WO2021219091A2 - Dérivé de quinoxalinone en tant qu'inhibiteur irréversible de la protéine mutante kras g12c - Google Patents

Dérivé de quinoxalinone en tant qu'inhibiteur irréversible de la protéine mutante kras g12c Download PDF

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WO2021219091A2
WO2021219091A2 PCT/CN2021/091102 CN2021091102W WO2021219091A2 WO 2021219091 A2 WO2021219091 A2 WO 2021219091A2 CN 2021091102 W CN2021091102 W CN 2021091102W WO 2021219091 A2 WO2021219091 A2 WO 2021219091A2
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alkylene
alkyl
haloalkyl
halogen
alkynyl
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WO2021219091A3 (fr
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赵焰平
王红军
张道广
肖绪枝
叶佳
冒莉
姜媛媛
禄立彦
黄淮
牛海涛
黄建宝
刘森
刘雪莲
周丽莹
刘亚男
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北京泰德制药股份有限公司
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Priority to CN202180015592.2A priority Critical patent/CN115135636A/zh
Publication of WO2021219091A2 publication Critical patent/WO2021219091A2/fr
Publication of WO2021219091A3 publication Critical patent/WO2021219091A3/fr

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    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicine. Specifically, the present invention provides a compound capable of irreversibly inhibiting KRAS G12C mutant protein, and a preparation method and application thereof.
  • RAS is one of the most frequently mutated proto-oncogenes. RAS mutations occur in about 30% of human cancers, of which KRAS is the most frequently mutated RAS subtype, accounting for about 80% of RAS mutations.
  • the protein encoded by the KARS gene is a small GTPase (GTPase), which belongs to the RAS protein superfamily.
  • GTPase GTPase
  • the KRAS protein changes between inactive and activated states. When KRAS binds to GDP (guanosine diphosphate), it is in an inactive state, and when it binds to GTP (guanosine triphosphate), it is in an activated state. And can activate downstream signal pathways.
  • GEF guanine nucleotide exchange factor
  • GAP GTPase activating protein
  • GAP GTPase activating protein
  • KRAS in most cells is in an inactive state. When it is activated, it can activate multiple downstream signaling pathways, including MAPK signaling pathway (RAS-RAF-MEK-ERK), PI3K signaling pathway (PI3K-AKT-mTOR) , And Ral-GEFs signaling pathways, etc. These signaling pathways play an important role in cell growth, differentiation, apoptosis and metastasis.
  • MAPK signaling pathway RAS-RAF-MEK-ERK
  • PI3K signaling pathway PI3K-AKT-mTOR
  • Ral-GEFs signaling pathways etc.
  • KRAS mutations are the most common in pancreatic cancer, non-small cell lung cancer and colorectal cancer, especially in pancreatic cancer up to 90%.
  • KRAS mutations mainly occur at the three positions of glycine at positions 12 and 13 and glutamine at position 61.
  • the mutant KRAS will affect its ability to bind to GAP protein, thereby inhibiting GAP-induced GTP hydrolysis and maintaining KRAS in an activated state. , Eventually leading to the activation of multiple downstream signaling pathways, inducing the occurrence and development of malignant tumors.
  • KRAS G12C mutation is a single point mutation in which glycine is replaced by cysteine at position 12. Epidemiological studies have shown that KRAS G12C mutation occurs in approximately 13% of lung adenocarcinoma patients, 3% of colorectal cancer patients, and 1-3 % Of other solid tumor patients.
  • the present invention provides compounds of formula (I), or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs thereof Types, prodrugs or isotopic variants, and their mixtures:
  • Ring A is C 6-10 aryl or 5-14 membered heteroaryl, preferably naphthyl or 9-10 membered heteroaryl, preferably naphthyl, benzo 5-membered heteroaryl or benzo 6-membered heteroaryl ;
  • R 6 is independently H, D, C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-NO 2 , C 1-6 alkyl, C 1- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a , C 0-6 alkylene-N( R 1a ) 2 , C 0-6 alkylene-C(O)R 1a , C 0-6 alkylene-C(O)OR 1a , C 0-6 alkylene-C(O)N(R 1a ) 2 or C 0-6 alkylene-S(O) m R 1a ; preferably, at least one of R 6 is -OR 1a ;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • L 1 is -H 1 -H 2 -H 3 -H 4 -;
  • H 1 is selected from -O-, -S-, -N(R H' )-, -C(R H )(R H )-, -C(R H )(R H )-C(R H ) (R H )-or -C(R H )(R H )-C(R H )(R H )-C(R H )(R H )-, H 2 , H 3 and H 4 are independently selected from -O-, -S-, -N(R H' )- or -C(R H )(R H )-;
  • One or two pairs of R H /R H'substituents can be combined to form a C 1-3 alkylene group
  • R H is H, D, C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-NO 2 , C 1-6 alkyl, C 1-6 haloalkane Group, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a or C 0-6 alkylene-N (R 1a ) 2 ;
  • R H' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 1 is C 1-6 haloalkyl
  • R a , R b and R c are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -N (R 1a ) 2 ;
  • R 'group; and R a and R b may form a chemical bond so that the triple bond becomes a double bond;
  • R' is H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -, -S-(C(R L2 )(R L2 )) p -, -N(R L2' )-(C( R L2 )(R L2 )) p -or-(C(R L2 )(R L2 )) p -;
  • R L2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R L2 /R L2' on adjacent atoms can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
  • R 2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -N (R 1a ) 2.
  • L 3 is a chemical bond or -(C(R L3 )(R L3 )) p -;
  • R L3 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a ,- SR 1a or -N(R 1a ) 2 ;
  • R L3 on adjacent atoms can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
  • R 3 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -N (R 1a ) 2.
  • R is H, D, C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-SF 5 , C 0-6 alkylene-NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a , C 0-6 alkylene-N(R 1a ) 2 , C 0-6 alkylene-C(O)R 1a , C 0-6 alkylene-C(O)OR 1a , C 0-6 alkylene Group-C(O)N(R 1a ) 2 , C 0-6 alkylene-S(O) m R 1a , C 0-6 alkylene-C 3-10 cycloalkyl, C 0-6 alkylene Alkyl-3-10-membered heterocyclic group, C 0-6 alkylene-C
  • r 0, 1, 2, 3, 4, 5, 6 or 7;
  • R 4 is H, D, halogen, -CN, -SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a , -N(R 1a ) 2 , C 3-10 cycloalkyl, C 3-10 halogenated cycloalkyl, 3-10 membered heterocyclic group, 3-10 membered halogenated heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl;
  • Z 1 is CR 5 or N
  • Z 2 is CR 5 or N
  • R 5 is independently H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • Z is O or S
  • R 1a is H, -C(O)H, -C(O)OH, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -S(O) m C 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 halocycloalkyl, 3-10 membered heterocyclic group, 3-10 membered Halogenated heterocyclic group, C 6-10 aryl group or 5-14 membered heteroaryl group;
  • each occurrence of R s is independently selected from: halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 halocycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl, 5-14 membered heteroaryl, C 6- 12 arylalkyl, -OR a ', -OC (O ) R a', -C (O) R a ', -C (O) OR a', -C (O) NR a 'R b', - S (O) q R a ' ,
  • R a'and R b'at each occurrence are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-O-, C 1-6 alkyl-S-, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl, 5-14 membered heteroaryl, and C 6-12 aralkyl.
  • the present invention provides a pharmaceutical composition containing a compound of the present invention, and optionally a pharmaceutically acceptable excipient.
  • the present invention provides a pharmaceutical composition containing a compound of the present invention and a pharmaceutically acceptable excipient, which also contains other therapeutic agents.
  • the present invention provides the use of the compound of the present invention in the preparation of a medicament for the treatment and/or prevention of diseases mediated by KRAS or its G12C mutant protein.
  • the present invention provides a method of treating and/or preventing a disease mediated by KRAS or its G12C mutant protein in a subject, comprising administering a compound of the present invention or a composition of the present invention to the subject.
  • the present invention provides a compound of the present invention or a composition of the present invention for use in the treatment and/or prevention of diseases mediated by KRAS or its G12C mutant protein.
  • the diseases treated by the present invention include cancers selected from the group consisting of acute myeloid leukemia, acute myeloid leukemia, juvenile cancer, childhood adrenal cortex cancer, AIDS-related cancers (such as lymphoma and Kaposi Sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Burkitt Lymphoma, Carcinoid Tumor, Atypical Teratoma, Embryonic Tumor, Germ Cell Tumor, Primary Lymphoma, Cervical Cancer, Childhood Cancer, Chordoma, Heart Tumor, Chronic Lymphocytic Leukemia (CLL), Chronic myelogenous leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, skin T-cell lymphoma, extrahepatic
  • C 1-6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1 -2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5 -6 alkyl.
  • C 1-6 alkyl refers to a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl is preferred. Examples of C 1-6 alkyl groups include: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl Base (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl ( C 5 ), 3-methyl-2-butyl (C 5 ), tert-amyl (C 5 ) and n-hexyl (C 6 ).
  • C 1-6 alkyl also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution.
  • Alkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • alkyl abbreviations include: Me(-CH 3 ), Et(-CH 2 CH 3 ), iPr(-CH(CH 3 ) 2 ), nPr(-CH 2 CH 2 CH 3 ), n-Bu(-CH 2 CH 2 CH 2 CH 3 ) or i-Bu(-CH 2 CH(CH 3 ) 2 ).
  • C 2-6 alkenyl group refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 alkenyl is preferred. Examples of C 2-6 alkenyl groups include: vinyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), etc.
  • C 2-6 alkenyl also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution.
  • Alkenyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 2-6 alkynyl refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 alkynyl is preferred. Examples of C 2-6 alkynyl groups include but are not limited to: ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), pentynyl (C 5 ), hexynyl (C 6 ), and so on.
  • C 2-6 alkynyl also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution.
  • An alkynyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene refers to the above-defined "C 1-6 alkyl, C 2-6 alkenyl or C 2-6 "Alkynyl” is a divalent group.
  • C 1-6 alkylene group refers to a divalent group formed by removing another hydrogen of the C 1-6 alkyl group, and may be substituted or unsubstituted. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-3 alkylene are preferred.
  • the unsubstituted alkylene group includes but is not limited to: methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene Group (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -) ,and many more.
  • alkylene groups substituted by one or more alkyl groups (methyl) include, but are not limited to: substituted methylene (-CH(CH 3 )- , -C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2- ), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 ) -, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 C(CH 3 ) 2 -), etc.
  • C 0-6 alkylene group means a chemical bond as well as the above-mentioned "C 1-6 alkylene group”.
  • C 2-6 alkynylene group refers to a divalent group formed by removing another hydrogen of the C 2-6 alkynyl group, and may be substituted or unsubstituted. In some embodiments, C 2-4 alkynylene is particularly preferred. Exemplary alkynylene groups include, but are not limited to, ethynylene (-C ⁇ C-), substituted or unsubstituted propynylene (-C ⁇ CCH 2 -), and the like.
  • C 1-6 heteroalkyl refers to a C 1-6 alkyl group as defined herein, and in the parent chain, it further contains one or more (for example, 1, 2, 3, or 4) heteroatoms (for example, oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein one or more heteroatoms are between adjacent carbon atoms in the parent carbon chain, and/or, one or more heteroatoms are in the carbon Between the atom and the parent molecule, that is, between the points of attachment.
  • the point of attachment between the C 1-6 heteroalkyl group and the parent molecule may be a carbon atom or a heteroatom.
  • C 2-6 heteroalkylene group refers to a divalent group formed by removing another hydrogen of a C 1-6 heteroalkyl group, and may be substituted or unsubstituted.
  • the point of attachment between the C 1-6 heteroalkylene group and other parts of the parent molecule can be two carbon atoms, two heteroatoms, or one carbon atom and one heteroatom.
  • Halo or "halogen” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • C 1-6 haloalkyl refers to the above-mentioned “C 1-6 alkyl", which is substituted with one or more halogen groups.
  • C 1-4 haloalkyl is particularly preferred, and C 1-2 haloalkyl is more preferred.
  • Exemplary haloalkyl groups include, but the are not limited to: -CF 3, -CH 2 F, -CHF 2, -CHFCH 2 F, -CH 2 CHF 2, -CF 2 CF 3, -CCl 3, -CH 2 Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc.
  • the haloalkyl group can be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 3-10 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, C 4-7 cycloalkyl and C 3-6 cycloalkyl are particularly preferred, and C 5-6 cycloalkyl is more preferred. Cycloalkyl also includes ring systems in which the above-mentioned cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases, the number of carbons continues to indicate The number of carbons in the cycloalkyl system.
  • Exemplary cycloalkyl groups include but are not limited to: cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptene Group (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), etc.
  • the cycloalkyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 3-10 halocycloalkyl group refers to the above-mentioned “C 3-10 cycloalkyl group", which is substituted with one or more halogen groups.
  • 3-12 membered heterocyclic group refers to a group of 3 to 12 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, Sulfur, boron, phosphorus and silicon.
  • the point of attachment may be a carbon or nitrogen atom.
  • a 4-12 membered heterocyclic group is preferred, which is a 4 to 12 membered non-aromatic ring system with ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3-10 membered Heterocyclic group, which is a 3 to 10-membered non-aromatic ring system with ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3-8 membered heterocyclic groups are preferred, which are ring carbon atoms and A 3 to 8 membered non-aromatic ring system with 1 to 4 ring heteroatoms; preferably a 3-6 membered heterocyclic group, which is a 3 to 6 membered non-aromatic ring system with ring carbon atoms and 1 to 3 ring heteroatoms; Preferably a 4-7 membered heterocyclic group, which is a 4 to 7 membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms;
  • Heterocyclyl also includes a ring system in which the aforementioned heterocyclyl ring is fused with one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or wherein the aforementioned heterocyclyl ring is connected to one or more aryl groups or Heteroaryl fused ring systems in which the point of attachment is on the heterocyclyl ring; and in this case, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system.
  • Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to: aziridinyl, oxiranyl, and thiorenyl.
  • Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietane.
  • Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione.
  • Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to: dioxolane, oxasulfuranyl, disulfuranyl, and oxasulfuranyl.
  • Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl.
  • Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiacyclohexyl, dioxanyl.
  • Exemplary 6-membered heterocyclic groups containing three heteroatoms include, but are not limited to: triazinanyl.
  • Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepanyl, oxepanyl, and thieppanyl.
  • Exemplary 5-membered heterocyclic groups fused to a C 6 aryl ring include, but are not limited to: indolinyl, isoindolinyl , Dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, etc.
  • Exemplary 6-membered heterocyclic groups fused to a C 6 aryl ring include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and many more.
  • the heterocyclyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the "3-12 membered halogenated heterocyclic group” refers to the above-mentioned “3-12 membered heterocyclic group", which is substituted with one or more halogen groups.
  • the "3-10 membered halogenated heterocyclic group” refers to the above-mentioned “3-10 membered heterocyclic group", which is substituted with one or more halogen groups.
  • C 6-10 aryl refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6-10 ring carbon atoms and zero heteroatoms) (e.g., having a ring arrangement Shared 6 or 10 ⁇ electrons) groups.
  • an aryl group having six ring carbon atoms ( “C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms ("C 10 aryl”; for example, naphthyl, for example, 1-naphthyl and 2-naphthyl).
  • the aryl group also includes a ring system in which the above-mentioned aryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the aryl ring.
  • the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system.
  • the aryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 6-12 aralkyl refers to the group -R-R', where R is an alkyl moiety, R'is an aryl moiety, and the alkyl group and the aryl group have 6-12 carbon atoms in total.
  • 5-14 membered heteroaryl group refers to a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms (for example, having a shared ring arrangement 6, 10, or 14 ⁇ electrons), where each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • the point of attachment may be a carbon or nitrogen atom.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl groups also include ring systems in which the above-mentioned heteroaryl ring is fused with one or more cycloalkyl or heterocyclic groups, and the point of attachment is on the heteroaryl ring, in this case, the carbon atom The number continues to indicate the number of carbon atoms in the heteroaryl ring system.
  • a 5-10 membered heteroaryl group is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms.
  • a 5-6 membered heteroaryl group is particularly preferred, which is a 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms .
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furyl, and thienyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl), and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl , Benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, Indenazinyl and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pterridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl .
  • Heteroaryl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group as defined herein are optionally substituted groups.
  • Each of Raa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two Raa groups are combined to form a heterocyclic group or Heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R dd groups Group replacement
  • Each of R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups are combined to form a heterocyclic ring Group or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R dd group substitution;
  • Each of R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, ring Alkyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups;
  • Each of R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, and heteroaryl, or two R ff groups are combined to form a heterocyclic group Or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently covered by 0, 1, 2, 3, 4 or 5 R gg Group substitution
  • KRAS G12C refers to a mutant form of the mammalian KRAS protein, which contains an amino acid substitution of cysteine to glycine at the 12th amino acid.
  • the location of the amino acid codons and residue positions of human KRAS is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116:Variantp.Glyl2Cys.
  • KRAS G12C inhibitor refers to the compounds of the present invention, which can negatively modulate or inhibit all or part of the enzyme activity of KRAS G12C.
  • the KRAS G12C inhibitor of the present invention interacts and irreversibly binds to KRAS G12C by forming a covalent adduct with the sulfhydryl side chain of the cysteine residue at position 12, resulting in the inhibition of the enzyme activity of KRAS G12C.
  • cancer includes but is not limited to the following cancers: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, bile duct, buccal cavity and pharynx (mouth), lips, Tongue, oral cavity, pharynx, small intestine, colorectal, large intestine, rectum, brain and central nervous system cancer, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, Adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver cancer, kidney cancer, bone marrow disorder, lymphatic disorder, Hodgkin's disease, hair cell carcinoma and leukemia.
  • treatment relates to reversing, reducing, inhibiting the progression of or preventing the disorder or condition to which the term applies, or one or more symptoms of such a disorder or condition.
  • treatment refers to the act of verb therapy, the latter being as just defined.
  • pharmaceutically acceptable salt refers to those carboxylate and amino acid addition salts of the compounds of the present invention, which are suitable for contact with patient tissues within the scope of reliable medical judgment, and will not cause inappropriate toxicity, The irritation, allergies, etc., commensurate with a reasonable benefit/risk ratio, are effective for their intended application, including (where possible) the zwitterionic form of the compounds of the invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium and the like.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
  • Base addition salts of acidic compounds can be prepared by contacting the free acid form with a sufficient amount of the required base in a conventional manner to form the salt.
  • the free acid can be regenerated by contacting the salt form with the acid in a conventional manner, and then separating the free acid.
  • the free acid forms are somewhat different from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, the salts are still equivalent to their respective free acids.
  • the salt can be sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate prepared from inorganic acid Salt, chloride, bromide, iodide, acid such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc.
  • Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurel Acid salt, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, Methanesulfonate, glucoheptonate, lactobionate, laurylsulfonate and isethionate, etc.
  • Salts can also be prepared from organic acids, such as aliphatic mono- and di-carboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • organic acids such as aliphatic mono- and di-carboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • Representative salts include acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, horse Lysoate, mandelate, benzoate, chlorobenzoic acid basin, methyl benzoate, dinitrobenzoate, naphthoate, benzene sulfonate, tosylate, phenyl ethyl Acid salt, citrate, lactate, maleate, tartrate, methanesulfonate, etc.
  • Pharmaceutically acceptable salts may include cations based on alkali metals and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, etc., and non-toxic ammonium, quaternary ammonium and amine cations, including but not limited to ammonium, tetramethyl Ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also encompasses salts of amino acids, such as arginine, gluconate, galacturonate, etc. (see, for example, Berge SMet al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1- 19. This is incorporated as a reference).
  • the "subject" to be administered includes, but is not limited to: humans (ie, men or women of any age group, for example, pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adults, middle-aged adults or older adults)) and/or non-human animals, for example, mammals, for example, primates (for example, cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep , Goats, rodents, cats and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "human", “patient” and “subject” are used interchangeably herein.
  • treatment includes the effect that occurs when a subject suffers from a specific disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the disease, disorder Or the development of a condition ("therapeutic treatment"), and also includes effects that occur before the subject begins to suffer from a specific disease, disorder, or condition ("prophylactic treatment").
  • an "effective amount" of a compound refers to an amount sufficient to cause a target biological response.
  • the effective amount of the compound of the present invention may vary according to the following factors: for example, the biological target, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the subject’s Age health and symptoms.
  • the effective amount includes a therapeutically effective amount and a preventively effective amount.
  • the "therapeutically effective amount” of the compound used herein is an amount sufficient to provide a therapeutic benefit during the treatment of a disease, disorder, or condition, or to cause one or more symptoms associated with the disease, disorder, or condition The amount of delay or minimization.
  • the therapeutically effective amount of a compound refers to the amount of the therapeutic agent when used alone or in combination with other therapies, which provides therapeutic benefits in the course of treating diseases, disorders or conditions.
  • the term “therapeutically effective amount” may include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.
  • the “prophylactically effective amount” of the compound used herein is an amount sufficient to prevent a disease, disorder, or condition, or an amount sufficient to prevent one or more symptoms related to the disease, disorder, or condition, or prevent a disease , The amount of recurrence of the disorder or condition.
  • the prophylactically effective amount of a compound refers to the amount of the therapeutic agent when used alone or in combination with other agents, which provides preventive benefits in the process of preventing diseases, disorders or conditions.
  • the term “prophylactically effective amount” may include an amount that improves overall prevention, or an amount that enhances the preventive effect of other preventive agents.
  • Combination and related terms refer to the simultaneous or sequential administration of the compound of the present invention and other therapeutic agents.
  • the compound of the present invention can be administered simultaneously or sequentially in separate unit dosage forms with other therapeutic agents, or simultaneously administered in a single unit dosage form with other therapeutic agents.
  • compounds of the present invention refers to the following compounds of formula (I) (including sub-general formulas, such as formula (I-1), formula (II), etc.), their pharmaceutically acceptable salts, enantiomers Conformers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof.
  • the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, poly Crystal forms, prodrugs or isotopic variants, and their mixtures:
  • Ring A is C 6-10 aryl or 5-14 membered heteroaryl, preferably naphthyl or 9-10 membered heteroaryl, preferably naphthyl, benzo 5-membered heteroaryl or benzo 6-membered heteroaryl ;
  • R 6 is independently H, D, C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-NO 2 , C 1-6 alkyl, C 1- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a , C 0-6 alkylene-N( R 1a ) 2 , C 0-6 alkylene-C(O)R 1a , C 0-6 alkylene-C(O)OR 1a , C 0-6 alkylene-C(O)N(R 1a ) 2 or C 0-6 alkylene-S(O) m R 1a ; preferably, at least one of R 6 is -OR 1a ;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • L 1 is -H 1 -H 2 -H 3 -H 4 -;
  • H 1 is selected from -O-, -S-, -N(R H' )-, -C(R H )(R H )-, -C(R H )(R H )-C(R H ) (R H )-or -C(R H )(R H )-C(R H )(R H )-C(R H )(R H )-, H 2 , H 3 and H 4 are independently selected from -O-, -S-, -N(R H' )- or -C(R H )(R H )-;
  • One or two pairs of R H /R H'substituents can be combined to form a C 1-3 alkylene group
  • R H is H, D, C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-NO 2 , C 1-6 alkyl, C 1-6 haloalkane Group, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a or C 0-6 alkylene-N (R 1a ) 2 ;
  • R H' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 1 is C 1-6 haloalkyl
  • R a , R b and R c are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -N (R 1a ) 2 ;
  • R 'group; and R a and R b may form a chemical bond so that the triple bond becomes a double bond;
  • R' is H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -, -S-(C(R L2 )(R L2 )) p -, -N(R L2' )-(C( R L2 )(R L2 )) p -or-(C(R L2 )(R L2 )) p -;
  • R L2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R L2 /R L2' on adjacent atoms can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
  • R 2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -N (R 1a ) 2 , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by r R;
  • L 3 is a chemical bond or -(C(R L3 )(R L3 )) p -;
  • R L3 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a ,- SR 1a or -N(R 1a ) 2 ;
  • R L3 on adjacent atoms can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
  • R 3 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -N (R 1a ) 2.
  • R is H, D, C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-SF 5 , C 0-6 alkylene-NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a , C 0-6 alkylene-N(R 1a ) 2 , C 0-6 alkylene-C(O)R 1a , C 0-6 alkylene-C(O)OR 1a , C 0-6 alkylene Group-C(O)N(R 1a ) 2 , C 0-6 alkylene-S(O) m R 1a , C 0-6 alkylene-C 3-10 cycloalkyl, C 0-6 alkylene Alkyl-3-10-membered heterocyclic group, C 0-6 alkylene-C
  • r 0, 1, 2, 3, 4, 5, 6 or 7;
  • R 4 is H, D, halogen, -CN, -SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a , -N(R 1a ) 2 , C 3-10 cycloalkyl, C 3-10 halogenated cycloalkyl, 3-10 membered heterocyclic group, 3-10 membered halogenated heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl;
  • Z 1 is CR 5 or N
  • Z 2 is CR 5 or N
  • R 5 is independently H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • Z is O or S
  • R 1a is H, -C(O)H, -C(O)OH, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -S(O) m C 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 halocycloalkyl, 3-10 membered heterocyclic group, 3-10 membered Halogenated heterocyclic group, C 6-10 aryl group or 5-14 membered heteroaryl group;
  • each occurrence of R s is independently selected from: halogen, hydroxyl, amino, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 3-10 halocycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl, 5-14 membered heteroaryl, C 6- 12 arylalkyl, -OR a ', -OC (O ) R a', -C (O) R a ', -C (O) OR a', -C (O) NR a 'R b', - S (O) q R a ' ,
  • R a'and R b'at each occurrence are each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl-O-, C 1-6 alkyl-S-, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl, 5-14 membered heteroaryl, and C 6-12 aralkyl.
  • ring A is C 6-10 aryl; in another specific embodiment, ring A is 5-14 membered heteroaryl; in another specific embodiment, ring A is naphthyl; In another specific embodiment, ring A is a 9-10 membered heteroaryl group; in another specific embodiment, ring A is a benzo 5-membered heteroaryl group, such as benzopyrrolyl, benzopyrazolyl, Benzothiazolyl, indazolyl, benzothienyl or benzofuranyl, preferably benzothiazolyl and indazolyl; in another specific embodiment, ring A is a benzo 6-membered heteroaryl group, such as benzene Pyridyl, benzopyridazinyl, benzopyrazinyl, benzopyrimidinyl or benzotriazinyl.
  • R 6 is independently H; in another specific embodiment, R 6 is independently D; in another specific embodiment, R 6 is independently C 0-6 alkylene- Halogen; in another specific embodiment, R 6 is independently Co -6 alkylene-CN; in another specific embodiment, R 6 is independently C 0-6 alkylene-NO 2 ; in another specific embodiment, R 6 is independently C 1-6 alkyl; in another specific embodiment, R 6 is independently C 1-6 haloalkyl; in another specific embodiment, R 6 is independently for C 2-6 alkenyl group; in another particular embodiment, R 6 is independently C 2-6 alkynyl; in another particular embodiment, R 6 is independently C 0-6 alkylene group - OR 1a , preferably -OH; in another specific embodiment, R 6 is independently C 0-6 alkylene-SR 1a ; in another specific embodiment, R 6 is independently C 0-6 alkylene group -N (R 1a) 2; in another particular embodiment, R 6 is independently C 0-6 alkylene -C (O)
  • Z 3 , Z 4 and Z 5 are independently CR 6 or N; ring B is phenyl or 5-6 membered heteroaryl; in another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific embodiment, for In another specific
  • L 1 is -H 1 -H 2 -H 3 -H 4 -, wherein H 1 is selected from -O-, -S-, -N(R H' )-, -C(R H )(R H )- , -C(R H )(R H )-C(R H )(R H )-or -C(R H )(R H )-C(R H )(R H )-C(R H )( R H )-, H 2 , H 3 and H 4 are independently selected from -O-, -S-, -N(R H' )- or -C(R H )(R H )-.
  • L 1 is -CCCN-framework; in another specific embodiment, L 1 is -NCCN-framework; in another specific embodiment, L 1 is -OCCN-framework; in another specific embodiment, L 1 is -OCCN-framework; In a specific embodiment, L 1 is -SCCN-framework; in another specific embodiment, L 1 is -NCCO-framework; in another specific embodiment, L 1 is -NCCS-framework; in another specific embodiment In the scheme, L 1 is -CCCCN-skeleton; in another specific embodiment, L 1 is -CCCCCN-skeleton.
  • H 1 is -O-; in another specific embodiment, H 1 is -S-; in another specific embodiment, H 1 is -N(R H' )-; In another specific embodiment, H 1 is -C(R H )(R H )-; in another specific embodiment, H 1 is -C(R H )(R H )-C(R H ) (R H )-; In another specific embodiment, H 1 is -C(R H )(R H )-C(R H )(R H )-C(R H )(R H )-;
  • H 2 is -O-; in another specific embodiment, H 2 is -S-; in another specific embodiment, H 2 is -N(R H' )-; In another specific embodiment, H 2 is -C(R H )(R H )-;
  • H 3 is -O-; in another specific embodiment, H 3 is -S-; in another specific embodiment, H 3 is -N(R H' )-; In another specific embodiment, H 3 is -C(R H )(R H )-;
  • H 4 is -O-; in another specific embodiment, H 4 is -S-; in another specific embodiment, H 4 is -N(R H' )-; In another specific embodiment, H 4 is -C(R H )(R H )-.
  • a pair of R H /R H'substituents on H 1 and H 3 can be combined to form a C 1-3 alkylene group; in another specific embodiment, H 1 and H 4 are A pair of R H /R H'substituents can be combined to form a C 1-3 alkylene group; in another specific embodiment, a pair of R H /R H'substituents on H 2 and H 4 can be combined to form C 1-3 alkylene.
  • L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is In another specific embodiment, L 1 is in another specific embodiment, L 1 is in another specific embodiment, L 1 is in another specific embodiment, L 1 is in another specific embodiment, L 1 is in another specific embodiment, L 1 is in another specific embodiment, L 1 is in another specific embodiment, L 1 is in another specific embodiment, L 1 is in another specific embodiment, L 1 is in another specific embodiment, L 1 is in another specific embodiment, L 1 is in another specific
  • R 1 is C 1-6 haloalkyl; in another specific embodiment, R 1 is halomethyl, preferably chloromethyl; in another specific embodiment, R 1 is Wherein R a , R b and R c are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -N (R 1a ) 2; optionally R 'group; and R a and R b may form a chemical bond so that the triple bond becomes a double bond.
  • R 1 is In a specific embodiment, R 1 is In another specific embodiment, R 1 is In another specific embodiment, R 1 is In another specific embodiment, R 1 is In another specific embodiment, R 1 is
  • L 2 is a chemical bond; in another specific embodiment, L 2 is -O-(C(R L2 )(R L2 )) p -; in another specific embodiment, L 2 Is -S-(C(R L2 )(R L2 )) p -; in another specific embodiment, L 2 is -N(R L2' )-(C(R L2 )(R L2 )) p- ; In another specific embodiment, L 2 is -(C(R L2 )(R L2 )) p -; In another specific embodiment, L 2 is -O-; In another specific embodiment, L 2 is -OCH 2 -; in another specific embodiment, L 2 is -OCH 2 CH 2 -; in another specific embodiment, L 2 is -OCH 2 CH 2 CH 2 -; in another specific embodiment In an embodiment, L 2 is -NH-; in another specific embodiment, L 2 is -NHCH 2 -; in another specific embodiment, L 2 is
  • R 2 is H; in another specific embodiment, R 2 is D; in another specific embodiment, R 2 is halogen; in another specific embodiment, R 2 is- CN; In another specific embodiment, R 2 is -NO 2 ; In another specific embodiment, R 2 is C 1-6 alkyl; In another specific embodiment, R 2 is C 1-6 Haloalkyl; in another specific embodiment, R 2 is C 2-6 alkenyl; in another specific embodiment, R 2 is C 2-6 alkynyl; in another specific embodiment, R 2 is -OR 1a ; in another specific embodiment, R 2 is -N(R 1a ) 2 ; in another specific embodiment, R 2 is C 3-10 cycloalkyl; in another specific embodiment, R 2 is a 3-10 membered heterocyclic group; in another specific embodiment, R 2 is a C 6-10 aryl group; in another specific embodiment, R 2 is a 5-14 membered heteroaryl group; In another specific embodiment, R 2 is substituted with r R.
  • R 2 is In another specific embodiment, R 2 is
  • L 3 is a chemical bond; in another specific embodiment, L 3 is -(C(R L3 )(R L3 )) p -; in another specific embodiment, L 3 is- CH 2 -; In another specific embodiment, L 3 is -CH 2 CH 2 -.
  • R 3 is H; in another specific embodiment, R 3 is D; in another specific embodiment, R 3 is halogen; in another specific embodiment, R 3 is- CN; In another specific embodiment, R 3 is -NO 2 ; In another specific embodiment, R 3 is C 1-6 alkyl; In another specific embodiment, R 3 is C 1-6 Haloalkyl; in another specific embodiment, R 3 is C 2-6 alkenyl; in another specific embodiment, R 3 is C 2-6 alkynyl; in another specific embodiment, R 3 is -N(R 1a ) 2 ; In another specific embodiment, R 3 is C 3-10 cycloalkyl; in another specific embodiment, R 3 is 3-10 membered heterocyclyl; in another specific embodiment In an embodiment, R 3 is a C 6-10 aryl group; in another specific embodiment, R 3 is a 5-14 membered heteroaryl group; in another specific embodiment, R 3 is substituted with r R groups.
  • R 3 is In another specific embodiment, R 3 is
  • R is H; in another specific embodiment, R is D; in another specific embodiment, R is C 0-6 alkylene-halogen; in another specific embodiment , R is C 0-6 alkylene-CN; in another specific embodiment, R is C 0-6 alkylene-SF 5 ; in another specific embodiment, R is C 0-6 alkylene group -NO 2; in another embodiment, R is C 1-6 alkyl; in another embodiment, R is C 1-6 haloalkyl; in another embodiment, R is C 2-6 alkenyl; in another specific embodiment, R is C 2-6 alkynyl; in another specific embodiment, R is C 0-6 alkylene-OR 1a ; in another specific embodiment Where R is C 0-6 alkylene-SR 1a ; in another specific embodiment, R is C 0-6 alkylene-N(R 1a ) 2 ; in another specific embodiment, R is C 0-6 alkylene-C(O)R 1a ; in another specific embodiment, R is C 0-6 alky
  • R 4 is H; in another specific embodiment, R 4 is D; in another specific embodiment, R 4 is halogen, preferably Cl and F, more preferably Cl; in another In a specific embodiment, R 4 is -CN; in another specific embodiment, R 4 is -SF 5 ; in another specific embodiment, R 4 is C 1-6 alkyl; in another specific embodiment In another specific embodiment, R 4 is C 1-6 haloalkyl; in another specific embodiment, R 4 is C 2-6 alkenyl; in another specific embodiment, R 4 is C 2-6 alkynyl; in another specific embodiment, R 4 is C 2-6 alkynyl; In a specific embodiment, R 4 is -OR 1a ; in another specific embodiment, R 4 is -SR 1a ; in another specific embodiment, R 4 is -N(R 1a ) 2 ; in another In a specific embodiment, R 4 is C 3-10 cycloalkyl; in another specific embodiment, R 4 is C 3-10 halocycloalkyl; in another specific
  • Z 1 is CR 5 ; in another specific embodiment, Z 1 is N.
  • Z 2 is CR 5 ; in another specific embodiment, Z 2 is N.
  • R 5 is independently H; in another specific embodiment, R 5 is independently D; in another specific embodiment, R 5 is independently halogen; in another specific embodiment In another specific embodiment, R 5 is independently -CN; in another specific embodiment, R 5 is independently C 1-6 alkyl; in another specific embodiment, R 5 is independently C 1-6 haloalkyl; In another specific embodiment, R 5 is independently C 2-6 alkenyl; in another specific embodiment, R 5 is independently C 2-6 alkynyl; in another specific embodiment, R 5 Independently -OR 1a ; in another specific embodiment, R 5 is independently -SR 1a ; in another specific embodiment, R 5 is independently -N(R 1a ) 2 .
  • any technical solution or any combination of any of the above specific embodiments can be combined with any technical solution or any combination of other specific embodiments.
  • any technical solution of R 1 or any combination thereof can be combined with any of L 1 , L 2 , L 3 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m, n, etc.
  • Technical solutions or any combination thereof The present invention is intended to include all the combinations of these technical solutions, limited to space, and will not be listed one by one.
  • the present invention provides the above-mentioned (I) compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Compounds, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 6 is independently H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkane Group or -OR 1a ; preferably, R 6 is independently -OR 1a , preferably -OH; preferably, at least one R 6 is a non-H group.
  • the present invention provides the above-mentioned (I) compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Compounds, polymorphs, prodrugs or isotopic variants, and their mixtures,
  • Z 3 , Z 4 and Z 5 are independently CR 6 or N; ring B is phenyl or 5-6 membered heteroaryl;
  • the present invention provides the above-mentioned (I) compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Compounds, polymorphs, prodrugs or isotopic variants, and their mixtures,
  • L 1 is: Preferably, L 1 is
  • the present invention provides the above-mentioned (I) compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Compounds, polymorphs, prodrugs or isotopic variants, and their mixtures,
  • R 1 is Preferably, R 1 is
  • the present invention provides the above-mentioned (I) compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Compounds, polymorphs, prodrugs or isotopic variants, and their mixtures,
  • L 2 is a chemical bond, -O-, -OCH 2 -, -OCH 2 CH 2 -, -OCH 2 CH 2 CH 2 -, -NH-, -NHCH 2 -, -NHCH 2 CH 2 -, -NHCH 2 CH 2 CH 2 -, -NMeCH 2 CH 2 -or -CH 2 CH 2 -, preferably -OCH 2 -or -OCH 2 CH 2 -;
  • L 3 is -CH 2 -or -CH 2 CH 2 -.
  • the present invention provides the above-mentioned (I) compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Compounds, polymorphs, prodrugs or isotopic variants, and their mixtures,
  • R 2 or R 3 is H, -N(R 1a ) 2 , C 3-6 cycloalkyl, 4-7 membered heterocyclic group, phenyl or 5-6 membered heteroaryl, preferably -NMe 2 , Preferred H,
  • R 2 or R 3 is substituted by 1-3 R, wherein R is selected from C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a , C 0-6 alkylene-N(R 1a ) 2 , C 0-6 alkylene-C(O)R 1a , C 0-6 alkylene-C(O)OR 1a , C 0-6 Alkylene-C(O)N(R 1a ) 2 , C 0-6 alkylene-S(O) m R 1a , C 0-6 alkylene-C 3-10 cycloalkyl, C 0- 6 -alkylene-3-10-membered heterocyclic group, C 0-6 alkylene-
  • the present invention provides the above-mentioned (I) compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Compounds, polymorphs, prodrugs or isotopic variants, and their mixtures,
  • R 4 is H, halogen, -CN, -SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkane Group or C 3-10 halocycloalkyl group, preferably halogen, more preferably Cl.
  • the present invention provides the compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, in which:
  • L 1 is -H 1 -H 2 -H 3 -H 4 -;
  • H 1 is -C(R H )(R H )-
  • H 2 , H 3 and H 4 are independently selected from -O-, -S-, -N(R H' )- or -C(R H )(R H )-;
  • One or two pairs of R H /R H'substituents can be combined to form a C 1-3 alkylene group
  • R H is H, D, C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-NO 2 , C 1-6 alkyl, C 1-6 haloalkane Group, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a or C 0-6 alkylene-N (R 1a ) 2 ;
  • R H' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R a , R b and R c are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -N (R 1a ) 2 ;
  • R a and R b can form a chemical bond so that the double bond becomes a triple bond
  • L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -, -S-(C(R L2 )(R L2 )) p -, -N(R L2' )-(C( R L2 )(R L2 )) p -or-(C(R L2 )(R L2 )) p -;
  • R L2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R L2 /R L2' may be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
  • R 2 is halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -N(R 1a ) 2.
  • R is H, D, C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-SF 5 , C 0-6 alkylene-NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a , C 0-6 alkylene-N(R 1a ) 2 , C 0-6 alkylene-C(O)R 1a , C 0-6 alkylene-C(O)OR 1a , C 0-6 alkylene Group-C(O)N(R 1a ) 2 , C 0-6 alkylene-S(O) m R 1a , C 0-6 alkylene-C 3-10 cycloalkyl, C 0-6 alkylene Alkyl-3-10-membered heterocyclic group, C 0-6 alkylene-C
  • r 0, 1, 2, 3, 4, 5, 6 or 7;
  • R 4 is H, D, halogen, -CN, -SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a , -N(R 1a ) 2 , C 3-10 cycloalkyl, C 3-10 halogenated cycloalkyl, 3-10 membered heterocyclic group, 3-10 membered halogenated heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl;
  • Z 1 is CR 5 ;
  • Z 2 is CR 5 ;
  • R 5 is independently H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a Or -N(R 1a ) 2 ;
  • R 7 and -L 3 -R 3 form a double bond
  • R 1a is H, -C(O)H, -C(O)OH, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -S(O) m C 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 halocycloalkyl, 3-10 membered heterocyclic group, 3-10 membered Halogenated heterocyclic group, C 6-10 aryl group or 5-14 membered heteroaryl group.
  • the present invention provides the above-mentioned (I) compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Compounds, polymorphs, prodrugs or isotopic variants, and mixtures thereof, which have the following structure:
  • Ring B is phenyl or 5-6 membered heteroaryl
  • R N1 , R N2 and R N3 are independently H, C 1-6 alkyl or C 1-6 haloalkyl; alternatively, R N2 and R N3 may be combined to form a C 2-4 alkylene group;
  • the present invention provides a compound of formula (I-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or solvate thereof , Hydrates, polymorphs, prodrugs or isotopic variants, and their mixtures:
  • Ring B is phenyl or 5-6 membered heteroaryl
  • R 6 is independently H, D, C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-NO 2 , C 1-6 alkyl, C 1- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a or C 0-6 alkylene-N ( R 1a ) 2 , and at least one of R 6 is -OH;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • L 1 is -H 1 -H 2 -H 3 -H 4 -;
  • H 1 is -C(R H )(R H )-
  • H 2 , H 3 and H 4 are independently selected from -O-, -S-, -N(R H' )- or -C(R H )(R H )-;
  • One or two pairs of R H /R H'substituents can be combined to form a C 1-3 alkylene group
  • R H is H, D, C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-NO 2 , C 1-6 alkyl, C 1-6 haloalkane Group, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a or C 0-6 alkylene-N (R 1a ) 2 ;
  • R H' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R a , R b and R c are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -N (R 1a ) 2 ;
  • R a and R b can form a chemical bond so that the double bond becomes a triple bond
  • L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -, -S-(C(R L2 )(R L2 )) p -, -N(R L2' )-(C( R L2 )(R L2 )) p -or-(C(R L2 )(R L2 )) p -;
  • R L2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R L2 /R L2' can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group
  • R 2 is halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -N(R 1a ) 2.
  • R is H, D, C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-SF 5 , C 0-6 alkylene-NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a , C 0-6 alkylene-N(R 1a ) 2 , C 0-6 alkylene-C(O)R 1a , C 0-6 alkylene-C(O)OR 1a , C 0-6 alkylene Group-C(O)N(R 1a ) 2 , C 0-6 alkylene-S(O) m R 1a , C 0-6 alkylene-C 3-10 cycloalkyl, C 0-6 alkylene Alkyl-3-10-membered heterocyclic group, C 0-6 alkylene-C
  • r 0, 1, 2, 3, 4, 5, 6 or 7;
  • R 4 is H, D, halogen, -CN, -SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a , -N(R 1a ) 2 , C 3-10 cycloalkyl, C 3-10 halogenated cycloalkyl, 3-10 membered heterocyclic group, 3-10 membered halogenated heterocyclic group, C 6-10 Aryl or 5-14 membered heteroaryl;
  • R 5 is independently H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • R 1a is H, -C(O)H, -C(O)OH, -C(O)C 1-6 alkyl, -C(O)OC 1-6 alkyl, -S(O) m C 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 halocycloalkyl, 3-10 membered heterocyclic group, 3-10 membered Halogenated heterocyclic group, C 6-10 aryl group or 5-14 membered heteroaryl group.
  • the present invention provides the above-mentioned compound of formula (I-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or solvate thereof.
  • Ring B is phenyl
  • R 6 is independently H, D, C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-NO 2 , C 1-6 alkyl, C 1- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a or C 0-6 alkylene-N ( R 1a ) 2 , and at least one of R 6 is -OH;
  • n 0, 1, 2, 3, 4, 5, 6 or 7;
  • R a , R b and R c are independently selected from H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl; and R a and R b can form a chemical bond so that the double bond is changed Three keys;
  • L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -, -S-(C(R L2 )(R L2 )) p -or -N(R L2' )-(C( R L2 )(R L2 )) p -;
  • R L2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R L2 /R L2' can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group
  • R 2 is halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -N(R 1a ) 2.
  • R is H, D, C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-SF 5 , C 0-6 alkylene-NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a , C 0-6 alkylene-N(R 1a ) 2 , C 0-6 alkylene-C(O)R 1a , C 0-6 alkylene-C(O)OR 1a or C 0-6 alkylene ⁇ -C(O)N(R 1a ) 2 ;
  • r 0, 1, 2, 3, 4, 5, 6 or 7;
  • R 4 is H, D, halogen, -CN or -SF 5 ;
  • R 5 is independently H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1a is H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 3-10 halocycloalkyl, 3-10 membered heterocyclic group, 3-10 membered halide Substitute heterocyclic group, C 6-10 aryl group or 5-14 membered heteroaryl group.
  • the present invention provides the above-mentioned compound of formula (I-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or solvate thereof.
  • Ring B is phenyl
  • R 6 is independently H, D, halogen, -CN, -OH, -SH or -NH 2 , and at least one of R 6 is -OH;
  • n 0, 1, 2 or 3;
  • R a , R b and R c are independently selected from H, D, halogen or -CN;
  • L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -or -N(R L2' )-(C(R L2 )(R L2 )) p -;
  • R L2 is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R L2' is H
  • R L2 /R L2' may be combined to form a C 3-6 cycloalkyl group or a 4-7 membered heterocyclic group;
  • R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -OH, -N(R 1a ) 2 , C 3-6 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl Or 5-6 membered heteroaryl; it is optionally substituted by r R;
  • R is H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a , C 0-6 alkylene Alkyl-N(R 1a ) 2 ;
  • r 0, 1, 2, 3, 4, 5, 6 or 7;
  • R 4 is halogen
  • R 5 is independently H, D or halogen
  • R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Substances, polymorphs, prodrugs or isotopic variants, and their mixtures:
  • Ring B is phenyl or 5-6 membered heteroaryl
  • R 6 is independently H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • n 0, 1, 2, 3, 4 or 5;
  • R 1 is C 1-6 haloalkyl
  • R a , R b and R c are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -N (R 1a ) 2 ;
  • R 'group; and R a and R b may form a chemical bond so that the triple bond becomes a double bond;
  • R' is H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -, -S-(C(R L2 )(R L2 )) p -, -N(R L2' )-(C( R L2 )(R L2 )) p -or-(C(R L2 )(R L2 )) p -;
  • R L2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R L2 /R L2' on adjacent atoms can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
  • R 2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -N (R 1a ) 2.
  • R is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a , -N(R 1a ) 2 , C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl or 5-14 membered heteroaryl;
  • R 4 is H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a , -N (R 1a ) 2 , C 3-10 cycloalkyl or 3-10 membered heterocyclic group;
  • R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Substances, polymorphs, prodrugs or isotopic variants, and their mixtures:
  • R 1 is C 1-6 haloalkyl
  • R a , R b and R c are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -N (R 1a ) 2 ;
  • R 'group; and R a and R b may form a chemical bond so that the triple bond becomes a double bond;
  • R' is H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -, -S-(C(R L2 )(R L2 )) p -, -N(R L2' )-(C( R L2 )(R L2 )) p -or-(C(R L2 )(R L2 )) p -;
  • R L2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R L2 /R L2' on adjacent atoms can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
  • R 2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -N (R 1a ) 2.
  • R is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a , -N(R 1a ) 2 , C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl or 5-14 membered heteroaryl;
  • R 4 is halogen, -CN or -NO 2 ;
  • R 6 is halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N (R 1a ) 2 ;
  • R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Compounds, polymorphs, prodrugs or isotopic variants, and mixtures thereof, where
  • R 1 is C 1-6 haloalkyl
  • R a , R b and R c are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -N (R 1a ) 2 ;
  • R a and R b can form a chemical bond so that the double bond becomes a triple bond
  • L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -or -N(R L2' )-(C(R L2 )(R L2 )) p -;
  • R L2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl or C 1-6 haloalkyl;
  • R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -N (R 1a ) 2.
  • R is H, -OR 1a , -SR 1a , -N(R 1a ) 2 , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 4 is halogen
  • R 6 is halogen, -CN, -NO 2 or -OR 1a , preferably -OH;
  • R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides a compound of formula (IV), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Substances, polymorphs, prodrugs or isotopic variants, and their mixtures:
  • L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -, -S-(C(R L2 )(R L2 )) p -, -N(R L2' )-(C( R L2 )(R L2 )) p -or-(C(R L2 )(R L2 )) p -;
  • R L2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R L2 /R L2' can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group
  • R 2 is halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -N(R 1a ) 2 , C 3 -10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl; it is optionally substituted by 1-5 R;
  • R is H, D, C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-SF 5 , C 0-6 alkylene-NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a , C 0-6 alkylene-N(R 1a ) 2 , C 0-6 alkylene-C(O)R 1a , C 0-6 alkylene-C(O)OR 1a , C 0-6 alkylene Group-C(O)N(R 1a ) 2 , C 0-6 alkylene-S(O) m R 1a , C 0-6 alkylene-C 3-10 cycloalkyl, C 0-6 alkylene Alkyl-3-10-membered heterocyclic group, C 0-6 alkylene-C
  • R 4 is halogen, -CN or -NO 2 ;
  • R 6 is halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N (R 1a ) 2 ;
  • R a , R b and R c are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ; and R a and R b may form a chemical bond so that the triple bond becomes a double bond;
  • R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above-mentioned compound of formula (IV), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, among which,
  • L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -, -S-(C(R L2 )(R L2 )) p -or -N(R L2' )-(C( R L2 )(R L2 )) p -;
  • R L2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R L2' is H, C 1-6 alkyl or C 1-6 haloalkyl
  • R L2 /R L2' can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group
  • R 2 is halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -N(R 1a ) 2 , C 3 -10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by 1-5 R;
  • R is H, D, C 0-6 alkylene-halogen, C 0-6 alkylene-CN, C 0-6 alkylene-SF 5 , C 0-6 alkylene-NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 0-6 alkylene-OR 1a , C 0-6 alkylene-SR 1a or C 0-6 alkylene-N(R 1a ) 2 ;
  • R 4 is halogen, -CN or -NO 2 ;
  • R 6 is halogen, -CN, -NO 2 , -OH, -SH or -NH 2 ;
  • R a , R b and R c are independently selected from H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl; and R a and R b can form a chemical bond so that the double bond becomes Triple key
  • R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above-mentioned compound of formula (IV), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, among which,
  • L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -, -S-(C(R L2 )(R L2 )) p -or -N(R L2' )-(C( R L2 )(R L2 )) p -;
  • R L2 is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R L2' is H
  • R L2 /R L2' may be combined to form a C 3-6 cycloalkyl group or a 4-7 membered heterocyclic group;
  • R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -N (R 1a ) 2 , C 3-6 cycloalkyl, 4-7 membered heterocyclyl, C 6-10 aryl, 5- 6-membered heteroaryl; it is optionally substituted with 1-2 Rs;
  • R is H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl or -N(R 1a ) 2 ;
  • R 4 is halogen
  • R 6 is -OH
  • R a , R b and R c are independently selected from H, D, halogen or -CN;
  • R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides a compound of formula (IV), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Substances, polymorphs, prodrugs or isotopic variants, and their mixtures:
  • L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -, -S-(C(R L2 )(R L2 )) p -, -N(R L2' )-(C( R L2 )(R L2 )) p -or-(C(R L2 )(R L2 )) p -;
  • R L2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ;
  • R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R L2 /R L2' on adjacent atoms can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
  • R 2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -N (R 1a ) 2.
  • R is H, -N(R 1a ) 2 , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 4 is halogen, -CN or -NO 2 ;
  • R 6 is halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N (R 1a ) 2 ;
  • R a , R b and R c are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -N(R 1a ) 2 ; and R a and R b may form a chemical bond so that the triple bond becomes a double bond;
  • R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides a compound of formula (IV-1), (IV-2) or (IV-3), or a pharmaceutically acceptable salt, enantiomer, or diastereomer Isomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and their mixtures:
  • L 2 is a chemical bond, -O-, -S- or -N(R L2' )-;
  • R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 4 is halogen, -CN or -NO 2 ;
  • R 6 is halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 1a , -SR 1a or -N (R 1a ) 2 ;
  • R N1 , R N2 and R N3 are independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; alternatively, R N2 and R N3 may be combined To form a C 2-4 alkylene group;
  • R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides a compound of formula (IV-1), (IV-2) or (IV-3), or a pharmaceutically acceptable salt, enantiomer, or diastereomer Isomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein
  • L 2 is a chemical bond, -O-, -S- or -NH-, preferably -O-;
  • R 4 is halogen, preferably Cl
  • R 6 is halogen, -CN, -NO 2 or -OR 1a , preferably -OH;
  • R N1 , R N2 and R N3 are independently H, C 1-6 alkyl or C 1-6 haloalkyl; alternatively, R N2 and R N3 may be combined to form a C 2-4 alkylene group;
  • R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the following compounds, or pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, poly Crystal forms, prodrugs or isotopic variants, and mixtures thereof, wherein the compound is selected from:
  • the compounds of the present invention may include one or more asymmetric centers, and thus may exist in various stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (such as cis and trans isomers), or may be in the form of a mixture of stereoisomers, Including racemate mixtures and mixtures rich in one or more stereoisomers.
  • the isomers can be separated from the mixture by methods known to those skilled in the art, including: chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be separated by Prepared by asymmetric synthesis.
  • HPLC high pressure liquid chromatography
  • an organic compound can form a complex with a solvent, which reacts in the solvent or precipitates or crystallizes out of the solvent. These complexes are called “solvates”. When the solvent is water, the complex is called “hydrate”. The present invention covers all solvates of the compounds of the present invention.
  • solvate refers to a compound or a salt form thereof combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether and the like.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
  • “Solvate” includes a solvate in a solution state and an isolable solvate. Representative solvates include hydrates, ethanolates and methanolates.
  • hydrate refers to a compound that binds to water. Generally, the ratio of the number of water molecules contained in the hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Therefore, a hydrate of a compound can be represented by, for example, the general formula R ⁇ x H 2 O, where R is the compound, and x is a number greater than zero.
  • a given compound can form more than one type of hydrate, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, for example, hemihydrate (R ⁇ 0.5 H 2 O)) and polyhydrates (x is a number greater than 1, for example, dihydrate (R ⁇ 2 H 2 O) and hexahydrate (R ⁇ 6 H 2 O)).
  • monohydrate x is 1
  • lower hydrate x is a number greater than 0 and less than 1, for example, hemihydrate (R ⁇ 0.5 H 2 O)
  • polyhydrates x is a number greater than 1, for example, dihydrate (R ⁇ 2 H 2 O) and hexahydrate (R ⁇ 6 H 2 O)).
  • the compounds of the invention may be in amorphous or crystalline form (polymorphs).
  • the compounds of the present invention may exist in one or more crystalline forms. Therefore, the present invention includes all amorphous or crystalline forms of the compounds of the present invention within its scope.
  • polymorph refers to a crystalline form (or a salt, hydrate or solvate thereof) of a compound in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, photoelectric properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can cause one crystalline form to dominate.
  • Various polymorphs of the compound can be prepared by crystallization under different conditions.
  • the present invention also includes isotopically-labeled compounds (isotopic variants), which are equivalent to those described in formula (I), but one or more atoms whose atomic mass or mass number is different from the atomic mass or mass number common in nature Replaced.
  • isotopes that can be introduced into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, and 18 respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • Tritium, i.e. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred because they are easy to prepare and detect. Further, substituted with heavier isotopes such as deuterium, i.e.
  • Isotopically-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared in this way.
  • readily available isotope-labeled reagents are used instead of non-isotopes. Labeled reagents.
  • prodrugs are also included in the context of the present invention.
  • the term "prodrug” as used herein refers to a compound that is converted into its active form with a medical effect by, for example, hydrolysis in the blood in the body.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, ASSymposium Series Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon, and H. Barbra "Improved oral drug delivery: solubility limits overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each introduced This article serves as a reference.
  • a prodrug is any covalently bonded compound of the invention, and when such a prodrug is administered to a patient, it releases the parent compound in the body.
  • Prodrugs are usually prepared by modifying functional groups, and the modification is performed in such a way that the modification can be performed by conventional operations or cleavage in vivo to produce the parent compound.
  • Prodrugs include, for example, the compounds of the present invention in which a hydroxyl, amino, or sulfhydryl group is bonded to any group, which can be cleaved to form a hydroxyl, amino, or sulfhydryl group when administered to a patient.
  • prodrugs include, but are not limited to, acetate/amide, formate/amide, and benzoate/amide derivatives of the hydroxyl, sulfhydryl, and amino functional groups of the compound of formula (I).
  • esters such as methyl esters, ethyl esters and the like can be used.
  • the ester itself can be active and/or can be hydrolyzed under conditions in the human body.
  • Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those groups that are easily decomposed in the human body to release the parent acid or salt thereof.
  • the present invention also provides a pharmaceutical preparation comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient. All these forms belong to the present invention.
  • the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of a compound of the invention.
  • the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention.
  • the pharmaceutical composition comprises a prophylactically effective amount of a compound of the invention.
  • the pharmaceutically acceptable excipient used in the present invention refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound formulated together.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the composition of the present invention include (but are not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum white Protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated plant fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , Sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene- Block polymers, polyethylene glycol and
  • kits e.g., pharmaceutical packaging.
  • the kit provided may include the compound of the present invention, other therapeutic agents, and first and second containers (for example, vials, ampoules, bottles, syringes, and/or dispersible packages or other Suitable container).
  • the provided kit may also optionally include a third container, which contains pharmaceutical excipients for diluting or suspending the compound of the present invention and/or other therapeutic agents.
  • the compound of the present invention and the other therapeutic agent provided in the first container and the second container are combined to form a unit dosage form.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , Intracerebrospinal membrane administration, intralesional administration, and intracranial injection or infusion technology.
  • an effective amount of the compound provided herein is administered.
  • the doctor can determine the amount of the compound actually administered .
  • the compounds provided herein are administered to subjects at risk of developing the conditions, typically based on the doctor's advice and under the supervision of the doctor, and the dosage levels are as described above.
  • Subjects at risk of developing a particular disorder generally include subjects with a family history of the disorder, or those subjects who are particularly sensitive to the development of the disorder as determined by genetic testing or screening.
  • long-term administration refers to the administration of the compound or its pharmaceutical composition over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or the administration can be continued indefinitely, For example, the rest of the subject's life.
  • long-term administration is intended to provide a constant level of the compound in the blood over a long period of time, for example, within a therapeutic window.
  • the pharmaceutical composition may be administered as a bolus, for example, to increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic level of the active ingredient passing through the body. For example, an intramuscular or subcutaneous bolus dose allows the active ingredient to be released slowly, while a bolus injection delivered directly to a vein (for example, by IV infusion) ) Can be delivered more quickly, so that the concentration of the active component in the blood quickly rises to an effective level.
  • the pharmaceutical composition may be administered as a continuous infusion, for example, by IV infusion, to provide a steady-state concentration of the active ingredient in the subject's body.
  • a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
  • Oral compositions can take the form of bulk liquid solutions or suspensions or bulk powders. However, more generally, in order to facilitate precise dosing, the composition is provided in unit dosage form.
  • unit dosage form refers to physically discrete units suitable as unit dosages for human patients and other mammals, each unit containing a predetermined number of active substances suitable for producing the desired therapeutic effect and suitable pharmaceutical excipients.
  • Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. in the case of solid compositions.
  • the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), and the remaining part is useful for forming the desired administration form.
  • Kinds of carriers or excipients and processing aids are used for forming the desired administration form.
  • the representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides about 0.01 to about 20 mg/kg of the compound of the present invention, with preferred doses each providing about 0.1 to about 10 mg/kg, especially about 1 to about 5 mg/kg.
  • the transdermal dose is usually selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, and preferably about 0.1 To about 10% by weight, and more preferably about 0.5 to about 15% by weight.
  • the injection dose level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour.
  • a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be given.
  • the maximum total dose cannot exceed approximately 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffers, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • the solid form may include, for example, any of the following components, or compounds with similar properties: binders, for example, microcrystalline cellulose, tragacanth, or gelatin; excipients, for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or flavoring agents, for example, mint, water Methyl salicylate or orange flavoring agent.
  • binders for example, microcrystalline cellulose, tragacanth, or gelatin
  • excipients for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art.
  • the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • the transdermal composition is typically formulated as a topical ointment or cream containing the active ingredients.
  • the active ingredient When formulated as an ointment, the active ingredient is typically combined with paraffin or a water-miscible ointment base.
  • the active ingredient can be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art, and generally include other components for enhancing the active ingredient or stable skin penetration of the formulation. All such known transdermal preparations and components are included within the scope provided by the present invention.
  • transdermal administration can be achieved using a reservoir or porous membrane type, or a variety of solid matrix patches.
  • compositions for oral administration, injection or topical administration are only representative.
  • Other materials and processing techniques are described in Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania in Part 8, which is incorporated herein by reference.
  • the compounds of the present invention can also be administered in a sustained release form or from a sustained release drug delivery system.
  • sustained-release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention also relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation contains water.
  • the formulation comprises a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ - and ⁇ -cyclodextrins composed of 6, 7 and 8 ⁇ -1,4-linked glucose units, respectively, which optionally include one on the linked sugar moiety Or multiple substituents, including but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitution.
  • the cyclodextrin is a sulfoalkyl ether ⁇ -cyclodextrin, for example, sulfobutyl ether ⁇ -cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645.
  • the formulation includes hexapropyl- ⁇ -cyclodextrin (e.g., 10-50% in water).
  • the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, Anti-hormones, angiogenesis inhibitors and anti-androgens.
  • N-(5-Bromo-4-fluoro-2-nitrophenyl)glycine methyl ester (3.9 g, 11.3 mmol) was dissolved in ethanol (60 mL) and water (15 mL). Under stirring at room temperature, iron powder (100 mesh, 6.3 g, 112.5 mmol) and ammonium chloride (6.1 g, 114.0 mmol) were added and reacted at 90°C for 2 hours.
  • 6-Bromo-7-fluoro-3,4-dihydroquinoxaline-2(1H)-one (3.1 g, 12.65 mmol) was dissolved in dichloromethane (20 mL) and methanol (20 mL). At room temperature, slowly pour manganese dioxide powder (9.5g, 109.2mmol), stir for 16 hours, filter through Celite, wash the filter cake with methanol: dichloromethane (10%, 200mL), and then concentrate under reduced pressure.
  • the seventh step is a first step.
  • N-(5-bromo-4-chloro-2-nitrophenyl)glycine methyl ester (4.0 g, 11.11 mmol) was dissolved in ethanol (76 mL) and water (20 mL). Under stirring at room temperature, iron powder (100 mesh, 6.2 g, 111.1 mmol) and ammonium chloride (5.9 g, 111.1 mmol) were added and reacted at 90°C for 2 hours.
  • ESI-MS 261,263[M+H] + .
  • 6-Bromo-7-chloro-3,4-dihydroquinoxaline-2(1H)-one (2.8 g, 10.7 mmol) was dissolved in dichloromethane (50 mL) and methanol (50 mL). At room temperature, slowly pour manganese dioxide powder (4.6g, 52.9mmol), stir for 16 hours, filter through Celite, wash the filter cake with methanol: dichloromethane (50%, 400mL), and then concentrate under reduced pressure.
  • 6-bromo-7-chloroquinoxaline-2(1H)-one (364mg, 1.41mmol)
  • 3-(bromomethyl)azetidine-1-carboxylic acid tert-butyl ester 527 mg, 2.11 mmol
  • potassium carbonate 776 mg, 5.62 mmol
  • DMF N,N-dimethylformamide
  • the seventh step is a first step.
  • Example Compounds 15, 22 and 23 were prepared:
  • Example 3 1-((1-acryloylazetidin-3-yl)methyl)-3-(2-(dimethylamino)ethoxy)-7-fluoro-6-(3 -Hydroxynaphthyl-1-yl)quinoxaline-2(1H)-one
  • ESI-MS 444.1[M+H] + .
  • Example 9 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-3-(2-(dimethylamino)ethoxy)-6-(3 -Hydroxynaphthalene-1-yl)quinoxaline-2(1H)-one
  • ESI-MS 540,542 [M+H] + .
  • Example 13 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-3-(3-(dimethylamino)azetidin-1-yl )-6-(3-hydroxynaphthalene-1-yl)quinoxaline-2(1H)-one
  • reaction solution was cooled to 0° C., under a nitrogen atmosphere, diisopropyl azodicarboxylate (450 mg, 2.2 mmol) was slowly added dropwise to the system, and after the addition, the temperature was raised to room temperature and stirred for 1 hour.
  • Example Compounds 19 and 42 were prepared:
  • the yield was 58%.
  • reaction solution was cooled to 0° C., under a nitrogen atmosphere, diisopropyl azodicarboxylate (606 mg, 3.0 mmol) was slowly added dropwise to the system, and after the addition, the temperature was raised to room temperature and stirred for 1 hour.
  • the cell phosphorylation inhibition test was performed on the compound of the present invention to verify the phosphorylation inhibitory effect of the compound of the present invention on KRAS G12C mutant NCI-H358 human non-small cell lung cancer.
  • BioTek microplate reader cell culture flask, 96-well cell culture plate, 384-well microplate, CO2 constant temperature incubator, 10 ⁇ L 12-channel pipette, 100 ⁇ L 12-channel pipette, 200 ⁇ L 12-channel pipette.
  • NCI-H358 cell suspension to the 96-well cell culture plate, which contains 25,000 cells, and place it in a carbon dioxide incubator for overnight culture.
  • the test compound was diluted 3-fold, and 9 concentration points (from 10000 nM to 1.52 nM) were added to the corresponding wells of the cell culture plate, and then placed in the incubator for 3 hours.
  • the operating instructions of the Advanced Phosphor-ERK1/2 (THR202/TYR204) kit perform cell lysis for 30 minutes, incubate the antibody for 4 hours, and read the plate with BioTek.
  • the IC 50 result was analyzed by the GraphPad Prism 6.0 software of IDBS.
  • the IC50 data of the phosphorylation inhibition rate of the compounds of the present invention on NCI-H358 (G12C mutation) cells are:
  • a protein binding test was performed on the compound of the present invention to verify whether the compound of the present invention binds to the KRAS G12C mutant protein structure.
  • KRAS-4B-G12C protein was mixed with 20 times the protein concentration of GDP 1:1, incubated at room temperature for 1.5 hours, and then GDP-loaded KRAS-4B-G12C protein was diluted to 20 ⁇ M, 5 ⁇ L protein, 5 ⁇ L 30 ⁇ M compound in 12.5mM Hepes, Incubate in a 75mM NaCl, 1mM MgCl 2 reaction system for 5 minutes or 30 minutes; add 5 ⁇ L of 5% formic acid to terminate the reaction. The sample was centrifuged at 15000 rpm for 10 minutes, and the sample was loaded for testing.
  • % Bound to KRAS (G12C) peak height of the complex/[peak height of the complex + peak height of unbound KRAS G12C] X 100.
  • Example number POC (%, 5min) POC (%, 30min) Example 1 7.9 69.2
  • Example 2 22.4 90.6
  • Example 4 9.8 74.0
  • Example 3 54.2 92.1
  • Example 10 67.5 93.2
  • Example 11 60.1 93.4
  • Example 12 76.8 92.7
  • Example 13 57.9 90.1
  • Example 14 13.0 52.4
  • Example 15 3.3 16.4
  • Example 18 21.7 69.2
  • Example 19 59.6 90.7
  • Example 20 9.5 45.5
  • Example 21 71.6 92.4
  • Example 22 3.2 18.8
  • Example 23 5.2 29.0
  • Example 24 75.9 92.4
  • Example 25 58.8 85.3
  • Example 26 62.6 86.9
  • Example 27 35.9 75.5
  • Example 28 50.2 84.0
  • Example 29 26.7 73.1
  • Example 30 59.9 89.3
  • Example 31 82.5 92.9
  • Example 32
  • Example 45 34.5 81.3
  • Example 46 50.9 81.2
  • Example 47 55.7 84.6
  • Example 48 47.1 85.9
  • Example 49 53.8 85.9
  • Example 50 67.1 92.6
  • Example 51 80.9 92.7
  • Example 52 75.0 92.7
  • Example 53 81.9 94.5
  • Example 54 77.0 94.5
  • Example 55 57.7 91.5
  • Example 56 64.6 91.9
  • Example 59 54.8 78.6
  • Example 60 5.8 13.2
  • Example 61 15.2 65.0
  • Example 62 29.3 82.3

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Abstract

La présente invention concerne un nouveau dérivé de quinoxalinone, qui peut être utilisé comme inhibiteur irréversible de la protéine mutante KRAS G12C. La présente invention concerne également une composition pharmaceutique contenant le dérivé de quinoxalinone ainsi qu'un procédé de préparation et d'utilisation correspondant.
PCT/CN2021/091102 2020-04-29 2021-04-29 Dérivé de quinoxalinone en tant qu'inhibiteur irréversible de la protéine mutante kras g12c WO2021219091A2 (fr)

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US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
WO2023114954A1 (fr) 2021-12-17 2023-06-22 Genzyme Corporation Composés pyrazolopyrazine utilisés comme inhibiteurs de la shp2
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
EP4227307A1 (fr) 2022-02-11 2023-08-16 Genzyme Corporation Composés pyrazolopyrazine en tant qu'inhibiteurs de shp2
US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
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KR20230164602A (ko) * 2022-05-25 2023-12-04 주식회사 엘지화학 다이아실글리세롤 키나아제 저해제로서 헤테로사이클 화합물 및 이의 용도
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US11548888B2 (en) 2019-01-10 2023-01-10 Mirati Therapeutics, Inc. KRas G12C inhibitors
US11453683B1 (en) 2019-08-29 2022-09-27 Mirati Therapeutics, Inc. KRas G12D inhibitors
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US11890285B2 (en) 2019-09-24 2024-02-06 Mirati Therapeutics, Inc. Combination therapies
US11702418B2 (en) 2019-12-20 2023-07-18 Mirati Therapeutics, Inc. SOS1 inhibitors
WO2022111527A1 (fr) * 2020-11-24 2022-06-02 成都百裕制药股份有限公司 Dérivé de pipérazine-2,3-dione et son application en médecine
WO2022266206A1 (fr) 2021-06-16 2022-12-22 Erasca, Inc. Conjugués d'inhibiteurs de kras
WO2023114954A1 (fr) 2021-12-17 2023-06-22 Genzyme Corporation Composés pyrazolopyrazine utilisés comme inhibiteurs de la shp2
EP4227307A1 (fr) 2022-02-11 2023-08-16 Genzyme Corporation Composés pyrazolopyrazine en tant qu'inhibiteurs de shp2

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