₂ CH ₃ , —CONHCH ₂ CH ₂ OCH ₃ , CF ₃ , methyl, ethyl, methoxy, ethoxy, -CH ₂ CN, ethynyl, Phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl,

R ^b6 is selected from

R ^b7 is selected from H, F, CF ₃ , methyl, methoxy;

Preferably, Selected from

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

The present invention relates to the following compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table E-2 below:

Table E-2

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

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

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

In some embodiments, the disease associated with inhibition or degradation of KRAS is cancer (eg, gastric cancer, esophageal cancer, or pancreatic cancer).

The present invention relates to a pharmaceutical composition or a pharmaceutical preparation, wherein the pharmaceutical composition or the pharmaceutical preparation comprises a therapeutically effective amount of the present The compound of the invention or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal and 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").

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

"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, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 4 0-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1500mg, 80-1000mg, 80-800mg;

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

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

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

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

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

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

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

"CN" refers to cyano.

"Halogen" refers to F, Cl, Br or I.

"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.

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

"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.

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

"Alkenyl" refers to substituted or unsubstituted straight-chain or branched unsaturated hydrocarbon groups having at least one, typically 1, 2 or 3 carbon-carbon double bonds, the main chain includes but is not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, etc.; the alkenyl group can be monovalent, divalent, trivalent or tetravalent.

"Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a main chain comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the main chain and 2 to 4 carbon atoms in the main chain. Examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like; alkynyl groups can be monovalent, divalent, trivalent or tetravalent.

"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.

"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.

"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 or S. The C, N, S selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, and can be connected to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl, "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

"Spiro" or "spirocyclic group" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom). The number of ring atoms in the spirocyclic system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 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 may optionally contain 0 to 5 heteroatoms selected from N, O or S(=O) _n (n is 0, 1 or 2).

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

"Cyclic" or "Cyclic radical" 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 cyclic 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 cyclic system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include: "Bicyclic" or "bicyclic group" can be monovalent, divalent, trivalent or tetravalent.

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

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

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

"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.

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

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

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

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

"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.

"Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O or S(=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, n is 1, 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furanyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, and 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.

"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, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring group, spirocyclyl, cyclocyclyl, 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 ) _mS (=O) _nR ^a , -( _CH2 ) _m -alkenyl-R ^a , OR ^d , or -( _CH2 ) _m -alkynyl-R ^a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR ^b R ^c , wherein R ^b and R ^c are independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, as an option, R ^b and R ^c can form a five- or six-membered cycloalkyl or heterocyclyl, ^Ra and R ^d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spiro ring or cycloalkyl.

"1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from...", X is selected from any integer between 1 and 10. For example, "1 to 4 R ^k substituted" means substituted 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.

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

_Cxy carbocycle (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, cyclic carbocycle or bridged carbocycle) includes _Cx , Cx ₊₁ , _Cx+2 , Cx ₊₃ , Cx ₊₄ ... _Cy -membered ring (x is an integer, and 3≤x＜y, y is selected from any integer between 4 and 20), for example. "C _3-6 cycloalkyl" means C ₃ , C ₄ , C ₅ or C ₆ cycloalkyl;

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

When the listed connecting 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, A-L-B, when L is selected from -M-W-, includes A-M-W-B and A-W-M-B.

"Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes situations where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.

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

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

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

"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.

Synthesis method 1:

Referring to the route and method of WO2023099624, compound D-1-6 of the general formula was obtained;

The general formula compound D-1-6 reacts with selenium powder and malonic acid under alkaline conditions to obtain the general formula compound D-1-7;

The compound of the general formula D-1-7 and the compound of the general formula D-1-8 are reacted by nucleophilic substitution reaction, coupling reaction, etc. to obtain the compound of the general formula (D-1-9);

R ^D-1-1 is selected from a leaving group, preferably halogen, OMs, OTs or OTf;

R ^D-1-4 is selected from H or a hydroxyl protecting group;

L ₁ is selected from a bond or a 5-12 membered nitrogen-containing heterocyclic ring;

The definitions of the remaining groups are consistent with the description.

DETAILED DESCRIPTION

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.

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.

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

For MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));

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

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;

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

Example 1: Synthesis of Compound 1

Step 1: Synthesis of compound 1B

1A (referenced in Nature, 2023, 619, 160-166.) (580 mg, 1.83 mmol) and (S)-4-N-tert-butyloxycarbonyl-2-methylpiperazine (1.1 g, 5.49 mmol) were dissolved in 12 mL of dry acetonitrile, and DIPEA (708 mg, 5.49 mmol) was added dropwise at room temperature, and the mixture was reacted at 110° C. overnight. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain 1B (720 mg, 82%).

LCMS m/z＝482.3[M+1] ⁺

Step 2: Synthesis of 1C

At room temperature, 1B (360 mg, 0.75 mmol) and selenium powder (89 mg, 1.12 mmol) were placed in a pressure tube, and after three replacements with nitrogen, a solution of malononitrile (74 mg, 1.12 mmol) in ethanol (4 mL) and triethylamine (4 mL) were added, and the mixture was reacted at 110°C for 40 hours. The reaction solution was filtered and concentrated, and the residue was purified by silica gel column chromatography to obtain 1C (55 mg, 12%).

LCMS m/z＝610.2[M+1] ⁺

Step 3: Synthesis of Compound 1

1C (65 mg, 0.10 mmol) was dissolved in 2 mL of dichloromethane, and a solution of hydrochloric acid in dioxane (4 N, 2 mL) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by preparative HPLC (preparation conditions: instrument: SHIMADZU LC-20AP; column: C18 column; mobile phase: A is 10mmol/L _{NH4HCO3 aqueous} solution, B is acetonitrile; elution condition: B from 30% to 60% in 10min; flow rate: 25mL/min; column temperature: room temperature; detection wavelength: 220nm) to purify compound 1 (26mg, 51%).

Compound 1 was prepared by chiral SFC to obtain compound 1-1 (8.2 mg, chiral HPLC retention time: 1.374 min) and compound 1-2 (5.1 mg, chiral HPLC retention time: 1.909 min). One of compound 1-1 or compound 1-2 is structure 1-A, and the other is structure 1-B.

(SFC separation conditions: Instrument: Waters 150Prep-SFC; Chromatographic column: Chiral Whelk column; Mobile phase: A is CO ₂ ; B is 0.1% ammonia in methanol; Elution conditions: 55% B in A solution; Flow rate: 100 mL/min; Pressure: 100 bar; Column temperature: room temperature; Detection wavelength: 220 nm; Chiral HPLC detection method: Instrument: SHIMADZU LC-30AD sf; Chromatographic column: Chiral Whelk column; Mobile phase: A: CO ₂ ; B: 0.05% diethylamine in methanol solution; Mobile phase: 40% B; Flow rate: 3 mL/min; Pressure: 100 bar; Column temperature: 35°C; Detection wavelength: 220 nm)

Compound 1-1: LCMS m/z=510.1[M+1] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ8.46(d,1H),7.18-7.11(m,2H),7.08(d,1H),4.76-4.63(m,1H),4.38-4.29(m,1H),3.11-2.94 (m,3H),2.86-2.75(m,2H),2.66-2.55(m,4H),2.09-1.89(m,4H),1.88-1.73(m,4H),1.20(d,3H).

Compound 1-2: LCMS m/z=510.1[M+1] ⁺

¹ H NMR (400MHz, DMSO-d ₆ )δ8.46(d,1H),7.19-7.11(m,2H),7.09(d,1H),4.76-4.67(m,1H),4.39-4.31(m,1H),3.09-2.95 (m,3H),2.88-2.78(m,2H),2.66-2.56(m,4H),2.11-1.90(m,4H),1.89-1.74(m,4H),1.22(d,3H).

Example 2: Preparation of Compound 2

Step 1: Synthesis of 2B

Under nitrogen protection, 2A (reference: WO2023099624) (300 mg, 0.68 mmol), methyl 3-pyrazolecarboxylate (170 mg, 1.36 mmol) and cesium carbonate (550 mg, 1.7 mmol) were placed in a sealed tube, and dry THF (10 mL) was added and stirred at 65 ° C for 16 h. Water (10 mL) was added to the reaction solution for dilution, and the aqueous phase was extracted with ethyl acetate (30 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and 2B (334 mg, yield: 92%) was obtained by silica gel column chromatography.

LC-Ms m/z(ESI):535.2[M+H] ⁺

Step 2: Synthesis of 2C

2B (334 mg, 0.63 mmol) was dissolved in 8 mL of tetrahydrofuran and 1 mL of water, and lithium hydroxide monohydrate (131 mg, 3.13mmol), react at room temperature for 3h. Adjust pH to 4 with 1N hydrochloric acid, extract the organic phase with dichloromethane (20mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and perform silica gel column chromatography to obtain 2C (291mg, yield: 87%).

LC-Ms m/z(ESI):521.2[M+H] ⁺

Step 3: 2D Synthesis

Under nitrogen protection, 2C (291 mg, 0.56 mmol) and (R)-tetrahydrofuran-3-amine (73 mg, 0.84 mmol) were dissolved in dry DMF (10 mL), and DIPEA (290 mg, 2.24 mmol) and HATU (426 mg, 1.12 mmol) were added in sequence. The mixture was stirred at room temperature overnight, and ethyl acetate (80 mL) was added. The mixture was washed with water (20 mL × 2) and saturated brine (20 mL × 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and chromatographed on a silica gel column to obtain 2D (250 mg, yield: 76%).

LC-Ms m/z(ESI):590.2[M+H] ⁺

Step 4: Synthesis of Compound 2

Under nitrogen atmosphere, 2D (200 mg, 0.34 mmol), malononitrile (23 mg, 0.51 mmol) and selenium powder (40 mg, 0.51 mmol) were placed in a sealed tube, and ultra-dry ethanol (0.5 mL) and triethylamine (0.5 mL) were added, and the mixture was reacted overnight at 110° C. After the solvent was removed under reduced pressure, the residue was purified by preparative HPLC to give compound 2 (10 mg, yield: 4%). (Preparation conditions: primary preparation: instrument: SHIMADZU LC-20AP; chromatographic column: C18 column; mobile phase: A is 0.1% TFA in water, B is acetonitrile; elution condition: B from 20% to 50% in 15min; flow rate: 75mL/min; column temperature: room temperature; detection wavelength: 210nm &254nm; secondary preparation: instrument: SHIMADZU LC-20AP; chromatographic column: C18 column; mobile phase: A is 10mmol/L _{NH4HCO3 in} water, B is acetonitrile; elution condition: B from 45% to 66% in 15min; flow rate: 75mL/min; column temperature: room temperature; detection wavelength: 210nm & 254nm)

LC-Ms m/z(ESI):718.2[M+H] ⁺

¹ H NMR (400 MHz, DMSO-d ₆ )δ8.65-8.54(m,2H),7.51(s,1H),7.20-7.12(m,2H),6.97(d,1H),5.53-5.4 3(m,1H),4.56-4.45(m,1H),3.93-3.83(m,2H),3.77-3.69(m,1H),3.67-3.60 (m,1H),3.18-3.09(m,1H),3.02-2.93(m,1H),2.78-2.60(m,4H),2.42-2.36( m,3H),2.26-2.13(m,2H),2.10-1.92(m,5H),1.91-1.61(m,8H),1.31(d,3H).

Compound 2 was prepared by chiral SFC to give compound 2-1 (3.1 mg, chiral HPLC retention time: 0.805 min) and compound 2-2 (2.7 mg, chiral HPLC retention time: 1.713 min). (SFC separation conditions: Instrument: Waters 150Prep-SFC; Chromatographic column: Chiral AS column; Mobile phase: A is CO ₂ ; B is 0.1% ammonia in isopropanol and acetonitrile solution; Elution conditions: 65% B in A solution; Flow rate: 100mL/min; Pressure: 100bar; Column temperature: room temperature; Detection wavelength: 220nm. HPLC purification method: Instrument: SHIMADZU LC-20AP; Chromatographic column: C18 column; Mobile phase: A is water containing 10mmol/LNH4HCO3; B is acetonitrile; Elution conditions: Gradient elution, B 40% to 70% in 12min; Flow rate: 30mL/min; Column temperature: room temperature; Detection wavelength: 220nm. Chiral HPLC detection analysis method: Instrument: SHIMADZU LC-30AD sf; Chromatographic column: Chiral IK column; Mobile phase: A: CO ₂ ; B: 0.05% diethanolamine in isopropanol acetonitrile solution; mobile phase: 50% B elution; flow rate: 3 mL/min; pressure: 100 bar; column temperature: 35 ° C; detection wavelength: 220 nm).

One of the compound 2-1 or the compound 2-2 has the structure 2-A, and the other has the structure 2-B.

Compound 2-1:

¹ H NMR (400MHz, CD ₃ OD)δ8.84(d,1H),7.47(s,1H),6.98(d,1H),5.52-5.43(m,1H),4.67-4.59(m,1H),4 .56-4.49(m,1H),4.06-3.94(m,2H),3.88-3.81(m,1H),3.79-3.74(m,1H),3.30-3.2 1(m,1H),3.15-3.07(m,1H),2.92-2.64(m,4H),2.56(s,3H),2.49-2.39(m,1H),2.37 -2.27(m,1H),2.20-2.03(m,6H),2.00-1.90(m,3H),1.88-1.72(m,3H),1.42(d,3H).

Compound 2-2:

¹ H NMR (400MHz, CD ₃ OD)δ8.84(d,1H),7.47(s,1H),6.98(d,1H),5.55-5.47(m,1H),4.67-4.59(m,1 H),4.56-4.49(m,1H),4.06-3.94(m,2H),3.90-3.82(m,1H),3.80-3.72(m,1H), 3.25-3.17(m,1H),3.14-3.06(m,1H),2.92-2.64(m,4H),2.55(s,3H),2.48-2.2 7(m,2H),2.20-2.03(m,6H),2.01-1.90(m,3H),1.86-1.73(m,3H),1.42(d,3H).

Example 6: Preparation of Compound 6

Step 1: Synthesis of 6A

Under nitrogen protection, 2C (1.1 g, 2.11 mmol) and 3-methylaminooxetane (280 mg, 3.17 mmol) were dissolved in dry DMF (12 mL), and DIPEA (0.7 mL, 4.22 mmol) and HATU (1.2 g, 3.17 mmol) were added in sequence. The mixture was stirred at room temperature overnight, and ethyl acetate (80 mL) was added. The mixture was washed with water (20 mL × 2) and saturated brine (20 mL × 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and 6A (650 mg, yield: 52.17%) was obtained by silica gel column chromatography.

LC-Ms m/z(ESI):590.5[M+H] ⁺

Step 2: Synthesis of compound 6

6A (650 mg, 1.10 mmol), malononitrile (110 mg, 1.65 mmol) and selenium powder (870 mg, 11 mmol) were added to the sealed tube, and ultra-dry ethanol (6 mL) and triethylamine (6 mL) were added, and nitrogen was replaced for protection, and the reaction was carried out at 90° C. for 20 hours. After the solvent was removed under reduced pressure, the residue was purified by preparative HPLC to obtain compound 6 (22 mg, yield: 2.79%). (First preparation conditions: Instrument: Shimadzu LC-20AP; Preparation column: C18; Mobile phase: A is 10mmol/L NH4HCO3 aqueous solution; B is acetonitrile; Elution conditions: 40% to 58% B in A solution gradient elution for 20 minutes; Flow rate: 90mL/min; Column temperature: room temperature; Detection wavelength: 210&254nm; Second preparation conditions: Instrument: Shimadzu LC-20AP; Preparation column: C18; Mobile phase: A is 10mmol/L _{NH4HCO3 aqueous} solution; B is acetonitrile; Elution conditions: 55% to 85% B in A solution gradient elution for 20 minutes; Flow rate: 25mL/min; Column temperature: room temperature; Detection wavelength: 210&254nm;)

LC-Ms m/z(ESI):718.2[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD)δ8.90-8.81(m,1H),7.27(d,1H),6.88(d,1H),5.80-5.29(m,2H),4.95-4.83(m,4H),3.48-3.31(m ,3H),3.27-3.18(m,1H),3.14-3.0 4(m,1H),2.96-2.63(m,4H),2.58-2.49(m,3H),2.47-2.36(m,1H),2.21-2.13(m,2H),2.13-1.89(m,7H ),1.88-1.72(m,3H),1.42(d,3H).

Compound 6 was prepared by chiral SFC to obtain compound 6-1 (6.9 mg; chiral SFC retention time: 1.007 min) and compound 6-2 (5.7 mg, 1.718 min); (SFC separation conditions: instrument: Waters 150Prep-SFC; chromatographic column: Chiral IK column; mobile phase: A is CO ₂ ; B is 0.1% ammonia in methanol and acetonitrile solution; elution conditions: 55% B in A solution; flow rate: 100 mL/min; pressure: 100 bar; column temperature: room temperature; detection wavelength: 220 nm. Chiral SFC detection and analysis method: instrument: SHIMADZU LC-30AD SFC; chromatographic column: Chiral IK column; mobile phase: A: CO ₂ ; B: 0.05% diethanolamine in methanol and acetonitrile; mobile phase: 50% B elution; flow rate: 3mL/min; pressure: 100bar; column temperature: 35℃; detection wavelength: 220nm)

One of compound 6-1 and compound 6-2 has structure 6-A, and the other has structure 6-B.

Compound 6-1:

¹ H NMR (400MHz, CD ₃ OD)δ8.87(d,1H),7.26(d,1H),6.88(d,1H),5.80-5.30(m,2H),4.95-4.83(m,4H),3.50-3.31(m,3H ),3.30-3.05(m,2H), 2.94-2.62(m,4H),2.55(s,3H),2.47-2.36(m,1H),2.23-2.02(m,6H),2.02-1.89(m,3H),1.88-1.73(m,3H ),1.42(d,3H).

Compound 6-2:

¹ H NMR (400MHz, CD ₃ OD)δ8.86(d,1H),7.26(d,1H),6.88(d,1H),5.80-5.31(m,2H),4.93-4.82(m,4H),3.50-3.31(m,3H ),3.26-3.07(m,2H), 2.97-2.63(m,4H),2.55(s,3H),2.50-2.40(m,1H),2.21-2.02(m,6H),2.01-1.90(m,3H),1.89-1.74(m,3H ),1.42(d,3H).

Example 7: Preparation of Compound 7

Compound 7 (53 mg) was prepared by referring to the synthesis of compound 6. (Preparation conditions: instrument: Shimadzu LC-20AP; preparation column: C18; mobile phase: A is 10 mmol/L NH ₄ HCO ₃ aqueous solution; B is acetonitrile; elution conditions: gradient elution of 45% to 62% B in A solution for 20 minutes; flow rate: 90 mL/min; column temperature: room temperature; detection wavelength: 210 & 254 nm;)

LC-Ms m/z(ESI):706.2[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD)δ8.88-8.83(m,1H),7.46(s,1H),7.03-6.99(m,1H),5.55-5.44(m,1H),4.69-4.63(m,1H),3.25-3.14 (m,2H),2.97-2.81(m,3H), 2.78-2.64(m,2H),2.62-2.55(m,3H),2.54-2.43(m,1H),2.21-1.91(m,9H),1.89-1.75(m,3H),1.47-1.39(m ,3H),1.26-1.14(m,2H).

Compound 7 was prepared by chiral SFC to obtain compound 7-1 (17.2 mg; chiral SFC retention time: 0.702 min) and compound 7-2 (18.4 mg; chiral SFC retention time: 1.098 min); (SFC separation conditions: instrument: Waters 150 Prep-SFC; chromatographic column: Chiral IK column; mobile phase: A is CO ₂ ; B is 0.1% ammonia in methanol and acetonitrile solution; elution conditions: 55% B in A solution; flow rate: 100 mL/min; pressure: 100 bar; column temperature: room temperature; detection wavelength: 220 nm. Chiral SFC detection and analysis method: instrument: SHIMADZU LC-30AD SFC; chromatographic column: Chiral IK column; mobile phase: A: CO ₂ ; B: 0.05% diethanolamine in methanol and acetonitrile; mobile phase: 50% B elution; flow rate: 3mL/min; pressure: 100bar; column temperature: 35℃; detection wavelength: 220nm)

One of compound 7-1 and compound 7-2 has structure 7-A, and the other has structure 7-B.

Compound 7-1

¹ H NMR (400MHz, CD ₃ OD)δ8.86(d,1H),7.45(s,1H),7.00(d,1H),5.51-5.42(m,1H),4.82-4.63(m,1H),3.30-3.21(m,1H ),3.15-3.06(m,1H),2.93-2.6 3(m,5H),2.56(s,3H),2.49-2.37(m,1H),2.21-2.03(m,6H),2.01-1.90(m,3H),1.88-1.72(m,3H), 1.42(d,3H),1.27-1.14(m,2H).

Compound 7-2

¹ H NMR (400MHz, CD ₃ OD)δ8.84(d,1H),7.44(s,1H),7.00(d,1H),5.55-5.45(m,1H),4.85-4.62(m,1H),3.25-3.07(m,2H ),2.96-2.65(m,5H), 2.56(s,3H),2.51-2.41(m,1H),2.20-2.01(m,6H),2.01-1.90(m,3H),1.88-1.74(m,3H),1.43(d,3H), 1.27-1.14(m,2H).

Example 8: Preparation of Compound 8

Compound 8 (75 mg) was prepared by referring to the synthesis of compound 6. (First preparation conditions: instrument: Shimadzu LC-20AP; preparation column: C18; mobile phase: A is 10 mmol/L NH ₄ HCO ₃ aqueous solution; B is acetonitrile; elution conditions: gradient elution of A solution from 35% to 65% B for 25 minutes; flow rate: 80 mL/min; column temperature: room temperature; detection wavelength: 210 & 254 nm; second preparation conditions: instrument: Shimadzu LC-20AP; preparation column: C18; mobile phase: A is 10 mmol/L NH ₄ HCO ₃ aqueous solution; B is acetonitrile; elution conditions: gradient elution of A solution from 63% to 93% B for 20 minutes; flow rate: 25 mL/min; column temperature: room temperature; detection wavelength: 210 & 254 nm;)

LC-Ms m/z(ESI):753.2[M+H] ⁺

¹ H NMR (400MHz, CD ₃ OD)δ8.88-8.81(m,1H),8.54(d,1H),7.85-7.77(m,1H),7.52-7.46(m,2H),7.34-7.28 (m,1H),6.99(d,1H),5.57-5.45(m,1H),5.36-5.26(m,1H),3.26-3.18(m,1H),3.13-3 .03(m,1H),2.98-2.83(m,1H),2.81-2.63(m,3H),2.59-2.50(m,3H),2.45-2.34(m,1H ),2.21-2.13(m,2H),2.13-2.88(m,7H),1.87-1.73(m,3H),1.62(d,3H),1.43(d,3H).

Compound 8 was prepared by chiral SFC to obtain compound 8-1 (26.8 mg; chiral SFC retention time: 0.850 min) and compound 8-2 (34.2 mg; chiral SFC retention time: 1.382 min); (SFC separation conditions: instrument: Waters 150Prep-SFC; chromatographic column: Chiral IK column; mobile phase: A is CO ₂ ; B is 0.1% ammonia in methanol and acetonitrile solution; elution conditions: 50% B in A solution; flow rate: 100 mL/min; pressure: 100 bar; column temperature: room temperature; detection wavelength: 220 nm. Chiral SFC detection and analysis method: instrument: SHIMADZU LC-30AD SFC; chromatographic column: Chiral IK column; mobile phase: A: CO ₂ ; B: 0.05% diethanolamine in methanol and acetonitrile; mobile phase: 50% B elution; flow rate: 3mL/min; pressure: 100bar; column temperature: 35℃; detection wavelength: 220nm)

One of compound 8-1 and compound 8-2 has structure 8-A, and the other has structure 8-B.

Compound 8-1:

¹ H NMR (400MHz, CD ₃ OD) δ8.86(d,1H),8.56-8.52(m,1H),7.84-7.78(m,1H),7.52-7.47 (m,2H),7.34-7.28(m,1H),6.99(d,1H),5.53-5.44(m,1H),5.35-5.27(m,1H),3.30-3.21(m,1H),3.14 -3.07(m,1H),2.93-2. 63(m,4H),2.55(d,3H),2.47-2.38(m,1H),2.20-2.03(m,6H),2.01-1.90(m,3H),1.87-1.72(m,3H), 1.62(d,3H),1.43(d,3H).

Compound 8-2:

¹ H NMR (400 MHz, CD ₃ OD)δ8.85(d,1H),8.56-8.51(m,1H),7.85-7.77(m,1H),7.53-7.46(m,2H) ,7.34-7.27(m,1H),6.99(d,1H),5.57-5.48(m,1H),5.35-5.27(m,1H),3.2 6-3.07(m,2H),2.97-2.63(m,4H),2.55(d,3H),2.48-2.38(m,1H),2.21-2. 02(m,6H),2.01-1.90(m,3H),1.89-1.74(m,3H),1.62(d,3H),1.43(d,3H).

Example 9: Preparation of Compound 9

Compound 9 (70 mg) was prepared by referring to the synthesis of compound 6. (First preparation conditions: instrument: Shimadzu LC-20AP; preparation column: C18; mobile phase: A is 10 mmol/L NH ₄ HCO ₃ aqueous solution; B is acetonitrile; elution conditions: gradient elution of A solution from 35% to 65% B for 25 minutes; flow rate: 80 mL/min; column temperature: room temperature; detection wavelength: 210 & 254 nm; second preparation conditions: instrument: Shimadzu LC-20AP; preparation column: C18; mobile phase: A is 10 mmol/L NH ₄ HCO ₃ aqueous solution; B is acetonitrile; elution conditions: gradient elution of A solution from 63% to 93% B for 20 minutes; flow rate: 25 mL/min; column temperature: room temperature; detection wavelength: 210 & 254 nm;)

LC-Ms m/z(ESI):706.2[M+H] ⁺

¹ H NMR (400 MHz, CD ₃ OD)δ8.87-8.83(m,1H),7.47-7.41(m,1H),7.02-6.97(m,1H),5.54-5.42(m ,1H),4.85-4.62(m,1H),3.30-3.16(m,1H),3.12-3.02(m,1H),2.96-2.81(m ,2H),2.80-2.63(m,3H),2.56-2.49(m,3H),2.45-2.34(m,1H),2.21-2.12(m ,2H),2.12-1.89(m,7H),1.86-1.70(m,3H),1.42(d,3H),1.26-1.13(m,2H).

Compound 9 was prepared by chiral SFC to obtain compound 9-1 (25.8 mg; chiral SFC retention time: 0.682 min) and compound 9-2 (25.7 mg; chiral SFC retention time: 1.054 min); (SFC separation conditions: instrument: Waters 150Prep-SFC; chromatographic column: Chiral IK column; mobile phase: A is CO ₂ ; B is 0.1% ammonia in methanol and acetonitrile solution; elution conditions: 55% B in A solution; flow rate: 100 mL/min; pressure: 100 bar; column temperature: room temperature; detection wavelength: 220 nm. Chiral SFC detection and analysis method: instrument: SHIMADZU LC-30AD SFC; chromatographic column: Chiral IK column; mobile phase: A: CO ₂ ; B: 0.05% diethanolamine in methanol and acetonitrile; mobile phase: 50% B elution; flow rate: 3mL/min; pressure: 100bar; column temperature: 35℃; detection wavelength: 220nm)

One of compound 9-1 and compound 9-2 has structure 9-A, and the other has structure 9-B.

Compound 9-1:

¹ H NMR (400MHz, CD ₃ OD)δ8.86(d,1H),7.44(s,1H),7.00(d,1H),5.51-5.43(m,1H),4.85-4.63(m,1H),3.30-3.05(m,2H ),2.93-2.63(m,6H), 2.55(s,3H),2.46-2.36(m,1H),2.19-2.03(m,6H),2.02-1.91(m,3H),1.87-1.71(m,3H),1.42(d,3H), 1.26-1.14(m,2H).

Compound 9-2:

¹ H NMR (400MHz, CD ₃ OD)δ8.84(d,1H),7.44(s,1H),7.00(d,1H),5.54-5.46(m,1H),4.85-4.63(m,1H),3.24-3.06(m,2H ),2.96-2.63(m,6H), 2.54(s,3H),2.47-2.36(m,1H),2.21-2.03(m,6H),2.01-1.89(m,3H),1.87-1.72(m,3H),1.42(d,3H), 1.26-1.13(m,2H).

Biological test 1: In vitro KRAS G12D binding assay

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

The signal ratio was calculated using the formula Ratio = [Signal 665] / [Signal 615] × 10 ⁴ , and the inhibition rate was calculated using Formula 2, where R _sample was the signal ratio of the compound wells, R _min was the signal ratio of the control wells without KRAS G12D protein, and R _max was the signal ratio of the control wells containing 1% DMSO solvent. GraphPad Prism software was used to perform curve fitting using four parameters and calculate the IC ₅₀ value.

Inhibition%=(1-(R _sample -R _min )/(R _max -R _min ))×100% (Formula 1)

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

Biological test 2: Cell proliferation inhibition experiment

ASPC-1 cell culture conditions: RPMI-1640 + 10% FBS + 1% double antibody, cultured at 37 ° C, 5% CO ₂ 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, cultured overnight in a 37 ° C, 5% CO ₂ incubator, and T ₀ 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% CO ₂ incubator for 6 days. On the second day, the CellTiter-Glo kit was used to detect the T ₀ plate while adding drugs, recorded as RLU _0. After the culture was completed, 25 μL of detection solution (Cell 4Viability 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 ₅₀ value of the compound when the proliferation inhibition rate was 50%. RLU _compound is the reading of the drug treatment group, and RLU _control is the average value of the solvent control group.

Inhibition % = (1-(RLU _compound -RLU ₀ )/(RLU _control - RLU ₀ ))×100% Formula (2)

Conclusion: The compounds of the present invention, such as the example compounds, have good proliferation inhibitory activity against ASPC-1 cells (Kras G12D). Specifically, compound 1-1 has an inhibitory activity against ASPC cells with IC50=345.3 nM, and compound 2-1 has an inhibitory activity against ASPC cells with IC50=58.8 nM.

Biological test 3: Cell proliferation inhibition experiment

Human non-small cell lung cancer cells H358 (KRAS G12C) were purchased from ATCC, and the complete cell culture medium was RPMI-1640 + 10% FBS + 1% antibiotic-antifungal dual antibody, and cultured at 37 ° C, 5% CO ₂ incubator. On the first day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the corresponding concentration with complete culture medium for plating, so that the cells were 1000/well, and the volume was 90 μL per well. On the next day, 10 μL of compounds of different concentrations were added, and the cells were placed in a CO ₂ incubator for 6 days. After the culture was completed, according to the operating instructions of the CellTiter-Glo kit (Promega, G7573), 50 μL of CTG solution pre-melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes, and the fluorescence signal value RLU was measured with an enzyme plate reader (BMG). The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1-(RLU compound-RLU blank control)/(RLU solvent control-RLU blank control))*100%. The inhibition rates of different concentrations of the compound were calculated in Excel, and then the inhibition curves were plotted and related parameters, including the minimum inhibition rate, maximum inhibition rate and _IC50 , were calculated using GraphPad Prism software.

Human colon cancer cells SW620 (KRAS G12V), the complete cell culture medium is RPMI-1640 + 10% FBS + 1% antibiotic-antifungal dual antibody, cultured at 37 ° C, 5% CO ₂ incubator. On the first day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the corresponding concentration with complete culture medium for plating, so that the cells were 500/well, and the volume was 90 μL per well. The next day, 10 μL of compounds of different concentrations were added and placed in a CO ₂ incubator for incubation for 6 days. After the culture was completed, according to the operating instructions of the CellTiter-Glo kit (Promega, G7573), 50 μL of CTG solution pre-melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes, and the fluorescence signal value RLU was measured with an enzyme plate reader (BMG). The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1-(RLU compound-RLU blank control)/(RLU solvent control-RLU blank control))*100%. The inhibition rates of different concentrations of the compound were calculated in Excel, and then the inhibition curves were plotted and related parameters, including the minimum inhibition rate, maximum inhibition rate and _IC50 , were calculated using GraphPad Prism software.

Human epidermal cancer cells A431 (KRAS WT) were purchased from ATCC. The complete cell culture medium was RPMI-1640 + 10% FBS + 1% antibiotic-antifungal dual antibody, and cultured at 37 ° C, 5% CO ₂ incubator. On the first day, cells in the exponential growth phase were collected, and the cell suspension was adjusted to the corresponding concentration with complete culture medium for plating, so that the cells were 1000/well, and the volume was 90 μL per well. On the next day, 10 μL of compounds of different concentrations were added, and the cells were placed in a CO ₂ incubator for 6 days. After the culture was completed, according to the operating instructions of the CellTiter-Glo kit (Promega, G7573), 50 μL of CTG solution pre-melted and equilibrated to room temperature was added to each well, mixed with a microplate shaker for 2 minutes, and placed at room temperature for 10 minutes, and the fluorescence signal value RLU was measured with an enzyme plate reader (BMG). The inhibition rate (IR) of the test compound was calculated using the following formula: IR (%) = (1-(RLU compound-RLU blank control)/(RLU solvent control-RLU blank control))*100%. The inhibition rates of different concentrations of the compound were calculated in Excel, and then the inhibition curves were plotted and related parameters, including the minimum inhibition rate, maximum inhibition rate and _IC50 , were calculated using GraphPad Prism software.

Test results:

Conclusion: The compounds of the present invention, such as the example compounds, have good proliferation inhibitory activity against H358 cells (Kras G12C) and SW620 cells (KRAS G12V). Combined with the proliferation inhibitory activity against A431 cells (Kras WT), the compounds of the present invention have good selectivity.

MRC-5 cell proliferation assay

Human embryonic lung cells MRC-5 were purchased from ATCC, and the cell culture medium was EMEM + 10% FBS, and cultured in a 37°C, 5% CO ₂ incubator. When the cell density was 60% to 80%, the culture medium was discarded, PBS was washed once, and trypsin-EDTA (0.25%) was added to digest the cells. Fresh culture medium was used to terminate the digestion, and the live cells were counted using a Countess ^TM II fully automatic cell counter. The cell suspension was adjusted to an appropriate concentration using cell culture medium, and 195 μL of cell suspension was added to each well of a 96-well cell culture plate to make 300 cells/well. Different concentrations of compounds were added the next day, and the plates were placed in an incubator and cultured for 6 days. After the culture is completed, the CellTiter-Glo reagent (CTG, Vazyme, DD1101-03) and the culture plate are taken out and restored to room temperature, 100 μL of the cell culture medium is discarded, and 60 μL of CTG reagent is added, and the cells are shaken for 2 minutes to fully lyse the cells. After standing at room temperature for 30 minutes, the fluorescence signal value is read with an enzyme reader (PHERAstar FSX). The culture medium well is set as the negative control, the DMSO well is set as the positive control, and the inhibitory activity percentage of the compound is standardized by the readings of the negative and positive controls. The inhibition rate calculation formula is:

Inhibition rate (%) = (fluorescence value of positive control group - fluorescence value of experimental group) / (fluorescence value of positive control group - fluorescence value of negative control group) * 100%

Data were analyzed by 4-parameter curve fitting or Excel and _IC50 values (half inhibitory concentration) were calculated.

Conclusion: The compounds of the present invention have weak inhibitory activity on MRC-5 cells. Combined with the proliferation inhibitory activity on H358, ASPC-1 and SW620, the compounds of the present invention have good selectivity.

Biological test 4: Rat pharmacokinetic test

Experimental animals: Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

Experimental design: On the day of the experiment, 6 SD rats/compound were randomly divided into groups according to body weight. The rats were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration.

Dosing Information

Note: Solvent for intravenous administration: 5% DMA + 5% Solutol + 90% Saline; Solvent for oral administration: 0.5% MC.

(DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; Saline: physiological saline; 0.5% MC: 0.5% aqueous solution of methylcellulose.

Before and after drug administration, 0.10 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in rats.

Mouse pharmacokinetic test

Experimental animals: Male BALB/c mice, 20-25 g, 6 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.

Experimental design: On the day of the experiment, six BALB/c mice were randomly divided into groups according to their body weight. They were fasted but not watered for 12-14 hours one day before administration, and were fed 4 hours after administration.

Note: Solvent for intravenous administration: 5% DMA + 5% Solutol + 90% Saline; Solvent for oral administration: 0.5% MC.

Before and after drug administration, 0.06 mL of blood was collected from the eye socket under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, and centrifuged at 5000 rpm at 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

Conclusion: The compounds of the present invention, such as the compounds in the examples, have good pharmacokinetic properties in mice.

Beagle dog pharmacokinetic testing

Experimental animals: Male beagle dogs, about 8-11 kg, 5-6 per compound, purchased from Beijing Mas Biotechnology Co., Ltd.

Test method: On the test day, 5-6 beagle dogs/compound were randomly divided into groups according to body weight. The dogs were fasted but not watered for 12-14 hours one day before administration, and food was given 4 hours after administration.

Note: Solvent for intravenous administration: 5% DMA + 5% Solutol + 90% Saline; Solvent for oral administration: 0.5% MC.

Before and after administration, 1 ml of blood was collected from the jugular vein or limb vein and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group in the G1 and G2 groups were: 0, 5, 15, 30 min, 1, 2, 4, 6, 8, 10, 12, 24, 48 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

Conclusion: The compounds of the present invention, such as the compounds in the examples, have good oral absorption properties in beagle dogs.

Monkey pharmacokinetic testing

Experimental animals: male cynomolgus monkeys, 3-5 kg, 3-6 years old, 4-6 per compound. Purchased from Suzhou Xishan Biotechnology Co., Ltd.

Test method: On the test day, 4-6 monkeys/compound were randomly divided into groups according to body weight. The monkeys were fasted but not watered for 14-18 hours one day before administration and were fed 4 hours after administration.

Note: Solvent for intravenous administration: 5% DMA + 5% Solutol + 90% Saline; Solvent for oral administration: 0.5% MC.

Before and after administration, 1.0 mL of blood was collected from the limb veins and placed in an EDTAK2 centrifuge tube. The blood was centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. The blood collection time points for the intravenous group and the gavage group were: 0, 5 min, 15 min, 30 min, 1, 2, 4, 6, 8, 10, 12, 24 h. Before analysis and testing, all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.

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

Caco2 permeability test

The experiment used a monolayer of Caco-2 cells and three parallel incubations were performed in a 96-well Transwell plate. A transport buffer solution (HBSS, 10mM HEPES, pH 7.4±0.05) containing the compound of the present invention (5μM) was added to the dosing port hole on the apical side or the basolateral side. A transport buffer solution containing DMSO was added to the corresponding receiving port hole. After incubation at 37±1°C for 2 hours, the cell plate was removed and appropriate amounts of samples were taken from the top and bottom ends to a new 96-well plate. Subsequently, acetonitrile containing an internal standard was added to precipitate the protein. The samples were analyzed using LC MS/MS and the concentrations of the compounds of the present invention and the control compounds were determined. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical side to the basolateral side of the monolayer cells and from the basolateral side to the apical side, thereby calculating the efflux rate. The integrity of the monolayer cells after 2 hours of incubation was evaluated by leakage of fluorescent yellow.

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

Liver microsome stability test

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

At 37°C, 1 μM of the test substance was incubated with microsomal proteins and coenzyme NADPH. After a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing internal standard was added to terminate the reaction. The concentration of the test substance in the sample was detected by LC-MS/MS. T _1/2 was calculated by the ln value of the drug residual rate in the incubation system and the incubation time, and the liver microsomal intrinsic clearance CLint(mic) and liver intrinsic clearance CLint(Liver) were further calculated.

Conclusion: The compounds of the present invention, such as the compounds in the examples, have good metabolic stability in liver microsomes.

CYP450 enzyme inhibition testing

The purpose of this study was to evaluate the effects of the test substances on the activities of five isoenzymes of human liver microsomal cytochrome P450 (CYP) (CYP1A2, CYP2C9, CYP2D6, and CYP3A4) using an in vitro test system. Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH). After the reaction, the samples were treated and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The changes in CYP enzyme activity were determined, and the IC ₅₀ values were calculated to evaluate the inhibitory potential of the test substances on each CYP enzyme subtype CYP1A2, CYP2C9, CYP2D6, and CYP3A4-M (with midazolam as substrate).

Conclusion: The compounds of the present invention, such as the compounds in the examples, have no significant inhibitory effect on any subtype of CYP enzymes.

hERG potassium channel function test

Experimental platform: electrophysiological manual patch clamp system

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

Experimental methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents using the whole-cell patch clamp technique at room temperature. The glass microelectrode was pulled from a glass electrode blank (BF150-86-10, Sutter) by a puller. The tip resistance after perfusion of the electrode liquid was about 2-5MΩ. The glass microelectrode was inserted into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording were controlled and recorded by pClamp 10 software through a computer, with a sampling frequency of 10kHz and a filter frequency of 2kHz. After obtaining the whole-cell recording, the cell was clamped at -80mV, and the step voltage to induce the hERG potassium current (I hERG) was given a 2s depolarization voltage from -80mV to +20mV, then repolarized to -50mV, and returned to -80mV after 1s. This voltage stimulation was given every 10s, and the drug administration process was started after the hERG potassium current was determined to be stable (at least 1 minute). Compounds were administered for at least 1 min at each tested concentration, and at least 2 cells (n≥2) were tested at each concentration.

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

Inhibition%=[1-(I/Io)]×100%

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

The _IC50 of the compounds was calculated using GraphPad Prism 5 software by fitting the following equation:

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)×HillSlope))

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

Conclusion: The compounds of the present invention, such as the compounds in the examples, have no obvious hERG inhibitory activity or weak inhibitory activity.

Claims (10)

A compound or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compounds represented by general formula (I),
U, V, and W are each independently selected from N or CR ^b7 ; Z is selected from O or Se; Ring B ₄ is selected from 5-membered heteroaryl, and said ring B ₄ is optionally substituted by 1 to 4 R ^b4 ; R ^b1 is selected from CN or ethynyl; R ^b2 , R ^b4 , and R ^b7 are each independently selected from H, deuterium, halogen, CN, OH, COOH, CONH ₂ , NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, C _2-6 alkenyl, C 2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-6 carbocyclyl, 4- to 7-membered heterocyclyl, -C _1-2 alkylene- _{C 3-6 carbocyclyl} , -C _1-2 alkylene-4- to 7-membered heterocyclyl, and the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclyl, and heterocyclyl are optionally substituted by 1 to 4 R ^z ; R ^b3 is selected from H, deuterium, halogen, CN, OH, NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , C _1-6 alkyl, wherein the alkyl and alkylene groups are optionally substituted with 1 to 4 R ^z ; Alternatively, R ^b3 and any R ^b4 are directly linked to form a C _4-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R ^z ; R ^b5 is selected from H, deuterium, halogen, CN or one of the following groups which are optionally substituted: C _1-6 alkyl, C _1-6 alkoxy, C _3-12 carbocyclyl, 4 to 12 membered heterocyclyl, when substituted, optionally substituted with 1 to 4 selected from R ^b5e ; R ^b6 is selected from H, C _3-12 carbocyclyl, 4 to 12-membered heterocyclyl, -OC _1-4 alkylene-C _3-12 carbocyclyl, -OC _1-4 alkylene-4 to 12-membered heterocyclyl, wherein the alkylene, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R ^b6a ; R ^b5e , R ^b6a are each independently selected from deuterium, halogen, CN, OH, ═O, COOH, CONH ₂ , NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , -Y ₁ -C _1-6 alkyl, -Y ₁ -C _0-4 alkylene-C _3-6 carbocyclyl, -Y ₁ -C _0-4 alkylene-4 to 7-membered heterocyclyl, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 alkylthio, C _3-6 carbocyclyl, 4 to 7-membered heterocyclyl, -C _1-2 alkylene-C _3-6 carbocyclyl, -C _1-2 alkylene-4 to 7-membered heterocyclyl, -C _1-2 alkylene-NHC _1-6 alkyl, -C _1-2 alkylene-N(C _1-6 alkyl) ₂ , the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic group, heterocyclic group is optionally substituted by 1 to 4 R ^z ; Y ₁ is selected from C(=O), S(=O) ₂ , -NR ^y1 -, -C(=O)NR ^y1 -, -S(=O) ₂ NR ^y1 -, -NR ^y1 C(=O )-,-OC(＝O)NR ^y1 -,-NR ^y1 C(＝O)O-,-NR ^y1 S(＝O) ₂ -, -C(=O)O-, -OC(=O)-; R ^y1 is selected from H, C _1-6 alkyl, -C _0-4 alkylene-C _3-6 carbocyclyl, wherein the alkyl, alkylene or carbocyclyl is optionally substituted by 1 to 4 R ^z ; R ^b8 is selected from NH ₂ , NHC _1-6 alkyl, N(C _1-6 alkyl) ₂ , NHC _3-6 carbocyclyl, N(C _1-6 alkyl)C _3-6 carbocyclyl, wherein the alkyl or carbocyclyl is optionally substituted by 1 to 4 R ^z ; R ^b5 and R ^b6 are not H at the same time; ^{Rz is} each independently selected from deuterium, F, Cl, Br, I, OH, =O, _SF5 , CN, _NO2 , COOH, _CONH2 , _NH2 , _NHC1-4 alkyl, N( _C1-4 alkyl) ₂ , _C1-4 alkyl, _C2-4 alkenyl, _C2-4 alkynyl, _C1-4 alkoxy, _-SC1-4 alkyl, -C0-4 alkylene- _C3-6 carbocyclyl, _-C0-4 alkylene- ₄ to 7 membered heterocyclyl, wherein the alkyl, alkylene, alkoxy, alkenyl, alkynyl, carbocyclyl or heterocyclyl is optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl, _C1-4 alkoxy; b1 is selected from 0, 1 or 2; b2 is selected from 0, 1, 2, 3, 4 or 5. The compound according to claim 1 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R ^b2 , R ^b4 , and R ^b7 are each independently selected from H, deuterium, halogen, CN, OH, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, and C _3-6 cycloalkyl, wherein the alkyl, alkoxy, alkylthio, and cycloalkyl are optionally substituted by 1 to 4 R ^z ; R ^b3 is selected from H; Alternatively, R ^b3 and any R ^b4 are directly linked to form a C _4-6 carbocyclic group or a 4- to 7-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R ^z ; R ^b5 is selected from H, deuterium, halogen, OH, CN or one of the following groups which are optionally substituted: C _6-10 aryl, 5-10 membered heteroaryl, 4-12 membered heterocyclyl, when substituted, optionally substituted with 1 to 4 R ^b5e ; R ^b6 is selected from H, C _3-6 carbocyclyl, 4 to 7 membered heterocyclyl, -OC _1-4 alkylene-C _3-6 carbocyclyl, -OC _1-4 alkylene-4 to 7 membered heterocyclyl, wherein the alkylene, heteroaryl, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R ^b6a ; R ^b5e , R ^b6a are each independently selected from deuterium, halogen, CN, OH, ＝O, COOH, CONH ₂ , NH ₂ , NHC _1-4 alkyl, N(C _1-4 alkyl) ₂ , -Y ₁ -C _1-4 alkyl, -Y ₁ -C _0-2 alkylene-C _3-6 carbocyclyl, -Y ₁ -C _0-2 alkylene-4 to 7 membered heterocyclyl, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, wherein the alkyl, alkylene, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclyl, heterocyclyl is optionally substituted by 1 to 4 R ^z ; R ^b8 is selected from NH ₂ . The compound according to claim 2 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R ^b5 is selected from H, one of the following groups which are optionally substituted: phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered monocyclic heterocycloalkyl, 6- to 12-membered cycloheterocycloalkyl, 6- to 12-membered spirocyclic heterocycloalkyl, 6- to 12-membered bridged heterocycloalkyl, and when substituted, is optionally substituted with 1 to 4 R ^b5e ; R ^b6 is selected from H, C _3-6 carbocyclyl, 4 to 7 membered heterocyclyl, -OC _1-2 alkylene-C _3-6 carbocyclyl, -OC _1-2 alkylene-4 to 7 membered heterocyclyl, wherein the alkylene, carbocyclyl or heterocyclyl is optionally substituted by 1 to 4 R ^b6a ; ^{Rz is} 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, and the methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, OH, CN, _C1-4 alkyl, _C1-4 alkoxy. The compound according to claim 3 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, Metabolites, pharmaceutically acceptable salts or co-crystals, wherein the compound represented by general formula (I) is selected from (Ib)
Any two of U, V, and W are selected from N, and the other one is selected from CR ^b7 ; Ring B ₄ is selected from oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, and the ring B ₄ is optionally substituted by 1 R ^b4 ; R ^b3 is selected from H; R ^b2 and R ^b4 are each independently selected from deuterium, F, Cl, Br, I, CN, OH or one of the following groups optionally substituted with 1 to 4 R ^z : methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; Alternatively, R ^b3 and R ^b4 are directly linked to form a C _5-6 carbocyclic group, wherein the carbocyclic group is optionally substituted by 1 to 4 R ^z ; R ^b5 is selected from H or one of the following groups which are optionally substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, furanyl, thienyl, when substituted, optionally substituted with 1 to 4 selected from R ^b5e ; R ^b5e are each independently selected from deuterium, F, Cl, Br, I, CN, OH, =O, COOH, CONH ₂ , -Y ₁ -CH ₃ , -Y ₁ -CH ₂ CH ₃ , -Y ₁ -oxetanyl, -Y ₁ -tetrahydrofuranyl, -Y 1 -oxetanyl, -Y _{1 -azetidinyl, -Y 1 -pyrrolidinyl} , -Y ₁ -piperidinyl, -Y ₁ -piperazinyl, -Y _{1 -morpholinyl} , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, azetidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl, oxetanyl, piperidinyl, piperazinyl, morpholinyl are optionally substituted by 1 to 4 groups selected from deuterium, F, Cl, Br, I, CN, OH, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , methyl, ethyl, methoxy, ethoxy; Y ₁ is selected from -C(=O)NH-, -C(=O)N(CH ₃ )-, -NHC(=O)-, -N(CH ₃ )C(=O)-; R ^b6 is selected from one of the following groups optionally substituted with 1 to 4 R ^6a : azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, azepanyl, 1,4-diazepanyl, oxetanyl, tetrahydrofuranyl, oxhexyl, -OCH ₂ -cyclopropyl, -OCH ₂ -cyclobutyl, -OCH ₂ -cyclopentyl, -OCH 2 -azetidinyl, -OCH ₂ -pyrrolidinyl, -OCH ₂ -piperidinyl _{, -OCH 2 -piperazinyl} ; R ^6a are each independently selected from deuterium, F, Cl, Br, I, CN, OH, CONH ₂ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH ₂ , CF ₃ , CD ₃ , methyl or ethyl; R ^b7 is selected from H, deuterium, F, Cl, Br, I, CN, OH, CONH ₂ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ or one of the following groups optionally substituted with 1 to 4 R ^z : methyl, ethyl, propyl, isopropyl; Preferably, Selected from The compound according to claim 4 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,
Selected from R ^b5 is selected from H or one of the following groups which are optionally substituted: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, furanyl, thienyl, when substituted, optionally substituted with 1 to 4 R ^b5e ; R ^b5e are each independently selected from deuterium, F, Cl, Br, I, CN, OH, ═O, COOH, CONH ₂ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , —CONHCH ₃ , —CONHCH ₂ CH ₃ , —CONHCH ₂ CH ₂ OCH ₃ , CF ₃ , methyl, ethyl, methoxy, ethoxy, -CH ₂ CN, ethynyl, Phenyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, R ^b6 is selected from R ^b7 is selected from H, F, CF ₃ , methyl, methoxy; Preferably, Selected from A compound or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from one of the structures shown in Table E-2. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1 to 1500 mg of a compound according to any one of claims 1 to 6 or a stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof. Use of the compound according to any one of claims 1 to 6 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating a disease associated with KRAS activity or expression. Use of the compound according to any one of claims 1 to 6 or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the pharmaceutical composition according to claim 7 in the preparation of a medicament for treating and inhibiting or degrading KRAS-related diseases, preferably cancer (e.g., gastric cancer, esophageal cancer or pancreatic cancer). A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound according to any one of claims 1 to 6 or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, or a pharmaceutical composition according to claim 7, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being selected from cancer (e.g., gastric cancer, esophageal cancer or pancreatic cancer).