WO2025002430A1 - Dérivés hétéroaryles à cinq chaînons et leur utilisation médicale - Google Patents

Dérivés hétéroaryles à cinq chaînons et leur utilisation médicale Download PDF

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WO2025002430A1
WO2025002430A1 PCT/CN2024/102681 CN2024102681W WO2025002430A1 WO 2025002430 A1 WO2025002430 A1 WO 2025002430A1 CN 2024102681 W CN2024102681 W CN 2024102681W WO 2025002430 A1 WO2025002430 A1 WO 2025002430A1
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alkyl
alkylene
optionally substituted
carbocyclyl
deuterium
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Chinese (zh)
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张晨
何平
魏琦
宁文涛
李瑶
严庞科
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Tibet Haisco Pharmaceutical Co Ltd
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Tibet Haisco Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D421/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D421/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having selenium, tellurium, or halogen atoms as ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D517/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D517/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms in which the condensed system contains two hetero rings
    • C07D517/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • 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.
  • 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).
  • GEF guanine nucleotide exchange factor
  • GAP
  • 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.
  • KRAS mutant protein inhibitors 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.
  • 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
  • G12C accounts for a high proportion in lung adenocarcinoma.
  • 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),
  • the compound represented by general formula (I) is selected from (Ib), (Ie)
  • U, V, W are each independently selected from N or CR b7 ;
  • any two of U, V, and W are selected from N, and the other one is selected from CR b7 ;
  • Z is selected from O, S or Se
  • Ring B 4 is selected from 5-membered heteroaryl, said Ring B 4 being optionally substituted with 1 to 4 R b4 ;
  • 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 ;
  • 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 with 1 to 4 R z ;
  • 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, alkyl
  • 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;
  • 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 -cycl
  • 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 ;
  • 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 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 ;
  • 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 ;
  • R b3 is selected from H, methyl, ethyl, propyl or isopropyl;
  • 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 ;
  • 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 ;
  • 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 ;
  • 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 cycloal
  • 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
  • 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,
  • 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 ;
  • 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 ;
  • 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 ;
  • 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,
  • 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 ;
  • 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 ;
  • R y1 is selected from H, C 1-4 alkyl
  • R y1 is selected from H or methyl
  • 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 ;
  • 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 ,
  • 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 alkyl
  • 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, isopropy
  • 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 e
  • 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 ;
  • 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 ;
  • 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;
  • R b5 is selected from
  • 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 ;
  • 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,
  • R b5 is selected from H or pyrazolyl, which is optionally substituted with R b5e ;
  • R b5 is selected from
  • R b6 is selected from
  • R b6 is selected from
  • R b7 is selected from H, F, CF 3 , methyl, methoxy
  • 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 ;
  • 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-
  • 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;
  • b1 is selected from 0, 1 or 2;
  • b2 is selected from 0, 1, 2, 3, 4 or 5.
  • 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
  • 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 b8 is selected from NH 2 ;
  • 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 ;
  • the compound represented by the general formula (I) is selected from (Ib)
  • 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;
  • 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 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;
  • 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
  • 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:
  • 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.
  • the disease associated with inhibition or degradation of KRAS is cancer (eg, gastric cancer, esophageal cancer, or pancreatic cancer).
  • 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 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.
  • 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.
  • 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.
  • an "effective amount” for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.
  • 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
  • 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 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 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
  • 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
  • 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.
  • 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.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include pro
  • 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-oc
  • 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.
  • 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, te
  • Spiro or “spirocyclic group” refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom).
  • Spirocycle or “spirocyclyl” can be monovalent, divalent, trivalent or tetravalent.
  • 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.
  • Carbospirocycle refers to a “spirocycle” wherein the ring system consists of only carbon atoms.
  • Carbocyclic refers to a “cyclic” ring system consisting of only carbon atoms.
  • Carbobridged ring refers to a “bridged ring” wherein the ring system consists of only carbon atoms.
  • Heteromonocycle refers to a monocyclic ring system of "heterocyclyl” or “heterocycle”,
  • Heterocyclic ring refers to a "cyclo" containing a heteroatom.
  • Heterospirocycle refers to a “spirocycle” containing a heteroatom.
  • Heterobridged ring 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 examples 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.
  • 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.
  • 4--7 membered heteromonocyclic rings refer to 4-, 5-, 6- or 7-membered heteromonocyclic rings
  • 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;
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • 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.
  • 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
  • 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.
  • 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.
  • Stepoisomers 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.
  • 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;
  • 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 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.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • 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;
  • 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).
  • compound 1-1 or compound 1-2 is structure 1-A, and the other is structure 1-B.
  • 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.
  • Second 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;)
  • 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°C; detection wavelength: 220nm)
  • One of compound 6-1 and compound 6-2 has structure 6-A, and the other has structure 6-B.
  • 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°C; detection wavelength: 220nm)
  • One of compound 7-1 and compound 7-2 has structure 7-A, and the other has structure 7-B.
  • 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;
  • 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°C; detection wavelength: 220nm)
  • One of compound 8-1 and compound 8-2 has structure 8-A, and the other has structure 8-B.
  • 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°C; detection wavelength: 220nm)
  • One of compound 9-1 and compound 9-2 has structure 9-A, and the other has structure 9-B.
  • 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)
  • the compounds of the present invention have good inhibitory activity on the protein interaction between KRAS G12D and RAF1.
  • ASPC-1 cell culture conditions RPMI-1640 + 10% FBS + 1% double antibody, cultured at 37 ° C, 5% CO 2 incubator.
  • ASPC-1 cells in the exponential growth phase were collected and plated on 96-well culture plates, 80 ⁇ L 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.
  • 20 ⁇ L 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.
  • the CellTiter-Glo kit was used to detect the T 0 plate while adding drugs, recorded as RLU 0.
  • 25 ⁇ L of detection solution Cell 4Viability Assay, Promega
  • 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
  • RLU control is the average value of the solvent control group.
  • Inhibition % (1-(RLU compound -RLU 0 )/(RLU control - RLU 0 )) ⁇ 100%
  • KRAS G12C Human non-small cell lung cancer cells H358
  • the complete cell culture medium was RPMI-1640 + 10% FBS + 1% antibiotic-antifungal dual antibody, and cultured at 37 ° C, 5% CO 2 incubator.
  • 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 ⁇ L per well.
  • 10 ⁇ L of compounds of different concentrations were added, and the cells were placed in a CO 2 incubator for 6 days.
  • 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.
  • 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 ⁇ L per well.
  • 10 ⁇ L of compounds of different concentrations were added and placed in a CO 2 incubator for incubation for 6 days.
  • 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.
  • KRAS WT Human epidermal cancer cells A431
  • the complete cell culture medium was RPMI-1640 + 10% FBS + 1% antibiotic-antifungal dual antibody, and cultured at 37 ° C, 5% CO 2 incubator.
  • 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 ⁇ L per well.
  • 10 ⁇ L of compounds of different concentrations were added, and the cells were placed in a CO 2 incubator for 6 days.
  • 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.
  • the compounds of the present invention 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.
  • 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 ⁇ L of cell suspension was added to each well of a 96-well cell culture plate to make 300 cells/well.
  • 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%
  • 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.
  • mice Male SD rats, about 220 g, 6 to 8 weeks old, 6 rats/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice 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.
  • 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.
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic properties in rats.
  • mice Male BALB/c mice, 20-25 g, 6 mice/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice 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.
  • Solvent for intravenous administration 5% DMA + 5% Solutol + 90% Saline; Solvent for oral administration: 0.5% MC.
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic properties in mice.
  • mice 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.
  • Solvent for intravenous administration 5% DMA + 5% Solutol + 90% Saline; Solvent for oral administration: 0.5% MC.
  • the compounds of the present invention such as the compounds in the examples, have good oral absorption properties in beagle dogs.
  • mice 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.
  • Solvent for intravenous administration 5% DMA + 5% Solutol + 90% Saline; Solvent for oral administration: 0.5% MC.
  • 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.
  • all samples were stored at -80°C and quantitatively analyzed by LC-MS/MS.
  • the compounds of the present invention such as the compounds in the examples, have good oral absorption properties in monkeys.
  • 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 (5 ⁇ M) 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.
  • 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.
  • the compounds of the present invention such as the compounds in the examples, have good Caco2 permeability.
  • 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.
  • 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.
  • the compounds of the present invention such as the compounds in the examples, have good metabolic stability in liver microsomes.
  • CYP human liver microsomal cytochrome P450
  • CYP1A2, CYP2C9, CYP2D6, and CYP3A4 isoenzymes of human liver microsomal cytochrome P450
  • 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).
  • LC-MS/MS liquid chromatography-tandem mass spectrometry
  • CYP enzyme activity was 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).
  • the compounds of the present invention have no significant inhibitory effect on any subtype of CYP enzymes.
  • Cell line Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel
  • 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 2-5M ⁇ .
  • 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.
  • 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.
  • Inhibition% represents the inhibition percentage of the compound on hERG potassium current
  • 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:
  • X is the Log value of the test sample detection concentration
  • Y is the inhibition percentage at the corresponding concentration
  • Bottom and Top are the minimum and maximum inhibition percentages, respectively.
  • the compounds of the present invention such as the compounds in the examples, have no obvious hERG inhibitory activity or weak inhibitory activity.

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Abstract

L'invention concerne des composés représentés par la formule générale (I), ou des stéréoisomères, des tautomères, des substances deutérées, des solvates, des promédicaments, des métabolites, et des sels pharmaceutiquement acceptables ou des cristaux eutectiques de ceux-ci, un intermédiaire de ceux-ci, et leur utilisation dans des maladies associées à l'inhibition ou à la dégradation de KRAS telles que des cancers.
PCT/CN2024/102681 2023-06-29 2024-06-28 Dérivés hétéroaryles à cinq chaînons et leur utilisation médicale Ceased WO2025002430A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026050446A1 (fr) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026072904A2 (fr) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions et méthodes de traitement du cancer du poumon

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025190342A1 (fr) * 2024-03-15 2025-09-18 苏州浦合医药科技有限公司 Composé spiro en tant qu'inhibiteur mutant de kras
CN119751476B (zh) * 2025-03-05 2025-06-03 苏州共康医药科技有限公司 螺环类化合物及其在医药上的应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018140599A1 (fr) * 2017-01-26 2018-08-02 Araxes Pharma Llc Composés à base de benzothiophène et de benzothiazole et leurs procédés d'utilisation
CN114920738A (zh) * 2020-11-06 2022-08-19 泰励生物科技（上海）有限公司 用于癌症治疗的KRas抑制剂
WO2022177917A2 (fr) * 2021-02-16 2022-08-25 Theras, Inc. Compositions et procédés d'inhibition de ras
WO2023004102A2 (fr) * 2021-07-23 2023-01-26 Theras, Inc. Compositions et procédés d'inhibition de ras
WO2023072188A1 (fr) * 2021-10-29 2023-05-04 贝达药业股份有限公司 Inhibiteurs de kras g12d et leur utilisation en médecine
CN116253748A (zh) * 2021-12-09 2023-06-13 苏州浦合医药科技有限公司 取代的双环杂芳基化合物作为kras g12d抑制剂

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018140599A1 (fr) * 2017-01-26 2018-08-02 Araxes Pharma Llc Composés à base de benzothiophène et de benzothiazole et leurs procédés d'utilisation
CN114920738A (zh) * 2020-11-06 2022-08-19 泰励生物科技（上海）有限公司 用于癌症治疗的KRas抑制剂
WO2022177917A2 (fr) * 2021-02-16 2022-08-25 Theras, Inc. Compositions et procédés d'inhibition de ras
WO2023004102A2 (fr) * 2021-07-23 2023-01-26 Theras, Inc. Compositions et procédés d'inhibition de ras
WO2023072188A1 (fr) * 2021-10-29 2023-05-04 贝达药业股份有限公司 Inhibiteurs de kras g12d et leur utilisation en médecine
CN116253748A (zh) * 2021-12-09 2023-06-13 苏州浦合医药科技有限公司 取代的双环杂芳基化合物作为kras g12d抑制剂

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12448400B2 (en) 2023-09-08 2025-10-21 Gilead Sciences, Inc. KRAS G12D modulating compounds
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026050446A1 (fr) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026072904A2 (fr) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions et méthodes de traitement du cancer du poumon

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