WO2021219091A2 - Quinoxalinone derivative as irreversible inhibitor of kras g12c mutant protein - Google Patents

Quinoxalinone derivative as irreversible inhibitor of kras g12c mutant protein 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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French (fr)
Chinese (zh)
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WO2021219091A3 (en
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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/en
Publication of WO2021219091A2 publication Critical patent/WO2021219091A2/en
Publication of WO2021219091A3 publication Critical patent/WO2021219091A3/en

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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
    • 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

Abstract

The present invention relates to a novel quinoxalinone derivative, which can be used as an irreversible inhibitor of the KRAS G12C mutant protein. The present invention also relates to a pharmaceutical composition containing the quinoxalinone derivative, and a preparation method and use thereof.

Description

喹喔啉酮衍生物作为KRAS G12C突变蛋白的不可逆抑制剂Quinoxalinone derivatives as irreversible inhibitors of KRAS G12C mutant protein 技术领域Technical field
本发明涉及医药领域，具体地，本发明提供了能够不可逆抑制KRAS G12C突变蛋白的化合物及其制备方法和应用。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.
背景技术Background technique
RAS是突变频率最高的原癌基因之一。RAS突变发生在大约30％的人类癌症中，其中KRAS是最常发生突变的RAS亚型，占RAS突变的80％左右。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.
KARS基因编码的蛋白是一种小GTP酶(GTPase)，属于RAS蛋白超家族。在细胞内，KRAS蛋白在失活和激活状态之间转变，当KRAS与GDP(鸟苷二磷酸)结合时，处于失活状态，当与GTP(鸟苷三磷酸)结合时，处于激活状态，并且可以激活下游信号通路。KRAS在失活与激活状态之间的转换受到两类因子的调节。一类是鸟嘌呤核苷酸交换因子(GEF)，这类蛋白催化KRAS与GTP的结合，从而促进KRAS的激活，其中包括SOS蛋白。另一类是GTP酶激活蛋白(GAP)，这类蛋白能够促进与KRAS结合的GTP水解成为GDP，从而抑制KRAS的活性。The protein encoded by the KARS gene is a small GTPase (GTPase), which belongs to the RAS protein superfamily. In the cell, 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. The transition of KRAS between inactivated and activated states is regulated by two types of factors. One type is guanine nucleotide exchange factor (GEF), this type of protein catalyzes the binding of KRAS and GTP, thereby promoting the activation of KRAS, including SOS protein. The other type is GTPase activating protein (GAP), which can promote the hydrolysis of GTP bound to KRAS into GDP, thereby inhibiting the activity of KRAS.
大部分细胞中的KRAS处于失活状态，当它被激活后，可以激活多条下游信号通路，其中包括MAPK信号通路(RAS-RAF-MEK-ERK)，PI3K信号通路(PI3K-AKT-mTOR)，和Ral-GEFs信号通路等，这些信号通路在细胞生长、分化、凋亡和转移等方面具有重要作用。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.
KRAS突变在胰腺癌、非小细胞肺癌和结直肠癌中最为常见,特别是在胰腺癌中高达90％。KRAS突变主要发生在12、13位甘氨酸和61位谷氨酰胺3个位点，突变后的KRAS会影响其与GAP蛋白的结合能力，从而抑制GAP诱导的GTP水解，进而使KRAS维持在激活状态，最终导致其下游的多条信号通路被激活，诱发恶性肿瘤的发生与发展。KRAS G12C突变是12位甘氨酸被半胱氨酸替代的单点突变，流行病学研究显示，KRAS G12C突变发生于约13％的肺腺癌患者、3％的结直肠癌患者、以及1-3％的其他实体瘤患者中。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.
为了解决癌症患者的临床需求，本领域迫切需要安全有效的KRAS G12C突变蛋白的抑制剂，尤其是不可逆抑制剂。In order to solve the clinical needs of cancer patients, there is an urgent need in the art for safe and effective inhibitors of KRAS G12C mutant proteins, especially irreversible inhibitors.
发明内容Summary of the invention
在一个方面，本发明提供了式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：In one aspect, 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:
Figure PCTCN2021091102-appb-000001
Figure PCTCN2021091102-appb-000001
其中，in,
环A为C 6-10芳基或5-14元杂芳基，优选为萘基或9-10元杂芳基，优选萘基、苯并5元杂芳基或苯并6元杂芳基； 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独立地为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a、C 0-6亚烷基-C(O)N(R 1a) 2或C 0-6亚烷基-S(O) mR 1a；优选地，其中至少一个R 6为-O-R 1a； 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 ;
m＝1或2；m=1 or 2;
n＝0、1、2、3、4、5、6或7；n=0, 1, 2, 3, 4, 5, 6 or 7;
L 1为-H 1-H 2-H 3-H 4-； L 1 is -H 1 -H 2 -H 3 -H 4 -;
其中H 1选自-O-、-S-、-N(R H’)-、-C(R H)(R H)-、-C(R H)(R H)-C(R H)(R H)-或-C(R H)(R H)-C(R H)(R H)-C(R H)(R H)-，H 2、H 3和H 4独立地选自-O-、-S-、-N(R H’)-或-C(R H)(R H)-； 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 )-;
并且，H 1和H 3上的R H/R H’取代基、H 1和H 4上的R H/R H’取代基、和H 2和H 4上的R H/R H’取代基中的一对或两对R H/R H’取代基可以结合形成C 1-3亚烷基； And, H 1 and H R H on 3 / R H 'substituent group, H 1 and H R H on 4 / R H' substituent group, and H 2 and H R H on 4 / R H 'substituent One or two pairs of R H /R H'substituents can be combined to form a C 1-3 alkylene group;
R H为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a或C 0-6亚烷基-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R H'is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R 1为C 1-6卤代烷基或
Figure PCTCN2021091102-appb-000002
R 1 is C 1-6 haloalkyl or
Figure PCTCN2021091102-appb-000002
其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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 ;
其任选被R’取代；并且R a和R b可以形成化学键从而使得双键变为叁键； Optionally R 'group; and R a and R b may form a chemical bond so that the triple bond becomes a double bond;
其中R’为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； Wherein 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为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-、-N(R L2’)-(C(R L2)(R L2)) p-或-(C(R L2)(R L2)) p-； 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 -;
其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
并且，相邻原子上的R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, 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为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被r个R取代； 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. 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为化学键或-(C(R L3)(R L3)) p-； L 3 is a chemical bond or -(C(R L3 )(R L3 )) p -;
其中R L3为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； Wherein 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 ;
并且，相邻原子上的R L3可以结合形成C 3-10环烷基或3-10元杂环基； In addition, 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为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被r个R取代； 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. C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by r R;
其中R为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-SF 5、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a、C 0-6亚烷基-C(O)N(R 1a) 2、C 0-6亚烷基-S(O) mR 1a、C 0-6亚烷基-C 3-10环烷基、C 0-6亚烷基-3-10元杂环基、C 0-6亚烷基-C 6-10芳基或C 0-6亚烷基-5-14元杂芳基； Wherein 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 6-10 aryl or C 0-6 alkylene-5-14-membered heteroaryl;
r＝0、1、2、3、4、5、6或7；r=0, 1, 2, 3, 4, 5, 6 or 7;
R 4为H、D、卤素、-CN、-SF 5、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基； 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为CR 5或N； Z 1 is CR 5 or N;
Z 2为CR 5或N； Z 2 is CR 5 or N;
R 5独立地为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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为H，或者R 7与-L 3-R 3形成双键，或R 7与-L 2-R 2形成＝Z； R 7 is H, or R 7 and -L 3 -R 3 form a double bond, or R 7 and -L 2 -R 2 form = Z;
Z为O或S；Z is O or S;
R 1a为H、-C(O)H、-C(O)OH、-C(O)C 1-6烷基、-C(O)OC 1-6烷基、-S(O) mC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基； 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;
上述各基团中含有的OH、NH、NH 2、CH、CH 2、CH 3基团在每次出现时各自任选地被1、2、3或更多个R s及其同位素变体取代，其中所述R s在每次出现时独立地选自：卤素、羟基、氨基、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-OR a’、-OC(O)R a’、-C(O)R a’、-C(O)OR a’、-C(O)NR a’R b’、-S(O) qR a’、-S(O) qOR a’、-S(O) qNR a’R b’、-NR a’R b’、-NR a’C(O)R b’、-NR a’-C(O)OR b’、-NR a’-S(O) q-R b’、-NR a’C(O)NR a’R b’、-C 1-6亚烷基-R a’、-C 1-6亚烷基-OR a’、-C 1-6亚烷基-OC(O)R a’、-C 1-6亚烷基-C(O)OR a’、-C 1-6亚烷基-S(O) qR a’、-C 1-6亚烷基-S(O) qOR a’、-C 1-6亚烷基-OC(O)NR a’R b’、-C 1-6亚烷基-C(O)NR a’R b’、-C 1-6亚烷基-NR a’-C(O)NR a’R b’、-C 1-6亚烷基-OS(O) qR a’、-C 1-6亚烷基-S(O) qNR a’R b’、-C 1-6亚烷基-NR a’-S(O) qNR a’R b’、-C 1-6亚烷基-NR a’R b’和-O-C 1-6亚烷基-NR a’R b’，并且其中关于取代基R s所述的羟基、氨基、烷基、亚烷基、环烷基、杂环基、芳基、杂芳基和芳烷基进一步任选地被1、2、3或更多个独立地选自下列的取代基及其同位素变体取代：卤素、OH、氨基、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷基羟基、C 3-6环烷基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基； The OH, NH, NH 2 , CH, CH 2 , and CH 3 groups contained in each of the above groups are each optionally substituted by 1, 2, 3 or more R s and its isotopic variants each time it appears , Wherein 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 ' , -S (O) q OR a', -S (O) q NR a 'R b', -NR a 'R b', -NR a 'C (O) R b ', -NR a' -C (O ) OR b ', -NR a' -S (O) q -R b ', -NR a' C (O) NR a 'R b', -C 1-6 Alkylene-R a' , -C 1-6 alkylene-OR a' , -C 1-6 alkylene-OC(O)R a' , -C 1-6 alkylene-C(O ) OR a' , -C 1-6 alkylene-S(O) q R a' , -C 1-6 alkylene-S(O) q OR a' , -C 1-6 alkylene- OC (O) NR a 'R b', -C 1-6 alkylene -C (O) NR a 'R b', -C 1-6 alkylene -NR a '-C (O) NR a 'R b', -C 1-6 alkylene -OS (O) q R a ' , -C 1-6 alkylene -S (O) q NR a' R b ', -C 1-6 alkylene alkyl -NR a '-S (O) q NR a' R b ', -C 1-6 alkylene -NR a' R b 'and -OC 1-6 alkylene group -NR a' R b ' , And wherein the hydroxyl group, amino group, alkyl group, alkylene group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group and aralkyl group described with respect to the substituent R s are further optionally substituted by 1, 2, 3 Or more substituents independently selected from the following substituents and isotopic variants thereof: halogen, OH, amino, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Group hydroxyl, C 3-6 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl, 5-14 membered heteroaryl and C 6-12 aralkyl;
q每次出现时各自独立地为1或2；Each time q appears independently 1 or 2;
R a’和R b’在每次出现时各自独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基-O-、C 1-6烷基-S-、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基。 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.
在另一个方面，本发明提供了一种药物组合物，所述药物组合物含有本发明化合物，和任选地药学上可接受的赋形剂。In another aspect, the present invention provides a pharmaceutical composition containing a compound of the present invention, and optionally a pharmaceutically acceptable excipient.
在另一个方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物，其还含有其它治疗剂。In another aspect, 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.
在另一个方面，本发明提供了本发明化合物在制备用于治疗和/或预防KRAS或其G12C突变蛋白介导的疾病的药物中的用途。In another aspect, 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.
在另一个方面，本发明提供了在受试者中治疗和/或预防KRAS或其G12C突变蛋白介导的疾病的方法，包括向所述受试者给药本发明化合物或本发明组合物。In another aspect, 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.
在另一个方面，本发明提供了本发明化合物或本发明组合物，其用于治疗和/或预防KRAS或其G12C突变蛋白介导的疾病。In another aspect, 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.
在具体实施方案中，本发明治疗的疾病包括选自以下的癌症：急性髓细胞样白血病、急性髓细胞样白血病、青少年癌症、儿童肾上腺皮质癌、AIDS相关的癌症(例如淋巴瘤和卡波西氏肉瘤)、肛门癌、阑尾癌、星形细胞瘤、非典型畸胎样、基底细胞癌、胆管癌、膀胱癌、骨癌、脑干神经胶质瘤、脑瘤、乳腺癌、支气管肿瘤、伯基特淋巴瘤、类癌瘤、非典型畸胎样、胚胎肿瘤、生殖细胞肿瘤、原发性淋巴瘤、宫颈癌、儿童癌症、脊索瘤、心脏肿瘤、慢性淋巴细胞性白血病(CLL)、慢性髓细胞性白血病(CML)、慢性骨髓增殖性病症、结肠癌、结肠直肠癌、颅咽管瘤、皮肤T细胞淋巴瘤、肝外导管原位癌(DCIS)、胚胎肿瘤、CNS癌症、子宫内膜癌、室管膜瘤、食道癌、嗅神经母细胞瘤、尤文氏肉瘤、颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、眼癌、骨骼的纤维组织细胞瘤、胆囊癌、胃癌、胃肠道类癌瘤、胃肠道间质瘤(GIST)、生殖细胞肿瘤、妊娠滋养细胞肿瘤、毛细胞白血病、头颈癌、心脏癌、肝癌、霍奇金氏淋巴瘤、下咽癌、眼内黑色素瘤、胰岛细胞瘤、胰腺神经内分泌瘤、肾癌、喉癌、唇和口腔癌、肝癌、小叶原位癌(LCIS)、肺癌、淋巴瘤、转移性鳞状颈癌伴隐匿原发灶、中线道癌、口腔癌、多发性内分泌瘤综合征、多发性骨髓瘤/浆细胞瘤、蕈样真菌病、骨髓发育不良综合征、骨髓发育不良/骨髓增殖性瘤、多发性骨髓瘤、梅克尔细胞癌、恶性间皮瘤、骨骼的恶性纤维组织细胞瘤和骨肉瘤、鼻腔和鼻窦癌、鼻咽癌、神经母细胞瘤、非霍奇金氏淋巴瘤、非小细胞肺癌(NSCLC)、口腔癌、唇和口腔癌、口咽癌、卵巢癌、胰腺癌、乳头瘤、副神经节瘤、鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、咽癌、胸膜肺母细胞瘤、原发性中枢神经系统(CNS)淋巴瘤、前列腺癌、直肠癌、移行性细胞癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、皮肤癌、胃癌、小细胞肺癌、小肠癌、软组织肉瘤、细胞淋巴瘤、睾丸癌、喉癌、胸腺瘤和胸腺癌、甲状腺癌、肾盂和输尿管的移行性细胞癌、滋养细胞肿瘤、儿童罕见的癌症、尿道癌、子宫肉瘤、阴道癌、外阴癌或病毒诱导的癌症。In specific embodiments, 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 ductal carcinoma in situ (DCIS), embryonic tumor, CNS cancer, uterus Endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, bone fibrous histiocytoma, gallbladder cancer, gastric cancer, stomach Intestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular cancer Melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary tumors, Midline tract cancer, oral cancer, multiple endocrine tumor syndrome, multiple myeloma/plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplasia/myeloproliferative tumor, multiple myeloma, Meike Malignant cell carcinoma, malignant mesothelioma, bone malignant fibrous histiocytoma and osteosarcoma, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin’s lymphoma, non-small cell lung cancer (NSCLC), Oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary Central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, cell lymphoma Cancer .
由随后的具体实施方案、实施例和权利要求，本发明的其它目的和优点将对于本领域技术人员显而易见。From the following specific embodiments, examples and claims, other objects and advantages of the present invention will be apparent to those skilled in the art.
定义definition
化学定义Chemical definition
下面更详细地描述具体官能团和化学术语的定义。The definitions of specific functional groups and chemical terms are described in more detail below.
当列出数值范围时，既定包括每个值和在所述范围内的子范围。例如“C 1-6烷基”包括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和C 5-6烷基。 When listing numerical ranges, it is intended to include each value and sub-ranges within the stated range. For example, "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烷基”是指具有1至6个碳原子的直链或支链饱和烃基团。在一些实施方案中，C 1-4烷基是优选的。C 1-6烷基的例子包括：甲基(C 1)、乙基(C 2)、正丙基(C 3)、异丙基(C 3)、正丁基(C 4)、叔丁基(C 4)、仲丁基(C 4)、 异丁基(C 4)、正戊基(C 5)、3-戊基(C 5)、戊基(C 5)、新戊基(C 5)、3-甲基-2-丁基(C 5)、叔戊基(C 5)和正己基(C 6)。术语“C 1-6烷基”还包括杂烷基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。常规烷基缩写包括：Me(-CH 3)、Et(-CH 2CH 3)、iPr(-CH(CH 3) 2)、nPr(-CH 2CH 2CH 3)、n-Bu(-CH 2CH 2CH 2CH 3)或i-Bu(-CH 2CH(CH 3) 2)。 "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 ). The term "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. Conventional 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烯基”是指具有2至6个碳原子和至少一个碳碳双键的直链或支链烃基团。在一些实施方案中，C 2-4烯基是优选的。C 2-6烯基的例子包括：乙烯基(C 2)、1-丙烯基(C 3)、2-丙烯基(C 3)、1-丁烯基(C 4)、2-丁烯基(C 4)、丁二烯基(C 4)、戊烯基(C 5)、戊二烯基(C 5)、己烯基(C 6)，等等。术语“C 2-6烯基”还包括杂烯基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烯基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。 The "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. The term "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炔基”是指具有2至6个碳原子、至少一个碳-碳叁键以及任选地一个或多个碳-碳双键的直链或支链烃基团。在一些实施方案中，C 2-4炔基是优选的。C 2-6炔基的例子包括但不限于：乙炔基(C 2)、1-丙炔基(C 3)、2-丙炔基(C 3)、1-丁炔基(C 4)、2-丁炔基(C 4)，戊炔基(C 5)、己炔基(C 6)，等等。术语“C 2-6炔基”还包括杂炔基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。炔基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。 "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. The term "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亚烷基、C 2-6亚烯基或C 2-6亚炔基”指的是上述定义的“C 1-6烷基、C 2-6烯基或C 2-6炔基”的二价基团。 "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亚烷基”是指除去C 1-6烷基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C 1-4亚烷基、C 2-4亚烷基和C 1-3亚烷基是优选的。未取代的所述亚烷基包括但不限于：亚甲基(-CH 2-)、亚乙基(-CH 2CH 2-)、亚丙基(-CH 2CH 2CH 2-)、亚丁基(-CH 2CH 2CH 2CH 2-)、亚戊基(-CH 2CH 2CH 2CH 2CH 2-)、亚己基(-CH 2CH 2CH 2CH 2CH 2CH 2-)，等等。示例性的取代的所述亚烷基，例如，被一个或多个烷基(甲基)取代的所述亚烷基，包括但不限于：取代的亚甲基(-CH(CH 3)-、-C(CH 3) 2-)、取代的亚乙基(-CH(CH 3)CH 2-、-CH 2CH(CH 3)-、-C(CH 3) 2CH 2-、-CH 2C(CH 3) 2-)、取代的亚丙基(-CH(CH 3)CH 2CH 2-、-CH 2CH(CH 3)CH 2-、-CH 2CH 2CH(CH 3)-、-C(CH 3) 2CH 2CH 2-、-CH 2C(CH 3) 2CH 2-、-CH 2CH 2C(CH 3) 2-)，等等。 The "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 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -) ,and many more. Exemplary substituted alkylene groups, for example, 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亚烷基”是指化学键以及上述“C 1-6亚烷基”。 The "C 0-6 alkylene group" means a chemical bond as well as the above-mentioned "C 1-6 alkylene group".
“C 2-6亚烯基”是指除去C 2-6烯基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C 2-4亚烯基是特别优选的。示例性的未取代的所述亚烯基包括但不限于：亚乙烯基(-CH＝CH-)和亚丙烯基(例如，-CH＝CHCH 2-、-CH 2-CH＝CH-)。示例性的取代的所述亚烯基，例如，被一个或多个烷基(甲基)取代的亚烯基，包括但不限于：取代的亚乙基(-C(CH 3)＝CH-、-CH＝C(CH 3)-)、取代的亚丙烯基(-C(CH 3)＝CHCH 2-、-CH＝C(CH 3)CH 2-、-CH＝CHCH(CH 3)-、-CH＝CHC(CH 3) 2-、-CH(CH 3)-CH＝CH-、-C(CH 3) 2-CH＝CH-、-CH 2-C(CH 3)＝CH-、-CH 2-CH＝C(CH 3)-)，等等。 The "C 2-6 alkenylene group" refers to a divalent group formed by removing another hydrogen of the C 2-6 alkenyl group, and may be substituted or unsubstituted. In some embodiments, C 2-4 alkenylene is particularly preferred. Exemplary unsubstituted alkenyl groups include the alkylene but are not limited to: ethenylene (-CH = CH-) and propenylene (e.g., -CH = CHCH 2 -, - CH 2 -CH = CH-). Exemplary substituted alkenylene groups, for example, alkenylene groups substituted with one or more alkyl (methyl) groups, include but are not limited to: substituted ethylene (-C(CH 3 )=CH- , -CH=C(CH 3 )-), substituted propenylene (-C(CH 3 )=CHCH 2 -, -CH=C(CH 3 )CH 2 -, -CH=CHCH(CH 3 )- , -CH=CHC(CH 3 ) 2 -, -CH(CH 3 ) -CH=CH-, -C(CH 3 ) 2 -CH=CH-, -CH 2 -C(CH 3 )=CH-, -CH 2 -CH=C(CH 3 )-), etc.
“C 2-6亚炔基”是指除去C 2-6炔基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C 2-4亚炔基是特别优选的。示例性的所述亚炔基包括但不限于：亚乙炔基(-C≡C-)、取代或未取代的亚丙炔基(-C≡CCH 2-)，等等。 The "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杂烷基”是指本文所定义的C 1-6烷基，并且在母体链内，它进一步含有一或多个(例如，1、2、3或 4个)杂原子(例如，氧、硫、氮、硼、硅、磷)，其中，一个或多个杂原子在所述母体碳链内的相邻碳原子之间，和/或，一个或多个杂原子在碳原子和母体分子之间，即，在连接点之间。C 1-6杂烷基与母体分子的连接点可为碳原子，也可为杂原子。 "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亚杂烷基”是指除去C 1-6杂烷基的另一个氢而形成的二价基团，并且可以是取代或未取代的。C 1-6亚杂烷基与母体分子其他部分的连接点可为两个碳原子，也可为两个杂原子，还可为一个碳原子和一个杂原子。 The "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.
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
因此，“C 1-6卤代烷基”是指上述“C 1-6烷基”，其被一个或多个卤素基团取代。在一些实施方案中，C 1-4卤代烷基是特别优选的，更优选C 1-2卤代烷基。示例性的所述卤代烷基包括但不限于：-CF 3、-CH 2F、-CHF 2、-CHFCH 2F、-CH 2CHF 2、-CF 2CF 3、-CCl 3、-CH 2Cl、-CHCl 2、2,2,2-三氟-1,1-二甲基-乙基，等等。卤代烷基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。 Therefore, "C 1-6 haloalkyl" refers to the above-mentioned "C 1-6 alkyl", which is substituted with one or more halogen groups. In some embodiments, 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环烷基”是指具有3至10个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中，C 4-7环烷基和C 3-6环烷基是特别优选的，更优选C 5-6环烷基。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在环烷基环上，且在这样的情况中，碳的数目继续表示环烷基体系中的碳的数目。示例性的所述环烷基包括但不限于：环丙基(C 3)、环丙烯基(C 3)、环丁基(C 4)、环丁烯基(C 4)、环戊基(C 5)、环戊烯基(C 5)、环己基(C 6)、环己烯基(C 6)、环已二烯基(C 6)、环庚基(C 7)、环庚烯基(C 7)、环庚二烯基(C 7)、环庚三烯基(C 7)，等等。环烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。 "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卤代环烷基”是指上述“C 3-10环烷基”，其被一个或多个卤素基团取代。 The "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元杂环基”是指具有环碳原子和1至5个环杂原子的3至12元非芳香环系的基团，其中，每个杂原子独立地选自氮、氧、硫、硼、磷和硅。在包含一个或多个氮原子的杂环基中，只要化合价允许，连接点可为碳或氮原子。在一些实施方案中，优选4-12元杂环基，其为具有环碳原子和1至5个环杂原子的4至12元非芳香环系；在一些实施方案中，优选3-10元杂环基，其为具有环碳原子和1至5个环杂原子的3至10元非芳香环系；在一些实施方案中，优选3-8元杂环基，其为具有环碳原子和1至4个环杂原子的3至8元非芳香环系；优选3-6元杂环基，其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系；优选4-7元杂环基，其为具有环碳原子和1至3个环杂原子的4至7元非芳香环系；更优选5-6元杂环基，其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系。杂环基还包括其中上述杂环基环与一个或多个环烷基稠合的环体系，其中连接点在环烷基环上，或其中上述杂环基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在杂环基环上；且在这样的情况下，环成员的数目继续表示在杂环基环体系中环成员的数目。示例性的包含一个杂原子的3元杂环基包括但不限于：氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl)。示例性的含有一个杂原子的4元杂环基包括但不限于：氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于：四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于：二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2- 酮。示例性的包含三个杂原子的5元杂环基包括但不限于：三唑啉基、噁二唑啉基和噻二唑啉基。示例性的包含一个杂原子的6元杂环基包括但不限于：哌啶基、四氢吡喃基、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环基包括但不限于：哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6元杂环基包括但不限于：六氢三嗪基(triazinanyl)。示例性的含有一个杂原子的7元杂环基包括但不限于：氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的与C 6芳基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于：二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基，等等。示例性的与C 6芳基环稠合的6元杂环基(本文还指的是6,6-双环杂环基)包括但不限于：四氢喹啉基、四氢异喹啉基，等等。杂环基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。 "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. In a heterocyclic group containing one or more nitrogen atoms, as long as the valence permits, the point of attachment may be a carbon or nitrogen atom. In some embodiments, 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; more preferably a 5-6 membered heterocyclic group, which has ring carbon atoms and A 5- to 6-membered non-aromatic ring system with 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. Oxazolidine-2-one. 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 (also referred to herein as 5,6-bicyclic heterocyclic groups) include, but are not limited to: indolinyl, isoindolinyl , Dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused to a C 6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclic groups) 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.
“3-12元卤代杂环基”是指上述“3-12元杂环基”，其被一个或多个卤素基团取代。类似地，“3-10元卤代杂环基”是指上述“3-10元杂环基”，其被一个或多个卤素基团取代。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. Similarly, 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.
“4-12元亚杂环基”和“5-6元亚杂环基”分别表示上述“4-12元杂环基”和“5-6元杂环基”，其中另一个氢被除去而形成的二价基团，并且可以是取代或未取代的。"4-12 membered heterocyclylene" and "5-6 membered heterocyclylene" respectively represent the above-mentioned "4-12 membered heterocyclic group" and "5-6 membered heterocyclic group" in which the other hydrogen is removed The formed divalent group can be substituted or unsubstituted.
“C 6-10芳基”是指具有6-10个环碳原子和零个杂原子的单环或多环的(例如，双环)4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团。在一些实施方案中，芳基具有六个环碳原子(“C 6芳基”；例如，苯基)。在一些实施方案中，芳基具有十个环碳原子(“C 10芳基”；例如，萘基，例如，1-萘基和2-萘基)。芳基还包括其中上述芳基环与一个或多个环烷基或杂环基稠合的环系统，而且连接点在所述芳基环上，在这种情况下，碳原子的数目继续表示所述芳基环系统中的碳原子数目。芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。 "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 π electrons) groups. In some embodiments, an aryl group having six ring carbon atoms ( "C 6 aryl"; e.g., phenyl). In some embodiments, 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. In this case, 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芳烷基”表示基团-R-R’，其中R为烷基部分，R’为芳基部分，并且烷基和芳基总共具有6-12个碳原子。 "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元杂芳基”是指具有环碳原子和1-4个环杂原子的5-14元单环或双环的4n+2芳族环体系(例如，具有以环状排列共享的6、10或14个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个环烷基或杂环基稠合的环系统，而且连接点在所述杂芳基环上，在这种情况下，碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。在一些实施方案中，5-10元杂芳基是优选的，其为具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系。在另一些实施方案中，5-6元杂芳基是特别优选的，其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系。示例性的含有一个杂原子的5元杂芳基包括但不限于：吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于：咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于：三唑基、噁二唑基(例如，1,2,4-噁二唑基)和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于：四唑基。 示例性的含有一个杂原子的6元杂芳基包括但不限于：吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于：哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于：三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于：氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于：吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于：萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。杂芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。"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 π electrons), where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, as long as the valence allows, 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. In some embodiments, 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. In other embodiments, 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.
“氧代”表示＝O。"Oxo" means =0.
本文定义的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基等为任选取代的基团。The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group as defined herein are optionally substituted groups.
示例性的碳原子上的取代基包括但不局限于：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OR aa、-ON(R bb) 2、-N(R bb) 2、-N(R bb) 3 +X -、-N(OR cc)R bb、-SH、-SR aa、-SSR cc、-C(＝O)R aa、-CO 2H、-CHO、-C(OR cc) 2、-CO 2R aa、-OC(＝O)R aa、-OCO 2R aa、-C(＝O)N(R bb) 2、-OC(＝O)N(R bb) 2、-NR bbC(＝O)R aa、-NR bbCO 2R aa、-NR bbC(＝O)N(R bb) 2、-C(＝NR bb)R aa、-C(＝NR bb)OR aa、-OC(＝NR bb)R aa、-OC(＝NR bb)OR aa、-C(＝NR bb)N(R bb) 2、-OC(＝NR bb)N(R bb) 2、-NR bbC(＝NR bb)N(R bb) 2、-C(＝O)NR bbSO 2R aa、-NR bbSO 2R aa、-SO 2N(R bb) 2、-SO 2R aa、-SO 2OR aa、-OSO 2R aa、-S(＝O)R aa、-OS(＝O)R aa、-Si(R aa) 3、-OSi(R aa) 3、-C(＝S)N(R bb) 2、-C(＝O)SR aa、-C(＝S)SR aa、-SC(＝S)SR aa、-SC(＝O)SR aa、-OC(＝O)SR aa、-SC(＝O)OR aa、-SC(＝O)R aa、-P(＝O) 2R aa、-OP(＝O) 2R aa、-P(＝O)(R aa) 2、-OP(＝O)(R aa) 2、-OP(＝O)(OR cc) 2、-P(＝O) 2N(R bb) 2、-OP(＝O) 2N(R bb) 2、-P(＝O)(NR bb) 2、-OP(＝O)(NR bb) 2、-NR bbP(＝O)(OR cc) 2、-NR bbP(＝O)(NR bb) 2、-P(R cc) 2、-P(R cc) 3、-OP(R cc) 2、-OP(R cc) 3、-B(R aa) 2、-B(OR cc) 2、-BR aa(OR cc)、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代； Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR aa , -ON (R bb ) 2, -N (R bb) 2, -N (R bb) 3 + X -, -N (OR cc) R bb, -SH, -SR aa, -SSR cc, -C (= O) R aa , -CO 2 H, -CHO, -C(OR cc ) 2 , -CO 2 R aa , -OC(=O)R aa , -OCO 2 R aa , -C(=O)N(R bb ) 2 , -OC(=O)N(R bb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 R aa , -NR bb C(=O)N(R bb ) 2 , -C (=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb ) 2. -OC(=NR bb )N(R bb ) 2 , -NR bb C(=NR bb )N(R bb ) 2 , -C(=O)NR bb SO 2 R aa , -NR bb SO 2 R aa , -SO 2 N(R bb ) 2 , -SO 2 R aa , -SO 2 OR aa , -OSO 2 R aa , -S(=O)R aa , -OS(=O)R aa ,- Si(R aa ) 3 , -OSi(R aa ) 3 , -C(=S)N(R bb ) 2 , -C(=O)SR aa , -C(=S)SR aa , -SC(= S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O) 2 R aa , -OP(=O) 2 R aa , -P(=O)(R aa ) 2 , -OP(=O)(R aa ) 2 , -OP(=O)(OR cc ) 2 , -P( =O) 2 N(R bb ) 2 , -OP(=O) 2 N(R bb ) 2 , -P(=O)(NR bb ) 2 , -OP(=O)(NR bb ) 2 ,- NR bb P(=O)(OR cc ) 2 , -NR bb P(=O)(NR bb ) 2 , -P(R cc ) 2 , -P(R cc ) 3 , -OP(R cc ) 2 , -OP(R cc ) 3 , -B(R aa ) 2 , -B(OR cc ) 2 , -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and hetero Aryl groups, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups ；
或者在碳原子上的两个偕氢被基团＝O、＝S、＝NN(R bb) 2、＝NNR bbC(＝O)R aa、＝NNR bbC(＝O)OR aa、＝NNR bbS(＝O) 2R aa、＝NR bb或＝NOR cc取代； Or the two geminal hydrogens on the carbon atom are grouped by =0, =S, =NN(R bb ) 2 , =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , = Replace with NNR bb S(=O) 2 R aa , =NR bb or =NOR cc ;
R aa的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个R aa基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代； 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
R bb的每个独立地选自：氢、-OH、-OR aa、-N(R cc) 2、-CN、-C(＝O)R aa、-C(＝O)N(R cc) 2、-CO 2R aa、-SO 2R aa、-C(＝NR cc)OR aa、-C(＝NR cc)N(R cc) 2、-SO 2N(R cc) 2、-SO 2R cc、-SO 2OR cc、-SOR aa、-C(＝S)N(R cc) 2、-C(＝O)SR cc、-C(＝S)SR cc、-P(＝O) 2R aa、-P(＝O)(R aa) 2、-P(＝O) 2N(R cc) 2、-P(＝O)(NR cc) 2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个R bb基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代； Each of R bb is independently selected from: hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2. -CO 2 R aa , -SO 2 R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O ) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 , alkyl, haloalkyl, alkene Group, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb groups combined to form a heterocyclyl or heteroaryl ring, wherein each alkyl, alkenyl, alkyne Cycloalkyl, heterocyclyl, aryl and heteroaryl are independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;
R cc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个R cc基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独 立地被0、1、2、3、4或5个R dd基团取代； 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;
R dd的每个独立地选自：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OR ee、-ON(R ff) 2、-N(R ff) 2,、-N(R ff) 3 +X -、-N(OR ee)R ff、-SH、-SR ee、-SSR ee、-C(＝O)R ee、-CO 2H、-CO 2R ee、-OC(＝O)R ee、-OCO 2R ee、-C(＝O)N(R ff) 2、-OC(＝O)N(R ff) 2、-NR ffC(＝O)R ee、-NR ffCO 2R ee、-NR ffC(＝O)N(R ff) 2、-C(＝NR ff)OR ee、-OC(＝NR ff)R ee、-OC(＝NR ff)OR ee、-C(＝NR ff)N(R ff) 2、-OC(＝NR ff)N(R ff) 2、-NR ffC(＝NR ff)N(R ff) 2、-NR ffSO 2R ee、-SO 2N(R ff) 2、-SO 2R ee、-SO 2OR ee、-OSO 2R ee、-S(＝O)R ee、-Si(R ee) 3、-OSi(R ee) 3、-C(＝S)N(R ff) 2、-C(＝O)SR ee、-C(＝S)SR ee、-SC(＝S)SR ee、-P(＝O) 2R ee、-P(＝O)(R ee) 2、-OP(＝O)(R ee) 2、-OP(＝O)(OR ee) 2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代，或者两个偕R dd取代基可结合以形成＝O或＝S； Each of R dd is independently selected from: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR ee , -ON(R ff ) 2 , -N (R ff) 2 ,, - N (R ff) 3 + X -, -N (OR ee) R ff, -SH, -SR ee, -SSR ee, -C (= O) R ee, -CO 2 H, -CO 2 R ee , -OC(=O)R ee , -OCO 2 R ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 ,- NR ff C(=O)R ee , -NR ff CO 2 R ee , -NR ff C(=O)N(R ff ) 2 , -C(=NR ff )OR ee , -OC(=NR ff ) R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff ) 2 , -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff ) N(R ff ) 2 , -NR ff SO 2 R ee , -SO 2 N(R ff ) 2 , -SO 2 R ee , -SO 2 OR ee , -OSO 2 R ee , -S(=O)R ee , -Si(R ee ) 3 , -OSi(R ee ) 3 , -C(=S)N(R ff ) 2 , -C(=O)SR ee , -C(=S)SR ee ,- SC(=S)SR ee , -P(=O) 2 R ee , -P(=O)(R ee ) 2 , -OP(=O)(R ee ) 2 , -OP(=O)(OR ee ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group The group, the aryl group and the heteroaryl group are independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups, or two geminal R dd substituents may be combined to form =O or =S;
R ee的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代； 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;
R ff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个R ff基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R gg基团取代； 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
R gg的每个独立地是：卤素、-CN、-NO 2、-N 3、-SO 2H、-SO 3H、-OH、-OC 1-6烷基、-ON(C 1-6烷基) 2、-N(C 1-6烷基) 2、-N(C 1-6烷基) 3 +X -、-NH(C 1-6烷基) 2 +X -、-NH 2(C 1-6烷基) +X -、-NH 3 +X -、-N(OC 1-6烷基)(C 1-6烷基)、-N(OH)(C 1-6烷基)、-NH(OH)、-SH、-SC 1-6烷基、-SS(C 1-6烷基)、-C(＝O)(C 1-6烷基)、-CO 2H、-CO 2(C 1-6烷基)、-OC(＝O)(C 1-6烷基)、-OCO 2(C 1-6烷基)、-C(＝O)NH 2、-C(＝O)N(C 1-6烷基) 2、-OC(＝O)NH(C 1-6烷基)、-NHC(＝O)(C 1-6烷基)、-N(C 1-6烷基)C(＝O)(C 1-6烷基)、-NHCO 2(C 1-6烷基)、-NHC(＝O)N(C 1-6烷基) 2、-NHC(＝O)NH(C 1-6烷基)、-NHC(＝O)NH 2、-C(＝NH)O(C 1-6烷基)、-OC(＝NH)(C 1-6烷基)、-OC(＝NH)OC 1-6烷基、-C(＝NH)N(C 1-6烷基) 2、-C(＝NH)NH(C 1-6烷基)、-C(＝NH)NH 2、-OC(＝NH)N(C 1-6烷基) 2、-OC(NH)NH(C 1-6烷基)、-OC(NH)NH 2、-NHC(NH)N(C 1-6烷基) 2、-NHC(＝NH)NH 2、-NHSO 2(C 1-6烷基)、-SO 2N(C 1-6烷基) 2、-SO 2NH(C 1-6烷基)、-SO 2NH 2、-SO 2C 1-6烷基、-SO 2OC 1-6烷基、-OSO 2C 1-6烷基、-SOC 1-6烷基、-Si(C 1-6烷基) 3、-OSi(C 1-6烷基) 3、-C(＝S)N(C 1-6烷基) 2、C(＝S)NH(C 1-6烷基)、C(＝S)NH 2、-C(＝O)S(C 1-6烷基)、-C(＝S)SC 1-6烷基、-SC(＝S)SC 1-6烷基、-P(＝O) 2(C 1-6烷基)、-P(＝O)(C 1-6烷基) 2、-OP(＝O)(C 1-6烷基) 2、-OP(＝O)(OC 1-6烷基) 2、C 1-6烷基、C 1-6卤代烷基、C 2-C 6烯基、C 2-C 6炔基、C 3-C 7环烷基、C 6-C 10芳基、C 3-C 7杂环基、C 5-C 10杂芳基；或者两个偕R gg取代基可结合形成＝O或＝S；其中，X -为反离子。 Each of R gg is independently: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OC 1-6 alkyl, -ON (C 1-6 alkyl) 2, -N (C 1-6 alkyl) 2, -N (C 1-6 alkyl) 3 + X -, -NH ( C 1-6 alkyl) 2 + X -, -NH 2 (C 1-6 alkyl) + X -, -NH 3 + X -, -N (OC 1-6 alkyl) (C 1-6 alkyl), - N (OH) ( C 1-6 alkyl ), -NH(OH), -SH, -SC 1-6 alkyl, -SS (C 1-6 alkyl), -C(=O) (C 1-6 alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O) (C 1-6 alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 , -C (=O)N(C 1-6 alkyl) 2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 ,- NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1- 6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl) 2 , -C(=NH)NH(C 1-6 alkyl) , -C(=NH)NH 2 , -OC(=NH)N(C 1-6 alkyl) 2 , -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1-6 alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1-6 alkyl), -SO 2 N(C 1-6 alkyl) 2 , -SO 2 NH (C 1-6 alkyl), -SO 2 NH 2 , -SO 2 C 1-6 alkyl, -SO 2 OC 1-6 alkyl, -OSO 2 C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl) 3 , -OSi(C 1-6 alkyl) 3 , -C(=S)N(C 1-6 alkyl) 2 , C (=S)NH(C 1-6 alkyl), C(=S)NH 2 , -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 alkyl , -SC(=S)SC 1-6 alkyl, -P(=O) 2 (C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2 , -OP(= O)(C 1-6 alkyl) 2 , -OP(= O) (OC 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl , C 6 -C 10 aryl, C 3 -C 7 heterocyclyl, C 5 -C 10 heteroaryl; or two geminal R gg substituents can be combined to form =O or =S; where X - is the opposite ion.
示例性的氮原子上取代基包括但不局限于：氢、-OH、-OR aa、-N(R cc) 2、-CN、-C(＝O)R aa、-C(＝O)N(R cc) 2、-CO 2R aa、-SO 2R aa、-C(＝NR bb)R aa、-C(＝NR cc)OR aa、-C(＝NR cc)N(R cc) 2、-SO 2N(R cc) 2、-SO 2R cc、-SO 2OR cc、-SOR aa、-C(＝S)N(R cc) 2、-C(＝O)SR cc、-C(＝S)SR cc、-P(＝O) 2R aa、-P(＝O)(R aa) 2、-P(＝O) 2N(R cc) 2、-P(＝O)(NR cc) 2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者连接至氮原子的两个R cc基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个R dd基团取代，且其中R aa、R bb、R cc和R dd如上所述。 Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N (R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2. -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O ) (NR cc ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc groups connected to a nitrogen atom combine 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 The dd group is substituted, and wherein R aa , R bb , R cc and R dd are as described above.
其它定义Other definitions
术语“KRAS G12C”是指哺乳动物KRAS蛋白的突变形式，其在12位氨基酸处含有半胱氨酸对甘氨酸的氨基酸取代。人KRAS的氨基酸密码子和残基位置的定位是基于由UniProtKB/Swiss-Prot Ρ01116:Variantρ.Glyl2Cys鉴定的氨基酸序列。The term "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.
术语“KRAS G12C抑制剂”是指本发明化合物，这些化合物能够负性调制或抑制KRAS G12C的全部或部分酶活性。本发明的KRAS G12C抑制剂通过与12位处半胱氨酸残基的巯基侧链形成共价加合物而与KRAS G12C相互作用和不可逆地结合，导致抑制KRAS G12C的酶活性。The term "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.
术语“癌症”包括但不限于下列癌症：乳腺、卵巢、子宫颈、前列腺、睾丸、食道、胃、皮肤、肺、骨、结肠、胰腺、甲状腺、胆道、颊腔与咽(口)、唇、舌、口腔、咽、小肠、结肠直肠、大肠、直肠、脑与中枢神经系统的癌症、成胶质细胞瘤、神经母细胞瘤、角化棘皮瘤、表皮样癌、大细胞癌、腺癌、腺瘤、滤泡癌、未分化的癌、乳头状癌、精原细胞瘤、黑色素瘤、肉瘤、膀胱癌、肝癌、肾癌、骨髓障碍、淋巴障碍、霍奇金氏病、毛细胞癌和白血病。The term "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.
本文所用的术语“治疗”涉及逆转、减轻、抑制该术语适用的障碍或病症的进展或者预防之，或者这类障碍或病症的一种或多种症状。本文所用的名词“治疗”涉及动词治疗的动作，后者是如刚才所定义的。The term "treatment" as used herein 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. As used herein, the term "treatment" refers to the act of verb therapy, the latter being as just defined.
本文所用的术语“药学上可接受的盐”表示本发明化合物的那些羧酸盐、氨基酸加成盐，它们在可靠的医学判断范围内适用于与患者组织接触，不会产生不恰当的毒性、刺激作用、变态反应等，与合理的益处/风险比相称，就它们的预期应用而言是有效的，包括(可能的话)本发明化合物的两性离子形式。The term "pharmaceutically acceptable salt" as used herein 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.
药学上可接受的碱加成盐是与金属或胺生成的，例如碱金属与碱土金属氢氧化物或有机胺。用作阳离子的金属的实例有钠、钾、镁、钙等。适合的胺的实例有N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因。Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
酸性化合物的碱加成盐可以这样制备，按照常规方式使游离酸形式与足量所需的碱接触，生成盐。按照常规方式使盐形式与酸接触，再分离游离酸，可以使游离酸再生。游离酸形式在某些物理性质上多少不同于它们各自的盐形式，例如在极性溶剂中的溶解度，但是出于本发明的目的，盐还是等价于它们各自的游离酸。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.
盐可以是从无机酸制备的硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物，酸例如盐酸、硝酸、硫酸、氢溴酸、氢碘酸、磷酸等。代表性盐包括：氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘甲酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐、月桂基磺酸盐和羟乙磺酸盐等。盐也可以是从有机酸制备的，例如脂肪族一元与二元羧酸、苯基取代的烷酸、羟基烷酸、烷二酸、芳香族酸、脂肪族与芳香族磺酸等。代表性盐包括乙酸盐、丙酸盐、辛酸盐、异丁酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、扁桃酸盐、苯甲酸盐、氯苯甲酸盆、甲基苯甲酸盐、二硝基苯甲酸盐、萘甲酸盐、苯磺酸盐、甲苯磺酸盐、苯乙酸盐、柠檬酸盐、乳酸盐、马来酸盐、酒石酸盐、甲磺酸盐等。药学上可接受的盐可以包括基于碱金属与碱土金 属的阳离子，例如钠、锂、钾、钙、镁等，以及无毒的铵、季铵和胺阳离子，包括但不限于铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。还涵盖氨基酸的盐，例如精氨酸盐、葡糖酸盐、半乳糖醛酸盐等(例如参见Berge S.M.et al.，"Pharmaceutical Salts,”J.Pharm.Sci.，1977；66:1-19，引入此作为参考)。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. 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).
给药的“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人))和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在一些实施方案中，受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。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. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.
“疾病”、“障碍”和“病症”在本文中可互换地使用。"Disease", "disorder" and "condition" are used interchangeably herein.
除非另作说明，否则，本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用，它降低疾病、障碍或病症的严重程度，或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”)，还包括在受试者开始患有具体疾病、障碍或病症之前发生的作用(“预防性治疗”)。Unless otherwise specified, the term "treatment" as used herein 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").
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药代动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗有效量和预防有效量。Generally, an "effective amount" of a compound refers to an amount sufficient to cause a target biological response. As understood by those of ordinary skill in the art, 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.
除非另作说明，否则，本文使用的化合物的“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗益处的量，或使与疾病、障碍或病症有关的一或多种症状延迟或最小化的量。化合物的治疗有效量是指单独使用或与其它疗法联用时，治疗剂的量，它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其它治疗剂的治疗效果的量。Unless otherwise specified, 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.
除非另作说明，否则，本文使用的化合物的“预防有效量”是足以预防疾病、障碍或病症的量，或足以预防与疾病、障碍或病症有关的一或多种症状的量，或防止疾病、障碍或病症复发的量。化合物的预防有效量是指单独使用或与其它药剂联用时，治疗剂的量，它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的量，或增强其它预防药剂的预防效果的量。Unless otherwise specified, 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.
“组合”以及相关术语是指同时或依次给药本发明化合物和其它治疗剂。例如，本发明化合物可以与其它治疗剂以分开的单位剂型同时或依次给药，或与其它治疗剂一起在单一单位剂型中同时给药。"Combination" and related terms refer to the simultaneous or sequential administration of the compound of the present invention and other therapeutic agents. For example, 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.
具体实施方案Specific implementation plan
本文中，“本发明化合物”指的是以下的式(I)化合物(包括子通式，例如式(I-1)、式(II)等)、其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物。As used herein, "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.
本文中，化合物使用标准的命名法命名。具有非对称中心的化合物，应该明白(除非另有说明)所有的光学异构体及其混合物均包含在内。此外，除非另有规定，本发明所包括的所有异构体化合物与碳碳双键可 能以Z和E的形式出现。在不同的互变异构形式存在的化合物，一个所述化合物并不局限于任何特定的互变异构体，而是旨在涵盖所有的互变异构形式。In this article, compounds are named using standard nomenclature. For compounds with an asymmetric center, it should be understood (unless otherwise specified) that all optical isomers and mixtures thereof are included. In addition, unless otherwise specified, all isomer compounds and carbon-carbon double bonds included in the present invention may appear in the form of Z and E. Compounds that exist in different tautomeric forms, a said compound is not limited to any particular tautomer, but is intended to cover all tautomeric forms.
在一个实施方案中，本发明涉及式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：In one embodiment, 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:
Figure PCTCN2021091102-appb-000003
Figure PCTCN2021091102-appb-000003
其中，in,
环A为C 6-10芳基或5-14元杂芳基，优选为萘基或9-10元杂芳基，优选萘基、苯并5元杂芳基或苯并6元杂芳基； 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独立地为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a、C 0-6亚烷基-C(O)N(R 1a) 2或C 0-6亚烷基-S(O) mR 1a；优选地，其中至少一个R 6为-O-R 1a； 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 ;
m＝1或2；m=1 or 2;
n＝0、1、2、3、4、5、6或7；n=0, 1, 2, 3, 4, 5, 6 or 7;
L 1为-H 1-H 2-H 3-H 4-； L 1 is -H 1 -H 2 -H 3 -H 4 -;
其中H 1选自-O-、-S-、-N(R H’)-、-C(R H)(R H)-、-C(R H)(R H)-C(R H)(R H)-或-C(R H)(R H)-C(R H)(R H)-C(R H)(R H)-，H 2、H 3和H 4独立地选自-O-、-S-、-N(R H’)-或-C(R H)(R H)-； 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 )-;
并且，H 1和H 3上的R H/R H’取代基、H 1和H 4上的R H/R H’取代基、和H 2和H 4上的R H/R H’取代基中的一对或两对R H/R H’取代基可以结合形成C 1-3亚烷基； And, H 1 and H R H on 3 / R H 'substituent group, H 1 and H R H on 4 / R H' substituent group, and H 2 and H R H on 4 / R H 'substituent One or two pairs of R H /R H'substituents can be combined to form a C 1-3 alkylene group;
R H为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a或C 0-6亚烷基-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R H'is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R 1为C 1-6卤代烷基或
Figure PCTCN2021091102-appb-000004
R 1 is C 1-6 haloalkyl or
Figure PCTCN2021091102-appb-000004
其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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 ;
其任选被R’取代；并且R a和R b可以形成化学键从而使得双键变为叁键； Optionally R 'group; and R a and R b may form a chemical bond so that the triple bond becomes a double bond;
其中R’为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； Wherein 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为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-、-N(R L2’)-(C(R L2)(R L2)) p-或-(C(R L2)(R L2)) p-； 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 -;
其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
并且，相邻原子上的R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, 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为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被r个R取代； 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为化学键或-(C(R L3)(R L3)) p-； L 3 is a chemical bond or -(C(R L3 )(R L3 )) p -;
其中R L3为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； Wherein 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 ;
并且，相邻原子上的R L3可以结合形成C 3-10环烷基或3-10元杂环基； In addition, 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为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被r个R取代； 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. C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by r R;
其中R为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-SF 5、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a、C 0-6亚烷基-C(O)N(R 1a) 2、C 0-6亚烷基-S(O) mR 1a、C 0-6亚烷基-C 3-10环烷基、C 0-6亚烷基-3-10元杂环基、C 0-6亚烷基-C 6-10芳基或C 0-6亚烷基-5-14元杂芳基； Wherein 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 6-10 aryl or C 0-6 alkylene-5-14-membered heteroaryl;
r＝0、1、2、3、4、5、6或7；r=0, 1, 2, 3, 4, 5, 6 or 7;
R 4为H、D、卤素、-CN、-SF 5、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基； 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为CR 5或N； Z 1 is CR 5 or N;
Z 2为CR 5或N； Z 2 is CR 5 or N;
R 5独立地为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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为H，或者R 7与-L 3-R 3形成双键，或R 7与-L 2-R 2形成＝Z； R 7 is H, or R 7 and -L 3 -R 3 form a double bond, or R 7 and -L 2 -R 2 form = Z;
Z为O或S；Z is O or S;
R 1a为H、-C(O)H、-C(O)OH、-C(O)C 1-6烷基、-C(O)OC 1-6烷基、-S(O) mC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基； 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;
上述各基团中含有的OH、NH、NH 2、CH、CH 2、CH 3基团在每次出现时各自任选地被1、2、3或更多个R s及其同位素变体取代，其中所述R s在每次出现时独立地选自：卤素、羟基、氨基、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-OR a’、-OC(O)R a’、-C(O)R a’、-C(O)OR a’、-C(O)NR a’R b’、-S(O) qR a’、-S(O) qOR a’、-S(O) qNR a’R b’、-NR a’R b’、-NR a’C(O)R b’、-NR a’-C(O)OR b’、-NR a’-S(O) q-R b’、-NR a’C(O)NR a’R b’、-C 1-6亚烷基-R a’、-C 1-6亚烷基-OR a’、-C 1-6亚烷基-OC(O)R a’、-C 1-6亚烷基-C(O)OR a’、-C 1-6亚烷基-S(O) qR a’、-C 1-6亚烷基-S(O) qOR a’、-C 1-6亚烷基-OC(O)NR a’R b’、-C 1-6亚烷基-C(O)NR a’R b’、-C 1-6亚烷基-NR a’-C(O)NR a’R b’、-C 1-6亚烷基-OS(O) qR a’、-C 1-6亚烷基-S(O) qNR a’R b’、-C 1-6亚烷基-NR a’-S(O) qNR a’R b’、-C 1-6亚烷基-NR a’R b’和-O-C 1-6亚烷基-NR a’R b’，并且其中关于取代基R s所述的羟基、氨基、烷基、亚烷基、环烷基、杂环基、芳基、杂芳基和芳烷基进一步任选地被1、2、3或更多个独立地选自下列的取代基及其同位素变体取代：卤素、OH、 氨基、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷基羟基、C 3-6环烷基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基； The OH, NH, NH 2 , CH, CH 2 , and CH 3 groups contained in each of the above groups are each optionally substituted by 1, 2, 3 or more R s and its isotopic variants each time it appears , Wherein 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 ' , -S (O) q OR a', -S (O) q NR a 'R b', -NR a 'R b', -NR a 'C (O) R b ', -NR a' -C (O ) OR b ', -NR a' -S (O) q -R b ', -NR a' C (O) NR a 'R b', -C 1-6 Alkylene-R a' , -C 1-6 alkylene-OR a' , -C 1-6 alkylene-OC(O)R a' , -C 1-6 alkylene-C(O ) OR a' , -C 1-6 alkylene-S(O) q R a' , -C 1-6 alkylene-S(O) q OR a' , -C 1-6 alkylene- OC (O) NR a 'R b', -C 1-6 alkylene -C (O) NR a 'R b', -C 1-6 alkylene -NR a '-C (O) NR a 'R b', -C 1-6 alkylene -OS (O) q R a ' , -C 1-6 alkylene -S (O) q NR a' R b ', -C 1-6 alkylene alkyl -NR a '-S (O) q NR a' R b ', -C 1-6 alkylene -NR a' R b 'and -OC 1-6 alkylene group -NR a' R b ' , And wherein the hydroxyl group, amino group, alkyl group, alkylene group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group and aralkyl group described with respect to the substituent R s are further optionally substituted by 1, 2, 3 Or more substituents independently selected from the following substituents and isotopic variants thereof: halogen, OH, amino, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Hydroxy group, C 3-6 cycloalkyl group, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-14 membered heteroaryl group and C 6-12 aralkyl group;
q每次出现时各自独立地为1或2；Each time q appears independently 1 or 2;
R a’和R b’在每次出现时各自独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基-O-、C 1-6烷基-S-、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基。 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.
环ARing A
在一个具体实施方案中，环A为C 6-10芳基；在另一个具体实施方案中，环A为5-14元杂芳基；在另一个具体实施方案中，环A为萘基；在另一个具体实施方案中，环A为9-10元杂芳基；在另一个具体实施方案中，环A为苯并5元杂芳基，例如苯并吡咯基、苯并吡唑基、苯并噻唑基、吲唑基、苯并噻吩基或苯并呋喃基，优选苯并噻唑基和吲唑基；在另一个具体实施方案中，环A为苯并6元杂芳基，例如苯并吡啶基、苯并哒嗪基、苯并吡嗪基、苯并嘧啶基或苯并三嗪基。 In a specific embodiment, 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 R 6
在一个具体实施方案中，R 6独立地为H；在另一个具体实施方案中，R 6独立地为D；在另一个具体实施方案中，R 6独立地为C 0-6亚烷基-卤素；在另一个具体实施方案中，R 6独立地为C 0-6亚烷基-CN；在另一个具体实施方案中，R 6独立地为C 0-6亚烷基-NO 2；在另一个具体实施方案中，R 6独立地为C 1-6烷基；在另一个具体实施方案中，R 6独立地为C 1-6卤代烷基；在另一个具体实施方案中，R 6独立地为C 2-6烯基；在另一个具体实施方案中，R 6独立地为C 2-6炔基；在另一个具体实施方案中，R 6独立地为C 0-6亚烷基-O-R 1a，优选-OH；在另一个具体实施方案中，R 6独立地为C 0-6亚烷基-S-R 1a；在另一个具体实施方案中，R 6独立地为C 0-6亚烷基-N(R 1a) 2；在另一个具体实施方案中，R 6独立地为C 0-6亚烷基-C(O)R 1a；在另一个具体实施方案中，R 6独立地为C 0-6亚烷基-C(O)OR 1a；在另一个具体实施方案中，R 6独立地为C 0-6亚烷基-C(O)N(R 1a) 2；在另一个具体实施方案中，R 6独立地为C 0-6亚烷基-S(O) mR 1a；在另一个具体实施方案中，R 6为非H基团；在另一个具体实施方案中，其中至少一个R 6为-O-R 1a。 In a specific embodiment, 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 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) R 1a; in another particular embodiment, R 6 is independently C 0-6 alkylene-C(O)OR 1a ; in another specific embodiment, R 6 is independently C 0-6 alkylene-C(O)N(R 1a ) 2 ; in another In a specific embodiment, R 6 is independently C 0-6 alkylene-S(O) m R 1a ; in another specific embodiment, R 6 is a group other than H; in another specific embodiment, At least one of R 6 is -OR 1a .
mm
在一个具体实施方案中，m＝1；在另一个具体实施方案中，m＝2。In a specific embodiment, m=1; in another specific embodiment, m=2.
nn
在一个具体实施方案中，n＝0；在另一个具体实施方案中，n＝1；在另一个具体实施方案中，n＝2；在另一个具体实施方案中，n＝3；在另一个具体实施方案中，n＝4；在另一个具体实施方案中，n＝5；在另一个具体实施方案中，n＝6；在另一个具体实施方案中，n＝7。In one specific embodiment, n=0; in another specific embodiment, n=1; in another specific embodiment, n=2; in another specific embodiment, n=3; in another In a specific embodiment, n=4; in another specific embodiment, n=5; in another specific embodiment, n=6; in another specific embodiment, n=7.
在一个具体实施方案中，
Figure PCTCN2021091102-appb-000005
为
Figure PCTCN2021091102-appb-000006
其中Z 3、Z 4和Z 5独立地为CR 6或N；环B为苯基或5-6 元杂芳基；在另一个具体实施方案中，
Figure PCTCN2021091102-appb-000007
为
Figure PCTCN2021091102-appb-000008
在另一个具体实施方案中，
Figure PCTCN2021091102-appb-000009
为
Figure PCTCN2021091102-appb-000010
在另一个具体实施方案中，
Figure PCTCN2021091102-appb-000011
为
Figure PCTCN2021091102-appb-000012
在另一个具体实施方案中，
Figure PCTCN2021091102-appb-000013
为
Figure PCTCN2021091102-appb-000014
在另一个具体实施方案中，
Figure PCTCN2021091102-appb-000015
为
Figure PCTCN2021091102-appb-000016
在另一个具体实施方案中，
Figure PCTCN2021091102-appb-000017
为
Figure PCTCN2021091102-appb-000018
在另一个具体实施方案中，
Figure PCTCN2021091102-appb-000019
为
Figure PCTCN2021091102-appb-000020
在另一个具体实施方案中，
Figure PCTCN2021091102-appb-000021
为
Figure PCTCN2021091102-appb-000022
在另一个具体实施方案中，
Figure PCTCN2021091102-appb-000023
为
Figure PCTCN2021091102-appb-000024
在另一个具体实施方案中，
Figure PCTCN2021091102-appb-000025
为
Figure PCTCN2021091102-appb-000026
在另一个具体实施方案中，
Figure PCTCN2021091102-appb-000027
为
Figure PCTCN2021091102-appb-000028
在另一个具体实施方案中，
Figure PCTCN2021091102-appb-000029
为
Figure PCTCN2021091102-appb-000030
在另一个具体实施方案中，
Figure PCTCN2021091102-appb-000031
为
Figure PCTCN2021091102-appb-000032
在另一个具体实施方案中，
Figure PCTCN2021091102-appb-000033
为
Figure PCTCN2021091102-appb-000034
Figure PCTCN2021091102-appb-000035
在另一个具体实施方案中，
Figure PCTCN2021091102-appb-000036
为
Figure PCTCN2021091102-appb-000037
In a specific embodiment,
Figure PCTCN2021091102-appb-000005
for
Figure PCTCN2021091102-appb-000006
Wherein 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,
Figure PCTCN2021091102-appb-000007
for
Figure PCTCN2021091102-appb-000008
In another specific embodiment,
Figure PCTCN2021091102-appb-000009
for
Figure PCTCN2021091102-appb-000010
In another specific embodiment,
Figure PCTCN2021091102-appb-000011
for
Figure PCTCN2021091102-appb-000012
In another specific embodiment,
Figure PCTCN2021091102-appb-000013
for
Figure PCTCN2021091102-appb-000014
In another specific embodiment,
Figure PCTCN2021091102-appb-000015
for
Figure PCTCN2021091102-appb-000016
In another specific embodiment,
Figure PCTCN2021091102-appb-000017
for
Figure PCTCN2021091102-appb-000018
In another specific embodiment,
Figure PCTCN2021091102-appb-000019
for
Figure PCTCN2021091102-appb-000020
In another specific embodiment,
Figure PCTCN2021091102-appb-000021
for
Figure PCTCN2021091102-appb-000022
In another specific embodiment,
Figure PCTCN2021091102-appb-000023
for
Figure PCTCN2021091102-appb-000024
In another specific embodiment,
Figure PCTCN2021091102-appb-000025
for
Figure PCTCN2021091102-appb-000026
In another specific embodiment,
Figure PCTCN2021091102-appb-000027
for
Figure PCTCN2021091102-appb-000028
In another specific embodiment,
Figure PCTCN2021091102-appb-000029
for
Figure PCTCN2021091102-appb-000030
In another specific embodiment,
Figure PCTCN2021091102-appb-000031
for
Figure PCTCN2021091102-appb-000032
In another specific embodiment,
Figure PCTCN2021091102-appb-000033
for
Figure PCTCN2021091102-appb-000034
Figure PCTCN2021091102-appb-000035
In another specific embodiment,
Figure PCTCN2021091102-appb-000036
for
Figure PCTCN2021091102-appb-000037
L 1 L 1
L 1为-H 1-H 2-H 3-H 4-，其中H 1选自-O-、-S-、-N(R H’)-、-C(R H)(R H)-、-C(R H)(R H)-C(R H)(R H)-或-C(R H)(R H)-C(R H)(R H)-C(R H)(R H)-，H 2、H 3和H 4独立地选自-O-、-S-、-N(R H’)-或-C(R H)(R H)-。在一个具体实施方案中，L 1为-C-C-C-N-骨架；在另一个具体实施方案中，L 1为-N-C-C-N-骨架；在另一个具体实施方案中，L 1为-O-C-C-N-骨架；在另一个具体实施方案中，L 1为-S-C-C-N-骨架；在另一个具体实施方案中，L 1为-N-C-C-O-骨架；在另一个具体实施方案中，L 1为-N-C-C-S-骨架；在另一个具体实施方案中，L 1为-C-C-C-C-N-骨架；在另一个具体实施方案中，L 1为-C-C-C-C-C-N-骨架。 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 )-. In a specific embodiment, 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.
在另一个具体实施方案中，H 1为-O-；在另一个具体实施方案中，H 1为-S-；在另一个具体实施方案中，H 1为-N(R H’)-；在另一个具体实施方案中，H 1为-C(R H)(R H)-；在另一个具体实施方案中，H 1为-C(R H)(R H)-C(R H)(R H)-；在另一个具体实施方案中，H 1为-C(R H)(R H)-C(R H)(R H)-C(R H)(R H)-； In another specific embodiment, 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 )-;
在另一个具体实施方案中，H 2为-O-；在另一个具体实施方案中，H 2为-S-；在另一个具体实施方案中，H 2为-N(R H’)-；在另一个具体实施方案中，H 2为-C(R H)(R H)-； In another specific embodiment, 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 )-;
在另一个具体实施方案中，H 3为-O-；在另一个具体实施方案中，H 3为-S-；在另一个具体实施方案中，H 3为-N(R H’)-；在另一个具体实施方案中，H 3为-C(R H)(R H)-； In another specific embodiment, 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 )-;
在另一个具体实施方案中，H 4为-O-；在另一个具体实施方案中，H 4为-S-；在另一个具体实施方案中，H 4为-N(R H’)-；在另一个具体实施方案中，H 4为-C(R H)(R H)-。 In another specific embodiment, 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 )-.
在另一个具体实施方案中，H 1和H 3上的一对R H/R H’取代基可以结合形成C 1-3亚烷基；在另一个具体实施方案中，H 1和H 4上的一对R H/R H’取代基可以结合形成C 1-3亚烷基；在另一个具体实施方案中，H 2和H 4上的一对R H/R H’取代基可以结合形成C 1-3亚烷基。 In another specific embodiment, 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.
在另一个具体实施方案中，L 1为
Figure PCTCN2021091102-appb-000038
在另一个具体实施方案中，L 1为
Figure PCTCN2021091102-appb-000039
在另一个具体实施方案中，L 1为
Figure PCTCN2021091102-appb-000040
在另一个具体实施方案中，L 1为
Figure PCTCN2021091102-appb-000041
在另一个具体实施方案中，L 1为
Figure PCTCN2021091102-appb-000042
在另一个具体实施方案中，L 1为
Figure PCTCN2021091102-appb-000043
在另一个具体实施方案中，L 1为
Figure PCTCN2021091102-appb-000044
在另一个具体实施方案中，L 1为
Figure PCTCN2021091102-appb-000045
在另一个具体实施方案中，L 1为
Figure PCTCN2021091102-appb-000046
在另一个具体实施方案中，L 1为
Figure PCTCN2021091102-appb-000047
在另一个具体实施方案中，L 1为
Figure PCTCN2021091102-appb-000048
在另一个具体实施方案中，L 1为
Figure PCTCN2021091102-appb-000049
在另一个具体实施方案中，L 1为
Figure PCTCN2021091102-appb-000050
在另一个具体实施方案中，L 1为
Figure PCTCN2021091102-appb-000051
In another specific embodiment, L 1 is
Figure PCTCN2021091102-appb-000038
In another specific embodiment, L 1 is
Figure PCTCN2021091102-appb-000039
In another specific embodiment, L 1 is
Figure PCTCN2021091102-appb-000040
In another specific embodiment, L 1 is
Figure PCTCN2021091102-appb-000041
In another specific embodiment, L 1 is
Figure PCTCN2021091102-appb-000042
In another specific embodiment, L 1 is
Figure PCTCN2021091102-appb-000043
In another specific embodiment, L 1 is
Figure PCTCN2021091102-appb-000044
In another specific embodiment, L 1 is
Figure PCTCN2021091102-appb-000045
In another specific embodiment, L 1 is
Figure PCTCN2021091102-appb-000046
In another specific embodiment, L 1 is
Figure PCTCN2021091102-appb-000047
In another specific embodiment, L 1 is
Figure PCTCN2021091102-appb-000048
In another specific embodiment, L 1 is
Figure PCTCN2021091102-appb-000049
In another specific embodiment, L 1 is
Figure PCTCN2021091102-appb-000050
In another specific embodiment, L 1 is
Figure PCTCN2021091102-appb-000051
R 1 R 1
在一个具体实施方案中，R 1为C 1-6卤代烷基；在另一个具体实施方案中，R 1为卤代甲基，优选氯甲基；在另一个具体实施方案中，R 1为
Figure PCTCN2021091102-appb-000052
其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基、 C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2；其任选被R’取代；并且R a和R b可以形成化学键从而使得双键变为叁键。 In a specific embodiment, R 1 is C 1-6 haloalkyl; in another specific embodiment, R 1 is halomethyl, preferably chloromethyl; in another specific embodiment, R 1 is
Figure PCTCN2021091102-appb-000052
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.
在一个具体实施方案中，R 1为
Figure PCTCN2021091102-appb-000053
在另一个具体实施方案中，R 1为
Figure PCTCN2021091102-appb-000054
在另一个具体实施方案中，R 1为
Figure PCTCN2021091102-appb-000055
在另一个具体实施方案中，R 1为
Figure PCTCN2021091102-appb-000056
In a specific embodiment, R 1 is
Figure PCTCN2021091102-appb-000053
In another specific embodiment, R 1 is
Figure PCTCN2021091102-appb-000054
In another specific embodiment, R 1 is
Figure PCTCN2021091102-appb-000055
In another specific embodiment, R 1 is
Figure PCTCN2021091102-appb-000056
L 2 L 2
在一个具体实施方案中，L 2为化学键；在另一个具体实施方案中，L 2为-O-(C(R L2)(R L2)) p-；在另一个具体实施方案中，L 2为-S-(C(R L2)(R L2)) p-；在另一个具体实施方案中，L 2为-N(R L2’)-(C(R L2)(R L2)) p-；在另一个具体实施方案中，L 2为-(C(R L2)(R L2)) p-；在另一个具体实施方案中，L 2为-O-；在另一个具体实施方案中，L 2为-OCH 2-；在另一个具体实施方案中，L 2为-OCH 2CH 2-；在另一个具体实施方案中，L 2为-OCH 2CH 2CH 2-；在另一个具体实施方案中，L 2为-NH-；在另一个具体实施方案中，L 2为-NHCH 2-；在另一个具体实施方案中，L 2为-NHCH 2CH 2-；在另一个具体实施方案中，L 2为-NHCH 2CH 2CH 2-；在另一个具体实施方案中，L 2为-NMeCH 2CH 2-；在另一个具体实施方案中，L 2为-CH 2CH 2-；在另一个具体实施方案中，L 2为-O-、-OCH 2-、-OCH 2CH 2-、-OCH 2CH 2CH 2-、-NH-、-NHCH 2-、-NHCH 2CH 2-或-NHCH 2CH 2CH 2-。 In a specific embodiment, 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 -NHCH 2 CH 2 -; in another specific embodiment In the scheme, L 2 is -NHCH 2 CH 2 CH 2 -; in another specific embodiment, L 2 is -NMeCH 2 CH 2 -; in another specific embodiment, L 2 is -CH 2 CH 2- ; In another specific embodiment, L 2 is -O-, -OCH 2 -, -OCH 2 CH 2 -, -OCH 2 CH 2 CH 2 -, -NH-, -NHCH 2 -, -NHCH 2 CH 2 -or -NHCH 2 CH 2 CH 2 -.
在一个更具体的实施方案中，p＝0；在另一个更具体的实施方案中，p＝1；在另一个更具体的实施方案中，p＝2；在另一个更具体的实施方案中，p＝3；在另一个更具体的实施方案中，p＝4。In a more specific embodiment, p=0; in another more specific embodiment, p=1; in another more specific embodiment, p=2; in another more specific embodiment , P=3; in another more specific embodiment, p=4.
R 2 R 2
在一个具体实施方案中，R 2为H；在另一个具体实施方案中，R 2为D；在另一个具体实施方案中，R 2为卤素；在另一个具体实施方案中，R 2为-CN；在另一个具体实施方案中，R 2为-NO 2；在另一个具体实施方案中，R 2为C 1-6烷基；在另一个具体实施方案中，R 2为C 1-6卤代烷基；在另一个具体实施方案中，R 2为C 2-6烯基；在另一个具体实施方案中，R 2为C 2-6炔基；在另一个具体实施方案中，R 2为-O-R 1a；在另一个具体实施方案中，R 2为-N(R 1a) 2；在另一个具体实施方案中，R 2为C 3-10环烷基；在另一个具体实施方案中，R 2为3-10元杂环基；在另一个具体实施方案中，R 2为C 6-10芳基；在另一个具体实施方案中，R 2为5-14元杂芳基；；在另一个具体实施方案中，R 2被r个R取代。 In a specific embodiment, 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.
在另一个具体实施方案中，R 2为
Figure PCTCN2021091102-appb-000057
在另一个具体实施方案中，R 2为
Figure PCTCN2021091102-appb-000058
In another specific embodiment, R 2 is
Figure PCTCN2021091102-appb-000057
In another specific embodiment, R 2 is
Figure PCTCN2021091102-appb-000058
在另一个具体实施方案中，-L 2-R 2为
Figure PCTCN2021091102-appb-000059
Figure PCTCN2021091102-appb-000060
In another specific embodiment, -L 2 -R 2 is
Figure PCTCN2021091102-appb-000059
Figure PCTCN2021091102-appb-000060
Figure PCTCN2021091102-appb-000061
Figure PCTCN2021091102-appb-000061
L 3 L 3
在一个具体实施方案中，L 3为化学键；在另一个具体实施方案中，L 3为-(C(R L3)(R L3)) p-；在另一个具体实施方案中，L 3为-CH 2-；在另一个具体实施方案中，L 3为-CH 2CH 2-。 In a specific embodiment, 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 R 3
在一个具体实施方案中，R 3为H；在另一个具体实施方案中，R 3为D；在另一个具体实施方案中，R 3为卤素；在另一个具体实施方案中，R 3为-CN；在另一个具体实施方案中，R 3为-NO 2；在另一个具体实施方案中，R 3为C 1-6烷基；在另一个具体实施方案中，R 3为C 1-6卤代烷基；在另一个具体实施方案中，R 3为C 2-6烯基；在另一个具体实施方案中，R 3为C 2-6炔基；在另一个具体实施方案中，R 3为-N(R 1a) 2；在另一个具体实施方案中，R 3为C 3-10环烷基；在另一个具体实施方案中，R 3为3-10元杂环基；在另一个具体实施方案中，R 3为C 6-10芳基；在另一个具体实施方案中，R 3为5-14元杂芳基；在另一个具体实施方案中，R 3被r个R取代。 In a specific embodiment, 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.
在另一个具体实施方案中，R 3为
Figure PCTCN2021091102-appb-000062
在另一个具体实施方案中，R 3为
Figure PCTCN2021091102-appb-000063
In another specific embodiment, R 3 is
Figure PCTCN2021091102-appb-000062
In another specific embodiment, R 3 is
Figure PCTCN2021091102-appb-000063
RR
在一个具体实施方案中，R为H；在另一个具体实施方案中，R为D；在另一个具体实施方案中，R为C 0-6亚烷基-卤素；在另一个具体实施方案中，R为C 0-6亚烷基-CN；在另一个具体实施方案中，R为C 0-6亚烷基-SF 5；在另一个具体实施方案中，R为C 0-6亚烷基-NO 2；在另一个具体实施方案中，R为C 1-6烷基；在另一个具体实施方案中，R为C 1-6卤代烷基；在另一个具体实施方案中，R为C 2-6烯基；在另一个具体实施方案中，R为C 2-6炔基；在另一个具体实施方案中，R为C 0-6亚烷基-O-R 1a；在另一个具体实施方案中，R为C 0-6亚烷基-S-R 1a；在另一个具体实施方案中，R为C 0-6亚烷基-N(R 1a) 2；在另一个具体实施方案中，R为 C 0-6亚烷基-C(O)R 1a；在另一个具体实施方案中，R为C 0-6亚烷基-C(O)OR 1a；在另一个具体实施方案中，R为C 0-6亚烷基-C(O)N(R 1a) 2；在另一个具体实施方案中，R为C 0-6亚烷基-S(O) mR 1a；在另一个具体实施方案中，R为C 0-6亚烷基-C 3-10环烷基；在另一个具体实施方案中，R为C 0-6亚烷基-3-10元杂环基；在另一个具体实施方案中，R为C 0-6亚烷基-C 6-10芳基；在另一个具体实施方案中，R为C 0-6亚烷基-5-14元杂芳基。 In a specific embodiment, 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 alkylene-C(O)OR 1a ; in another specific embodiment, R is C 0-6 alkylene-C(O)N(R 1a ) 2 ; in another embodiment, R is C 0-6 alkylene-S(O) m R 1a ; in another embodiment In the scheme, R is C 0-6 alkylene-C 3-10 cycloalkyl; in another specific embodiment, R is C 0-6 alkylene-3-10 membered heterocyclyl; in another In a specific embodiment, R is C 0-6 alkylene-C 6-10 aryl; in another specific embodiment, R is C 0-6 alkylene-5-14 membered heteroaryl.
rr
在一个具体实施方案中，r＝0；在另一个具体实施方案中，r＝1；在另一个具体实施方案中，r＝2；在另一个具体实施方案中，r＝3；在另一个具体实施方案中，r＝4；在另一个具体实施方案中，r＝5；在另一个具体实施方案中，r＝6；在另一个具体实施方案中，r＝7。In one specific embodiment, r=0; in another specific embodiment, r=1; in another specific embodiment, r=2; in another specific embodiment, r=3; in another specific embodiment, r=3; In a specific embodiment, r=4; in another specific embodiment, r=5; in another specific embodiment, r=6; in another specific embodiment, r=7.
R 4 R 4
在一个具体实施方案中，R 4为H；在另一个具体实施方案中，R 4为D；在另一个具体实施方案中，R 4为卤素，优选Cl和F，更优选Cl；在另一个具体实施方案中，R 4为-CN；在另一个具体实施方案中，R 4为-SF 5；在另一个具体实施方案中，R 4为C 1-6烷基；在另一个具体实施方案中，R 4为C 1-6卤代烷基；在另一个具体实施方案中，R 4为C 2-6烯基；在另一个具体实施方案中，R 4为C 2-6炔基；在另一个具体实施方案中，R 4为-O-R 1a；在另一个具体实施方案中，R 4为-S-R 1a；在另一个具体实施方案中，R 4为-N(R 1a) 2；在另一个具体实施方案中，R 4为C 3-10环烷基；在另一个具体实施方案中，R 4为C 3-10卤代环烷基；在另一个具体实施方案中，R 4为3-10元杂环基；在另一个具体实施方案中，R 4为3-10元卤代杂环基；在另一个具体实施方案中，R 4为C 6-10芳基；在另一个具体实施方案中，R 4为5-14元杂芳基。 In a specific embodiment, 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 embodiment, R 4 is 3- 10-membered heterocyclyl; in another specific embodiment, R 4 is a 3-10 membered halogenated heterocyclic group; in another specific embodiment, R 4 is C 6-10 aryl; in another specific embodiment In the scheme, R 4 is a 5-14 membered heteroaryl group.
Z 1和Z 2 Z 1 and Z 2
在一个具体实施方案中，Z 1为CR 5；在另一个具体实施方案中，Z 1为N。 In a specific embodiment, Z 1 is CR 5 ; in another specific embodiment, Z 1 is N.
在一个具体实施方案中，Z 2为CR 5；在另一个具体实施方案中，Z 2为N。 In a specific embodiment, Z 2 is CR 5 ; in another specific embodiment, Z 2 is N.
R 5 R 5
在一个具体实施方案中，R 5独立地为H；在另一个具体实施方案中，R 5独立地为D；在另一个具体实施方案中，R 5独立地为卤素；在另一个具体实施方案中，R 5独立地为-CN；在另一个具体实施方案中，R 5独立地为C 1-6烷基；在另一个具体实施方案中，R 5独立地为C 1-6卤代烷基；在另一个具体实施方案中，R 5独立地为C 2-6烯基；在另一个具体实施方案中，R 5独立地为C 2-6炔基；在另一个具体实施方案中，R 5独立地为-O-R 1a；在另一个具体实施方案中，R 5独立地为-S-R 1a；在另一个具体实施方案中，R 5独立地为-N(R 1a) 2。 In a specific embodiment, 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 .
R 7 R 7
在一个具体实施方案中，R 7为H；在另一个具体实施方案中，R 7与-L 3-R 3形成双键；在另一个具体实施方案中，R 7与-L 2-R 2形成＝Z；在另一个具体实施方案中，R 7与-L 2-R 2形成＝O；在另一个具体实施方案中，R 7与-L 2-R 2形成＝S。 In a specific embodiment, R 7 is H; in another specific embodiment, R 7 and -L 3 -R 3 form a double bond; in another specific embodiment, R 7 and -L 2 -R 2 Form = Z; in another specific embodiment, R 7 and -L 2 -R 2 form =O; in another specific embodiment, R 7 and -L 2 -R 2 form =S.
以上任一具体实施方案中的任一技术方案或其任意组合，可以与其它具体实施方案中的任一技术方案或其任意组合进行组合。例如，R 1的任一技术方案或其任意组合，可以与L 1、L 2、L 3、R 2、R 3、R 4、R 5、R 6、R 7、m和n等的任一技术方案或其任意组合进行组合。本发明旨在包括所有这些技术方案的组合，限于篇幅，不再一一列出。 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. For example, 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.
在更具体的实施方案中，本发明提供了上述(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，R 6独立地为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基或-O-R 1a；优选地，R 6独立地为-O-R 1a、优选-OH；优选地，至少一个R 6为非H基团。 In a more specific embodiment, 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.
在更具体的实施方案中，本发明提供了上述(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，In a more specific embodiment, 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,
其中，
Figure PCTCN2021091102-appb-000064
为
Figure PCTCN2021091102-appb-000065
其中Z 3、Z 4和Z 5独立地为CR 6或N；环B为苯基或5-6元杂芳基； in,
Figure PCTCN2021091102-appb-000064
for
Figure PCTCN2021091102-appb-000065
Wherein Z 3 , Z 4 and Z 5 are independently CR 6 or N; ring B is phenyl or 5-6 membered heteroaryl;
优选地，
Figure PCTCN2021091102-appb-000066
为
Figure PCTCN2021091102-appb-000067
优选地为：
Figure PCTCN2021091102-appb-000068
Figure PCTCN2021091102-appb-000069
优选
Figure PCTCN2021091102-appb-000070
更优选
Figure PCTCN2021091102-appb-000071
Preferably,
Figure PCTCN2021091102-appb-000066
for
Figure PCTCN2021091102-appb-000067
Preferably:
Figure PCTCN2021091102-appb-000068
Figure PCTCN2021091102-appb-000069
Preferred
Figure PCTCN2021091102-appb-000070
More preferred
Figure PCTCN2021091102-appb-000071
在更具体的实施方案中，本发明提供了上述(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，In a more specific embodiment, 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,
其中，L 1为：
Figure PCTCN2021091102-appb-000072
Figure PCTCN2021091102-appb-000073
优选地，L 1为
Figure PCTCN2021091102-appb-000074
Among them, L 1 is:
Figure PCTCN2021091102-appb-000072
Figure PCTCN2021091102-appb-000073
Preferably, L 1 is
Figure PCTCN2021091102-appb-000074
在更具体的实施方案中，本发明提供了上述(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，In a more specific embodiment, 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,
其中，R 1为
Figure PCTCN2021091102-appb-000075
优选地，R 1为
Figure PCTCN2021091102-appb-000076
Where R 1 is
Figure PCTCN2021091102-appb-000075
Preferably, R 1 is
Figure PCTCN2021091102-appb-000076
在更具体的实施方案中，本发明提供了上述(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，In a more specific embodiment, 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,
其中，L 2为化学键、-O-、-OCH 2-、-OCH 2CH 2-、-OCH 2CH 2CH 2-、-NH-、-NHCH 2-、-NHCH 2CH 2-、-NHCH 2CH 2CH 2-、-NMeCH 2CH 2-或-CH 2CH 2-，优选-OCH 2-或-OCH 2CH 2-；L 3为-CH 2-或-CH 2CH 2-。 Among them, 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 -.
在更具体的实施方案中，本发明提供了上述(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，In a more specific embodiment, 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,
其中，R 2或R 3为H、-N(R 1a) 2、C 3-6环烷基、4-7元杂环基、苯基或5-6元杂芳基，优选-NMe 2、
Figure PCTCN2021091102-appb-000077
Figure PCTCN2021091102-appb-000078
Figure PCTCN2021091102-appb-000079
优选H、
Figure PCTCN2021091102-appb-000080
Among them, 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 ,
Figure PCTCN2021091102-appb-000077
Figure PCTCN2021091102-appb-000078
Figure PCTCN2021091102-appb-000079
Preferred H,
Figure PCTCN2021091102-appb-000080
优选地，R 2或R 3被1-3个R取代，其中R选自C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-SF 5、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a、C 0-6亚烷基-C(O)N(R 1a) 2、C 0-6亚烷基-S(O) mR 1a、C 0-6亚烷基-C 3-10环烷基、C 0-6亚烷基-3-10元杂环基、C 0-6亚烷基-C 6-10芳基或C 0-6亚烷基-5-14元杂芳基。 Preferably, 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-C 6-10 aryl or C 0-6 alkylene-5-14-membered heteroaryl.
在更具体的实施方案中，本发明提供了上述(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，In a more specific embodiment, 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,
其中，R 4为H、卤素、-CN、-SF 5、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基或C 3-10卤代环烷基，优选卤素，更优选Cl。 Wherein, 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.
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中：In a more specific embodiment, 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:
Figure PCTCN2021091102-appb-000081
选自
Figure PCTCN2021091102-appb-000082
Figure PCTCN2021091102-appb-000081
Selected from
Figure PCTCN2021091102-appb-000082
L 1为-H 1-H 2-H 3-H 4-； L 1 is -H 1 -H 2 -H 3 -H 4 -;
其中H 1为-C(R H)(R H)-，H 2、H 3和H 4独立地选自-O-、-S-、-N(R H’)-或-C(R H)(R H)-； Wherein 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 )-;
并且，H 1和H 3上的R H/R H’取代基、H 1和H 4上的R H/R H’取代基、和H 2和H 4上的R H/R H’取代基中的一对或两对R H/R H’取代基可以结合形成C 1-3亚烷基； And, H 1 and H R H on 3 / R H 'substituent group, H 1 and H R H on 4 / R H' substituent group, and H 2 and H R H on 4 / R H 'substituent One or two pairs of R H /R H'substituents can be combined to form a C 1-3 alkylene group;
R H为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a或C 0-6亚烷基-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R H'is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R 1为
Figure PCTCN2021091102-appb-000083
R 1 is
Figure PCTCN2021091102-appb-000083
其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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 ;
并且R a和R b可以形成化学键从而使得双键变为叁键； And R a and R b can form a chemical bond so that the double bond becomes a triple bond;
L 2为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-、-N(R L2’)-(C(R L2)(R L2)) p-或-(C(R L2)(R L2)) p-； 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 -;
其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
并且，R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, R L2 /R L2' may be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
R 2为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被r个R取代； 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. C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by r R;
其中R为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-SF 5、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a、C 0-6亚烷基-C(O)N(R 1a) 2、C 0-6亚烷基-S(O) mR 1a、C 0-6亚烷基-C 3-10环烷基、C 0-6亚烷基-3-10元杂环基、C 0-6亚烷基-C 6-10芳基或C 0-6亚烷基-5-14元杂芳基； Wherein 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 6-10 aryl or C 0-6 alkylene-5-14-membered heteroaryl;
r＝0、1、2、3、4、5、6或7；r=0, 1, 2, 3, 4, 5, 6 or 7;
m＝1或2；m=1 or 2;
R 4为H、D、卤素、-CN、-SF 5、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基； 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为CR 5； Z 1 is CR 5 ;
Z 2为CR 5； Z 2 is CR 5 ;
其中R 5独立地为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； Wherein 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与-L 3-R 3形成双键； R 7 and -L 3 -R 3 form a double bond;
R 1a为H、-C(O)H、-C(O)OH、-C(O)C 1-6烷基、-C(O)OC 1-6烷基、-S(O) mC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基。 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.
在更具体的实施方案中，本发明提供了上述(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有以下结 构：In a more specific embodiment, 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:
Figure PCTCN2021091102-appb-000084
Figure PCTCN2021091102-appb-000084
其中，in,
环B为苯基或5-6元杂芳基；Ring B is phenyl or 5-6 membered heteroaryl;
R N1、R N2和R N3独立地为H、C 1-6烷基或C 1-6卤代烷基；或者，R N2和R N3可以结合形成C 2-4亚烷基； 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;
其他基团如上文所定义。The other groups are as defined above.
在更具体的实施方案中，本发明提供了式(I-1)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：In a more specific embodiment, 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:
Figure PCTCN2021091102-appb-000085
Figure PCTCN2021091102-appb-000085
其中，in,
环B为苯基或5-6元杂芳基；Ring B is phenyl or 5-6 membered heteroaryl;
R 6独立地为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a或C 0-6亚烷基-N(R 1a) 2，并且其中至少一个R 6为-OH； 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或7；n=0, 1, 2, 3, 4, 5, 6 or 7;
L 1为-H 1-H 2-H 3-H 4-； L 1 is -H 1 -H 2 -H 3 -H 4 -;
其中H 1为-C(R H)(R H)-，H 2、H 3和H 4独立地选自-O-、-S-、-N(R H’)-或-C(R H)(R H)-； Wherein 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 )-;
并且，H 1和H 3上的R H/R H’取代基、H 1和H 4上的R H/R H’取代基、和H 2和H 4上的R H/R H’取代基中的一对或两对R H/R H’取代基可以结合形成C 1-3亚烷基； And, H 1 and H R H on 3 / R H 'substituent group, H 1 and H R H on 4 / R H' substituent group, and H 2 and H R H on 4 / R H 'substituent One or two pairs of R H /R H'substituents can be combined to form a C 1-3 alkylene group;
R H为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a或C 0-6亚烷基-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R H'is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R 1为
Figure PCTCN2021091102-appb-000086
R 1 is
Figure PCTCN2021091102-appb-000086
其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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 ;
并且R a和R b可以形成化学键从而使得双键变为叁键； And R a and R b can form a chemical bond so that the double bond becomes a triple bond;
L 2为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-、-N(R L2’)-(C(R L2)(R L2)) p-或-(C(R L2)(R L2)) p-； 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 -;
其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
并且，R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, R L2 /R L2' can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
R 2为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被r个R取代； 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. C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by r R;
其中R为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-SF 5、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a、C 0-6亚烷基-C(O)N(R 1a) 2、C 0-6亚烷基-S(O) mR 1a、C 0-6亚烷基-C 3-10环烷基、C 0-6亚烷基-3-10元杂环基、C 0-6亚烷基-C 6-10芳基或C 0-6亚烷基-5-14元杂芳基； Wherein 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 6-10 aryl or C 0-6 alkylene-5-14-membered heteroaryl;
r＝0、1、2、3、4、5、6或7；r=0, 1, 2, 3, 4, 5, 6 or 7;
R 4为H、D、卤素、-CN、-SF 5、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基； 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独立地为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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 ;
m＝1或2；m=1 or 2;
R 1a为H、-C(O)H、-C(O)OH、-C(O)C 1-6烷基、-C(O)OC 1-6烷基、-S(O) mC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基。 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.
在更具体的实施方案中，本发明提供了上述式(I-1)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，In a more specific embodiment, the present invention provides the above-mentioned compound of formula (I-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or solvate thereof. Compounds, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein,
环B为苯基；Ring B is phenyl;
R 6独立地为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a或C 0-6亚烷基-N(R 1a) 2，并且其中至少一个R 6为-OH； 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或7；n=0, 1, 2, 3, 4, 5, 6 or 7;
L 1为
Figure PCTCN2021091102-appb-000087
L 1 is
Figure PCTCN2021091102-appb-000087
R 1为
Figure PCTCN2021091102-appb-000088
R 1 is
Figure PCTCN2021091102-appb-000088
其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基或C 1-6卤代烷基；并且R a和R b可以形成化学键从而使得双键变为叁键； Wherein 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为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-或-N(R L2’)-(C(R L2)(R L2)) p-； 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 -;
其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
并且，R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, R L2 /R L2' can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
R 2为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被r个R取代； 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. C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by r R;
其中R为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-SF 5、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a或C 0-6亚烷基-C(O)N(R 1a) 2； Wherein 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基-C(O)N(R 1a ) 2 ;
r＝0、1、2、3、4、5、6或7；r=0, 1, 2, 3, 4, 5, 6 or 7;
R 4为H、D、卤素、-CN或-SF 5； R 4 is H, D, halogen, -CN or -SF 5 ;
R 5独立地为H、D、卤素、-CN、C 1-6烷基或C 1-6卤代烷基； R 5 is independently H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl;
m＝1或2；m=1 or 2;
R 1a为H、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基。 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.
在更具体的实施方案中，本发明提供了上述式(I-1)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，In a more specific embodiment, the present invention provides the above-mentioned compound of formula (I-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, or solvate thereof. Compounds, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein,
环B为苯基；Ring B is phenyl;
R 6独立地为H、D、卤素、-CN、-OH、-SH或-NH 2，并且其中至少一个R 6为-OH； 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或3；n=0, 1, 2 or 3;
L 1为
Figure PCTCN2021091102-appb-000089
L 1 is
Figure PCTCN2021091102-appb-000089
R 1为
Figure PCTCN2021091102-appb-000090
R 1 is
Figure PCTCN2021091102-appb-000090
其中R a、R b和R c独立地选自H、D、卤素或-CN； Wherein R a , R b and R c are independently selected from H, D, halogen or -CN;
L 2为化学键、-O-(C(R L2)(R L2)) p-或-N(R L2’)-(C(R L2)(R L2)) p-； L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -or -N(R L2' )-(C(R L2 )(R L2 )) p -;
其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
R L2为H、D、卤素、C 1-6烷基或C 1-6卤代烷基； R L2 is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R L2’为H； R L2' is H;
并且，R L2/R L2’可以结合形成C 3-6环烷基或4-7元杂环基； In addition, R L2 /R L2' may be combined to form a C 3-6 cycloalkyl group or a 4-7 membered heterocyclic group;
R 2为C 1-6烷基、C 1-6卤代烷基、-OH、-N(R 1a) 2、C 3-6环烷基、4-7元杂环基、C 6-10芳基或5-6元杂芳基；其任选被r个R取代； 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;
其中R为H、D、卤素、C 1-6烷基、C 1-6卤代烷基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2； Wherein 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或7；r=0, 1, 2, 3, 4, 5, 6 or 7;
R 4为卤素； R 4 is halogen;
R 5独立地为H、D或卤素； R 5 is independently H, D or halogen;
m＝1或2；m=1 or 2;
R 1a为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了式(II)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：In a more specific embodiment, 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:
Figure PCTCN2021091102-appb-000091
Figure PCTCN2021091102-appb-000091
其中，in,
环B为苯基或5-6元杂芳基；Ring B is phenyl or 5-6 membered heteroaryl;
R 6独立地为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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或5；n=0, 1, 2, 3, 4 or 5;
R 1为C 1-6卤代烷基或
Figure PCTCN2021091102-appb-000092
R 1 is C 1-6 haloalkyl or
Figure PCTCN2021091102-appb-000092
其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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 ;
其任选被R’取代；并且R a和R b可以形成化学键从而使得双键变为叁键； Optionally R 'group; and R a and R b may form a chemical bond so that the triple bond becomes a double bond;
R’为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-、-N(R L2’)-(C(R L2)(R L2)) p-或-(C(R L2)(R L2)) p-； 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 -;
其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
并且，相邻原子上的R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, 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为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被1-7个R取代； 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. C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by 1-7 R;
其中R为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基； Where 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为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 3-10环烷基或3-10元杂环基； 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为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了式(III)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：In a more specific embodiment, 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:
Figure PCTCN2021091102-appb-000093
Figure PCTCN2021091102-appb-000093
其中，in,
R 1为C 1-6卤代烷基或
Figure PCTCN2021091102-appb-000094
R 1 is C 1-6 haloalkyl or
Figure PCTCN2021091102-appb-000094
其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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 ;
其任选被R’取代；并且R a和R b可以形成化学键从而使得双键变为叁键； Optionally R 'group; and R a and R b may form a chemical bond so that the triple bond becomes a double bond;
R’为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-、-N(R L2’)-(C(R L2)(R L2)) p-或-(C(R L2)(R L2)) p-； 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 -;
其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
并且，相邻原子上的R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, 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为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被1-7个R取代； 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. C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by 1-7 R;
其中R为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基； Where 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为卤素、-CN或-NO 2； R 4 is halogen, -CN or -NO 2 ;
R 6为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 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为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了式(III)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中In a more specific embodiment, 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为C 1-6卤代烷基或
Figure PCTCN2021091102-appb-000095
R 1 is C 1-6 haloalkyl or
Figure PCTCN2021091102-appb-000095
其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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 ;
并且R a和R b可以形成化学键从而使得双键变为叁键； And R a and R b can form a chemical bond so that the double bond becomes a triple bond;
L 2为化学键、-O-(C(R L2)(R L2)) p-或-N(R L2’)-(C(R L2)(R L2)) p-； L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -or -N(R L2' )-(C(R L2 )(R L2 )) p -;
其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基或C 1-6卤代烷基； R L2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl or C 1-6 haloalkyl;
R L2’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R 2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基或3-10元杂环基；其任选被1-5个R取代； 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. C 3-10 cycloalkyl or 3-10 membered heterocyclic group; it is optionally substituted by 1-5 R;
其中R为H、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 1-6烷基或C 1-6卤代烷基； Wherein R is H, -OR 1a , -SR 1a , -N(R 1a ) 2 , C 1-6 alkyl or C 1-6 haloalkyl;
R 4为卤素； R 4 is halogen;
R 6为卤素、-CN、-NO 2或-O-R 1a，优选-OH； R 6 is halogen, -CN, -NO 2 or -OR 1a , preferably -OH;
R 1a为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了式(IV)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：In a more specific embodiment, 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:
Figure PCTCN2021091102-appb-000096
Figure PCTCN2021091102-appb-000096
其中，in,
L 2为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-、-N(R L2’)-(C(R L2)(R L2)) p-或-(C(R L2)(R L2)) p-； 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 -;
其中p＝1、2、3或4；Where p = 1, 2, 3 or 4;
R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
并且，R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, R L2 /R L2' can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
R 2为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-14元杂芳基；其任选被1-5个R取代； 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;
其中R为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-SF 5、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a、C 0-6亚烷基-C(O)N(R 1a) 2、C 0-6亚烷基-S(O) mR 1a、C 0-6亚烷基-C 3-10环烷基、C 0-6亚烷基-3-10元杂环基、C 0-6亚烷基-C 6-10芳基或C 0-6亚烷基-5-14元杂芳基； Wherein 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 6-10 aryl or C 0-6 alkylene-5-14-membered heteroaryl;
其中m＝1或2；Where m=1 or 2;
R 4为卤素、-CN或-NO 2； R 4 is halogen, -CN or -NO 2 ;
R 6为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 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和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2；并且R a和R b可以形成化学键从而使得双键变为叁键； 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为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(IV)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，In a more specific embodiment, 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为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-或-N(R L2’)-(C(R L2)(R L2)) p-； 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 -;
其中p＝1、2、3或4；Where p = 1, 2, 3 or 4;
R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； 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’为H、C 1-6烷基或C 1-6卤代烷基； R L2' is H, C 1-6 alkyl or C 1-6 haloalkyl;
并且，R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, R L2 /R L2' can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
R 2为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被1-5个R取代； 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;
其中R为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-SF 5、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a或C 0-6亚烷基-N(R 1a) 2； Where 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为卤素、-CN或-NO 2； R 4 is halogen, -CN or -NO 2 ;
R 6为卤素、-CN、-NO 2、-OH、-SH或-NH 2； R 6 is halogen, -CN, -NO 2 , -OH, -SH or -NH 2 ;
R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基或C 1-6卤代烷基；并且R a和R b可以形成化学键从而使得双键变为叁键； 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为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(IV)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，In a more specific embodiment, 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为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-或-N(R L2’)-(C(R L2)(R L2)) p-； 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 -;
其中p＝1、2、3或4；Where p = 1, 2, 3 or 4;
R L2为H、D、卤素、C 1-6烷基或C 1-6卤代烷基； R L2 is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R L2’为H； R L2' is H;
并且，R L2/R L2’可以结合形成C 3-6环烷基或4-7元杂环基； In addition, R L2 /R L2' may be combined to form a C 3-6 cycloalkyl group or a 4-7 membered heterocyclic group;
R 2为C 1-6烷基、C 1-6卤代烷基、-N(R 1a) 2、C 3-6环烷基、4-7元杂环基、C 6-10芳基、5-6元杂芳基；其任选被1-2个R取代； 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;
其中R为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基或-N(R 1a) 2； Wherein R is H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl or -N(R 1a ) 2 ;
R 4为卤素； R 4 is halogen;
R 6为-OH； R 6 is -OH;
R a、R b和R c独立地选自H、D、卤素或-CN； R a , R b and R c are independently selected from H, D, halogen or -CN;
R 1a为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了式(IV)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：In a more specific embodiment, 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:
Figure PCTCN2021091102-appb-000097
Figure PCTCN2021091102-appb-000097
其中，in,
L 2为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-、-N(R L2’)-(C(R L2)(R L2)) p-或-(C(R L2)(R L2)) p-； 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 -;
其中p＝1、2、3或4；Where p = 1, 2, 3 or 4;
R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
并且，相邻原子上的R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, 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为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-14元杂芳基；其任选被1-5个R取代； 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. C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl; it is optionally substituted by 1-5 R;
其中R为H、-N(R 1a) 2、C 1-6烷基或C 1-6卤代烷基； Wherein R is H, -N(R 1a ) 2 , C 1-6 alkyl or C 1-6 haloalkyl;
R 4为卤素、-CN或-NO 2； R 4 is halogen, -CN or -NO 2 ;
R 6为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 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和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2；并且R a和R b可以形成化学键从而使得双键变为叁键； 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为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了式(IV-1)、(IV-2)或(IV-3)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：In a more specific embodiment, 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:
Figure PCTCN2021091102-appb-000098
Figure PCTCN2021091102-appb-000098
Figure PCTCN2021091102-appb-000099
Figure PCTCN2021091102-appb-000099
其中，in,
L 2为化学键、-O-、-S-或-N(R L2’)-； L 2 is a chemical bond, -O-, -S- or -N(R L2' )-;
其中R L2’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； Wherein R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
R 4为卤素、-CN或-NO 2； R 4 is halogen, -CN or -NO 2 ;
R 6为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 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和R N3独立地为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基；或者，R N2和R N3可以结合形成C 2-4亚烷基； 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为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了式(IV-1)、(IV-2)或(IV-3)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中In a more specific embodiment, 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为化学键、-O-、-S-或-NH-，优选-O-； L 2 is a chemical bond, -O-, -S- or -NH-, preferably -O-;
R 4为卤素，优选Cl； R 4 is halogen, preferably Cl;
R 6为卤素、-CN、-NO 2或-O-R 1a，优选-OH； R 6 is halogen, -CN, -NO 2 or -OR 1a , preferably -OH;
R N1、R N2和R N3独立地为H、C 1-6烷基或C 1-6卤代烷基；或者，R N2和R N3可以结合形成C 2-4亚烷基； 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为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了以下化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中所述化合物选自：In a more specific embodiment, 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:
Figure PCTCN2021091102-appb-000100
Figure PCTCN2021091102-appb-000100
Figure PCTCN2021091102-appb-000101
Figure PCTCN2021091102-appb-000101
Figure PCTCN2021091102-appb-000102
Figure PCTCN2021091102-appb-000102
Figure PCTCN2021091102-appb-000103
Figure PCTCN2021091102-appb-000103
Figure PCTCN2021091102-appb-000104
Figure PCTCN2021091102-appb-000104
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋体混合物和富含一种或多种立体异 构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来制备。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. For example, 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.
本领域技术人员将理解，有机化合物可以与溶剂形成复合物，其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时，复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。Those skilled in the art will understand that 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.
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下，所述溶剂合物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。The term "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. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether and the like. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. 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.
术语“水合物”是指与水相结合的化合物。通常，包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此，化合物的水合物可用例如通式R·x H 2O代表，其中R是该化合物，和x是大于0的数。给定化合物可形成超过一种水合物类型，包括，例如，单水合物(x为1)、低级水合物(x是大于0且小于1的数，例如，半水合物(R·0.5 H 2O))和多水合物(x为大于1的数，例如，二水合物(R·2 H 2O)和六水合物(R·6 H 2O))。 The term "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)).
本发明化合物可以是无定形或结晶形式(多晶型)。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型物”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。The compounds of the invention may be in amorphous or crystalline form (polymorphs). In addition, 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. The term "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.
本发明还包括同位素标记的化合物(同位素变体)，它们等同于式(I)所述的那些，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如 2H、 3H、 13C、 11C、 14C、 15N、 18O、 17O、 31P、 32P、 35S、 18F和 36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如 3H和 14C)的那些可用于药物和/或底物组织分布测定。氚、即 3H和碳-14、即 14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘、即 2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式(I)化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。 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. Examples of 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. The compounds of the present invention containing the above-mentioned isotopes and/or other isotopes of other atoms, their prodrugs, and the compounds or pharmaceutically acceptable salts of the prodrugs all fall within the scope of the present invention. Certain isotopically-labeled compounds of the invention, such as those incorporating radioisotopes (e.g. 3 H and 14 C), can be used for drug and/or substrate tissue distribution assays. 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. 2 H, may provide greater metabolic stability, since the therapeutic benefit, such as increased in vivo half-life or reduced dosage requirements, which in some cases may be preferred. Isotopically-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared in this way. When performing the processes disclosed in the following procedures and/or examples and preparation examples, readily available isotope-labeled reagents are used instead of non-isotopes. Labeled reagents.
此外，前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。药学上可接受的前药描述于T.Higuchi和V.Stella，Prodrugs as  Novel Delivery Systems，A.C.S.Symposium Series的Vol.14，Edward B.Roche，ed.，Bioreversible Carriers in Drug Design，American Pharmaceutical Association and Pergamon Press，1987，以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery：solubility limitations overcome by the use of prodrugs”，Advanced Drug Delivery Reviews(1996)19(2)115-130，每篇引入本文作为参考。In addition, 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.
前药为任何共价键合的本发明化合物，当将这种前药给予患者时，其在体内释放母体化合物。通常通过修饰官能团来制备前药，修饰是以使得该修饰可以通过常规操作或在体内裂解产生母体化合物的方式进行的。前药包括，例如，其中羟基、氨基或巯基与任意基团键合的本发明化合物，当将其给予患者时，可以裂解形成羟基、氨基或巯基。因此，前药的代表性实例包括(但不限于)式(I)化合物的羟基、巯基和氨基官能团的乙酸酯/酰胺、甲酸酯/酰胺和苯甲酸酯/酰胺衍生物。另外，在羧酸(-COOH)的情况下，可以使用酯，例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人体体内条件下水解。合适的药学上可接受的体内可水解的酯基包括容易在人体中分解而释放母体酸或其盐的那些基团。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. Therefore, representative examples of 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). In addition, in the case of carboxylic acid (-COOH), 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.
本发明还提供药物制剂，包含治疗有效量的式(I)化合物或其治疗学上可接受的盐和其药学上可接受的载体、稀释剂或赋形剂。所有这些形式都属于本发明。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.
药物组合物和试剂盒Pharmaceutical composition and kit
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的本发明化合物。在一些实施方案中，所述药物组合物包含治疗有效量的本发明化合物。在一些实施方案中，所述药物组合物包含预防有效量的本发明化合物。In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the invention.
用于本发明的药学上可接受的赋形剂是指不会破坏一起调配的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。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 lanolin.
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。The present invention also includes 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). In some embodiments, 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. In some embodiments, 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.
给药Dosing
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如，本文使 用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。The pharmaceutical composition provided by the present invention can be administered by many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, oral administration, vaginal administration Drugs, administration via implants or other modes of administration. For example, 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.
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。Generally, an effective amount of the compound provided herein is administered. According to the relevant circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient’s symptoms, etc., the doctor can determine the amount of the compound actually administered .
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。When used to prevent the conditions of the present invention, 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.
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述化合物的恒定水平，例如，在治疗窗内。The pharmaceutical compositions provided herein can also be administered chronically ("long-term administration"). 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. In some embodiments, 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.
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度提高至有效水平。推注剂量取决于通过身体的活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物组合物，而后持续输液。Various administration methods can be used to further deliver the pharmaceutical composition of the present invention. For example, in some embodiments, 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. In other embodiments, 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. In addition, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。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. The term "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. In this composition, 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.
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是两个至四个口服剂量，典型地是三个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本发明化合物，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约1至大约5mg/kg。For oral doses, the representative regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these dosing modes, 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.
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％重量，且更优选大约0.5至大约15％重量。In order to provide a blood level similar to or lower than the injected dose, 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.
从大约1至大约120小时，尤其是24至96小时，注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平，还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说，最大总剂量不能超过大约2g/天。From about 1 to about 120 hours, especially 24 to 96 hours, the injection dose level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. In order to obtain a sufficient steady-state level, a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more can also be given. For human patients of 40 to 80 kg, the maximum total dose cannot exceed approximately 2 g/day.
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖，崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。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.
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As mentioned earlier, in such compositions, 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.
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。The transdermal composition is typically formulated as a topical ointment or cream containing the active ingredients. When formulated as an ointment, the active ingredient is typically combined with paraffin or a water-miscible ointment base. Alternatively, 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.
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。The compounds of the invention can also be administered via transdermal devices. Therefore, transdermal administration can be achieved using a reservoir or porous membrane type, or a variety of solid matrix patches.
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中，本文以引用的方式引入该文献。The above-mentioned components of the composition 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.
本发明化合物还可以以持续释放形式给予，或从持续释放给药系统中给予。代表性的持续释放材料的描述可在Remington's Pharmaceutical Sciences中找到。The compounds of the present invention can also be administered in a sustained release form or from a sustained release drug delivery system. A description of representative sustained-release materials can be found in Remington's Pharmaceutical Sciences.
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation contains water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins composed of 6, 7 and 8 α-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. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol. See, for example, U.S. 5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., 10-50% in water).
药物联用Drug combination
目前本领域中已知的许多化学治疗剂可与本发明化合物组合使用。在一些实施方案中，化学治疗剂选自有丝分裂抑制剂、烷化剂、抗代谢物、嵌入抗生素、生长因子抑制剂、细胞周期抑制剂、酶、拓扑异构酶抑制剂、生物反应调节剂、抗激素、血管生成抑制剂和抗雄激素。Many chemotherapeutic agents currently known in the art can be used in combination with the compounds of the present invention. In some embodiments, 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.
实施例Example
本文所用的材料或试剂为可购买到的或由本领域通常已知的合成方法制备。The materials or reagents used herein are commercially available or prepared by synthetic methods generally known in the art.
实施例1：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氟-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮的制备Example 1: 1-((1-acryloylazetidin-3-yl)methyl)-7-fluoro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2(1H) -Preparation of ketones
Figure PCTCN2021091102-appb-000105
Figure PCTCN2021091102-appb-000105
第一步：first step:
将1-溴-2,5-二氟-4-硝基苯(5.0g，21.0mmol)溶解在乙腈(ACN)(100mL)中，加入二异丙基乙基胺(DIEA)(10.8g,83.7mmol)。0℃下，缓慢加入甘氨酸甲酯盐酸盐(2.9g，23.0mmol)。室温搅拌16小时。体系直接减压浓缩，浓缩物经中压flash硅胶柱层析(洗脱剂：乙酸乙酯:石油醚＝0-30％)分离纯化，得到N-(5-溴-4-氟-2-硝基苯基)甘氨酸甲酯(3.9g)，为黄色固体，收率53％。ESI-MS:307,309[M+H] +。 Dissolve 1-bromo-2,5-difluoro-4-nitrobenzene (5.0g, 21.0mmol) in acetonitrile (ACN) (100mL), add diisopropylethylamine (DIEA) (10.8g, 83.7mmol). At 0°C, glycine methyl ester hydrochloride (2.9 g, 23.0 mmol) was slowly added. Stir at room temperature for 16 hours. The system was directly concentrated under reduced pressure, and the concentrate was separated and purified by medium-pressure flash silica gel column chromatography (eluent: ethyl acetate: petroleum ether=0-30%) to obtain N-(5-bromo-4-fluoro-2- Nitrophenyl) glycine methyl ester (3.9 g), yellow solid, yield 53%. ESI-MS: 307,309 [M+H] + .
第二步：The second step:
将N-(5-溴-4-氟-2-硝基苯基)甘氨酸甲酯(3.9g，11.3mmol)，溶解在乙醇(60mL)和水(15mL)中。室温搅拌状态下，加入铁粉(100目，6.3g，112.5mmol)，氯化铵(6.1g，114.0mmol)，90℃反应2小时。冷却至室温后通过硅藻土过滤，滤饼用乙醇(100mL)和乙酸乙酯(100mL)洗涤，滤液减压浓缩，所得水相用乙酸乙酯(3 x 100mL)萃取，再用饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，浓缩物经中压flash硅胶柱层析(洗脱剂：甲醇:二氯甲烷＝0-10％)分离纯化，得到6-溴-7-氟-3,4-二氢喹喔啉-2(1H)-酮(2.3g)，为棕色油状液体，收率82％。ESI-MS:245,247[M+H] +。 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. After cooling to room temperature, it was filtered through Celite, the filter cake was washed with ethanol (100 mL) and ethyl acetate (100 mL), the filtrate was concentrated under reduced pressure, and the resulting aqueous phase was extracted with ethyl acetate (3 x 100 mL), and then saturated chlorinated Wash with sodium solution, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrate is separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol: dichloromethane=0-10%) to obtain 6-bromo-7- Fluoro-3,4-dihydroquinoxaline-2(1H)-one (2.3g) is a brown oily liquid with a yield of 82%. ESI-MS: 245,247[M+H] + .
第三步：third step:
将6-溴-7-氟-3,4-二氢喹喔啉-2(1H)-酮(3.1g，12.65mmol)溶解在二氯甲烷(20mL)和甲醇(20mL)中。室温下，缓慢倒入二氧化锰粉末(9.5g,109.2mmol)，搅拌16小时，通过硅藻土过滤，滤饼用甲醇:二氯甲烷(10％，200mL)洗涤，然后减压浓缩后的浓缩物经中压flash硅胶柱层析(洗脱剂：甲醇:二氯甲烷＝0-10％)分离纯化，得到6-溴-7-氟喹喔啉-2(1H)-酮(1.2g)，为白色固体，收率39％。ESI-MS:243,245[M+H] +。 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 concentrate was separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol:dichloromethane=0-10%) to obtain 6-bromo-7-fluoroquinoxaline-2(1H)-one (1.2g) ), is a white solid with a yield of 39%. ESI-MS: 243,245 [M+H] + .
第四步：the fourth step:
N2氛围下，将6-溴-7-氟喹喔啉-2(1H)-酮(260mg，1.07mmol)，3-(溴甲基)氮杂环丁烷-1-羧酸叔丁酯(535mg，2.14mmol)，碳酸钾(590mg，4.28mmol)分散在N,N-二甲基甲酰胺(DMF)(8mL)中。于室温搅拌16小时。体系用水(10mL)淬灭后，加入乙酸乙酯(100mL)，用水(3 x 20mL)洗涤，最后用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤并减压浓缩有机相后用中压flash硅胶柱层析(洗脱剂：乙酸乙酯:石油醚＝0-50％) 分离纯化，得到3-((6-溴-7-氟-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(220mg)，为浅棕色固体，收率49％。ESI-MS:412,414[M+H] +。 Under N2 atmosphere, 6-bromo-7-fluoroquinoxaline-2(1H)-one (260mg, 1.07mmol), 3-(bromomethyl)azetidine-1-carboxylic acid tert-butyl ester ( 535 mg, 2.14 mmol), potassium carbonate (590 mg, 4.28 mmol) were dispersed in N,N-dimethylformamide (DMF) (8 mL). Stir at room temperature for 16 hours. After the system was quenched with water (10mL), ethyl acetate (100mL) was added, washed with water (3 x 20mL), and finally washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Medium-pressure flash silica gel column chromatography (eluent: ethyl acetate: petroleum ether=0-50%) separation and purification to obtain 3-((6-bromo-7-fluoro-2-oxoquinoxaline-1( 2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (220 mg), as a light brown solid, with a yield of 49%. ESI-MS: 412,414 [M+H] + .
第五步：the fifth step:
N2氛围下，将3-((6-溴-7-氟-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(120mg，0.29mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)萘-2-醇(95mg，0.35mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl 2，22mg，0.03mmol)，碳酸钾(121mg，0.88mmol)分散在1,4-二氧六环/水(5:1，6mL)中。加热至100℃，搅拌2小时。体系减压浓缩后用中压flash硅胶柱层析(洗脱剂：甲醇:二氯甲烷＝0-10％)分离纯化，得到3-((7-氟-6-(3-羟基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(60mg)，为浅棕色固体，收率43％。ESI-MS:476[M+H] +。 Under N2 atmosphere, add tert-butyl 3-((6-bromo-7-fluoro-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylate (120mg , 0.29mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (95mg, 0.35mmol) , [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl 2 , 22mg, 0.03mmol), potassium carbonate (121mg, 0.88mmol) dispersed in 1,4 -Dioxane/water (5:1, 6mL). Heat to 100°C and stir for 2 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol:dichloromethane=0-10%) to obtain 3-((7-fluoro-6-(3-hydroxynaphthalene-1) -Yl)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (60 mg), as a light brown solid, with a yield of 43%. ESI-MS: 476[M+H] + .
第六步：The sixth step:
将3-((7-氟-6-(3-羟基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(60mg，0.13mmol)溶解在二氯甲烷(5mL)中。室温下，缓慢滴加三氟乙酸(0.3mL)，搅拌2小时，然后减压浓缩后得到1-(氮杂环丁烷-3-基甲基)-7-氟-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(47mg)。为棕色固体，收率(100％)。ESI-MS:376[M+H] +。 Add 3-((7-fluoro-6-(3-hydroxynaphthalen-1-yl)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid Tert-butyl ester (60 mg, 0.13 mmol) was dissolved in dichloromethane (5 mL). At room temperature, trifluoroacetic acid (0.3 mL) was slowly added dropwise, stirred for 2 hours, and then concentrated under reduced pressure to obtain 1-(azetidin-3-ylmethyl)-7-fluoro-6-(3-hydroxyl Naphth-1-yl)quinoxaline-2(1H)-one (47 mg). Brown solid, yield (100%). ESI-MS: 376[M+H] + .
第七步：The seventh step:
N 2氛围下，将1-(氮杂环丁烷-3-基甲基)-7-氟-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(47mg，0.13mmol)溶解在二氯甲烷(4mL)中，加入三乙胺(128mg,1.22mmol)。冷却至0℃，将丙烯酰氯(13mg，0.14mmol)的二氯甲烷(1mL)溶液缓慢滴加到体系中，并于0℃搅拌0.5小时。体系用prep-TLC(洗脱剂：MeOH:DCM＝10:1)分离纯化，得到的粗品再用二甲基亚砜(DMSO)(2mL)溶解，然后用C 18反相柱进行纯化(洗脱剂：ACN:5mmol/L NH 4HCO 3水溶液＝0-40％)。冻干得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氟-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(9.96mg)，为白色固体，收率18％。ESI-MS:430[M+H] +。 Under N 2 atmosphere, add 1-(azetidin-3-ylmethyl)-7-fluoro-6-(3-hydroxynaphthalene-1-yl)quinoxaline-2(1H)-one (47mg , 0.13mmol) was dissolved in dichloromethane (4mL), and triethylamine (128mg, 1.22mmol) was added. After cooling to 0°C, a solution of acryloyl chloride (13 mg, 0.14 mmol) in dichloromethane (1 mL) was slowly added dropwise to the system, and stirred at 0°C for 0.5 hours. The system was separated and purified by prep-TLC (eluent: MeOH:DCM=10:1), and the obtained crude product was dissolved in dimethyl sulfoxide (DMSO) (2 mL), and then purified with a C 18 reverse phase column (washing Removal agent: ACN: 5mmol/L NH 4 HCO 3 aqueous solution=0-40%). Lyophilized to obtain 1-((1-acryloylazetidin-3-yl)methyl)-7-fluoro-6-(3-hydroxynaphthalene-1-yl)quinoxaline-2(1H)- Ketone (9.96mg), white solid, yield 18%. ESI-MS: 430[M+H] + .
1H-NMR(400MHz,DMSO-d 6)δ:ppm 10.00(s,1H),8.28(s,1H),8.95～7.90(m,2H),7.82～7.80(m,1H),7.47～7.40(m,2H),7.28～7.25(m,2H),7.10(d,1H,J＝2.4Hz),6.36～6.29(m,1H),6.11(dd,1H,J＝17.2,2.4Hz),5.68(dd,1H,J＝10.4,2.4Hz),4.55～4.60(m,2H),4.32～4.27(m,1H),4.16～4.12(m,1H),4.01～3.97(m,1H),3.89～3.84(m,1H),3.22～3.17(m,1H)。 1 H-NMR(400MHz,DMSO-d 6 )δ:ppm 10.00(s,1H), 8.28(s,1H), 8.95～7.90(m,2H), 7.82～7.80(m,1H),7.47～7.40 (m,2H), 7.28～7.25(m,2H), 7.10(d,1H,J=2.4Hz), 6.36～6.29(m,1H), 6.11(dd,1H,J=17.2,2.4Hz), 5.68(dd,1H,J=10.4,2.4Hz), 4.55～4.60(m,2H), 4.32～4.27(m,1H), 4.16～4.12(m,1H), 4.01～3.97(m,1H), 3.89～3.84(m,1H), 3.22～3.17(m,1H).
实施例2：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮的制备Example 2: 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2(1H) -Preparation of ketones
Figure PCTCN2021091102-appb-000106
Figure PCTCN2021091102-appb-000106
第一步：first step:
将1-溴-2-氯-5-氟-4-硝基苯(5.0g，19.7mmol)溶解在乙腈(ACN)(100mL)中，加入二异丙基乙基胺(DIEA)(12.7g,98.4mmol)。0℃下，缓慢加入甘氨酸甲酯盐酸盐(4.91g，39.4mmol)。室温搅拌16小时。体系直接减压浓缩，将浓缩物经中压flash硅胶柱层析(洗脱剂：乙酸乙酯:二氯甲烷＝0-10％)分离纯化，得到N-(5-溴-4-氯-2-硝基苯基)甘氨酸甲酯(6.3g)，为黄色固体，收率99％。ESI-MS:323,325[M+H] +。 Dissolve 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (5.0g, 19.7mmol) in acetonitrile (ACN) (100mL), add diisopropylethylamine (DIEA) (12.7g , 98.4mmol). At 0°C, glycine methyl ester hydrochloride (4.91 g, 39.4 mmol) was slowly added. Stir at room temperature for 16 hours. The system was directly concentrated under reduced pressure, and the concentrate was separated and purified by medium-pressure flash silica gel column chromatography (eluent: ethyl acetate: dichloromethane=0-10%) to obtain N-(5-bromo-4-chloro- 2-Nitrophenyl)glycine methyl ester (6.3g) was a yellow solid with a yield of 99%. ESI-MS: 323,325[M+H] + .
第二步：The second step:
将N-(5-溴-4-氯-2-硝基苯基)甘氨酸甲酯(4.0g，11.11mmol)溶解在乙醇(76mL)和水(20mL)中。室温搅拌状态下，加入铁粉(100目，6.2g，111.1mmol)，氯化铵(5.9g，111.1mmol)，90℃反应2小时。冷却至室温后通过硅藻土过滤，滤饼用乙醇(100mL)和乙酸乙酯(100mL)洗涤，滤液减压浓缩，所得水相用乙酸乙酯(3 x 100mL)萃取，再用饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，将浓缩物经中压flash硅胶柱层析(洗脱剂：甲醇:二氯甲烷＝0-10％)分离纯化，得到6-溴-7-氯-3,4-二氢喹喔啉-2(1H)-酮(3.0g)，为棕色油状液体，收率100％。ESI-MS:261,263[M+H] +。 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. After cooling to room temperature, it was filtered through Celite, the filter cake was washed with ethanol (100 mL) and ethyl acetate (100 mL), the filtrate was concentrated under reduced pressure, and the resulting aqueous phase was extracted with ethyl acetate (3 x 100 mL), and then saturated chlorinated Wash with sodium solution, dry with anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrate is separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol:dichloromethane=0-10%) to obtain 6-bromo-7 -Chloro-3,4-dihydroquinoxaline-2(1H)-one (3.0g), a brown oily liquid, with a yield of 100%. ESI-MS: 261,263[M+H] + .
第三步：third step:
将6-溴-7-氯-3,4-二氢喹喔啉-2(1H)-酮(2.8g，10.7mmol)溶解在二氯甲烷(50mL)和甲醇(50mL)中。室温下，缓慢倒入二氧化锰粉末(4.6g,52.9mmol)，搅拌16小时，通过硅藻土过滤，滤饼用甲醇:二氯甲烷(50％，400mL)洗涤，然后减压浓缩后的浓缩物经中压flash硅胶柱层析(洗脱剂：甲醇:二氯甲烷＝0-10％)分离纯化，得到6-溴-7-氯喹喔啉-2(1H)-酮(1.8g)，为白色固体，收率64％。ESI-MS:259,261[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. The concentrate was separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol:dichloromethane=0-10%) to obtain 6-bromo-7-chloroquinoxaline-2(1H)-one (1.8g) , Is a white solid with a yield of 64%. ESI-MS: 259,261 [M+H] + .
第四步：the fourth step:
N 2氛围下，将6-溴-7-氯喹喔啉-2(1H)-酮(364mg，1.41mmol)，3-(溴甲基)氮杂环丁烷-1-羧酸叔丁酯(527mg，2.11mmol)，碳酸钾(776mg，5.62mmol)分散在N,N-二甲基甲酰胺(DMF)(5mL)中。于室温搅拌16小时。体系用水(10mL)淬灭后，加入乙酸乙酯(100mL)，用水(3 x 20mL)洗涤，最后用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤减压浓缩后用中压flash硅胶柱层析(洗脱剂：乙酸乙酯:石油醚＝0-50％)分离纯 化，得到3-((6-溴-7-氯-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(300mg)，为浅棕色固体，收率50％。ESI-MS:428,430[M+H] +。 Under N 2 atmosphere, 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) were dispersed in N,N-dimethylformamide (DMF) (5 mL). Stir at room temperature for 16 hours. After the system was quenched with water (10mL), ethyl acetate (100mL) was added, washed with water (3 x 20mL), and finally washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, then used medium pressure flash Silica gel column chromatography (eluent: ethyl acetate: petroleum ether=0-50%) was separated and purified to obtain 3-((6-bromo-7-chloro-2-oxoquinoxaline-1(2H)- (Yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (300mg), light brown solid, yield 50%. ESI-MS: 428,430[M+H] + .
第五步：the fifth step:
N 2氛围下，将3-((6-溴-7-氯-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(140mg，0.33mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧杂硼环戊烷-2-基)萘-2-醇(106mg，0.39mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl 2，24mg，0.033mmol)，碳酸钾(135mg，0.98mmol)分散在1,4-二氧六环/水(5:1，6mL)中。加热至100℃，搅拌2小时。体系减压浓缩后用中压flash硅胶柱层析(洗脱剂：甲醇:二氯甲烷＝0-10％)分离纯化，得到3-((7-氯-6-(3-羟基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(160mg)，为浅棕色固体，收率99％。ESI-MS:492[M+H] +。 Under N 2 atmosphere, 3-((6-bromo-7-chloro-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester ( 140mg, 0.33mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (106mg, 0.39mmol) , [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl 2 , 24mg, 0.033mmol), potassium carbonate (135mg, 0.98mmol) dispersed in 1,4 -Dioxane/water (5:1, 6mL). Heat to 100°C and stir for 2 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol:dichloromethane=0-10%) to obtain 3-((7-chloro-6-(3-hydroxynaphthalene-1) -Yl)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (160 mg), light brown solid, yield 99%. ESI-MS: 492[M+H] + .
第六步：The sixth step:
将3-((7-氯-6-(3-羟基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(160mg，0.33mmol)溶解在二氯甲烷(4mL)中。室温下，缓慢滴加三氟乙酸(0.6mL)，搅拌2小时，然后减压浓缩后得到1-(氮杂环丁烷-3-基甲基)-7-氯-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(127mg)，为棕色固体，收率100％。ESI-MS:392[M+H] +。 3-((7-chloro-6-(3-hydroxynaphthalen-1-yl)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid Tert-butyl ester (160 mg, 0.33 mmol) was dissolved in dichloromethane (4 mL). At room temperature, trifluoroacetic acid (0.6 mL) was slowly added dropwise, stirred for 2 hours, and then concentrated under reduced pressure to obtain 1-(azetidin-3-ylmethyl)-7-chloro-6-(3-hydroxyl Naphthalene-1-yl)quinoxaline-2(1H)-one (127 mg), as a brown solid, with a yield of 100%. ESI-MS: 392[M+H] + .
第七步：The seventh step:
N 2氛围下，将1-(氮杂环丁烷-3-基甲基)-7-氯-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(64mg，0.16mmol)溶解在二氯甲烷(3mL)中，加入三乙胺(164mg,1.6mmol)。冷却至0℃，将丙烯酰氯(16mg，0.18mmol)的二氯甲烷(2mL)溶液缓慢滴加到体系中，并于0℃搅拌0.5小时。体系用prep-TLC(洗脱剂：MeOH:DCM＝1:10)分离纯化，得到的粗品再用二甲基亚砜(DMSO)(2mL)溶解后，用C18反相柱进行纯化(洗脱剂：ACN:5mmol/L NH 4HCO 3水溶液＝0-40％)。冻干得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(7.84mg)，为白色固体，收率11％。ESI-MS:446[M+H] +。 Under N 2 atmosphere, add 1-(azetidine-3-ylmethyl)-7-chloro-6-(3-hydroxynaphthalene-1-yl)quinoxaline-2(1H)-one (64mg , 0.16mmol) was dissolved in dichloromethane (3mL), and triethylamine (164mg, 1.6mmol) was added. After cooling to 0°C, a solution of acryloyl chloride (16 mg, 0.18 mmol) in dichloromethane (2 mL) was slowly added dropwise to the system, and stirred at 0°C for 0.5 hours. The system was separated and purified by prep-TLC (eluent: MeOH:DCM=1:10), and the resulting crude product was dissolved in dimethyl sulfoxide (DMSO) (2 mL), and then purified with a C18 reverse phase column (elution Agent: ACN: 5mmol/L NH 4 HCO 3 aqueous solution=0-40%). Lyophilized to obtain 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2(1H)- Ketone (7.84mg), white solid, yield 11%. ESI-MS: 446[M+H] + .
1H-NMR(400MHz,DMSO-d 6)δ:ppm 9.94(s,1H),8.31(s,1H),8.11(d,1H,J＝2.8Hz),7.83(s,1H),7.80(d,1H,J＝8.0Hz),7.44～7.40(m,1H),7.24～7.22(m,3H),7.02(d,1H,J＝2.4Hz),6.32(dd,1H,J＝17.2,10.4Hz),6.11(dd,1H,J＝16.8,2.4Hz),5.67(dd,1H,J＝10.4,2.4Hz),4.63～4.59(m,2H),4.33～4.28(m,1H),4.16～4.12(m,1H),4.03～3.98(m,1H),3.90～3.84(m,1H),3.24～3.13(m,1H)。 1 H-NMR(400MHz, DMSO-d 6 )δ: ppm 9.94(s,1H), 8.31(s,1H), 8.11(d,1H,J=2.8Hz), 7.83(s,1H), 7.80( d,1H,J=8.0Hz),7.44～7.40(m,1H),7.24～7.22(m,3H),7.02(d,1H,J=2.4Hz),6.32(dd,1H,J＝17.2, 10.4Hz), 6.11(dd,1H,J=16.8,2.4Hz), 5.67(dd,1H,J=10.4,2.4Hz), 4.63～4.59(m,2H),4.33～4.28(m,1H), 4.16～4.12(m,1H), 4.03～3.98(m,1H), 3.90～3.84(m,1H), 3.24～3.13(m,1H).
通过参考以上实施例化合物2的制备方法和使用不同的反应原料，制备了以下实施例化合物15、22和23：By referring to the preparation method of Example Compound 2 above and using different reaction materials, the following Example Compounds 15, 22 and 23 were prepared:
Figure PCTCN2021091102-appb-000107
Figure PCTCN2021091102-appb-000107
Figure PCTCN2021091102-appb-000108
Figure PCTCN2021091102-appb-000108
实施例3：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-3-(2-(二甲基氨基)乙氧基)-7-氟-6-(3-羟基萘基-1-基)喹喔啉-2(1H)-酮的制备Example 3: 1-((1-acryloylazetidin-3-yl)methyl)-3-(2-(dimethylamino)ethoxy)-7-fluoro-6-(3 -Hydroxynaphthyl-1-yl)quinoxaline-2(1H)-one
Figure PCTCN2021091102-appb-000109
Figure PCTCN2021091102-appb-000109
第一步：first step:
N 2氛围下，将3-((6-溴-7-氟-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(230mg，0.54mmol)，2-(二甲基氨基)乙醇(96mg，1.07mmol)，三苯基膦(280mg，1.07mmol)分散在四氢呋喃(THF)(5mL)中。降至0℃后，将偶氮二甲酸二异丙酯(216mg，1.07mmol)的四氢呋喃(THF)(1mL)溶液缓慢滴加到体系中，缓慢升至室温，于室温搅拌16小时。体系减压浓缩后用中压flash硅胶柱层析(洗脱剂：甲醇:二氯甲烷＝0–10％)分离纯化，得到3-((6-溴-3-(2-(二甲基氨基)乙氧基)-7-氟-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯和3-((6-溴-4-(2-(二甲基氨基)乙基)-7-氟-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯的混合物(187mg)，为黄色固体，收率70％。ESI-MS:499,501[M+H] +。 Under N 2 atmosphere, 3-((6-bromo-7-fluoro-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine Tert-butyl alkane-1-carboxylate (230mg, 0.54mmol), 2-(dimethylamino)ethanol (96mg, 1.07mmol), triphenylphosphine (280mg, 1.07mmol) dispersed in tetrahydrofuran (THF) (5mL )middle. After falling to 0°C, a solution of diisopropyl azodicarboxylate (216 mg, 1.07 mmol) in tetrahydrofuran (THF) (1 mL) was slowly added dropwise to the system, slowly rising to room temperature, and stirring at room temperature for 16 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol: dichloromethane=0-10%) to obtain 3-((6-bromo-3-(2-(dimethyl Amino)ethoxy)-7-fluoro-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester and 3-((6-bromo -4-(2-(Dimethylamino)ethyl)-7-fluoro-2,3-dioxo-3,4-dihydroquinoxalin-1(2H)-yl)methyl)aza The mixture of tert-butyl cyclobutane-1-carboxylate (187 mg) was a yellow solid with a yield of 70%. ESI-MS: 499,501 [M+H] + .
第二步：The second step:
N 2氛围下，将3-((6-溴-3-(2-(二甲基氨基)乙氧基)-7-氟-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯和3-((6-溴-4-(2-(二甲基氨基)乙基)-7-氟-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯的混合物(187mg，0.37mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)萘-2-醇(121mg，0.45mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl 2，28mg，0.037mmol)，碳酸钾(156mg，1.12mmol)分散在1,4-二氧六环/水(5:1，5mL)中。加热至100℃，搅拌2小时。体系减压浓缩后用中压flash硅胶柱层析(洗脱剂：甲醇:二氯甲烷＝0-10％)分离纯化，得到3-((3-(2-(二甲基氨基)乙氧基)-7-氟-6-(3-羟基萘-1- 基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(120mg)，为紫黑色固体，收率57％。ESI-MS:563[M+H] +。 Under N 2 atmosphere, 3-((6-bromo-3-(2-(dimethylamino)ethoxy)-7-fluoro-2-oxoquinoxaline-1(2H)-yl)methyl Yl) tert-butyl azetidine-1-carboxylate and 3-((6-bromo-4-(2-(dimethylamino)ethyl)-7-fluoro-2,3-dioxo -3,4-Dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl mixture (187mg, 0.37mmol), 4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (121mg, 0.45mmol), [1,1'-bis(diphenyl Phosphine) ferrocene] palladium dichloride (Pd(dppf)Cl 2 , 28mg, 0.037mmol), potassium carbonate (156mg, 1.12mmol) dispersed in 1,4-dioxane/water (5:1, 5mL). Heat to 100°C and stir for 2 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol:dichloromethane=0-10%) to obtain 3-((3-(2-(dimethylamino)ethoxy (Yl)-7-fluoro-6-(3-hydroxynaphthalene-1-yl)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl Ester (120mg), purple black solid, yield 57%. ESI-MS: 563[M+H] + .
第三步：third step:
将3-((3-(2-(二甲基氨基)乙氧基)-7-氟-6-(3-羟基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁酮烷-1-羧酸叔丁酯(143mg，0.25mmol)溶解在二氯甲烷(6mL)中。室温下，缓慢滴加三氟乙酸(0.6mL)，搅拌2小时，然后减压浓缩得到1-(氮杂环丁烷-3-基甲基)-3-(2-(二甲基氨基)乙氧基)-7-氟-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(118mg)，为棕色固体，收率(100％)。ESI-MS:463[M+H] +。 Add 3-((3-(2-(dimethylamino)ethoxy)-7-fluoro-6-(3-hydroxynaphthalene-1-yl)-2-oxoquinoxaline-1(2H) -Yl)methyl)azetidinone-1-carboxylic acid tert-butyl ester (143 mg, 0.25 mmol) was dissolved in dichloromethane (6 mL). At room temperature, trifluoroacetic acid (0.6mL) was slowly added dropwise, stirred for 2 hours, and then concentrated under reduced pressure to obtain 1-(azetidin-3-ylmethyl)-3-(2-(dimethylamino) Ethoxy)-7-fluoro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2(1H)-one (118mg), brown solid, yield (100%). ESI-MS: 463[M+H] + .
第四步：the fourth step:
N 2氛围下，将1-(氮杂环丁烷-3-基甲基)-3-(2-(二甲基氨基)乙氧基)-7-氟-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(118mg，0.25mmol)溶解在二氯甲烷(4mL)中，加入三乙胺(257mg,2.5mmol)。冷却至0℃，将丙烯酰氯(23mg，0.25mmol)的二氯甲烷(1mL)溶液缓慢滴加到体系中，并于0℃搅拌0.5小时。体系用prep-TLC(洗脱剂：MeOH:DCM＝1:10)分离纯化，得到的粗品再用二甲基亚砜(DMSO)(2mL)溶解，然后用C18反相柱进行纯化(洗脱剂：ACN:5mmol/L NH 4HCO 3水溶液＝0-40％)。冻干得1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-3-(2-(二甲基氨基)乙氧基)-7-氟-6-(3-羟基萘基-1-基)喹喔啉-2(1H)-酮(12.47mg)，为白色固体，收率9％。ESI-MS:517[M+H] +。 Under N 2 atmosphere, 1-(azetidin-3-ylmethyl)-3-(2-(dimethylamino)ethoxy)-7-fluoro-6-(3-hydroxynaphthalene- 1-yl)quinoxaline-2(1H)-one (118 mg, 0.25 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (257 mg, 2.5 mmol) was added. After cooling to 0°C, a solution of acryloyl chloride (23 mg, 0.25 mmol) in dichloromethane (1 mL) was slowly added dropwise to the system, and stirred at 0°C for 0.5 hours. The system was separated and purified by prep-TLC (eluent: MeOH:DCM=1:10), and the obtained crude product was dissolved in dimethyl sulfoxide (DMSO) (2 mL), and then purified with a C18 reverse phase column (elution Agent: ACN: 5mmol/L NH 4 HCO 3 aqueous solution=0-40%). Lyophilized to give 1-((1-acryloylazetidin-3-yl)methyl)-3-(2-(dimethylamino)ethoxy)-7-fluoro-6-(3- Hydroxynaphthyl-1-yl)quinoxaline-2(1H)-one (12.47mg), white solid, yield 9%. ESI-MS: 517[M+H] + .
1H-NMR(400MHz,DMSO-d 6)δ:ppm 9.99(s,1H),7.81～7.72(m,2H),7.47～7.42(m,3H),7.29～7.25(m,2H),7.10(d,1H,J＝2.4Hz),6.32(dd,1H,J＝16.8,10.0Hz),6.11(dd,1H,J＝16.8,2.4Hz),5.67(dd,1H,J＝10.4,2.4Hz),4.52～4.50(m,2H),4.32～4.22(m,3H),4.14～4.10(m,1H),4.02～3.97(m,1H),3.86～3.82(m,1H),3.21～3.14(m,1H),2.52～2.51(m,2H),2.10(s,6H)。 1 H-NMR(400MHz,DMSO-d 6 )δ:ppm 9.99(s,1H),7.81～7.72(m,2H),7.47～7.42(m,3H),7.29～7.25(m,2H),7.10 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 16.8, 10.0 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.52～4.50(m,2H), 4.32～4.22(m,3H), 4.14～4.10(m,1H), 4.02～3.97(m,1H), 3.86～3.82(m,1H), 3.21～ 3.14 (m, 1H), 2.52～2.51 (m, 2H), 2.10 (s, 6H).
实施例4：7-氯-1-((1-(2-氯乙酰基)氮杂环丁烷-3-基)甲基)-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮的制备Example 4: 7-chloro-1-((1-(2-chloroacetyl)azetidin-3-yl)methyl)-6-(3-hydroxynaphthalene-1-yl)quinoxaline Preparation of -2(1H)-ketone
Figure PCTCN2021091102-appb-000110
Figure PCTCN2021091102-appb-000110
N 2氛围下，将1-(氮杂环丁烷-3-基甲基)-7-氯-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(64mg，0.16mmol)溶解在二氯甲烷(3mL)中，加入三乙胺(164mg,1.6mmol)。冷却至0℃，将氯乙酰氯(20mg，0.18mmol)的二氯甲烷(2mL)溶液缓慢滴加到体系中，并于0℃搅拌0.5小时。体系用prep-TLC(洗脱剂：MeOH:DCM＝10:1)分离纯化，得到的粗品再用二甲基亚砜(DMSO)(2mL)溶解，然后用C18反相柱进行纯化(洗脱剂：ACN:5mmol/L NH 4HCO 3水溶液＝0-40％)。冻干得到7-氯-1-((1-(2-氯乙酰基)氮杂环丁烷-3-基)甲基)-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(15.16mg)，为白色固体，收率20％。 Under N 2 atmosphere, add 1-(azetidine-3-ylmethyl)-7-chloro-6-(3-hydroxynaphthalene-1-yl)quinoxaline-2(1H)-one (64mg , 0.16mmol) was dissolved in dichloromethane (3mL), and triethylamine (164mg, 1.6mmol) was added. After cooling to 0°C, a solution of chloroacetyl chloride (20 mg, 0.18 mmol) in dichloromethane (2 mL) was slowly added dropwise to the system, and stirred at 0°C for 0.5 hours. The system was separated and purified by prep-TLC (eluent: MeOH:DCM=10:1), and the obtained crude product was dissolved in dimethyl sulfoxide (DMSO) (2 mL), and then purified with a C18 reverse phase column (elution Agent: ACN: 5mmol/L NH 4 HCO 3 aqueous solution=0-40%). Lyophilized to obtain 7-chloro-1-((1-(2-chloroacetyl)azetidin-3-yl)methyl)-6-(3-hydroxynaphthalene-1-yl)quinoxaline- 2(1H)-ketone (15.16mg), white solid, yield 20%.
ESI-MS:468[M+H] +。 ESI-MS: 468[M+H] + .
1H-NMR(400MHz,DMSO-d 6)δ:ppm 9.94(s,1H),8.31(s,1H),8.09(d,1H,J＝2.4Hz),7.83(s,1H),7.79 (d,1H,J＝8.4Hz),7.44～7.40(m,1H),7.24～7.22(m,3H),7.01(d,1H,J＝2.4Hz),4.68～4.61(m,1H),4.60～4.53(m,1H),4.32～4.29(m,1H),4.17～4.15(m,1H),4.13～4.10(m,3H),4.01～3.96(m,1H),3.89～3.84(m,1H)。 1 H-NMR(400MHz, DMSO-d 6 )δ: ppm 9.94(s,1H), 8.31(s,1H), 8.09(d,1H,J=2.4Hz), 7.83(s,1H), 7.79 ( d, 1H, J=8.4Hz), 7.44～7.40(m,1H), 7.24～7.22(m,3H), 7.01(d,1H,J=2.4Hz), 4.68～4.61(m,1H), 4.60 ～4.53(m,1H), 4.32～4.29(m,1H), 4.17～4.15(m,1H), 4.13～4.10(m,3H), 4.01～3.96(m,1H), 3.89～3.84(m, 1H).
实施例5：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(8-甲基萘-1-基)喹喔啉-2(1H)-酮的合成Example 5: 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(8-methylnaphthalene-1-yl)quinoxaline-2(1H )-Synthesis of ketones
Figure PCTCN2021091102-appb-000111
Figure PCTCN2021091102-appb-000111
第一步：first step:
将1-溴-8-甲基萘(200mg，0.9mmol)溶解在异丙醇(5mL)中，加入乙酸钾(260mg，2.7mmol)，频哪醇联硼酸酯(348mg，1.35mmol)和Pd(dppf)Cl 2(131mg，0.18mmol)。氮气保护下加热至80℃，搅拌1小时，反应液冷却后过滤，滤液减压浓缩，浓缩物经硅胶柱层析(洗脱剂：石油醚:乙酸乙酯＝10:1)分离纯化，得到(8-甲基萘-1-基)硼酸频哪醇酯(180mg)，为白色固体，收率75％。ESI-MS:269[M+H] +。 Dissolve 1-bromo-8-methylnaphthalene (200mg, 0.9mmol) in isopropanol (5mL), add potassium acetate (260mg, 2.7mmol), pinacol diborate (348mg, 1.35mmol) and Pd(dppf)Cl 2 (131 mg, 0.18 mmol). Under the protection of nitrogen, it was heated to 80°C and stirred for 1 hour. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to obtain (8-Methylnaphthalene-1-yl) boronic acid pinacol ester (180 mg), a white solid, with a yield of 75%. ESI-MS: 269 [M+H] + .
第二步：The second step:
将3-((6-溴-7-氯-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(150mg，0.35mmol)溶解在异丙醇(5mL)中，加入碳酸钾(138mg，1.0mmol)，(8-甲基萘-1-基)硼酸频哪醇酯(113mg，0.42mmol)和Pd(dppf)Cl 2(49mg，0.07mmol)。氮气保护下加热至80℃，搅拌1小时，反应液冷却后过滤，滤液减压浓缩，将浓缩物经硅胶柱层析(洗脱剂：石油醚:乙酸乙酯＝2:1)分离纯化，得到3-((7-氯-6-(8-甲基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(80mg)，为白色固体，收率48％。ESI-MS:490[M+H] +。 Add 3-((6-bromo-7-chloro-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (150mg, 0.35mmol) Dissolve in isopropanol (5mL), add potassium carbonate (138mg, 1.0mmol), (8-methylnaphthalene-1-yl) borate pinacol ester (113mg, 0.42mmol) and Pd(dppf)Cl 2 ( 49mg, 0.07mmol). Under the protection of nitrogen, it was heated to 80°C and stirred for 1 hour. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1). Obtain 3-((7-chloro-6-(8-methylnaphthalene-1-yl)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxy Tert-butyl ester (80 mg), a white solid, with a yield of 48%. ESI-MS: 490[M+H] + .
第三步：third step:
将3-((7-氯-6-(8-甲基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(60mg,0.12mmol)溶于二氯甲烷(2.5mL)中，加入三氟乙酸(0.5mL)，在室温下搅拌1小时，然后减压浓缩得到1-(氮杂环丁烷-3-基甲基)-7-氯-6-(8-甲基萘-1-基)喹喔啉-2(1H)-酮(40mg)，为淡黄色固体，收率85％。ESI-MS:390[M+H] +。 Add 3-((7-chloro-6-(8-methylnaphthalene-1-yl)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxy Tert-butyl ester (60mg, 0.12mmol) was dissolved in dichloromethane (2.5mL), trifluoroacetic acid (0.5mL) was added, stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain 1-(azetidine -3-ylmethyl)-7-chloro-6-(8-methylnaphthalen-1-yl)quinoxalin-2(1H)-one (40mg), a pale yellow solid, with a yield of 85%. ESI-MS: 390[M+H] + .
第四步：the fourth step:
将1-(氮杂环丁烷-3-基甲基)-7-氯-6-(8-甲基萘-1-基)喹喔啉-2(1H)-酮(40mg，0.1mmol)溶解在二氯甲烷(1mL)中，加入三乙胺(30mg，0.3mmol)，在氮气保护和-78℃条件下，缓慢滴加丙烯酰氯(14mg，0.15mmol)的二氯甲烷溶液(0.5mL)，在-78℃搅拌10分钟后继续搅拌1小时，将反应液减压浓缩，残余物经prep-HPLC纯化(洗脱剂：乙腈:水(5mmol/L NH 4HCO 3)＝25％～45％)分离纯化，得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(8-甲基萘-1-基)喹喔啉-2(1H)-酮(12mg)，为淡黄色固体，收率26％。ESI-MS:444.1[M+H] +。 Add 1-(azetidine-3-ylmethyl)-7-chloro-6-(8-methylnaphthalen-1-yl)quinoxaline-2(1H)-one (40mg, 0.1mmol) Dissolve in dichloromethane (1mL), add triethylamine (30mg, 0.3mmol), under nitrogen protection and -78℃, slowly add acryloyl chloride (14mg, 0.15mmol) in dichloromethane solution (0.5mL) ), stirred at -78°C for 10 minutes and continued stirring for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (eluent: acetonitrile: water (5mmol/L NH 4 HCO 3 ) = 25%~ 45%) separation and purification to obtain 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(8-methylnaphthalene-1-yl)quinoxaline- 2(1H)-ketone (12mg), a pale yellow solid, with a yield of 26%. ESI-MS: 444.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.31(d,J＝5.0Hz,1H),7.97(dd,J＝10.2,2.3Hz,2H),7.87(dd,J＝10.4,2.5Hz,2H),7.51(d,J＝2.3Hz,1H),7.35(dd,J＝10.4,3.6Hz,1H),7.29(d,J＝3.5Hz,2H),6.33–6.20(m,1H), 6.08(t,J＝7.6Hz,1H),5.70–5.56(m,1H),4.58(m,2H),4.28(m,1H),4.11(m,1H),3.97(m,1H),3.82(m,1H),3.11(m,1H),1.97(s,3H)。 1 H NMR(400MHz,DMSO-d6)δ8.31(d,J=5.0Hz,1H),7.97(dd,J=10.2,2.3Hz,2H),7.87(dd,J=10.4,2.5Hz,2H ), 7.51 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 10.4, 3.6 Hz, 1H), 7.29 (d, J = 3.5 Hz, 2H), 6.33-6.20 (m, 1H), 6.08 (t,J=7.6Hz,1H), 5.70–5.56(m,1H),4.58(m,2H), 4.28(m,1H), 4.11(m,1H), 3.97(m,1H), 3.82( m, 1H), 3.11 (m, 1H), 1.97 (s, 3H).
实施例6：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(6-氟-1H-吲哚-4-基)喹喔啉-2(1H)-酮的制备Example 6: 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(6-fluoro-1H-indol-4-yl)quinoxaline- Preparation of 2(1H)-ketone
Figure PCTCN2021091102-appb-000112
Figure PCTCN2021091102-appb-000112
将1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-溴-7-氯喹喔啉-2(1H)-酮(60mg，0.16mmol)溶解在异丙醇(1mL)中，加入碳酸钾(66mg，0.48mmol)，6-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲哚(46mg，0.19mmol)和Pd(dppf)Cl 2(22mg，0.03mmol)。氮气保护下加热至80℃，搅拌1小时，反应液冷却后过滤，滤液减压浓缩，残余物经prep-HPLC(洗脱剂：乙腈:水(5mmol/L NH 4HCO 3)＝20％～45％)分离纯化，得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(6-氟-1H-吲哚-4-基)喹喔啉-2(1H)-酮(5.0mg)，为淡黄色固体，收率7％。ESI-MS:437.1[M+H] +。 Dissolve 1-((1-acryloylazetidin-3-yl)methyl)-6-bromo-7-chloroquinoxaline-2(1H)-one (60mg, 0.16mmol) in isopropanol (1mL), add potassium carbonate (66mg, 0.48mmol), 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -Yl)-1H-indole (46 mg, 0.19 mmol) and Pd(dppf)Cl 2 (22 mg, 0.03 mmol). Under the protection of nitrogen, it was heated to 80°C and stirred for 1 hour. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to prep-HPLC (eluent: acetonitrile: water (5mmol/L NH 4 HCO 3 ) = 20%~ 45%) separation and purification to obtain 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(6-fluoro-1H-indol-4-yl)quine Oxalin-2(1H)-one (5.0 mg) is a pale yellow solid with a yield of 7%. ESI-MS: 437.1 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),8.26(s,1H),8.06(s,1H),7.83(s,1H),7.36(s,1H),7.24(d,J＝9.7Hz,1H),6.88(d,J＝10.4Hz,1H),6.35–6.19(m,1H),6.07(d,J＝18.7Hz,2H),5.63(d,J＝10.1Hz,1H),4.55(d,J＝7.6Hz,2H),4.25(t,J＝8.4Hz,1H),4.08(d,J＝8.8Hz,1H),3.95(t,J＝9.2Hz,1H),3.79(m,1H),3.12(m,1H)。 1 H NMR(400MHz,DMSO-d6)δ11.34(s,1H), 8.26(s,1H), 8.06(s,1H), 7.83(s,1H), 7.36(s,1H), 7.24(d ,J=9.7Hz,1H),6.88(d,J=10.4Hz,1H),6.35-6.19(m,1H),6.07(d,J=18.7Hz,2H),5.63(d,J=10.1Hz ,1H),4.55(d,J=7.6Hz,2H),4.25(t,J=8.4Hz,1H),4.08(d,J=8.8Hz,1H),3.95(t,J=9.2Hz,1H ), 3.79 (m, 1H), 3.12 (m, 1H).
实施例7：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(1H-吲哚-4-基)喹喔啉-2(1H)-酮的制备Example 7: 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(1H-indol-4-yl)quinoxaline-2(1H) -Preparation of ketones
Figure PCTCN2021091102-appb-000113
Figure PCTCN2021091102-appb-000113
第一步：first step:
将3-((6-溴-7-氯-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(200mg，0.47mmol)溶于二氯甲烷(2.5mL)中,加入三氟乙酸(0.5mL)，在室温下搅拌1小时，然后减压浓缩后得到1-(氮杂环丁烷-3-基)甲基)-6-溴-7-氯喹喔啉-2(1H)-酮(120mg)，为淡黄色固体，收率78％。ESI-MS:328,330[M+H] +。 Add 3-((6-bromo-7-chloro-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (200mg, 0.47mmol) Dissolve in dichloromethane (2.5mL), add trifluoroacetic acid (0.5mL), stir at room temperature for 1 hour, and then concentrate under reduced pressure to obtain 1-(azetidin-3-yl)methyl)- 6-Bromo-7-chloroquinoxaline-2(1H)-one (120mg) is a pale yellow solid with a yield of 78%. ESI-MS: 328,330[M+H] + .
第二步：The second step:
将1-(氮杂环丁烷-3-基)甲基)-6-溴-7-氯喹喔啉-2(1H)-酮(120mg，0.37mmol)溶解在二氯甲烷(2mL)中，加入三乙胺(112mg，1.11mmol)，在氮气保护，-78℃下，缓慢滴加丙烯酰氯(40mg，0.45mmol)的二氯甲烷溶液(0.5mL)，在-78℃搅拌10分钟后继续搅拌1小时，将反应液减压浓缩，浓缩物经硅胶柱层析(洗脱剂：二氯甲烷:甲醇＝15:1)分离纯化，得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-溴-7-氯喹喔啉-2(1H)-酮(120mg)，为淡黄色固体，收率86％。ESI-MS:382,384[M+H] +。 Dissolve 1-(azetidin-3-yl)methyl)-6-bromo-7-chloroquinoxaline-2(1H)-one (120mg, 0.37mmol) in dichloromethane (2mL), Add triethylamine (112mg, 1.11mmol), under nitrogen protection, slowly add acryloyl chloride (40mg, 0.45mmol) in dichloromethane solution (0.5mL) dropwise at -78°C, continue stirring at -78°C for 10 minutes After stirring for 1 hour, the reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 15:1) to obtain 1-((1-acryloylazetidine) -3-yl)methyl)-6-bromo-7-chloroquinoxaline-2(1H)-one (120 mg), as a pale yellow solid, with a yield of 86%. ESI-MS: 382,384 [M+H] + .
第三步：third step:
将1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-溴-7-氯喹喔啉-2(1H)-酮(60mg，0.16mmol)溶解在异丙醇(1mL)中，加入碳酸钾(66mg，0.48mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲哚(45mg，0.19mmol)和Pd(dppf)Cl 2(22mg，0.03mmol)。氮气保护下加热至80℃，搅拌1小时，反应液冷却后过滤，滤液减压浓缩，残余物经prep-HPLC(洗脱剂：乙腈:水(5mmol/L NH 4HCO 3)＝20％～45％)分离纯化，得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(1H-吲哚-4-基)喹喔啉-2(1H)-酮(8mg)，为白色固体，收率12％。ESI-MS:419.1[M+H] +。 Dissolve 1-((1-acryloylazetidin-3-yl)methyl)-6-bromo-7-chloroquinoxaline-2(1H)-one (60mg, 0.16mmol) in isopropanol (1mL), add potassium carbonate (66mg, 0.48mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-Indole (45 mg, 0.19 mmol) and Pd(dppf)Cl 2 (22 mg, 0.03 mmol). Under the protection of nitrogen, it was heated to 80°C and stirred for 1 hour. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to prep-HPLC (eluent: acetonitrile: water (5mmol/L NH 4 HCO 3 ) = 20%~ 45%) separation and purification to obtain 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(1H-indol-4-yl)quinoxaline-2 (1H)-ketone (8mg), white solid, yield 12%. ESI-MS: 419.1 [M+H] + .
1H NMR(400MHz,DMSO-d6).δ11.27(s,1H),8.25(s,1H),8.03(s,1H),7.80(s,1H),7.43(s,1H),7.36(s,1H),7.16(d,J＝12.7Hz,1H),6.97(s,1H),6.26(d,J＝16.7Hz,1H),6.07(d,J＝23.0Hz,2H),5.63(d,J＝12.4Hz,1H),4.55(s,2H),4.26(m,1H),4.09(d,J＝3.4Hz,1H),3.94(m,1H),3.82(m,1H),3.13(m,1H)。 1 H NMR (400MHz, DMSO-d6).δ 11.27 (s, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.80 (s, 1H), 7.43 (s, 1H), 7.36 ( s, 1H), 7.16 (d, J = 12.7 Hz, 1H), 6.97 (s, 1H), 6.26 (d, J = 16.7 Hz, 1H), 6.07 (d, J = 23.0 Hz, 2H), 5.63 ( d, J = 12.4Hz, 1H), 4.55 (s, 2H), 4.26 (m, 1H), 4.09 (d, J = 3.4 Hz, 1H), 3.94 (m, 1H), 3.82 (m, 1H), 3.13 (m, 1H).
实施例8：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮的制备Example 8: Preparation of 1-((1-acryloylazetidin-3-yl)methyl)-6-(3-hydroxynaphthalene-1-yl)quinoxaline-2(1H)-one
Figure PCTCN2021091102-appb-000114
Figure PCTCN2021091102-appb-000114
第一步first step
将6-溴喹喔啉-2(1H)-酮(600mg，2.7mmol)，3-(碘甲基)氮杂环丁烷-1-羧酸叔丁酯(1g,3.2mmol)和碳酸钾(1.12g,8.4mmol)溶解在DMF(10mL)中，混合液在50℃搅拌3小时。反应结束后，加入乙酸乙酯(30mL)稀释，用饱和食盐水洗涤三次后，用无水硫酸钠干燥，减压浓缩，浓缩物经硅胶柱层析(洗脱剂：正己烷:乙酸乙酯＝1:1)分离纯化，得到3-((6-溴-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(0.3g)，为白色固体，收率28％。ESI-MS:394[M+H] +。 Combine 6-bromoquinoxaline-2(1H)-one (600mg, 2.7mmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (1g, 3.2mmol) and potassium carbonate (1.12 g, 8.4 mmol) was dissolved in DMF (10 mL), and the mixture was stirred at 50°C for 3 hours. After the reaction, the mixture was diluted with ethyl acetate (30 mL), washed three times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography (eluent: n-hexane: ethyl acetate). =1:1) separation and purification to obtain 3-((6-bromo-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (0.3 g) It is a white solid with a yield of 28%. ESI-MS: 394[M+H] + .
第二步Second step
将3-((6-溴-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(300mg，0.76mmol)溶解在1,4-二氧六环/水(5mL/1mL)中，加入碳酸钾(318mg，2.28mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)萘-2-醇(240mg，0.76mmol)和Pd(dppf)Cl 2(56mg，0.076mmol)。氮气保护下加热至100℃，搅拌1小时，反应液冷却后过滤，滤液减压浓缩，将残余物直接浓缩，浓缩物经硅胶柱层析(洗脱剂：正己烷:乙酸乙酯＝1:1)分离纯化得3-((6-(3-羟基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(300mg)，为白色固体，收率86.2％。ESI-MS:458[M+H] +。 3-((6-Bromo-2-oxoquinoxaline-1(2H)-yl)methyl) tert-butyl azetidine-1-carboxylate (300mg, 0.76mmol) was dissolved in 1, 4-Dioxane/water (5mL/1mL), add potassium carbonate (318mg, 2.28mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Cyclopentane-2-yl)naphthalene-2-ol (240 mg, 0.76 mmol) and Pd(dppf)Cl 2 (56 mg, 0.076 mmol). Under the protection of nitrogen, it was heated to 100°C and stirred for 1 hour. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure. The residue was directly concentrated. The concentrate was subjected to silica gel column chromatography (eluent: n-hexane: ethyl acetate = 1: 1) Isolation and purification to obtain 3-((6-(3-hydroxynaphthalene-1-yl)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid Tert-butyl ester (300 mg), a white solid, with a yield of 86.2%. ESI-MS: 458[M+H] + .
第三步third step
将3-((6-(3-羟基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(300mg，0.72mmol)溶于二氯甲烷(3mL)中，加入三氟乙酸(0.6mL)，在室温下搅拌1小时，然后减压浓缩得到粗产物1-(氮杂环丁烷-3-基甲基)-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(250mg)，为淡黄色固体，收率98％。ESI-MS:358[M+H] +。 Add 3-((6-(3-hydroxynaphthalene-1-yl)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester ( 300mg, 0.72mmol) was dissolved in dichloromethane (3mL), trifluoroacetic acid (0.6mL) was added, stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain the crude product 1-(azetidin-3-yl Methyl)-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2(1H)-one (250mg), a pale yellow solid, with a yield of 98%. ESI-MS: 358[M+H] + .
第四步the fourth step
将1-(氮杂环丁烷-3-基甲基)-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(250mg,0.70mol)和三乙胺(220mg,2.1mmol)溶于二氯甲烷(5ml)，然后在0℃下将丙烯酰氯(71mg,0.8mmol)的二氯甲烷溶液(0.5mL)滴加到反应液中。滴加完后在室温下搅拌10分钟，然后将反应液倒入到水中，用乙酸乙酯萃取，合并有机相后经无水硫酸钠干燥，过滤后减压浓缩。残余物经制备的TLC(DCM:CH 3OH＝10:1)纯化，得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(27mg)，为白色固体，收率(10％)。 Combine 1-(azetidine-3-ylmethyl)-6-(3-hydroxynaphthalene-1-yl)quinoxaline-2(1H)-one (250mg, 0.70mol) and triethylamine ( 220 mg, 2.1 mmol) was dissolved in dichloromethane (5 ml), and then a dichloromethane solution (0.5 mL) of acryloyl chloride (71 mg, 0.8 mmol) was added dropwise to the reaction solution at 0°C. After the dropwise addition, the mixture was stirred at room temperature for 10 minutes, then the reaction solution was poured into water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (DCM:CH 3 OH=10:1) to obtain 1-((1-acryloylazetidin-3-yl)methyl)-6-(3-hydroxynaphthalene- 1-yl)quinoxaline-2(1H)-one (27mg), white solid, yield (10%).
ESI-MS:412[M+H] +。 ESI-MS: 412[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ9.93(s,1H),8.33(s,1H),7.91-7.89(m,2H),7.80-7.76(m,2H),7.67-.7.64(m,1H)7.45-7.42(m,1H),7.28-7.21(m,2H),7.08(d,J＝2Hz,1H),6.35-6.28(m,1H),6.13-6.08(m,1H),5.68-5.65(m,1H),4.62(d,J＝7.48Hz,1H),4.32-4.28(m,1H),4.18-4.14(m,1H),4.02-3.98(m,1H),3.90-3.86(m,1H),3.23-3.18(m,1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ9.93 (s, 1H), 8.33 (s, 1H), 7.91-7.89 (m, 2H), 7.80-7.76 (m, 2H), 7.67-.7.64 ( m,1H)7.45-7.42(m,1H),7.28-7.21(m,2H),7.08(d,J=2Hz,1H),6.35-6.28(m,1H),6.13-6.08(m,1H) ,5.68-5.65(m,1H),4.62(d,J=7.48Hz,1H),4.32-4.28(m,1H),4.18-4.14(m,1H),4.02-3.98(m,1H),3.90 -3.86 (m, 1H), 3.23-3.18 (m, 1H).
实施例9：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-3-(2-(二甲基氨基)乙氧基)-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮的制备Example 9: 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-3-(2-(dimethylamino)ethoxy)-6-(3 -Hydroxynaphthalene-1-yl)quinoxaline-2(1H)-one
Figure PCTCN2021091102-appb-000115
Figure PCTCN2021091102-appb-000115
第一步first step
N 2氛围下，将3-((6-溴-7-氯-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(430 mg，0.97mmol)，2-(二甲基氨基)乙醇(172mg，1.93mmol)，三苯基膦(508mg，1.94mmol)分散在四氢呋喃(THF)(8mL)中。体系温度降至0℃后，将偶氮二甲酸二异丙酯(392mg，1.94mmol)的四氢呋喃(THF)(2mL)溶液缓慢滴加到体系中，缓慢升至室温，于室温搅拌16小时。体系减压浓缩后用中压flash硅胶柱层析(洗脱剂：甲醇:二氯甲烷＝0–10％)分离纯化，得到3-((6-溴-7-氯-3-(2-(二甲基氨基)乙氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(170mg)，为黄色固体，收率34％。ESI-MS:515、517[M+H] +。 Under N 2 atmosphere, 3-((6-bromo-7-chloro-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine Tert-butyl alkane-1-carboxylate (430 mg, 0.97 mmol), 2-(dimethylamino)ethanol (172 mg, 1.93 mmol), triphenylphosphine (508 mg, 1.94 mmol) were dispersed in tetrahydrofuran (THF) ( 8mL). After the temperature of the system dropped to 0°C, a solution of diisopropyl azodicarboxylate (392 mg, 1.94 mmol) in tetrahydrofuran (THF) (2 mL) was slowly added dropwise to the system, slowly raised to room temperature, and stirred at room temperature for 16 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol: dichloromethane=0-10%) to obtain 3-((6-bromo-7-chloro-3-(2- (Dimethylamino)ethoxy)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (170mg), as a yellow solid, The yield was 34%. ESI-MS: 515, 517 [M+H] + .
第二步Second step
N 2氛围下，将3-((6-溴-7-氯-3-(2-(二甲基氨基)乙氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(170mg，0.33mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环烷-2-基)萘-2-醇(107mg，0.40mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl 2，24mg，0.033mmol)，碳酸钾(137mg，0.99mmol)分散在1,4-二氧六环/水(5:1，5mL)中。加热至100℃，搅拌2小时。体系减压浓缩后用中压flash硅胶柱层析(洗脱剂：甲醇:二氯甲烷＝0-10％)分离纯化，得到3-((7-氯-3-(2-(二甲基氨基)乙氧基)-6-(3-羟基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(144mg)，为黑色固体，收率75％。ESI-MS:579[M+H] +。 Under N 2 atmosphere, 3-((6-bromo-7-chloro-3-(2-(dimethylamino)ethoxy)-2-oxoquinoxaline-1(2H)-yl)methyl Yl) tert-butyl azetidine-1-carboxylate (170mg, 0.33mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)naphthalene-2-ol (107mg, 0.40mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl 2 , 24mg, 0.033 mmol), potassium carbonate (137 mg, 0.99 mmol) was dispersed in 1,4-dioxane/water (5:1, 5 mL). Heat to 100°C and stir for 2 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol: dichloromethane=0-10%) to obtain 3-((7-chloro-3-(2-(dimethyl (Amino)ethoxy)-6-(3-hydroxynaphthalene-1-yl)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl Ester (144mg), black solid, yield 75%. ESI-MS: 579[M+H] + .
第三步third step
将3-((7-氯-3-(2-(二甲基氨基)乙氧基)-6-(3-羟基萘-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(144mg，0.25mmol)溶解在二氯甲烷(6mL)中。室温下，缓慢滴加三氟乙酸(0.6mL)，搅拌2小时，然后减压浓缩得到1-(氮杂环丁烷-3-基甲基)-7-氯-3-(2-(二甲基氨基)乙氧基)-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(119mg)，为棕色固体，收率(100％)。ESI-MS:479[M+H] +。 Add 3-((7-chloro-3-(2-(dimethylamino)ethoxy)-6-(3-hydroxynaphthalene-1-yl)-2-oxoquinoxaline-1(2H) -Yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (144 mg, 0.25 mmol) was dissolved in dichloromethane (6 mL). At room temperature, trifluoroacetic acid (0.6 mL) was slowly added dropwise, stirred for 2 hours, and then concentrated under reduced pressure to obtain 1-(azetidin-3-ylmethyl)-7-chloro-3-(2-(二Methylamino)ethoxy)-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2(1H)-one (119mg), brown solid, yield (100%). ESI-MS: 479[M+H] + .
第四步the fourth step
N 2氛围下，将1-(氮杂环丁烷-3-基甲基)-7-氯-3-(2-(二甲基氨基)乙氧基)-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(119mg，0.25mmol)溶解在二氯甲烷(4mL)中，加入三乙胺(252mg,2.5mmol)。冷却至0℃，将丙烯酰氯(25mg，0.27mmol)的二氯甲烷(1mL)溶液缓慢滴加到体系中，并于0℃搅拌0.5小时。体系用prep-TLC(洗脱剂：MeOH:DCM＝1:10)分离纯化，得到的粗品再用二甲基亚砜(DMSO)(2mL)溶解后，用C18反相柱进行纯化(洗脱剂：ACN:5mmol/L NH 4HCO 3水溶液＝0-50％)。冻干得1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-3-(2-(二甲基氨基)乙氧基)-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(12.23mg)，为白色固体，收率9％。 Under N 2 atmosphere, 1-(azetidin-3-ylmethyl)-7-chloro-3-(2-(dimethylamino)ethoxy)-6-(3-hydroxynaphthalene- 1-yl)quinoxaline-2(1H)-one (119 mg, 0.25 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (252 mg, 2.5 mmol) was added. After cooling to 0°C, a solution of acryloyl chloride (25 mg, 0.27 mmol) in dichloromethane (1 mL) was slowly added dropwise to the system, and stirred at 0°C for 0.5 hours. The system was separated and purified by prep-TLC (eluent: MeOH:DCM=1:10), and the resulting crude product was dissolved in dimethyl sulfoxide (DMSO) (2 mL), and then purified with a C18 reverse phase column (elution Agent: ACN: 5mmol/L NH 4 HCO 3 aqueous solution=0-50%). Lyophilized to give 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-3-(2-(dimethylamino)ethoxy)-6-(3- Hydroxynaphthalene-1-yl)quinoxaline-2(1H)-one (12.23mg), white solid, yield 9%.
ESI-MS:533[M+H] +。 ESI-MS: 533[M+H] + .
1H-NMR(400MHz,DMSO-d 6)δ:ppm 9.90(s,1H),7.98(d,1H,J＝3.2Hz),7.78(d,1H,J＝8.4Hz),7.51(s,1H),7.43～7.39(m,1H),7.22～7.21(m,3H),6.99(d,1H,J＝2.4Hz),6.32(dd,1H,J＝16.8,10.0Hz),6.11(dd,1H,J＝13.2,2.4Hz),5.67(dd,1H,J＝10.4,2.4Hz),4.61(d,2H,J＝7.6Hz),4.43(t,2H,J＝6.0Hz),4.32～4.28(m,1H),4.16～4.12(m,1H),4.02～3.98(m,1H),3.88～3.84(m,1H),3.21～3.15(m,1H),2.67(t,2H,J＝6.0Hz),2.21(s,6H)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: ppm 9.90 (s, 1H), 7.98 (d, 1H, J = 3.2 Hz), 7.78 (d, 1H, J = 8.4 Hz), 7.51 (s, 1H),7.43～7.39(m,1H),7.22～7.21(m,3H),6.99(d,1H,J=2.4Hz),6.32(dd,1H,J=16.8,10.0Hz),6.11(dd ,1H,J＝13.2,2.4Hz), 5.67(dd,1H,J＝10.4,2.4Hz), 4.61(d,2H,J＝7.6Hz), 4.43(t,2H,J＝6.0Hz), 4.32 ～4.28(m,1H), 4.16～4.12(m,1H), 4.02～3.98(m,1H), 3.88～3.84(m,1H), 3.21～3.15(m,1H), 2.67(t,2H, J = 6.0 Hz), 2.21 (s, 6H).
实施例10：(S)-1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮的制备Example 10: (S)-1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(3-hydroxynaphthalen-1-yl)-3-( Preparation of (1-methylpyrrolidin-2-yl)methoxy)quinoxaline-2(1H)-one
Figure PCTCN2021091102-appb-000116
Figure PCTCN2021091102-appb-000116
第一步first step
N 2氛围下，将3-((6-溴-7-氯-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(630mg，1.42mmol)，(S)-(1-甲基吡咯烷-2-基)甲醇(327mg，2.84mmol)，三苯基膦(744mg，2.84mmol)分散在四氢呋喃(THF)(18mL)中。体系温度降至0℃后，将偶氮二甲酸二异丙酯(574mg，2.84mmol)的四氢呋喃(THF)(2mL)溶液缓慢滴加到体系中，缓慢升至室温，于室温搅拌16小时。体系减压浓缩后用中压flash硅胶柱层析(洗脱剂：甲醇:二氯甲烷＝0–10％)分离纯化，得到(S)-3-((6-溴-7-氯-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯和(S)-3-((6-溴-7-氯-4-((1-甲基吡咯烷-2-基)甲基)-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯的混合物(750mg)，为黄色固体，收率98％。ESI-MS:541,543[M+H] +。 Under N 2 atmosphere, 3-((6-bromo-7-chloro-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine Tert-butyl alkane-1-carboxylate (630mg, 1.42mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (327mg, 2.84mmol), triphenylphosphine (744mg, 2.84mmol) Disperse in tetrahydrofuran (THF) (18 mL). After the temperature of the system dropped to 0°C, a solution of diisopropyl azodicarboxylate (574 mg, 2.84 mmol) in tetrahydrofuran (THF) (2 mL) was slowly added dropwise to the system, slowly raised to room temperature, and stirred at room temperature for 16 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol:dichloromethane=0-10%) to obtain (S)-3-((6-bromo-7-chloro-3) -((1-Methylpyrrolidin-2-yl)methoxy)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester And (S)-3-((6-bromo-7-chloro-4-((1-methylpyrrolidin-2-yl)methyl)-2,3-dioxo-3,4-dihydro A mixture of quinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (750 mg) was a yellow solid with a yield of 98%. ESI-MS: 541,543[M+H] + .
第二步Second step
N 2氛围下，将(S)-3-((6-溴-7-氯-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯和(S)-3-((6-溴-7-氯-4-((1-甲基吡咯烷-2-基)甲基)-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯的混合物(400mg，0.74mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)萘-2-醇(240mg，0.89mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl 2，54mg，0.074mmol)，碳酸钾(306mg，2.22mmol)分散在1,4-二氧六环/水(5:1，6mL)中。加热至100℃，搅拌2小时。体系减压浓缩后用中压flash硅胶柱层析(洗脱剂：甲醇:二氯甲烷＝0-10％)分离纯化，得到(S)-3-((7-氯-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(220mg)，为黑色固体，收率49％。ESI-MS:605[M+H] +。 Under N 2 atmosphere, (S)-3-((6-bromo-7-chloro-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxoquinoxaline- 1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester and (S)-3-((6-bromo-7-chloro-4-((1-methylpyrrolidine) -2-yl)methyl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester The mixture (400mg, 0.74mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (240mg , 0.89mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl 2 , 54mg, 0.074mmol), potassium carbonate (306mg, 2.22mmol) dispersed In 1,4-dioxane/water (5:1, 6mL). Heat to 100°C and stir for 2 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol: dichloromethane=0-10%) to obtain (S)-3-((7-chloro-6-(3- Hydroxynaphthalene-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine Tert-butyl alkane-1-carboxylate (220 mg), as a black solid, with a yield of 49%. ESI-MS: 605[M+H] + .
第三步third step
将(S)-3-((7-氯-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(220mg，0.36mmol)溶解在二氯甲烷(6mL)中。室温下，缓慢滴加三氟乙酸(0.6mL)，搅拌2小时，然后减压浓缩得到(S)-1-(氮杂环丁烷-3-基甲基)-7-氯-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮(184mg)，为棕色固体，收率(100％)。ESI-MS:505[M+H] +。 (S)-3-((7-chloro-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxo Quinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (220 mg, 0.36 mmol) was dissolved in dichloromethane (6 mL). At room temperature, trifluoroacetic acid (0.6 mL) was slowly added dropwise, stirred for 2 hours, and then concentrated under reduced pressure to obtain (S)-1-(azetidin-3-ylmethyl)-7-chloro-6-( 3-hydroxynaphthalene-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)quinoxaline-2(1H)-one (184mg), brown solid, yield ( 100%). ESI-MS: 505[M+H] + .
第四步the fourth step
N 2氛围下，将(S)-1-(氮杂环丁烷-3-基甲基)-7-氯-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮(184mg，0.36mmol)溶解在二氯甲烷(4mL)中，加入三乙胺(401mg,4.0mmol)。冷却至0℃，将 丙烯酰氯(40mg，0.44mmol)的二氯甲烷(2mL)溶液缓慢滴加到体系中，并于0℃搅拌0.5小时。体系用prep-TLC(洗脱剂：MeOH:DCM＝1:10)分离纯化，得到的粗品再用二甲基亚砜(DMSO)(2mL)溶解后，用C18反相柱进行纯化(洗脱剂：ACN:5mmol/L NH 4HCO 3水溶液＝0-50％)。冻干得(S)-1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮(2.88mg)，为白色固体，收率1％。 Under N 2 atmosphere, (S)-1-(azetidin-3-ylmethyl)-7-chloro-6-(3-hydroxynaphthalene-1-yl)-3-((1-methyl Pyrrolidin-2-yl)methoxy)quinoxaline-2(1H)-one (184 mg, 0.36 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (401 mg, 4.0 mmol) was added. After cooling to 0°C, a solution of acryloyl chloride (40 mg, 0.44 mmol) in dichloromethane (2 mL) was slowly added dropwise to the system, and stirred at 0°C for 0.5 hours. The system was separated and purified by prep-TLC (eluent: MeOH:DCM=1:10), and the resulting crude product was dissolved in dimethyl sulfoxide (DMSO) (2 mL), and then purified with a C18 reverse phase column (elution Agent: ACN: 5mmol/L NH 4 HCO 3 aqueous solution=0-50%). (S)-1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(3-hydroxynaphthalene-1-yl)-3-(( 1-Methylpyrrolidin-2-yl)methoxy)quinoxaline-2(1H)-one (2.88 mg), a white solid, with a yield of 1%.
ESI-MS:559[M+H] +。 ESI-MS: 559[M+H] + .
1H-NMR(400MHz,DMSO-d 6)δ:ppm 9.94(s,1H),7.97(d,1H,J＝3.2Hz),7.78(d,1H,J＝8.0Hz),7.51(s,1H),7.43～7.39(m,1H),7.22～7.21(m,3H),6.99(d,1H,J＝2.0Hz),6.33(dd,1H,J＝16.8,10.0Hz),6.11(dd,1H,J＝16.8,2.4Hz),5.67(dd,1H,J＝10.4,2.4Hz),4.61(d,2H,J＝7.6Hz),4.32～4.24(m,3H),4.16～4.12(m,1H),4.02～3.98(m,1H),3.87～3.83(m,1H),3.21～3.16(m,1H),2.96～2.93(m,1H),2.68～2.66(m,1H),2.37(d,3H,J＝1.6Hz),2.20～2.16(m,2H),2.02～1.94(m,2H),1.70～1.62(m,1H)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: ppm 9.94 (s, 1H), 7.97 (d, 1H, J = 3.2 Hz), 7.78 (d, 1H, J = 8.0 Hz), 7.51 (s, 1H),7.43～7.39(m,1H),7.22～7.21(m,3H),6.99(d,1H,J=2.0Hz),6.33(dd,1H,J=16.8,10.0Hz),6.11(dd ,1H,J=16.8,2.4Hz), 5.67(dd,1H,J=10.4,2.4Hz), 4.61(d,2H,J=7.6Hz), 4.32～4.24(m,3H), 4.16～4.12( m,1H), 4.02～3.98(m,1H), 3.87～3.83(m,1H), 3.21～3.16(m,1H), 2.96～2.93(m,1H), 2.68～2.66(m,1H), 2.37 (d, 3H, J = 1.6 Hz), 2.20 ~ 2.16 (m, 2H), 2.02 ~ 1.94 (m, 2H), 1.70 ~ 1.62 (m, 1H).
实施例11：(S)-1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氟-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮的制备Example 11: (S)-1-((1-acryloylazetidin-3-yl)methyl)-7-fluoro-6-(3-hydroxynaphthalen-1-yl)-3-( Preparation of (1-methylpyrrolidin-2-yl)methoxy)quinoxaline-2(1H)-one
Figure PCTCN2021091102-appb-000117
Figure PCTCN2021091102-appb-000117
第一步first step
N 2氛围下，将3-((6-溴-7-氟-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(300mg，0.70mmol)，(S)-(1-甲基吡咯烷-2-基)甲醇(161mg，1.40mmol)，三苯基膦(367mg，1.40mmol)分散在四氢呋喃(THF)(5mL)中。体系温度降至0℃后，将偶氮二甲酸二异丙酯(283mg，1.40mmol)的四氢呋喃(THF)(1mL)溶液缓慢滴加到体系中，缓慢升至室温，于室温搅拌16小时。体系减压浓缩后用中压flash硅胶柱层析(洗脱剂：甲醇:二氯甲烷＝0–10％)分离纯化，得到(S)-3-((6-溴-7-氟-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯和(S)-3-((6-溴-7-氟-4-((1-甲基吡咯烷-2-基)甲基)-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯的混合物(350mg)，为黄色固体。 Under N 2 atmosphere, 3-((6-bromo-7-fluoro-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine Tert-butyl alkane-1-carboxylate (300mg, 0.70mmol), (S)-(1-methylpyrrolidin-2-yl)methanol (161mg, 1.40mmol), triphenylphosphine (367mg, 1.40mmol) Disperse in tetrahydrofuran (THF) (5 mL). After the temperature of the system dropped to 0°C, a solution of diisopropyl azodicarboxylate (283 mg, 1.40 mmol) in tetrahydrofuran (THF) (1 mL) was slowly added dropwise to the system, slowly raised to room temperature, and stirred at room temperature for 16 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol:dichloromethane=0-10%) to obtain (S)-3-((6-bromo-7-fluoro-3) -((1-Methylpyrrolidin-2-yl)methoxy)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester And (S)-3-((6-Bromo-7-fluoro-4-((1-methylpyrrolidin-2-yl)methyl)-2,3-dioxo-3,4-dihydro A mixture of tert-butyl quinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylate (350 mg) as a yellow solid.
混合物溶于二甲基亚砜(DMSO)(2mL)后，用C18反相柱进行纯化(洗脱剂：ACN:5mmol/L NH 4HCO 3水溶液＝0-80％)。冻干得(S)-3-((6-溴-7-氟-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(110mg)，为白色固体，收率30％。ESI-MS:525,527[M+H] +。 After the mixture was dissolved in dimethyl sulfoxide (DMSO) (2 mL), it was purified with a C18 reverse phase column (eluent: ACN: 5 mmol/L NH 4 HCO 3 aqueous solution=0-80%). (S)-3-((6-Bromo-7-fluoro-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxoquinoxaline-1(2H )-Yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (110 mg), as a white solid, with a yield of 30%. ESI-MS: 525,527 [M+H] + .
第二步Second step
N 2氛围下，将(S)-3-((6-溴-7-氟-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷 -1-羧酸叔丁酯(110mg，0.21mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)萘-2-醇(68mg，0.25mmol)，四(三苯膦)钯(Pd(PPh 3) 4，24mg，0.021mmol)，碳酸钠(67mg，0.63mmol)分散在1,4-二氧六环/水(4:1，5mL)中。加热至70℃，搅拌2小时。体系减压浓缩后用中压flash硅胶柱层析(洗脱剂：含1％氨水的甲醇:二氯甲烷＝0-10％)分离纯化，得到(S)-3-((7-氟-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(100mg)，为棕黑色固体，收率81％。ESI-MS:589[M+H] +。 Under N 2 atmosphere, (S)-3-((6-bromo-7-fluoro-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxoquinoxaline- 1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (110mg, 0.21mmol), 4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)naphthalene-2-ol (68mg, 0.25mmol), tetrakis(triphenylphosphine) palladium (Pd(PPh 3 ) 4 , 24mg, 0.021mmol), sodium carbonate ( 67mg, 0.63mmol) was dispersed in 1,4-dioxane/water (4:1, 5mL). Heat to 70°C and stir for 2 hours. After the system was concentrated under reduced pressure, it was separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol containing 1% ammonia water: dichloromethane=0-10%) to obtain (S)-3-((7-fluoro- 6-(3-Hydroxynaphthalene-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxoquinoxaline-1(2H)-yl)methyl ) Tert-butyl azetidine-1-carboxylate (100 mg), brown-black solid, yield 81%. ESI-MS: 589[M+H] + .
第三步third step
将(S)-3-((7-氟-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-羧酸叔丁酯(100mg，0.17mmol)溶解在二氯甲烷(5mL)中。室温下，缓慢滴加三氟乙酸(0.5mL)，搅拌2小时，然后减压浓缩得到(S)-1-(氮杂环丁烷-3-基甲基)-7-氟-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮(83mg)，为棕色固体，收率(100％)。ESI-MS:489[M+H] +。 (S)-3-((7-fluoro-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxo Quinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (100 mg, 0.17 mmol) was dissolved in dichloromethane (5 mL). At room temperature, trifluoroacetic acid (0.5 mL) was slowly added dropwise, stirred for 2 hours, and then concentrated under reduced pressure to obtain (S)-1-(azetidin-3-ylmethyl)-7-fluoro-6-( 3-hydroxynaphthalene-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)quinoxaline-2(1H)-one (83mg), brown solid, yield ( 100%). ESI-MS: 489[M+H] + .
第四步the fourth step
N 2氛围下，将(S)-1-(氮杂环丁烷-3-基甲基)-7-氟-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮(83mg，0.17mmol)溶解在二氯甲烷(4mL)中，加入三乙胺(172mg,1.7mmol)。冷却至0℃，将丙烯酰氯(17mg，0.19mmol)的二氯甲烷(2mL)溶液缓慢滴加到体系中，并于0℃搅拌0.5小时。体系用prep-TLC(洗脱剂：NH 3·H 2O:MeOH:DCM＝0.01:1:10)分离纯化，得到的粗品再用二甲基亚砜(DMSO)(2mL)溶解后，用C18反相柱进行纯化(洗脱剂：ACN:5mmol/L NH 4HCO 3水溶液＝0-50％)。冻干得(S)-1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氟-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮(25.25mg)，为白色固体，收率27％。 Under N 2 atmosphere, (S)-1-(azetidin-3-ylmethyl)-7-fluoro-6-(3-hydroxynaphthalene-1-yl)-3-((1-methyl Pyrrolidin-2-yl)methoxy)quinoxaline-2(1H)-one (83 mg, 0.17 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (172 mg, 1.7 mmol) was added. After cooling to 0°C, a solution of acryloyl chloride (17 mg, 0.19 mmol) in dichloromethane (2 mL) was slowly added dropwise to the system, and stirred at 0°C for 0.5 hours. The system was separated and purified by prep-TLC (eluent: NH 3 ·H 2 O: MeOH: DCM = 0.01:1:10), and the obtained crude product was dissolved in dimethyl sulfoxide (DMSO) (2 mL), and then used Purification was performed on a C18 reversed-phase column (eluent: ACN: 5mmol/L NH 4 HCO 3 aqueous solution=0-50%). (S)-1-((1-acryloylazetidin-3-yl)methyl)-7-fluoro-6-(3-hydroxynaphthalene-1-yl)-3-(( 1-Methylpyrrolidin-2-yl)methoxy)quinoxaline-2(1H)-one (25.25mg), a white solid, with a yield of 27%.
ESI-MS:543[M+H] +。 ESI-MS: 543[M+H] + .
1H-NMR(400MHz,DMSO-d 6)δ:ppm 9.96(s,1H),7.83～7.78(m,2H),7.57(d,1H,J＝7.6Hz),7.45～7.40(m,2H),7.28～7.23(m,2H),7.07(d,1H,J＝2.4Hz),6.33(dd,1H,J＝16.8,10.0Hz),6.11(dd,1H,J＝16.8,2.4Hz),5.67(dd,1H,J＝10.4,2.4Hz),4.58(d,2H,J＝7.2Hz),4.32～4.24(m,3H),4.16～4.13(m,1H),4.02～3.97(m,1H),3.88～3.84(m,1H),3.20～3.17(m,1H),2.96～2.93(m,1H),2.66～2.63(m,1H),2.38(s,3H),2.20～2.17(m,2H),2.01～1.94(m,2H),1.71～1.62(m,1H)。 1 H-NMR(400MHz,DMSO-d 6 )δ:ppm 9.96(s,1H),7.83～7.78(m,2H),7.57(d,1H,J=7.6Hz),7.45～7.40(m,2H ), 7.28～7.23(m,2H), 7.07(d,1H,J=2.4Hz), 6.33(dd,1H,J=16.8,10.0Hz), 6.11(dd,1H,J=16.8,2.4Hz) ,5.67(dd,1H,J=10.4,2.4Hz),4.58(d,2H,J=7.2Hz), 4.32～4.24(m,3H), 4.16～4.13(m,1H),4.02～3.97(m ,1H), 3.88～3.84(m,1H), 3.20～3.17(m,1H), 2.96～2.93(m,1H), 2.66～2.63(m,1H), 2.38(s,3H), 2.20～2.17 (m,2H), 2.01～1.94(m,2H), 1.71～1.62(m,1H).
实施例12：(2S)-2-(((4-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-氯-7-(3-羟基萘-1-基)-3-氧代-3,4-二氢喹喔啉-2-基)氨基)甲基)-1-甲基吡咯烷-1-鎓2,2,2-三氟乙酸盐的制备Example 12: (2S)-2-(((4-((1-acryloylazetidin-3-yl)methyl)-6-chloro-7-(3-hydroxynaphthalene-1-yl )-3-oxo-3,4-dihydroquinoxalin-2-yl)amino)methyl)-1-methylpyrrolidine-1-ium 2,2,2-trifluoroacetate
Figure PCTCN2021091102-appb-000118
Figure PCTCN2021091102-appb-000118
第一步first step
将3-((6-溴-7-氯-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(2.0g，4.51mmol)溶解在1,2-二氧乙烷(25mL)中，加入氯化亚砜(5.32g，45.1mmol)，缓慢滴加N,N-二甲基甲酰胺(330mg，4.51mmol)，室温下搅拌直至溶液变为澄清，反应结束将反应液减压浓缩，粗品用三乙胺中和残余的氯化亚砜后，用硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝5:1)分离纯化，得到3-((6-溴-3,7-二氯-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(1.1g)，为黄色固体。收率53％。ESI-MS:462,464[M+H] +。 Add 3-((6-bromo-7-chloro-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid Tert-butyl ester (2.0g, 4.51mmol) was dissolved in 1,2-dioxane (25mL), thionyl chloride (5.32g, 45.1mmol) was added, and N,N-dimethylformamide was slowly added dropwise (330mg, 4.51mmol). Stir at room temperature until the solution becomes clear. After the reaction, the reaction solution is concentrated under reduced pressure. After the crude product is neutralized with triethylamine and residual thionyl chloride, it is chromatographed with silica gel column (eluent: Petroleum ether: ethyl acetate = 5:1) separation and purification to obtain 3-((6-bromo-3,7-dichloro-2-oxoquinoxaline-1(2H)-yl)methyl)aza Tert-butyl cyclobutane-1-carboxylate (1.1 g) as a yellow solid. The yield was 53%. ESI-MS: 462,464 [M+H] + .
第二步Second step
将3-((6-溴-3,7-二氯-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(150mg，0.32mmol)，N,N-二异丙基乙胺(206mg，1.6mmol)和(S)-(1-甲基吡咯烷-2-基)甲胺(74mg，0.64mmol)均匀混合在一起，加热至100℃搅拌1小时，反应液冷却后，将反应液减压浓缩，浓缩物经硅胶柱层析(洗脱剂：二氯甲烷:甲醇＝15:1)分离纯化，得到(S)-3-((6-溴-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)氨基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(140mg)，为淡黄色固体。收率81％。ESI-MS:540,542[M+H] +。 Add tert-butyl 3-((6-bromo-3,7-dichloro-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylate (150mg, 0.32 mmol), N,N-diisopropylethylamine (206mg, 1.6mmol) and (S)-(1-methylpyrrolidin-2-yl)methylamine (74mg, 0.64mmol) were mixed together uniformly, heated Stir at 100°C for 1 hour. After the reaction solution is cooled, the reaction solution is concentrated under reduced pressure. The concentrate is separated and purified by silica gel column chromatography (eluent: dichloromethane:methanol=15:1) to obtain (S)-3 -((6-Bromo-7-chloro-3-(((1-methylpyrrolidin-2-yl)methyl)amino)-2-oxoquinoxaline-1(2H)-yl)methyl ) Tert-Butyl azetidine-1-carboxylate (140 mg) as a pale yellow solid. The yield was 81%. ESI-MS: 540,542 [M+H] + .
第三步third step
将(S)-3-((6-溴-7-氯-3-(((1-甲基吡咯烷)-2-基)甲基)氨基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(140mg，0.26mmol)溶于二氯甲烷(1mL)中，加入三氟乙酸(0.2mL)，在室温下搅拌1小时，然后减压浓缩得到(S)-1-(氮杂环丁烷-3-基甲基)-6-溴-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)氨基)喹喔啉-2(1H)-酮(100mg)，为淡黄色固体。收率83％。ESI-MS:440,442[M+H] +。 (S)-3-((6-Bromo-7-chloro-3-(((1-methylpyrrolidin)-2-yl)methyl)amino)-2-oxoquinoxaline-1( 2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (140mg, 0.26mmol) was dissolved in dichloromethane (1mL), trifluoroacetic acid (0.2mL) was added, and the mixture was stirred at room temperature for 1 Hours, then concentrated under reduced pressure to obtain (S)-1-(azetidin-3-ylmethyl)-6-bromo-7-chloro-3-(((1-methylpyrrolidin-2-yl )Methyl)amino)quinoxaline-2(1H)-one (100mg), as a pale yellow solid. The yield was 83%. ESI-MS: 440,442 [M+H] + .
第四步the fourth step
将(S)-1-(氮杂环丁烷-3-基甲基)-6-溴-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)氨基)喹喔啉-2(1H)-酮(100mg，0.23mmol)溶解在二氯甲烷(2mL)中，加入三乙胺(70.0mg，0.70mmol)，在氮气保护，-78℃下，缓慢滴加丙烯酰氯(25mg，0.27mmol)的二氯甲烷溶液(0.5mL)，在-78℃下继续搅拌1小时，将反应液减压浓缩，浓缩物经硅胶柱层析(洗脱剂：二氯甲烷:甲醇＝15:1)分离纯化，得到(S)-1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-溴-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)氨基)喹喔啉-2(1H)-酮(85mg)，为淡黄色固体。收率76％。ESI-MS:494,496[M+H] +。 (S)-1-(azetidin-3-ylmethyl)-6-bromo-7-chloro-3-(((1-methylpyrrolidin-2-yl)methyl)amino) Quinoxaline-2(1H)-one (100mg, 0.23mmol) was dissolved in dichloromethane (2mL), triethylamine (70.0mg, 0.70mmol) was added, and under nitrogen protection, slowly added dropwise at -78°C A dichloromethane solution (0.5mL) of acryloyl chloride (25mg, 0.27mmol) was stirred at -78°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography (eluent: dichloromethane). : Methanol=15:1) separation and purification to obtain (S)-1-((1-acryloylazetidin-3-yl)methyl)-6-bromo-7-chloro-3-((( 1-Methylpyrrolidin-2-yl)methyl)amino)quinoxaline-2(1H)-one (85 mg), as a pale yellow solid. The yield was 76%. ESI-MS: 494,496 [M+H] + .
第五步the fifth step
将(S)-1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-溴-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)氨基)喹喔啉-2(1H)- 酮(85mg，0.17mmol)溶解在异丙醇(2mL)中，加入碳酸钾(71mg，0.51mmol)，(3-羟基萘-1-基)硼酸(39mg，0.2mmol)和Pd(dppf)Cl 2(25mg，0.03mmol)。氮气保护下加热至70℃，搅拌1小时，反应液冷却后过滤，滤液减压浓缩，残余物经prep-HPLC(洗脱剂：乙腈:水(0.1％TFA)＝25％～45％)分离纯化，得到(2S)-2-(((4-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-氯-7-(3-羟基萘-1-基)-3-氧代-3,4-二氢喹喔啉-2-基)氨基)甲基)-1-甲基吡咯烷-1-鎓2,2,2-三氟乙酸盐(50mg)，为白色固体，收率44％。 Add (S)-1-((1-acryloylazetidin-3-yl)methyl)-6-bromo-7-chloro-3-(((1-methylpyrrolidin-2-yl) )Methyl)amino)quinoxaline-2(1H)-one (85mg, 0.17mmol) was dissolved in isopropanol (2mL), potassium carbonate (71mg, 0.51mmol), (3-hydroxynaphthalene-1- Yl)boronic acid (39 mg, 0.2 mmol) and Pd(dppf)Cl 2 (25 mg, 0.03 mmol). Under the protection of nitrogen, heat to 70°C and stir for 1 hour. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure. The residue was separated by prep-HPLC (eluent: acetonitrile: water (0.1% TFA) = 25% ~ 45%) Purified to obtain (2S)-2-(((4-((1-acryloylazetidin-3-yl)methyl)-6-chloro-7-(3-hydroxynaphthalene-1-yl) -3-oxo-3,4-dihydroquinoxalin-2-yl)amino)methyl)-1-methylpyrrolidine-1-ium 2,2,2-trifluoroacetate (50mg) , Is a white solid with a yield of 44%.
ESI-MS:558.2[M+H] + ESI-MS: 558.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),9.24(s,1H),8.20(m,1H),7.85(d,1H),7.73(d,1H),7.37(m,2H),7.21(m,2H),6.95(d,J＝16.2Hz,1H),6.35–6.20(m,1H),6.08(d,J＝17.4Hz,1H),5.69–5.51(m,1H),4.60(m,2H),4.30(m,1H),4.11(m,1H),3.97(m,1H),3.85(m,1H),3.77–3.45(m,4H),3.16(m,1H),3.05(m,1H),2.94(d,3H),2.10(m,1H),1.86(m,3H)。 1 H NMR(400MHz,DMSO-d6)δ9.91(s,1H), 9.24(s,1H), 8.20(m,1H), 7.85(d,1H), 7.73(d,1H), 7.37(m , 2H), 7.21 (m, 2H), 6.95 (d, J = 16.2 Hz, 1H), 6.35-6.20 (m, 1H), 6.08 (d, J = 17.4 Hz, 1H), 5.69-5.51 (m, 1H), 4.60 (m, 2H), 4.30 (m, 1H), 4.11 (m, 1H), 3.97 (m, 1H), 3.85 (m, 1H), 3.77 - 3.45 (m, 4H), 3.16 (m , 1H), 3.05 (m, 1H), 2.94 (d, 3H), 2.10 (m, 1H), 1.86 (m, 3H).
实施例13：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-3-(3-(二甲基氨基)氮杂环丁烷-1-基)-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮的制备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
Figure PCTCN2021091102-appb-000119
Figure PCTCN2021091102-appb-000119
第一步first step
将3-((6-溴-3,7-二氯-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(120mg，0.26mmol)，N,N-二异丙基乙胺(100mg，0.78mmol)和N,N-二甲基氮杂环丁烷-3-胺(52mg，0.52mmol)均匀混合在一起，加热至100℃搅拌1小时，反应液冷却后，将反应液减压浓缩，浓缩物经硅胶柱层析(洗脱剂：二氯甲烷:甲醇＝15:1)分离纯化，得到3-((6-溴-7-氯-3-(3-(二甲基氨基)氮杂环丁烷-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(110mg)，为白色固体，收率81％。ESI-MS:526,528[M+H] +。 Add tert-butyl 3-((6-bromo-3,7-dichloro-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylate (120mg, 0.26 mmol), N,N-diisopropylethylamine (100mg, 0.78mmol) and N,N-dimethylazetidine-3-amine (52mg, 0.52mmol) mixed together uniformly, heated to 100 After stirring for 1 hour at ℃, the reaction solution was cooled, the reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 15:1) to obtain 3-((6-bromo -7-chloro-3-(3-(dimethylamino)azetidin-1-yl)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine Tert-Butyl-1-carboxylate (110 mg), a white solid, with a yield of 81%. ESI-MS: 526,528 [M+H] + .
第二步Second step
将3-((6-溴-7-氯-3-(3-(二甲基氨基)氮杂环丁烷-1-基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(110mg，0.21mmol)溶解在二氯甲烷(2.5mL)中，加入三氟乙酸(0.5mL)，在室温下搅拌1小时，然后减压浓缩得到1-(氮杂环丁烷-3-基甲基)-6-溴-7-氯-3-(3-(二甲基氨基)氮杂环丁烷-1-基)喹喔啉-2(1H)-酮(75mg)，为白色固体,收率85％。ESI-MS:426,428[M+H] +。 The 3-((6-bromo-7-chloro-3-(3-(dimethylamino)azetidin-1-yl)-2-oxoquinoxalin-1(2H)-yl) (Methyl)azetidine-1-carboxylate (110mg, 0.21mmol) was dissolved in dichloromethane (2.5mL), trifluoroacetic acid (0.5mL) was added, stirred at room temperature for 1 hour, and then reduced Press and concentrate to obtain 1-(azetidin-3-ylmethyl)-6-bromo-7-chloro-3-(3-(dimethylamino)azetidin-1-yl)quinoxa Lin-2(1H)-one (75mg), white solid, yield 85%. ESI-MS: 426,428 [M+H] + .
第三步third step
将1-(氮杂环丁烷-3-基甲基)-6-溴-7-氯-3-(3-(二甲基氨基)氮杂环丁烷-1-基)喹喔啉-2(1H)-酮(75mg，0.18mmol)溶解在二氯甲烷(2mL)中，加入三乙胺(55.0mg，0.54mmol)，在氮气保护，-78℃下，缓慢滴加丙烯酰氯(20mg，0.22mmol)的二氯甲烷溶液(0.5mL)，在-78℃下继续搅拌1小时，将反应液减压浓缩，浓缩物经硅胶柱层析(洗脱剂：二氯甲烷:甲醇＝15:1)分离纯化，得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-溴-7-氯-3-(3-(二甲基氨基)氮杂环丁烷-1-基)喹喔啉-2(1H)-酮(80mg)，为白色固体，收率95％。ESI-MS:480,482[M+H] +。 Add 1-(azetidin-3-ylmethyl)-6-bromo-7-chloro-3-(3-(dimethylamino)azetidin-1-yl)quinoxaline- 2(1H)-ketone (75mg, 0.18mmol) was dissolved in dichloromethane (2mL), triethylamine (55.0mg, 0.54mmol) was added, and acryloyl chloride (20mg , 0.22mmol) in dichloromethane (0.5mL), stirring at -78°C for 1 hour, the reaction solution was concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography (eluent: dichloromethane: methanol = 15 : 1) Separation and purification to obtain 1-((1-acryloylazetidin-3-yl)methyl)-6-bromo-7-chloro-3-(3-(dimethylamino)aza Cyclobutan-1-yl)quinoxaline-2(1H)-one (80mg), a white solid, with a yield of 95%. ESI-MS: 480,482[M+H] + .
第四步the fourth step
将1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-溴-7-氯-3-(3-(二甲基氨基)氮杂环丁烷-1-基)喹喔啉-2(1H)-酮(60mg，0.13mmol)溶解在异丙醇(2mL)中，加入碳酸钾(52mg，0.38mmol)，(3-羟基萘-1-基)硼酸(32mg，0.15mmol)和Pd(dppf)Cl 2(18mg，0.03mmol)。氮气保护下加热至70℃，搅拌1小时，反应液冷却后过滤，滤液减压浓缩，残余物经prep-HPLC(洗脱剂：乙腈:水(10mM NH 4HCO 3)＝25％～45％)分离纯化，得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-3-(3-(二甲基氨基)氮杂环丁烷-1-基)-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮(23.0mg)，为白色固体，收率34％。 Add 1-((1-acryloylazetidin-3-yl)methyl)-6-bromo-7-chloro-3-(3-(dimethylamino)azetidine-1- Yl)quinoxaline-2(1H)-one (60mg, 0.13mmol) was dissolved in isopropanol (2mL), potassium carbonate (52mg, 0.38mmol), (3-hydroxynaphthalene-1-yl)boronic acid ( 32 mg, 0.15 mmol) and Pd(dppf)Cl 2 (18 mg, 0.03 mmol). Under the protection of nitrogen, heat to 70°C and stir for 1 hour. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to prep-HPLC (eluent: acetonitrile: water (10mM NH 4 HCO 3 ) = 25%-45%) ) Isolation and purification to obtain 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-3-(3-(dimethylamino)azetidine-1- Yl)-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2(1H)-one (23.0 mg), a white solid, with a yield of 34%.
ESI-MS:544.2[M+H] +。 ESI-MS: 544.2 [M+H] + .
1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),7.72(m,2H),7.42–7.30(m,1H),7.21(s,1H),7.20–7.13(m,3H),6.92(s,1H),6.29(dd,J＝16.9,10.2Hz,1H),6.07(d,J＝16.7Hz,1H),5.64(d,J＝10.9Hz,1H),4.50(m,3H),4.27(t,J＝8.5Hz,2H),4.07(d,J＝8.0Hz,2H),3.95(d,J＝9.1Hz,1H),3.80(d,J＝11.5Hz,2H),3.10(d,J＝18.3Hz,2H),2.06(s,6H)。 1 H NMR (400MHz, DMSO-d6) δ 9.85 (s, 1H), 7.72 (m, 2H), 7.42-7.30 (m, 1H), 7.21 (s, 1H), 7.20-7.13 (m, 3H) , 6.92 (s, 1H), 6.29 (dd, J = 16.9, 10.2 Hz, 1H), 6.07 (d, J = 16.7 Hz, 1H), 5.64 (d, J = 10.9 Hz, 1H), 4.50 (m, 3H), 4.27(t,J=8.5Hz,2H),4.07(d,J=8.0Hz,2H), 3.95(d,J=9.1Hz,1H), 3.80(d,J=11.5Hz,2H) , 3.10 (d, J = 18.3 Hz, 2H), 2.06 (s, 6H).
通过参考以上实施例化合物13的制备方法和使用不同的反应原料，制备了以下实施例化合物：By referring to the preparation method of the above example compound 13 and using different reaction materials, the following example compounds were prepared:
Figure PCTCN2021091102-appb-000120
Figure PCTCN2021091102-appb-000120
Figure PCTCN2021091102-appb-000121
Figure PCTCN2021091102-appb-000121
Figure PCTCN2021091102-appb-000122
Figure PCTCN2021091102-appb-000122
Figure PCTCN2021091102-appb-000123
Figure PCTCN2021091102-appb-000123
Figure PCTCN2021091102-appb-000124
Figure PCTCN2021091102-appb-000124
Figure PCTCN2021091102-appb-000125
Figure PCTCN2021091102-appb-000125
Figure PCTCN2021091102-appb-000126
Figure PCTCN2021091102-appb-000126
实施例18：1-(1-丙烯酰基哌啶-4-基)-7-氯-3-(2-(二甲基氨基)乙氧基)-6-(3-羟基萘-1-基)喹喔啉-2(1H)-酮的制备Example 18: 1-(1-acryloylpiperidin-4-yl)-7-chloro-3-(2-(dimethylamino)ethoxy)-6-(3-hydroxynaphthalen-1-yl) ) Preparation of quinoxaline-2(1H)-one
Figure PCTCN2021091102-appb-000127
Figure PCTCN2021091102-appb-000127
第一步first step
将1-溴-2-氯-4-氟-5-硝基苯(2g,7.9mmol)、4-氨基哌啶-1-羧酸叔丁酯(1.8g,8.3mmol)和三乙胺(2.4g,23.8mmol)溶解于乙腈(20mL)中，于60℃温度下搅拌2h。待反应完毕后将反应液浓缩干，加入水(20mL)搅拌20分钟,过滤弃滤液，固体烘干得到4-((4-溴-5-氯-2-硝基苯基)氨基)哌啶-1-甲酸叔丁酯2.8克，为白色固体，产率为81.8％。ESI-MS:434[M+H] +。 Combine 1-bromo-2-chloro-4-fluoro-5-nitrobenzene (2g, 7.9mmol), tert-butyl 4-aminopiperidine-1-carboxylate (1.8g, 8.3mmol) and triethylamine ( 2.4g, 23.8mmol) was dissolved in acetonitrile (20mL) and stirred at 60°C for 2h. After the completion of the reaction, the reaction solution was concentrated to dryness, water (20mL) was added and stirred for 20 minutes, the filtrate was filtered out, and the solid was dried to obtain 4-((4-bromo-5-chloro-2-nitrophenyl)amino)piperidine 2.8 g of tert-butyl-1-carboxylate was a white solid, and the yield was 81.8%. ESI-MS: 434[M+H] + .
第二步Second step
将4-((4-溴-5-氯-2-硝基苯基)氨基)哌啶-1-甲酸叔丁酯(2g,4mmol)、氯化铵(647mg,11.5mmol)及铁粉(618mg,11.5mmol)分散于乙醇(8mL)和水(2mL)的混合溶液中，反应于90℃搅拌2h。反应完毕后，将反应液冷却到室温后，用硅藻土层过滤，以乙醇洗涤固体三次。有机相浓缩，浓缩物经柱层析(DCM:EA＝10:1)分离纯化得4-((2-氨基-4-溴-5-氯苯基)氨基)哌啶-1-甲酸叔丁酯(0.6g)，为白色固体，产率为64.5％。ESI-MS:404[M+H] +。 Combine 4-((4-bromo-5-chloro-2-nitrophenyl)amino)tert-butyl piperidine-1-carboxylate (2g, 4mmol), ammonium chloride (647mg, 11.5mmol) and iron powder ( 618mg, 11.5mmol) was dispersed in a mixed solution of ethanol (8mL) and water (2mL), and the reaction was stirred at 90°C for 2h. After the completion of the reaction, the reaction solution was cooled to room temperature, filtered through a Celite layer, and the solid was washed three times with ethanol. The organic phase was concentrated, and the concentrate was separated and purified by column chromatography (DCM:EA=10:1) to obtain tert-butyl 4-((2-amino-4-bromo-5-chlorophenyl)amino)piperidine-1-carboxylate The ester (0.6 g) was a white solid with a yield of 64.5%. ESI-MS: 404[M+H] + .
第三步third step
将4-((2-氨基-4-溴-5-氯苯基)氨基)哌啶-1-甲酸叔丁酯(1.2g,3mmol)、2-氯-2-氧代乙酸甲酯(1.5g,12mmol)和三乙胺(2.4g,24mmol)溶解于四氢呋喃(10mL)中，于90℃反应2h，经液质检测反应完毕，将反应液直接浓缩，浓缩物经柱层析(PE:EA＝2:1)分离纯化得4-(6-溴-7-氯-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)哌啶-1-甲酸叔丁酯(1g),为白色固体，产率(72.7％)，ESI-MS:458[M+H] +。 Combine 4-((2-amino-4-bromo-5-chlorophenyl)amino)tert-butyl piperidine-1-carboxylate (1.2g, 3mmol), methyl 2-chloro-2-oxoacetate (1.5 g, 12mmol) and triethylamine (2.4g, 24mmol) were dissolved in tetrahydrofuran (10mL) and reacted at 90°C for 2h. After liquid quality detection, the reaction was completed, the reaction solution was directly concentrated, and the concentrate was subjected to column chromatography (PE: EA=2:1) was separated and purified to obtain 4-(6-bromo-7-chloro-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)piperidine-1- Tert-Butyl formate (1g), white solid, yield (72.7%), ESI-MS: 458[M+H] + .
第四步the fourth step
将4-(6-溴-7-氯-2,3-二氧代-3,4-二氢-1(2H)-喹喔啉)哌啶-1-甲酸叔丁酯(500mg，1.1mmol)溶解在四氢呋喃(10mL)中，向其中加入2-(二甲基氨基)乙醇(120mg，1.3mmol)和三苯基膦(580mg，2.2mmol)。反应液冷却至0℃，在氮气氛围下，将偶氮二甲酸二异丙酯(450mg，2.2mmol)缓慢滴加到体系中，滴加完后升至室温搅拌1小时。反应完成后将反应液减压浓缩，残余物经prep-HPLC(洗脱剂：乙腈:水(10mM NH 4HCO 3)＝50％～85％)分离纯化，得到4-(6-溴-7-氯-3-(2-(二甲基氨基)乙氧基)-2-氧代喹喔啉-1(2H)-基)哌啶-1-甲酸叔丁酯(230mg)，为白色固体，收率35％。ESI-MS:529,531[M+H] +。 The 4-(6-bromo-7-chloro-2,3-dioxo-3,4-dihydro-1(2H)-quinoxaline) piperidine-1-carboxylic acid tert-butyl ester (500mg, 1.1mmol ) Was dissolved in tetrahydrofuran (10 mL), and 2-(dimethylamino)ethanol (120 mg, 1.3 mmol) and triphenylphosphine (580 mg, 2.2 mmol) were added thereto. The 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. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by prep-HPLC (eluent: acetonitrile: water (10mM NH 4 HCO 3 )=50%-85%) to obtain 4-(6-bromo-7 -Chloro-3-(2-(dimethylamino)ethoxy)-2-oxoquinoxaline-1(2H)-yl)piperidine-1-carboxylic acid tert-butyl ester (230mg), as a white solid , The yield is 35%. ESI-MS: 529,531 [M+H] + .
第五步the fifth step
将4-(6-溴-7-氯-3-(2-(二甲基氨基)乙氧基)-2-氧代喹喔啉-1(2H)-基)哌啶-1-甲酸叔丁酯(230mg，0.43mmol)溶解在二氯甲烷(10.0mL)中，加入三氟乙酸(2.0mL)，在室温下搅拌1小时，然后减压浓缩得到6-溴-7-氯-3-(2-(二甲基氨基)乙氧基)-1-(哌啶-4-基)喹喔啉-2(1H)-酮(150mg)，为淡黄色固体。收率81％。ESI-MS:429,431[M+H] +。 The 4-(6-bromo-7-chloro-3-(2-(dimethylamino)ethoxy)-2-oxoquinoxaline-1(2H)-yl)piperidine-1-carboxylic acid tert Butyl ester (230mg, 0.43mmol) was dissolved in dichloromethane (10.0mL), trifluoroacetic acid (2.0mL) was added, stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain 6-bromo-7-chloro-3- (2-(Dimethylamino)ethoxy)-1-(piperidin-4-yl)quinoxaline-2(1H)-one (150 mg), as a pale yellow solid. The yield was 81%. ESI-MS: 429,431 [M+H] + .
第六步Sixth step
将6-溴-7-氯-3-(2-(二甲基氨基)乙氧基)-1-(哌啶-4-基)喹喔啉-2(1H)-酮(150mg，0.35mmol)溶解在二氯甲烷(2.0mL)中，加入三乙胺(106mg，1.05mmol)，在氮气保护，降温至-78℃，在此温度下缓慢滴加丙烯酰氯(118mg，1.32mmol)的二氯甲烷溶液(0.5mL)，并维持温度搅拌反应1小时，反应完成后将反应液减压浓缩，浓缩物经硅胶柱层析(洗脱剂：二氯甲烷:甲醇＝15:1)分离纯化，得到1-(1-丙烯酰基哌啶-4-基)-6-溴-7-氯-3-(2-(二甲基氨基)乙氧基)喹喔啉-2(1H)-酮(140mg)，为淡黄色固体。收率83％。ESI-MS:483,485[M+H] +。 The 6-bromo-7-chloro-3-(2-(dimethylamino)ethoxy)-1-(piperidin-4-yl)quinoxaline-2(1H)-one (150mg, 0.35mmol ) Was dissolved in dichloromethane (2.0mL), triethylamine (106mg, 1.05mmol) was added, and the temperature was reduced to -78°C under nitrogen protection. At this temperature, acryloyl chloride (118mg, 1.32mmol) was slowly added dropwise. Methyl chloride solution (0.5 mL), and the temperature was maintained for 1 hour while stirring. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 15:1) To obtain 1-(1-acryloylpiperidin-4-yl)-6-bromo-7-chloro-3-(2-(dimethylamino)ethoxy)quinoxaline-2(1H)-one (140mg), is a pale yellow solid. The yield was 83%. ESI-MS: 483,485[M+H] + .
第七步Seventh step
将1-(1-丙烯酰基哌啶-4-基)-6-溴-7-氯-3-(2-(二甲基氨基)乙氧基)喹喔啉-2(1H)-酮(80mg，0.17mmol)溶解在异丙醇(1mL)中，加入碳酸钾(71mg，0.51mmol)，(3-羟基萘-1-基)硼酸(39mg，0.20mmol)和Pd(dppf)Cl 2(25mg，0.03mmol)。在氮气保护下加热至70℃，搅拌1小时，反应液冷却后过滤，滤液减压浓缩，残余物经prep-HPLC(洗脱剂：乙腈:水(10mM NH 4HCO 3)＝25％～45％)分离纯化，得1-(1-丙烯酰基哌啶-4-基)-7-氯-3-(2-(二甲基氨基)乙氧基)-6-(3-羟基-1-萘)喹喔啉-2(1H)-酮(10mg)，为白色固体，收率11％。 Add 1-(1-acryloylpiperidin-4-yl)-6-bromo-7-chloro-3-(2-(dimethylamino)ethoxy)quinoxaline-2(1H)-one ( 80mg, 0.17mmol) was dissolved in isopropanol (1mL), potassium carbonate (71mg, 0.51mmol), (3-hydroxynaphthalene-1-yl)boronic acid (39mg, 0.20mmol) and Pd(dppf)Cl 2 ( 25mg, 0.03mmol). Under the protection of nitrogen, it was heated to 70°C and stirred for 1 hour. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to prep-HPLC (eluent: acetonitrile: water (10mM NH 4 HCO 3 ) = 25%～45 %) separation and purification to obtain 1-(1-acryloylpiperidin-4-yl)-7-chloro-3-(2-(dimethylamino)ethoxy)-6-(3-hydroxy-1- Naphthalene)quinoxaline-2(1H)-one (10mg), a white solid, with a yield of 11%.
ESI-MS:[M+H] +＝547.2 ESI-MS: [M+H] + ＝547.2
1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.77(d,J＝8.3Hz,1H),7.50(s,1H),7.41(m,1H),7.26–7.18(m,3H),6.99(d,J＝2.4Hz,1H),6.90(dd,J＝16.7,10.5Hz,1H),6.16(dd,J＝16.7,2.5Hz,1H),5.71(dd,J＝10.4,2.5Hz,1H),4.98(s,1H),4.59(d,J＝12.8Hz,1H),4.40(t,J＝5.8Hz,2H),4.21(d,J＝13.6Hz,1H),3.37(m,1H),2.94(t,J＝12.8Hz,1H),2.67–2.55(m,3H),2.48(m,1H),2.20(s,6H),1.75(m,2H). 1 H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.77(d,J=8.3Hz,1H),7.50(s,1H),7.41(m,1H),7.26–7.18(m , 3H), 6.99 (d, J = 2.4 Hz, 1H), 6.90 (dd, J = 16.7, 10.5 Hz, 1H), 6.16 (dd, J = 16.7, 2.5 Hz, 1H), 5.71 (dd, J = 10.4, 2.5Hz, 1H), 4.98 (s, 1H), 4.59 (d, J = 12.8 Hz, 1H), 4.40 (t, J = 5.8 Hz, 2H), 4.21 (d, J = 13.6 Hz, 1H) , 3.37 (m, 1H), 2.94 (t, J = 12.8 Hz, 1H), 2.67-2.55 (m, 3H), 2.48 (m, 1H), 2.20 (s, 6H), 1.75 (m, 2H).
通过参考以上实施例18化合物的制备方法和使用不同的反应原料，制备了以下实施例化合物19和42：By referring to the preparation method of the compound of Example 18 above and using different reaction materials, the following Example Compounds 19 and 42 were prepared:
Figure PCTCN2021091102-appb-000128
Figure PCTCN2021091102-appb-000128
实施例58：(S)-1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-(2-氨基苯并[d]噻唑-4-基)-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)氨基)喹喔啉-2(1H)-酮的制备Example 58: (S)-1-((1-acryloylazetidin-3-yl)methyl)-6-(2-aminobenzo[d]thiazol-4-yl)-7- Preparation of chloro-3-(((1-methylpyrrolidin-2-yl)methyl)amino)quinoxaline-2(1H)-one
Figure PCTCN2021091102-appb-000129
Figure PCTCN2021091102-appb-000129
第一步first step
在氮气保护下，将DMAP(214mg,1.75mmol)和DIEA(6.8g,52.5mmol)加入到2-氨基-4-溴苯并噻唑(4g,17.5mmol)的四氢呋喃(50ml)溶液中，然后将Boc 2O(4.6g,21mmol)加入到上述反应体系中，在室温搅拌2.5小时。反应结束后，继续在室温搅拌1小时，然后加饱和碳酸氢钠溶液(5mL)淬灭，用乙酸乙酯(20mL)萃取三次，有机相以无水硫酸钠干燥，减压浓缩有机相，浓缩残余物经硅胶柱层析(洗脱剂：正己烷:乙酸乙酯＝5:1)分离纯化，得到产品(4-溴苯并[d]噻唑-2-基)氨基甲酸叔丁酯4克，为白色固体，产率(70％)。ESI-MS:330[M+H]+。 Under nitrogen protection, DMAP (214mg, 1.75mmol) and DIEA (6.8g, 52.5mmol) were added to 2-amino-4-bromobenzothiazole (4g, 17.5mmol) in tetrahydrofuran (50ml) solution, and then Boc 2 O (4.6 g, 21 mmol) was added to the above reaction system and stirred at room temperature for 2.5 hours. After the reaction is over, continue to stir at room temperature for 1 hour, then add saturated sodium bicarbonate solution (5 mL) to quench, extract three times with ethyl acetate (20 mL), dry the organic phase with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure, and concentrate The residue was separated and purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 5:1) to obtain the product (4-bromobenzo[d]thiazol-2-yl) tert-butyl carbamate 4 g , Is a white solid, yield (70%). ESI-MS: 330[M+H]+.
第二步Second step
在氮气保护下，将(4-溴苯并[d]噻唑-2-基)氨基甲酸叔丁酯(2g,6.0mmol)和硼酸三异丙酯(2.3g，12mmol)溶于干燥四氢呋喃(27mL)中，将体系温度降至-78℃，然后将n-BuLi(7.2mL,18mmol,2.5mol/L正己烷溶液)缓慢滴入到上述反应中，滴加过程中温度控制在-60℃以下，滴完后升温至-30℃反应30min。反应完毕后，反应液用饱和氯化铵淬灭，以二氯甲烷萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥，将有机相减压浓缩，残余物经C18反相柱层析(洗脱剂：CH 3CN:H 2O＝6:4)分离纯化，得到(2-((叔丁氧基羰基)氨基)苯并[d]噻唑-4-基)硼酸400mg，产率(22.6％)，为白色固体。ESI-MS:295[M+H] +。 Under nitrogen protection, (4-bromobenzo[d]thiazol-2-yl) tert-butyl carbamate (2g, 6.0mmol) and triisopropyl borate (2.3g, 12mmol) were dissolved in dry tetrahydrofuran (27mL) ), the temperature of the system is reduced to -78℃, and then n-BuLi (7.2mL, 18mmol, 2.5mol/L n-hexane solution) is slowly dropped into the above reaction, and the temperature is controlled below -60℃ during the dropping After dripping, the temperature was raised to -30°C and reacted for 30 minutes. After the reaction, the reaction solution was quenched with saturated ammonium chloride, extracted with dichloromethane, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and the residue was subjected to C18 reversed-phase column chromatography (Eluent: CH 3 CN: H 2 O = 6:4) was separated and purified to obtain (2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)boronic acid 400mg, yield (22.6%), a white solid. ESI-MS: 295[M+H] + .
第三步third step
在N 2保护下，将(2-((叔丁氧基羰基)氨基)苯并[d]噻唑-4-基)硼酸(98mg，0.33mmol)、(S)-3-((6-溴-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)氨基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(150mg，0.28mmol)、Pd(dppf)Cl 2(41mg,0.055mmol)和碳酸钾(115mg，0.83mmol)分散在异丙醇/水(4:1，5mL)中，加热至80℃并在此温度下搅拌反应16小时。反应完成后，将反应液减压浓缩，得到的残余物用中压flash硅胶柱层析(洗脱剂：甲醇(含1％氨水):二氯甲烷＝0-10％)分离纯化，得到(S)-3-((6-(2-((叔丁氧羰基)氨基)苯并[d]噻唑-4-基)-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)氨基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(133mg)，为棕色固体，收率68％。ESI-MS:710、712[M+H] +。 Under N 2 protection, (2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)boronic acid (98mg, 0.33mmol), (S)-3-((6-bromo -7-chloro-3-(((1-methylpyrrolidin-2-yl)methyl)amino)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine Tert-Butyl-1-carboxylate (150mg, 0.28mmol), Pd(dppf)Cl 2 (41mg, 0.055mmol) and potassium carbonate (115mg, 0.83mmol) dispersed in isopropanol/water (4:1, 5mL) , Heated to 80°C and stirred at this temperature for 16 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol (containing 1% ammonia): dichloromethane = 0-10%) to obtain ( S)-3-((6-(2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)-7-chloro-3-(((1-methylpyrrolidine-2 -Yl)methyl)amino)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (133mg), brown solid, yield 68 %. ESI-MS: 710, 712[M+H] + .
第四步the fourth step
将(S)-3-((6-(2-((叔丁氧羰基)氨基)苯并[d]噻唑-4-基)-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)氨基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(133mg，0.19mmol)溶解在二氯甲烷(5mL)中。在室温下，缓慢滴加三氟乙酸(1mL)，滴加完毕后在室温下搅拌反应2小时。反应完成后减压浓缩得到(S)-6-(2-氨基苯并[d]噻唑-4-基)-1-(氮杂环丁烷-3-基甲基)-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)氨基)喹喔啉-2(1H)-酮(114mg)，为棕色固体，收率(100％)。ESI-MS:510、512[M+H] +。 (S)-3-((6-(2-((tert-butoxycarbonyl)amino)benzo(d)thiazol-4-yl)-7-chloro-3-(((1-methylpyrrolidine) -2-yl)methyl)amino)-2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (133mg, 0.19mmol) was dissolved in two Methyl chloride (5mL). At room temperature, trifluoroacetic acid (1 mL) was slowly added dropwise, and after the addition was completed, the reaction was stirred at room temperature for 2 hours. After the reaction is completed, it is concentrated under reduced pressure to obtain (S)-6-(2-aminobenzo[d]thiazol-4-yl)-1-(azetidine-3-ylmethyl)-7-chloro-3 -(((1-methylpyrrolidin-2-yl)methyl)amino)quinoxaline-2(1H)-one (114mg), brown solid, yield (100%). ESI-MS: 510, 512[M+H] + .
第五步the fifth step
在N 2保护下，将(S)-6-(2-氨基苯并[d]噻唑-4-基)-1-(氮杂环丁烷-3-基甲基)-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)氨基)喹喔啉-2(1H)-酮(114mg，0.19mmol)溶解在二氯甲烷(4mL)中，加入三乙胺(189mg,1.87mmol)，让反应体系冷却至-78℃，将丙烯酰氯(18mg，0.20mmol)的二氯甲烷(2mL)溶液缓慢滴加到体系中，并于-78℃搅拌反应1小时。反应完成后减压浓缩反应液，残余物用prep-TLC(洗脱剂：NH 3·H 2O:MeOH:DCM＝0.01:1:10)初步分离，得到的粗品再以二甲基亚砜(DMSO)(2mL)溶解，用高压制备反相色谱分离纯化，收集馏分并冷冻干燥得到(S)-1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-(2-氨基苯并[d]噻唑 -4-基)-7-氯-3-(((1-甲基吡咯烷-2-基)甲基)氨基)喹喔啉-2(1H)-酮(21.57mg)，为白色固体，收率20％。 Under N 2 protection, (S)-6-(2-aminobenzo[d]thiazol-4-yl)-1-(azetidin-3-ylmethyl)-7-chloro-3 -(((1-Methylpyrrolidin-2-yl)methyl)amino)quinoxaline-2(1H)-one (114mg, 0.19mmol) was dissolved in dichloromethane (4mL), and triethylamine was added (189mg, 1.87mmol), the reaction system was cooled to -78°C, a solution of acryloyl chloride (18mg, 0.20mmol) in dichloromethane (2mL) was slowly added dropwise to the system, and the reaction was stirred at -78°C for 1 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was preliminarily separated by prep-TLC (eluent: NH 3 ·H 2 O: MeOH: DCM = 0.01:1:10), and the obtained crude product was then treated with dimethyl sulfoxide (DMSO) (2mL) was dissolved, separated and purified by high-pressure preparative reverse-phase chromatography, the fractions were collected and freeze-dried to obtain (S)-1-((1-acryloylazetidin-3-yl)methyl)-6 -(2-Aminobenzo[d]thiazol-4-yl)-7-chloro-3-(((1-methylpyrrolidin-2-yl)methyl)amino)quinoxaline-2(1H) -Ketone (21.57mg), white solid, yield 20%.
ESI-MS:564、566[M+H] +。 ESI-MS: 564, 566 [M+H] + .
1H-NMR(400MHz,DMSO-d6)δ:ppm 7.71～7.69(m,2H),7.56(s,2H),7.40(brs,1H),7.31(s,1H),7.14～7.06(m,2H),6.31(dd,1H,J＝16.8,10.4Hz),6.10(dd,1H,J＝16.8,2.4Hz),5.67(dd,1H,J＝10.4,2.4Hz),4.64～4.53(m,2H),4.33～4.28(m,1H),4.13～4.10(m,1H),4.02～3.96(m,1H),3.86～3.82(m,1H),3.63～3.56(m,2H),3.30～3.24(m,2H),3.18～3.11(m,1H),3.00～2.96(m,1H),2.31(s,3H),2.18～2.12(m,1H),1.85～1.80(m,1H),1.66～1.56(m,2H)。 1 H-NMR(400MHz,DMSO-d6)δ:ppm 7.71～7.69(m,2H),7.56(s,2H),7.40(brs,1H),7.31(s,1H),7.14～7.06(m, 2H), 6.31 (dd, 1H, J = 16.8, 10.4 Hz), 6.10 (dd, 1H, J = 16.8, 2.4 Hz), 5.67 (dd, 1H, J = 10.4, 2.4 Hz), 4.64～4.53 (m ,2H),4.33～4.28(m,1H),4.13～4.10(m,1H),4.02～3.96(m,1H),3.86～3.82(m,1H),3.63～3.56(m,2H),3.30 ～3.24(m,2H),3.18～3.11(m,1H),3.00～2.96(m,1H),2.31(s,3H),2.18～2.12(m,1H),1.85～1.80(m,1H) ,1.66～1.56(m,2H).
实施例59：(S)-1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-5-氟-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮的制备Example 59: (S)-1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-5-fluoro-6-(3-hydroxynaphthalene-1-yl) Preparation of -3-((1-methylpyrrolidin-2-yl)methoxy)quinoxaline-2(1H)-one
Figure PCTCN2021091102-appb-000130
Figure PCTCN2021091102-appb-000130
第一步first step
将5-氯-1,3-二氟-2-硝基苯(6.0g，31.0mmol)溶解在乙腈(100mL)中，向其中加入3-(氨基甲基)氮杂环丁烷-1-羧酸叔丁酯(5.78g，31.0mmol)和无水碳酸钾(12.8g，93.0mmol)。反应在室温下搅拌16小时。反应液过滤，滤液减压浓缩，得到3-(((5-氯-3-氟-2-硝基苯基)氨基)甲基)氮杂环丁烷-1-羧酸叔丁酯(10.0g)，为橙红色固体，收率90％，粗品直接用于下一步反应。ESI-MS:360[M+H] + Dissolve 5-chloro-1,3-difluoro-2-nitrobenzene (6.0 g, 31.0 mmol) in acetonitrile (100 mL), and add 3-(aminomethyl)azetidine-1- Tert-butyl carboxylate (5.78 g, 31.0 mmol) and anhydrous potassium carbonate (12.8 g, 93.0 mmol). The reaction was stirred at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 3-(((5-chloro-3-fluoro-2-nitrophenyl)amino)methyl)azetidine-1-carboxylate (10.0 g), it is orange-red solid, the yield is 90%, and the crude product is directly used in the next reaction. ESI-MS:360[M+H] +
第二步Second step
将3-(((5-氯-3-氟-2-硝基苯基)氨基)甲基)氮杂环丁烷-1-羧酸叔丁酯(10.0g，27.8mmol)溶解在乙醇(100mL)和水(20mL)中，加入氯化铵(14.9g，278mmol)和铁粉(7.8g，139mmol)。反应在90℃下搅拌1小时，反应液冷却后过滤，滤液减压浓缩除去乙醇，混合液用二氯甲烷(3 x 100mL)萃取，合并有机相，有机相经饱和食盐水洗涤(100mL)，无水硫酸钠干燥，过滤。滤液浓缩得残余物，残余物经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝2:1)分离纯化，得到3-(((2-氨基-5-氯-3-氟苯基)氨基)甲基)氮杂环丁烷-1-羧酸叔丁酯(8.0g)，为白色固体。收率88％。ESI-MS:330[M+H] + 3-(((5-chloro-3-fluoro-2-nitrophenyl)amino)methyl)tert-butyl azetidine-1-carboxylate (10.0g, 27.8mmol) was dissolved in ethanol ( 100 mL) and water (20 mL) were added ammonium chloride (14.9 g, 278 mmol) and iron powder (7.8 g, 139 mmol). The reaction was stirred at 90°C for 1 hour. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure to remove ethanol. The mixture was extracted with dichloromethane (3 x 100 mL). The organic phases were combined and the organic phase was washed with saturated brine (100 mL). Dry with anhydrous sodium sulfate and filter. The filtrate was concentrated to obtain a residue, and the residue was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to obtain 3-(((2-amino-5-chloro-3-fluorobenzene) (Yl)amino)methyl)tert-butyl azetidine-1-carboxylate (8.0 g) as a white solid. The yield was 88%. ESI-MS:330[M+H] +
第三步third step
将3-(((2-氨基-5-氯-3-氟苯基)氨基)甲基)氮杂环丁烷-1-羧酸叔丁酯(1.5g,4.56mmol)溶于四氢呋喃(30 mL)中，加入三乙胺(4.60g，45.56mmol)，在冰浴条件下，缓慢滴加草酰氯单甲酯(2.78g，22.8mmol)溶液，在室温下搅拌反应1小时，然后升温至90℃并搅拌3小时，反应液冷却后减压浓缩，浓缩物经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝1:1)分离纯化，得到3-((7-氯-5-氟-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(1.0g)，为白色固体。收率58％。ESI-MS:384[M+H] +。 3-(((2-Amino-5-chloro-3-fluorophenyl)amino)methyl)azetidine-1-carboxylic acid tert-butyl ester (1.5g, 4.56mmol) was dissolved in tetrahydrofuran (30 mL), add triethylamine (4.60g, 45.56mmol), slowly add dropwise a solution of oxalyl monomethyl chloride (2.78g, 22.8mmol) in an ice bath, stir and react at room temperature for 1 hour, and then warm to After stirring at 90°C for 3 hours, the reaction solution was cooled and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 1:1) to obtain 3-((7-chloro- 5-fluoro-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (1.0g), White solid. The yield was 58%. ESI-MS: 384[M+H] + .
第四步the fourth step
将3-((7-氯-5-氟-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(1.0g，2.08mmol)溶解在N,N-二甲基甲酰胺(10mL)中，加入乙酸(125mg，2.08mmol)，缓慢滴加溴素(986mg，6.24mmol)，在室温下搅拌1h，反应结束后加饱和碳酸氢钠溶液(20mL)淬灭，用二氯甲烷(20mL)萃取三次，有机相经无水硫酸钠干燥后减压浓缩，浓缩残余物经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝1:1)分离纯化，得到3-((6-溴-7-氯-5-氟-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(700mg)，为白色固体。收率73％。ESI-MS:462,464[M+H] +。 Add 3-((7-chloro-5-fluoro-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid Tert-butyl ester (1.0g, 2.08mmol) was dissolved in N,N-dimethylformamide (10mL), acetic acid (125mg, 2.08mmol) was added, bromine (986mg, 6.24mmol) was slowly added dropwise, at room temperature After stirring for 1 h, after the reaction was completed, saturated sodium bicarbonate solution (20 mL) was added to quench, and the mixture was extracted with dichloromethane (20 mL) three times. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue was subjected to silica gel column chromatography ( Eluent: petroleum ether: ethyl acetate = 1:1) separation and purification to obtain 3-((6-bromo-7-chloro-5-fluoro-2,3-dioxo-3,4-dihydroquine Tert-butyl oxaline-1(2H)-yl)methyl)azetidine-1-carboxylate (700 mg) as a white solid. The yield was 73%. ESI-MS: 462,464 [M+H] + .
第五步the fifth step
将3-((6-溴-7-氯-5-氟-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(700mg，1.5mmol)溶解在四氢呋喃(10mL)中，向其中加入(S)-(1-甲基吡咯烷-2-基)甲醇(207mg，1.8mmol)和三苯基膦(789mg，3.0mmol)。将反应液冷却至0℃，在氮气氛围下，将偶氮二甲酸二异丙酯(606mg，3.0mmol)缓慢滴加到体系中，滴加完后升至室温搅拌1小时。然后将反应液减压浓缩，浓缩残余物经硅胶柱层析(洗脱剂：二氯甲烷:甲醇＝20:1)分离纯化，得到(S)-3-((6-溴-7-氯-5-氟-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(200mg)，为白色固体。收率24％。ESI-MS:561,563[M+H] +。 Add 3-((6-bromo-7-chloro-5-fluoro-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine Tert-Butyl-1-carboxylate (700mg, 1.5mmol) was dissolved in tetrahydrofuran (10mL), and (S)-(1-methylpyrrolidin-2-yl)methanol (207mg, 1.8mmol) and triphenyl were added to it Phosphine (789 mg, 3.0 mmol). The 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. Then the reaction solution was concentrated under reduced pressure, and the concentrated residue was separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20:1) to obtain (S)-3-((6-bromo-7-chloro -5-fluoro-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl) Tert-Butyl azetidine-1-carboxylate (200 mg) as a white solid. The yield was 24%. ESI-MS: 561,563 [M+H] + .
第六步Sixth step
将(S)-3-((6-溴-7-氯-5-氟-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(200mg，0.36mmol)溶解在1,4-二氧六环(5mL)和水(1mL)中，加入碳酸钠(115mg，1.08mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)萘-2-醇(116mg，0.43mmol)和RuPhos Pd G3(58mg，0.07mmol)。氮气保护下加热至80℃，搅拌1小时，反应液冷却后过滤，滤液减压浓缩，浓缩物经硅胶柱层析(洗脱剂：二氯甲烷:甲醇＝15:1)分离纯化，得到(S)-3-((7-氯-5-氟-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(120mg)，为白色固体。收率54％。ESI-MS:623[M+H] +。 (S)-3-((6-Bromo-7-chloro-5-fluoro-3-((1-methylpyrrolidin-2-yl)methoxy)-2-oxo-3,4- Dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (200mg, 0.36mmol) was dissolved in 1,4-dioxane (5mL) and water ( 1mL), add sodium carbonate (115mg, 1.08mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene- 2-alcohol (116 mg, 0.43 mmol) and RuPhos Pd G3 (58 mg, 0.07 mmol). Under the protection of nitrogen, it was heated to 80°C and stirred for 1 hour. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 15:1) to obtain ( S)-3-((7-chloro-5-fluoro-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)-2- Tert-butyl oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylate (120 mg) as a white solid. The yield was 54%. ESI-MS: 623[M+H] + .
第七步Seventh step
将(S)-3-((7-氯-5-氟-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)-2-氧代喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(120mg,0.19mmol)溶于二氯甲烷(5mL)中，加入三氟乙酸(1mL)，在室温下搅拌1小时，然后减压浓缩得到1-(氮杂环丁烷-3-基甲基)-7-氯-5-氟-6-(3-羟基萘-1-基)-3-(((S)-1-甲基吡咯烷基-2-基)甲氧基)喹喔啉-2(1H)-酮(80mg)，为白色固体。收率80％。ESI-MS:523[M+H] +。 Add (S)-3-((7-chloro-5-fluoro-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy)- 2-oxoquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (120mg, 0.19mmol) was dissolved in dichloromethane (5mL), and trifluoroacetic acid was added (1mL), stirred at room temperature for 1 hour, and then concentrated under reduced pressure to obtain 1-(azetidin-3-ylmethyl)-7-chloro-5-fluoro-6-(3-hydroxynaphthalene-1- Yl)-3-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinoxaline-2(1H)-one (80 mg) as a white solid. The yield is 80%. ESI-MS: 523[M+H] + .
第八步Eighth step
1-(氮杂环丁烷-3-基甲基)-7-氯-5-氟-6-(3-羟基萘-1-基)-3-(((S)-1-甲基吡咯烷基-2-基)甲氧基)喹喔啉-2(1H)-酮(80mg，0.15mmol)溶解在二氯甲烷(1mL)中，加入三乙胺(46mg，0.45mmol)，在氮气保护下，降 温至-78℃，在-78℃下，缓慢滴加丙烯酰氯(16mg，0.18mmol)的二氯甲烷溶液(0.5mL)，在此温度下继续搅拌1小时，将反应液减压浓缩，残余物经prep-HPLC(洗脱剂：乙腈:水(10mM NH 4HCO 3)＝35％～60％)分离纯化，得到(S)-1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-5-氟-6-(3-羟基萘-1-基)-3-((1-甲基吡咯烷-2-基)甲氧基)喹喔啉-2(1H)-酮(14mg)，为白色固体，收率17％。 1-(azetidine-3-ylmethyl)-7-chloro-5-fluoro-6-(3-hydroxynaphthalene-1-yl)-3-(((S)-1-methylpyrrole Alkyl-2-yl)methoxy)quinoxaline-2(1H)-one (80mg, 0.15mmol) was dissolved in dichloromethane (1mL), triethylamine (46mg, 0.45mmol) was added, and the Under protection, the temperature was lowered to -78°C, and acryloyl chloride (16mg, 0.18mmol) in dichloromethane (0.5mL) was slowly added dropwise at -78°C. Stirring was continued at this temperature for 1 hour, and the reaction solution was reduced in pressure After concentration, the residue was separated and purified by prep-HPLC (eluent: acetonitrile: water (10mM NH 4 HCO 3 ) = 35% to 60%) to obtain (S)-1-((1-acryloylazetidine) Alkyl-3-yl)methyl)-7-chloro-5-fluoro-6-(3-hydroxynaphthalen-1-yl)-3-((1-methylpyrrolidin-2-yl)methoxy) Quinoxaline-2(1H)-one (14mg) is a white solid with a yield of 17%.
ESI-MS:577[M+H] + ESI-MS:577[M+H] +
1H NMR(400MHz,DMSO-d 6)δ9.98(s,1H),7.88(s,1H),7.80(d,J＝8.3Hz,1H),7.44(ddd,J＝8.1,6.4,1.6Hz,1H),7.30–7.17(m,3H),7.04(d,J＝2.4Hz,1H),6.32(dd,J＝16.9,10.2Hz,1H),6.11(dd,J＝17.0,2.3Hz,1H),5.67(dd,J＝10.2,2.4Hz,1H),4.60(d,J＝7.4Hz,2H),4.32(ddd,J＝17.6,11.6,6.8Hz,3H),4.13(t,J＝7.2Hz,1H),3.99(t,J＝9.4Hz,1H),3.89–3.81(m,1H),3.21–3.11(m,1H),2.95(s,1H),2.67(s,1H),2.39–2.36(m,3H),2.19(d,J＝17.0Hz,1H),1.97(td,J＝11.7,10.3,6.9Hz,2H),1.73–1.64(m,2H). 1 H NMR(400MHz,DMSO-d 6 )δ9.98(s,1H),7.88(s,1H),7.80(d,J=8.3Hz,1H),7.44(ddd,J=8.1,6.4,1.6 Hz, 1H), 7.30–7.17 (m, 3H), 7.04 (d, J = 2.4 Hz, 1H), 6.32 (dd, J = 16.9, 10.2 Hz, 1H), 6.11 (dd, J = 17.0, 2.3 Hz ,1H), 5.67 (dd, J = 10.2, 2.4 Hz, 1H), 4.60 (d, J = 7.4 Hz, 2H), 4.32 (ddd, J = 17.6, 11.6, 6.8 Hz, 3H), 4.13 (t, J=7.2Hz,1H),3.99(t,J=9.4Hz,1H),3.89–3.81(m,1H),3.21–3.11(m,1H),2.95(s,1H),2.67(s,1H) ), 2.39–2.36 (m, 3H), 2.19 (d, J = 17.0 Hz, 1H), 1.97 (td, J = 11.7, 10.3, 6.9 Hz, 2H), 1.73–1.64 (m, 2H).
生物测试Biological test
测试例1：细胞磷酸化抑制试验Test Example 1: Cell Phosphorylation Inhibition Test
实验目的：Purpose:
对本发明化合物进行细胞磷酸化抑制试验，以验证本发明化合物对KRAS G12C突变的NCI-H358人非小细胞肺癌的磷酸化抑制效果。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.
主要试剂：Main reagents:
细胞株NCI-H358，Advanced Phosphor-ERK1/2(THR202/TYR204)KITS，RPMI1640培养基，胎牛血清，0.25％胰蛋白酶-EDTA消化液，PBS，细胞培养级DMSO，青链霉素。Cell line NCI-H358, Advanced Phosphor-ERK1/2 (THR202/TYR204) KITS, RPMI1640 medium, fetal bovine serum, 0.25% trypsin-EDTA digestion solution, PBS, cell culture grade DMSO, penicillin streptomycin.
主要仪器：Main instruments:
BioTek酶标仪，细胞培养瓶，96孔细胞培养板，384孔酶标板，CO2恒温培养箱，10μL 12道移液器，100μL 12道移液器，200μL 12道移液器。BioTek microplate reader, cell culture flask, 96-well cell culture plate, 384-well microplate, CO2 constant temperature incubator, 10μL 12-channel pipette, 100μL 12-channel pipette, 200μL 12-channel pipette.
试验方法：experiment method:
在96孔细胞培养板中加入NCI-H358细胞悬液，其中包含25000个细胞，放入二氧化碳培养箱过夜培养。将待测化合物3倍稀释，9个浓度点(从10000nM到1.52nM)，分别加入到细胞培养板对应的孔中，然后放入培养箱培养3小时。然后根据Advanced Phosphor-ERK1/2(THR202/TYR204)试剂盒的操作说明，进行细胞裂解30分钟，抗体孵育4小时，用BioTek读板。Add 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. Then, according to 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.
数据分析：data analysis:
IC 50结果由IDBS公司的GraphPad Prism 6.0软件分析获得。 The IC 50 result was analyzed by the GraphPad Prism 6.0 software of IDBS.
试验结果：test results:
本发明化合物对于NCI-H358(G12C突变)细胞的磷酸化抑制率IC50的数据为：The IC50 data of the phosphorylation inhibition rate of the compounds of the present invention on NCI-H358 (G12C mutation) cells are:
受试化合物Test compound NCI-H358 IC 50(nM) NCI-H358 IC 50 (nM)
实施例2Example 2 367.7367.7
实施例3Example 3 19231923
实施例9Example 9 365.6365.6
实施例10Example 10 215.3215.3
实施例11Example 11 340.6340.6
实施例12Example 12 75.6975.69
实施例13Example 13 108.5108.5
实施例14Example 14 37503750
实施例18Example 18 12131213
实施例19Example 19 201.1201.1
实施例20Example 20 28762876
实施例21Example 21 191.7191.7
实施例22Example 22 42304230
实施例23Example 23 ＞10000＞10000
实施例24Example 24 621.4621.4
实施例25Example 25 359.9359.9
实施例26Example 26 113.9113.9
实施例27Example 27 474.9474.9
实施例28Example 28 249.5249.5
实施例29Example 29 938.6938.6
实施例30Example 30 110.8110.8
实施例31Example 31 151.0151.0
实施例32Example 32 492.1492.1
实施例33Example 33 122.9122.9
实施例34Example 34 132.4132.4
实施例35Example 35 14691469
实施例36Example 36 ＞10000＞10000
实施例37Example 37 22032203
实施例38Example 38 206.2206.2
实施例39Example 39 184.4184.4
实施例40Example 40 178.6178.6
实施例41Example 41 367.4367.4
实施例42Example 42 464.1464.1
实施例44Example 44 552.3552.3
实施例45Example 45 12211221
实施例46Example 46 328.3328.3
实施例47Example 47 390.9390.9
实施例48Example 48 335.9335.9
实施例49Example 49 277.3277.3
实施例50Example 50 375.2375.2
实施例51Example 51 204.6204.6
实施例52Example 52 451.5451.5
实施例53Example 53 163.5163.5
实施例54Example 54 189.1189.1
实施例55Example 55 174.4174.4
实施例56Example 56 125.2125.2
实施例57Example 57 ＞10000＞10000
实施例58Example 58 398.2398.2
实施例59Example 59 291.6291.6
实施例60Example 60 ＞10000＞10000
实施例62Example 62 ＞1000＞1000
测试例2：蛋白结合试验Test Example 2: Protein binding test
试验目的：Test purposes:
对本发明化合物进行蛋白结合试验，以验证本发明化合物是否结合在KRAS G12C突变的蛋白结构中。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.
主要试剂：Main reagents:
Hepes，NaCl，MgCl 2，EDTA，DTT，GDP，KRAS-4B-G12C，DMSO，MilliQ H2O，ACN，甲酸。 Hepes, NaCl, MgCl 2 , EDTA, DTT, GDP, KRAS-4B-G12C, DMSO, MilliQ H2O, ACN, formic acid.
主要仪器：Main instruments:
Waters Acquity I Class UPLC-Xevo G2-XS QTOF，Sepax Bio-C4，2.1 X 50mm，3μmWaters Acquity Class UPLC-Xevo G2-XS QTOF, Sepax Bio-C4, 2.1 X 50mm, 3μm
试验方法：experiment method:
KRAS-4B-G12C蛋白与20倍蛋白浓度的GDP1:1混合，室温孵育1.5小时，然后将GDP-loaded KRAS-4B-G12C蛋白稀释至20μM，5μL的蛋白，5μL 30μM的化合物在12.5mM Hepes，75mM NaCl，1mM MgCl 2反应体系中孵育5分钟或30分钟；加入5μL 5％的甲酸，终止反应。样品15000rpm离心10分钟，上样检测。 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 20μM, 5μL protein, 5μL 30μM compound in 12.5mM Hepes, Incubate in a 75mM NaCl, 1mM MgCl 2 reaction system for 5 minutes or 30 minutes; add 5μL 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.
UPLC条件：UPLC conditions:
Figure PCTCN2021091102-appb-000131
Figure PCTCN2021091102-appb-000131
LC的梯度时间表LC gradient schedule
Figure PCTCN2021091102-appb-000132
Figure PCTCN2021091102-appb-000132
TOF MS参数TOF MS parameters
Figure PCTCN2021091102-appb-000133
Figure PCTCN2021091102-appb-000133
Figure PCTCN2021091102-appb-000134
Figure PCTCN2021091102-appb-000134
数据分析：data analysis:
％结合至KRAS(G12C)＝复合物的峰高/[复合物的峰高+未结合的KRAS G12C的峰高]X 100.% Bound to KRAS (G12C) = peak height of the complex/[peak height of the complex + peak height of unbound KRAS G12C] X 100.
试验结果：test results:
测试结果如下表所示：The test results are shown in the following table:
实施例号Example number POC(％，5min)POC (%, 5min) POC(％，30min)POC (%, 30min)
实施例1Example 1 7.97.9 69.269.2
实施例2Example 2 22.422.4 90.690.6
实施例4Example 4 9.89.8 74.074.0
实施例3Example 3 54.254.2 92.192.1
实施例9Example 9 73.773.7 94.894.8
实施例10Example 10 67.567.5 93.293.2
实施例11Example 11 60.160.1 93.493.4
实施例12Example 12 76.876.8 92.792.7
实施例13Example 13 57.957.9 90.190.1
实施例14Example 14 13.013.0 52.452.4
实施例15Example 15 3.33.3 16.416.4
实施例16Example 16 2.22.2 12.512.5
实施例17Example 17 1.81.8 8.38.3
实施例18Example 18 21.721.7 69.269.2
实施例19Example 19 59.659.6 90.790.7
实施例20Example 20 9.59.5 45.545.5
实施例21Example 21 71.671.6 92.492.4
实施例22Example 22 3.23.2 18.818.8
实施例23Example 23 5.25.2 29.029.0
实施例24Example 24 75.975.9 92.492.4
实施例25Example 25 58.858.8 85.385.3
实施例26Example 26 62.662.6 86.986.9
实施例27Example 27 35.935.9 75.575.5
实施例28Example 28 50.250.2 84.084.0
实施例29Example 29 26.726.7 73.173.1
实施例30Example 30 59.959.9 89.389.3
实施例31Example 31 82.582.5 92.992.9
实施例32Example 32 54.454.4 89.989.9
实施例33Example 33 87.487.4 93.193.1
实施例34Example 34 57.157.1 87.987.9
实施例35Example 35 14.814.8 47.647.6
实施例36Example 36 62.862.8 80.780.7
实施例37Example 37 11.911.9 39.039.0
实施例38Example 38 60.160.1 90.390.3
实施例39Example 39 62.762.7 89.589.5
实施例40Example 40 55.955.9 84.484.4
实施例41Example 41 80.680.6 93.393.3
实施例42Example 42 53.353.3 88.088.0
实施例43Example 43 31.731.7 68.668.6
实施例44Example 44 38.038.0 78.578.5
实施例45Example 45 34.534.5 81.381.3
实施例46Example 46 50.950.9 81.281.2
实施例47Example 47 55.755.7 84.684.6
实施例48Example 48 47.147.1 85.985.9
实施例49Example 49 53.853.8 85.985.9
实施例50Example 50 67.167.1 92.692.6
实施例51Example 51 80.980.9 92.792.7
实施例52Example 52 75.075.0 92.792.7
实施例53Example 53 81.981.9 94.594.5
实施例54Example 54 77.077.0 94.594.5
实施例55Example 55 57.757.7 91.591.5
实施例56Example 56 64.664.6 91.991.9
实施例57Example 57 48.948.9 77.977.9
实施例58Example 58 20.420.4 64.264.2
实施例59Example 59 54.854.8 78.678.6
实施例60Example 60 5.85.8 13.213.2
实施例61Example 61 15.215.2 65.065.0
实施例62Example 62 29.329.3 82.382.3
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明，不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干简单推演或替换，都应当视为属于本发明的保护范围。The above content is a further detailed description of the present invention in combination with specific preferred embodiments, and it cannot be considered that the specific implementation of the present invention is limited to these descriptions. For those of ordinary skill in the technical field to which the present invention belongs, a number of simple deductions or substitutions can be made without departing from the concept of the present invention, which should be regarded as falling within the protection scope of the present invention.

Claims (28)

  1. 式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：The compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof , And their mixtures:
    Figure PCTCN2021091102-appb-100001
    Figure PCTCN2021091102-appb-100001
    其中，in,
    环A为C 6-10芳基或5-14元杂芳基，优选为萘基或9-10元杂芳基，优选萘基、苯并5元杂芳基或苯并6元杂芳基； 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独立地为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a、C 0-6亚烷基-C(O)N(R 1a) 2或C 0-6亚烷基-S(O) mR 1a；优选地，其中至少一个R 6为-O-R 1a； 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 ;
    m＝1或2；m=1 or 2;
    n＝0、1、2、3、4、5、6或7；n=0, 1, 2, 3, 4, 5, 6 or 7;
    L 1为-H 1-H 2-H 3-H 4-； L 1 is -H 1 -H 2 -H 3 -H 4 -;
    其中H 1选自-O-、-S-、-N(R H’)-、-C(R H)(R H)-、-C(R H)(R H)-C(R H)(R H)-或-C(R H)(R H)-C(R H)(R H)-C(R H)(R H)-，H 2、H 3和H 4独立地选自-O-、-S-、-N(R H’)-或-C(R H)(R H)-； 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 )-;
    并且，H 1和H 3上的R H/R H’取代基、H 1和H 4上的R H/R H’取代基、和H 2和H 4上的R H/R H’取代基中的一对或两对R H/R H’取代基可以结合形成C 1-3亚烷基； And, H 1 and H R H on 3 / R H 'substituent group, H 1 and H R H on 4 / R H' substituent group, and H 2 and H R H on 4 / R H 'substituent One or two pairs of R H /R H'substituents can be combined to form a C 1-3 alkylene group;
    R H为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a或C 0-6亚烷基-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R H'is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    R 1为C 1-6卤代烷基或
    Figure PCTCN2021091102-appb-100002
    R 1 is C 1-6 haloalkyl or
    Figure PCTCN2021091102-appb-100002
    其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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 ;
    其任选被R’取代；并且R a和R b可以形成化学键从而使得双键变为叁键； Optionally R 'group; and R a and R b may form a chemical bond so that the triple bond becomes a double bond;
    其中R’为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； Wherein 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为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-、-N(R L2’)-(C(R L2)(R L2)) p-或-(C(R L2)(R L2)) p-； 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 -;
    其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
    R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    并且，相邻原子上的R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, 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为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被r个R取代； 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. 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为化学键或-(C(R L3)(R L3)) p-； L 3 is a chemical bond or -(C(R L3 )(R L3 )) p -;
    其中R L3为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； Wherein 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 ;
    并且，相邻原子上的R L3可以结合形成C 3-10环烷基或3-10元杂环基； In addition, 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为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被r个R取代； 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. C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by r R;
    其中R为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-SF 5、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a、C 0-6亚烷基-C(O)N(R 1a) 2、C 0-6亚烷基-S(O) mR 1a、C 0-6亚烷基-C 3-10环烷基、C 0-6亚烷基-3-10元杂环基、C 0-6亚烷基-C 6-10芳基或C 0-6亚烷基-5-14元杂芳基； Wherein 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 6-10 aryl or C 0-6 alkylene-5-14-membered heteroaryl;
    r＝0、1、2、3、4、5、6或7；r=0, 1, 2, 3, 4, 5, 6 or 7;
    R 4为H、D、卤素、-CN、-SF 5、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基； 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为CR 5或N； Z 1 is CR 5 or N;
    Z 2为CR 5或N； Z 2 is CR 5 or N;
    R 5独立地为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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为H，或者R 7与-L 3-R 3形成双键，或R 7与-L 2-R 2形成＝Z； R 7 is H, or R 7 and -L 3 -R 3 form a double bond, or R 7 and -L 2 -R 2 form = Z;
    Z为O或S；Z is O or S;
    R 1a为H、-C(O)H、-C(O)OH、-C(O)C 1-6烷基、-C(O)OC 1-6烷基、-S(O) mC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基； 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;
    上述各基团中含有的OH、NH、NH 2、CH、CH 2、CH 3基团在每次出现时各自任选地被1、2、3或更多个R s及其同位素变体取代，其中所述R s在每次出现时独立地选自：卤素、羟基、氨基、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、C 6-10芳基、5-14元杂芳基、C 6-12芳烷基、-OR a’、-OC(O)R a’、-C(O)R a’、-C(O)OR a’、-C(O)NR a’R b’、-S(O) qR a’、-S(O) qOR a’、-S(O) qNR a’R b’、-NR a’R b’、-NR a’C(O)R b’、-NR a’-C(O)OR b’、-NR a’-S(O) q-R b’、-NR a’C(O)NR a’R b’、-C 1-6亚烷基-R a’、-C 1-6亚烷基-OR a’、-C 1-6亚烷基-OC(O)R a’、-C 1-6亚烷基-C(O)OR a’、-C 1-6亚烷基-S(O) qR a’、-C 1-6亚烷基-S(O) qOR a’、-C 1-6亚烷基-OC(O)NR a’R b’、-C 1-6亚烷基-C(O)NR a’R b’、-C 1-6亚烷基-NR a’-C(O)NR a’R b’、-C 1-6亚烷基-OS(O) qR a’、-C 1-6亚烷基-S(O) qNR a’R b’、-C 1-6亚烷基-NR a’-S(O) qNR a’R b’、-C 1-6亚烷基-NR a’R b’和-O-C 1-6亚烷基-NR a’R b’，并且其中关于取代基R s所述的羟基、氨基、烷基、亚烷基、环烷基、杂环基、芳基、杂芳基和芳烷基进一步任选地被1、2、3或更多个独立地选自下列的取代基及其同位素变体取代：卤素、OH、氨基、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷基羟基、C 3-6环烷基、3-10元杂环基、C 6-10芳基、5-14 元杂芳基和C 6-12芳烷基； The OH, NH, NH 2 , CH, CH 2 , and CH 3 groups contained in each of the above groups are each optionally substituted by 1, 2, 3 or more R s and its isotopic variants each time it appears , Wherein 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 ' , -S (O) q OR a', -S (O) q NR a 'R b', -NR a 'R b', -NR a 'C (O) R b ', -NR a' -C (O ) OR b ', -NR a' -S (O) q -R b ', -NR a' C (O) NR a 'R b', -C 1-6 Alkylene-R a' , -C 1-6 alkylene-OR a' , -C 1-6 alkylene-OC(O)R a' , -C 1-6 alkylene-C(O ) OR a' , -C 1-6 alkylene-S(O) q R a' , -C 1-6 alkylene-S(O) q OR a' , -C 1-6 alkylene- OC (O) NR a 'R b', -C 1-6 alkylene -C (O) NR a 'R b', -C 1-6 alkylene -NR a '-C (O) NR a 'R b', -C 1-6 alkylene -OS (O) q R a ' , -C 1-6 alkylene -S (O) q NR a' R b ', -C 1-6 alkylene alkyl -NR a '-S (O) q NR a' R b ', -C 1-6 alkylene -NR a' R b 'and -OC 1-6 alkylene group -NR a' R b ' , And wherein the hydroxyl group, amino group, alkyl group, alkylene group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group and aralkyl group described with respect to the substituent R s are further optionally substituted by 1, 2, 3 Or more substituents independently selected from the following substituents and isotopic variants thereof: halogen, OH, amino, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkane Group hydroxyl, C 3-6 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl group, 5-14 membered heteroaryl group and C 6-12 aralkyl group;
    q每次出现时各自独立地为1或2；Each time q appears independently 1 or 2;
    R a’和R b’在每次出现时各自独立地选自H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷基-O-、C 1-6烷基-S-、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-14元杂芳基和C 6-12芳烷基。 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.
  2. 权利要求1的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，R 6独立地为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基或-O-R 1a；优选地，R 6独立地为-O-R 1a、优选-OH；优选地，至少一个R 6为非H基团。 The compound of formula (I) of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, wherein R 6 is independently H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl or -OR 1a ; preferably , R 6 is independently -OR 1a , preferably -OH; preferably, at least one R 6 is a non-H group.
  3. 权利要求1或2的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, Prodrugs or isotopic variants, and their mixtures,
    其中，
    Figure PCTCN2021091102-appb-100003
    为
    Figure PCTCN2021091102-appb-100004
    其中Z 3、Z 4和Z 5独立地为CR 6或N；环B为苯基或5-6元杂芳基；     in,
    Figure PCTCN2021091102-appb-100003
    for
    Figure PCTCN2021091102-appb-100004
    Wherein Z 3 , Z 4 and Z 5 are independently CR 6 or N; ring B is phenyl or 5-6 membered heteroaryl;
    优选地，
    Figure PCTCN2021091102-appb-100005
    为
    Figure PCTCN2021091102-appb-100006
    优选地为：
    Figure PCTCN2021091102-appb-100007
    Figure PCTCN2021091102-appb-100008
    优选
    Figure PCTCN2021091102-appb-100009
    Preferably,
    Figure PCTCN2021091102-appb-100005
    for
    Figure PCTCN2021091102-appb-100006
    Preferably:
    Figure PCTCN2021091102-appb-100007
    Figure PCTCN2021091102-appb-100008
    Preferred
    Figure PCTCN2021091102-appb-100009
  4. 权利要求1-3中任一项的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Polymorphs, prodrugs or isotopic variants, and their mixtures,
    其中，L 1为：
    Figure PCTCN2021091102-appb-100010
    Figure PCTCN2021091102-appb-100011
    优选地，L 1为
    Figure PCTCN2021091102-appb-100012
    Among them, L 1 is:
    Figure PCTCN2021091102-appb-100010
    Figure PCTCN2021091102-appb-100011
    Preferably, L 1 is
    Figure PCTCN2021091102-appb-100012
  5. 权利要求1-4中任一项的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Polymorphs, prodrugs or isotopic variants, and their mixtures,
    其中，R 1为
    Figure PCTCN2021091102-appb-100013
    优选地，R 1为
    Figure PCTCN2021091102-appb-100014
    Where R 1 is
    Figure PCTCN2021091102-appb-100013
    Preferably, R 1 is
    Figure PCTCN2021091102-appb-100014
  6. 权利要求1-5中任一项的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Polymorphs, prodrugs or isotopic variants, and their mixtures,
    其中，L 2为化学键、-O-、-OCH 2-、-OCH 2CH 2-、-OCH 2CH 2CH 2-、-NH-、-NHCH 2-、-NHCH 2CH 2-、-NMeCH 2CH 2-或-CH 2CH 2-，优选-OCH 2-或-OCH 2CH 2-；L 3为-CH 2-或-CH 2CH 2-。 Among them, 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 -, -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 -.
  7. 权利要求1-6中任一项的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Polymorphs, prodrugs or isotopic variants, and their mixtures,
    其中，R 2或R 3为H、-N(R 1a) 2、C 3-6环烷基、4-7元杂环基、苯基或5-6元杂芳基，优选H、
    Figure PCTCN2021091102-appb-100015
    Among them, 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 H,
    Figure PCTCN2021091102-appb-100015
    优选地，R 2或R 3被1-3个R取代，其中R选自C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-SF 5、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a、C 0-6亚烷基-C(O)N(R 1a) 2、C 0-6亚烷基-S(O) mR 1a、C 0-6亚烷基-C 3-10环烷基、C 0-6亚烷基-3-10元杂环基、C 0-6亚烷基-C 6-10芳基或C 0-6亚烷基-5-14元杂芳基。 Preferably, 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-C 6-10 aryl or C 0-6 alkylene-5-14-membered heteroaryl.
  8. 权利要求1-7中任一项的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，The compound of formula (I) according to any one of claims 1-7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Polymorphs, prodrugs or isotopic variants, and their mixtures,
    其中，R 4为H、卤素、-CN、-SF 5、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-10环烷基或C 3-10卤代环烷基，优选卤素，更优选Cl。 Wherein, 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.
  9. 权利要求1-8中任一项的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其具有以下结构：The compound of formula (I) according to any one of claims 1-8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Polymorphs, prodrugs or isotopic variants, and mixtures thereof, have the following structure:
    Figure PCTCN2021091102-appb-100016
    Figure PCTCN2021091102-appb-100016
    其中，in,
    环B为苯基或5-6元杂芳基；Ring B is phenyl or 5-6 membered heteroaryl;
    R N1、R N2和R N3独立地为H、C 1-6烷基或C 1-6卤代烷基；或者，R N2和R N3可以结合形成C 2-4亚烷基； 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;
    其他基团如权利要求1-8中任一项所定义。Other groups are as defined in any one of claims 1-8.
  10. 式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：The compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof , And their mixtures:
    Figure PCTCN2021091102-appb-100017
    Figure PCTCN2021091102-appb-100017
    其中：in:
    Figure PCTCN2021091102-appb-100018
    选自
    Figure PCTCN2021091102-appb-100019
    Figure PCTCN2021091102-appb-100018
    Selected from
    Figure PCTCN2021091102-appb-100019
    L 1为-H 1-H 2-H 3-H 4-； L 1 is -H 1 -H 2 -H 3 -H 4 -;
    其中H 1为-C(R H)(R H)-，H 2、H 3和H 4独立地选自-O-、-S-、-N(R H’)-或-C(R H)(R H)-； Wherein 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 )-;
    并且，H 1和H 3上的R H/R H’取代基、H 1和H 4上的R H/R H’取代基、和H 2和H 4上的R H/R H’取代基中的一对或两对R H/R H’取代基可以结合形成C 1-3亚烷基； And, H 1 and H R H on 3 / R H 'substituent group, H 1 and H R H on 4 / R H' substituent group, and H 2 and H R H on 4 / R H 'substituent One or two pairs of R H /R H'substituents can be combined to form a C 1-3 alkylene group;
    R H为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a或C 0-6亚烷基-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R H'is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    R 1为
    Figure PCTCN2021091102-appb-100020
    R 1 is
    Figure PCTCN2021091102-appb-100020
    其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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 ;
    并且R a和R b可以形成化学键从而使得双键变为叁键； And R a and R b can form a chemical bond so that the double bond becomes a triple bond;
    L 2为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-、-N(R L2’)-(C(R L2)(R L2)) p-或-(C(R L2)(R L2)) p-； 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 -;
    其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
    R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    并且，R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, R L2 /R L2' can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
    R 2为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被r个R取代； 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. C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by r R;
    其中R为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-SF 5、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a、C 0-6亚烷基-C(O)N(R 1a) 2、C 0-6亚烷基-S(O) mR 1a、C 0-6亚烷基-C 3-10环烷基、C 0-6亚烷基-3-10元杂环基、C 0-6亚烷基-C 6-10芳基或C 0-6亚烷基-5-14元杂芳基； Wherein 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 6-10 aryl or C 0-6 alkylene-5-14-membered heteroaryl;
    r＝0、1、2、3、4、5、6或7；r=0, 1, 2, 3, 4, 5, 6 or 7;
    m＝1或2；m=1 or 2;
    R 4为H、D、卤素、-CN、-SF 5、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基； 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为CR 5； Z 1 is CR 5 ;
    Z 2为CR 5； Z 2 is CR 5 ;
    其中R 5独立地为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； Wherein 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与-L 3-R 3形成双键； R 7 and -L 3 -R 3 form a double bond;
    R 1a为H、-C(O)H、-C(O)OH、-C(O)C 1-6烷基、-C(O)OC 1-6烷基、-S(O) mC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基。 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.
  11. 式(I-1)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物：The compound of formula (I-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotope thereof Variants, and their mixtures:
    Figure PCTCN2021091102-appb-100021
    Figure PCTCN2021091102-appb-100021
    其中，in,
    环B为苯基或5-6元杂芳基；Ring B is phenyl or 5-6 membered heteroaryl;
    R 6独立地为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a或C 0-6亚烷基-N(R 1a) 2，并且其中至少一个R 6为-OH； 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或7；n=0, 1, 2, 3, 4, 5, 6 or 7;
    L 1为-H 1-H 2-H 3-H 4-； L 1 is -H 1 -H 2 -H 3 -H 4 -;
    其中H 1为-C(R H)(R H)-，H 2、H 3和H 4独立地选自-O-、-S-、-N(R H’)-或-C(R H)(R H)-； Wherein 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 )-;
    并且，H 1和H 3上的R H/R H’取代基、H 1和H 4上的R H/R H’取代基、和H 2和H 4上的R H/R H’取代基中的一对或两对R H/R H’取代基可以结合形成C 1-3亚烷基； And, H 1 and H R H on 3 / R H 'substituent group, H 1 and H R H on 4 / R H' substituent group, and H 2 and H R H on 4 / R H 'substituent One or two pairs of R H /R H'substituents can be combined to form a C 1-3 alkylene group;
    R H为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a或C 0-6亚烷基-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R H'is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    R 1为
    Figure PCTCN2021091102-appb-100022
    R 1 is
    Figure PCTCN2021091102-appb-100022
    其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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 ;
    并且R a和R b可以形成化学键从而使得双键变为叁键； And R a and R b can form a chemical bond so that the double bond becomes a triple bond;
    L 2为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-、-N(R L2’)-(C(R L2)(R L2)) p-或-(C(R L2)(R L2)) p-； 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 -;
    其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
    R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    并且，R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, R L2 /R L2' can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
    R 2为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被r个R取代； 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. C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by r R;
    其中R为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-SF 5、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a、C 0-6亚烷基-C(O)N(R 1a) 2、C 0-6亚烷基-S(O) mR 1a、C 0-6亚烷基-C 3-10环烷基、C 0-6亚烷基-3-10元杂环基、C 0-6亚烷基-C 6-10芳基或C 0-6亚烷基-5-14元杂芳基； Wherein 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 6-10 aryl or C 0-6 alkylene-5-14-membered heteroaryl;
    r＝0、1、2、3、4、5、6或7；r=0, 1, 2, 3, 4, 5, 6 or 7;
    R 4为H、D、卤素、-CN、-SF 5、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基； 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独立地为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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 ;
    m＝1或2；m=1 or 2;
    R 1a为H、-C(O)H、-C(O)OH、-C(O)C 1-6烷基、-C(O)OC 1-6烷基、-S(O) mC 1-6烷基、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基。 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.
  12. 权利要求11的式(I-1)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，The compound of formula (I-1) according to claim 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, Prodrugs or isotopic variants, and their mixtures, in which,
    环B为苯基；Ring B is phenyl;
    R 6独立地为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a或C 0-6亚烷基-N(R 1a) 2，并且其中至少一个R 6为-OH； 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或7；n=0, 1, 2, 3, 4, 5, 6 or 7;
    L 1为
    Figure PCTCN2021091102-appb-100023
    L 1 is
    Figure PCTCN2021091102-appb-100023
    R 1为
    Figure PCTCN2021091102-appb-100024
    R 1 is
    Figure PCTCN2021091102-appb-100024
    其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基或C 1-6卤代烷基；并且R a和R b可以形成化学键从而使得双键变为叁键； Wherein 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为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-或-N(R L2’)-(C(R L2)(R L2)) p-； 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 -;
    其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
    R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    并且，R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, R L2 /R L2' can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
    R 2为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被r个R取代； 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. C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by r R;
    其中R为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-SF 5、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a或C 0-6亚烷基-C(O)N(R 1a) 2； Wherein 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基-C(O)N(R 1a ) 2 ;
    r＝0、1、2、3、4、5、6或7；r=0, 1, 2, 3, 4, 5, 6 or 7;
    R 4为H、D、卤素、-CN或-SF 5； R 4 is H, D, halogen, -CN or -SF 5 ;
    R 5独立地为H、D、卤素、-CN、C 1-6烷基或C 1-6卤代烷基； R 5 is independently H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl;
    m＝1或2；m=1 or 2;
    R 1a为H、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、C 3-10卤代环烷基、3-10元杂环基、3-10元卤代杂环基、C 6-10芳基或5-14元杂芳基。 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.
  13. 权利要求11的式(I-1)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，The compound of formula (I-1) according to claim 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, Prodrugs or isotopic variants, and their mixtures, in which,
    环B为苯基；Ring B is phenyl;
    R 6独立地为H、D、卤素、-CN、-OH、-SH或-NH 2，并且其中至少一个R 6为-OH； 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或3；n=0, 1, 2 or 3;
    L 1为
    Figure PCTCN2021091102-appb-100025
    L 1 is
    Figure PCTCN2021091102-appb-100025
    R 1为
    Figure PCTCN2021091102-appb-100026
    R 1 is
    Figure PCTCN2021091102-appb-100026
    其中R a、R b和R c独立地选自H、D、卤素或-CN； Wherein R a , R b and R c are independently selected from H, D, halogen or -CN;
    L 2为化学键、-O-(C(R L2)(R L2)) p-或-N(R L2’)-(C(R L2)(R L2)) p-； L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -or -N(R L2' )-(C(R L2 )(R L2 )) p -;
    其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
    R L2为H、D、卤素、C 1-6烷基或C 1-6卤代烷基； R L2 is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R L2’为H； R L2' is H;
    并且，R L2/R L2’可以结合形成C 3-6环烷基或4-7元杂环基； In addition, R L2 /R L2' may be combined to form a C 3-6 cycloalkyl group or a 4-7 membered heterocyclic group;
    R 2为C 1-6烷基、C 1-6卤代烷基、-OH、-N(R 1a) 2、C 3-6环烷基、4-7元杂环基、C 6-10芳基或5-6元杂芳基；其任选被r个R取代； 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;
    其中R为H、D、卤素、C 1-6烷基、C 1-6卤代烷基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2； Wherein 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或7；r=0, 1, 2, 3, 4, 5, 6 or 7;
    R 4为卤素； R 4 is halogen;
    R 5独立地为H、D或卤素； R 5 is independently H, D or halogen;
    m＝1或2；m=1 or 2;
    R 1a为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  14. 权利要求9的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其为式(II)化合物：The compound of formula (I) of claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, which are compounds of formula (II):
    Figure PCTCN2021091102-appb-100027
    Figure PCTCN2021091102-appb-100027
    其中，in,
    环B为苯基或5-6元杂芳基；Ring B is phenyl or 5-6 membered heteroaryl;
    R 6独立地为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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或5；n=0, 1, 2, 3, 4 or 5;
    R 1为C 1-6卤代烷基或
    Figure PCTCN2021091102-appb-100028
    R 1 is C 1-6 haloalkyl or
    Figure PCTCN2021091102-appb-100028
    其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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 ;
    其任选被R’取代；并且R a和R b可以形成化学键从而使得双键变为叁键； Optionally R 'group; and R a and R b may form a chemical bond so that the triple bond becomes a double bond;
    R’为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-、-N(R L2’)-(C(R L2)(R L2)) p-或-(C(R L2)(R L2)) p-； 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 -;
    其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
    R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    并且，相邻原子上的R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, 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为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被1-7个R取代； 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. C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by 1-7 R;
    其中R为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基； Where 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为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 3-10环烷基或3-10元杂环基； 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为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  15. 权利要求9的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其为式(III)化合物：The compound of formula (I) of claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, which are compounds of formula (III):
    Figure PCTCN2021091102-appb-100029
    Figure PCTCN2021091102-appb-100029
    其中，in,
    R 1为C 1-6卤代烷基或
    Figure PCTCN2021091102-appb-100030
    R 1 is C 1-6 haloalkyl or
    Figure PCTCN2021091102-appb-100030
    其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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 ;
    其任选被R’取代；并且R a和R b可以形成化学键从而使得双键变为叁键； Optionally R 'group; and R a and R b may form a chemical bond so that the triple bond becomes a double bond;
    R’为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-、-N(R L2’)-(C(R L2)(R L2)) p-或-(C(R L2)(R L2)) p-； 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 -;
    其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
    R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    并且，相邻原子上的R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, 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为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被1-7个R取代； 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. C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-14 membered heteroaryl; it is optionally substituted by 1-7 R;
    其中R为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基； Where 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为卤素、-CN或-NO 2； R 4 is halogen, -CN or -NO 2 ;
    R 6为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 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为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  16. 权利要求15的式(III)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中The compound of formula (III) of claim 15, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and their mixtures, where
    R 1为C 1-6卤代烷基或
    Figure PCTCN2021091102-appb-100031
    R 1 is C 1-6 haloalkyl or
    Figure PCTCN2021091102-appb-100031
    其中R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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 ;
    并且R a和R b可以形成化学键从而使得双键变为叁键； And R a and R b can form a chemical bond so that the double bond becomes a triple bond;
    L 2为化学键、-O-(C(R L2)(R L2)) p-或-N(R L2’)-(C(R L2)(R L2)) p-； L 2 is a chemical bond, -O-(C(R L2 )(R L2 )) p -or -N(R L2' )-(C(R L2 )(R L2 )) p -;
    其中p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
    R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基或C 1-6卤代烷基； R L2 is H, D, halogen, -CN, -NO 2 , C 1-6 alkyl or C 1-6 haloalkyl;
    R L2’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    R 2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基或3-10元杂环基；其任选被1-5个R取代； 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. C 3-10 cycloalkyl or 3-10 membered heterocyclic group; it is optionally substituted by 1-5 R;
    其中R为H、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 1-6烷基或C 1-6卤代烷基； Wherein R is H, -OR 1a , -SR 1a , -N(R 1a ) 2 , C 1-6 alkyl or C 1-6 haloalkyl;
    R 4为卤素； R 4 is halogen;
    R 6为卤素、-CN、-NO 2或-O-R 1a，优选-OH； R 6 is halogen, -CN, -NO 2 or -OR 1a , preferably -OH;
    R 1a为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  17. 权利要求9的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其为式(IV)化合物：The compound of formula (I) of claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, which are compounds of formula (IV):
    Figure PCTCN2021091102-appb-100032
    Figure PCTCN2021091102-appb-100032
    其中，in,
    L 2为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-、-N(R L2’)-(C(R L2)(R L2)) p-或-(C(R L2)(R L2)) p-； 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 -;
    其中p＝1、2、3或4；Where p = 1, 2, 3 or 4;
    R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    并且，R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, R L2 /R L2' can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
    R 2为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-14元杂芳基；其任选被1-5个R取代； 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;
    其中R为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-SF 5、C 0-6亚烷基-NO 2、C 1-6烷基、 C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a、C 0-6亚烷基-N(R 1a) 2、C 0-6亚烷基-C(O)R 1a、C 0-6亚烷基-C(O)OR 1a、C 0-6亚烷基-C(O)N(R 1a) 2、C 0-6亚烷基-S(O) mR 1a、C 0-6亚烷基-C 3-10环烷基、C 0-6亚烷基-3-10元杂环基、C 0-6亚烷基-C 6-10芳基或C 0-6亚烷基-5-14元杂芳基； Where 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 6-10 aryl or C 0-6 alkylene-5-14-membered heteroaryl;
    其中m＝1或2；Where m=1 or 2;
    R 4为卤素、-CN或-NO 2； R 4 is halogen, -CN or -NO 2 ;
    R 6为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 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和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2；并且R a和R b可以形成化学键从而使得双键变为叁键； 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为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  18. 权利要求17的式(IV)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，The compound of formula (IV) of claim 17, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and their mixtures, in which,
    L 2为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-或-N(R L2’)-(C(R L2)(R L2)) p-； 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 -;
    其中p＝1、2、3或4；Where p = 1, 2, 3 or 4;
    R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； 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’为H、C 1-6烷基或C 1-6卤代烷基； R L2' is H, C 1-6 alkyl or C 1-6 haloalkyl;
    并且，R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, R L2 /R L2' can be combined to form a C 3-10 cycloalkyl group or a 3-10 membered heterocyclic group;
    R 2为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基或5-14元杂芳基；其任选被1-5个R取代； 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;
    其中R为H、D、C 0-6亚烷基-卤素、C 0-6亚烷基-CN、C 0-6亚烷基-SF 5、C 0-6亚烷基-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 0-6亚烷基-O-R 1a、C 0-6亚烷基-S-R 1a或C 0-6亚烷基-N(R 1a) 2； Where 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为卤素、-CN或-NO 2； R 4 is halogen, -CN or -NO 2 ;
    R 6为卤素、-CN、-NO 2、-OH、-SH或-NH 2； R 6 is halogen, -CN, -NO 2 , -OH, -SH or -NH 2 ;
    R a、R b和R c独立地选自H、D、卤素、-CN、C 1-6烷基或C 1-6卤代烷基；并且R a和R b可以形成化学键从而使得双键变为叁键； 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为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  19. 权利要求17的式(IV)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中，The compound of formula (IV) of claim 17, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and their mixtures, in which,
    L 2为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-或-N(R L2’)-(C(R L2)(R L2)) p-； 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 -;
    其中p＝1、2、3或4；Where p = 1, 2, 3 or 4;
    R L2为H、D、卤素、C 1-6烷基或C 1-6卤代烷基； R L2 is H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R L2’为H； R L2' is H;
    并且，R L2/R L2’可以结合形成C 3-6环烷基或4-7元杂环基； In addition, R L2 /R L2' may be combined to form a C 3-6 cycloalkyl group or a 4-7 membered heterocyclic group;
    R 2为C 1-6烷基、C 1-6卤代烷基、-N(R 1a) 2、C 3-6环烷基、4-7元杂环基、C 6-10芳基、5-6元杂芳基；其任选被1-2个R取代； 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;
    其中R为H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基或-N(R 1a) 2； Wherein R is H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl or -N(R 1a ) 2 ;
    R 4为卤素； R 4 is halogen;
    R 6为-OH； R 6 is -OH;
    R a、R b和R c独立地选自H、D、卤素或-CN； R a , R b and R c are independently selected from H, D, halogen or -CN;
    R 1a为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  20. 权利要求9的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其为式(IV)化合物：The compound of formula (I) of claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, which are compounds of formula (IV):
    Figure PCTCN2021091102-appb-100033
    Figure PCTCN2021091102-appb-100033
    其中，in,
    L 2为化学键、-O-(C(R L2)(R L2)) p-、-S-(C(R L2)(R L2)) p-、-N(R L2’)-(C(R L2)(R L2)) p-或-(C(R L2)(R L2)) p-； 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 -;
    其中p＝1、2、3或4；Where p = 1, 2, 3 or 4;
    R L2为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 2； 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’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    并且，相邻原子上的R L2/R L2’可以结合形成C 3-10环烷基或3-10元杂环基； In addition, 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为H、D、卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-N(R 1a) 2、C 3-10环烷基、3-10元杂环基、C 6-10芳基、5-14元杂芳基；其任选被1-5个R取代； 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. C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered heteroaryl; it is optionally substituted by 1-5 R;
    其中R为H、-N(R 1a) 2、C 1-6烷基或C 1-6卤代烷基； Wherein R is H, -N(R 1a ) 2 , C 1-6 alkyl or C 1-6 haloalkyl;
    R 4为卤素、-CN或-NO 2； R 4 is halogen, -CN or -NO 2 ;
    R 6为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 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和R c独立地选自H、D、卤素、-CN、C 1-6烷基、C 1-6卤代烷基、-O-R 1a、-S-R 1a或-N(R 1a) 2；并且R a和R b可以形成化学键从而使得双键变为叁键； 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为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  21. 权利要求9的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其为式(IV-1)、(IV-2)或(IV-3)化合物：The compound of formula (I) of claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, which are compounds of formula (IV-1), (IV-2) or (IV-3):
    Figure PCTCN2021091102-appb-100034
    Figure PCTCN2021091102-appb-100034
    其中，in,
    L 2为化学键、-O-、-S-或-N(R L2’)-； L 2 is a chemical bond, -O-, -S- or -N(R L2' )-;
    其中R L2’为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基； Wherein R L2' is H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    R 4为卤素、-CN或-NO 2； R 4 is halogen, -CN or -NO 2 ;
    R 6为卤素、-CN、-NO 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、-O-R 1a、-S-R 1a或-N(R 1a) 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和R N3独立地为H、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基或C 2-6炔基；或者，R N2和R N3可以结合形成C 2-4亚烷基； 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为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  22. 权利要求21的式(IV-1)、(IV-2)或(IV-3)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中The compound of formula (IV-1), (IV-2) or (IV-3) of claim 21, or a pharmaceutically acceptable salt, enantiomer, diastereomer, or racemate thereof , Solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein
    L 2为化学键、-O-、-S-或-NH-，优选-O-； L 2 is a chemical bond, -O-, -S- or -NH-, preferably -O-;
    R 4为卤素，优选Cl； R 4 is halogen, preferably Cl;
    R 6为卤素、-CN、-NO 2或-O-R 1a，优选-OH； R 6 is halogen, -CN, -NO 2 or -OR 1a , preferably -OH;
    R N1、R N2和R N3独立地为H、C 1-6烷基或C 1-6卤代烷基；或者，R N2和R N3可以结合形成C 2-4亚烷基； 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为H、C 1-6烷基或C 1-6卤代烷基。 R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  23. 权利要求1的式(I)化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，以及它们的混合物，其中所述化合物选自：The compound of formula (I) of claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, wherein the compound is selected from:
    Figure PCTCN2021091102-appb-100035
    Figure PCTCN2021091102-appb-100035
    Figure PCTCN2021091102-appb-100036
    Figure PCTCN2021091102-appb-100036
    Figure PCTCN2021091102-appb-100037
    Figure PCTCN2021091102-appb-100037
    Figure PCTCN2021091102-appb-100038
    Figure PCTCN2021091102-appb-100038
    Figure PCTCN2021091102-appb-100039
    Figure PCTCN2021091102-appb-100039
  24. 药物组合物，其含有权利要求1-23中任一项的化合物，或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体，和药学上可接受的赋形剂；优选地，其还含有其它治疗剂。A pharmaceutical composition containing the compound of any one of claims 1-23, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, or hydrate thereof Compounds, polymorphs, prodrugs or isotopic variants, and pharmaceutically acceptable excipients; preferably, it also contains other therapeutic agents.
  25. 权利要求1-23中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体在制备用于治疗和/或预防KRAS或其G12C突变蛋白介导的疾病的药物中的用途。The compound of any one of claims 1-23 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, pro Use of drugs or isotopic variants in the preparation of drugs for the treatment and/or prevention of diseases mediated by KRAS or its G12C mutant protein.
  26. 一种在受试者中治疗和/或预防KRAS或其G12C突变蛋白介导的疾病的方法，所述方法包括向所述受试者给药权利要求1-23中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体或权利要求24的药物组合物。A method for treating and/or preventing a disease mediated by KRAS or its G12C mutant protein in a subject, the method comprising administering to the subject the compound of any one of claims 1-23 or Pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants or the pharmaceutical composition of claim 24 .
  27. 权利要求1-23中任一项的化合物或其药学上可接受的盐、对映异构体、非对映异构体、外消旋体、溶剂合物、水合物、多晶型、前药或同位素变体或权利要求24的药物组合物，其用于治疗和/或预防KRAS或其G12C突变蛋白介导的疾病。The compound of any one of claims 1-23 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, pro The drug or isotope variant or the pharmaceutical composition of claim 24, which is used for the treatment and/or prevention of diseases mediated by KRAS or its G12C mutant protein.
  28. 权利要求25的用途或权利要求26的方法或权利要求27的化合物或组合物的用途，其中所述KRAS或其G12C突变蛋白介导的疾病包括选自以下的癌症：急性髓细胞样白血病、急性髓细胞样白血病、青少年癌症、儿童肾上腺皮质癌、AIDS相关的癌症(例如淋巴瘤和卡波西氏肉瘤)、肛门癌、阑尾癌、星形细胞瘤、非典型畸胎样、基底细胞癌、胆管癌、膀胱癌、骨癌、脑干神经胶质瘤、脑瘤、乳腺癌、支气管肿瘤、伯基特淋巴瘤、类癌瘤、非典型畸胎样、胚胎肿瘤、生殖细胞肿瘤、原发性淋巴瘤、宫颈癌、儿童癌症、脊索瘤、心脏肿瘤、慢性淋巴细胞性白血病(CLL)、慢性髓细胞性白血病(CML)、慢性骨髓增殖性病症、结肠癌、结肠直肠癌、颅咽管瘤、皮肤T细胞淋巴瘤、肝外导管原位癌(DCIS)、胚胎肿瘤、CNS癌症、子宫内膜癌、室管膜瘤、食道癌、嗅神经母细胞瘤、尤文氏肉瘤、颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、眼癌、骨骼的纤维组织细胞瘤、胆囊癌、胃癌、胃肠道类癌瘤、胃肠道间质瘤(GIST)、生殖细胞肿瘤、妊娠滋养细胞肿瘤、毛细胞白血病、头颈癌、心脏癌、肝癌、霍奇金氏淋巴瘤、下咽癌、眼内黑色素瘤、胰岛细胞瘤、胰腺神经内分泌瘤、肾癌、喉癌、唇和口腔癌、肝癌、小叶原位癌(LCIS)、肺癌、淋巴瘤、转移性鳞状颈癌伴隐匿原发灶、中线道癌、口腔癌、多发性内分泌瘤综合征、多发性骨髓瘤/浆细胞瘤、蕈样真菌病、骨髓发育不良综合征、骨髓发育不良/骨髓增殖性瘤、多发性骨髓瘤、梅克尔细胞癌、恶性间皮瘤、骨骼的恶性纤维组织细胞瘤和骨肉瘤、鼻腔和鼻窦癌、鼻咽癌、神经母细胞瘤、非霍奇金氏淋巴瘤、非小细胞肺癌(NSCLC)、口腔癌、唇和口腔癌、口咽癌、卵巢癌、胰腺癌、乳头瘤、副神经节瘤、鼻窦和鼻腔癌、甲状旁腺癌、阴茎癌、咽癌、胸膜肺母细胞瘤、原发性中枢神经系统(CNS)淋巴瘤、前列腺癌、直肠癌、移 行性细胞癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、皮肤癌、胃癌、小细胞肺癌、小肠癌、软组织肉瘤、细胞淋巴瘤、睾丸癌、喉癌、胸腺瘤和胸腺癌、甲状腺癌、肾盂和输尿管的移行性细胞癌、滋养细胞肿瘤、儿童罕见的癌症、尿道癌、子宫肉瘤、阴道癌、外阴癌或病毒诱导的癌症。The use of claim 25 or the method of claim 26 or the use of the compound or composition of claim 27, wherein the disease mediated by KRAS or its G12C mutant protein includes cancer selected from the group consisting of acute myeloid leukemia, acute Myeloid leukemia, juvenile cancer, childhood adrenal cortical cancer, AIDS-related cancers (such as lymphoma and Kaposi’s sarcoma), anal cancer, appendix cancer, astrocytoma, atypical teratoma, basal cell carcinoma, Cholangiocarcinoma, bladder cancer, bone cancer, brainstem 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 Disorders, Colon Cancer, Colorectal Cancer, Craniopharyngeal Tube Tumors, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonic tumors, CNS cancer, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing's sarcoma, extracranial reproduction Cell tumor, extragonadal germ cell tumor, eye cancer, bone fibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, Hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, kidney cancer, laryngeal cancer, lip and oral cavity cancer, liver cancer, Lobular carcinoma in situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with occult primary tumor, midline tract cancer, oral cancer, multiple endocrine tumor syndrome, multiple myeloma/plasmacytoma, mushroom Fungal disease, myelodysplastic syndrome, myelodysplastic/myeloproliferative tumor, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of the bone, nasal cavity and sinus cancer, Nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma , Sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleuropulmonary blastoma, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma , Rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, Trophoblastic tumors, rare childhood cancers, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.
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