WO2021219090A1 - Quinoxaline dione derivative as irreversible inhibitor of kras g12c mutant protein - Google Patents

Quinoxaline dione derivative as irreversible inhibitor of kras g12c mutant protein Download PDF

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WO2021219090A1
WO2021219090A1 PCT/CN2021/091100 CN2021091100W WO2021219090A1 WO 2021219090 A1 WO2021219090 A1 WO 2021219090A1 CN 2021091100 W CN2021091100 W CN 2021091100W WO 2021219090 A1 WO2021219090 A1 WO 2021219090A1
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alkyl
alkylene
haloalkyl
halogen
cancer
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PCT/CN2021/091100
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French (fr)
Chinese (zh)
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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 CN202180015895.4A priority Critical patent/CN115151532B/en
Publication of WO2021219090A1 publication Critical patent/WO2021219090A1/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.
  • 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., as well as 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, -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.
  • 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 benzo6-membered heteroaryl group, such as quinoline Alrinyl, isoquinolinyl, benzopyridinyl, benzopyridazinyl, benzopyrazinyl, benzopyrimidinyl or benzotriazinyl; in another specific embodiment, ring A is phenyl or 6-membered heteroary
  • 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 specific embodiment, R 6 is independently -NHC(O)R 1a
  • 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 or In another specific embodiment, for Preferred
  • 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 -OCH 2 -; In another specific embodiment , L 2 is -OCH 2 CH 2 -.
  • 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 -N(R 1a ) 2 ; In another specific embodiment, R 2 is C 3-10 cycloalkyl; in another specific embodiment, R 2 is 3-10 membered heterocyclyl; in another specific embodiment In an 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 Preferred
  • 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 -OCH 2 -or -OCH 2 CH 2 -;
  • L 3 is a chemical bond, -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 , phenyl or 5-6 membered heteroaryl, preferably
  • R 3 is Preferred
  • 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 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.
  • 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 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
  • 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, which are compounds of formula (II):
  • 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 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, 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 the compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, which are compounds of formula (III) or (III-1):
  • 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' is H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -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 or C 2-6 alkynyl;
  • 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, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R 4 is halogen
  • 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 the above formula (III) or (III-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemic Forms, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, 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 ; and R a and R b may form a chemical bond so that the triple bond becomes a double bond;
  • L 3 is a chemical bond, -CH 2 -or -CH 2 CH 2 -;
  • 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, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • 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 the compound of formula (I) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, which are compounds of formula (IV) or (IV-1):
  • 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' is H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkyl, -OR 1a , -SR 1a or -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 or C 2-6 alkynyl;
  • 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, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • 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 the above formula (IV) or (IV-1): a compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, exo Racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, 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 ; and R a and R b may form a chemical bond so that the triple bond becomes a double bond;
  • L 3 is a chemical bond, -CH 2 -or -CH 2 CH 2 -;
  • 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, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • 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 (V), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Substances, polymorphs, prodrugs or isotopic variants, and their mixtures:
  • R a , R b and R c are independently selected from H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl or C 1-6 haloalkyl group is optionally replaced by D, halo, -CN, -OR 1a, -SR 1a, or -N (R 1a) 2-substituted; preferably, R a, R b and R c are independently selected from H, D, halogen, or - CN;
  • Q 1 is selected from N or CR 3b ;
  • Q 2 is selected from N or CR 3c ;
  • Q 3 is selected from N or CR 3d ;
  • Q 4 is selected from N or CR 3e ;
  • R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from H, D, halogen, -CN, -OR 1a , -SR 1a , -N(R 1a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic group;
  • Z is N or CR 6a ;
  • R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkene Group, C 2-6 alkynyl group, -OR 1a , -SR 1a , -N(R 1a ) 2 or -NHC(O)R 1a ; preferably, at least one of them is -OH, -NH(R 1a ) or -NHC(O)R 1a ;
  • R 6a , R 6b , R 6c , R 6d and R 6e may be combined to form a phenyl group or a 5-6 membered heteroaryl group, which is optionally selected from -OH by 1, 2 or 3 , -NH(R 1a ) or -NHC(O)R 1a group substitution;
  • R 4 is halogen
  • R 5 is H or halogen
  • R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of formula (V) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 6b is -OH, -NH(R 1a ) or -NHC(O)R 1a .
  • the present invention provides the compound of formula (V) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 6e is -OH, -NH(R 1a ) or -NHC(O)R 1a .
  • the present invention provides the compound of formula (V) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 4 is Cl.
  • the present invention provides the compound of formula (V) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl; preferably, R 3a is C 1-6 alkyl or C 1-6 haloalkyl, more preferably Isopropyl.
  • the present invention provides the compound of formula (V) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from H, D, halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic group.
  • the present invention provides the compound of formula (V) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, where Z is CR 6a .
  • the present invention provides the compound of formula (V) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein one of R 6b or R 6b is -OH, -NH(R 1a ) or -NHC(O)R 1a ; preferably R 6b or One of R 6b is -OH or -NH 2 .
  • the present invention provides a compound of formula (VI), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Substances, polymorphs, prodrugs or isotopic variants, and their mixtures:
  • R a , R b and R c are independently selected from H, D, halogen, -CN, C 1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl or C 1-6 haloalkyl group is optionally replaced by D, halo, -CN, -OR 1a, -SR 1a, or -N (R 1a) 2-substituted; preferably, R a, R b and R c are independently selected from H, D, halogen, or - CN;
  • Q 1 is selected from N or CR 3b ;
  • Q 2 is selected from N or CR 3c ;
  • Q 3 is selected from N or CR 3d ;
  • Q 4 is selected from N or CR 3e ;
  • R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from H, D, halogen, -CN, -OR 1a , -SR 1a , -N(R 1a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic group;
  • R 4 is halogen; preferably Cl;
  • R 6 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 or -NHC(O)R 1a ;
  • R 1a is H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above-mentioned compound of formula (VI), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl; preferably, R 3a is C 1-6 alkyl or C 1-6 haloalkyl, more preferably Isopropyl.
  • the present invention provides the above-mentioned compound of formula (VI), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 6 is -OH, -NH(R 1a ) or -NHC(O)R 1a , more preferably -OH.
  • 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 compound provided herein is administered to a subject at risk of developing the condition, typically based on the doctor's recommendation and under the supervision of the doctor, and the dosage level is 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.
  • 4,6-Dichloropyrimidin-5-amine (5.0g, 30.0mmol) was dissolved in toluene (100mL), potassium phosphate (19.0g, 90.0mmol), cyclopropylboronic acid (3.1g, 36.0mmol), Sphos (6.4g, 12.0mmol) and Pd 2 (dba) 3 (5.5g, 6.0mmol) were heated to 100°C under nitrogen protection and stirred for 1 hour. The reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure.
  • Example 1 1-((1-acryloylazetidin-3-yl)methyl)-7-fluoro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2,3( 1H,4H)-diketone preparation
  • the 1-(azetidin-3-ylmethyl)-4-(2-(dimethylamino)ethyl)-7-fluoro-6-(3-hydroxynaphthalene-1 -Yl)quinoxaline-2,3(1H,4H)-dione (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 1-(azetidin-3-ylmethyl)-7-chloro-4-(2-(dimethylamino)ethyl)-6-(3-hydroxynaphthalene-1 -Yl)quinoxaline-2,3(1H,4H)-dione (100 mg, 0.21 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (210 mg, 2.1 mmol) was added. After cooling to 0°C, a solution of acryloyl chloride (22 mg, 0.21 mmol) in dichloromethane (1 mL) was slowly added dropwise to the system, and stirred at 0°C for 0.5 hours.
  • Example 7 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(3-hydroxynaphthalene-1-yl)-4-(2-isopropyl Preparation of phenyl)quinoxaline-2,3(1H,4H)-dione
  • Example 7 By referring to the above preparation method of Example 7 compound and using different reaction materials, the following example compounds were prepared:
  • reaction solution was cooled and filtered, the filtrate was decompressed to remove ethanol, the mixed solution was extracted with dichloromethane (3 ⁇ 100 mL), the organic phases were combined, the organic phases were washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, and filtered.
  • the diketone (6.0 mg) is a white solid with a yield of 9%.
  • Example 14 1-(1-acryloylpiperidin-4-yl)-7-chloro-6-(3-hydroxynaphthalene-1-yl)-4-(2-isopropyl-6-methylbenzene Base)-1,4-dihydroquinoxaline-2,3-dione
  • ESI-MS 590,592 [M+H] + .
  • Example 16 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(2,3-difluoro-6-hydroxyphenyl)-4-( Preparation of 2-isopropylphenyl)-1,4-dihydroquinoxaline-2,3-dione
  • ESI-MS 407,409 [M+H] + .
  • Example 18 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(2,4-dichloro-5-hydroxyphenyl)-5-fluoro Preparation of -4-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione
  • Benzoyl isothiocyanate (2.2g, 13.50mmol) was dissolved in tetrahydrofuran (18mL), and after the temperature was lowered to 5°C under N 2 atmosphere, 5-fluoro-2-methoxyaniline (1.7mL, 13.88mmol) was added dropwise to the system, keeping the temperature not higher than 10°C, after the dropwise addition, the temperature was raised to room temperature and the reaction was stirred for 30min. Then sodium hydroxide solution (3.2mL, 16.0mmol, 5N) and water (4mL) were added, heated to 80°C and stirred for 3.5 hours.
  • ESI-MS 339[M+H] + .
  • Example 20 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(2-hydroxy-5-(trifluoromethyl)phenyl)-4 -(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione
  • the 1-(azetidin-3-ylmethyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-6-(2-methyl Oxy-5-(trifluoromethyl)phenyl)-1,4-dihydroquinoxaline-2,3-dione (187mg, 0.33mmol) was dissolved in dichloromethane (3mL), and triethyl was added Amine (331mg, 3.28mmol), the reaction system was cooled to -78°C, a solution of dichloromethane (2mL) dissolved in acryloyl chloride (27mg, 0.30mmol) was slowly added dropwise to the system at -78°C, and The reaction was stirred at -78°C for 0.5 hour.
  • ESI-MS 626[M+H] + .
  • Example 21 1-((1-acryloylazetidin-3-yl)methyl)-6-(5-amino-2-(trifluoromethyl)phenyl)-7-chloro-4 -(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione
  • reaction solution was concentrated under reduced pressure.
  • Example 21a (74mg), and Example 21b (63mg) were obtained.
  • Example 23 1-((1-acryloylazetidin-3-yl)methyl)-6-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2- Yl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione
  • 6-Chloro-4-methylpyridin-2-amine (1.5 g, 10.6 mmol) was dissolved in acetonitrile (15 mL), NIS (2.4 g, 10.6 mmol) was added, and the mixture was stirred at 25° C. for 2 h.
  • reaction solution was cooled to room temperature and extracted three times with ethyl acetate.
  • organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography.
  • ESI-MS 626[M+H] + .
  • Example 24 By referring to the preparation method of Example 24 above and using different reaction materials, the following example compounds were prepared:
  • 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:
  • Example 5 1851
  • Example 6 866.1
  • Example 8 >10000
  • Example 9 >10000
  • Example 10 >10000
  • Example 12 83.22
  • Example 13 >10000
  • Example 14 363.3 Example 15 27.30 Example 15a >1000 Example 15b 11.44 Example 15c 410.5 Example 16a 130.1 Example 16b 100.5 Example 17 >10000 Example 18 >1000 Example 19 347.1 Example 20 >1000 Example 21 19.76 Example 21a 9.242 Example 21b 185.2 Example 22 113.9 Example 23 8.384 Example 23a 7.981 Example 23b 238.0 Example 24 72.22 Example 25 709.7 Example 27a 26.58 Example 27b 2693 Example 29 459.1 Example 30 6.367 Example 30a 5.823 Example 30b 164.3 Example 31 7.673 Example 31a 2.19 Example 31b 389 Example 32 >1000 Example 33 138.2 Example 34 8.304 Example 36 242.1 Example 37 >10000 Example 39 349.8 Example 40 >1000 Example 41a 63.32 Example 41b 42.57 Example 41c 43.34 Example 41d >10000 Example 42a >1000 Example 42b 12.82 Example 43a >10000 Example 43b 9.784 Example 44 168.2 Example 47 >10000 Example 49 13.15 Example 51 126.8 Example 52 24.31
  • 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 (%, 5mins) POC (%, 30mins) Example 1 12.6 53.2 Example 2 36.7 85.6
  • Example 4 18.8 63.3
  • Example 5 55.2 90.7
  • Example 7 65.4
  • Example 10 4.8 25.6
  • Example 11 65.3 91.4
  • Example 12 61.8 73.0
  • Example 13 6.9 33.6
  • Example 14 49.0 80.2
  • Example 15 71.4 79.9
  • Example 17 37.1 77.4
  • Example 19 52.8 70.7
  • Example 20 49.3 78.5
  • Example 21 69.2 94.0 Example 21a 93.4 94.8
  • Example 22 56.9 81.5
  • Example 23b 26.5 56.4
  • Example 24 46.3 75.2
  • Example 25 36.9 72.2
  • Example 26b 63.3 1.5
  • Example 39 40.7 75.5 Example 40 52.1 89.5 Example 41a 35.1 63.6 Example 41b 59.0 75.9 Example 42a 15.2 50.1 Example 42b 70.2 85.0 Example 43a 7.8 34.0 Example 43b 83.4 87.2 Example 44 56.5 86.8 Example 46 18.6 51.7 Example 47 15.2 48.3 Example 48 23.5 46.2 Example 49 84.2 96.5 Example 50 36.0 61.9 Example 51 68.4 90.3 Example 52 79.3 92.7 Example 53 84.2 96.8 Example 54a 56.0 89.3 Example 55a 57.9 88.6 Example 56a 55.2 87.5 Example 57b 88.1 95.2 Example 58a 73.4 90.2 Example 59 90.8 92.5 Example 60 57.0 74.9 Example 61 76.7 92.9 Example 62b 65.0 76.9 Example 63 24.7 52.8 Example 64 55.7 79.2 Example 65 50.6 73.7 Example 66 76.2 87.5 Example 66a 92.3 93.8 Example 67 70.3 80.7 Example 68 52.1 76.1 Example 69 40.3 73.5 Example 70 40.7
  • Example 83 35.2 63.9
  • Example 84 86.1 95.3
  • Example 86 61.3 90.8
  • Example 90b 48.3 88.6 Example 90c 94.8 95.6
  • Example 92 40.3 76.4
  • Example 93 56.4 79.0
  • Example 97 67.2 85.8 Example 97a 66.5 94.6
  • Example 99 67.8 94.3 Example 100 56.5 93.8

Abstract

A quinoxaline-2,3(1H,4H)-dione derivative as represented by formula (I), a preparation method therefor, and a pharmaceutical composition comprising the derivative. This class of compounds can be used as irreversible inhibitors of KRAS G12C mutant proteins for treating diseases such as cancers.

Description

喹喔啉二酮衍生物作为KRAS G12C突变蛋白的不可逆抑制剂Quinoxaline dione 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.
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 PCTCN2021091100-appb-000001
Figure PCTCN2021091100-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 PCTCN2021091100-appb-000002
R 1 is C 1-6 haloalkyl or
Figure PCTCN2021091100-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)、***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、***、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、***瘤、副神经节瘤、鼻窦和鼻腔癌、甲状旁腺癌、***癌、咽癌、胸膜肺母细胞瘤、原发性中枢神经***(CNS)淋巴瘤、***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、***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 by 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：***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. Oxazolidin-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***，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***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***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***，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***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：***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***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 Group, 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、***、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***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、***状癌、***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、***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., as well as 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 PCTCN2021091100-appb-000003
Figure PCTCN2021091100-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 PCTCN2021091100-appb-000004
R 1 is C 1-6 haloalkyl or
Figure PCTCN2021091100-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、-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.
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，例如喹啉基、异喹啉基、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；在另一个具体实施方案中，环A为苯基或6元杂芳基，例如苯基或吡啶基。 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 benzo6-membered heteroaryl group, such as quinoline Alrinyl, isoquinolinyl, benzopyridinyl, benzopyridazinyl, benzopyrazinyl, benzopyrimidinyl or benzotriazinyl; in another specific embodiment, ring A is phenyl or 6-membered heteroaryl, such as phenyl or pyridyl.
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-NHC(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)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 specific embodiment, R 6 is independently -NHC(O)R 1a ; in another specific embodiment, R 6 is independently C 0-6 alkylene -C(O)R 1a ; In another specific 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 specific embodiment, R 6 is independently C 0-6 alkylene-S(O) m R 1a ; in another In a specific embodiment, R 6 is a non-H group; 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 a specific embodiment, n=0; in another specific embodiment, n=1; in another specific embodiment, n=2; in another specific embodiment, n=3; in another specific embodiment 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 PCTCN2021091100-appb-000005
为
Figure PCTCN2021091100-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 PCTCN2021091100-appb-000007
为
Figure PCTCN2021091100-appb-000008
在另一个具体实施方案中，
Figure PCTCN2021091100-appb-000009
为
Figure PCTCN2021091100-appb-000010
在另一个具体实施方案中，
Figure PCTCN2021091100-appb-000011
为
Figure PCTCN2021091100-appb-000012
在另一个具体实施方案中，
Figure PCTCN2021091100-appb-000013
为
Figure PCTCN2021091100-appb-000014
在另一个具体实施方案中，
Figure PCTCN2021091100-appb-000015
为
Figure PCTCN2021091100-appb-000016
在另一个具体实施方案中，
Figure PCTCN2021091100-appb-000017
为
Figure PCTCN2021091100-appb-000018
在另一个具体实施方案中，
Figure PCTCN2021091100-appb-000019
为
Figure PCTCN2021091100-appb-000020
在另一个具体实施方案中，
Figure PCTCN2021091100-appb-000021
为
Figure PCTCN2021091100-appb-000022
在另一个具体实施方案中，
Figure PCTCN2021091100-appb-000023
为
Figure PCTCN2021091100-appb-000024
在另一个具体实施方案中，
Figure PCTCN2021091100-appb-000025
为
Figure PCTCN2021091100-appb-000026
在另一个具体实施方案中，
Figure PCTCN2021091100-appb-000027
为
Figure PCTCN2021091100-appb-000028
在另一个具体实施方案中，
Figure PCTCN2021091100-appb-000029
为
Figure PCTCN2021091100-appb-000030
在另一个具体实施方案中，
Figure PCTCN2021091100-appb-000031
为
Figure PCTCN2021091100-appb-000032
在另一个具体实施方案中，
Figure PCTCN2021091100-appb-000033
为
Figure PCTCN2021091100-appb-000034
Figure PCTCN2021091100-appb-000035
Figure PCTCN2021091100-appb-000036
在另一个具体 实施方案中，
Figure PCTCN2021091100-appb-000037
为
Figure PCTCN2021091100-appb-000038
或
Figure PCTCN2021091100-appb-000039
在另一个具体实施方案中，
Figure PCTCN2021091100-appb-000040
为
Figure PCTCN2021091100-appb-000041
Figure PCTCN2021091100-appb-000042
Figure PCTCN2021091100-appb-000043
优选
Figure PCTCN2021091100-appb-000044
In a specific embodiment,
Figure PCTCN2021091100-appb-000005
for
Figure PCTCN2021091100-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 PCTCN2021091100-appb-000007
for
Figure PCTCN2021091100-appb-000008
In another specific embodiment,
Figure PCTCN2021091100-appb-000009
for
Figure PCTCN2021091100-appb-000010
In another specific embodiment,
Figure PCTCN2021091100-appb-000011
for
Figure PCTCN2021091100-appb-000012
In another specific embodiment,
Figure PCTCN2021091100-appb-000013
for
Figure PCTCN2021091100-appb-000014
In another specific embodiment,
Figure PCTCN2021091100-appb-000015
for
Figure PCTCN2021091100-appb-000016
In another specific embodiment,
Figure PCTCN2021091100-appb-000017
for
Figure PCTCN2021091100-appb-000018
In another specific embodiment,
Figure PCTCN2021091100-appb-000019
for
Figure PCTCN2021091100-appb-000020
In another specific embodiment,
Figure PCTCN2021091100-appb-000021
for
Figure PCTCN2021091100-appb-000022
In another specific embodiment,
Figure PCTCN2021091100-appb-000023
for
Figure PCTCN2021091100-appb-000024
In another specific embodiment,
Figure PCTCN2021091100-appb-000025
for
Figure PCTCN2021091100-appb-000026
In another specific embodiment,
Figure PCTCN2021091100-appb-000027
for
Figure PCTCN2021091100-appb-000028
In another specific embodiment,
Figure PCTCN2021091100-appb-000029
for
Figure PCTCN2021091100-appb-000030
In another specific embodiment,
Figure PCTCN2021091100-appb-000031
for
Figure PCTCN2021091100-appb-000032
In another specific embodiment,
Figure PCTCN2021091100-appb-000033
for
Figure PCTCN2021091100-appb-000034
Figure PCTCN2021091100-appb-000035
Figure PCTCN2021091100-appb-000036
In another specific embodiment,
Figure PCTCN2021091100-appb-000037
for
Figure PCTCN2021091100-appb-000038
or
Figure PCTCN2021091100-appb-000039
In another specific embodiment,
Figure PCTCN2021091100-appb-000040
for
Figure PCTCN2021091100-appb-000041
Figure PCTCN2021091100-appb-000042
Figure PCTCN2021091100-appb-000043
Preferred
Figure PCTCN2021091100-appb-000044
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 PCTCN2021091100-appb-000045
在另一个具体实施方案中，L 1为
Figure PCTCN2021091100-appb-000046
在另一个具体实施方案中，L 1为
Figure PCTCN2021091100-appb-000047
在另一个具体实施方案中，L 1为
Figure PCTCN2021091100-appb-000048
在另一个具体实施方案中，L 1为
Figure PCTCN2021091100-appb-000049
在另一个具体实施方案中，L 1为
Figure PCTCN2021091100-appb-000050
在另一个具体实施方案中，L 1为
Figure PCTCN2021091100-appb-000051
在另一个具体实施方案中，L 1为
Figure PCTCN2021091100-appb-000052
在另一个具体实施方案中，L 1为
Figure PCTCN2021091100-appb-000053
在另一个具体实施方案中，L 1为
Figure PCTCN2021091100-appb-000054
在另一个具体实施方案中，L 1为
Figure PCTCN2021091100-appb-000055
在另一个具体实施方案中，L 1为
Figure PCTCN2021091100-appb-000056
在另一个具体实施方案中，L 1为
Figure PCTCN2021091100-appb-000057
在另一个具体实施方案中，L 1为
Figure PCTCN2021091100-appb-000058
In another specific embodiment, L 1 is
Figure PCTCN2021091100-appb-000045
In another specific embodiment, L 1 is
Figure PCTCN2021091100-appb-000046
In another specific embodiment, L 1 is
Figure PCTCN2021091100-appb-000047
In another specific embodiment, L 1 is
Figure PCTCN2021091100-appb-000048
In another specific embodiment, L 1 is
Figure PCTCN2021091100-appb-000049
In another specific embodiment, L 1 is
Figure PCTCN2021091100-appb-000050
In another specific embodiment, L 1 is
Figure PCTCN2021091100-appb-000051
In another specific embodiment, L 1 is
Figure PCTCN2021091100-appb-000052
In another specific embodiment, L 1 is
Figure PCTCN2021091100-appb-000053
In another specific embodiment, L 1 is
Figure PCTCN2021091100-appb-000054
In another specific embodiment, L 1 is
Figure PCTCN2021091100-appb-000055
In another specific embodiment, L 1 is
Figure PCTCN2021091100-appb-000056
In another specific embodiment, L 1 is
Figure PCTCN2021091100-appb-000057
In another specific embodiment, L 1 is
Figure PCTCN2021091100-appb-000058
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 PCTCN2021091100-appb-000059
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 PCTCN2021091100-appb-000059
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 PCTCN2021091100-appb-000060
在另一个具体实施方案中，R 1为
Figure PCTCN2021091100-appb-000061
在另一个具体实施方案中，R 1为
Figure PCTCN2021091100-appb-000062
在另一个具体实施方案中，R 1为
Figure PCTCN2021091100-appb-000063
In a specific embodiment, R 1 is
Figure PCTCN2021091100-appb-000060
In another specific embodiment, R 1 is
Figure PCTCN2021091100-appb-000061
In another specific embodiment, R 1 is
Figure PCTCN2021091100-appb-000062
In another specific embodiment, R 1 is
Figure PCTCN2021091100-appb-000063
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-OCH 2-；在另一个具体实施方案中，L 2为-OCH 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 -OCH 2 -; In another specific embodiment , L 2 is -OCH 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-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 -N(R 1a ) 2 ; In another specific embodiment, R 2 is C 3-10 cycloalkyl; in another specific embodiment, R 2 is 3-10 membered heterocyclyl; in another specific embodiment In an 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 PCTCN2021091100-appb-000064
在另一个具体实施方案中，R 2为
Figure PCTCN2021091100-appb-000065
In another specific embodiment, R 2 is
Figure PCTCN2021091100-appb-000064
In another specific embodiment, R 2 is
Figure PCTCN2021091100-appb-000065
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 PCTCN2021091100-appb-000066
Figure PCTCN2021091100-appb-000067
Figure PCTCN2021091100-appb-000068
优选
Figure PCTCN2021091100-appb-000069
Figure PCTCN2021091100-appb-000070
In another specific embodiment, R 3 is
Figure PCTCN2021091100-appb-000066
Figure PCTCN2021091100-appb-000067
Figure PCTCN2021091100-appb-000068
Preferred
Figure PCTCN2021091100-appb-000069
Figure PCTCN2021091100-appb-000070
在另一个具体实施方案中，R 3为
Figure PCTCN2021091100-appb-000071
在另一个具体实施方案中，R 3为
Figure PCTCN2021091100-appb-000072
In another specific embodiment, R 3 is
Figure PCTCN2021091100-appb-000071
In another specific embodiment, R 3 is
Figure PCTCN2021091100-appb-000072
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 PCTCN2021091100-appb-000073
为
Figure PCTCN2021091100-appb-000074
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 PCTCN2021091100-appb-000073
for
Figure PCTCN2021091100-appb-000074
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 PCTCN2021091100-appb-000075
为
Figure PCTCN2021091100-appb-000076
优选地为：
Figure PCTCN2021091100-appb-000077
Figure PCTCN2021091100-appb-000078
优选
Figure PCTCN2021091100-appb-000079
优选地，
Figure PCTCN2021091100-appb-000080
为
Figure PCTCN2021091100-appb-000081
Figure PCTCN2021091100-appb-000082
Figure PCTCN2021091100-appb-000083
优选地，
Figure PCTCN2021091100-appb-000084
为
Figure PCTCN2021091100-appb-000085
优选地，
Figure PCTCN2021091100-appb-000086
为
Figure PCTCN2021091100-appb-000087
Figure PCTCN2021091100-appb-000088
Figure PCTCN2021091100-appb-000089
优选
Figure PCTCN2021091100-appb-000090
Preferably,
Figure PCTCN2021091100-appb-000075
for
Figure PCTCN2021091100-appb-000076
Preferably:
Figure PCTCN2021091100-appb-000077
Figure PCTCN2021091100-appb-000078
Preferred
Figure PCTCN2021091100-appb-000079
Preferably,
Figure PCTCN2021091100-appb-000080
for
Figure PCTCN2021091100-appb-000081
Figure PCTCN2021091100-appb-000082
Figure PCTCN2021091100-appb-000083
Preferably,
Figure PCTCN2021091100-appb-000084
for
Figure PCTCN2021091100-appb-000085
Preferably,
Figure PCTCN2021091100-appb-000086
for
Figure PCTCN2021091100-appb-000087
Figure PCTCN2021091100-appb-000088
Figure PCTCN2021091100-appb-000089
Preferred
Figure PCTCN2021091100-appb-000090
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 PCTCN2021091100-appb-000091
Figure PCTCN2021091100-appb-000092
优选地，L 1为
Figure PCTCN2021091100-appb-000093
Among them, L 1 is:
Figure PCTCN2021091100-appb-000091
Figure PCTCN2021091100-appb-000092
Preferably, L 1 is
Figure PCTCN2021091100-appb-000093
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 PCTCN2021091100-appb-000094
优选地，R 1为
Figure PCTCN2021091100-appb-000095
Where R 1 is
Figure PCTCN2021091100-appb-000094
Preferably, R 1 is
Figure PCTCN2021091100-appb-000095
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-OCH 2-或-OCH 2CH 2-；L 3为化学键、-CH 2-或-CH 2CH 2-。 Wherein, L 2 is -OCH 2 -or -OCH 2 CH 2 -; L 3 is a chemical bond, -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、苯基或5-6元杂芳基，优选
Figure PCTCN2021091100-appb-000096
Among them, R 2 or R 3 is H, -N(R 1a ) 2 , phenyl or 5-6 membered heteroaryl, preferably
Figure PCTCN2021091100-appb-000096
优选地，R 3为
Figure PCTCN2021091100-appb-000097
Figure PCTCN2021091100-appb-000098
Figure PCTCN2021091100-appb-000099
优选
Figure PCTCN2021091100-appb-000100
Figure PCTCN2021091100-appb-000101
Preferably, R 3 is
Figure PCTCN2021091100-appb-000097
Figure PCTCN2021091100-appb-000098
Figure PCTCN2021091100-appb-000099
Preferred
Figure PCTCN2021091100-appb-000100
Figure PCTCN2021091100-appb-000101
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 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 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(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 PCTCN2021091100-appb-000102
Figure PCTCN2021091100-appb-000102
其中，in,
环B为苯基或5-6元杂芳基；Ring B is phenyl or 5-6 membered heteroaryl;
各基团如上文所定义。Each group is as defined above.
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，其为式(II)化合物：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, which are compounds of formula (II):
Figure PCTCN2021091100-appb-000103
Figure PCTCN2021091100-appb-000103
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 PCTCN2021091100-appb-000104
R 1 is C 1-6 haloalkyl or
Figure PCTCN2021091100-appb-000104
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 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p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
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； 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1-7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 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，其为式(III)或(III-1)化合物：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, which are compounds of formula (III) or (III-1):
Figure PCTCN2021091100-appb-000105
Figure PCTCN2021091100-appb-000105
其中，in,
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； 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;
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 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p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
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烯基或C 2-6炔基； R L3 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 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5-10元杂芳基；其任选被1-7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 5-10 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烯基或C 2-6炔基； Wherein R 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 4为卤素； R 4 is halogen;
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，本发明提供了上述式(III)或(III-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 a compound of the above formula (III) or (III-1), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemic Forms, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein
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;
L 3为化学键、-CH 2-或-CH 2CH 2-； L 3 is a chemical bond, -CH 2 -or -CH 2 CH 2 -;
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5-10元杂芳基；其任选被1-5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 5-10 membered heteroaryl; it is optionally substituted by 1-5 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烯基或C 2-6炔基； Wherein R 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 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，其为式(IV)或(IV-1)化合物：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, which are compounds of formula (IV) or (IV-1):
Figure PCTCN2021091100-appb-000106
Figure PCTCN2021091100-appb-000106
其中，in,
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； 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;
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 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p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
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烯基或C 2-6炔基； R L3 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 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5-10元杂芳基；其任选被1-5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 5-10 membered heteroaryl; it is optionally substituted by 1-5 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烯基或C 2-6炔基； Wherein R 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 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，本发明提供了上述式(IV)或(IV-1)化合物：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 the above formula (IV) or (IV-1): a compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, exo Racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein
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;
L 3为化学键、-CH 2-或-CH 2CH 2-； L 3 is a chemical bond, -CH 2 -or -CH 2 CH 2 -;
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、苯基或5-6元杂芳基；其任选被1-3个R取代；其任选被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, phenyl or 5-6 membered heteroaryl; it is optionally substituted by 1-3 R; it is optionally substituted by 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烯基或C 2-6炔基； Wherein R 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 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(V)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 (V), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Substances, polymorphs, prodrugs or isotopic variants, and their mixtures:
Figure PCTCN2021091100-appb-000107
Figure PCTCN2021091100-appb-000107
其中，in,
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；其中所述C 1-6烷基或C 1-6卤代烷基任选被D、卤素、-CN、-O-R 1a、-S-R 1a或-N(R 1a) 2取代；优选地，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, -CN, C 1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl or C 1-6 haloalkyl group is optionally replaced by D, halo, -CN, -OR 1a, -SR 1a, or -N (R 1a) 2-substituted; preferably, R a, R b and R c are independently selected from H, D, halogen, or - CN;
Q 1选自N或CR 3b； Q 1 is selected from N or CR 3b ;
Q 2选自N或CR 3c； Q 2 is selected from N or CR 3c ;
Q 3选自N或CR 3d； Q 3 is selected from N or CR 3d ;
Q 4选自N或CR 3e； Q 4 is selected from N or CR 3e ;
R 3a、R 3b、R 3c、R 3d和R 3e独立地选自H、D、卤素、-CN、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或4-6元杂环基； R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from H, D, halogen, -CN, -OR 1a , -SR 1a , -N(R 1a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic group;
Z为N或CR 6a； Z is N or CR 6a ;
R 6a、R 6b、R 6c、R 6d和R 6e独立地选自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或-NHC(O)R 1a；优选地，其中至少一个为-OH、-NH(R 1a)或-NHC(O)R 1a； R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkene Group, C 2-6 alkynyl group, -OR 1a , -SR 1a , -N(R 1a ) 2 or -NHC(O)R 1a ; preferably, at least one of them is -OH, -NH(R 1a ) or -NHC(O)R 1a ;
或者，R 6a、R 6b、R 6c、R 6d和R 6e中相邻的两个可以结合形成苯基或5-6元杂芳基，其任选被1、2或3个选自-OH、-NH(R 1a)或-NHC(O)R 1a的基团取代； Alternatively, two adjacent ones of R 6a , R 6b , R 6c , R 6d and R 6e may be combined to form a phenyl group or a 5-6 membered heteroaryl group, which is optionally selected from -OH by 1, 2 or 3 , -NH(R 1a ) or -NHC(O)R 1a group substitution;
R 4为卤素； R 4 is halogen;
R 5为H或卤素； R 5 is H or halogen;
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(V)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 6b为-OH、-NH(R 1a)或-NHC(O)R 1a。 In a more specific embodiment, the present invention provides the compound of formula (V) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 6b is -OH, -NH(R 1a ) or -NHC(O)R 1a .
在更具体的实施方案中，本发明提供了上述式(V)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 6e为-OH、-NH(R 1a)或-NHC(O)R 1a。 In a more specific embodiment, the present invention provides the compound of formula (V) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 6e is -OH, -NH(R 1a ) or -NHC(O)R 1a .
在更具体的实施方案中，本发明提供了上述式(V)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 4为Cl。 In a more specific embodiment, the present invention provides the compound of formula (V) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 4 is Cl.
在更具体的实施方案中，本发明提供了上述式(V)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 3a、R 3b、R 3c、R 3d和R 3e独立地选自H、D、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基或C 3-6环烷基；优选地，R 3a为C 1-6烷基或C 1-6卤代烷基，更优选异丙基。 In a more specific embodiment, the present invention provides the compound of formula (V) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl; preferably, R 3a is C 1-6 alkyl or C 1-6 haloalkyl, more preferably Isopropyl.
在更具体的实施方案中，本发明提供了上述式(V)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 3a、R 3b、R 3c、R 3d和R 3e独立地选自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、C 3-6环烷基或4-6元杂环基。 In a more specific embodiment, the present invention provides the compound of formula (V) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from H, D, halogen, -CN, C 1- 6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic group.
在更具体的实施方案中，本发明提供了上述式(V)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Z为CR 6a。 In a more specific embodiment, the present invention provides the compound of formula (V) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, where Z is CR 6a .
在更具体的实施方案中，本发明提供了上述式(V)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 6b或R 6b之一为-OH、-NH(R 1a)或-NHC(O)R 1a；优选R 6b或R 6b之一为-OH或-NH 2。 In a more specific embodiment, the present invention provides the compound of formula (V) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein one of R 6b or R 6b is -OH, -NH(R 1a ) or -NHC(O)R 1a ; preferably R 6b or One of R 6b is -OH or -NH 2 .
在更具体的实施方案中，本发明提供了式(VI)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 (VI), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate Substances, polymorphs, prodrugs or isotopic variants, and their mixtures:
Figure PCTCN2021091100-appb-000108
Figure PCTCN2021091100-appb-000108
其中，in,
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；其中所述C 1-6烷基或C 1-6卤代烷基任选被D、卤素、-CN、-O-R 1a、-S-R 1a或-N(R 1a) 2取代；优选地，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, -CN, C 1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl or C 1-6 haloalkyl group is optionally replaced by D, halo, -CN, -OR 1a, -SR 1a, or -N (R 1a) 2-substituted; preferably, R a, R b and R c are independently selected from H, D, halogen, or - CN;
Q 1选自N或CR 3b； Q 1 is selected from N or CR 3b ;
Q 2选自N或CR 3c； Q 2 is selected from N or CR 3c ;
Q 3选自N或CR 3d； Q 3 is selected from N or CR 3d ;
Q 4选自N或CR 3e； Q 4 is selected from N or CR 3e ;
R 3a、R 3b、R 3c、R 3d和R 3e独立地选自H、D、卤素、-CN、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或4-6元杂环基； R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from H, D, halogen, -CN, -OR 1a , -SR 1a , -N(R 1a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic group;
R 4为卤素；优选为Cl； R 4 is halogen; preferably Cl;
R 6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或-NHC(O)R 1a； R 6 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 or -NHC(O)R 1a ;
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(VI)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 3a、R 3b、R 3c、R 3d和R 3e独立地选自H、D、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基或C 3-6环烷基；优选地，R 3a为C 1-6烷基或C 1-6卤代烷基，更优选异丙基。 In a more specific embodiment, the present invention provides the above-mentioned compound of formula (VI), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl; preferably, R 3a is C 1-6 alkyl or C 1-6 haloalkyl, more preferably Isopropyl.
在更具体的实施方案中，本发明提供了上述式(VI)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为-OH、-NH(R 1a)或-NHC(O)R 1a，更优选为-OH。 In a more specific embodiment, the present invention provides the above-mentioned compound of formula (VI), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, Hydrates, polymorphs, prodrugs or isotopic variants, and mixtures thereof, wherein R 6 is -OH, -NH(R 1a ) or -NHC(O)R 1a , more preferably -OH.
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 PCTCN2021091100-appb-000109
Figure PCTCN2021091100-appb-000109
Figure PCTCN2021091100-appb-000110
Figure PCTCN2021091100-appb-000110
Figure PCTCN2021091100-appb-000111
Figure PCTCN2021091100-appb-000111
Figure PCTCN2021091100-appb-000112
Figure PCTCN2021091100-appb-000112
Figure PCTCN2021091100-appb-000113
Figure PCTCN2021091100-appb-000113
Figure PCTCN2021091100-appb-000114
Figure PCTCN2021091100-appb-000114
Figure PCTCN2021091100-appb-000115
Figure PCTCN2021091100-appb-000115
Figure PCTCN2021091100-appb-000116
Figure PCTCN2021091100-appb-000116
Figure PCTCN2021091100-appb-000117
Figure PCTCN2021091100-appb-000117
Figure PCTCN2021091100-appb-000118
Figure PCTCN2021091100-appb-000118
Figure PCTCN2021091100-appb-000119
Figure PCTCN2021091100-appb-000119
Figure PCTCN2021091100-appb-000120
Figure PCTCN2021091100-appb-000120
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、***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、***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 condition of the present invention, the compound provided herein is administered to a subject at risk of developing the condition, typically based on the doctor's recommendation and under the supervision of the doctor, and the dosage level is 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***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***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.
中间体1：3-溴-N-甲基-4-(三氟甲基)苯胺的制备Intermediate 1: Preparation of 3-bromo-N-methyl-4-(trifluoromethyl)aniline
Figure PCTCN2021091100-appb-000121
Figure PCTCN2021091100-appb-000121
第一步：first step:
将甲酸(20mL)和3-溴-4-(三氟甲基)苯胺(4.5g，18.8mmol)的混合溶液在70℃搅拌16小时。将反应液减压浓缩，残余物加二氯甲烷(20mL)稀释，加饱和碳酸氢钠调节溶液的PH值至8，有机相先后用饱和氯化 铵溶液和水洗涤，无水硫酸钠干燥，减压浓缩得到N-(3-溴-4-(三氟甲基)苯基)甲酰胺(4.0g)，为白色固体。收率80％。ESI-MS:268,270[M+H] +。 A mixed solution of formic acid (20 mL) and 3-bromo-4-(trifluoromethyl)aniline (4.5 g, 18.8 mmol) was stirred at 70°C for 16 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with dichloromethane (20 mL), saturated sodium bicarbonate was added to adjust the pH of the solution to 8, the organic phase was washed with saturated ammonium chloride solution and water, and dried with anhydrous sodium sulfate. Concentration under reduced pressure gave N-(3-bromo-4-(trifluoromethyl)phenyl)formamide (4.0 g) as a white solid. The yield is 80%. ESI-MS: 268,270 [M+H] + .
第二步：The second step:
将N-(3-溴-4-(三氟甲基)苯基)甲酰胺(2.0g，7.5mmol)溶解在无水四氢呋喃(20mL)中。在冰浴和氮气保护条件下，缓慢加入四氢铝锂(LiAlH 4)(2.5M的THF溶液)(4.5mL，11.25mmol)，反应升至室温搅拌1小时。依次加入水(4mL)，15％氢氧化钠溶液(2mL)，水(4mL)淬灭反应，用二氯甲烷(20mL)萃取三次，无水硫酸钠干燥，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＝5:1)分离纯化，得到3-溴-N-甲基-4-(三氟甲基)苯胺(1.5g)，为无色油状物。收率78％。ESI-MS:254,256[M+H] +。 Dissolve N-(3-bromo-4-(trifluoromethyl)phenyl)carboxamide (2.0 g, 7.5 mmol) in dry tetrahydrofuran (20 mL). Under ice bath and nitrogen protection, lithium tetrahydroaluminum (LiAlH 4 ) (2.5M THF solution) (4.5 mL, 11.25 mmol) was slowly added, and the reaction was raised to room temperature and stirred for 1 hour. The reaction was quenched by adding water (4mL), 15% sodium hydroxide solution (2mL) and water (4mL) successively, extracted three times with dichloromethane (20mL), dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the concentrate was passed on silica gel Column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) was separated and purified to obtain 3-bromo-N-methyl-4-(trifluoromethyl)aniline (1.5g) as a colorless oil Things. The yield was 78%. ESI-MS: 254,256[M+H] + .
中间体2：4,6-二环丙基嘧啶-5-胺的制备Intermediate 2: Preparation of 4,6-dicyclopropylpyrimidin-5-amine
Figure PCTCN2021091100-appb-000122
Figure PCTCN2021091100-appb-000122
将4,6-二氯嘧啶-5-胺(5.0g，30.0mmol)溶解于甲苯(100mL)中，加入磷酸钾(19.0g，90.0mmol)、环丙基硼酸(3.1g，36.0mmol)、Sphos(6.4g，12.0mmol)和Pd 2(dba) 3(5.5g，6.0mmol)，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，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4,6-二环丙基嘧啶-5-胺(4.0g)，为白色固体，收率76％。ESI-MS:176[M+H] +。 4,6-Dichloropyrimidin-5-amine (5.0g, 30.0mmol) was dissolved in toluene (100mL), potassium phosphate (19.0g, 90.0mmol), cyclopropylboronic acid (3.1g, 36.0mmol), Sphos (6.4g, 12.0mmol) and Pd 2 (dba) 3 (5.5g, 6.0mmol) were heated to 100°C under nitrogen protection 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) to obtain 4,6-dicyclopropylpyrimidine-5- Amine (4.0g), white solid, yield 76%. ESI-MS: 176[M+H] + .
中间体3：(5-氨基-2,4-二氯苯基)硼酸频哪醇酯的制备Intermediate 3: Preparation of (5-amino-2,4-dichlorophenyl) borate pinacol ester
Figure PCTCN2021091100-appb-000123
Figure PCTCN2021091100-appb-000123
第一步：first step:
将1-溴-2,4-二氯-5-硝基苯(10.0g，37.2mmol)溶解于乙醇(200mL)和水(100mL)的混合溶液中，加入氯化铵(19.7g，372.0mol)和铁粉(10.4g，186.0mmol)，反应在90℃下搅拌1小时。反应液冷却后过滤，滤液减压除去乙醇，混合液用二氯甲烷(3*200mL)进行萃取，合并有机相，经饱和食盐水洗涤(100mL)，无水硫酸钠干燥，过滤，滤液浓缩后经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝2:1)分离纯化，得到5-溴-2,4-二氯苯胺(8.0g)，为白色固体。收率90％。ESI-MS:240,242[M+H] +。 Dissolve 1-bromo-2,4-dichloro-5-nitrobenzene (10.0g, 37.2mmol) in a mixed solution of ethanol (200mL) and water (100mL), add ammonium chloride (19.7g, 372.0mol) ) And iron powder (10.4g, 186.0mmol), the reaction was stirred at 90°C for 1 hour. The reaction solution was cooled and filtered. The filtrate was decompressed to remove ethanol. The mixed solution was extracted with dichloromethane (3*200mL). The organic phases were combined, washed with saturated brine (100mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. After separation and purification by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1), 5-bromo-2,4-dichloroaniline (8.0 g) was obtained as a white solid. The yield was 90%. ESI-MS: 240,242[M+H] + .
第二步：The second step:
将5-溴-2,4-二氯苯胺(4.0g，16.7mmol)溶解在1,4-二氧六环(50mL)中，加入乙酸钾(4.9g，50.1mmol)、联硼酸频那醇酯(6.36g，25.05mmol)和Pd(dppf)Cl 2(2.45g，3.34mmol)，在氮气保护下加热至100℃，搅拌反应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(石油醚：乙酸乙酯＝1:1)分离纯化，得到(5-氨基-2,4-二氯苯基)硼酸频哪醇酯(2.0g)，为白色固体。收率42％。ESI-MS:288[M+H] +。 Dissolve 5-bromo-2,4-dichloroaniline (4.0g, 16.7mmol) in 1,4-dioxane (50mL), add potassium acetate (4.9g, 50.1mmol) and pinacol diborate The ester (6.36g, 25.05mmol) and Pd(dppf)Cl 2 (2.45g, 3.34mmol) were heated to 100°C under the protection of nitrogen, and the reaction was 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 (petroleum ether: ethyl acetate = 1:1) to obtain (5-amino-2,4-dichlorophenyl) boronic acid. Alcohol ester (2.0g), a white solid. The yield was 42%. ESI-MS: 288[M+H] + .
中间体4：N-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-4-(三氟甲基)苯基)乙酰胺的制备Intermediate 4: N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl) Preparation of phenyl)acetamide
Figure PCTCN2021091100-appb-000124
Figure PCTCN2021091100-appb-000124
将3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-4-(三氟甲基)苯胺(200mg，0.70mmol)溶于醋酸酐(1mL)中，在室温下搅拌反应16小时。反应完成后将反应体系减压浓缩得到N-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-4-(三氟甲基)苯基)乙酰胺(210mg)，为黄色固体，收率92％。Add 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (200mg, 0.70mmol ) Was dissolved in acetic anhydride (1 mL), and the reaction was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction system was concentrated under reduced pressure to obtain N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4- (Trifluoromethyl)phenyl)acetamide (210mg), yellow solid, yield 92%.
中间体5：2-环丙基-6-甲基苯胺的制备Intermediate 5: Preparation of 2-cyclopropyl-6-methylaniline
Figure PCTCN2021091100-appb-000125
Figure PCTCN2021091100-appb-000125
在氮气气氛下，将2-溴-6-甲基苯胺(4.58g，24.6mmol)、环丙基硼酸(4.23g，49.2mmol)、无水磷酸钾(23.5g,111mmol)和Pd(dppf)Cl 2(1.8g,2.46mmol)加入到70mL的1,4-二氧六环中，加热到90℃，反应3小时。反应完成后停止加热，冷却到室温，垫硅藻土过滤，滤液减压浓缩，残余物用CombiFlash快速制备仪(石油醚：乙酸乙酯＝10:1)分离纯化，得到产品2.9g，为白色固体，产率(80.5％)。ESI-MS:148[M+H] +。 Under a nitrogen atmosphere, mix 2-bromo-6-methylaniline (4.58g, 24.6mmol), cyclopropylboronic acid (4.23g, 49.2mmol), anhydrous potassium phosphate (23.5g, 111mmol) and Pd(dppf) Cl 2 (1.8 g, 2.46 mmol) was added to 70 mL of 1,4-dioxane, heated to 90° C., and reacted for 3 hours. After the reaction was completed, the heating was stopped, cooled to room temperature, filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. The residue was separated and purified with a CombiFlash rapid preparation instrument (petroleum ether: ethyl acetate = 10:1) to obtain 2.9 g of white product. Solid, yield (80.5%). ESI-MS: 148[M+H] + .
中间体6：6-氯-N-甲基-5-(三氟甲基)吡啶-2-胺的制备Intermediate 6: Preparation of 6-chloro-N-methyl-5-(trifluoromethyl)pyridin-2-amine
Figure PCTCN2021091100-appb-000126
Figure PCTCN2021091100-appb-000126
将2,6-二氯-3-(三氟甲基)吡啶(10g，46.2mmol)溶解在DMF(50mL)中，将甲胺盐酸盐(3.1g,46.2mmol)和三乙胺(14.0g,138.6mmol)加入体系，反应在室温搅拌8小时。反应结束后，加入乙酸乙酯(300mL)稀释，用饱和食盐水洗涤有机相三次，然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＝5:1)分离纯化，得到6-氯-N-甲基-5-(三氟甲基)吡啶-2-胺(5.2g)，为白色固体，收率53.6％。ESI-MS:211[M+H] +。 2,6-Dichloro-3-(trifluoromethyl)pyridine (10g, 46.2mmol) was dissolved in DMF (50mL), methylamine hydrochloride (3.1g, 46.2mmol) and triethylamine (14.0 g, 138.6 mmol) was added to the system, and the reaction was stirred at room temperature for 8 hours. After the reaction was completed, ethyl acetate (300 mL) was added to dilute, the organic phase was washed three times with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography (eluent: n-hexane: acetic acid). Ethyl ester=5:1) was separated and purified to obtain 6-chloro-N-methyl-5-(trifluoromethyl)pyridin-2-amine (5.2g) as a white solid with a yield of 53.6%. ESI-MS: 211[M+H] + .
中间体7：(2-氨基苯并[d]噻唑-4-基)硼酸的制备Intermediate 7: Preparation of (2-aminobenzo[d]thiazol-4-yl)boronic acid
Figure PCTCN2021091100-appb-000127
Figure PCTCN2021091100-appb-000127
第一步：first step:
在氮气气氛下，将DMAP(214mg,1.75mmol)和DIEA(6.8g,52.5mmol)加入到2-氨基-4-溴苯并噻唑(4 g,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，室温搅拌3.5小时。反应结束后，加饱和碳酸氢钠溶液(5mL)淬灭，用乙酸乙酯(20mL)萃取三次，合并有机相并用无水硫酸钠干燥，减压浓缩有机相，浓缩物经硅胶柱层析(洗脱剂：正己烷:乙酸乙酯＝5:1)分离纯化，得到产品4克，为白色固体，产率(70％)。ESI-MS:330[M+H] +。 Under a nitrogen atmosphere, DMAP (214mg, 1.75mmol) and DIEA (6.8g, 52.5mmol) were added to a solution of 2-amino-4-bromobenzothiazole (4 g, 17.5mmol) in tetrahydrofuran (50ml), and then Boc 2 O (4.6 g, 21 mmol) was added to the above reaction system and stirred at room temperature for 3.5 hours. After the reaction, it was quenched by adding saturated sodium bicarbonate solution (5 mL), extracted with ethyl acetate (20 mL) three times, and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography ( Eluent: n-hexane: ethyl acetate = 5:1) Separation and purification, 4 grams of product is obtained as a white solid, and the yield is (70%). ESI-MS: 330[M+H] + .
第二步：The second step:
在氮气气氛下，将(4-溴苯并[d]噻唑-2-基)氨基甲酸叔丁酯(2g,6mol)溶于干燥四氢呋喃(27mL)中，体系温度降至-78℃，在此温度下将n-BuLi(7.2mL,18mmol,2.5mol/L正己烷溶液)缓慢滴入到上述反应中，温度控制在-60℃以下，滴完后升温至-30℃并反应30min。反应完毕后，用饱和氯化铵淬灭，二氯甲烷萃取，有机相经饱和食盐水洗涤并用无水硫酸钠干燥，浓缩有机相，浓缩物经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 a nitrogen atmosphere, (4-bromobenzo[d]thiazol-2-yl) tert-butyl carbamate (2g, 6mol) was dissolved in dry tetrahydrofuran (27mL), and the temperature of the system dropped to -78°C. Slowly drip n-BuLi (7.2mL, 18mmol, 2.5mol/L n-hexane solution) into the above reaction under temperature, and control the temperature below -60℃. After the dripping, the temperature was raised to -30℃ and reacted for 30min. After the reaction, it was quenched with saturated ammonium chloride, extracted with dichloromethane, the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate, the organic phase was concentrated, and the concentrate was subjected to C18 reverse phase column chromatography (eluent: CH 3 CN:H 2 O=6:4) was separated and purified to obtain 400 mg of (2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)boronic acid with a yield of 22.6%. White solid. ESI-MS: 295[M+H] + .
第三步：third step:
将2-((叔丁氧基羰基)氨基)苯并[d]噻唑-4-基)硼酸(200mg,67.7mmol)溶解于二氯甲烷(5mL)中，往体系中加入三氟乙酸(1mL)，在室温下搅拌反应30min。反应结束后，将反应液浓缩得到粗产品(2-氨基苯并[d]噻唑-4-基)硼酸(120mg)，产率91％，为淡黄色固体，粗品直接用于下一步反应。ESI-MS:195[M+H] +。 Dissolve 2-((tert-butoxycarbonyl)amino)benzo[d]thiazol-4-yl)boronic acid (200mg, 67.7mmol) in dichloromethane (5mL), add trifluoroacetic acid (1mL) to the system ), the reaction was stirred at room temperature for 30 min. After the completion of the reaction, the reaction solution was concentrated to obtain the crude product (2-aminobenzo[d]thiazol-4-yl)boronic acid (120 mg), with a yield of 91%, as a pale yellow solid, and the crude product was directly used in the next reaction. ESI-MS: 195[M+H] + .
中间体8：3-((6-溴-7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-3,4-二氢喹喔啉-1(H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯的制备Intermediate 8: 3-((6-Bromo-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline -1(H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester
Figure PCTCN2021091100-appb-000128
Figure PCTCN2021091100-appb-000128
第一步first step
将1-溴-2-氯-5-氟-4-硝基苯(50.6g，200mmol)、氟化钾(34.8g，600mmol)和2-异丙基-6-甲基苯胺(29.8g，200mmol)均匀混合在一起，反应在180℃下搅拌8小时。反应液冷却后用水(500mL)稀释，再用乙酸乙酯(3*500mL)萃取，合并有机相并经饱和食盐水洗涤(100mL),无水硫酸钠干燥，过滤，然后减压浓缩得到5-溴-4-氯-N-(2-异丙基-6-甲基苯基)-2-硝基苯胺(75.0g)，为黄色固体，收率97％。ESI-MS:383,385[M+H] +。 Combine 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (50.6g, 200mmol), potassium fluoride (34.8g, 600mmol) and 2-isopropyl-6-methylaniline (29.8g, 200mmol) were mixed together uniformly, and the reaction was stirred at 180°C for 8 hours. The reaction solution was cooled and diluted with water (500mL), and then extracted with ethyl acetate (3*500mL). The organic phases were combined and washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5- Bromo-4-chloro-N-(2-isopropyl-6-methylphenyl)-2-nitroaniline (75.0 g), as a yellow solid, with a yield of 97%. ESI-MS: 383,385[M+H] + .
第二步Second step
将5-溴-4-氯-N-(2-异丙基-6-甲基苯基)-2-硝基苯胺(75.0g，196mmol)溶解在乙醇(1.5L)和水(800mL)中， 加入氯化铵(103.9g，1.96mol)和铁粉(54.9g，980mmol)，反应在90℃下搅拌1小时。反应结束后将反应液冷却并过滤，滤液减压除去乙醇，混合液用二氯甲烷(3*800mL)萃取，合并有机相，有机相经饱和食盐水洗涤(500mL)，无水硫酸钠干燥，过滤，滤液浓缩后经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝5:1)分离纯化，得到5-溴-4-氯-N-(2-异丙基-6-甲基苯基)苯-1,2-二胺(50g)，为白色固体，收率73％。ESI-MS:353,355[M+H] +。 Dissolve 5-bromo-4-chloro-N-(2-isopropyl-6-methylphenyl)-2-nitroaniline (75.0g, 196mmol) in ethanol (1.5L) and water (800mL) , Ammonium chloride (103.9g, 1.96mol) and iron powder (54.9g, 980mmol) were added, and the reaction was stirred at 90°C for 1 hour. After the reaction, the reaction solution was cooled and filtered. The filtrate was decompressed to remove ethanol. The mixed solution was extracted with dichloromethane (3*800mL). The organic phases were combined. The organic phases were washed with saturated brine (500mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated and separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 5-bromo-4-chloro-N-(2-isopropyl-6-methyl) (Phenyl)benzene-1,2-diamine (50g), white solid, yield 73%. ESI-MS: 353,355 [M+H] + .
第三步third step
将5-溴-4-氯-N-(2-异丙基-6-甲基苯基)苯-1,2-二胺(50g,142mmol)溶于四氢呋喃(800mL)中，加入三乙胺(72g，710mmol)，在冰浴条件下，缓慢滴加草酰氯单甲酯(52g，426mmol)溶液，在室温下搅拌1小时后，升温至90℃下继续搅拌3小时。反应液冷却并减压浓缩，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7-溴-6-氯-1-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(40g)，为白色固体，收率70％。ESI-MS:407,409[M+H] +。 Dissolve 5-bromo-4-chloro-N-(2-isopropyl-6-methylphenyl)benzene-1,2-diamine (50g, 142mmol) in tetrahydrofuran (800mL) and add triethylamine (72g, 710mmol), slowly dropwise add a solution of oxalyl chloride monomethyl ester (52g, 426mmol) in an ice bath. After stirring for 1 hour at room temperature, the temperature was raised to 90°C and the stirring was continued 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 7-bromo-6-chloro-1-(2-isopropyl) 6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (40g), white solid, yield 70%. ESI-MS: 407,409 [M+H] + .
第四步the fourth step
将7-溴-6-氯-1-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(40g，98.5mmol)溶于N,N-二甲基甲酰胺(100mL)中，加入碳酸钾(40.8g，295.5mmol)和3-(碘甲基)氮杂环丁烷-1-甲酸叔丁酯(35.0g，118mmol)，反应在室温下搅拌16小时。反应完毕后将反应液用水(200mL)稀释，再用乙酸乙酯(3*200mL)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，滤液浓缩除溶剂，浓缩残余物用硅胶柱层析(石油醚：乙酸乙酯＝1:1)分离纯化得到3-((6-溴-7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-3,4-二氢喹喔啉-1(H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(35g)，为白色固体，收率62％。ESI-MS:576,578[M+H] +。 Dissolve 7-bromo-6-chloro-1-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (40g, 98.5mmol) To N,N-dimethylformamide (100mL), add potassium carbonate (40.8g, 295.5mmol) and tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (35.0g, 118mmol) The reaction was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction solution was diluted with water (200 mL), and then extracted with ethyl acetate (3*200 mL). The organic phases were combined, washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove Solvent, concentrate the residue and separate and purify it with silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to obtain 3-((6-bromo-7-chloro-4-(2-isopropyl-6-methyl) (Phenyl)-2,3-dioxo-3,4-dihydroquinoxaline-1(H)-yl)methyl)azetidine-1-carboxylate (35g), white Solid, the yield was 62%. ESI-MS: 576,578 [M+H] + .
中间体9：3-碘-2-异丙基-4-甲基吡啶的制备Intermediate 9: Preparation of 3-iodo-2-isopropyl-4-methylpyridine
Figure PCTCN2021091100-appb-000129
Figure PCTCN2021091100-appb-000129
在N 2氛围下，将2-异丙基-4-甲基吡啶-3-胺(8.0g,53.3mmoL)、亚硝酸叔丁酯(27.5g，267.0mmoL)、碘化钾(44.3g，266.9mmoL)和碘化亚铜(12.2g，64.2mmoL)分散于乙腈(100mL)中，维持在80℃温度下搅拌16小时。反应完毕后体系降至室温，反应液过滤，EA(50mL)洗涤滤饼。滤液浓缩后经flash硅胶柱层析(洗脱剂：EA:PE＝0-15％)分离纯化得到3-碘-2-异丙基-4-甲基吡啶(11.8g)，为浅黄色液体，收率85％。 Under N 2 atmosphere, mix 2-isopropyl-4-methylpyridine-3-amine (8.0g, 53.3mmoL), tert-butyl nitrite (27.5g, 267.0mmoL), potassium iodide (44.3g, 266.9mmoL) ) And cuprous iodide (12.2g, 64.2mmoL) were dispersed in acetonitrile (100mL) and kept at 80°C and stirred for 16 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, and the filter cake was washed with EA (50 mL). The filtrate was concentrated and separated and purified by flash silica gel column chromatography (eluent: EA:PE=0-15%) to obtain 3-iodo-2-isopropyl-4-methylpyridine (11.8g), which was a pale yellow liquid , The yield is 85%.
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-2,3(1H,4H)-二酮的制备Example 1: 1-((1-acryloylazetidin-3-yl)methyl)-7-fluoro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2,3( 1H,4H)-diketone preparation
Figure PCTCN2021091100-appb-000130
Figure PCTCN2021091100-appb-000130
第一步：first step:
N 2氛围下，将1-溴-2,4-二氟-5-硝基苯(500mg，2.1mmol)，3-(氨基甲基)氮杂环丁烷-1-甲酸叔丁酯(430mg，2.3mmol)，碳酸钾(870mg，6.3mmol)分散在乙腈(ACN)(10mL)中。于室温搅拌2小时后，50℃搅拌16小时。体系减压浓缩后用中压flash硅胶柱层析(洗脱剂：乙酸乙酯:石油醚＝0–30％)分离纯化，得到3-(((4-溴-5-氟-2-硝基苯基)氨基)甲基)氮杂环丁烷-1-甲酸叔丁酯(460mg)，为黄色固体，收率54％。ESI-MS:404,406[M+H] +。 Under N 2 atmosphere, 1-bromo-2,4-difluoro-5-nitrobenzene (500mg, 2.1mmol), tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (430mg , 2.3 mmol), potassium carbonate (870 mg, 6.3 mmol) were dispersed in acetonitrile (ACN) (10 mL). After stirring at room temperature for 2 hours, it was stirred at 50°C 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: ethyl acetate: petroleum ether=0-30%) to obtain 3-(((4-bromo-5-fluoro-2-nitro (Phenyl)amino)methyl)tert-butyl azetidine-1-carboxylate (460 mg), as a yellow solid, with a yield of 54%. ESI-MS: 404,406 [M+H] + .
第二步：The second step:
将3-(((4-溴-5-氟-2-硝基苯基)氨基)甲基)氮杂环丁烷-1-甲酸叔丁酯(460mg，1.14mmol)溶于乙醇(20mL)后，室温搅拌条件下依次加入铁粉(680mg，11.4mmol)，氯化铵(609mg，11.4mmol)，水(5mL)，置于100℃，搅拌2小时。体系冷却后，经硅藻土减压过滤后，滤饼用乙酸乙酯(100mL)和乙醇(50mL)冲洗后，滤液减压浓缩。浓缩后加入水(30mL)，用乙酸乙酯(3x50mL)萃取，有机相用无水硫酸钠干燥后，抽滤，减压浓缩后的粗品用中压flash硅胶柱层析(洗脱剂：乙酸乙酯:二氯甲烷＝0-70％)分离纯化，得到3-(((2-氨基-4-溴-5-氟苯基)氨基)甲基)氮杂环丁烷-1-甲酸叔丁酯(340mg)，为紫黑色固体，收率80％。ESI-MS:374,376[M+H] +。 3-(((4-Bromo-5-fluoro-2-nitrophenyl)amino)methyl) tert-butyl azetidine-1-carboxylate (460mg, 1.14mmol) was dissolved in ethanol (20mL) Afterwards, iron powder (680 mg, 11.4 mmol), ammonium chloride (609 mg, 11.4 mmol), and water (5 mL) were sequentially added under stirring at room temperature, placed at 100° C., and stirred for 2 hours. After the system was cooled and filtered through Celite under reduced pressure, the filter cake was washed with ethyl acetate (100 mL) and ethanol (50 mL), and the filtrate was concentrated under reduced pressure. After concentration, water (30mL) was added and extracted with ethyl acetate (3x50mL). The organic phase was dried over anhydrous sodium sulfate and filtered with suction. The crude product after concentration under reduced pressure was chromatographed on medium-pressure flash silica gel column (eluent: acetic acid). Ethyl: dichloromethane=0-70%) was separated and purified to obtain tert-(((2-amino-4-bromo-5-fluorophenyl)amino)methyl)azetidine-1-carboxylic acid tert Butyl ester (340mg) is a purple-black solid with a yield of 80%. ESI-MS: 374,376 [M+H] + .
第三步：third step:
将3-(((2-氨基-4-溴-5-氟苯基)氨基)甲基)氮杂环丁烷-1-甲酸叔丁酯(340mg，0.91mmol)、三乙胺(734mg，7.27mmol)溶解在四氢呋喃(4mL)中。降至0℃，缓慢滴加2-氯-2-氧代乙酸甲酯(447mg，3.63mmol)，缓慢升至室温后，于80℃反应2小时(反应过程中有大量气体生成)。体系降至室温后，减压浓缩后的粗品用中压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-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(340mg)，为棕色固体，收率97％。ESI-MS:428,430[M+H] +。 3-(((2-Amino-4-bromo-5-fluorophenyl)amino)methyl)tert-butyl azetidine-1-carboxylate (340mg, 0.91mmol), triethylamine (734mg, 7.27 mmol) was dissolved in tetrahydrofuran (4 mL). After the temperature was lowered to 0°C, methyl 2-chloro-2-oxoacetate (447mg, 3.63mmol) was slowly added dropwise, and after slowly rising to room temperature, the reaction was carried out at 80°C for 2 hours (a large amount of gas was generated during the reaction). After the system was cooled to room temperature, the crude product after concentration under reduced pressure was separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol: dichloromethane=0-10%) to obtain 3-((6-bromo-7- Fluoro-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (340mg), as a brown solid, The yield was 97%. ESI-MS: 428,430[M+H] + .
第四步：the fourth 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-甲酸叔丁酯(140mg，0.33mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-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(136mg，0.99mmol)分散在1,4-二氧六环/水(5:1，4mL)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)-2,3-二氧代-3,4-二羟基喹喔啉-1(2H)-基)甲基)氮化环丁烷-1-甲酸叔丁酯(118mg)，为紫黑色固体，收率73％。ESI-MS:492[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 (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 ( 136mg, 0.99mmol) was dispersed in 1,4-dioxane/water (5:1, 4mL). 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)-2,3-dioxo-3,4-dihydroxyquinoxaline-1(2H)-yl)methyl)nitrocyclobutane-1-carboxylic acid tert-butyl ester (118mg), as purple Black solid, the yield is 73%. ESI-MS: 492[M+H] + .
第五步：the fifth step:
将3-((7-氟-6-(3-羟基萘-1-基)-2,3-二氧代-3,4-二羟基喹喔啉-1(2H)-基)甲基)氮化环丁烷-1-甲酸叔丁酯(118mg，0.24mmol)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-2,3(1H,4H)-二酮(94mg)，为棕色固体，收率100％。ESI-MS:392[M+H] +。 Add 3-((7-fluoro-6-(3-hydroxynaphthalene-1-yl)-2,3-dioxo-3,4-dihydroxyquinoxaline-1(2H)-yl)methyl) Tert-butyl nitrate cyclobutane-1-carboxylate (118 mg, 0.24 mmol) was dissolved in dichloromethane (5 mL). At room temperature, trifluoroacetic acid (0.5mL) 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 Naphthalene-1-yl)quinoxaline-2,3(1H,4H)-dione (94mg), brown solid, yield 100%. ESI-MS: 392[M+H] + .
第六步：The sixth 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-2,3(1H,4H)-二酮(94mg，0.24mmol)溶解在二氯甲烷(3mL)中，加入三乙胺(242mg,2.4mmol)。冷却至0℃，将丙烯酰氯(22mg，0.24mmol)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＝0-40％)。冻干得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-2,3(1H,4H)-二酮(7.03mg)，为白色固体，收率6.6％。ESI-MS:446[M+H] +。 Under N 2 atmosphere, 1-(azetidin-3-ylmethyl)-7-fluoro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2,3(1H,4H) -The diketone (94 mg, 0.24 mmol) was dissolved in dichloromethane (3 mL), and triethylamine (242 mg, 2.4 mmol) was added. After cooling to 0°C, a solution of acryloyl chloride (22 mg, 0.24 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=0-40%). Lyophilized to give 1-((1-acryloylazetidin-3-yl)methyl)-7-fluoro-6-(3-hydroxynaphthalene-1-yl)quinoxaline-2,3(1H ,4H)-diketone (7.03mg), white solid, yield 6.6%. ESI-MS: 446[M+H] + .
1H-NMR(300MHz,DMSO-d 6)δ:ppm 12.10(s,1H),9.95(s,1H),7.79(d,1H,J＝7.8Hz),7.68(d,1H,J＝11.7Hz),7.46～7.41(m,2H),7.29～7.23(m,2H),7.16(d,1H,J＝7.2Hz),7.03～7.02(m,1H),6.33～6.27(m,1H),6.10(dd,1H,J＝16.8,2.1Hz),5.67(dd,1H,J＝10.2,2.4Hz),4.48～4.46(m,2H),4.35～4.25(m,1H),4.15～4.08(m,1H),4.05～3.95(m,1H),3.89～3.80(m,1H),3.20～3.12(m,1H)。 1 H-NMR (300MHz, DMSO-d 6 ) δ: ppm 12.10 (s, 1H), 9.95 (s, 1H), 7.79 (d, 1H, J = 7.8 Hz), 7.68 (d, 1H, J = 11.7 Hz),7.46～7.41(m,2H),7.29～7.23(m,2H),7.16(d,1H,J=7.2Hz),7.03～7.02(m,1H),6.33～6.27(m,1H) ,6.10(dd,1H,J=16.8,2.1Hz), 5.67(dd,1H,J=10.2,2.4Hz), 4.48～4.46(m,2H), 4.35～4.25(m,1H), 4.15～4.08 (m,1H), 4.05～3.95(m,1H), 3.89～3.80(m,1H), 3.20～3.12(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-2,3(1H,4H)-二酮的制备Example 2: 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2,3( 1H,4H)-diketone preparation
Figure PCTCN2021091100-appb-000131
Figure PCTCN2021091100-appb-000131
第一步：first step:
N 2氛围下，将1-溴-2-氯-4-氟-5-硝基苯(1000mg，3.9mmol)，3-(氨基甲基)氮杂环丁烷-1-甲酸叔丁酯(1098mg，5.9mmol)，碳酸钾(1630mg，11.8mmol)分散在乙腈(ACN)(20mL)中。于室温搅拌2小时后，50℃搅拌16小时。体系减压浓缩后用中压flash硅胶柱层析(洗脱剂：乙酸乙酯:石油醚＝0–30％)分离纯化，得到3-(((4-溴-5-氯-2-硝基苯基)氨基)甲基)氮杂环丁烷-1-甲酸叔丁酯(1600mg)，为黄色固体，收率97％。ESI-MS:420,422[M+H] +。 Under N 2 atmosphere, add 1-bromo-2-chloro-4-fluoro-5-nitrobenzene (1000mg, 3.9mmol), tert-butyl 3-(aminomethyl)azetidine-1-carboxylate ( 1098 mg, 5.9 mmol), potassium carbonate (1630 mg, 11.8 mmol) were dispersed in acetonitrile (ACN) (20 mL). After stirring at room temperature for 2 hours, it was stirred at 50°C 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: ethyl acetate: petroleum ether=0-30%) to obtain 3-(((4-bromo-5-chloro-2-nitro (Phenyl)amino)methyl)tert-butyl azetidine-1-carboxylate (1600 mg), as a yellow solid, with a yield of 97%. ESI-MS: 420,422[M+H] + .
第二步：The second step:
将3-(((4-溴-5-氯-2-硝基苯基)氨基)甲基)氮杂环丁烷-1-甲酸叔丁酯(1600mg，3.81mmol)溶于乙醇(70mL)后，室温搅拌条件下依次加入铁粉(2133mg，38.1mmol)，氯化铵(2038mg，38.1mmol)，水(18mL)，置于100℃，搅拌2小时。体系冷却后，经硅藻土减压过滤后，滤饼用乙酸乙酯(100mL)和乙醇(100mL)冲洗后，滤液减压浓缩。浓缩后加入水(50mL)，用乙酸乙酯(3x50mL)萃取，有机相用无水硫酸钠干燥后，抽滤，减压浓缩后的粗品用中压flash硅胶柱层析(洗脱剂：乙酸乙酯:二氯甲烷＝0-70％)分离纯化，得到3-(((2-氨基-4-溴-5-氯苯基)氨基)甲基)氮杂环丁烷-1-甲酸叔丁酯(1400mg)，为淡棕色固体，收率94％。ESI-MS:390,392[M+H] +。 3-(((4-Bromo-5-chloro-2-nitrophenyl)amino)methyl) tert-butyl azetidine-1-carboxylate (1600mg, 3.81mmol) was dissolved in ethanol (70mL) Afterwards, iron powder (2133 mg, 38.1 mmol), ammonium chloride (2038 mg, 38.1 mmol), water (18 mL) were sequentially added under stirring at room temperature, placed at 100° C., and stirred for 2 hours. After the system was cooled and filtered through Celite under reduced pressure, the filter cake was washed with ethyl acetate (100 mL) and ethanol (100 mL), and the filtrate was concentrated under reduced pressure. After concentration, water (50mL) was added and extracted with ethyl acetate (3x50mL). The organic phase was dried over anhydrous sodium sulfate and filtered with suction. The crude product after concentration under reduced pressure was chromatographed with medium pressure flash silica gel (eluent: acetic acid) Ethyl: dichloromethane=0-70%) was separated and purified to obtain 3-(((2-amino-4-bromo-5-chlorophenyl)amino)methyl)azetidine-1-carboxylic acid tert Butyl ester (1400 mg), light brown solid, yield 94%. ESI-MS: 390,392[M+H] + .
第三步：third step:
将3-(((2-氨基-4-溴-5-氯苯基)氨基)甲基)氮杂环丁烷-1-甲酸叔丁酯(1400mg，3.59mmol)、三乙胺(2901mg，28.72mmol)溶解在四氢呋喃(20mL)中。降至0℃，缓慢滴加2-氯-2-氧代乙酸甲酯(1766mg，14.36mmol)，缓慢升至室温后，于80℃反应2小时(反应过程中有大量气体生成)。体系降至室温后，减压浓缩后的粗品用中压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-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(1500mg)，为黄色固体，收率94％。ESI-MS:444,446[M+H] +。 3-(((2-Amino-4-bromo-5-chlorophenyl)amino)methyl) tert-butyl azetidine-1-carboxylate (1400 mg, 3.59 mmol), triethylamine (2901 mg, 28.72 mmol) was dissolved in tetrahydrofuran (20 mL). After the temperature was lowered to 0°C, methyl 2-chloro-2-oxoacetate (1766mg, 14.36mmol) was slowly added dropwise, and after slowly rising to room temperature, the reaction was carried out at 80°C for 2 hours (a large amount of gas was generated during the reaction). After the system was cooled to room temperature, the crude product after concentration under reduced pressure was separated and purified by medium-pressure flash silica gel column chromatography (eluent: methanol: dichloromethane=0-10%) to obtain 3-((6-bromo-7- Tert-butyl chloro-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylate (1500mg), as a yellow solid, The yield was 94%. ESI-MS: 444,446 [M+H] + .
第四步：the fourth 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-甲酸叔丁酯(150mg，0.34mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)萘-2-醇(109mg，0.40mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(Pd(dppf)Cl 2，25mg，0.034mmol)，碳酸钾(140mg，1.01mmol)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-6-(3-羟基萘-1-基)-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(156mg)，为棕黑色固体，收率91％。ESI-MS:508[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 (150mg, 0.34mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene -2-ol (109mg, 0.40mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl 2 , 25mg, 0.034mmol), potassium carbonate ( 140 mg, 1.01 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-6-(3-hydroxynaphthalene-1) -Yl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (156mg), brown Black solid, the yield is 91%. ESI-MS: 508[M+H] + .
第五步：the fifth step:
将3-((7-氯-6-(3-羟基萘-1-基)-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(156mg，0.31mmol)溶解在二氯甲烷(7mL)中。室温下，缓慢滴加三氟乙酸(0.7mL)，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-6-(3-羟基萘-1-基)喹喔啉-2,3(1H,4H)-二酮(125mg)，为棕色固体，收率100％。ESI-MS:408[M+H] +。 Add 3-((7-chloro-6-(3-hydroxynaphthalene-1-yl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl) Tert-butyl azetidine-1-carboxylate (156 mg, 0.31 mmol) was dissolved in dichloromethane (7 mL). At room temperature, trifluoroacetic acid (0.7 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-hydroxynaphthalene -1-yl)quinoxaline-2,3(1H,4H)-dione (125mg), brown solid, yield 100%. ESI-MS: 408[M+H] + .
第六步：The sixth 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-2,3(1H,4H)-二酮(125mg，0.31 mmol)溶解在二氯甲烷(5mL)中，加入三乙胺(310mg,3.1mmol)。冷却至0℃，将丙烯酰氯(31mg，0.34mmol)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＝0-40％)。冻干得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-2,3(1H,4H)-二酮(11.73mg)，为白色固体，收率8％。ESI-MS:462[M+H] +。 Under N 2 atmosphere, 1-(azetidin-3-ylmethyl)-7-chloro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2,3(1H,4H) -The diketone (125 mg, 0.31 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (310 mg, 3.1 mmol) was added. After cooling to 0°C, a solution of acryloyl chloride (31 mg, 0.34 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=0-40%). Lyophilized to give 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(3-hydroxynaphthalene-1-yl)quinoxaline-2,3(1H ,4H)-diketone (11.73mg), white solid, yield 8%. ESI-MS: 462[M+H] + .
1H-NMR(400MHz,DMSO-d 6)δ:ppm 12.18(s,1H),9.96(s,1H),7.82～7.77(m,2H),7.44～7.41(m,1H),7.23～7.22(m,3H),7.11(s,1H),6.95(d,1H,J＝2.4Hz),6.32(dd,1H,J＝17.2,10.4Hz),6.11(dd,1H,J＝16.8,2.4Hz),5.68(dd,1H,J＝16.8,2.4Hz),4.51～4.49(m,2H),4.32～4.28(m,1H),4.12～4.09(m,1H),4.02～3.97(m,1H),3.85～3.81(m,1H),3.17～3.10(m,1H)。 1 H-NMR(400MHz,DMSO-d 6 )δ:ppm 12.18(s,1H),9.96(s,1H),7.82～7.77(m,2H),7.44～7.41(m,1H),7.23～7.22 (m, 3H), 7.11 (s, 1H), 6.95 (d, 1H, J = 2.4 Hz), 6.32 (dd, 1H, J = 17.2, 10.4 Hz), 6.11 (dd, 1H, J = 16.8, 2.4 Hz),5.68(dd,1H,J=16.8,2.4Hz),4.51～4.49(m,2H), 4.32～4.28(m,1H), 4.12～4.09(m,1H),4.02～3.97(m, 1H), 3.85～3.81(m,1H), 3.17～3.10(m,1H).
实施例3：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-4-(2-(二甲基氨基)乙基)-7-氟-6-(3-羟基萘-1-基)喹喔啉-2,3(1H,4H)-二酮的合成Example 3: 1-((1-acryloylazetidin-3-yl)methyl)-4-(2-(dimethylamino)ethyl)-7-fluoro-6-(3- Synthesis of hydroxynaphthalene-1-yl)quinoxaline-2,3(1H,4H)-dione
Figure PCTCN2021091100-appb-000132
Figure PCTCN2021091100-appb-000132
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-甲酸叔丁酯(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-甲酸叔丁酯和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-甲酸叔丁酯的混合物(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-dihydroquinoxaline-1(2H)-yl)methyl)azacyclo The mixture of tert-butyl butane-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-甲酸叔丁酯和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-甲酸叔丁酯的混合物(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-((4-(2-(二甲基氨基)乙基)-7-氟-6-(3-羟基萘-1-基)-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(60mg)，为紫黑色固体，收率28％。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(diphenylphosphino) )Ferrocene]palladium dichloride (Pd(dppf)Cl 2 , 28mg, 0.037mmol), potassium carbonate (156mg, 1.12mmol) dispersed in 1,4-dioxane/water (5:1, 5mL) middle. 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-((4-(2-(dimethylamino)ethyl )-7-fluoro-6-(3-hydroxynaphthalene-1-yl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azacyclo Tert-butyl butane-1-carboxylate (60 mg), a purple-black solid, with a yield of 28%. ESI-MS: 563[M+H] + .
第三步：third step:
将3-((4-(2-(二甲基氨基)乙基)-7-氟-6-(3-羟基萘-1-基)-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(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，然后减压浓缩后得到1-(氮杂环丁烷-3-基甲基)-4-(2-(二甲基氨基)乙基)-7-氟-6-(3-羟基萘-1-基)喹喔啉-2,3(1H,4H)-二酮(118mg)，为棕色固体，收率100％。ESI-MS:463[M+H] +。 Add 3-((4-(2-(dimethylamino)ethyl)-7-fluoro-6-(3-hydroxynaphthalene-1-yl)-2,3-dioxo-3,4-di Hydroquinoxaline-1(2H)-yl)methyl)azetidine-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)-4-(2-(dimethylamino) )Ethyl)-7-fluoro-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2,3(1H,4H)-dione (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)-4-(2-(二甲基氨基)乙基)-7-氟-6-(3-羟基萘-1-基)喹喔啉-2,3(1H,4H)-二酮(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)-4-(2-(二甲基氨基)乙基)-7-氟-6-(3-羟基萘-1-基)喹喔啉-2,3(1H,4H)-二酮(12.47mg)，为白色固体，收率9％。 Under N 2 atmosphere, the 1-(azetidin-3-ylmethyl)-4-(2-(dimethylamino)ethyl)-7-fluoro-6-(3-hydroxynaphthalene-1 -Yl)quinoxaline-2,3(1H,4H)-dione (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 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 give 1-((1-acryloylazetidin-3-yl)methyl)-4-(2-(dimethylamino)ethyl)-7-fluoro-6-(3-hydroxyl Naphthalene-1-yl)quinoxaline-2,3(1H,4H)-dione (12.47mg), white solid, yield 9%.
ESI-MS:517[M+H] +。 ESI-MS: 517[M+H] + .
1H-NMR(400MHz,DMSO-d 6)δ:ppm 9.96(s,1H),7.83～7.78(m,2H),7.58～7.56(m,1H),7.45～7.40(m,2H),7.27～7.24(m,2H),7.08(d,1H,J＝2.4Hz),6.36～6.29(m,1H),6.14～6.09(m,1H),5.69～5.66(m,1H),4.59～4.57(m,2H),4.44～4.41(m,2H),4.31～4.27(m,1H),4.16～4.12(m,1H),4.02～3.98(m,1H),3.88～3.84(m,1H),3.17～3.15(m,1H),2.69～2.66(m,2H),2.22(s,6H)。 1 H-NMR(400MHz,DMSO-d 6 )δ:ppm 9.96(s,1H),7.83～7.78(m,2H),7.58～7.56(m,1H),7.45～7.40(m,2H),7.27 ～7.24(m,2H),7.08(d,1H,J=2.4Hz), 6.36～6.29(m,1H), 6.14～6.09(m,1H), 5.69～5.66(m,1H), 4.59～4.57 (m,2H), 4.44～4.41(m,2H), 4.31～4.27(m,1H), 4.16～4.12(m,1H), 4.02～3.98(m,1H), 3.88～3.84(m,1H) , 3.17～3.15(m,1H), 2.69～2.66(m,2H), 2.22(s,6H).
实施例4：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-4-(2-(二甲基氨基)乙基)-6-(3-羟基萘-1-基)喹喔啉-2,3(1H,4H)-二酮的制备Example 4: 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-4-(2-(dimethylamino)ethyl)-6-(3- Preparation of hydroxynaphthalene-1-yl)quinoxaline-2,3(1H,4H)-dione
Figure PCTCN2021091100-appb-000133
Figure PCTCN2021091100-appb-000133
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(2氢)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(430mg，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。降至0℃后，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-4-(2-(二甲基氨基)乙基)-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(117mg)，为黄色固体，收率23％。ESI-MS:515,517[M+H] +。 Under N 2 atmosphere, 3-((6-bromo-7-chloro-2,3-dioxo-3,4-dihydroquinoxaline-1(2hydro)-yl)methyl)azacyclo Tert-butyl butane-1-carboxylate (430mg, 0.97mmol), 2-(dimethylamino)ethanol (172mg, 1.93mmol), triphenylphosphine (508mg, 1.94mmol) dispersed in tetrahydrofuran (THF) (8mL )middle. After falling 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 warming 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-7-chloro-4-(2- (Dimethylamino)ethyl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (117mg), as a yellow solid, with a yield of 23%. ESI-MS: 515,517 [M+H] + .
第二步Second step
N 2氛围下，将3-((6-溴-7-氯-4-(2-(二甲基氨基)乙基)-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(170mg，0.33mmol)，4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-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-4-(2-(二甲基氨基)乙基)-6-(3-羟基萘-1-基)-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(144mg)，为黑色固体，收率75％。ESI-MS:579[M+H] +。 Under N 2 atmosphere, 3-((6-bromo-7-chloro-4-(2-(dimethylamino)ethyl)-2,3-dioxo-3,4-dihydroquinoxaline -1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (170mg, 0.33mmol), 4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaborolan-2-yl)naphthalene-2-ol (107mg, 0.40mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd (dppf) Cl 2 , 24 mg, 0.033 mmol), potassium carbonate (137 mg, 0.99 mmol) were 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-4-(2-(dimethyl (Amino)ethyl)-6-(3-hydroxynaphthalene-1-yl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azacyclo Tert-butyl butane-1-carboxylate (144 mg), as a black solid, with a yield of 75%. ESI-MS: 579[M+H] + .
第三步third step
将3-((7-氯-4-(2-(二甲基氨基)乙基)-6-(3-羟基萘-1-基)-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(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，然后减压浓缩后得到1-(氮杂环丁烷-3-基甲基)-7-氯-4-(2-(二甲基氨基)乙基)-6-(3-羟基萘-1-基)喹喔啉-2,3(1H,4H)-二酮(100mg)，为棕色固体，收率85％。ESI-MS:479[M+H] +。 Add 3-((7-chloro-4-(2-(dimethylamino)ethyl)-6-(3-hydroxynaphthalene-1-yl)-2,3-dioxo-3,4-di Hydroquinoxaline-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-4-(2-( Dimethylamino)ethyl)-6-(3-hydroxynaphthalen-1-yl)quinoxaline-2,3(1H,4H)-dione (100mg), brown solid, yield 85%. 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-4-(2-(二甲基氨基)乙基)-6-(3-羟基萘-1-基)喹喔啉-2,3(1H,4H)-二酮(100mg，0.21mmol)溶解在二氯甲烷(4mL)中，加入三乙胺(210mg,2.1mmol)。冷却至0℃，将丙烯酰氯(22mg，0.21mmol)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(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-4-(2-(二甲基氨基)乙基)-6-(3-羟基萘-1-基)喹喔啉-2,3(1H,4H)-二酮(28mg)，为白色固体，收率25％。 Under N 2 atmosphere, the 1-(azetidin-3-ylmethyl)-7-chloro-4-(2-(dimethylamino)ethyl)-6-(3-hydroxynaphthalene-1 -Yl)quinoxaline-2,3(1H,4H)-dione (100 mg, 0.21 mmol) was dissolved in dichloromethane (4 mL), and triethylamine (210 mg, 2.1 mmol) was added. After cooling to 0°C, a solution of acryloyl chloride (22 mg, 0.21 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 (2 mL), and then purified with a C18 reverse phase column (eluent: ACN : 5mmol/L NH 4 HCO 3 aqueous solution=0-50%). Lyophilized to give 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-4-(2-(dimethylamino)ethyl)-6-(3-hydroxyl Naphth-1-yl)quinoxaline-2,3(1H,4H)-dione (28mg), white solid, yield 25%.
ESI-MS:533[M+H] + ESI-MS:533[M+H] +
1H-NMR(400MHz,DMSO-d 6)δ:ppm 9.94(s,1H),7.84-7.77(m,2H),7.44-7.40(m,2H),7.27-7.23(m,3H),7.02(d,J＝2.1Hz,1H),6.37-6.31(m,1H),6.28-6.08(m,1H),5.70-5.66(m,1H),4.55(d,1H,J＝6.9Hz,2H),4.31-4.19(m,4H),4.14-4.01(m,1H),3.98-3.85(m,1H),3.32～3.16(m,1H),2.21(s,6H)。 1 H-NMR (400MHz, DMSO-d 6 ) δ: ppm 9.94 (s, 1H), 7.84-7.77 (m, 2H), 7.44-7.40 (m, 2H), 7.27-7.23 (m, 3H), 7.02 (d,J=2.1Hz,1H),6.37-6.31(m,1H),6.28-6.08(m,1H),5.70-5.66(m,1H),4.55(d,1H,J=6.9Hz,2H ), 4.31-4.19(m,4H), 4.14-4.01(m,1H), 3.98-3.85(m,1H), 3.32～3.16(m,1H), 2.21(s,6H).
实施例5：(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)-4-((1-甲基吡咯烷-2-基)甲基)喹喔啉-2,3(1H,4H)-二酮的制备Example 5: (S)-1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(3-hydroxynaphthalen-1-yl)-4-( Preparation of (1-methylpyrrolidin-2-yl)methyl)quinoxaline-2,3(1H,4H)-dione
Figure PCTCN2021091100-appb-000134
Figure PCTCN2021091100-appb-000134
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-甲酸叔丁酯(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。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-甲酸叔丁酯和(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-甲酸叔丁酯的混合物(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) dispersed In tetrahydrofuran (THF) (18 mL). After falling 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 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 (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-dihydroquine A mixture of tert-butyl oxaline-1(2H)-yl)methyl)azetidine-1-carboxylate (750 mg), 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-甲酸叔丁酯和(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-甲酸叔丁酯的混合物(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)-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-甲酸叔丁酯(217mg)，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 (400mg, 0.74mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (240mg, 0.89 mmol), [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. The system was concentrated under reduced pressure and then 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)-4-((1-methylpyrrolidin-2-yl)methyl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)- (Yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (217 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)-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-甲酸叔丁酯(217mg，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，然后减压浓缩后得到(S)-1-(氮杂环丁烷-3-基甲基)-7-氯-6-(3-羟基萘-1-基)-4-((1-甲基吡咯烷-2-基)甲基)喹喔啉-2,3(1H,4H)-二酮(181mg)，为棕色固体，收率100％。ESI-MS:505[M+H] +。 (S)-3-((7-chloro-6-(3-hydroxynaphthalen-1-yl)-4-((1-methylpyrrolidin-2-yl)methyl)-2,3-di Oxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (217mg, 0.36mmol) was dissolved in dichloromethane (6mL) . 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)-4-((1-methylpyrrolidin-2-yl)methyl)quinoxaline-2,3(1H,4H)-dione (181mg), brown Solid, 100% yield. 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)-4-((1-甲基吡咯烷-2-基)甲基)喹喔啉-2,3(1H,4H)-二酮(181mg，0.36mmol)溶解在二氯甲烷(4mL)中，加入三乙胺(363mg,3.6mmol)。冷却至0℃， 将丙烯酰氯(36mg，0.40mmol)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)-4-((1-甲基吡咯烷-2-基)甲基)喹喔啉-2,3(1H,4H)-二酮(17.7mg)，为白色固体，收率9％。 Under N 2 atmosphere, (S)-1-(azetidin-3-ylmethyl)-7-chloro-6-(3-hydroxynaphthalene-1-yl)-4-((1-methyl Pyrrolidin-2-yl)methyl)quinoxaline-2,3(1H,4H)-dione (181mg, 0.36mmol) was dissolved in dichloromethane (4mL), and triethylamine (363mg, 3.6 mmol). After cooling to 0°C, a solution of acryloyl chloride (36 mg, 0.40 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)-4-(( 1-Methylpyrrolidin-2-yl)methyl)quinoxaline-2,3(1H,4H)-dione (17.7mg), white solid, yield 9%.
ESI-MS:559[M+H] +。 ESI-MS: 559[M+H] + .
1H-NMR(400MHz,DMSO-d 6)δ:ppm 9.95(s,1H),7.85～7.84(m,1H),7.78(d,1H,J＝8.0Hz),7.56(d,1H,J＝2.8Hz),7.44～7.40(m,1H),7.30～7.23(m,3H),7.01～7.00(m,1H),6.32(ddd,1H,J＝17.2,6.4,3.2Hz),6.11(dd,1H,J＝17.2,2.4Hz),5.68(dd,1H,J＝10.4,2.4Hz),4.57～4.53(m,2H),4.31～4.29(m,1H),4.22～4.18(m,1H),4.13～4.06(m,2H),4.03～3.99(m,1H),3.85～3.81(m,1H),3.18～3.15(m,2H),2.90～2.82(m,2H),2.62～2.60(m,2H),2.17～1.99(m,4H),1.79～1.76(m,1H)。 1 H-NMR(400MHz,DMSO-d 6 )δ:ppm 9.95(s,1H),7.85～7.84(m,1H),7.78(d,1H,J=8.0Hz),7.56(d,1H,J ＝2.8Hz),7.44～7.40(m,1H),7.30～7.23(m,3H),7.01～7.00(m,1H),6.32(ddd,1H,J＝17.2,6.4,3.2Hz),6.11( dd,1H,J=17.2,2.4Hz),5.68(dd,1H,J=10.4,2.4Hz),4.57～4.53(m,2H),4.31～4.29(m,1H),4.22～4.18(m, 1H), 4.13～4.06(m,2H), 4.03～3.99(m,1H), 3.85～3.81(m,1H), 3.18～3.15(m,2H), 2.90～2.82(m,2H), 2.62～ 2.60(m,2H), 2.17～1.99(m,4H), 1.79～1.76(m,1H).
实施例6：(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)-4-((1-甲基吡咯烷-2-基)甲基)喹喔啉-2,3(1H,4H)-二酮的制备Example 6: (S)-1-((1-acryloylazetidin-3-yl)methyl)-7-fluoro-6-(3-hydroxynaphthalen-1-yl)-4-( Preparation of (1-methylpyrrolidin-2-yl)methyl)quinoxaline-2,3(1H,4H)-dione
Figure PCTCN2021091100-appb-000135
Figure PCTCN2021091100-appb-000135
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-甲酸叔丁酯(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-甲酸叔丁酯和(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-甲酸叔丁酯的混合物(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) dispersed 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-dihydroquine A mixture of tert-butyl oxaline-1(2H)-yl)methyl)azetidine-1-carboxylate (350 mg) as a yellow solid.
将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％)。冻干得到(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-甲酸叔丁酯(186mg)，为白色固体，收率51％。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%). Lyophilized to obtain (S)-3-((6-bromo-7-fluoro-4-((1-methylpyrrolidin-2-yl)methyl)-2,3-dioxo-3,4- Dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (186 mg), a white solid, with a yield of 51%. ESI-MS: 525,527 [M+H] + .
第二步Second step
N 2氛围下，将(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-甲酸叔丁酯(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)-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-甲酸叔丁酯(100mg)，为棕黄色固体，收率81％。ESI-MS:589[M+H] +。 Under N 2 atmosphere, (S)-3-((6-bromo-7-fluoro-4-((1-methylpyrrolidin-2-yl)methyl)-2,3-dioxo-3 ,4-Dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (110mg, 0.21mmol), 4-(4,4,5,5-tetra Methyl-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) were 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)-4-((1-methylpyrrolidin-2-yl)methyl)-2,3-dioxo-3,4-dihydroquinoxaline- 1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (100mg) is a brown-yellow solid with a yield of 81%. ESI-MS: 589[M+H] + .
第三步third step
将(S)-3-((7-氟-6-(3-羟基萘-1-基)-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-甲酸叔丁酯(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)-4-((1-甲基吡咯烷-2-基)甲基)喹喔啉-2,3(1H,4H)-二酮(83mg)，为棕色固体，收率100％。ESI-MS:489[M+H] +。 Add (S)-3-((7-fluoro-6-(3-hydroxynaphthalen-1-yl)-4-((1-methylpyrrolidin-2-yl)methyl)-2,3-di Oxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylate (100mg, 0.17mmol) was dissolved in dichloromethane (5mL) . 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)-4-((1-methylpyrrolidin-2-yl)methyl)quinoxaline-2,3(1H,4H)-dione (83mg), as a brown solid , The yield is 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)-4-((1-甲基吡咯烷-2-基)甲基)喹喔啉-2,3(1H,4H)-二酮(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。体系浓缩后用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，然后用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)-4-((1-甲基吡咯烷-2-基)甲基)喹喔啉-2,3(1H,4H)-二酮(17.7mg)，为白色固体，收率26％。 Under N 2 atmosphere, (S)-1-(azetidin-3-ylmethyl)-7-fluoro-6-(3-hydroxynaphthalene-1-yl)-4-((1-methyl Pyrrolidin-2-yl)methyl)quinoxaline-2,3(1H,4H)-dione (83mg, 0.17mmol) was dissolved in dichloromethane (4mL), and triethylamine (172mg, 1.7 mmol). 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. After the system was concentrated, it 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). Then it was purified with a C18 reverse 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)-4-(( 1-Methylpyrrolidin-2-yl)methyl)quinoxaline-2,3(1H,4H)-dione (17.7mg), white solid, yield 26%.
ESI-MS:543[M+H] +。 ESI-MS: 543[M+H] + .
1H-NMR(400MHz,DMSO-d 6)δ:ppm 9.98(s,1H),7.80(d,1H,J＝8.0Hz),7.75～7.72(m,1H),7.58(d,1H,J＝7.2Hz),7.50～7.42(m,2H),7.29～7.24(m,2H),7.10(brs,1H),6.32(ddd,1H,J＝16.8,10.0,3.2Hz),6.11(dd,1H,J＝16.8,2.4Hz),5.67(dd,1H,J＝10.4,2.4Hz),4.57～4.45(m,2H),4.32～4.24(m,2H),4.14～4.10(m,2H),4.03～3.97(m,1H),3.85～3.82(m,1H),3.21～3.16(m,2H),2.95～2.89(m,2H),2.69～2.67(m,2H),2.34～2.01(m,4H),1.99～1.81(m,1H)。 1 H-NMR(400MHz,DMSO-d 6 )δ:ppm 9.98(s,1H),7.80(d,1H,J=8.0Hz),7.75～7.72(m,1H),7.58(d,1H,J ＝7.2Hz), 7.50～7.42(m,2H), 7.29～7.24(m,2H), 7.10(brs,1H), 6.32(ddd,1H,J=16.8,10.0,3.2Hz), 6.11(dd, 1H,J=16.8,2.4Hz), 5.67(dd,1H,J=10.4,2.4Hz), 4.57～4.45(m,2H), 4.32～4.24(m,2H), 4.14～4.10(m,2H) ,4.03～3.97(m,1H), 3.85～3.82(m,1H), 3.21～3.16(m,2H), 2.95～2.89(m,2H), 2.69～2.67(m,2H), 2.34～2.01( m,4H),1.99～1.81(m,1H).
实施例7：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(3-羟基萘-1-基)-4-(2-异丙基苯基)喹喔啉-2,3(1H,4H)-二酮的制备Example 7: 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(3-hydroxynaphthalene-1-yl)-4-(2-isopropyl Preparation of phenyl)quinoxaline-2,3(1H,4H)-dione
Figure PCTCN2021091100-appb-000136
Figure PCTCN2021091100-appb-000136
第一步first step
将1-溴-2-氯-5-氟-4-硝基苯(1.0g，3.95mmol)溶解在乙腈(20mL)中，加入碳酸铯(1.64g，11.85mmol)和2-异丙基苯胺(536mg，3.95mmol)，反应在110℃下搅拌16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＝5:1)分离纯化，得到5-溴-4-氯-N-(2-异丙基苯基)-2-硝基苯胺(1.0g)，为黄色固体。收率69％。Dissolve 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (1.0g, 3.95mmol) in acetonitrile (20mL), add cesium carbonate (1.64g, 11.85mmol) and 2-isopropylaniline (536mg, 3.95mmol), the reaction was stirred at 110°C for 16 hours, the reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) After separation and purification, 5-bromo-4-chloro-N-(2-isopropylphenyl)-2-nitroaniline (1.0 g) was obtained as a yellow solid. The yield was 69%.
第二步Second step
将5-溴-4-氯-N-(2-异丙基苯基)-2-硝基苯胺(1.0g，2.72mmol)溶解在乙醇(20mL)和水(4mL)中，加入氯化铵(1.44g，27.2mmol)和铁粉(1.52g，27.2mmol)。反应在90℃下搅拌1小时，反应液冷却后过滤，滤液减压除去乙醇，混合液用二氯甲烷(3x20mL)进行萃取，合并有机相，经饱和食盐水洗涤(20ml)，无水硫酸钠干燥，过滤。将滤液浓缩得到5-溴-4-氯-N 1-(2-异丙基苯基)苯-1,2-二胺(700mg)，为棕色油状物。收率76％。ESI-MS:339[M+H] +。 Dissolve 5-bromo-4-chloro-N-(2-isopropylphenyl)-2-nitroaniline (1.0g, 2.72mmol) in ethanol (20mL) and water (4mL), add ammonium chloride (1.44g, 27.2mmol) and iron powder (1.52g, 27.2mmol). The reaction was stirred at 90°C for 1 hour. The reaction solution was cooled and filtered. The filtrate was decompressed to remove ethanol. The mixture was extracted with dichloromethane (3x20mL). The organic phases were combined, washed with saturated brine (20ml), and anhydrous sodium sulfate. Dry and filter. The filtrate was concentrated to obtain 5-bromo-4-chloro-N 1 -(2-isopropylphenyl)benzene-1,2-diamine (700 mg) as a brown oil. The yield was 76%. ESI-MS: 339[M+H] + .
第三步third step
将5-溴-4-氯-N 1-(2-异丙基苯基)苯-1,2-二胺(500mg,1.48mmol)溶于四氢呋喃(10mL)中，加入三乙胺(1.49g，14.8mmol)，在冰浴条件下，缓慢滴加草酰氯单甲酯(903mg，7.4mmol)溶液，在室温下继续搅拌1小时后，升90℃下搅拌3小时，反应液冷却减压浓缩，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7-溴-6-氯-1-(2-异丙基苯基)喹喔啉-2,3(1H,4H)-二酮(480mg)，为白色固体。收率83％。ESI-MS:393[M+H] +。 Dissolve 5-bromo-4-chloro-N 1 -(2-isopropylphenyl)benzene-1,2-diamine (500mg, 1.48mmol) in tetrahydrofuran (10mL), add triethylamine (1.49g , 14.8mmol), slowly dropwise add oxalyl monomethyl chloride (903mg, 7.4mmol) solution in an ice bath, continue stirring at room temperature for 1 hour, and then stir at 90°C for 3 hours. The reaction solution is cooled and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 15:1) to obtain 7-bromo-6-chloro-1-(2-isopropylphenyl)quinoxaline- 2,3(1H,4H)-dione (480mg), a white solid. The yield was 83%. ESI-MS: 393[M+H] + .
第四步the fourth step
将7-溴-6-氯-1-(2-异丙基苯基)喹喔啉(1H,4H)-2,3-二酮(480mg,1.22mmol)溶于N,N-二甲基甲酰胺(5mL)中，加入碳酸钾(508mg,3.68mmol)和3-(碘甲基)氮杂环丁烷-1-甲酸叔丁酯(546mg,1.84mmol)，反应在室温下搅拌16小时，反应液用水(20ml)稀释，再用乙酸乙酯(3x20ml)萃取。合并有机相，经饱和食盐水洗涤(100ml)，无水硫酸钠干燥，过滤。残余物用硅胶柱层析(石油醚：乙酸乙酯＝1:1)纯化得到3-((6-溴-7-氯-4-(2-异丙基苯基)-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(450mg)，为白色固体。收率68％。ESI-MS:562[M+H] +。 Dissolve 7-bromo-6-chloro-1-(2-isopropylphenyl)quinoxaline (1H,4H)-2,3-dione (480mg, 1.22mmol) in N,N-dimethyl To formamide (5 mL), potassium carbonate (508 mg, 3.68 mmol) and tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (546 mg, 1.84 mmol) were added, and the reaction was stirred at room temperature for 16 hours The reaction solution was diluted with water (20ml), and then extracted with ethyl acetate (3x20ml). The organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and filtered. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 3-((6-bromo-7-chloro-4-(2-isopropylphenyl)-2,3-di Tert-butyl oxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylate (450 mg) as a white solid. The yield was 68%. ESI-MS: 562[M+H] + .
第五步the fifth step
将3-((6-溴-7-氯-4-(2-异丙基苯基)-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(200mg，0.36mmol)溶解在异丙醇(5mL)中，加入碳酸钾(149mg，1.1mmol)，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Pd(dppf)Cl 2(52mg，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：石油醚:乙酸乙酯＝1:2)分离纯化，得到3-((7-氯-6-(3-羟基萘-1-基)-4-(2-异丙基苯基)-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(150mg)，为白色固体。收率67％。ESI-MS:626[M+H] +。 The 3-((6-bromo-7-chloro-4-(2-isopropylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl) Tert-butyl methyl)azetidine-1-carboxylate (200mg, 0.36mmol) was dissolved in isopropanol (5mL), potassium carbonate (149mg, 1.1mmol) was added, 4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (116 mg, 0.43 mmol) and Pd(dppf)Cl 2 (52 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: petroleum ether: ethyl acetate = 1:2) to obtain 3-((7-chloro-6-(3-hydroxynaphthalen-1-yl)-4-(2-isopropylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline Tert-butyl -1(2H)-yl)methyl)azetidine-1-carboxylate (150 mg) as a white solid. The yield was 67%. ESI-MS: 626[M+H] + .
第六步Sixth step
将3-((7-氯-6-(3-羟基萘-1-基)-4-(2-异丙基苯基)-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(150mg,0.24mmol)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)-7-氯-6-(3-羟基萘-1-基)-4-(2-异丙基苯基)喹喔啉-2,3(1H,4H)-二酮(40mg)，为白色固体。收率80％。ESI-MS:526[M+H] +。 3-((7-chloro-6-(3-hydroxynaphthalen-1-yl)-4-(2-isopropylphenyl)-2,3-dioxo-3,4-dihydroquinoxa Tert-butyl lin-1(2H)-yl)methyl)azetidine-1-carboxylate (150mg, 0.24mmol) was dissolved in dichloromethane (2.5mL), trifluoroacetic acid (0.5mL) was added, Stir at room temperature for 1 hour, and then concentrate under reduced pressure to obtain 1-(azetidin-3-ylmethyl)-7-chloro-6-(3-hydroxynaphthalene-1-yl)-4-(2 -Isopropylphenyl)quinoxaline-2,3(1H,4H)-dione (40mg), a white solid. The yield is 80%. ESI-MS: 526[M+H] + .
第七步Seventh step
将1-(氮杂环丁烷-3-基甲基)-7-氯-6-(3-羟基萘-1-基)-4-(2-异丙基苯基)喹喔啉-2,3(1H,4H)-二酮(100mg，0.19mmol)溶解在二氯甲烷(1mL)中，加入三乙胺(58mg，0.57mmol)，在氮气保护，-78℃下，缓慢滴加丙烯酰氯(21mg，0.23mmol)的二氯甲烷溶液(0.5mL)，在-78℃继续搅拌1小时，将反应液减压浓缩，残余物prep-HPLC纯化(洗脱剂：乙腈:水(10mM NH 4HCO 3)＝25％～50％)分离纯化，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)-4-(2-异丙基苯基)喹喔啉-2,3(1H,4H)-二酮(45mg)，为白色固体，收率41％。 Add 1-(azetidine-3-ylmethyl)-7-chloro-6-(3-hydroxynaphthalene-1-yl)-4-(2-isopropylphenyl)quinoxaline-2 ,3(1H,4H)-dione (100mg, 0.19mmol) was dissolved in dichloromethane (1mL), triethylamine (58mg, 0.57mmol) was added, and propylene was slowly added dropwise under nitrogen protection at -78℃ Dichloromethane solution (0.5mL) of acid chloride (21mg, 0.23mmol), stirring at -78°C for 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (eluent: acetonitrile: water (10mM NH) 4 HCO 3 )=25%～50%) separated and purified to obtain 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(3-hydroxynaphthalene-1 -Yl)-4-(2-isopropylphenyl)quinoxaline-2,3(1H,4H)-dione (45mg), white solid, yield 41%.
ESI-MS:＝580.1[M+H] + ESI-MS:=580.1[M+H] +
1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),7.91(s,1H),7.67(d,J＝8.3Hz,1H),7.55–7.28(m,3H),7.24(m,1H),7.07(m,3H),6.72(d,J＝26.5Hz,1H),6.30(m,1H),6.09(m,3H),5.66(d,J＝11.8Hz,1H),4.66(m,1H),4.47(m,1H),4.32(m,1H),4.16(m,1H),4.02(m,1H),3.89(m,1H),3.22(m,1H),2.75(m,1H),1.02(m,6H). 1 H NMR (400MHz, DMSO-d6) δ 9.87 (s, 1H), 7.91 (s, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.55-7.28 (m, 3H), 7.24 (m ,1H), 7.07 (m, 3H), 6.72 (d, J = 26.5Hz, 1H), 6.30 (m, 1H), 6.09 (m, 3H), 5.66 (d, J = 11.8Hz, 1H), 4.66 (m, 1H), 4.47 (m, 1H), 4.32 (m, 1H), 4.16 (m, 1H), 4.02 (m, 1H), 3.89 (m, 1H), 3.22 (m, 1H), 2.75 ( m,1H),1.02(m,6H).
通过参考以上实施例7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：By referring to the above preparation method of Example 7 compound and using different reaction materials, the following example compounds were prepared:
Figure PCTCN2021091100-appb-000137
Figure PCTCN2021091100-appb-000137
Figure PCTCN2021091100-appb-000138
Figure PCTCN2021091100-appb-000138
Figure PCTCN2021091100-appb-000139
Figure PCTCN2021091100-appb-000139
Figure PCTCN2021091100-appb-000140
Figure PCTCN2021091100-appb-000140
Figure PCTCN2021091100-appb-000141
Figure PCTCN2021091100-appb-000141
Figure PCTCN2021091100-appb-000142
Figure PCTCN2021091100-appb-000142
Figure PCTCN2021091100-appb-000143
Figure PCTCN2021091100-appb-000143
Figure PCTCN2021091100-appb-000144
Figure PCTCN2021091100-appb-000144
Figure PCTCN2021091100-appb-000145
Figure PCTCN2021091100-appb-000145
Figure PCTCN2021091100-appb-000146
Figure PCTCN2021091100-appb-000146
Figure PCTCN2021091100-appb-000147
Figure PCTCN2021091100-appb-000147
Figure PCTCN2021091100-appb-000148
Figure PCTCN2021091100-appb-000148
Figure PCTCN2021091100-appb-000149
Figure PCTCN2021091100-appb-000149
Figure PCTCN2021091100-appb-000150
Figure PCTCN2021091100-appb-000150
Figure PCTCN2021091100-appb-000151
Figure PCTCN2021091100-appb-000151
部分化合物手性拆分条件Conditions for chiral resolution of some compounds
Figure PCTCN2021091100-appb-000152
Figure PCTCN2021091100-appb-000152
Figure PCTCN2021091100-appb-000153
Figure PCTCN2021091100-appb-000153
Figure PCTCN2021091100-appb-000154
Figure PCTCN2021091100-appb-000154
Figure PCTCN2021091100-appb-000155
Figure PCTCN2021091100-appb-000155
实施例13：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-5-氟-6-(2-氟-6-羟基苯基)-1,4-二氢喹喔啉-2,3-二酮的制备Example 13: 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-1, Preparation of 4-dihydroquinoxaline-2,3-dione
Figure PCTCN2021091100-appb-000156
Figure PCTCN2021091100-appb-000156
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-甲酸叔丁酯(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。反应完成后将反应液过滤，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-甲酸叔丁酯(13-1)(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- With tert-butyl formate (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. After the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 3-(((5-chloro-3-fluoro-2-nitrophenyl)amino)methyl)azetidine-1-carboxylic acid tert-butyl Ester (13-1) (10.0g) is an orange-red solid with a yield of 90%. 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-甲酸叔丁酯(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。反应完成后反应液冷却并过滤，滤液减压除去乙醇，混合液用二氯甲烷(3x100mL)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。滤液浓缩后用硅胶柱层析(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-甲酸叔丁酯(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 (100mL ) And water (20 mL), ammonium chloride (14.9 g, 278 mmol) and iron powder (7.8 g, 139 mmol) were added, and the reaction was stirred at 90°C for 1 hour. After the completion of the reaction, the reaction solution was cooled and filtered, the filtrate was decompressed to remove ethanol, the mixed solution was extracted with dichloromethane (3×100 mL), the organic phases were combined, the organic phases were washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to obtain 3-(((2-amino-5-chloro-3-fluorophenyl)amino)methane Yl) tert-butyl azetidine-1-carboxylate (8.0 g), a white solid, with a yield of 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-甲酸叔丁酯(1.5g,4.56mmol)溶于四氢呋喃(30mL)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)的四氢呋喃(10mL)溶液，在室温下搅拌1小时后，升温至90℃并继续搅拌3小时。反应完成后反应液冷却并减压浓缩，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] +。 Dissolve 3-(((2-amino-5-chloro-3-fluorophenyl)amino)methyl) tert-butyl azetidine-1-carboxylate (1.5g, 4.56mmol) in tetrahydrofuran (30mL) Add triethylamine (4.60g, 45.56mmol), slowly add dropwise a solution of oxalyl chloride monomethyl ester (2.78g, 22.8mmol) in tetrahydrofuran (10mL) under ice bath conditions. After stirring for 1 hour at room temperature, The temperature was raised to 90°C and stirring was continued for 3 hours. After the completion of the reaction, 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, yield The rate is 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。反应结束加入饱和碳酸氢钠溶液(20mL)淬灭，用二氯甲烷(20mL)萃取三次，无水硫酸钠干燥，有机相减压浓缩，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-((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 Stir for 1h. At the end of the reaction, it was quenched by adding saturated sodium bicarbonate solution (20mL), extracted with dichloromethane (20mL) three times, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography (eluent: petroleum ether ：Ethyl acetate=1:1) was separated and purified to obtain 3-((6-bromo-7-chloro-5-fluoro-2,3-dioxo-3,4-dihydroquinoxaline-1(2H )-Yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (700 mg), as a white solid, with a yield of 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(200mg，0.44mmol)溶解在1,4-二氧六环(5mL)和水(1mL)中，加入碳酸钠(140.0mg，1.32mmol)、(2-氟-6-羟基苯基)硼酸(81.0mg，0.52mmol)和RuPhos Pd G3(72.0mg，0.09mmol)，在氮气保护下加热至80℃，搅拌反应1小时。反应结束后将反应液冷却并过滤，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3-((7-氯-5-氟-6-(2-氟-6-羟基苯基)-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(100mg)，为白色固体，收率46％。ESI-MS:494[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 (200mg, 0.44mmol) was dissolved in 1,4-dioxane (5mL) and water (1mL), sodium carbonate (140.0mg, 1.32mmol), (2-fluoro-6 -Hydroxyphenyl)boronic acid (81.0mg, 0.52mmol) and RuPhos Pd G3 (72.0mg, 0.09mmol), heated to 80°C under the protection of nitrogen, and stirred for reaction for 1 hour. After the reaction, 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 3-((7-chloro-5). -Fluoro-6-(2-fluoro-6-hydroxyphenyl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine Tert-Butyl-1-carboxylate (100 mg), a white solid, with a yield of 46%. ESI-MS: 494[M+H] + .
第六步Sixth step
将3-((7-氯-5-氟-6-(2-氟-6-羟基苯基)-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(90mg,0.18mmol)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。反应完成后减压浓缩得到1-(氮杂环丁烷-3-基甲基)-7-氯-5-氟-6-(2-氟-6-羟基苯基)-1,4-二氢喹喔啉-2,3-二酮(60mg)，为白色固体，收率85％。ESI-MS:394[M+H] +。 Add 3-((7-chloro-5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)- (Yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (90 mg, 0.18 mmol) was dissolved in dichloromethane (2.5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction is completed, it is concentrated under reduced pressure to obtain 1-(azetidine-3-ylmethyl)-7-chloro-5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-1,4-di Hydroquinoxaline-2,3-dione (60mg) is a white solid with a yield of 85%. ESI-MS: 394[M+H] + .
第七步Seventh step
将1-(氮杂环丁烷-3-基甲基)-7-氯-5-氟-6-(2-氟-6-羟基苯基)-1,4-二氢喹喔啉-2,3-二酮(60mg，0.15mmol)溶解在二氯甲烷(1mL)中，加入三乙胺(46mg，0.45mmol)，在氮气保护和-78℃条件下，缓慢滴加丙烯酰氯(16mg，0.18mmol)的二氯甲烷溶液(0.3mL)，在-78℃搅拌反应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)＝35％～60％)分离纯化,得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-5-氟-6-(2-氟-6-羟基苯基)-1,4-二氢喹喔啉-2,3-二酮(6.0mg)，为白色固体，收率9％。 Add 1-(azetidine-3-ylmethyl)-7-chloro-5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-1,4-dihydroquinoxaline-2 ,3-Dione (60mg, 0.15mmol) was dissolved in dichloromethane (1mL), triethylamine (46mg, 0.45mmol) was added, and acryloyl chloride (16mg, 0.18mmol) in dichloromethane solution (0.3mL), 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 separated and purified by prep-HPLC (eluent: acetonitrile: water (10mM NH 4 HCO 3 ) = 35% to 60%) to obtain 1-((1-acryloyl) Azetidine-3-yl)methyl)-7-chloro-5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-1,4-dihydroquinoxaline-2,3- The diketone (6.0 mg) is a white solid with a yield of 9%.
ESI-MS:448[M+H] +。 ESI-MS: 448[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ12.14(s,1H),10.19(s,1H),7.62(s,1H),7.35–7.29(m,1H),6.82(d,J＝8.3Hz,1H),6.77(t,J＝8.7Hz,1H),6.30(dd,J＝17.0,10.2Hz,1H),6.10(dd,J＝17.0,2.3Hz,1H),5.66(dd,J＝10.3,2.4Hz,1H),4.44(d,J＝7.5Hz,2H),4.27(t,J＝8.5Hz,1H),4.10–4.05(m,1H),3.97(dd,J＝10.1,8.6Hz,1H),3.80(dd,J＝10.3,5.6Hz,1H),3.09(m,1H). 1 H NMR(400MHz,DMSO-d 6 )δ12.14(s,1H),10.19(s,1H),7.62(s,1H),7.35-7.29(m,1H),6.82(d,J=8.3 Hz, 1H), 6.77 (t, J = 8.7 Hz, 1H), 6.30 (dd, J = 17.0, 10.2 Hz, 1H), 6.10 (dd, J = 17.0, 2.3 Hz, 1H), 5.66 (dd, J = 10.3, 2.4 Hz, 1H), 4.44 (d, J = 7.5 Hz, 2H), 4.27 (t, J = 8.5 Hz, 1H), 4.10-4.05 (m, 1H), 3.97 (dd, J = 10.1, 8.6Hz, 1H), 3.80 (dd, J = 10.3, 5.6 Hz, 1H), 3.09 (m, 1H).
通过参考以上实施例13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：By referring to the preparation method of the compound in Example 13 above and using different reaction materials, the following example compounds were prepared:
Figure PCTCN2021091100-appb-000157
Figure PCTCN2021091100-appb-000157
实施例14：1-(1-丙烯酰基哌啶-4-基)-7-氯-6-(3-羟基萘-1-基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮的制备Example 14: 1-(1-acryloylpiperidin-4-yl)-7-chloro-6-(3-hydroxynaphthalene-1-yl)-4-(2-isopropyl-6-methylbenzene Base)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTCN2021091100-appb-000158
Figure PCTCN2021091100-appb-000158
第一步first step
将1-溴-2-氯-4-氟-5-硝基苯(10.0g，40.0mmol)溶解在乙腈(120mL)中，向其中加入4-氨基哌啶-1-甲酸叔丁酯(8.0g，40.0mmol)和无水碳酸钾(16.5g，120.0mmol)，在室温下搅拌反应16小时。反应完成后将反应液过滤，滤液减压浓缩，得到4-((4-溴-5-氯-2-硝基苯基)氨基)哌啶-1-甲酸叔丁酯(12.0g)粗品，为橙红色固体，收率70％。粗品直接用于下一步反应。ESI-MS:434,436[M+H] +。 Dissolve 1-bromo-2-chloro-4-fluoro-5-nitrobenzene (10.0g, 40.0mmol) in acetonitrile (120mL), and add tert-butyl 4-aminopiperidine-1-carboxylate (8.0 g, 40.0 mmol) and anhydrous potassium carbonate (16.5 g, 120.0 mmol), and the reaction was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of tert-butyl 4-((4-bromo-5-chloro-2-nitrophenyl)amino)piperidine-1-carboxylate (12.0g). It is orange-red solid with a yield of 70%. The crude product was directly used in the next reaction. ESI-MS: 434,436 [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(12.0g，27.7mmol)溶解在乙醇(120mL)和水(30mL)中，加入氯化铵(14.7g，277mmol)和铁粉(7.7g，139mmol)，在90℃下搅拌反应1小时。反应完成后反应液冷却并过滤，滤液减压浓缩除去乙醇，混合液用二氯甲烷(3*100mL)进行萃取，合并有机相并经饱和食盐水洗涤(100mL)，无水硫酸钠干燥，过滤。滤液浓缩后经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝2:1)分离纯化，得到4-((2-氨基-4-溴-5-氯苯基)氨基)哌啶-1-甲酸叔丁酯(8.2g)，为白色固体，收率75％。ESI-MS:404,406[M+H] +。 Dissolve 4-((4-bromo-5-chloro-2-nitrophenyl)amino)piperidine-1-carboxylic acid tert-butyl ester (12.0g, 27.7mmol) in ethanol (120mL) and water (30mL) , Ammonium chloride (14.7g, 277mmol) and iron powder (7.7g, 139mmol) were added, and the reaction was stirred at 90°C for 1 hour. After the completion of the reaction, the reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure to remove ethanol. The mixture was extracted with dichloromethane (3*100mL). The organic phases were combined and washed with saturated brine (100mL), dried with anhydrous sodium sulfate, and filtered. . The filtrate was concentrated and separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 2:1) to obtain 4-((2-amino-4-bromo-5-chlorophenyl)amino)piperidine Tert-Butyl-1-carboxylate (8.2 g), a white solid, with a yield of 75%. ESI-MS: 404,406 [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(1.0g，2.5mmol)溶解在1,4-二氧六环(10mL)中，加入碳酸铯(2.44g，7.5mmol)、2-碘-1-异丙基-3-甲基苯(780mg，3.0mmol)和RuPhos Pd G3(418mg，0.5mmol)，在氮气保护下加热至100℃，搅拌4小时。反应完成后反应液冷却并过滤，滤液减压浓缩，浓缩物经硅胶柱层析(洗脱剂：乙酸乙酯＝2:1)分离纯化，得到4-((4-溴-5-氯-2-((2-异丙基-6-甲基苯基)氨基)苯基)氨基)哌啶-1-甲酸叔丁酯(500mg)，为白色固体，收率37％。ESI-MS:536,538[M+H] +。 Dissolve 4-((2-amino-4-bromo-5-chlorophenyl)amino)piperidine-1-carboxylic acid tert-butyl ester (1.0g, 2.5mmol) in 1,4-dioxane (10mL) Add cesium carbonate (2.44g, 7.5mmol), 2-iodo-1-isopropyl-3-methylbenzene (780mg, 3.0mmol) and RuPhos Pd G3 (418mg, 0.5mmol), and heat under nitrogen Bring to 100°C and stir for 4 hours. After the completion of the reaction, 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: ethyl acetate = 2:1) to obtain 4-((4-bromo-5-chloro- Tert-butyl 2-((2-isopropyl-6-methylphenyl)amino)phenyl)amino)piperidine-1-carboxylate (500 mg), a white solid, with a yield of 37%. ESI-MS: 536,538 [M+H] + .
第四步the fourth step
将4-((4-溴-5-氯-2-((2-异丙基-6-甲基苯基)氨基)苯基)氨基)哌啶-1-甲酸叔丁酯(500mg,0.93mmol)溶于四氢呋喃(10mL)中，加入三乙胺(930mg，9.3mmol)，在冰浴条件下，缓慢滴加草酰氯单甲酯(572mg，4.7mmol)的四氢呋喃(3mL)溶液，在室温下搅拌1小时后，升温至90℃继续搅拌3小时。然后将反应液冷却并减压浓缩，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4-(6-溴-7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)哌啶-1-甲酸叔丁酯(300mg)，为白色固体，收率56％。ESI-MS:590,592[M+H] +。 4-((4-Bromo-5-chloro-2-((2-isopropyl-6-methylphenyl)amino)phenyl)amino)piperidine-1-carboxylic acid tert-butyl ester (500mg, 0.93 mmol) was dissolved in tetrahydrofuran (10mL), triethylamine (930mg, 9.3mmol) was added, and oxalyl monomethyl chloride (572mg, 4.7mmol) in tetrahydrofuran (3mL) was slowly added dropwise under ice bath conditions. After stirring for 1 hour, the temperature was raised to 90°C and stirring was continued for 3 hours. Then 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 4-(6-bromo-7-chloro-4- (2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)piperidine-1-carboxylic acid tert-butyl ester ( 300mg), white solid, yield 56%. ESI-MS: 590,592 [M+H] + .
第五步the fifth step
将4-(6-溴-7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)哌啶-1-甲酸叔丁酯(300mg，0.51mmol)溶解于1,4-二氧六环(5mL)和水(1mL)中，加入碳酸钾(211mg，1.53mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)萘-2-醇(165mg，0.61mmol)和RuPhos Pd G3(83mg，0.1mmol)，在氮气保护下加热至80℃，搅拌1小时。反应完成后反应液冷却并过滤，滤液减压浓缩，浓缩物经硅胶柱层析(洗脱剂：二氯甲烷:甲醇＝25:1)分离纯化，得到4-(7-氯-6-(3-羟基萘-1-基)-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)哌啶-1-甲酸叔丁酯(200mg)，为白色固体，收率60％。ESI-MS:654[M+H] +。 The 4-(6-bromo-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H )-Yl) tert-butyl piperidine-1-carboxylate (300mg, 0.51mmol) was dissolved in 1,4-dioxane (5mL) and water (1mL), potassium carbonate (211mg, 1.53mmol), 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalene-2-ol (165mg, 0.61mmol) and RuPhos Pd G3 (83mg , 0.1mmol), heated to 80°C under the protection of nitrogen, and stirred for 1 hour. After the completion of the reaction, the reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 25:1) to obtain 4-(7-chloro-6-( 3-hydroxynaphthalene-1-yl)-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)- Tert-butyl piperidine-1-carboxylate (200 mg), a white solid, with a yield of 60%. ESI-MS: 654[M+H] + .
第六步Sixth step
将4-(7-氯-6-(3-羟基萘-1-基)-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-3,4-二氢喹喔啉-1(2H)-基)哌啶-1-甲酸叔丁酯(200mg,0.3mmol)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6-氯-7-(3-羟基萘-1-基)-1-(2-异丙基-6-甲基苯基)-4-(哌啶-4-基)-1,4-二氢喹喔啉-2,3-二酮(120mg)，为白色固体，收率73％。ESI-MS:554[M+H] +。 The 4-(7-chloro-6-(3-hydroxynaphthalene-1-yl)-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4- Dihydroquinoxaline-1(2H)-yl)piperidine-1-carboxylic acid tert-butyl ester (200mg, 0.3mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was added, and the mixture was stirred at room temperature 1 hour. Then concentrated under reduced pressure to obtain 6-chloro-7-(3-hydroxynaphthalene-1-yl)-1-(2-isopropyl-6-methylphenyl)-4-(piperidin-4-yl)- 1,4-Dihydroquinoxaline-2,3-dione (120mg) was a white solid, the yield was 73%. ESI-MS: 554[M+H] + .
第七步Seventh step
将6-氯-7-(3-羟基萘-1-基)-1-(2-异丙基-6-甲基苯基)-4-(哌啶-4-基)-1,4-二氢喹喔啉-2,3-二酮(120mg，0.22mmol)溶解在二氯甲烷(1mL)中，加入三乙胺(66mg，0.66mmol)，在氮气保护，-78℃下，缓慢滴加丙烯酰氯(24mg，0.26mmol)的二氯甲烷溶液(0.5mL)，在-78℃条件下搅拌1小时。然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)＝35％～60％)分离纯化，得到1-(1-丙烯酰基哌啶-4-基)-7-氯-6-(3-羟基萘-1-基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(40mg)，为白色固体，收率30％。 Add 6-chloro-7-(3-hydroxynaphthalene-1-yl)-1-(2-isopropyl-6-methylphenyl)-4-(piperidin-4-yl)-1,4- Dihydroquinoxaline-2,3-dione (120mg, 0.22mmol) was dissolved in dichloromethane (1mL), triethylamine (66mg, 0.66mmol) was added, and under nitrogen protection, slowly dripping at -78℃ Add a dichloromethane solution (0.5 mL) of acryloyl chloride (24 mg, 0.26 mmol) and stir at -78°C for 1 hour. Then 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 ) = 35% to 60%) to obtain 1-(1-acryloylpiperidine- 4-yl)-7-chloro-6-(3-hydroxynaphthalene-1-yl)-4-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2 ,3-diketone (40mg), white solid, yield 30%.
ESI-MS:608[M+H] +。 ESI-MS: 608[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ9.91(s,1H),8.12(d,J＝3.6Hz,1H),7.71(dd,J＝8.3,3.0Hz,1H),7.40–7.19(m,4H),7.19–7.05(m,3H),6.92(dd,J＝16.7,10.5Hz,1H),6.84–6.73(m,1H),6.22–6.12(m,2H),5.73(dd,J＝10.5,2.4Hz,1H),4.90(m,1H),4.63(d,J＝12.8Hz,1H),4.25(d,J＝13.6Hz,1H),3.40(m,1H),2.97(m,1H),2.76–2.56(m,3H),1.97(d,J＝16.3Hz,3H),1.10–0.89(m,6H). 1 H NMR(400MHz,DMSO-d 6 )δ9.91(s,1H), 8.12(d,J=3.6Hz,1H), 7.71(dd,J=8.3,3.0Hz,1H), 7.40–7.19( m,4H),7.19–7.05(m,3H), 6.92(dd,J=16.7,10.5Hz,1H), 6.84–6.73(m,1H), 6.22–6.12(m,2H), 5.73(dd, J = 10.5, 2.4 Hz, 1H), 4.90 (m, 1H), 4.63 (d, J = 12.8 Hz, 1H), 4.25 (d, J = 13.6 Hz, 1H), 3.40 (m, 1H), 2.97 ( m,1H), 2.76–2.56(m,3H), 1.97(d,J=16.3Hz,3H), 1.10–0.89(m,6H).
通过参考以上实施例14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：By referring to the preparation method of the compound of Example 14 above and using different reaction materials, the following example compounds were prepared:
Figure PCTCN2021091100-appb-000159
Figure PCTCN2021091100-appb-000159
Figure PCTCN2021091100-appb-000160
Figure PCTCN2021091100-appb-000160
实施例15：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-5-氟-6-(2-氟-6-羟基苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮的制备Example 15: 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-4- Preparation of (2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTCN2021091100-appb-000161
Figure PCTCN2021091100-appb-000161
第一步first step
将3-(((2-氨基-5-氯-3-氟苯基)氨基)甲基)氮杂环丁烷-1-甲酸叔丁酯(3.29g，10.0mmol)溶解在1,4-二氧六环(20mL)中，加入碳酸铯(9.78g，30.0mmol)、2-碘-1-异丙基-3-甲基苯(3.12g，12.0mmol)和RuPhos Pd G3 (1.67g，2.0mmol)，氮气保护下加热至100℃，搅拌反应4小时。将反应液冷却并过滤，滤液减压浓缩，浓缩物经硅胶柱层析(洗脱剂：乙酸乙酯＝4:1)分离纯化，得到3-(((5-氯-3-氟-2-((2-异丙基-6-甲基苯基)氨基)苯基)氨基)甲基)氮杂环丁烷-1-甲酸叔丁酯(1.5g)，为白色固体，收率32％。ESI-MS:462[M+H] +。 3-(((2-Amino-5-chloro-3-fluorophenyl)amino)methyl) tert-butyl azetidine-1-carboxylate (3.29g, 10.0mmol) was dissolved in 1,4- To dioxane (20mL), add cesium carbonate (9.78g, 30.0mmol), 2-iodo-1-isopropyl-3-methylbenzene (3.12g, 12.0mmol) and RuPhos Pd G3 (1.67g, 2.0mmol), heated to 100°C under the protection of nitrogen, and stirred for reaction for 4 hours. The reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (eluent: ethyl acetate = 4:1) to obtain 3-(((5-chloro-3-fluoro-2 -((2-isopropyl-6-methylphenyl)amino)phenyl)amino)methyl)azetidine-1-carboxylic acid tert-butyl ester (1.5g), white solid, yield 32 %. ESI-MS: 462[M+H] + .
第二步Second step
将3-(((5-氯-3-氟-2-((2-异丙基-6-甲基苯基)氨基)苯基)氨基)甲基)氮杂环丁烷-1-甲酸叔丁酯(1.5g,3.2mmol)溶于四氢呋喃(20mL)中，加入三乙胺3.23g，32.0mmol)，在冰浴条件下，缓慢滴加草酰氯单甲酯(1.95g，16mmol)的四氢呋喃(10mL)溶液，在室温下搅拌1小时后，升温至90℃继续搅拌3小时。然后将反应液冷却并减压浓缩，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-4-(2-异丙基-6-甲基苯基)-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(15-2)(1.2g),为白色固体，收率73％。ESI-MS:516[M+H] +。 Add 3-(((5-chloro-3-fluoro-2-((2-isopropyl-6-methylphenyl)amino)phenyl)amino)methyl)azetidine-1-carboxylic acid Tert-butyl ester (1.5g, 3.2mmol) was dissolved in tetrahydrofuran (20mL), triethylamine 3.23g, 32.0mmol) was added, and oxalyl chloride monomethyl ester (1.95g, 16mmol) was slowly added dropwise under ice bath conditions. After stirring the tetrahydrofuran (10 mL) solution at room temperature for 1 hour, the temperature was raised to 90° C. and the stirring was continued for 3 hours. Then 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-4 -(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine- Tert-Butyl 1-formate (15-2) (1.2g), white solid, yield 73%. ESI-MS: 516[M+H] + .
第三步third step
将3-((7-氯-5-氟-4-(2-异丙基-6-甲基苯基)-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(1.2g，2.3mmol)溶解在N,N-二甲基甲酰胺(15mL)中，加入乙酸(140mg，2.3mmol)，然后缓慢滴加溴素(1.09g，6.9mmol)，在室温下搅拌1h。反应结束后加饱和碳酸氢钠溶液(30mL)淬灭，用二氯甲烷(30mL)萃取三次，有机相用无水硫酸钠干燥，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-((6-溴-7-氯-5-氟-4-(2-异丙基-6-甲基苯基)-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73％。ESI-MS:594,596[M+H] +。 Add 3-((7-chloro-5-fluoro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline-1( 2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (1.2g, 2.3mmol) was dissolved in N,N-dimethylformamide (15mL), acetic acid (140mg, 2.3mmol) was added ), then slowly dropwise add bromine (1.09g, 6.9mmol), and stir at room temperature for 1h. After the reaction, it was quenched by adding saturated sodium bicarbonate solution (30 mL), extracted with dichloromethane (30 mL) three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was subjected to silica gel column chromatography (eluent: Petroleum ether: ethyl acetate=1:1) was separated and purified to obtain 3-((6-bromo-7-chloro-5-fluoro-4-(2-isopropyl-6-methylphenyl)-2, 3-Dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (1.0g), white solid, yield 73 %. ESI-MS: 594,596 [M+H] + .
第四步the fourth step
将3-((6-溴-7-氯-5-氟-4-(2-异丙基-6-甲基苯基)-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(800mg，1.37mmol)溶解在1,4-二氧六环(10mL)和水(2mL)中，加入碳酸钠(437mg，4.14mmol)、(2-氟-6-羟基苯基)硼酸(258mg，1.64mmol)和RuPhos Pd G3(251mg，0.3mmol)。在氮气保护下加热至80℃，搅拌1小时。然后将反应液冷却并过滤，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＝1:1)分离纯化，得到3-((7-氯-5-氟-6-(2-氟-6-羟基苯基)-4-(2-异丙基-6-甲基苯基)-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(120mg)，为白色固体，收率15％。ESI-MS:626[M+H] +。 3-((6-Bromo-7-chloro-5-fluoro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxa (2H)-yl)methyl)azetidine-1-carboxylate (800mg, 1.37mmol) was dissolved in 1,4-dioxane (10mL) and water (2mL), Sodium carbonate (437 mg, 4.14 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (258 mg, 1.64 mmol) and RuPhos Pd G3 (251 mg, 0.3 mmol) were added. Under the protection of nitrogen, heat to 80°C and stir for 1 hour. Then the reaction solution was cooled and filtered, the filtrate was concentrated under reduced pressure, and 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-6-(2-fluoro-6-hydroxyphenyl)-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline Tert-butyl -1(2H)-yl)methyl)azetidine-1-carboxylate (120 mg), a white solid, with a yield of 15%. ESI-MS: 626[M+H] + .
第五步the fifth step
将3-((7-氯-5-氟-6-(2-氟-6-羟基苯基)-4-(2-异丙基-6-甲基苯基)-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(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-(2-氟-6-羟基苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(80mg)，为白色固体，收率80％。ESI-MS:526[M+H] +。 Add 3-((7-chloro-5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-4-(2-isopropyl-6-methylphenyl)-2,3-diox (3,4-Dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (120mg, 0.19mmol) was dissolved in dichloromethane (5mL), Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature for 1 hour. Then concentrated under reduced pressure to obtain 1-(azetidine-3-ylmethyl)-7-chloro-5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-4-(2-isopropyl 6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (80mg), white solid, yield 80%. ESI-MS: 526[M+H] + .
第六步Sixth step
将1-(氮杂环丁烷-3-基甲基)-7-氯-5-氟-6-(2-氟-6-羟基苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(80mg，0.15mmol)溶解在二氯甲烷(1mL)中，加入三乙胺(46mg，0.45mmol)，在氮气保护及-78℃条件下，缓慢滴加丙烯酰氯(16mg，0.18mmol)的二氯甲烷(0.3mL)溶液，滴加完毕后在-78℃搅拌1小时。然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)＝35％～60％)分离纯化,得 到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-5-氟-6-(2-氟-6-羟基苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(17mg)，为白色固体，收率20％。 Add 1-(azetidine-3-ylmethyl)-7-chloro-5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-4-(2-isopropyl-6- Methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (80mg, 0.15mmol) was dissolved in dichloromethane (1mL), triethylamine (46mg, 0.45mmol) was added, and Under nitrogen protection and -78°C, slowly add a solution of acryloyl chloride (16mg, 0.18mmol) in dichloromethane (0.3mL) dropwise, and stir at -78°C for 1 hour after the addition is complete. Then 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 ) = 35% to 60%) to obtain 1-((1-acryloyl aza) Cyclobutan-3-yl)methyl)-7-chloro-5-fluoro-6-(2-fluoro-6-hydroxyphenyl)-4-(2-isopropyl-6-methylphenyl) -1,4-Dihydroquinoxaline-2,3-dione (17mg), a white solid, with a yield of 20%.
ESI-MS:580[M+H]+。ESI-MS: 580[M+H]+.
1H NMR(400MHz,DMSO-d 6)δ10.11(d,J＝1.8Hz,1H),7.76(s,1H),7.31–7.19(m,3H),7.12(dd,J＝7.6,1.8Hz,1H),6.71(d,J＝8.3Hz,1H),6.67(t,J＝8.7Hz,1H),6.34(ddd,J＝16.9,10.3,1.3Hz,1H),6.12(dd,J＝17.0,2.3Hz,1H),5.68(dd,J＝10.3,2.3Hz,1H),4.64–4.50(m,2H),4.35(m,1H),4.20–4.12(m,1H),4.05(td,J＝9.2,4.3Hz,1H),3.91–3.84(m,1H),3.25–3.17(m,1H),2.76(m,1H),2.02(s,3H),1.05(d,J＝6.8Hz,3H),0.96(d,J＝6.8Hz,3H). 1 H NMR(400MHz,DMSO-d 6 )δ10.11(d,J=1.8Hz,1H),7.76(s,1H),7.31-7.19(m,3H),7.12(dd,J=7.6,1.8 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.67 (t, J = 8.7 Hz, 1H), 6.34 (ddd, J = 16.9, 10.3, 1.3 Hz, 1H), 6.12 (dd, J = 17.0, 2.3 Hz, 1H), 5.68 (dd, J = 10.3, 2.3 Hz, 1H), 4.64–4.50 (m, 2H), 4.35 (m, 1H), 4.20–4.12 (m, 1H), 4.05 ( td,J=9.2,4.3Hz,1H), 3.91–3.84(m,1H), 3.25–3.17(m,1H), 2.76(m,1H), 2.02(s,3H), 1.05(d,J= 6.8Hz,3H),0.96(d,J=6.8Hz,3H).
第七步Seventh step
将实施例15的化合物经手性HPLC拆分：手性HPLC：CHIRALPAK IC-3(2*25cm；5um)；220nm检测；正己烷(0.5％2M NH 3-MeOH)/乙醇；流速＝20.0mL/min。得到实施例15a和实施例15b The compound of Example 15 was resolved by chiral HPLC: chiral HPLC: CHIRALPAK IC-3 (2*25cm; 5um); 220nm detection; n-hexane (0.5% 2M NH 3 -MeOH)/ethanol; flow rate = 20.0mL/ min. Obtain Example 15a and Example 15b
实施例15a： 1H NMR(400MHz,DMSO-d 6)δ10.11(s,1H),7.76(s,1H),7.31–7.19(m,3H),7.12(dd,J＝7.6,1.8Hz,1H),6.71(d,J＝8.3Hz,1H),6.67(t,J＝8.7Hz,1H),6.34(dd,J＝16.9,10.3Hz,1H),6.12(dd,J＝17.0,2.3Hz,1H),5.68(dd,J＝10.3,2.3Hz,1H),4.55(m,2H),4.35(m,1H),4.20–4.12(m,1H),4.05(m,1H),3.87(m,1H),3.25–3.17(m,1H),2.76(m,1H),2.02(s,3H),1.05(m,3H),0.96(d,J＝6.8Hz,3H). Example 15a: 1 H NMR (400MHz, DMSO-d 6 ) δ 10.11 (s, 1H), 7.76 (s, 1H), 7.31-7.19 (m, 3H), 7.12 (dd, J = 7.6, 1.8 Hz ,1H), 6.71 (d, J = 8.3 Hz, 1H), 6.67 (t, J = 8.7 Hz, 1H), 6.34 (dd, J = 16.9, 10.3 Hz, 1H), 6.12 (dd, J = 17.0, 2.3Hz, 1H), 5.68 (dd, J = 10.3, 2.3 Hz, 1H), 4.55 (m, 2H), 4.35 (m, 1H), 4.20-4.12 (m, 1H), 4.05 (m, 1H), 3.87 (m, 1H), 3.25-3.17 (m, 1H), 2.76 (m, 1H), 2.02 (s, 3H), 1.05 (m, 3H), 0.96 (d, J = 6.8 Hz, 3H).
实施例15b： 1H NMR(400MHz,DMSO-d 6)δ10.11(s,1H),7.76(s,1H),7.31–7.19(m,3H),7.12(d,J＝7.6Hz,1H),6.71(d,J＝8.3Hz,1H),6.67(t,J＝8.7Hz,1H),6.34(dd,J＝16.9,10.3 1H),6.12(dd,J＝17.0,2.3Hz,1H),5.68(dd,J＝10.3,2.3Hz,1H),4.55(m,2H),4.35(m,1H),4.20–4.12(m,1H),4.05(m,1H),3.87(m,1H),3.25–3.17(m,1H),2.76(m,1H),2.02(s,3H),1.05(m,3H),0.96(d,J＝6.8Hz,3H). Example 15b: 1 H NMR (400MHz, DMSO-d 6 ) δ 10.11 (s, 1H), 7.76 (s, 1H), 7.31-7.19 (m, 3H), 7.12 (d, J = 7.6 Hz, 1H ), 6.71 (d, J = 8.3 Hz, 1H), 6.67 (t, J = 8.7 Hz, 1H), 6.34 (dd, J = 16.9, 10.3 1H), 6.12 (dd, J = 17.0, 2.3 Hz, 1H) ), 5.68 (dd, J = 10.3, 2.3 Hz, 1H), 4.55 (m, 2H), 4.35 (m, 1H), 4.20-4.12 (m, 1H), 4.05 (m, 1H), 3.87 (m, 1H), 3.25–3.17(m,1H), 2.76(m,1H), 2.02(s,3H), 1.05(m,3H), 0.96(d,J=6.8Hz,3H).
通过参考以上实施例15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：By referring to the preparation method of the compound of Example 15 above and using different reaction materials, the following example compounds were prepared:
Figure PCTCN2021091100-appb-000162
Figure PCTCN2021091100-appb-000162
Figure PCTCN2021091100-appb-000163
Figure PCTCN2021091100-appb-000163
Figure PCTCN2021091100-appb-000164
Figure PCTCN2021091100-appb-000164
Figure PCTCN2021091100-appb-000165
Figure PCTCN2021091100-appb-000165
部分化合物手性拆分条件Conditions for chiral resolution of some compounds
Figure PCTCN2021091100-appb-000166
Figure PCTCN2021091100-appb-000166
Figure PCTCN2021091100-appb-000167
Figure PCTCN2021091100-appb-000167
实施例16：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(2,3-二氟-6-羟基苯基)-4-(2-异丙基苯基)-1,4-二氢喹喔啉-2,3-二酮的制备Example 16: 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(2,3-difluoro-6-hydroxyphenyl)-4-( Preparation of 2-isopropylphenyl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTCN2021091100-appb-000168
Figure PCTCN2021091100-appb-000168
第一步first step
将1-溴-2-氯-5-氟-4-硝基苯(50.6g，200mmol)、氟化钾(34.8g，600mmol)和2-异丙基-6-甲基苯胺(29.8g，200mmol)均匀混合在一起，反应在180℃下搅拌8小时。反应完成后反应液冷却并用水(500mL)稀释，再用乙酸乙酯(3*500mL)萃取，合并有机相并经饱和食盐水洗涤(100mL)，无水硫酸钠干燥，过滤，然后减压浓缩得到5-溴-4-氯-N-(2-异丙基-6-甲基苯基)-2-硝基苯胺(75.0g)，为黄色固体，收率97％。ESI-MS:383,385[M+H] +。 Combine 1-bromo-2-chloro-5-fluoro-4-nitrobenzene (50.6g, 200mmol), potassium fluoride (34.8g, 600mmol) and 2-isopropyl-6-methylaniline (29.8g, 200mmol) were mixed together uniformly, and the reaction was stirred at 180°C for 8 hours. After the completion of the reaction, the reaction solution was cooled and diluted with water (500mL), and then extracted with ethyl acetate (3*500mL). The organic phases were combined and washed with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 5-bromo-4-chloro-N-(2-isopropyl-6-methylphenyl)-2-nitroaniline (75.0 g) was obtained as a yellow solid with a yield of 97%. ESI-MS: 383,385[M+H] + .
第二步Second step
将5-溴-4-氯-N-(2-异丙基-6-甲基苯基)-2-硝基苯胺(75.0g，196mmol)溶解在乙醇(1.5L)和水(800mL)中，加入氯化铵(103.9g，1.96mol)和铁粉(54.9g，980mmol)，反应在90℃下搅拌1小时。反应结束后将反应液冷却并过滤，滤液减压除去乙醇，混合液用二氯甲烷(3*800mL)萃取，合并有机相，有机相经饱和食盐水洗涤(500mL)，无水硫酸钠干燥，过滤，滤液浓缩后经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝5:1)分离纯化，得到5-溴-4-氯-N-(2-异丙基-6-甲基苯基)苯-1,2-二胺(50g)，为白色固体，收率73％。ESI-MS:353,355[M+H] +。 Dissolve 5-bromo-4-chloro-N-(2-isopropyl-6-methylphenyl)-2-nitroaniline (75.0g, 196mmol) in ethanol (1.5L) and water (800mL) , Ammonium chloride (103.9g, 1.96mol) and iron powder (54.9g, 980mmol) were added, and the reaction was stirred at 90°C for 1 hour. After the reaction, the reaction solution was cooled and filtered. The filtrate was decompressed to remove ethanol. The mixed solution was extracted with dichloromethane (3*800mL). The organic phases were combined. The organic phases were washed with saturated brine (500mL) and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated and separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 5-bromo-4-chloro-N-(2-isopropyl-6-methyl) (Phenyl)benzene-1,2-diamine (50g), white solid, yield 73%. ESI-MS: 353,355 [M+H] + .
第三步third step
将5-溴-4-氯-N-(2-异丙基-6-甲基苯基)苯-1,2-二胺(50g,142mmol)溶于四氢呋喃(800mL)中，加入三乙 胺(72g，710mmol)，在冰浴条件下，缓慢滴加草酰氯单甲酯(52g，426mmol)溶液，在室温下继续搅拌1小时后，升温至90℃下继续搅拌3小时。反应完成后反应液冷却并减压浓缩，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7-溴-6-氯-1-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(40g)，为白色固体，收率70％。ESI-MS:407,409[M+H] +。 Dissolve 5-bromo-4-chloro-N-(2-isopropyl-6-methylphenyl)benzene-1,2-diamine (50g, 142mmol) in tetrahydrofuran (800mL) and add triethylamine (72g, 710mmol), slowly dropwise add a solution of oxalyl chloride monomethyl ester (52g, 426mmol) under ice bath conditions. After stirring at room temperature for 1 hour, the temperature is raised to 90°C and stirring is continued for 3 hours. After the completion of the reaction, 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 7-bromo-6-chloro-1-(2 -Isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (40g), white solid, yield 70%. ESI-MS: 407,409 [M+H] + .
第四步the fourth step
将7-溴-6-氯-1-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(40g，98.5mmol)溶于N,N-二甲基甲酰胺(100mL)中，加入碳酸钾(40.8g，295.5mmol)和3-(碘甲基)氮杂环丁烷-1-甲酸叔丁酯(35.0g，118mmol)，反应在室温下搅拌16小时。反应完毕后将反应液用水(200mL)稀释，再用乙酸乙酯(3*200mL)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，滤液浓缩除溶剂，残余物用硅胶柱层析(石油醚：乙酸乙酯＝1:1)分离纯化得到3-((6-溴-7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-3,4-二氢喹喔啉-1(H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(35g)，为白色固体，收率62％。ESI-MS:576,578[M+H] +。 Dissolve 7-bromo-6-chloro-1-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (40g, 98.5mmol) To N,N-dimethylformamide (100mL), add potassium carbonate (40.8g, 295.5mmol) and tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (35.0g, 118mmol) The reaction was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction solution was diluted with water (200 mL), and then extracted with ethyl acetate (3*200 mL). The organic phases were combined, washed with saturated brine (100 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to remove The solvent and the residue were separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate=1:1) to obtain 3-((6-bromo-7-chloro-4-(2-isopropyl-6-methylbenzene) Yl)-2,3-dioxo-3,4-dihydroquinoxaline-1(H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (35g), as a white solid , The yield is 62%. ESI-MS: 576,578 [M+H] + .
第五步the fifth step
将3-((6-溴-7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-3,4-二氢喹喔啉-1(H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(800mg，1.4mmol)溶解在1,4-二氧六环(10mL)和水(2mL)中，加入碳酸钾(580mg，4.2mmol)、(2,3-二氟-6-甲氧基苯基)硼酸频哪醇酯(403mg，1.68mmol)和RuPhos Pd G3(234mg，0.28mmol)，在氮气保护下加热至80℃，搅拌反应1小时。反应完毕后将反应液冷却并过滤，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＝1:1)分离纯化，得到3-((7-氯-6-(2,3-二氟-6-甲氧基苯基)-4-(2-异丙基-6-甲基苯基)-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(280mg)，为白色固体，收率35％。ESI-MS:640[M+H] +。 Add 3-((6-bromo-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline-1( H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (800mg, 1.4mmol) was dissolved in 1,4-dioxane (10mL) and water (2mL), and potassium carbonate ( 580mg, 4.2mmol), (2,3-difluoro-6-methoxyphenyl) borate pinacol ester (403mg, 1.68mmol) and RuPhos Pd G3 (234mg, 0.28mmol), heated to At 80°C, the reaction was stirred for 1 hour. After the reaction, 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 = 1:1) to obtain 3-((7-chloro- 6-(2,3-Difluoro-6-methoxyphenyl)-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydro Quinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (280 mg), a white solid, with a yield of 35%. ESI-MS: 640[M+H] + .
第六步Sixth step
将3-((7-氯-6-(2,3-二氟-6-甲氧基苯基)-4-(2-异丙基-6-甲基苯基)-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(280mg，0.44mmol)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-6-(2,3-二氟-6-甲氧基苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(200mg)，为白色固体，收率84％。ESI-MS:540[M+H] +。 Add 3-((7-chloro-6-(2,3-difluoro-6-methoxyphenyl)-4-(2-isopropyl-6-methylphenyl)-2,3-di Oxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (280mg, 0.44mmol) dissolved in dichloromethane (5mL) , Add trifluoroacetic acid (1 mL), and stir at room temperature for 1 hour. Then concentrated under reduced pressure to obtain 1-(azetidine-3-ylmethyl)-7-chloro-6-(2,3-difluoro-6-methoxyphenyl)-4-(2-iso Propyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (200mg), white solid, yield 84%. ESI-MS: 540[M+H] + .
第七步Seventh step
将1-(氮杂环丁烷-3-基甲基)-7-氯-6-(2,3-二氟-6-甲氧基苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(200mg，0.37mmol)溶解在二氯甲烷(10mL)中，加入三乙胺(112mg，1.11mmol)，在氮气保护和-78℃条件下，缓慢滴加丙烯酰氯(38mg，0.44mmol)的二氯甲烷(1mL)溶液，在-78℃温度下继续搅拌1小时。反应完成后反应液冷却并减压浓缩，浓缩物经硅胶柱层析(洗脱剂：二氯甲烷:甲醇＝20:1)分离纯化，得到1-((1-丙烯酰基氮杂环丁烷)-3-甲基)-7-氯-6-(2,3-二氟-6-甲氧基苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(100mg)，为白色固体，收率46％。ESI-MS:594[M+H] +。 Add 1-(azetidine-3-ylmethyl)-7-chloro-6-(2,3-difluoro-6-methoxyphenyl)-4-(2-isopropyl-6 -Methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (200mg, 0.37mmol) was dissolved in dichloromethane (10mL), triethylamine (112mg, 1.11mmol) was added, Under nitrogen protection and -78°C, a solution of acryloyl chloride (38 mg, 0.44 mmol) in dichloromethane (1 mL) was slowly added dropwise, and stirring was continued at -78°C for 1 hour. After the completion of the reaction, the reaction solution was cooled and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20:1) to obtain 1-((1-acryloylazetidine) )-3-methyl)-7-chloro-6-(2,3-difluoro-6-methoxyphenyl)-4-(2-isopropyl-6-methylphenyl)-1, 4-Dihydroquinoxaline-2,3-dione (100mg) is a white solid with a yield of 46%. ESI-MS:594[M+H] + .
第八步Eighth step
将1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(2,3-二氟-6-甲氧基苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(100mg，0.17mmol)溶解在二氯甲烷(2mL)中，在氮气保护和-78℃条件下，缓慢滴加 三溴化硼(1M的DCM溶液)(0.54mL)，升至室温继续搅拌1小时。反应结束后加饱和碳酸氢钠溶液(2mL)淬灭，用二氯甲烷(5mL)萃取三次，无水硫酸钠干燥有机相，减压浓缩有机相，残余物用prep-HPLC(洗脱剂：乙腈:水(10mM NH 4HCO 3)＝35％～60％)分离纯化，得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(2,3-二氟-6-羟基苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(40mg)，为白色固体，收率89％。 Add 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(2,3-difluoro-6-methoxyphenyl)-4-(2 -Isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (100mg, 0.17mmol) was dissolved in dichloromethane (2mL), protected by nitrogen and- Under the condition of 78°C, boron tribromide (1M DCM solution) (0.54 mL) was slowly added dropwise, and the temperature was raised to room temperature to continue stirring for 1 hour. After the reaction, it was quenched by adding saturated sodium bicarbonate solution (2mL), extracted with dichloromethane (5mL) three times, the organic phase was dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and the residue was subjected to prep-HPLC (eluent: Acetonitrile: water (10mM NH 4 HCO 3 )=35%～60%) was separated and purified to obtain 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-( 2,3-Difluoro-6-hydroxyphenyl)-4-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (40mg) , Is a white solid with a yield of 89%.
第九步Step 9
将实施例16化合物经手性HPLC拆分：CHIRALPAK IC-3(2*25cm；5um)；220nm检测；正己烷(0.5％2M NH 3-MeOH)/乙醇；流速＝20.0mL/min。得到实施例16a和实施例16b The compound of Example 16 was resolved by chiral HPLC: CHIRALPAK IC-3 (2*25cm; 5um); 220nm detection; n-hexane (0.5% 2M NH 3 -MeOH)/ethanol; flow rate = 20.0 mL/min. Obtain Example 16a and Example 16b
ESI-MS:580.1[M+H] +。 ESI-MS: 580.1 [M+H] + .
实施例16a： 1H NMR(400MHz,DMSO-d 6)δ10.17(s,1H),7.92(s,1H),7.40(d,J＝5.0Hz,2H),7.23(m,2H),6.68(td,J＝9.0,3.6Hz,1H),6.35(ddd,J＝17.1,10.3,2.8Hz,1H),6.17–6.07(m,2H),5.68(dd,J＝10.4,2.3Hz,1H),4.56(m,2H),4.36(q,J＝8.1Hz,1H),4.17(dd,J＝8.7,5.5Hz,1H),4.06(q,J＝8.4Hz,1H),3.92–3.85(m,1H),3.24(m,1H),2.67(t,J＝6.7Hz,1H),1.95(d,J＝13.8Hz,3H),1.08–0.91(m,6H). Example 16a: 1 H NMR (400MHz, DMSO-d 6 ) δ 10.17 (s, 1H), 7.92 (s, 1H), 7.40 (d, J = 5.0 Hz, 2H), 7.23 (m, 2H), 6.68 (td, J = 9.0, 3.6 Hz, 1H), 6.35 (ddd, J = 17.1, 10.3, 2.8 Hz, 1H), 6.17-6.07 (m, 2H), 5.68 (dd, J = 10.4, 2.3 Hz, 1H), 4.56 (m, 2H), 4.36 (q, J = 8.1 Hz, 1H), 4.17 (dd, J = 8.7, 5.5 Hz, 1H), 4.06 (q, J = 8.4 Hz, 1H), 3.92- 3.85 (m, 1H), 3.24 (m, 1H), 2.67 (t, J = 6.7 Hz, 1H), 1.95 (d, J = 13.8 Hz, 3H), 1.08-0.91 (m, 6H).
实施例16b： 1H NMR(400MHz,DMSO-d 6)δ10.17(s,1H),7.92(s,1H),7.40(d,J＝5.0Hz,2H),7.23(m,2H),6.68(m,1H),6.35(ddd,J＝17.1,10.3,2.8Hz,1H),6.17–6.07(m,2H),5.68(dd,J＝10.4,2.3Hz,1H),4.56(m,2H),4.36(q,J＝8.1Hz,1H),4.17(m,1H),4.06(q,J＝8.4Hz,1H),3.92–3.85(m,1H),3.24(m,1H),2.67(m,1H),1.95(d,J＝13.8Hz,3H),1.08–0.91(m,6H). Example 16b: 1 H NMR (400MHz, DMSO-d 6 ) δ 10.17 (s, 1H), 7.92 (s, 1H), 7.40 (d, J = 5.0 Hz, 2H), 7.23 (m, 2H), 6.68 (m, 1H), 6.35 (ddd, J = 17.1, 10.3, 2.8 Hz, 1H), 6.17-6.07 (m, 2H), 5.68 (dd, J = 10.4, 2.3 Hz, 1H), 4.56 (m, 2H), 4.36 (q, J = 8.1 Hz, 1H), 4.17 (m, 1H), 4.06 (q, J = 8.4 Hz, 1H), 3.92-3.85 (m, 1H), 3.24 (m, 1H), 2.67(m,1H),1.95(d,J=13.8Hz,3H),1.08-0.91(m,6H).
实施例17：2-(1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-1,2,3,4-四氢喹喔啉-6-基)-4-氨基苯甲酰胺的制备Example 17: 2-(1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)- Preparation of 2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-6-yl)-4-aminobenzamide
Figure PCTCN2021091100-appb-000169
Figure PCTCN2021091100-appb-000169
第一步first step
将3-((6-溴-7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-3,4-二氢喹喔啉-1(H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(1.0g，1.74mmol)溶解在1,4-二氧六环(10mL)和水(2mL)中，加入碳酸钾(720mg，5.22mmol)、(5-氨基-2-氰基苯基)硼酸338mg，2.08mmol)和Pd(PPh 3) 2Cl 2(242mg，0.35mmol)，在氮气保护下加热至80℃并搅拌反应1小时。反应完成后将反应液冷却并过滤，滤液减压浓缩，浓缩物用prep-HPLC(洗脱剂：乙腈:水(10mM NH 4HCO 3)＝20％～40％)分离纯化，得到3-((6-(5-氨基-2-氨基甲酰基苯基)-7-氯-4-(2-异丙基-6-甲基苯基)-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(240mg)，为白色固体，收率23％。ESI-MS:632[M+H] +。 Add 3-((6-bromo-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline-1( H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (1.0g, 1.74mmol) was dissolved in 1,4-dioxane (10mL) and water (2mL), and potassium carbonate was added (720mg, 5.22mmol), (5-amino-2-cyanophenyl)boronic acid 338mg, 2.08mmol) and Pd(PPh 3 ) 2 Cl 2 (242mg, 0.35mmol), heated to 80°C under nitrogen protection and The reaction was stirred for 1 hour. After the completion of the reaction, the reaction solution was cooled and filtered. The filtrate was concentrated under reduced pressure. The concentrate was separated and purified by prep-HPLC (eluent: acetonitrile: water (10mM NH 4 HCO 3 )=20%-40%) to obtain 3-( (6-(5-Amino-2-carbamoylphenyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4- Dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (240mg), a white solid, with a yield of 23%. ESI-MS: 632[M+H] + .
第二步Second step
将3-((6-(5-氨基-2-氨基甲酰基苯基)-7-氯-4-(2-异丙基-6-甲基苯基)-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(240mg，0.39mmol)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4-氨基-2-(1-(氮杂环丁烷-3-基甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二 氧代-1,2,3,4-四氢喹喔啉-6-基)苯甲酰胺(150mg)，为白色固体，收率73％。ESI-MS:532[M+H] +。 Add 3-((6-(5-amino-2-carbamoylphenyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo- 3,4-Dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (240mg, 0.39mmol) was dissolved in dichloromethane (5mL), and three Fluoroacetic acid (1mL), stirred at room temperature for 1 hour, and then concentrated under reduced pressure to give 4-amino-2-(1-(azetidin-3-ylmethyl)-7-chloro-4-(2- Isopropyl-6-methylphenyl)-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-6-yl)benzamide (150mg), white solid, yield The rate is 73%. ESI-MS: 532[M+H] + .
第三步third step
将4-氨基-2-(1-(氮杂环丁烷-3-基甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-1,2,3,4-四氢喹喔啉-6-基)苯甲酰胺(150mg，0.28mmol)溶解在二氯甲烷(10mL)中，加入三乙胺(85mg，0.84mmol)，在氮气保护和-78℃条件下，缓慢滴加丙烯酰氯(31mg，0.34mmol)的二氯甲烷(1mL)溶液，在-78℃温度下继续搅拌1小时。反应完成后将反应液冷却并减压浓缩，浓缩残余物用prep-HPLC(洗脱剂：乙腈:水(10mM NH 4HCO 3)＝35％～60％)分离纯化，得到2-(1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-1,2,3,4-四氢喹喔啉-6-基)-4-氨基苯甲酰胺(30mg)，为白色固体，收率20％。 Add 4-amino-2-(1-(azetidin-3-ylmethyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-di Oxo-1,2,3,4-tetrahydroquinoxalin-6-yl)benzamide (150mg, 0.28mmol) was dissolved in dichloromethane (10mL), and triethylamine (85mg, 0.84mmol) was added Under nitrogen protection and -78°C, slowly add dropwise a solution of acryloyl chloride (31mg, 0.34mmol) in dichloromethane (1mL), and continue stirring at -78°C for 1 hour. After the completion of the reaction, the reaction solution was cooled and concentrated under reduced pressure. The concentrated residue was separated and purified by prep-HPLC (eluent: acetonitrile: water (10mM NH 4 HCO 3 ) = 35% to 60%) to obtain 2-(1- ((1-Acryloylazetidin-3-yl)methyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-1 ,2,3,4-Tetrahydroquinoxalin-6-yl)-4-aminobenzamide (30mg), white solid, yield 20%.
ESI-MS:586[M+H] +。 ESI-MS: 586[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.74(s,1H),7.42–7.38(m,2H),7.34–7.23(m,2H),7.14(d,J＝30.6Hz,1H),6.61(m,1H),6.47(dd,J＝8.4,2.3Hz,1H),6.34(m,1H),6.14(t,J＝2.5Hz,1H),6.10(m,1H),6.08–6.00(m,1H),5.68(dd,J＝10.3,2.3Hz,1H),5.56(d,J＝6.9Hz,2H),4.55(m,2H),4.37(m,1H),4.17(t,J＝7.2Hz,1H),4.05(m,1H),3.89(m,1H),3.22(m,1H),2.68–2.57(m,1H),1.95(d,J＝6.2Hz,3H),1.09–0.95(m,6H). 1 H NMR(400MHz,DMSO-d 6 )δ7.74(s,1H), 7.42–7.38(m,2H), 7.34–7.23(m,2H), 7.14(d,J=30.6Hz,1H), 6.61(m,1H),6.47(dd,J=8.4,2.3Hz,1H),6.34(m,1H),6.14(t,J=2.5Hz,1H),6.10(m,1H),6.08–6.00 (m, 1H), 5.68 (dd, J = 10.3, 2.3 Hz, 1H), 5.56 (d, J = 6.9 Hz, 2H), 4.55 (m, 2H), 4.37 (m, 1H), 4.17 (t, J = 7.2Hz, 1H), 4.05 (m, 1H), 3.89 (m, 1H), 3.22 (m, 1H), 2.68-2.57 (m, 1H), 1.95 (d, J = 6.2 Hz, 3H), 1.09-0.95(m,6H).
实施例18：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(2,4-二氯-5-羟基苯基)-5-氟-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮的制备Example 18: 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(2,4-dichloro-5-hydroxyphenyl)-5-fluoro Preparation of -4-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTCN2021091100-appb-000170
Figure PCTCN2021091100-appb-000170
第一步first step
将5-溴-2,4-二氯苯酚(1.5g，6.25mmol)溶于N,N-二甲基甲酰胺(20mL)中，加入碳酸钾(2.58g，18.75mmol)和碘甲烷(1.06g，7.5mmol)，在室温下搅拌反应16小时。反应完成后将反应液用水(20mL)稀释，再用乙酸乙酯(3x20mL)萃取，合并有机相并经饱和食盐水洗涤(20mL)，无水硫酸钠干燥，过滤，浓缩滤液，浓缩残余物用硅胶层析柱(石油醚：乙酸乙酯＝5:1)分离纯化得到1-溴-2,4-二氯-5-甲氧基苯(1.4g)，为白色固体，收率88％。ESI-MS:256,258[M+H] +。 Dissolve 5-bromo-2,4-dichlorophenol (1.5g, 6.25mmol) in N,N-dimethylformamide (20mL), add potassium carbonate (2.58g, 18.75mmol) and methyl iodide (1.06 g, 7.5 mmol), the reaction was stirred at room temperature for 16 hours. After the completion of the reaction, the reaction solution was diluted with water (20mL), and then extracted with ethyl acetate (3x20mL). The organic phases were combined and washed with saturated brine (20mL), dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and concentrated the residue with Silica gel chromatography column (petroleum ether: ethyl acetate = 5:1) was separated and purified to obtain 1-bromo-2,4-dichloro-5-methoxybenzene (1.4g) as a white solid with a yield of 88%. ESI-MS: 256,258[M+H] + .
第二步Second step
将1-溴-2,4-二氯-5-甲氧基苯(1.4g，5.5mmol)溶解在1,4-二氧六环(20mL)中，加入乙酸钾(1.62g，16.5mmol)、联硼酸频那醇酯(2.1g，8.25mmol)和Pd(dppf)Cl 2(242mg，0.35mmol)，在氮气保护下加热至80℃ 并搅拌1小时。反应完成后反应液冷却并过滤，滤液减压浓缩，浓缩物用硅胶柱层析(石油醚：乙酸乙酯＝5:1)分离纯化，得到(2,4-二氯-5-甲氧基苯基)硼酸(1.0g)，为白色固体，收率83％。ESI-MS:220,222[M+H] +。 Dissolve 1-bromo-2,4-dichloro-5-methoxybenzene (1.4g, 5.5mmol) in 1,4-dioxane (20mL) and add potassium acetate (1.62g, 16.5mmol) , Pinacol diborate (2.1g, 8.25mmol) and Pd(dppf)Cl 2 (242mg, 0.35mmol), heated to 80°C under nitrogen protection and stirred for 1 hour. After the completion of the reaction, 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 (petroleum ether: ethyl acetate = 5:1) to obtain (2,4-dichloro-5-methoxy Phenyl)boronic acid (1.0 g), white solid, yield 83%. ESI-MS: 220,222[M+H] + .
第三步third step
将3-((6-溴-7-氯-5-氟-4-(2-异丙基-6-甲基苯基)-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(1.2g，2mmol)溶解在乙腈(20mL)和水(4mL)中，加入碳酸钾(580mg，4.2mmol)、(2,4-二氯-5-甲氧基苯基)硼酸(528mg，2.4mmol)和Pd(PPh 3) 2Cl 2(284mg，0.4mmol)，在氮气保护下加热至80℃并搅拌1小时。反应完成后反应液冷却并过滤，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＝1:1)分离纯化，得到3-((7-氯-6-(2,4-二氯-5-甲氧基苯基)-5-氟-4-(2-异丙基-6-甲基苯基)-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(800mg)，为白色固体，收率60％。ESI-MS:690[M+H] +。 3-((6-Bromo-7-chloro-5-fluoro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxa (2H)-yl)methyl)azetidine-1-carboxylate (1.2g, 2mmol) was dissolved in acetonitrile (20mL) and water (4mL), potassium carbonate (580mg, 4.2 mmol), (2,4-dichloro-5-methoxyphenyl)boronic acid (528mg, 2.4mmol) and Pd(PPh 3 ) 2 Cl 2 (284mg, 0.4mmol), heated to 80°C under the protection of nitrogen And stirred for 1 hour. After the completion of the reaction, 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 = 1:1) to obtain 3-((7-chloro-6 -(2,4-Dichloro-5-methoxyphenyl)-5-fluoro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4 -Dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (800mg), white solid, yield 60%. ESI-MS: 690[M+H] + .
第四步the fourth step
将3-((7-氯-6-(2,4-二氯-5-甲氧基苯基)-5-氟-4-(2-异丙基-6-甲基苯基)-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(800mg，1.2mmol)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-6-(2,4-二氯-5-甲氧基苯基)-5-氟-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(600mg)，为白色固体，收率85％。ESI-MS:590[M+H] +。 Add 3-((7-chloro-6-(2,4-dichloro-5-methoxyphenyl)-5-fluoro-4-(2-isopropyl-6-methylphenyl)-2 ,3-Dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (800mg, 1.2mmol) dissolved in dichloromethane (5mL), add trifluoroacetic acid (1mL), and stir at room temperature for 1 hour. Then concentrated under reduced pressure to obtain 1-(azetidine-3-ylmethyl)-7-chloro-6-(2,4-dichloro-5-methoxyphenyl)-5-fluoro-4- (2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (600mg), a white solid, the yield was 85%. ESI-MS: 590[M+H] + .
第五步the fifth step
将1-(氮杂环丁烷-3-基甲基)-7-氯-6-(2,4-二氯-5-甲氧基苯基)-5-氟-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(600mg，1mmol)溶解在二氯甲烷(10mL)中，加入三乙胺(303mg，3mmol)，在氮气保护和-78℃条件下，缓慢滴加丙烯酰氯(90mg，1mmol)的二氯甲烷(1mL)溶液，在-78℃继续搅拌1小时。反应完成后反应液冷却并减压浓缩，浓缩物经硅胶柱层析(洗脱剂：二氯甲烷:甲醇＝20:1)分离纯化，得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(2,4-二氯-5-甲氧基苯基)-5-氟-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(400mg)，为白色固体，收率62％。ESI-MS:644[M+H] +。 Add 1-(azetidin-3-ylmethyl)-7-chloro-6-(2,4-dichloro-5-methoxyphenyl)-5-fluoro-4-(2-iso Propyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (600mg, 1mmol) was dissolved in dichloromethane (10mL), and triethylamine (303mg, 3mmol) ), under nitrogen protection and -78°C, slowly add dropwise a solution of acryloyl chloride (90 mg, 1 mmol) in dichloromethane (1 mL), and continue stirring at -78°C for 1 hour. After the completion of the reaction, the reaction solution was cooled and concentrated under reduced pressure. The concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20:1) to obtain 1-((1-acryloylazetidine) -3-yl)methyl)-7-chloro-6-(2,4-dichloro-5-methoxyphenyl)-5-fluoro-4-(2-isopropyl-6-methylbenzene Yl)-1,4-dihydroquinoxaline-2,3-dione (400 mg), as a white solid, with a yield of 62%. ESI-MS: 644[M+H] + .
第六步Sixth step
将1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(2,4-二氯-5-甲氧基苯基)-5-氟-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(400mg，0.62mmol)溶解在二氯甲烷(5mL)中，在氮气保护和-78℃条件下，缓慢滴加三溴化硼(1M的DCM溶液)(1.86mL)，滴完后升至室温继续搅拌1小时。反应结束后加饱和碳酸氢钠溶液(5mL)淬灭，用二氯甲烷(10mL)萃取三次，无水硫酸钠干燥，减压浓缩，浓缩残余物用prep-HPLC(洗脱剂：乙腈:水(10mM NH 4HCO 3)＝35％～60％)分离纯化，得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(2,4-二氯-5-羟基苯基)-5-氟-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(65mg)，为白色固体，收率17％。 Add 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(2,4-dichloro-5-methoxyphenyl)-5-fluoro- 4-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (400mg, 0.62mmol) was dissolved in dichloromethane (5mL), in Under nitrogen protection and -78°C, boron tribromide (1M solution in DCM) (1.86 mL) was slowly added dropwise, and after the dropping, the temperature was raised to room temperature and stirring was continued for 1 hour. After the reaction, it was quenched by adding saturated sodium bicarbonate solution (5 mL), extracted with dichloromethane (10 mL) three times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and concentrated the residue with prep-HPLC (eluent: acetonitrile: water) (10mM NH 4 HCO 3 )=35%～60%) was separated and purified to obtain 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(2,4 -Dichloro-5-hydroxyphenyl)-5-fluoro-4-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (65mg ), is a white solid with a yield of 17%.
ESI-MS:630[M+H] +。 ESI-MS: 630[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ10.58(brs,1H),7.81(s,1H),7.59(s,1H),7.34–7.23(m,2H),7.13(d,J＝6.9Hz,1H),6.73(s,1H),6.34(ddd,J＝17.1,10.3,2.5Hz,1H),6.12(dd,J＝16.9,2.4Hz,1H),5.68(dd,J＝10.3,2.4Hz,1H),4.57(m,2H),4.35(t,J＝8.6Hz,1H),4.19–4.11(m,1H),4.05(t,J＝9.4Hz,1H),3.87(m,1H),3.24–3.16(m,1H),2.79(m,1H),2.00(s,3H),1.07(d,J＝6.7Hz,3H),0.98(d,J＝6.8Hz,3H). 1 H NMR(400MHz,DMSO-d 6 )δ10.58(brs,1H),7.81(s,1H),7.59(s,1H),7.34-7.23(m,2H),7.13(d,J=6.9 Hz, 1H), 6.73 (s, 1H), 6.34 (ddd, J = 17.1, 10.3, 2.5 Hz, 1H), 6.12 (dd, J = 16.9, 2.4 Hz, 1H), 5.68 (dd, J = 10.3, 2.4Hz, 1H), 4.57 (m, 2H), 4.35 (t, J = 8.6 Hz, 1H), 4.19-4.11 (m, 1H), 4.05 (t, J = 9.4 Hz, 1H), 3.87 (m, 1H), 3.24–3.16 (m, 1H), 2.79 (m, 1H), 2.00 (s, 3H), 1.07 (d, J = 6.7 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H).
实施例19：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-(2-氨基-7-氟苯并[d]噻唑-4-基)-7-氯-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮的制备Example 19: 1-((1-acryloylazetidin-3-yl)methyl)-6-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-7- Preparation of chloro-4-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTCN2021091100-appb-000171
Figure PCTCN2021091100-appb-000171
第一步first step
将苯甲酰基异硫氰酸酯(2.2g，13.50mmol)溶于四氢呋喃(18mL)中，在N 2氛围下降温至5℃后，将5-氟-2-甲氧基苯胺(1.7mL，13.88mmol)滴加入体系中，保持温度不高于10℃，滴加完毕升至室温并搅拌反应30min。然后加入氢氧化钠溶液(3.2mL，16.0mmol,5N)和水(4mL)，加热至80℃并搅拌反应3.5小时。反应完成后将体系降至室温，加入水(10mL)和乙酸乙酯(80mL)，然后加入浓盐酸将pH值调至pH 9～10，接着用乙酸乙酯萃取，有机相以无水硫酸钠干燥，过滤并浓缩后，加入乙酸乙酯(5mL)溶解浓缩物，往溶液中加入石油醚(20mL)析出固体，过滤得产品，烘干得到1-(5-氟-2-甲氧基苯基)硫脲(2.5g)，为白色固体，收率93％。ESI-MS:201[M+H] +。 Benzoyl isothiocyanate (2.2g, 13.50mmol) was dissolved in tetrahydrofuran (18mL), and after the temperature was lowered to 5°C under N 2 atmosphere, 5-fluoro-2-methoxyaniline (1.7mL, 13.88mmol) was added dropwise to the system, keeping the temperature not higher than 10°C, after the dropwise addition, the temperature was raised to room temperature and the reaction was stirred for 30min. Then sodium hydroxide solution (3.2mL, 16.0mmol, 5N) and water (4mL) were added, heated to 80°C and stirred for 3.5 hours. After the completion of the reaction, the system was cooled to room temperature, water (10mL) and ethyl acetate (80mL) were added, and then concentrated hydrochloric acid was added to adjust the pH to pH 9-10, and then extracted with ethyl acetate. The organic phase was extracted with anhydrous sodium sulfate. After drying, filtering and concentrating, add ethyl acetate (5mL) to dissolve the concentrate, add petroleum ether (20mL) to the solution to precipitate a solid, filter to obtain the product, and dry to obtain 1-(5-fluoro-2-methoxybenzene) Thiourea (2.5g), white solid, yield 93%. ESI-MS: 201[M+H] + .
第二步Second step
将1-(5-氟-2-甲氧基苯基)硫脲(2.5g，12.5mmol)溶于三氯甲烷(40mL)后降温至0-5℃，在N 2氛围下缓慢滴加Br 2(0.64mL，12.4mmol)并控制温度不高于5℃，在0℃搅拌0.5小时后，升温至86℃继续搅拌2.25小时。反应完成后加入冷石油醚稀释，抽滤得到7-氟-4-甲氧基苯并[d]噻唑-2-胺(3.2g)，为黄色固体，收率91％。ESI-MS:199[M+H] +。 Dissolve 1-(5-fluoro-2-methoxyphenyl)thiourea (2.5g, 12.5mmol) in chloroform (40mL), then cool to 0-5°C, slowly add Br dropwise under N 2 atmosphere 2 (0.64mL, 12.4mmol) and control the temperature not to be higher than 5°C. After stirring at 0°C for 0.5 hours, the temperature is raised to 86°C and stirring is continued for 2.25 hours. After the reaction was completed, cold petroleum ether was added to dilute, and 7-fluoro-4-methoxybenzo[d]thiazol-2-amine (3.2 g) was obtained by suction filtration as a yellow solid with a yield of 91%. ESI-MS: 199[M+H] + .
第三步third step
将7-氟-4-甲氧基苯并[d]噻唑-2-胺(3.2g，11.5mmol)分散在二氯甲烷(41mL)中，在N 2氛围下降温至0℃，然后滴加BBr 3(35mL，35.0mmol)，缓慢升至室温后，在室温下搅拌反应16小时。反应完成后将反应体系降温至0℃，加入MeOH(10mL)稀释反应液，控制体系温度不超过10℃，减压抽滤得固体，烘干得到2-氨基-7-氟苯并[d]噻唑-4-酚(2.13g)，为白色固体，收率72％。ESI-MS:185[M+H] +。 Disperse 7-fluoro-4-methoxybenzo[d]thiazol-2-amine (3.2g, 11.5mmol) in dichloromethane (41mL), lower the temperature to 0°C under N 2 atmosphere, and then add dropwise BBr 3 (35 mL, 35.0 mmol) was slowly raised to room temperature, and the reaction was stirred at room temperature for 16 hours. After the completion of the reaction, the temperature of the reaction system was cooled to 0°C, MeOH (10mL) was added to dilute the reaction solution, the temperature of the system was controlled not to exceed 10°C, and the solid was obtained by suction filtration under reduced pressure, and dried to obtain 2-amino-7-fluorobenzo[d] Thiazole-4-phenol (2.13g) was a white solid with a yield of 72%. ESI-MS: 185[M+H] + .
第四步the fourth step
将2-氨基-7-氟苯并[d]噻唑-4-酚(2.13g，8.04mmol)溶解在1,4-二氧六环(27mL)中，降温至10℃，然后滴加TEA(1.70g，16.88mmol)，保持体系温度不高于15℃，加入DMAP(49mg，0.40mmol)和Boc 2O(4.03 g，18.49mmol)，在室温下搅拌反应16小时。反应完成后往体系中加入乙酸乙酯和饱和食盐水，分液得到有机相，有机相经无水硫酸钠干燥，过滤并浓缩有机相，浓缩残余物用中压制备flash硅胶柱层析(洗脱剂：EA：PE＝0-40％)分离纯化，得到(7-氟-4-羟基苯并[d]噻唑-2-基)氨基甲酸叔丁酯(1.4g)，为浅棕色固体，收率48％。ESI-MS:285[M+H] +。 Dissolve 2-amino-7-fluorobenzo[d]thiazole-4-phenol (2.13g, 8.04mmol) in 1,4-dioxane (27mL), lower the temperature to 10°C, and then add TEA( 1.70 g, 16.88 mmol), keeping the system temperature not higher than 15°C, adding DMAP (49 mg, 0.40 mmol) and Boc 2 O (4.03 g, 18.49 mmol), stirring and reacting at room temperature for 16 hours. After the reaction was completed, ethyl acetate and saturated brine were added to the system to separate the liquids to obtain the organic phase. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated residue was used to prepare flash silica gel column chromatography (washing Removal agent: EA: PE=0-40%) separation and purification to obtain tert-butyl (7-fluoro-4-hydroxybenzo[d]thiazol-2-yl)carbamate (1.4g) as a light brown solid. The yield was 48%. ESI-MS: 285[M+H] + .
第五步the fifth step
将(7-氟-4-羟基苯并[d]噻唑-2-基)氨基甲酸叔丁酯(1.4g，4.93mmol)溶解于二氯甲烷(22mL)和吡啶(793mg，10.04mmol)中，降温至0℃，在N 2氛围下滴加Tf 2O(1.67g，5.92mmol)，滴加过程保持体系温度不高于10℃，滴加完毕升至室温并搅拌反应0.5小时。反应完成后往体系中加入饱和食盐水，用EA萃取，有机相用无水硫酸钠干燥，过滤并浓缩有机相，浓缩残余物用中压制备flash硅胶柱层析(洗脱剂：EA：PE＝0-10％)分离纯化，得到三氟甲磺酸2-((叔丁氧基羰基)氨基)-7-氟苯并[d]噻唑-4-基酯(760mg)，为白色固体，收率37％。ESI-MS:361[M+H] +。 Dissolve tert-butyl (7-fluoro-4-hydroxybenzo[d]thiazol-2-yl)carbamate (1.4g, 4.93mmol) in dichloromethane (22mL) and pyridine (793mg, 10.04mmol), The temperature was lowered to 0°C, and Tf 2 O (1.67 g, 5.92 mmol) was added dropwise under N 2 atmosphere. The temperature of the system was kept not higher than 10°C during the dropping process. After the dropping, the temperature was raised to room temperature and the reaction was stirred for 0.5 hours. After the reaction was completed, saturated brine was added to the system, extracted with EA, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated the organic phase, the concentrated residue was prepared by medium pressure flash silica gel column chromatography (eluent: EA: PE =0-10%) separation and purification to obtain trifluoromethanesulfonic acid 2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl ester (760mg) as a white solid. The yield was 37%. ESI-MS: 361[M+H] + .
第六步Sixth step
在N 2氛围下，将三氟甲磺酸2-((叔丁氧基羰基)氨基)-7-氟苯并[d]噻唑-4-基酯(760mg，1.83mmol)、联硼酸频那醇酯(3.71g，14.61mmol)、Pd(dppf)Cl 2(131mg,0.18mmol)和醋酸钾(531mg，5.42mmol)分散在1,4-二氧六环(10mL)中，加热至80℃后搅拌反应16小时。反应完成后将反应液减压浓缩，浓缩残余物用中压flash硅胶柱层析(洗脱剂：EA:PE＝0-30％)分离纯化，然后再经中压flash C18反相柱(洗脱剂：ACN:5mmol/L NH 4HCO 3＝50-95％，30min)分离纯化，冷冻干燥得到(7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯并[d]噻唑-2-基)氨基甲酸叔丁酯(216mg)，为浅棕色固体，收率30％。ESI-MS:339[M+H] +。 Under N 2 atmosphere, the trifluoromethanesulfonic acid 2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl ester (760mg, 1.83mmol), biboronic acid pina Alcohol ester (3.71g, 14.61mmol), Pd(dppf)Cl 2 (131mg, 0.18mmol) and potassium acetate (531mg, 5.42mmol) were dispersed in 1,4-dioxane (10mL) and heated to 80°C The reaction was stirred for 16 hours. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated residue was separated and purified by medium-pressure flash silica gel column chromatography (eluent: EA:PE=0-30%), and then passed through a medium-pressure flash C18 reversed-phase column (washing Removal agent: ACN: 5mmol/L NH 4 HCO 3 =50-95%, 30min) separation and purification, freeze-drying to obtain (7-fluoro-4-(4,4,5,5-tetramethyl-1,3, Tert-butyl 2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)carbamate (216 mg), as a light brown solid, with a yield of 30%. ESI-MS: 339[M+H] + .
第七步Seventh step
在N 2氛围下，将(7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯并[d]噻唑-2-基)氨基甲酸叔丁酯、3-((6-溴-7-氯-4-(2-异丙基-6-甲基苯基)-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(150mg，0.26mmol)、Xphos Pd G 3(22mg,0.026mmol)和磷酸三钾(165mg，0.78mmol)分散在1,4-二氧六环/水(4:1,7mL)中，加热至90℃并搅拌2小时。反应完成后将体系降至室温，加入水(20mL)，并用EA(3*30mL)萃取，无水硫酸钠干燥，过滤并减压浓缩有机相，残余物用中压flash C18反相柱(洗脱剂：ACN:5mmol/L NH 4HCO 3＝10-95％，30min)分离纯化，冷冻干燥得到3-(((6-(2-((叔丁氧基羰基)氨基)-7-氟苯并[d]噻唑-4-基)-7-氯-4-(2-异丙基-6-甲基苯基)-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(74mg)，为白色固体，收率37％。ESI-MS:608[M+H] +。 Under N 2 atmosphere, the (7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d ]Thiazol-2-yl) tert-butyl carbamate, 3-((6-bromo-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo- 3,4-Dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (150mg, 0.26mmol), Xphos Pd G 3 (22mg, 0.026mmol) and Tripotassium phosphate (165 mg, 0.78 mmol) was dispersed in 1,4-dioxane/water (4:1, 7 mL), heated to 90°C and stirred for 2 hours. After the completion of the reaction, the system was cooled to room temperature, water (20mL) was added, and it was extracted with EA (3*30mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Removal agent: ACN: 5mmol/L NH 4 HCO 3 =10-95%, 30min) separation and purification, freeze-drying to obtain 3-(((6-(2-((tert-butoxycarbonyl)amino)-7-fluoro Benzo[d]thiazol-4-yl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline Tert-butyl -1(2H)-yl)methyl)azetidine-1-carboxylate (74 mg), a white solid, with a yield of 37%. ESI-MS: 608 [M+H] + .
第八步Eighth step
将3-(((6-(2-((叔丁氧基羰基)氨基)-7-氟苯并[d]噻唑-4-基)-7-氯-4-(2-异丙基-6-甲基苯基)-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(74mg，0.097mmol)溶解在二氯甲烷(5mL)中，在室温下缓慢滴加三氟乙酸(1mL)，维持室温搅拌反应1小时。然后减压浓缩得到6-(2-氨基-7-氟苯并[d]噻唑-4-基)-1-(氮杂环丁烷-3-基甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(55mg)，为棕色固体，收率100％。ESI-MS:564[M+H] +。 Add 3-(((6-(2-((tert-butoxycarbonyl)amino)-7-fluorobenzo[d]thiazol-4-yl)-7-chloro-4-(2-isopropyl- 6-Methylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (74mg , 0.097mmol) was dissolved in dichloromethane (5mL), trifluoroacetic acid (1mL) was slowly added dropwise at room temperature, and the reaction was stirred at room temperature for 1 hour. Then concentrated under reduced pressure to obtain 6-(2-amino-7-fluorobenzene) And [d]thiazol-4-yl)-1-(azetidin-3-ylmethyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-1, 4-Dihydroquinoxaline-2,3-dione (55mg), brown solid, yield 100%. ESI-MS: 564[M+H] + .
第九步Step 9
在N 2氛围下，将6-(2-氨基-7-氟苯并[d]噻唑-4-基)-1-(氮杂环丁烷-3-基甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(55mg，0.097mmol)溶解于二氯甲烷(3mL)中，加入三乙胺(98mg,0.97mmol)。冷却至-78℃，在-78℃下将丙烯酰氯(9mg，1.02mmol)的二氯甲烷(2mL)溶液缓慢滴加到体系中，并于-78℃搅拌反应0.5小时。反应完成后减压浓缩，浓缩残余物用prep-TLC(洗脱剂：MeOH:DCM＝1:10)分离纯化，再用C18反相柱(洗脱剂：ACN:5mmol/LNH 4HCO 3＝10-60％，30min)分离纯化，冷冻干燥得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-(2-氨基-7-氟苯并[d]噻唑-4-基)-7-氯-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(24.93mg)，为白色固体，收率41％。 Under N 2 atmosphere, 6-(2-amino-7-fluorobenzo[d]thiazol-4-yl)-1-(azetidine-3-ylmethyl)-7-chloro-4 -(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (55mg, 0.097mmol) was dissolved in dichloromethane (3mL), and three Ethylamine (98mg, 0.97mmol). After cooling to -78°C, a solution of acryloyl chloride (9 mg, 1.02 mmol) in dichloromethane (2 mL) was slowly added dropwise to the system at -78°C, and the reaction was stirred at -78°C for 0.5 hours. After the reaction was completed, it was concentrated under reduced pressure, and the concentrated residue was separated and purified with prep-TLC (eluent: MeOH:DCM=1:10), and then applied to a C18 reverse phase column (eluent: ACN: 5mmol/LNH 4 HCO 3 = 10-60%, 30min) separation and purification, freeze-drying to obtain 1-((1-acryloylazetidin-3-yl)methyl)-6-(2-amino-7-fluorobenzo[d] Thiazol-4-yl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (24.93mg), White solid, the yield is 41%.
ESI-MS:618[M+H] +。 ESI-MS:618[M+H] + .
1H-NMR(400MHz,DMSO-d6)δ:ppm 7.85(s,1H),7.82(s,2H),7.38～7.37(m,2H),7.25～7.23(m,1H),6.92～6.88(m,2H),6.39～6.31(m,1H),6.15～6.10(m,2H),5.69(dd,1H,J＝10.4,2.4Hz),4.64～4.52(m,2H),4.36(q,1H,J＝8.0Hz),4.20～4.16(m,1H),4.09～4.03(m,1H),3.90(dd,1H,J＝10.4,5.6Hz),3.26～3.19(m,1H),2.69～2.63(m,1H),1.96(s,3H),1.05(d,3H,J＝6.8Hz),0.99(d,3H,J＝6.8Hz)。 1 H-NMR(400MHz,DMSO-d6)δ:ppm 7.85(s,1H),7.82(s,2H),7.38～7.37(m,2H),7.25～7.23(m,1H),6.92～6.88( m,2H), 6.39～6.31(m,1H), 6.15～6.10(m,2H), 5.69(dd,1H,J=10.4,2.4Hz), 4.64～4.52(m,2H), 4.36(q, 1H,J=8.0Hz), 4.20～4.16(m,1H), 4.09～4.03(m,1H), 3.90(dd,1H,J=10.4,5.6Hz), 3.26～3.19(m,1H), 2.69 ~ 2.63 (m, 1H), 1.96 (s, 3H), 1.05 (d, 3H, J = 6.8 Hz), 0.99 (d, 3H, J = 6.8 Hz).
实施例20:1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(2-羟基-5-(三氟甲基)苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮的制备Example 20: 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(2-hydroxy-5-(trifluoromethyl)phenyl)-4 -(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTCN2021091100-appb-000172
Figure PCTCN2021091100-appb-000172
第一步first step
将2-溴-4-(三氟甲基)苯酚(1.0g，4.15mmol)溶于DMF(10mL)中，加入K 2CO 3(1.718g，12.45mmol)，在室温下缓慢滴加MeI(766mg，5.39mmol)，滴加完成后在室温下搅拌16小时。反应完成后向体系中加入EA(100mL)，依次用水(3X30mL)和饱和食盐水(10mL)洗涤，有机相经无水硫酸钠干燥，过滤并浓缩有机相，浓缩残余物用中压制备flash硅胶柱层析(洗脱剂：EA：PE＝0-15％)分离纯化，得到2-溴-1-甲氧基-4-(三氟甲基)苯(1.04g)，为浅黄色油状液体，收率98％。 2-Bromo-4-(trifluoromethyl)phenol (1.0g, 4.15mmol) was dissolved in DMF (10mL), K 2 CO 3 (1.718g, 12.45mmol) was added, and MeI( 766mg, 5.39mmol). After the addition is complete, stir at room temperature for 16 hours. After the reaction was completed, EA (100mL) was added to the system, washed with water (3X30mL) and saturated brine (10mL) successively, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated the organic phase, and the residue was concentrated to prepare flash silica gel with medium pressure Column chromatography (eluent: EA: PE=0-15%) was separated and purified to obtain 2-bromo-1-methoxy-4-(trifluoromethyl)benzene (1.04g) as a pale yellow oily liquid , The yield is 98%.
第二步Second step
在N 2氛围下，将2-溴-1-甲氧基-4-(三氟甲基)苯(245mg，0.96mmol)、3-((7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷 -1-甲酸叔丁酯(300mg，0.48mmol)、Pd(PPh 3) 2Cl 2(68mg,0.097mmol)和碳酸钾(199mg，1.44mmol)分散在乙腈/水(4:1,8mL)中，将反应体系加热至60℃并在此温度下搅拌1小时。反应完成后将体系降至室温，减压浓缩反应液，浓缩残余物用中压flash硅胶柱层析(洗脱剂：EA:PE＝0-50％)分离纯化，得到3-((7-氯-4-(2-异丙基-6-甲基苯基)-6-(2-甲氧基-5-(三氟甲基)苯基)-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(240mg)，为黄色固体，收率74％。ESI-MS:616[M+H] +。 Under N 2 atmosphere, the 2-bromo-1-methoxy-4-(trifluoromethyl)benzene (245mg, 0.96mmol), 3-((7-chloro-4-(2-isopropyl- 6-methylphenyl)-2,3-dioxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,4-Dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (300mg, 0.48mmol), Pd(PPh 3 ) 2 Cl 2 (68mg , 0.097mmol) and potassium carbonate (199mg, 1.44mmol) were dispersed in acetonitrile/water (4:1, 8mL), the reaction system was heated to 60°C and stirred at this temperature for 1 hour. After the completion of the reaction, the system was cooled to room temperature, the reaction solution was concentrated under reduced pressure, and the concentrated residue was separated and purified by medium-pressure flash silica gel column chromatography (eluent: EA:PE=0-50%) to obtain 3-((7- Chloro-4-(2-isopropyl-6-methylphenyl)-6-(2-methoxy-5-(trifluoromethyl)phenyl)-2,3-dioxo-3, 4-Dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (240 mg), as a yellow solid, with a yield of 74%. ESI-MS: 616[M+H] + .
第三步third step
将3-((7-氯-4-(2-异丙基-6-甲基苯基)-6-(2-甲氧基-5-(三氟甲基)苯基)-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(220mg，0.33mmol)溶解在二氯甲烷(5mL)中，在室温下缓慢滴加三氟乙酸(0.5mL)，维持室温搅拌1小时。反应完成后减压浓缩得到1-(氮杂环丁烷-3-基甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-6-(2-甲氧基-5-(三氟甲基)苯基)-1,4-二氢喹喔啉-2,3-二酮(187mg)，为棕色固体，收率100％。ESI-MS:572[M+H] +。 Add 3-((7-chloro-4-(2-isopropyl-6-methylphenyl)-6-(2-methoxy-5-(trifluoromethyl)phenyl)-2,3 -Dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (220mg, 0.33mmol) dissolved in dichloromethane (5mL In ), trifluoroacetic acid (0.5 mL) was slowly added dropwise at room temperature, and stirring was maintained at room temperature for 1 hour. After the reaction is completed, it is concentrated under reduced pressure to obtain 1-(azetidin-3-ylmethyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-6-(2-methyl Oxyoxy-5-(trifluoromethyl)phenyl)-1,4-dihydroquinoxaline-2,3-dione (187 mg) is a brown solid with a yield of 100%. ESI-MS: 572[M+H] + .
第四步the fourth step
在N 2氛围下，将1-(氮杂环丁烷-3-基甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-6-(2-甲氧基-5-(三氟甲基)苯基)-1,4-二氢喹喔啉-2,3-二酮(187mg，0.33mmol)溶解在二氯甲烷(3mL)中，加入三乙胺(331mg,3.28mmol)，将反应体系冷却至-78℃，在-78℃条件下将溶解有丙烯酰氯(27mg，0.30mmol)的二氯甲烷(2mL)溶液缓慢滴加到体系中，并于-78℃搅拌反应0.5小时。反应完成后减压浓缩反应液，浓缩残余物用prep-TLC(洗脱剂：EA)分离纯化，然后再用C18反相柱(洗脱剂：ACN:5mmol/L NH 4HCO 3＝10-60％，30min)分离纯化，冷冻干燥得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-6-(2-甲氧基-5-(三氟甲基)苯基)-1,4-二氢喹喔啉-2,3-二酮(136mg)，为白色固体，收率66％。ESI-MS:626[M+H] +。 Under N 2 atmosphere, the 1-(azetidin-3-ylmethyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-6-(2-methyl Oxy-5-(trifluoromethyl)phenyl)-1,4-dihydroquinoxaline-2,3-dione (187mg, 0.33mmol) was dissolved in dichloromethane (3mL), and triethyl was added Amine (331mg, 3.28mmol), the reaction system was cooled to -78°C, a solution of dichloromethane (2mL) dissolved in acryloyl chloride (27mg, 0.30mmol) was slowly added dropwise to the system at -78°C, and The reaction was stirred at -78°C for 0.5 hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrated residue was separated and purified by prep-TLC (eluent: EA), and then used on a C18 reversed phase column (eluent: ACN: 5mmol/L NH 4 HCO 3 =10- 60%, 30min) separation and purification, freeze-drying to obtain 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-4-(2-isopropyl-6-methyl) Phenyl)-6-(2-methoxy-5-(trifluoromethyl)phenyl)-1,4-dihydroquinoxaline-2,3-dione (136mg), white solid, yield The rate is 66%. ESI-MS: 626[M+H] + .
第五步the fifth step
将1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-6-(2-甲氧基-5-(三氟甲基)苯基)-1,4-二氢喹喔啉-2,3-二酮(136g，0.22mmol)分散在二氯甲烷(5mL)中，在N 2氛围下降温至-78℃，在-78℃条件下滴加BBr 3(0.7mL，2.1mmol)，滴加完毕后继续搅拌5分钟，然后缓慢升至室温，在室温下搅拌2小时。反应完成后将体系降温至0℃，加入EA(20mL)稀释，将稀释的反应液缓慢滴加到0℃的饱和NaHCO 3溶液中，以EA萃取NaHCO 3溶液3次，合并有机相，有机相经无水硫酸钠干燥，过滤并浓缩有机相，浓缩残余物经高压制备色谱分离纯化，冷冻干燥得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(2-羟基-5-(三氟甲基)苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(24.93mg)，为白色固体，收率5％。 Add 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-6-(2-methyl Oxyoxy-5-(trifluoromethyl)phenyl)-1,4-dihydroquinoxaline-2,3-dione (136g, 0.22mmol) was dispersed in dichloromethane (5mL), in N 2 The temperature of the atmosphere was lowered to -78°C, BBr 3 (0.7 mL, 2.1 mmol) was added dropwise at -78°C, and stirring was continued after the addition was completed for 5 minutes, then slowly raised to room temperature, and stirred at room temperature for 2 hours. After completion of the reaction system to 0 ℃ cooled, diluted with EA was added (20 mL), the diluted reaction solution was slowly added dropwise to a 0 ℃ saturated NaHCO 3 solution, and extracted with EA NaHCO 3 solution three times, and the combined organic phases, the organic phase After drying over anhydrous sodium sulfate, filtering and concentrating the organic phase, the concentrated residue is separated and purified by high pressure preparative chromatography and freeze-dried to obtain 1-((1-acryloylazetidin-3-yl)methyl)-7- Chloro-6-(2-hydroxy-5-(trifluoromethyl)phenyl)-4-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2, 3-diketone (24.93mg), white solid, yield 5%.
ESI-MS:612[M+H] +。 ESI-MS: 612[M+H] + .
1H-NMR(400MHz,DMSO-d6)δ:ppm 10.55(brs,1H),7.90(s,1H),7.52(dd,1H,J＝8.4,2.4Hz),7.42～7.38(m,2H),7.27～7.24(m,2H),7.00(d,1H,J＝8.8Hz),6.39～6.31(m,1H),6.18(s,1H),6.12(dd,1H,J＝17.2,2.4Hz),5.68(dd,1H,J＝10.0,2.4Hz),4.66～4.52(m,2H),4.36(q,1H,J＝8.4Hz),4.20～4.15(m,1H),4.06(q,1H,J＝8.8Hz),3.91～3.87(m,1H),3.26～3.19(m,1H),2.71～2.64(m,1H),1.95(s,3H),1.04(d,3H,J＝6.8Hz),1.01(d,3H,J＝6.8Hz)。 1 H-NMR(400MHz,DMSO-d6)δ:ppm 10.55(brs,1H),7.90(s,1H),7.52(dd,1H,J=8.4,2.4Hz),7.42～7.38(m,2H) ,7.27～7.24(m,2H),7.00(d,1H,J=8.8Hz), 6.39～6.31(m,1H),6.18(s,1H),6.12(dd,1H,J=17.2,2.4Hz) ), 5.68(dd,1H,J=10.0,2.4Hz), 4.66～4.52(m,2H), 4.36(q,1H,J=8.4Hz), 4.20～4.15(m,1H),4.06(q, 1H,J=8.8Hz), 3.91～3.87(m,1H), 3.26～3.19(m,1H), 2.71～2.64(m,1H),1.95(s,3H),1.04(d,3H,J＝ 6.8 Hz), 1.01 (d, 3H, J = 6.8 Hz).
实施例21:1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-(5-氨基-2-(三氟甲基)苯基)-7-氯-4-(2-异丙基-6-甲基 苯基)-1,4-二氢喹喔啉-2,3-二酮的制备Example 21: 1-((1-acryloylazetidin-3-yl)methyl)-6-(5-amino-2-(trifluoromethyl)phenyl)-7-chloro-4 -(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTCN2021091100-appb-000173
Figure PCTCN2021091100-appb-000173
第一步first step
在N 2氛围下，将3-溴-4-(三氟甲基)苯胺(20g，83.33mmol)、联硼酸频那醇酯(84.67g，333.3mmol)、Pd(dppf)Cl 2(12.20g,16.67mmol)和醋酸钾(40.83g，416.6mmol)分散在1,4-二氧六环(400mL)中，将反应体系加热至100℃并在此温度下搅拌72小时。反应完成后过滤，滤液浓缩得残余物，残余物用中压flash硅胶柱层析(洗脱剂：EA:PE＝0-20％)分离纯化，得到3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-4-(三氟甲基)苯胺(24g)，为浅棕色固体，收率95％。ESI-MS:288[M+H] +。 Under N 2 atmosphere, 3-bromo-4-(trifluoromethyl)aniline (20g, 83.33mmol), pinacol diborate (84.67g, 333.3mmol), Pd(dppf)Cl 2 (12.20g) , 16.67 mmol) and potassium acetate (40.83 g, 416.6 mmol) were dispersed in 1,4-dioxane (400 mL), and the reaction system was heated to 100° C. and stirred at this temperature for 72 hours. After the reaction was completed, it was filtered, and the filtrate was concentrated to obtain a residue. The residue was separated and purified by medium-pressure flash silica gel column chromatography (eluent: EA:PE=0-20%) to obtain 3-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)aniline (24g) is a light brown solid with a yield of 95%. ESI-MS: 288[M+H] + .
第二步Second step
在N 2氛围下，将3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-4-(三氟甲基)苯胺(4.97g，17.35mmol)、3-((6-溴-7-氯-4-(2-异丙基-6-甲基苯基)-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(5.0g，8.65mmol)、Pd(PPh 3) 2Cl 2(910mg,1.3mmol)和碳酸钾(3.6g，26mmol)分散在乙腈/水(5:1,36mL)中，将反应体系加热至70℃并搅拌1.5小时。反应完成后将体系降至室温并加入EA(100mL)和饱和食盐水(20mL)，分液后用EA(4*50mL)进行萃取，合并有机相，有机相以无水硫酸钠干燥，过滤并减压浓缩有机相，浓缩残余物用中压flash C18反相柱(洗脱剂：ACN:5mmol/L NH 4HCO 3水溶液＝20-80％)分离纯化，得到3-((6-(5-氨基-2-(三氟甲基)苯基)-7-氯-4-(2-异丙基-6-甲基苯基)-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(5.6g)，为黄色固体，收率98％。ESI-MS:601[M+H] +。 Under N 2 atmosphere, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl) Aniline (4.97g, 17.35mmol), 3-((6-bromo-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4- Dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (5.0g, 8.65mmol), Pd(PPh 3 ) 2 Cl 2 (910mg, 1.3mmol) And potassium carbonate (3.6 g, 26 mmol) were dispersed in acetonitrile/water (5:1, 36 mL), and the reaction system was heated to 70° C. and stirred for 1.5 hours. After the completion of the reaction, the system was cooled to room temperature and EA (100mL) and saturated brine (20mL) were added, and the liquids were separated and extracted with EA (4*50mL). The organic phases were combined, and the organic phases were dried with anhydrous sodium sulfate and filtered. The organic phase was concentrated under reduced pressure, and the concentrated residue was separated and purified using a medium-pressure flash C18 reverse phase column (eluent: ACN: 5mmol/L NH 4 HCO 3 aqueous solution = 20-80%) to obtain 3-((6-(5 -Amino-2-(trifluoromethyl)phenyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydro Quinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (5.6g) is a yellow solid with a yield of 98%. ESI-MS: 601[M+H] + .
第三步third step
将3-((6-(5-氨基-2-(三氟甲基)苯基)-7-氯-4-(2-异丙基-6-甲基苯基)-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(5.6g，8.52mmol)溶解在二氯甲烷(100mL)中，在室温下缓慢滴加三氟乙酸(8.5mL)，搅拌反应1小时。然后减压浓缩得到6-(5-氨基-2-(三氟甲基)苯基)-1-(氮杂环丁烷-3-基甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(4.7g)，为黄色固体，收率100％。ESI-MS:572[M+H] +。 Add 3-((6-(5-amino-2-(trifluoromethyl)phenyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-di Oxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (5.6g, 8.52mmol) was dissolved in dichloromethane (100mL) In the medium, trifluoroacetic acid (8.5 mL) was slowly added dropwise at room temperature, and the reaction was stirred for 1 hour. Then concentrated under reduced pressure to obtain 6-(5-amino-2-(trifluoromethyl)phenyl)-1-(azetidine-3-ylmethyl)-7-chloro-4-(2-iso Propyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (4.7g), as a yellow solid, with a yield of 100%. ESI-MS: 572[M+H] + .
第四步the fourth step
在N 2氛围下，将6-(5-氨基-2-(三氟甲基)苯基)-1-(氮杂环丁烷-3-基甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(4.7g，8.52mmol)溶解在二氯甲烷(120mL)中，往其中加入三乙胺(8.7g,86.1mmol)，反应体系冷却至-78℃后，将丙烯酰氯(639mg，7.02mmol)的二氯甲烷(20mL)溶液缓慢滴加到体系中，并于-78℃搅拌0.5小时。反应完成后减压浓缩反应液，浓缩物经中压flash硅胶柱层析(洗脱剂：MeOH：DCM＝0-10％)分离纯化，然后再用中压flash C18反相柱(洗脱剂：ACN:5mmol/L NH 4HCO 3＝10-70％)分离纯化，冻干得产物1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-(5-氨基-2-(三氟甲基)苯基)-7-氯-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(2.8g)。 Under N 2 atmosphere, 6-(5-amino-2-(trifluoromethyl)phenyl)-1-(azetidin-3-ylmethyl)-7-chloro-4-(2 -Isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (4.7g, 8.52mmol) was dissolved in dichloromethane (120mL), and three Ethylamine (8.7g, 86.1mmol), after the reaction system was cooled to -78℃, a solution of acryloyl chloride (639mg, 7.02mmol) in dichloromethane (20mL) was slowly added dropwise to the system, and stirred at -78℃ for 0.5 Hour. After the completion of the reaction, the reaction solution was concentrated under reduced pressure. The concentrate was separated and purified by medium-pressure flash silica gel column chromatography (eluent: MeOH:DCM=0-10%), and then used on a medium-pressure flash C18 reversed-phase column (eluent ：ACN: 5mmol/L NH 4 HCO 3 ＝10-70%) was separated and purified, and lyophilized to obtain the product 1-((1-acryloylazetidin-3-yl)methyl)-6-(5- Amino-2-(trifluoromethyl)phenyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-di Ketone (2.8g).
ESI-MS:611[M+H] +。 ESI-MS: 611[M+H] + .
1H NMR(400MHz,DMSO-d6)δ7.86(d,J＝2.0Hz,1H),7.41～7.36(m,2H),7.31(d,J＝8.8Hz,1H),7.27～7.24(m,1H),6.62～6.57(m,1H),6.38～6.31(m,1H),6.24～6.22(m,1H),6.12(dd,J＝16.8,2.4Hz,1H),6.06(d,J＝8.8Hz,1H),5.92(d,J＝8.8Hz,2H),5.68(dd,J＝10.4,2.4Hz,1H),4.62～4.52(m,2H),4.39～4.32(m,1H),4.19～4.15(m,1H),4.09～4.02(m,1H),3.91～3.86(m,1H),3.24～3.18(m,1H),2.70～2.60(m,1H),1.92(d,J＝15.2Hz,3H),1.04(dd,J＝15.6,6.8Hz,3H),0.97～0.93(m,3H). 1 H NMR(400MHz,DMSO-d6)δ7.86(d,J=2.0Hz,1H), 7.41～7.36(m,2H), 7.31(d,J=8.8Hz,1H), 7.27～7.24(m ,1H),6.62～6.57(m,1H),6.38～6.31(m,1H),6.24～6.22(m,1H),6.12(dd,J=16.8,2.4Hz,1H),6.06(d,J ＝8.8Hz,1H),5.92(d,J＝8.8Hz,2H), 5.68(dd,J＝10.4,2.4Hz,1H), 4.62～4.52(m,2H), 4.39～4.32(m,1H) ,4.19～4.15(m,1H),4.09～4.02(m,1H),3.91～3.86(m,1H),3.24～3.18(m,1H),2.70～2.60(m,1H),1.92(d, J＝15.2Hz,3H),1.04(dd,J＝15.6,6.8Hz,3H),0.97～0.93(m,3H).
第五步the fifth step
将实施例21化合物经手性HPLC拆分：CHIRALPAK IC-3(2*25cm；5um)；220nm检测；正己烷(0.1％二乙胺)/异丙醇；流速＝20.0mL/min。得到实施例21a(74mg)，和实施例21b(63mg).The compound of Example 21 was resolved by chiral HPLC: CHIRALPAK IC-3 (2*25cm; 5um); 220nm detection; n-hexane (0.1% diethylamine)/isopropanol; flow rate = 20.0 mL/min. Example 21a (74mg), and Example 21b (63mg) were obtained.
实施例21a： 1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.42～7.36(m,2H),7.31(d,J＝8.8Hz,1H),7.28～7.24(m,1H),6.62～6.57(m,1H),6.38～6.30(m,1H),6.24～6.22(m,1H),6.12(dd,J＝16.8,2.4Hz,1H),6.06(d,J＝8.8Hz,1H),5.92(d,J＝8.8Hz,2H),5.68(dd,J＝10.4,2.4Hz,1H),4.66～4.52(m,2H),4.41～4.32(m,1H),4.20～4.13(m,1H),4.10～4.00(m,1H),3.91～3.86(m,1H),3.26～3.17(m,1H),2.70～2.60(m,1H),1.92(d,J＝15.2Hz,3H),1.04(dd,J＝15.6,6.8Hz,3H),0.97～0.93(m,3H). Example 21a: 1 H NMR (400MHz, DMSO-d6) δ 7.86 (s, 1H), 7.42 ~ 7.36 (m, 2H), 7.31 (d, J = 8.8 Hz, 1H), 7.28 ~ 7.24 (m, 1H), 6.62～6.57(m,1H), 6.38～6.30(m,1H), 6.24～6.22(m,1H), 6.12(dd,J=16.8,2.4Hz,1H), 6.06(d,J= 8.8Hz, 1H), 5.92 (d, J = 8.8 Hz, 2H), 5.68 (dd, J = 10.4, 2.4 Hz, 1H), 4.66 ~ 4.52 (m, 2H), 4.41 ~ 4.32 (m, 1H), 4.20～4.13(m,1H), 4.10～4.00(m,1H), 3.91～3.86(m,1H), 3.26～3.17(m,1H), 2.70～2.60(m,1H), 1.92(d,J ＝15.2Hz,3H),1.04(dd,J＝15.6,6.8Hz,3H),0.97～0.93(m,3H).
实施例21b： 1H NMR(400MHz,DMSO-d6)δ7.86(s,1H),7.42～7.36(m,2H),7.31(d,J＝8.8Hz,1H),7.28～7.24(m,1H),6.63～6.57(m,1H),6.39～6.29(m,1H),6.25～6.21(m,1H),6.12(dd,J＝16.8,2.4Hz,1H),6.06(d,J＝8.8Hz,1H),5.92(d,J＝8.8Hz,2H),5.68(dd,J＝10.4,2.4Hz,1H),4.66～4.51(m,2H),4.40～4.32(m,1H),4.20～4.13(m,1H),4.10～4.00(m,1H),3.91～3.86(m,1H),3.26～3.17(m,1H),2.70～2.60(m,1H),1.92(d,J＝15.2Hz,3H),1.04(dd,J＝15.6,6.8Hz,3H),0.98～0.92(m,3H). Example 21b: 1 H NMR (400MHz, DMSO-d6) δ 7.86 (s, 1H), 7.42 ~ 7.36 (m, 2H), 7.31 (d, J = 8.8 Hz, 1H), 7.28 ~ 7.24 (m, 1H), 6.63 ~ 6.57 (m, 1H), 6.39 ~ 6.29 (m, 1H), 6.25 ~ 6.21 (m, 1H), 6.12 (dd, J = 16.8, 2.4 Hz, 1H), 6.06 (d, J = 8.8Hz, 1H), 5.92 (d, J = 8.8 Hz, 2H), 5.68 (dd, J = 10.4, 2.4 Hz, 1H), 4.66 ~ 4.51 (m, 2H), 4.40 ~ 4.32 (m, 1H), 4.20～4.13(m,1H), 4.10～4.00(m,1H), 3.91～3.86(m,1H), 3.26～3.17(m,1H), 2.70～2.60(m,1H), 1.92(d,J ＝15.2Hz,3H),1.04(dd,J＝15.6,6.8Hz,3H),0.98～0.92(m,3H).
实施例22：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(3-氯-2-氟-6-羟基苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮的制备Example 22: 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(3-chloro-2-fluoro-6-hydroxyphenyl)-4- Preparation of (2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTCN2021091100-appb-000174
Figure PCTCN2021091100-appb-000174
第一步first step
在氮气氛围下，将1-氯-2-氟-4-甲氧基苯(5g,31mmol)溶解于干燥四氢呋喃(30mL)中，体系温度降至-78℃后，将正丁基锂(15ml,37.5mmol,2.5mol/L正己烷溶液)缓缓滴入到反应液中，反应温度控制在-60℃以下反应2小时。将碘单质(10.4g,40mmol)溶解于四氢呋喃(20mL)并置于滴液漏斗中缓慢滴入到反应体系中，温度控制在-60℃以下，待滴加完毕后，任其自然升温至0℃，反应在0℃下继续反应1小时。反应完成后加入饱和硫代硫酸钠水溶液淬灭体系，以乙酸乙酯萃取三次，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，有机相减压浓缩，浓缩物经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝20:1)分离纯化，得到1-氯-2-氟-3-碘-4-甲氧基苯(4.6g)，为淡黄色固体，收率52％。ESI-MS:287[M+H] +。 Under a nitrogen atmosphere, dissolve 1-chloro-2-fluoro-4-methoxybenzene (5g, 31mmol) in dry tetrahydrofuran (30mL). After the temperature of the system drops to -78°C, the n-butyllithium (15ml , 37.5mmol, 2.5mol/L n-hexane solution) was slowly dropped into the reaction solution, the reaction temperature was controlled below -60 ℃ for 2 hours. The elemental iodine (10.4g, 40mmol) was dissolved in tetrahydrofuran (20mL) and placed in a dropping funnel and slowly dripped into the reaction system. The temperature was controlled below -60°C. After the addition was completed, it was allowed to naturally heat up to 0. At 0°C, the reaction was continued for 1 hour at 0°C. After the completion of the reaction, the system was quenched by adding saturated aqueous sodium thiosulfate solution, extracted three times with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography ( Eluent: petroleum ether: ethyl acetate = 20:1) separation and purification to obtain 1-chloro-2-fluoro-3-iodo-4-methoxybenzene (4.6g) as a pale yellow solid, yield 52 %. ESI-MS: 287[M+H] + .
第二步Second step
在N 2氛围下，将1-氯-2-氟-3-碘-4-甲氧基苯(4.98g，17.35mmol)、3-((7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(5.0g，17.35mmol)、Pd(PPh 3) 2Cl 2(910mg,1.3mmol)和碳酸钾(3.59g，26mmol)分散在乙腈/水(5:1,36mL)中，将反应体系加热至70℃并搅拌反应1.5小时。反应完成后降至室温，加入EA(100mL)和饱和食盐水(20mL)，分液后用EA(4*50mL)进行萃取，合并有机相，以无水硫酸钠干燥，过滤，有机相减压浓缩除溶剂，浓缩残余物用中压flash C18反相柱(洗脱剂：ACN:5mmol/L NH 4HCO 3水溶液＝20-80％)分离纯化，得到3-((7-氯-6-(3-氯-2-氟-6-甲氧基苯基)-4-(2-异丙基-6-甲基苯基)-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5.6g，为黄色固体，收率(98％)。ESI-MS:601[M+H] +。 Under N 2 atmosphere, 1-chloro-2-fluoro-3-iodo-4-methoxybenzene (4.98g, 17.35mmol), 3-((7-chloro-4-(2-isopropyl- 6-methylphenyl)-2,3-dioxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,4-Dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (5.0g, 17.35mmol), Pd(PPh 3 ) 2 Cl 2 ( 910 mg, 1.3 mmol) and potassium carbonate (3.59 g, 26 mmol) were dispersed in acetonitrile/water (5:1, 36 mL), and the reaction system was heated to 70° C. and stirred for 1.5 hours. After the reaction was completed, the temperature was lowered to room temperature, EA (100 mL) and saturated brine (20 mL) were added, and the layers were separated and extracted with EA (4*50 mL). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the organic phase was decompressed Concentrate to remove the solvent. The concentrated residue is separated and purified using a medium-pressure flash C18 reversed-phase column (eluent: ACN: 5mmol/L NH 4 HCO 3 aqueous solution = 20-80%) to obtain 3-((7-chloro-6- (3-chloro-2-fluoro-6-methoxyphenyl)-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquine 5.6 g of tert-butyl oxaline-1(2H)-yl)methyl)azetidine-1-carboxylate was a yellow solid, the yield was (98%). ESI-MS: 601[M+H] + .
第三步third step
将3-((7-氯-6-(3-氯-2-氟-6-甲氧基苯基)-4-(2-异丙基-6-甲基苯基)-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(300mg，0.46mmol)溶解在二氯甲烷(10mL)中，在室温下缓慢滴加三氟乙酸(0.5mL)，搅拌反应1小时。然后减压浓缩得到1-(氮杂环丁烷-3-基甲基)-7-氯-6-(3-氯-2-氟-6-甲氧基苯 基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(254mg)，为黄色固体，收率100％。ESI-MS:556[M+H] +。 Add 3-((7-chloro-6-(3-chloro-2-fluoro-6-methoxyphenyl)-4-(2-isopropyl-6-methylphenyl)-2,3- Dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (300mg, 0.46mmol) dissolved in dichloromethane (10mL) In the medium, trifluoroacetic acid (0.5 mL) was slowly added dropwise at room temperature, and the reaction was stirred for 1 hour. Then concentrated under reduced pressure to obtain 1-(azetidine-3-ylmethyl)-7-chloro-6-(3-chloro-2-fluoro-6-methoxyphenyl)-4-(2- Isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (254mg), as a yellow solid, with a yield of 100%. ESI-MS: 556[M+H] + .
第四步the fourth step
在N 2氛围下，将1-(氮杂环丁烷-3-基甲基)-7-氯-6-(3-氯-2-氟-6-甲氧基苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(254mg，0.46mmol)溶解在二氯甲烷(10mL)中，加入三乙胺(461mg,4.56mmol)，反应体系冷却至-78℃后，将丙烯酰氯(37mg，0.41mmol)的二氯甲烷(5mL)溶液缓慢滴加到体系中，并于-78℃搅拌反应0.5小时。反应完成后减压浓缩除去溶剂，浓缩物经中压flash硅胶柱层析(洗脱剂：EA：PE＝0-100％)分离纯化，得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(3-氯-2-氟-6-甲氧基苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮208mg，为白色固体，收率75％。ESI-MS:610[M+H] +。 Under N 2 atmosphere, the 1-(azetidin-3-ylmethyl)-7-chloro-6-(3-chloro-2-fluoro-6-methoxyphenyl)-4-( 2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (254mg, 0.46mmol) was dissolved in dichloromethane (10mL), and triethylamine was added After the reaction system was cooled to -78°C (461mg, 4.56mmol), a solution of acryloyl chloride (37mg, 0.41mmol) in dichloromethane (5mL) was slowly added dropwise to the system, and the reaction was stirred at -78°C for 0.5 hours. After the reaction is completed, the solvent is removed by concentration under reduced pressure. The concentrate is separated and purified by medium-pressure flash silica gel column chromatography (eluent: EA: PE=0-100%) to obtain 1-((1-acryloylazetidine) -3-yl)methyl)-7-chloro-6-(3-chloro-2-fluoro-6-methoxyphenyl)-4-(2-isopropyl-6-methylphenyl)- 208 mg of 1,4-dihydroquinoxaline-2,3-dione is a white solid with a yield of 75%. ESI-MS: 610[M+H] + .
第五步the fifth step
将1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(3-氯-2-氟-6-甲氧基苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(100mg，0.16mmol)溶解于二氯甲烷(5mL)中，在N 2氛围下降温至-78℃，在此温度下滴加BBr 3(1.0mL，1.00mmol)，滴加完毕后缓慢升至室温，在室温下搅拌2小时。反应完成后体系降温至0℃，加入EA(20mL)稀释，将稀释液缓慢滴加入0℃的饱和NaHCO 3溶液中，EA萃取后合并有机相，有机相经无水硫酸钠干燥，过滤，减压浓缩滤液，浓缩残余物经高压制备色谱分离纯化，冷冻干燥得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-7-氯-6-(3-氯-2-氟-6-羟基苯基)-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(9.39mg)，为白色固体，收率10％。 Add 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(3-chloro-2-fluoro-6-methoxyphenyl)-4-( 2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (100mg, 0.16mmol) was dissolved in dichloromethane (5mL) under N 2 atmosphere The temperature was lowered to -78°C, BBr 3 (1.0 mL, 1.00 mmol) was added dropwise at this temperature, and after the addition, the temperature was slowly raised to room temperature, and the mixture was stirred at room temperature for 2 hours. After the completion of the reaction, the system was cooled to 0°C, added EA (20mL) to dilute, and the diluted solution was slowly added dropwise to a saturated NaHCO 3 solution at 0°C. After EA extraction, the organic phases were combined, and the organic phases were dried over anhydrous sodium sulfate, filtered, and reduced. The filtrate was concentrated by pressure, the concentrated residue was separated and purified by high-pressure preparative chromatography, and freeze-dried to obtain 1-((1-acryloylazetidin-3-yl)methyl)-7-chloro-6-(3-chloro- 2-Fluoro-6-hydroxyphenyl)-4-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (9.39mg), White solid, yield 10%.
ESI-MS:596[M+H] +。 ESI-MS: 596[M+H] + .
1H NMR(400MHz,DMSO-d6)δ10.25(brs,1H),7.91(s,1H),7.43～7.38(m,2H),7.34(t,J＝8.8Hz,1H),7.27～7.25(m,1H),6.71(d,J＝8.8Hz,1H),6.39～6.31(m,1H),6.14～6.10(m,2H),5.68(dd,J＝10.4,2.4Hz,1H),4.63～4.51(m,2H),4.36(q,J＝8.4Hz,1H),4.20～4.16(m,1H),4.06(q,J＝8.4Hz,1H),3.89(dd,J＝10.4,5.6Hz,1H),3.25～3.22(m,1H),2.68～2.64(m,1H),1.95(d,J＝12.4Hz,3H),1.08–0.91(m,6H). 1 H NMR(400MHz,DMSO-d6)δ10.25(brs,1H),7.91(s,1H),7.43～7.38(m,2H),7.34(t,J=8.8Hz,1H),7.27～7.25 (m, 1H), 6.71 (d, J = 8.8 Hz, 1H), 6.39 ~ 6.31 (m, 1H), 6.14 ~ 6.10 (m, 2H), 5.68 (dd, J = 10.4, 2.4 Hz, 1H), 4.63～4.51(m,2H), 4.36(q,J=8.4Hz,1H), 4.20～4.16(m,1H), 4.06(q,J=8.4Hz,1H), 3.89(dd,J=10.4, 5.6Hz,1H), 3.25～3.22(m,1H), 2.68～2.64(m,1H), 1.95(d,J=12.4Hz,3H), 1.08–0.91(m,6H).
实施例23：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-(6-氨基-4-甲基-3-(三氟甲基)吡啶-2-基)-7-氯-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮的制备Example 23: 1-((1-acryloylazetidin-3-yl)methyl)-6-(6-amino-4-methyl-3-(trifluoromethyl)pyridine-2- Yl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione
Figure PCTCN2021091100-appb-000175
Figure PCTCN2021091100-appb-000175
第一步first step
将6-氯-4-甲基吡啶-2-胺(1.5g，10.6mmol)溶解在乙腈(15mL)中，加入NIS(2.4g，10.6mmol)，在25℃下搅拌2h。反应结束后加入饱和硫代硫酸钠溶液(20mL)淬灭反应，用二氯甲烷(20mL)萃取三次，合并有机相并以无水硫酸钠干燥，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＝3:1)分离纯化，得到6-氯-5-碘-4-甲基吡啶-2-胺(2.1g)，为白色固体，收率74％。ESI-MS:269[M+H] +。 6-Chloro-4-methylpyridin-2-amine (1.5 g, 10.6 mmol) was dissolved in acetonitrile (15 mL), NIS (2.4 g, 10.6 mmol) was added, and the mixture was stirred at 25° C. for 2 h. After the reaction was completed, saturated sodium thiosulfate solution (20 mL) was added to quench the reaction, extracted with dichloromethane (20 mL) three times, the organic phases were combined and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography (Eluent: petroleum ether: ethyl acetate = 3:1) separation and purification, 6-chloro-5-iodo-4-methylpyridine-2-amine (2.1g) was obtained as a white solid, the yield was 74% . ESI-MS: 269 [M+H] + .
第二步Second step
将6-氯-5-碘-4-甲基吡啶-2-胺(2.1g，7.8mmol)、碳酸钾(3.25g，23.5mmol)和PMBCl(2.43g,15.6mmol)溶解在DMF(20mL)中，加热至80℃并搅拌反应2h。反应结束后滤除固体，减压浓缩滤液，浓缩物经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝5:1)分离纯化，得到6-氯-5-碘-N,N-双(4-甲氧基苄基)-4-甲基吡啶-2-胺(3.5g)，为白色固体，收率88％。ESI-MS:509[M+H] +。 Dissolve 6-chloro-5-iodo-4-methylpyridin-2-amine (2.1g, 7.8mmol), potassium carbonate (3.25g, 23.5mmol) and PMBCl (2.43g, 15.6mmol) in DMF (20mL) In, heated to 80°C and stirred for 2h. After the reaction, the solid was filtered off, the filtrate was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5:1) to obtain 6-chloro-5-iodo-N,N -Bis(4-methoxybenzyl)-4-methylpyridin-2-amine (3.5g), white solid, yield 88%. ESI-MS: 509[M+H] + .
第三步third step
将6-氯-5-碘-N,N-双(4-甲氧基苄基)-4-甲基吡啶-2-胺(3.5g，6.9mmol)、碘化亚铜(2.62g，13.8mmol)和2,2-二氟-2-(氟磺酰基)乙酸甲酯(2.65g,13.8mmol)溶解在DMF(20mL)中，在氮气气氛下加热至90℃并搅拌反应2h。反应结束后，将反应液冷却到室温，用水(100mL)稀释，再用乙酸乙酯(3*100mL)萃取。合并有机相，经饱和食盐水(3*200mL)洗涤，无水硫酸钠干燥，过滤，然后减压浓缩滤液，浓缩残余物经硅胶柱层析(洗脱剂：石油醚：乙酸乙酯＝5:1)分离纯化，得到6-氯-N,N-双(4-甲氧基苄基)-4-甲基-5-(三氟甲基)吡啶-2-胺(2.5g)，为白色固体，收率80.6％。ESI-MS:451[M+H] +。 Combine 6-chloro-5-iodo-N,N-bis(4-methoxybenzyl)-4-methylpyridine-2-amine (3.5g, 6.9mmol), cuprous iodide (2.62g, 13.8 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.65 g, 13.8 mmol) were dissolved in DMF (20 mL), heated to 90° C. under a nitrogen atmosphere, and stirred for reaction for 2 h. After the reaction, the reaction solution was cooled to room temperature, diluted with water (100 mL), and extracted with ethyl acetate (3*100 mL). The organic phases were combined, washed with saturated brine (3*200 mL), dried over anhydrous sodium sulfate, filtered, and then the filtrate was concentrated under reduced pressure. The concentrated residue was subjected to silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 5 1) Separation and purification to obtain 6-chloro-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine (2.5g) as White solid, the yield is 80.6%. ESI-MS: 451[M+H] + .
第四步the fourth step
在氮气气氛下，将3-((7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊 烷-2-基)-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(623mg,1mmol)、6-氯-N,N-双(4-甲氧基苄基)-4-甲基-5-(三氟甲基)吡啶-2-胺(600mg,1.1mmol)、Pd(PPh 3)Cl 2(70.2mg,0.1mmol)和碳酸钾(414mg,3mmol)溶解在乙腈(10mL)和水(2mL)的混合溶液中，反应在80℃下搅拌3h。反应结束后，将反应液冷却到室温，再用乙酸乙酯萃取三次，合并有机相并经饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，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-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-7-氯-4-(2-异丙基-6-甲基苯基)-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(300mg)，为白色固体，收率32.9％。ESI-MS:912[M+H] +。 Under a nitrogen atmosphere, 3-((7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-6-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine- Tert-Butyl 1-formate (623mg, 1mmol), 6-chloro-N,N-bis(4-methoxybenzyl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine ( 600mg, 1.1mmol), Pd(PPh 3 )Cl 2 (70.2mg, 0.1mmol) and potassium carbonate (414mg, 3mmol) were dissolved in a mixed solution of acetonitrile (10mL) and water (2mL), and the reaction was stirred at 80℃ 3h. After the reaction, the reaction solution was cooled to room temperature and extracted three times with ethyl acetate. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the concentrated residue was subjected to silica gel column chromatography. (Eluent: petroleum ether: ethyl acetate = 1:1) separation and purification to obtain 3-((6-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3- (Trifluoromethyl)pyridin-2-yl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxa Tert-butyl lin-1(2H)-yl)methyl)azetidine-1-carboxylate (300 mg), a white solid, with a yield of 32.9%. ESI-MS: 912[M+H] + .
第五步the fifth step
将3-((6-(6-(双(4-甲氧基苄基)氨基)-4-甲基-3-(三氟甲基)吡啶-2-基)-7-氯-4-(2-异丙基-6-甲基苯基)-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(300mg,0.32mmol)溶解在三氟乙酸(5mL)中，反应在50℃搅拌2h。反应结束后，浓缩反应液，浓缩残余物用Prep-HPLC(洗脱剂：乙腈:水(10mM NH 4HCO 3)＝35％～60％)分离纯化，得到6-(6-氨基-4-甲基-3-(三氟甲基)吡啶-2-基)-1-(氮杂环丁烷-3-基甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(70mg)，为白色固体，收率38.2％。ESI-MS:572[M+H] +。 Add 3-((6-(6-(bis(4-methoxybenzyl)amino)-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-7-chloro-4- (2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1 -Tert-butyl formate (300mg, 0.32mmol) was dissolved in trifluoroacetic acid (5mL), and the reaction was stirred at 50°C for 2h. After the reaction, the reaction solution was concentrated, and the concentrated residue was separated and purified by Prep-HPLC (eluent: acetonitrile: water (10mM NH 4 HCO 3 ) = 35% to 60%) to obtain 6-(6-amino-4- Methyl-3-(trifluoromethyl)pyridin-2-yl)-1-(azetidine-3-ylmethyl)-7-chloro-4-(2-isopropyl-6-methyl) (Phenyl)-1,4-dihydroquinoxaline-2,3-dione (70 mg), as a white solid, with a yield of 38.2%. ESI-MS: 572[M+H] + .
第六步Sixth step
将6-(6-氨基-4-甲基-3-(三氟甲基)吡啶-2-基)-1-(氮杂环丁烷-3-基甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(70mg，0.12mmol)溶解在二氯甲烷(5mL)中，加入三乙胺(36.3mg，0.36mmol)，在氮气保护和-78℃条件下，缓慢滴加丙烯酰氯(10.8mg，0.12mmol)的二氯甲烷溶液(2mL)，在-78℃继续搅拌10分钟。反应完成后减压浓缩反应液，浓缩物经硅胶柱层析(洗脱剂：二氯甲烷:甲醇＝20:1)分离纯化，得到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-(6-氨基-4-甲基-3-(三氟甲基)吡啶-2-基)-7-氯-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(40mg)，为白色固体，收率53.2％。ESI-MS:626[M+H] +。 Add 6-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-1-(azetidine-3-ylmethyl)-7-chloro-4- (2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (70mg, 0.12mmol) was dissolved in dichloromethane (5mL), and triethyl was added Amine (36.3mg, 0.36mmol), under nitrogen protection and -78°C, slowly add acryloyl chloride (10.8mg, 0.12mmol) in dichloromethane (2mL) dropwise, and continue stirring at -78°C for 10 minutes. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the concentrate was separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol = 20:1) to obtain 1-((1-acryloylazetidine-3) -Yl)methyl)-6-(6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl)-7-chloro-4-(2-isopropyl-6-methyl (Phenylphenyl)-1,4-dihydroquinoxaline-2,3-dione (40mg), white solid, yield 53.2%. ESI-MS: 626[M+H] + .
第七步Seventh step
将实施例23化合物经手性HPLC拆分：CHIRALPAK IC-3(2*25cm；5um)；220nm检测；正己烷(0.1％二乙胺)/异丙醇；流速＝20.0mL/min。得到实施例23a和实施例23b.The compound of Example 23 was resolved by chiral HPLC: CHIRALPAK IC-3 (2*25cm; 5um); 220nm detection; n-hexane (0.1% diethylamine)/isopropanol; flow rate = 20.0 mL/min. Obtain Example 23a and Example 23b.
实施例23a: 1H NMR(400MHz,DMSO-d6)δ7.84(d,J＝5.6Hz,1H),7.43-7.37(m,2H),7.29-7.25(m,1H),6.75(s,1H),6.66(s,1H),6.38-6.30(m,2H),6.11(d,J＝17.0Hz,1H),6.01(s,1H),5.70-5.60(m,1H),4.66-4.52(m,2H),4.39-4.30(m,1H),4.18-4.11(m,1H),4.08-4.00(m,1H),3.91–3.80(m,1H),3.25-3.15(m,1H),2.66-2.55(m,1H),2.25(s,3H),1.91(d,J＝16.2Hz,3H),1.07-0.94(m,6H). Example 23a: 1 H NMR (400MHz, DMSO-d6) δ 7.84 (d, J = 5.6 Hz, 1H), 7.43-7.37 (m, 2H), 7.29-7.25 (m, 1H), 6.75 (s, 1H),6.66(s,1H),6.38-6.30(m,2H),6.11(d,J=17.0Hz,1H),6.01(s,1H),5.70-5.60(m,1H),4.66-4.52 (m, 2H), 4.39-4.30 (m, 1H), 4.18-4.11 (m, 1H), 4.08-4.00 (m, 1H), 3.91-3.80 (m, 1H), 3.25-3.15 (m, 1H) ,2.66-2.55(m,1H),2.25(s,3H),1.91(d,J=16.2Hz,3H),1.07-0.94(m,6H).
实施例23b: 1H NMR(400MHz,DMSO-d6)δ7.84(d,J＝5.7Hz,1H),7.43-7.37(m,2H),7.31-7.23(m,1H),6.75(s,1H),6.66(s,1H),6.39–6.28(m,2H),6.16-6.08(m,1H),6.01(s,1H),5.70-5.66(m,1H),4.65-4.52(m,2H),4.38-4.31(m,1H),4.18-4.11(m,1H),4.08-4.00(m,1H),3.90-3.80(m,1H),3.25-3.13(m,1H),2.69-2.56(m,1H),2.25(s,3H),1.91(d,J＝16.2Hz,3H),1.08-0.94(m,6H)。 Example 23b: 1 H NMR (400MHz, DMSO-d6) δ 7.84 (d, J = 5.7 Hz, 1H), 7.43-7.37 (m, 2H), 7.31-7.23 (m, 1H), 6.75 (s, 1H), 6.66(s, 1H), 6.39--6.28(m, 2H), 6.16-6.08(m, 1H), 6.01(s, 1H), 5.70-5.66(m, 1H), 4.65-4.52(m, 2H), 4.38-4.31(m,1H), 4.18-4.11(m,1H), 4.08-4.00(m,1H), 3.90-3.80(m,1H), 3.25-3.13(m,1H), 2.69- 2.56 (m, 1H), 2.25 (s, 3H), 1.91 (d, J=16.2 Hz, 3H), 1.08-0.94 (m, 6H).
实施例24：1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-(2-氨基-6-氟苯基)-7-氯-4-(2-异丙基-6-甲基苯基)喹喔啉-2,3(1H,4H)-二酮的制备Example 24: 1-((1-acryloylazetidin-3-yl)methyl)-6-(2-amino-6-fluorophenyl)-7-chloro-4-(2-iso Preparation of propyl-6-methylphenyl)quinoxaline-2,3(1H,4H)-dione
Figure PCTCN2021091100-appb-000176
Figure PCTCN2021091100-appb-000176
第一步first step
将3-((6-溴-7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-3,4-二氢喹喔啉-1(H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(1.2g，2.02mmol)溶解在1,4-二氧六环(20mL)中，依次加入乙酸钾(594mg，6.06mmol)、联硼酸频那醇酯(608mg，2.14mmol)和Pd(dppf)Cl 2(292mg，0.40mmol)，在氮气保护下加热至80℃，搅拌1小时。反应液冷却后过滤，滤液减压浓缩，将浓缩物用硅胶柱层析(石油醚：乙酸乙酯＝2:1)分离纯化，得到3-((7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(600mg)，为白色固体，收率48％。ESI-MS:624[M+H] +。 Add 3-((6-bromo-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline-1( H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (1.2g, 2.02mmol) was dissolved in 1,4-dioxane (20mL), and potassium acetate (594mg, 6.06 mmol), pinacol diborate (608 mg, 2.14 mmol) and Pd(dppf)Cl 2 (292 mg, 0.40 mmol), heated to 80° C. under the protection of nitrogen, 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 (petroleum ether: ethyl acetate = 2:1) to obtain 3-((7-chloro-4-(2-isopropyl) Yl-6-methylphenyl)-2,3-dioxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-3,4-Dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (600mg), a white solid, with a yield of 48%. ESI-MS: 624[M+H] + .
第二步Second step
将3-((7-氯-4-(2-异丙基-6-甲基苯基)-2,3-二氧代-6-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,4-二氢喹喔啉-1(2H)-基)甲基)氮杂环丁烷-1-甲酸叔丁酯(500mg，0.80mmol)溶解在1,4-二氧六环(5mL)和水(1mL)中，加入碳酸钾(331mg，2.40mmol)、2-溴-3-氟苯胺(182mg，0.96mmol)和Pd(PPh 3) 2Cl 2(116mg，0.16mmol)，氮气保护下加热至80℃并搅拌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＝25:1)分离纯化，得到3-((6-(2-氨基-6-氟苯基)-7-氯-4-(2-异丙基-6-甲基苯基)-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(100mg)，为白色固体，收率21％。ESI-MS:607[M+H] +。 Add 3-((7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-6-(4,4,5,5-tetramethyl-1 ,3,2-Dioxaborolan-2-yl)-3,4-dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (500mg, 0.80mmol) was dissolved in 1,4-dioxane (5mL) and water (1mL), potassium carbonate (331mg, 2.40mmol), 2-bromo-3-fluoroaniline (182mg, 0.96mmol) were added And Pd(PPh 3 ) 2 Cl 2 (116 mg, 0.16 mmol), heated to 80° C. and stirred for 1 hour under the protection of nitrogen. 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 = 25:1) to obtain 3-((6-(2-amino-6- (Fluorophenyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3,4-dihydroquinoxaline-1(2H)-yl )Methyl)azetidine-1-carboxylic acid tert-butyl ester (100mg), white solid, yield 21%. ESI-MS: 607[M+H] + .
第三步third step
将3-((6-(2-氨基-6-氟苯基)-7-氯-4-(2-异丙基-6-甲基苯基)-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(100mg,0.16mmol)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6-(2-氨基-6-氟苯基)-1-(氮杂环丁烷-3-基甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(70mg)，为白色固体，收率86％。ESI-MS:507[M+H] +。 Add 3-((6-(2-amino-6-fluorophenyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)-2,3-dioxo-3, 4-Dihydroquinoxaline-1(2H)-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester (100mg, 0.16mmol) 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 6-(2-amino-6-fluorophenyl)-1-(azetidin-3-ylmethyl)-7-chloro- 4-(2-isopropyl-6-methylphenyl)-1,4-dihydroquinoxaline-2,3-dione (70 mg) was a white solid with a yield of 86%. ESI-MS: 507[M+H] + .
第四步the fourth step
将6-(2-氨基-6-氟苯基)-1-(氮杂环丁烷-3-基甲基)-7-氯-4-(2-异丙基-6-甲基苯基)-1,4-二氢喹喔啉-2,3-二酮(70mg，0.14mmol)溶解在二氯甲烷(10mL)中，加入三乙胺(42mg，0.42mmol)，在氮气保护和-78℃条件下，缓慢滴加丙烯酰氯(15mg，0.17mmol)的二氯甲烷溶液(0.5mL)，在-78℃搅拌反应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)＝35％～60％)分离纯化，得 到1-((1-丙烯酰基氮杂环丁烷-3-基)甲基)-6-(2-氨基-6-氟苯基)-7-氯-4-(2-异丙基-6-甲基苯基)喹喔啉-2,3(1H,4H)-二酮(12mg)，为白色固体，收率16％。 Add 6-(2-amino-6-fluorophenyl)-1-(azetidine-3-ylmethyl)-7-chloro-4-(2-isopropyl-6-methylphenyl) )-1,4-Dihydroquinoxaline-2,3-dione (70mg, 0.14mmol) was dissolved in dichloromethane (10mL), triethylamine (42mg, 0.42mmol) was added, and under nitrogen protection and- At 78°C, a dichloromethane solution (0.5 mL) of acryloyl chloride (15 mg, 0.17 mmol) was slowly added dropwise, 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 separated and purified by prep-HPLC (eluent: acetonitrile: water (10mM NH 4 HCO 3 ) = 35% to 60%) to obtain 1-((1-acryloyl) Azetidine-3-yl)methyl)-6-(2-amino-6-fluorophenyl)-7-chloro-4-(2-isopropyl-6-methylphenyl)quinoxaline Morino-2,3(1H,4H)-dione (12mg), a white solid, with a yield of 16%.
ESI-MS:561[M+H] +。 ESI-MS: 561[M+H] + .
1H NMR(400MHz,DMSO-d 6)δ7.88(s,1H),7.46–7.37(m,2H),7.28(dd,J＝5.9,3.2Hz,1H),6.87(t,J＝9.2Hz,1H),6.53(ddd,J＝8.8,4.2,2.8Hz,1H),6.34(ddd,J＝17.1,10.3,2.5Hz,1H),6.25(dd,J＝6.3,2.8Hz,1H),6.16–6.07(m,2H),5.68(dd,J＝10.3,2.3Hz,1H),5.07(brs,2H),4.67–4.48(m,2H),4.35(q,J＝8.5Hz,1H),4.17(m,1H),4.05(q,J＝8.8Hz,1H),3.88(dd,J＝10.2,5.6Hz,1H),3.27–3.19(m,1H),2.66(m,1H),1.95(s,3H),1.04(d,J＝6.7Hz,3H),0.98(d,J＝6.8Hz,3H). 1 H NMR(400MHz,DMSO-d 6 )δ7.88(s,1H),7.46-7.37(m,2H),7.28(dd,J=5.9,3.2Hz,1H), 6.87(t,J=9.2 Hz, 1H), 6.53 (ddd, J = 8.8, 4.2, 2.8 Hz, 1H), 6.34 (ddd, J = 17.1, 10.3, 2.5 Hz, 1H), 6.25 (dd, J = 6.3, 2.8 Hz, 1H) ,6.16-6.07(m,2H),5.68(dd,J=10.3,2.3Hz,1H),5.07(brs,2H),4.67-4.48(m,2H),4.35(q,J=8.5Hz,1H ), 4.17 (m, 1H), 4.05 (q, J = 8.8 Hz, 1H), 3.88 (dd, J = 10.2, 5.6 Hz, 1H), 3.27–3.19 (m, 1H), 2.66 (m, 1H) ,1.95(s,3H),1.04(d,J=6.7Hz,3H),0.98(d,J=6.8Hz,3H).
通过参考以上实施例24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 Example 24 above and using different reaction materials, the following example compounds were prepared:
Figure PCTCN2021091100-appb-000177
Figure PCTCN2021091100-appb-000177
Figure PCTCN2021091100-appb-000178
Figure PCTCN2021091100-appb-000178
Figure PCTCN2021091100-appb-000179
Figure PCTCN2021091100-appb-000179
Figure PCTCN2021091100-appb-000180
Figure PCTCN2021091100-appb-000180
Figure PCTCN2021091100-appb-000181
Figure PCTCN2021091100-appb-000181
部分化合物手性拆分条件Conditions for chiral resolution of some compounds
Figure PCTCN2021091100-appb-000182
Figure PCTCN2021091100-appb-000182
Figure PCTCN2021091100-appb-000183
Figure PCTCN2021091100-appb-000183
Figure PCTCN2021091100-appb-000184
Figure PCTCN2021091100-appb-000184
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5Example 5 18511851
实施例6Example 6 866.1866.1
实施例7Example 7 14.814.8
实施例8Example 8 ＞10000＞10000
实施例9Example 9 ＞10000＞10000
实施例10Example 10 ＞10000＞10000
实施例11Example 11 281.8281.8
实施例12Example 12 83.2283.22
实施例13Example 13 ＞10000＞10000
实施例14Example 14 363.3363.3
实施例15Example 15 27.3027.30
实施例15aExample 15a ＞1000＞1000
实施例15bExample 15b 11.4411.44
实施例15cExample 15c 410.5410.5
实施例16aExample 16a 130.1130.1
实施例16bExample 16b 100.5100.5
实施例17Example 17 ＞10000＞10000
实施例18Example 18 ＞1000＞1000
实施例19Example 19 347.1347.1
实施例20Example 20 ＞1000＞1000
实施例21Example 21 19.7619.76
实施例21aExample 21a 9.2429.242
实施例21bExample 21b 185.2185.2
实施例22Example 22 113.9113.9
实施例23Example 23 8.3848.384
实施例23aExample 23a 7.9817.981
实施例23bExample 23b 238.0238.0
实施例24Example 24 72.2272.22
实施例25Example 25 709.7709.7
实施例27aExample 27a 26.5826.58
实施例27bExample 27b 26932693
实施例29Example 29 459.1459.1
实施例30Example 30 6.3676.367
实施例30aExample 30a 5.8235.823
实施例30bExample 30b 164.3164.3
实施例31Example 31 7.6737.673
实施例31aExample 31a 2.192.19
实施例31bExample 31b 389389
实施例32Example 32 ＞1000＞1000
实施例33Example 33 138.2138.2
实施例34Example 34 8.3048.304
实施例36Example 36 242.1242.1
实施例37Example 37 ＞10000＞10000
实施例39Example 39 349.8349.8
实施例40Example 40 ＞1000＞1000
实施例41aExample 41a 63.3263.32
实施例41bExample 41b 42.5742.57
实施例41cExample 41c 43.3443.34
实施例41dExample 41d ＞10000＞10000
实施例42aExample 42a ＞1000＞1000
实施例42bExample 42b 12.8212.82
实施例43aExample 43a ＞10000＞10000
实施例43bExample 43b 9.7849.784
实施例44Example 44 168.2168.2
实施例47Example 47 ＞10000＞10000
实施例49Example 49 13.1513.15
实施例51Example 51 126.8126.8
实施例52Example 52 24.3124.31
实施例53Example 53 34.7034.70
实施例54aExample 54a 497.5497.5
实施例54bExample 54b ＞1000＞1000
实施例55aExample 55a 69.5369.53
实施例55bExample 55b ＞1000＞1000
实施例56aExample 56a 264.1264.1
实施例56bExample 56b ＞10000＞10000
实施例57Example 57 49.1549.15
实施例57aExample 57a ＞1000＞1000
实施例57bExample 57b 33.5333.53
实施例58Example 58 155.7155.7
实施例58aExample 58a 97.5797.57
实施例58bExample 58b ＞1000＞1000
实施例59Example 59 20.1920.19
实施例60Example 60 27.6127.61
实施例61Example 61 27.6327.63
实施例62aExample 62a ＞1000＞1000
实施例62bExample 62b 124.5124.5
实施例63Example 63 ＞1000＞1000
实施例64Example 64 101.8101.8
实施例65Example 65 ＞1000＞1000
实施例66Example 66 14.2614.26
实施例66aExample 66a 10.7310.73
实施例66bExample 66b ＞1000＞1000
实施例67Example 67 14.6214.62
实施例68Example 68 ＞1000＞1000
实施例69Example 69 234.4234.4
实施例70Example 70 319.7319.7
实施例71Example 71 194.0194.0
实施例72Example 72 144.9144.9
实施例73Example 73 ＞1000＞1000
实施例74Example 74 ＞1000＞1000
实施例75Example 75 12.9212.92
实施例75aExample 75a 5.4805.480
实施例75bExample 75b 392.8392.8
实施例76Example 76 28.9428.94
实施例77Example 77 18.6618.66
实施例78aExample 78a ＞1000＞1000
实施例78bExample 78b ＞1000＞1000
实施例79Example 79 289.3289.3
实施例80Example 80 209.9209.9
实施例81Example 81 29.2829.28
实施例82Example 82 102.2102.2
实施例83Example 83 ＞1000＞1000
实施例84Example 84 54.8254.82
实施例85Example 85 785.9785.9
实施例85aExample 85a ＞10000＞10000
实施例85bExample 85b 295.6295.6
实施例86Example 86 142.4142.4
实施例86aExample 86a ＞1000＞1000
实施例86bExample 86b 92.2692.26
实施例87Example 87 177.2177.2
实施例87aExample 87a 19.4319.43
实施例87bExample 87b ＞1000＞1000
实施例88Example 88 391.0391.0
实施例89Example 89 39.9439.94
实施例89aExample 89a 30.3930.39
实施例89bExample 89b ＞1000＞1000
实施例90Example 90 25.3325.33
实施例90aExample 90a ＞1000＞1000
实施例90bExample 90b ＞1000＞1000
实施例90cExample 90c 7.6337.633
实施例91Example 91 20.1120.11
实施例92Example 92 ＞1000＞1000
实施例93Example 93 531.7531.7
实施例94aExample 94a ＞1000＞1000
实施例94bExample 94b ＞1000＞1000
实施例95Example 95 ＞1000＞1000
实施例95aExample 95a 109.7109.7
实施例95bExample 95b ＞1000＞1000
实施例96aExample 96a 133.5133.5
实施例96bExample 96b 8.6068.606
实施例97Example 97 274.6274.6
实施例98Example 98 ＞1000＞1000
实施例99Example 99 45.1545.15
实施例100Example 100 43.0343.03
实施例102Example 102 69.0669.06
实施例103Example 103 7.0687.068
实施例104Example 104 206.3206.3
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-C4，2.1X50mm，3μmWaters Acquity I Class UPLC-Xevo G2-XS QTOF, Sepax Bio-C4, 2.1X50mm, 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 PCTCN2021091100-appb-000185
Figure PCTCN2021091100-appb-000185
LC的梯度时间表LC gradient schedule
Figure PCTCN2021091100-appb-000186
Figure PCTCN2021091100-appb-000186
TOF MS参数TOF MS parameters
Figure PCTCN2021091100-appb-000187
Figure PCTCN2021091100-appb-000187
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(％，5mins)POC (%, 5mins) POC(％，30mins)POC (%, 30mins)
实施例1Example 1 12.612.6 53.253.2
实施例2Example 2 36.736.7 85.685.6
实施例4Example 4 18.818.8 63.363.3
实施例5Example 5 55.255.2 90.790.7
实施例6Example 6 15.215.2 63.863.8
实施例7Example 7 65.465.4 90.790.7
实施例10Example 10 4.84.8 25.625.6
实施例11Example 11 65.365.3 91.491.4
实施例12Example 12 61.861.8 73.073.0
实施例13Example 13 6.96.9 33.633.6
实施例14Example 14 49.049.0 80.280.2
实施例15Example 15 71.471.4 79.979.9
实施例15bExample 15b 91.891.8 93.293.2
实施例16aExample 16a 64.364.3 90.890.8
实施例17Example 17 37.137.1 77.477.4
实施例18Example 18 64.364.3 82.582.5
实施例19Example 19 52.852.8 70.770.7
实施例20Example 20 49.349.3 78.578.5
实施例21Example 21 69.269.2 94.094.0
实施例21aExample 21a 93.493.4 94.894.8
实施例22Example 22 56.956.9 81.581.5
实施例23aExample 23a 79.279.2 94.394.3
实施例23bExample 23b 26.526.5 56.456.4
实施例24Example 24 46.346.3 75.275.2
实施例25Example 25 36.936.9 72.272.2
实施例26aExample 26a 28.628.6 40.340.3
实施例26bExample 26b 63.363.3 81.581.5
实施例27aExample 27a 82.382.3 83.183.1
实施例27bExample 27b 6.46.4 27.027.0
实施例29Example 29 55.355.3 78.678.6
实施例30Example 30 84.484.4 94.494.4
实施例30aExample 30a 89.989.9 90.990.9
实施例30bExample 30b 48.048.0 75.975.9
实施例31Example 31 88.388.3 95.895.8
实施例31aExample 31a 96.196.1 96.796.7
实施例31bExample 31b 49.749.7 88.688.6
实施例32Example 32 67.067.0 82.682.6
实施例33Example 33 57.157.1 81.681.6
实施例34Example 34 93.893.8 94.794.7
实施例36Example 36 42.242.2 70.870.8
实施例37Example 37 7.37.3 32.532.5
实施例38Example 38 12.312.3 48.948.9
实施例39Example 39 40.740.7 75.575.5
实施例40Example 40 52.152.1 89.589.5
实施例41aExample 41a 35.135.1 63.663.6
实施例41bExample 41b 59.059.0 75.975.9
实施例42aExample 42a 15.215.2 50.150.1
实施例42bExample 42b 70.270.2 85.085.0
实施例43aExample 43a 7.87.8 34.034.0
实施例43bExample 43b 83.483.4 87.287.2
实施例44Example 44 56.556.5 86.886.8
实施例46Example 46 18.618.6 51.751.7
实施例47Example 47 15.215.2 48.348.3
实施例48Example 48 23.523.5 46.246.2
实施例49Example 49 84.284.2 96.596.5
实施例50Example 50 36.036.0 61.961.9
实施例51Example 51 68.468.4 90.390.3
实施例52Example 52 79.379.3 92.792.7
实施例53Example 53 84.284.2 96.896.8
实施例54aExample 54a 56.056.0 89.389.3
实施例55aExample 55a 57.957.9 88.688.6
实施例56aExample 56a 55.255.2 87.587.5
实施例57bExample 57b 88.188.1 95.295.2
实施例58aExample 58a 73.473.4 90.290.2
实施例59Example 59 90.890.8 92.592.5
实施例60Example 60 57.057.0 74.974.9
实施例61Example 61 76.776.7 92.992.9
实施例62bExample 62b 65.065.0 76.976.9
实施例63Example 63 24.724.7 52.852.8
实施例64Example 64 55.755.7 79.279.2
实施例65Example 65 50.650.6 73.773.7
实施例66Example 66 76.276.2 87.587.5
实施例66aExample 66a 92.392.3 93.893.8
实施例67Example 67 70.370.3 80.780.7
实施例68Example 68 52.152.1 76.176.1
实施例69Example 69 40.340.3 73.573.5
实施例70Example 70 40.740.7 74.774.7
实施例71Example 71 42.842.8 84.684.6
实施例72Example 72 46.946.9 81.281.2
实施例73Example 73 55.755.7 82.582.5
实施例74Example 74 60.860.8 82.482.4
实施例75aExample 75a 96.096.0 96.596.5
实施例75bExample 75b 20.420.4 72.572.5
实施例76Example 76 96.196.1 96.896.8
实施例77Example 77 91.891.8 93.493.4
实施例78aExample 78a 4.54.5 32.932.9
实施例79Example 79 45.145.1 72.772.7
实施例80Example 80 43.143.1 82.082.0
实施例81Example 81 85.785.7 94.294.2
实施例81aExample 81a 93.993.9 95.395.3
实施例82aExample 82a 83.283.2 95.495.4
实施例83Example 83 35.235.2 63.963.9
实施例84Example 84 86.186.1 95.395.3
实施例84aExample 84a 93.893.8 95.495.4
实施例85Example 85 58.758.7 86.186.1
实施例85bExample 85b 61.461.4 95.295.2
实施例86Example 86 61.361.3 90.890.8
实施例86bExample 86b 88.988.9 95.995.9
实施例87Example 87 70.470.4 91.291.2
实施例87aExample 87a 92.492.4 93.193.1
实施例88Example 88 48.148.1 89.989.9
实施例89Example 89 78.078.0 93.093.0
实施例89aExample 89a 90.990.9 93.493.4
实施例90Example 90 49.449.4 86.486.4
实施例90bExample 90b 48.348.3 88.688.6
实施例90cExample 90c 94.894.8 95.695.6
实施例90dExample 90d 72.472.4 78.178.1
实施例91Example 91 65.465.4 82.882.8
实施例92Example 92 40.340.3 76.476.4
实施例93Example 93 56.456.4 79.079.0
实施例94aExample 94a 18.918.9 52.752.7
实施例95aExample 95a 85.385.3 95.695.6
实施例96aExample 96a 42.742.7 73.573.5
实施例96bExample 96b 94.294.2 95.195.1
实施例97Example 97 67.267.2 85.885.8
实施例97aExample 97a 66.566.5 94.694.6
实施例98Example 98 55.955.9 79.379.3
实施例99Example 99 67.867.8 94.394.3
实施例100Example 100 56.556.5 93.893.8
实施例102aExample 102a 89.689.6 93.493.4
实施例103Example 103 94.994.9 95.995.9
实施例104Example 104 87.187.1 92.392.3
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 (31)

  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 PCTCN2021091100-appb-100001
    Figure PCTCN2021091100-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 PCTCN2021091100-appb-100002
    R 1 is C 1-6 haloalkyl or
    Figure PCTCN2021091100-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 PCTCN2021091100-appb-100003
    为
    Figure PCTCN2021091100-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 PCTCN2021091100-appb-100003
    for
    Figure PCTCN2021091100-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 PCTCN2021091100-appb-100005
    为
    Figure PCTCN2021091100-appb-100006
    优选地为：
    Figure PCTCN2021091100-appb-100007
    Figure PCTCN2021091100-appb-100008
    Figure PCTCN2021091100-appb-100009
    优选
    Figure PCTCN2021091100-appb-100010
    Preferably,
    Figure PCTCN2021091100-appb-100005
    for
    Figure PCTCN2021091100-appb-100006
    Preferably:
    Figure PCTCN2021091100-appb-100007
    Figure PCTCN2021091100-appb-100008
    Figure PCTCN2021091100-appb-100009
    Preferred
    Figure PCTCN2021091100-appb-100010
  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 PCTCN2021091100-appb-100011
    Figure PCTCN2021091100-appb-100012
    优选地，L 1为
    Figure PCTCN2021091100-appb-100013
    Among them, L 1 is:
    Figure PCTCN2021091100-appb-100011
    Figure PCTCN2021091100-appb-100012
    Preferably, L 1 is
    Figure PCTCN2021091100-appb-100013
  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 PCTCN2021091100-appb-100014
    优选地，R 1为
    Figure PCTCN2021091100-appb-100015
    Where R 1 is
    Figure PCTCN2021091100-appb-100014
    Preferably, R 1 is
    Figure PCTCN2021091100-appb-100015
  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，R 7与-L 2-R 2形成＝Z；L 3为化学键、-CH 2-或-CH 2CH 2-。 Wherein, R 7 and -L 2 -R 2 form =Z; L 3 is a chemical bond, -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、苯基或5-6元杂芳基，优选
    Figure PCTCN2021091100-appb-100016
    Among them, R 2 or R 3 is H, -N(R 1a ) 2 , phenyl or 5-6 membered heteroaryl, preferably
    Figure PCTCN2021091100-appb-100016
    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 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 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 PCTCN2021091100-appb-100017
    Figure PCTCN2021091100-appb-100017
    Figure PCTCN2021091100-appb-100018
    Figure PCTCN2021091100-appb-100018
    其中，in,
    环B为苯基或5-6元杂芳基；Ring B is phenyl or 5-6 membered heteroaryl;
    各基团如权利要求1-8中任一项所定义。Each group is as defined in any one of claims 1-8.
  10. 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 PCTCN2021091100-appb-100019
    Figure PCTCN2021091100-appb-100019
    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 PCTCN2021091100-appb-100020
    R 1 is C 1-6 haloalkyl or
    Figure PCTCN2021091100-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 ;
    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 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p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
    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； 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1-7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 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.
  11. 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)或(III-1)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) or (III-1):
    Figure PCTCN2021091100-appb-100021
    Figure PCTCN2021091100-appb-100021
    其中，in,
    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； 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;
    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 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p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
    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烯基或C 2-6炔基； R L3 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 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5-10元杂芳基；其任选被1-7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 5-10 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烯基或C 2-6炔基； Wherein R 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 4为卤素； R 4 is halogen;
    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.
  12. 权利要求11的式(III)或(III-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 (III) or (III-1) of claim 11, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, Polymorphs, prodrugs or isotopic variants, and mixtures thereof, where
    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;
    L 3为化学键、-CH 2-或-CH 2CH 2-； L 3 is a chemical bond, -CH 2 -or -CH 2 CH 2 -;
    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5-10元杂芳基；其任选被1-5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 5-10 membered heteroaryl; it is optionally substituted by 1-5 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烯基或C 2-6炔基； Wherein R 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 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.
  13. 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)或(IV-1)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) or (IV-1):
    Figure PCTCN2021091100-appb-100022
    Figure PCTCN2021091100-appb-100022
    其中，in,
    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； 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;
    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 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p＝0、1、2、3或4；Where p=0, 1, 2, 3 or 4;
    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烯基或C 2-6炔基； R L3 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 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5-10元杂芳基；其任选被1-5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 5-10 membered heteroaryl; it is optionally substituted by 1-5 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烯基或C 2-6炔基； Wherein R 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 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.
  14. 权利要求13的式(IV)或(IV-1)化合物：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) or (IV-1) of claim 13: a compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate thereof Compounds, polymorphs, prodrugs or isotopic variants, and mixtures thereof, where
    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;
    L 3为化学键、-CH 2-或-CH 2CH 2-； L 3 is a chemical bond, -CH 2 -or -CH 2 CH 2 -;
    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、苯基或5-6元杂芳基；其任选被1-3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, phenyl or 5-6 membered heteroaryl; it is optionally substituted by 1-3 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烯基或C 2-6炔基； Wherein R 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 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.
  15. 式(V)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 (V), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof , And their mixtures:
    Figure PCTCN2021091100-appb-100023
    Figure PCTCN2021091100-appb-100023
    其中，in,
    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；其中所述C 1-6烷基或C 1-6卤代烷基任选被D、卤素、-CN、-O-R 1a、-S-R 1a或-N(R 1a) 2取代；优选地，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, -CN, C 1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl or C 1-6 haloalkyl group is optionally replaced by D, halo, -CN, -OR 1a, -SR 1a, or -N (R 1a) 2-substituted; preferably, R a, R b and R c are independently selected from H, D, halogen, or - CN;
    Q 1选自N或CR 3b； Q 1 is selected from N or CR 3b ;
    Q 2选自N或CR 3c； Q 2 is selected from N or CR 3c ;
    Q 3选自N或CR 3d； Q 3 is selected from N or CR 3d ;
    Q 4选自N或CR 3e； Q 4 is selected from N or CR 3e ;
    R 3a、R 3b、R 3c、R 3d和R 3e独立地选自H、D、卤素、-CN、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或4-6元杂环基； R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from H, D, halogen, -CN, -OR 1a , -SR 1a , -N(R 1a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic group;
    Z为N或CR 6a； Z is N or CR 6a ;
    R 6a、R 6b、R 6c、R 6d和R 6e独立地选自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或-NHC(O)R 1a；优选地，其中至少一个为-OH、-NH(R 1a)或-NHC(O)R 1a； R 6a , R 6b , R 6c , R 6d and R 6e are independently selected from H, D, halogen, -CN, -NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkene Group, C 2-6 alkynyl group, -OR 1a , -SR 1a , -N(R 1a ) 2 or -NHC(O)R 1a ; preferably, at least one of them is -OH, -NH(R 1a ) or -NHC(O)R 1a ;
    或者，R 6a、R 6b、R 6c、R 6d和R 6e中相邻的两个可以结合形成苯基或5-6元杂芳基，其任选被1、2或3个选自-OH、-NH(R 1a)或-NHC(O)R 1a的基团取代； Alternatively, two adjacent ones of R 6a , R 6b , R 6c , R 6d and R 6e may be combined to form a phenyl group or a 5-6 membered heteroaryl group, which is optionally selected from -OH by 1, 2 or 3 , -NH(R 1a ) or -NHC(O)R 1a group substitution;
    R 4为卤素； R 4 is halogen;
    R 5为H或卤素； R 5 is H or halogen;
    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(V)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 6b为-OH、-NH(R 1a)或-NHC(O)R 1a。 The compound of formula (V) of claim 15, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, wherein R 6b is -OH, -NH(R 1a ) or -NHC(O)R 1a .
  17. 权利要求15的式(V)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 6e为-OH、-NH(R 1a)或-NHC(O)R 1a。 The compound of formula (V) of claim 15, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, wherein R 6e is -OH, -NH(R 1a ) or -NHC(O)R 1a .
  18. 权利要求15的式(V)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 4为Cl。 The compound of formula (V) of claim 15, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, where R 4 is Cl.
  19. 权利要求15的式(V)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 3a、R 3b、R 3c、R 3d和R 3e独立地选自H、D、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基或C 3-6环烷基；优选地，R 3a为C 1-6烷基或C 1-6卤代烷基，更优选异丙基。 The compound of formula (V) of claim 15, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, wherein R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl; preferably, R 3a is C 1-6 alkyl or C 1-6 haloalkyl, more preferably isopropyl.
  20. 权利要求15的式(V)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 3a、R 3b、R 3c、R 3d和R 3e独立地选自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、C 3-6环烷基或4-6元杂环基。 The compound of formula (V) of claim 15, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, wherein R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from H, D, halogen, -CN, C 1-6 alkyl, C 1-6 haloalkane Group, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic group.
  21. 权利要求15的式(V)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Z为CR 6a。 The compound of formula (V) of claim 15, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, where Z is CR 6a .
  22. 权利要求21的式(V)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 6b或R 6b之一为-OH、-NH(R 1a)或-NHC(O)R 1a；优选R 6b或R 6b之一为-OH或-NH 2。 The compound of formula (V) of claim 21, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, wherein one of R 6b or R 6b is -OH, -NH(R 1a ) or -NHC(O)R 1a ; preferably one of R 6b or R 6b is -OH or- NH 2 .
  23. 式(VI)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 (VI), or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, prodrug or isotopic variant thereof , And their mixtures:
    Figure PCTCN2021091100-appb-100024
    Figure PCTCN2021091100-appb-100024
    其中，in,
    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；其中所述C 1-6烷基或C 1-6卤代烷基任选被D、卤素、-CN、-O-R 1a、-S-R 1a或-N(R 1a) 2取代；优选地，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, -CN, C 1-6 alkyl or C 1-6 haloalkyl; wherein said C 1-6 alkyl or C 1-6 haloalkyl group is optionally replaced by D, halo, -CN, -OR 1a, -SR 1a, or -N (R 1a) 2-substituted; preferably, R a, R b and R c are independently selected from H, D, halogen, or - CN;
    Q 1选自N或CR 3b； Q 1 is selected from N or CR 3b ;
    Q 2选自N或CR 3c； Q 2 is selected from N or CR 3c ;
    Q 3选自N或CR 3d； Q 3 is selected from N or CR 3d ;
    Q 4选自N或CR 3e； Q 4 is selected from N or CR 3e ;
    R 3a、R 3b、R 3c、R 3d和R 3e独立地选自H、D、卤素、-CN、-O-R 1a、-S-R 1a、-N(R 1a) 2、C 1-6烷基、C 1-6卤 代烷基、C 2-6烯基、C 2-6炔基、C 3-6环烷基或4-6元杂环基； R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from H, D, halogen, -CN, -OR 1a , -SR 1a , -N(R 1a ) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl or 4-6 membered heterocyclic group;
    R 4为卤素；优选为Cl； R 4 is halogen; preferably Cl;
    R 6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或-NHC(O)R 1a； R 6 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 or -NHC(O)R 1a ;
    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.
  24. 权利要求23的式(VI)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 3a、R 3b、R 3c、R 3d和R 3e独立地选自H、D、C 1-6烷基、C 1-6卤代烷基、C 2-6烯基、C 2-6炔基或C 3-6环烷基；优选地，R 3a为C 1-6烷基或C 1-6卤代烷基，更优选异丙基。 The compound of formula (VI) of claim 23, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, wherein R 3a , R 3b , R 3c , R 3d and R 3e are independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 2- 6 alkenyl, C 2-6 alkynyl or C 3-6 cycloalkyl; preferably, R 3a is C 1-6 alkyl or C 1-6 haloalkyl, more preferably isopropyl.
  25. 权利要求23的式(VI)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为-OH、-NH(R 1a)或-NHC(O)R 1a，更优选为-OH。 The compound of formula (VI) of claim 23, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, or prodrug thereof Or isotopic variants, and mixtures thereof, wherein R 6 is -OH, -NH(R 1a ) or -NHC(O)R 1a , more preferably -OH.
  26. 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 PCTCN2021091100-appb-100025
    Figure PCTCN2021091100-appb-100025
    Figure PCTCN2021091100-appb-100026
    Figure PCTCN2021091100-appb-100026
    Figure PCTCN2021091100-appb-100027
    Figure PCTCN2021091100-appb-100027
    Figure PCTCN2021091100-appb-100028
    Figure PCTCN2021091100-appb-100028
    Figure PCTCN2021091100-appb-100029
    Figure PCTCN2021091100-appb-100029
    Figure PCTCN2021091100-appb-100030
    Figure PCTCN2021091100-appb-100030
    Figure PCTCN2021091100-appb-100031
    Figure PCTCN2021091100-appb-100031
    Figure PCTCN2021091100-appb-100032
    Figure PCTCN2021091100-appb-100032
    Figure PCTCN2021091100-appb-100033
    Figure PCTCN2021091100-appb-100033
    Figure PCTCN2021091100-appb-100034
    Figure PCTCN2021091100-appb-100034
    Figure PCTCN2021091100-appb-100035
    Figure PCTCN2021091100-appb-100035
    Figure PCTCN2021091100-appb-100036
    Figure PCTCN2021091100-appb-100036
  27. 药物组合物，其含有权利要求1-26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 1-26, or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, or hydrate thereof And pharmaceutically acceptable excipients; preferably, it also contains other therapeutic agents.
  28. 权利要求1-26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 1-26 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, pro Use of drugs or isotopic variants in the preparation of drugs for treating and/or preventing diseases mediated by KRAS or its G12C mutant protein.
  29. 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1-26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27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 1-26 or Pharmaceutically acceptable salts, enantiomers, diastereomers, racemates, solvates, hydrates, polymorphs, prodrugs or isotopic variants or the pharmaceutical composition of claim 27 .
  30. 权利要求1-26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27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 1-26 or a pharmaceutically acceptable salt, enantiomer, diastereomer, racemate, solvate, hydrate, polymorph, pro The drug or isotope variant or the pharmaceutical composition of claim 27, which is used for the treatment and/or prevention of diseases mediated by KRAS or its G12C mutant protein.
  31. 权利要求28的用途或权利要求29的方法或权利要求30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)、***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、***、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、***瘤、副神经节瘤、鼻窦和鼻腔癌、甲状旁腺癌、***癌、咽癌、胸膜肺母细胞瘤、原发性中枢神经***(CNS)淋巴瘤、***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、***癌、外阴癌或病毒诱导的癌症。The use of claim 28 or the method of claim 29 or the use of the compound or composition of claim 30, wherein the disease mediated by KRAS or its G12C mutant protein comprises a 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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